Pharmacology

Immune checkpoint inhibitors (ICIs) have become important in oncology and represent an evolving area of therapeutics. Since their approval by the US Food and Drug Administration (FDA) in 2011, ICIs have been increasingly used as modalities in neoadjuvant and adjuvant treatment for resectable solid malignancies and in unresectable disease, such as advanced melanoma, and are associated with improved survival.¹

Immune checkpoints are present on the cell surface of activated T cells as well as other immune cells like B cells and natural killer cells. By regulating the length and amplitude of the body’s innate immune response, they maintain immune homeostasis and prevent its overactivation. Immune checkpoints are often thought of as the brakes on the immune system.²

Two glycoproteins that act as immune checkpoints and are targeted by ICIs are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 is upregulated on activated T cells. PD-1 is also expressed on activated T cells, as well as macrophages, B cells, and dendritic cells. Cancer cells can evade immune surveillance by exploiting immune checkpoint pathways. Inhibition of these checkpoints with ICIs reactivates T cells and enables the immune system to recognize and attack cancer cells more effectively. Ipilimumab blocks the activity of CTLA-4 on T cells. Nivolumab and pembrolizumab block the interaction between PD-1 on T cells and its ligand PD-L1 on cancer cells.^3,4

Inhibition of these checkpoints is often effective in cancer treatment but can result in the loss of immunologic tolerance with resultant immune-related adverse events (irAEs) and potentially permanent autoimmune disorders. Autoreactive T cells can damage host cell tissues including the colon, lungs, liver, pituitary gland, thyroid, and skin. Severe irAEs include type 1 diabetes mellitus, myositis, nephritis, colitis, pneumonitis, hepatitis, uveitis, hypophysitis, and adrenalitis.⁴

Hypophysitis is inflammation of the pituitary gland, often with thickening of the pituitary stalk, resulting in dysfunction and hormone deficiencies. While primary hypophysitis is idiopathic, secondary hypophysitis is the result of an underlying condition such as exposure to an ICI. Immune-mediated inflammation of the pituitary gland in hypophysitis may disrupt corticotroph function, leading to adrenocorticotropic hormone (ACTH) deficiency. Early warning features are often vague and nonspecific, such as headache, fatigue, and weakness, which makes diagnosis challenging.^3,5

CASE PRESENTATION

A 73-year-old male veteran with a history of metastatic melanoma on ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks (a standard combination regimen for advanced melanoma) presented to the emergency department (ED) with 2 weeks of cough, nausea, and severe headache 3 weeks after cycle 2 of combination ICI therapy. The patient had undergone excision of multiple sites of melanoma in situ with recurrence and disease progression after 5 cycles of pembrolizumab. He was subsequently started on combination ICI therapy.

On ED arrival, the patient was afebrile and saturating well on room air. He was normotensive but found to have orthostatic blood pressure. Physical examination was remarkable for dry oral mucosa and decreased skin turgor. Initial laboratory results were significant for hyponatremia of 123 mmol/L (reference range, 136-145 mmol/L), low-normal free thyroxine (T4) level of 0.5 ng/dL (reference range, 0.6-1.2 ng/dL), a low total triiodothyronine level of 32.14 ng/dL (reference range, 85-178 ng/dL), and a low thyrotropin level of 0.19 mIU/L (reference range, 0.35-5.50 mIU/L). Serum osmolarity was low at 259 mOsm/kg (reference range, 285-315 mOsm/kg), urine sodium was high at 168 mEq/L (reference, 20 mEq/L), and urine osmolarity was inappropriately concentrated at 726 mOsm/kg (reference range, 250-1000 mOsm/kg). The patient was admitted for additional testing. His morning cortisol level was within normal limits at 15 mcg/dL (reference range, 6.7-22.5 mcg/dL).

Computed tomography (CT) of the patient’s head revealed no acute findings. Chest CT revealed posterior right lower lobe mild ground-glass opacities, with possible ICI-induced pneumonitis. The patient received fluid resuscitation. Given concern for syndrome of inappropriate antidiuretic hormone secretion, the patient was started on 3 g salt tablets 3 times a day and urea 30 g powder daily. The etiology of the abnormal thyroid levels was unclear to endocrinology at that time. The differential diagnosis included a nonthyroidal illness or central hypothyroidism.

The patient started levothyroxine 75 mcg due to abnormal thyroid levels and persistent fatigue and fludrocortisone 0.1 mg daily to manage orthostatic hypotension. His sodium levels improved to 132 mmol/L over 6 days and he was discharged with levothyroxine 75 mcg daily, fludrocortisone 0.1 mg daily, 3 g salt tabs 3 times a day, urea 30 g powder daily, as well as oral cefpodoxime 500 mg twice daily for 3 days and azithromycin 500 mg once daily for 2 days (for a total of 10 days of antibiotic therapy) to treat potential occult pneumonia.

The patient returned to the ED 3 days after discharge following an outpatient oncology appointment with ongoing severe headaches and persistent nausea. There was concern for recurrent hyponatremia. His sodium level was within normal limits at 133 mmol/L. Repeat morning cortisol was low-normal at 9 mcg/dL. Magnetic resonance imaging (MRI) of the brain was negative for metastatic disease, but showed a slight interval increase in size of the pituitary gland compared with an MRI from 6 months prior, with mild fullness and a slightly convex superior margin near homogeneous enhancement, raising concern for infection or hypophysitis (Figure 1).

The patient was readmitted to the general medicine service and was given intravenous hydrocortisone 100 mg every 8 hours because of concern for central adrenal insufficiency due to grade 3 hypophysitis in the setting of MRI imaging and severe headaches (Table 1). He was not hypotensive at the time of hydrocortisone initiation and other vital signs were stable. A cosyntropin stimulation test—a standard diagnostic test for central adrenal insufficiency—was not performed because the patient had already started high-dose hydrocortisone. The patient’s free T4 on this admission remained low at 0.6 ng/dL.

No adjustments were made to his levothyroxine dose given that he recently began the medication and levels may lag after initiation. After a 4-day hospitalization, the decision was made to continue with the steroid taper and follow up with outpatient endocrinology to obtain a cosyntropin stimulation test to complete a full assessment of his pituitary axis (Figure 2). Repeat thyroid function testing for levothyroxine titration was arranged. The levothyroxine dosage was later increased to 88 mcg daily, but the patient discontinued the medication and remained euthyroid. Endocrinology attributed a nonthyroidal illness as the etiology of his hypothyroidism, likely euthyroid sick syndrome in the setting of illness. His hydrocortisone was tapered during outpatient care and fludrocortisone was discontinued due to hypertension.

One month after his second discharge, the patient presented to the ED with 2 weeks of dizziness, associated lightheadedness, and blurred vision when standing from a sitting position. Upon assessment, symptoms were attributed to poor oral intake. The patient’s vital signs were again positive for orthostatic hypotension, though refractory to adequate fluid replacement. Laboratory testing was significant for a low ACTH level of 3.0 pg/mL (reference range, 7.2-63.3 pg/mL). Given that the patient had not received steroids for 1 week, he underwent a cosyntropin stimulation test, which revealed a blunted response supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis (Table 2).

The patient was again readmitted to the general medicine service. A brain MRI showed interval shrinkage of the pituitary gland compared to imaging one month prior, which was attributed to hydrocortisone treatment during this month. CT of the patient’s abdomen demonstrated normal-sized adrenal glands. Positron emission tomography (PET)/CT showed no evidence of pituitary or adrenal metastases. Endocrinology recommended reinitiating oral hydrocortisone 50 mg in the morning and 50 mg around 3 pm daily with fludrocortisone 0.2 mg once daily, which resulted in near resolution of the patient’s symptoms. He was discharged after a 14-day hospitalization with home physical therapy services and endocrinology, nephrology, and oncology follow-up appointments.

The patient was readmitted twice to the general medicine service over the next 6 months for complications from hydrocortisone and fludrocortisone treatment including hypokalemia. He followed up with outpatient clinicians until his death 14 months later. He did not restart ICI therapy, and eventually joined a clinical trial for other advanced melanoma treatments at another institution. The patient’s family consented to the publication of this case report with the accompanying images.

DISCUSSION

The combination of ipilimumab (anti-CTLA-4 monoclonal antibody) and nivolumab (anti-PD-1 monoclonal antibody) is FDA-approved for treatment of advanced melanoma with the goal of harnessing complementary and synergistic mechanisms of dual therapy.^6-8 Combination therapy, however, can increase the incidence of irAEs, which are often endocrine-related and more common in patients treated with dual immunotherapy than with monotherapy.⁹ Hypophysitis has the lowest reported fatality rate among ICI-related irAEs (< 1%), compared with higher mortality rates seen in myocarditis (25%-50%) and pneumonitis (10%-20%).^4,10

The patient initially presented with ICI-related hypothyroidism, later identified as secondary (central) hypothyroidism. He was treated with levothyroxine until central hypothyroidism was confirmed. Subsequently, the patient developed headache, poor appetite, and lightheadedness, with MRI findings suggestive of hypophysitis, for which he was started on hydrocortisone. A component of primary adrenal insufficiency was initially considered, given the low ACTH level and blunted response to cosyntropin stimulation following prior high-dose steroid therapy. However, CT imaging demonstrated normal adrenal morphology without atrophy, supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis.

The estimated incidence of ICI-induced hypophysitis is 1.5% to 13.3% with anti-CTLA-4 agents, 0.3% to 3.0% with anti-PD-1 agents, and can be as high as 12.8% with combination therapy.¹ ICI-induced hypophysitis is believed to arise from the direct binding of ICI antibodies to their targets on anterior pituitary cells, such as corticotrophs, thyrotrophs, and gonadotrophs, triggering an immune response. One theory for targeting these cells is high CTLA-4 expression in the anterior pituitary gland.¹¹ PD-1 therapies tend to manifest as either hypothyroidism, hyperthyroidism, Graves’ disease, diabetes, or adrenal insufficiency.¹⁰

A concern in patients with advanced melanoma is metastasis. Melanoma has a high propensity for brain metastasis.¹² There was moderate suspicion for pituitary gland metastasis in this case, though pituitary metastasis more often manifests with symptoms of posterior pituitary gland deficiency, such as polyuria and polydipsia.¹³ The adrenal gland is the fourth-most common site for melanoma metastases, after the lung, liver, and bone.¹⁴ This patient had no evidence of pituitary or adrenal metastases on PET/CT. Therefore, his symptoms were most likely due to ICI therapy. Cases of ≥ 1 endocrine dysfunction have been reported as an ICI therapy irAE.¹⁵ In these situations, diagnosing primary and central adrenal insufficiency in the same patient is complex because hormone profiles are intertwined.

Many patients who develop hypophysitis from ICI therapy will require permanent replacement therapy. It is unclear whether low-dose replacement steroids have a significant effect on the efficacy of ICIs. Given that ICI treatment works by enhancing the immune system, medications that suppress the body’s immune system, such as steroids, could interfere with treatment efficacy. However, there are speculations that the development of irAEs is an indicator of effective treatment. In a phase 1 trial of a CTLA-4 blocker in patients with metastatic melanoma, there was a correlation between reduced CTLA-4 expression as well as low rates of melanoma recurrence and a higher incidence of irAEs.¹⁶

When assessing patients on ICI treatment, clinicians must remain vigilant for all potential irAEs, especially in patients receiving combination therapy. ICI-induced irAEs can present with vague and nonspecific symptoms. Concurrent endocrine irAEs, such as hypophysitis with thyroiditis or adrenalitis, are not uncommon in combination therapy and can complicate interpretation of hormone profiles. It is prudent for clinicians to review known risk factors. Hypophysitis is typically associated with older adult male patients.^17,18

The irAEs of ICI therapy deeply affected the quality of life of the patient in this case, as he was often experiencing many of the clinical symptoms of his hormone insufficiencies as well as the treatment modalities, thus requiring repeated hospital admissions. The risks and benefits of continuing ICI therapy should be an ongoing discussion between the physician and patient and should take into account the acuity and severity of irAEs and oncological disease burden, among other variables. Given the severity of his AEs, the patient stopped ICI therapy and instead opted to enroll in a clinical trial at another institution for continued alternative treatments.

CONCLUSIONS

This case offers a lesson in the diagnostic challenges of vague symptoms in patients with cancer who are receiving ICI therapy. ICI therapy is widely used in the treatment of solid malignancies, and as its use increases, it is expected that clinicians will likely see more cases of irAEs in hospitalized patients. The vague presentation of irAEs can often lead to treatment delays, especially when > 1 irAE presents concurrently. There are ongoing studies researching potential ways to predict the likelihood of developing these irAEs. It is imperative that clinicians are aware of these ICI-related complications and that more research be conducted to understand patient quality of life and treatment guidance based on irAE severity and disease burden.

Immune checkpoint inhibitors (ICIs) have become important in oncology and represent an evolving area of therapeutics. Since their approval by the US Food and Drug Administration (FDA) in 2011, ICIs have been increasingly used as modalities in neoadjuvant and adjuvant treatment for resectable solid malignancies and in unresectable disease, such as advanced melanoma, and are associated with improved survival.¹

Immune checkpoints are present on the cell surface of activated T cells as well as other immune cells like B cells and natural killer cells. By regulating the length and amplitude of the body’s innate immune response, they maintain immune homeostasis and prevent its overactivation. Immune checkpoints are often thought of as the brakes on the immune system.²

Two glycoproteins that act as immune checkpoints and are targeted by ICIs are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 is upregulated on activated T cells. PD-1 is also expressed on activated T cells, as well as macrophages, B cells, and dendritic cells. Cancer cells can evade immune surveillance by exploiting immune checkpoint pathways. Inhibition of these checkpoints with ICIs reactivates T cells and enables the immune system to recognize and attack cancer cells more effectively. Ipilimumab blocks the activity of CTLA-4 on T cells. Nivolumab and pembrolizumab block the interaction between PD-1 on T cells and its ligand PD-L1 on cancer cells.^3,4

Inhibition of these checkpoints is often effective in cancer treatment but can result in the loss of immunologic tolerance with resultant immune-related adverse events (irAEs) and potentially permanent autoimmune disorders. Autoreactive T cells can damage host cell tissues including the colon, lungs, liver, pituitary gland, thyroid, and skin. Severe irAEs include type 1 diabetes mellitus, myositis, nephritis, colitis, pneumonitis, hepatitis, uveitis, hypophysitis, and adrenalitis.⁴

Hypophysitis is inflammation of the pituitary gland, often with thickening of the pituitary stalk, resulting in dysfunction and hormone deficiencies. While primary hypophysitis is idiopathic, secondary hypophysitis is the result of an underlying condition such as exposure to an ICI. Immune-mediated inflammation of the pituitary gland in hypophysitis may disrupt corticotroph function, leading to adrenocorticotropic hormone (ACTH) deficiency. Early warning features are often vague and nonspecific, such as headache, fatigue, and weakness, which makes diagnosis challenging.^3,5

CASE PRESENTATION

A 73-year-old male veteran with a history of metastatic melanoma on ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks (a standard combination regimen for advanced melanoma) presented to the emergency department (ED) with 2 weeks of cough, nausea, and severe headache 3 weeks after cycle 2 of combination ICI therapy. The patient had undergone excision of multiple sites of melanoma in situ with recurrence and disease progression after 5 cycles of pembrolizumab. He was subsequently started on combination ICI therapy.

On ED arrival, the patient was afebrile and saturating well on room air. He was normotensive but found to have orthostatic blood pressure. Physical examination was remarkable for dry oral mucosa and decreased skin turgor. Initial laboratory results were significant for hyponatremia of 123 mmol/L (reference range, 136-145 mmol/L), low-normal free thyroxine (T4) level of 0.5 ng/dL (reference range, 0.6-1.2 ng/dL), a low total triiodothyronine level of 32.14 ng/dL (reference range, 85-178 ng/dL), and a low thyrotropin level of 0.19 mIU/L (reference range, 0.35-5.50 mIU/L). Serum osmolarity was low at 259 mOsm/kg (reference range, 285-315 mOsm/kg), urine sodium was high at 168 mEq/L (reference, 20 mEq/L), and urine osmolarity was inappropriately concentrated at 726 mOsm/kg (reference range, 250-1000 mOsm/kg). The patient was admitted for additional testing. His morning cortisol level was within normal limits at 15 mcg/dL (reference range, 6.7-22.5 mcg/dL).

Computed tomography (CT) of the patient’s head revealed no acute findings. Chest CT revealed posterior right lower lobe mild ground-glass opacities, with possible ICI-induced pneumonitis. The patient received fluid resuscitation. Given concern for syndrome of inappropriate antidiuretic hormone secretion, the patient was started on 3 g salt tablets 3 times a day and urea 30 g powder daily. The etiology of the abnormal thyroid levels was unclear to endocrinology at that time. The differential diagnosis included a nonthyroidal illness or central hypothyroidism.

The patient started levothyroxine 75 mcg due to abnormal thyroid levels and persistent fatigue and fludrocortisone 0.1 mg daily to manage orthostatic hypotension. His sodium levels improved to 132 mmol/L over 6 days and he was discharged with levothyroxine 75 mcg daily, fludrocortisone 0.1 mg daily, 3 g salt tabs 3 times a day, urea 30 g powder daily, as well as oral cefpodoxime 500 mg twice daily for 3 days and azithromycin 500 mg once daily for 2 days (for a total of 10 days of antibiotic therapy) to treat potential occult pneumonia.

The patient returned to the ED 3 days after discharge following an outpatient oncology appointment with ongoing severe headaches and persistent nausea. There was concern for recurrent hyponatremia. His sodium level was within normal limits at 133 mmol/L. Repeat morning cortisol was low-normal at 9 mcg/dL. Magnetic resonance imaging (MRI) of the brain was negative for metastatic disease, but showed a slight interval increase in size of the pituitary gland compared with an MRI from 6 months prior, with mild fullness and a slightly convex superior margin near homogeneous enhancement, raising concern for infection or hypophysitis (Figure 1).

The patient was readmitted to the general medicine service and was given intravenous hydrocortisone 100 mg every 8 hours because of concern for central adrenal insufficiency due to grade 3 hypophysitis in the setting of MRI imaging and severe headaches (Table 1). He was not hypotensive at the time of hydrocortisone initiation and other vital signs were stable. A cosyntropin stimulation test—a standard diagnostic test for central adrenal insufficiency—was not performed because the patient had already started high-dose hydrocortisone. The patient’s free T4 on this admission remained low at 0.6 ng/dL.

No adjustments were made to his levothyroxine dose given that he recently began the medication and levels may lag after initiation. After a 4-day hospitalization, the decision was made to continue with the steroid taper and follow up with outpatient endocrinology to obtain a cosyntropin stimulation test to complete a full assessment of his pituitary axis (Figure 2). Repeat thyroid function testing for levothyroxine titration was arranged. The levothyroxine dosage was later increased to 88 mcg daily, but the patient discontinued the medication and remained euthyroid. Endocrinology attributed a nonthyroidal illness as the etiology of his hypothyroidism, likely euthyroid sick syndrome in the setting of illness. His hydrocortisone was tapered during outpatient care and fludrocortisone was discontinued due to hypertension.

One month after his second discharge, the patient presented to the ED with 2 weeks of dizziness, associated lightheadedness, and blurred vision when standing from a sitting position. Upon assessment, symptoms were attributed to poor oral intake. The patient’s vital signs were again positive for orthostatic hypotension, though refractory to adequate fluid replacement. Laboratory testing was significant for a low ACTH level of 3.0 pg/mL (reference range, 7.2-63.3 pg/mL). Given that the patient had not received steroids for 1 week, he underwent a cosyntropin stimulation test, which revealed a blunted response supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis (Table 2).

The patient was again readmitted to the general medicine service. A brain MRI showed interval shrinkage of the pituitary gland compared to imaging one month prior, which was attributed to hydrocortisone treatment during this month. CT of the patient’s abdomen demonstrated normal-sized adrenal glands. Positron emission tomography (PET)/CT showed no evidence of pituitary or adrenal metastases. Endocrinology recommended reinitiating oral hydrocortisone 50 mg in the morning and 50 mg around 3 pm daily with fludrocortisone 0.2 mg once daily, which resulted in near resolution of the patient’s symptoms. He was discharged after a 14-day hospitalization with home physical therapy services and endocrinology, nephrology, and oncology follow-up appointments.

The patient was readmitted twice to the general medicine service over the next 6 months for complications from hydrocortisone and fludrocortisone treatment including hypokalemia. He followed up with outpatient clinicians until his death 14 months later. He did not restart ICI therapy, and eventually joined a clinical trial for other advanced melanoma treatments at another institution. The patient’s family consented to the publication of this case report with the accompanying images.

DISCUSSION

The combination of ipilimumab (anti-CTLA-4 monoclonal antibody) and nivolumab (anti-PD-1 monoclonal antibody) is FDA-approved for treatment of advanced melanoma with the goal of harnessing complementary and synergistic mechanisms of dual therapy.^6-8 Combination therapy, however, can increase the incidence of irAEs, which are often endocrine-related and more common in patients treated with dual immunotherapy than with monotherapy.⁹ Hypophysitis has the lowest reported fatality rate among ICI-related irAEs (< 1%), compared with higher mortality rates seen in myocarditis (25%-50%) and pneumonitis (10%-20%).^4,10

The patient initially presented with ICI-related hypothyroidism, later identified as secondary (central) hypothyroidism. He was treated with levothyroxine until central hypothyroidism was confirmed. Subsequently, the patient developed headache, poor appetite, and lightheadedness, with MRI findings suggestive of hypophysitis, for which he was started on hydrocortisone. A component of primary adrenal insufficiency was initially considered, given the low ACTH level and blunted response to cosyntropin stimulation following prior high-dose steroid therapy. However, CT imaging demonstrated normal adrenal morphology without atrophy, supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis.

The estimated incidence of ICI-induced hypophysitis is 1.5% to 13.3% with anti-CTLA-4 agents, 0.3% to 3.0% with anti-PD-1 agents, and can be as high as 12.8% with combination therapy.¹ ICI-induced hypophysitis is believed to arise from the direct binding of ICI antibodies to their targets on anterior pituitary cells, such as corticotrophs, thyrotrophs, and gonadotrophs, triggering an immune response. One theory for targeting these cells is high CTLA-4 expression in the anterior pituitary gland.¹¹ PD-1 therapies tend to manifest as either hypothyroidism, hyperthyroidism, Graves’ disease, diabetes, or adrenal insufficiency.¹⁰

A concern in patients with advanced melanoma is metastasis. Melanoma has a high propensity for brain metastasis.¹² There was moderate suspicion for pituitary gland metastasis in this case, though pituitary metastasis more often manifests with symptoms of posterior pituitary gland deficiency, such as polyuria and polydipsia.¹³ The adrenal gland is the fourth-most common site for melanoma metastases, after the lung, liver, and bone.¹⁴ This patient had no evidence of pituitary or adrenal metastases on PET/CT. Therefore, his symptoms were most likely due to ICI therapy. Cases of ≥ 1 endocrine dysfunction have been reported as an ICI therapy irAE.¹⁵ In these situations, diagnosing primary and central adrenal insufficiency in the same patient is complex because hormone profiles are intertwined.

Many patients who develop hypophysitis from ICI therapy will require permanent replacement therapy. It is unclear whether low-dose replacement steroids have a significant effect on the efficacy of ICIs. Given that ICI treatment works by enhancing the immune system, medications that suppress the body’s immune system, such as steroids, could interfere with treatment efficacy. However, there are speculations that the development of irAEs is an indicator of effective treatment. In a phase 1 trial of a CTLA-4 blocker in patients with metastatic melanoma, there was a correlation between reduced CTLA-4 expression as well as low rates of melanoma recurrence and a higher incidence of irAEs.¹⁶

When assessing patients on ICI treatment, clinicians must remain vigilant for all potential irAEs, especially in patients receiving combination therapy. ICI-induced irAEs can present with vague and nonspecific symptoms. Concurrent endocrine irAEs, such as hypophysitis with thyroiditis or adrenalitis, are not uncommon in combination therapy and can complicate interpretation of hormone profiles. It is prudent for clinicians to review known risk factors. Hypophysitis is typically associated with older adult male patients.^17,18

The irAEs of ICI therapy deeply affected the quality of life of the patient in this case, as he was often experiencing many of the clinical symptoms of his hormone insufficiencies as well as the treatment modalities, thus requiring repeated hospital admissions. The risks and benefits of continuing ICI therapy should be an ongoing discussion between the physician and patient and should take into account the acuity and severity of irAEs and oncological disease burden, among other variables. Given the severity of his AEs, the patient stopped ICI therapy and instead opted to enroll in a clinical trial at another institution for continued alternative treatments.

CONCLUSIONS

This case offers a lesson in the diagnostic challenges of vague symptoms in patients with cancer who are receiving ICI therapy. ICI therapy is widely used in the treatment of solid malignancies, and as its use increases, it is expected that clinicians will likely see more cases of irAEs in hospitalized patients. The vague presentation of irAEs can often lead to treatment delays, especially when > 1 irAE presents concurrently. There are ongoing studies researching potential ways to predict the likelihood of developing these irAEs. It is imperative that clinicians are aware of these ICI-related complications and that more research be conducted to understand patient quality of life and treatment guidance based on irAE severity and disease burden.

Immune checkpoint inhibitors (ICIs) have become important in oncology and represent an evolving area of therapeutics. Since their approval by the US Food and Drug Administration (FDA) in 2011, ICIs have been increasingly used as modalities in neoadjuvant and adjuvant treatment for resectable solid malignancies and in unresectable disease, such as advanced melanoma, and are associated with improved survival.¹

Immune checkpoints are present on the cell surface of activated T cells as well as other immune cells like B cells and natural killer cells. By regulating the length and amplitude of the body’s innate immune response, they maintain immune homeostasis and prevent its overactivation. Immune checkpoints are often thought of as the brakes on the immune system.²

Two glycoproteins that act as immune checkpoints and are targeted by ICIs are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 is upregulated on activated T cells. PD-1 is also expressed on activated T cells, as well as macrophages, B cells, and dendritic cells. Cancer cells can evade immune surveillance by exploiting immune checkpoint pathways. Inhibition of these checkpoints with ICIs reactivates T cells and enables the immune system to recognize and attack cancer cells more effectively. Ipilimumab blocks the activity of CTLA-4 on T cells. Nivolumab and pembrolizumab block the interaction between PD-1 on T cells and its ligand PD-L1 on cancer cells.^3,4

Inhibition of these checkpoints is often effective in cancer treatment but can result in the loss of immunologic tolerance with resultant immune-related adverse events (irAEs) and potentially permanent autoimmune disorders. Autoreactive T cells can damage host cell tissues including the colon, lungs, liver, pituitary gland, thyroid, and skin. Severe irAEs include type 1 diabetes mellitus, myositis, nephritis, colitis, pneumonitis, hepatitis, uveitis, hypophysitis, and adrenalitis.⁴

Hypophysitis is inflammation of the pituitary gland, often with thickening of the pituitary stalk, resulting in dysfunction and hormone deficiencies. While primary hypophysitis is idiopathic, secondary hypophysitis is the result of an underlying condition such as exposure to an ICI. Immune-mediated inflammation of the pituitary gland in hypophysitis may disrupt corticotroph function, leading to adrenocorticotropic hormone (ACTH) deficiency. Early warning features are often vague and nonspecific, such as headache, fatigue, and weakness, which makes diagnosis challenging.^3,5

CASE PRESENTATION

A 73-year-old male veteran with a history of metastatic melanoma on ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks (a standard combination regimen for advanced melanoma) presented to the emergency department (ED) with 2 weeks of cough, nausea, and severe headache 3 weeks after cycle 2 of combination ICI therapy. The patient had undergone excision of multiple sites of melanoma in situ with recurrence and disease progression after 5 cycles of pembrolizumab. He was subsequently started on combination ICI therapy.

On ED arrival, the patient was afebrile and saturating well on room air. He was normotensive but found to have orthostatic blood pressure. Physical examination was remarkable for dry oral mucosa and decreased skin turgor. Initial laboratory results were significant for hyponatremia of 123 mmol/L (reference range, 136-145 mmol/L), low-normal free thyroxine (T4) level of 0.5 ng/dL (reference range, 0.6-1.2 ng/dL), a low total triiodothyronine level of 32.14 ng/dL (reference range, 85-178 ng/dL), and a low thyrotropin level of 0.19 mIU/L (reference range, 0.35-5.50 mIU/L). Serum osmolarity was low at 259 mOsm/kg (reference range, 285-315 mOsm/kg), urine sodium was high at 168 mEq/L (reference, 20 mEq/L), and urine osmolarity was inappropriately concentrated at 726 mOsm/kg (reference range, 250-1000 mOsm/kg). The patient was admitted for additional testing. His morning cortisol level was within normal limits at 15 mcg/dL (reference range, 6.7-22.5 mcg/dL).

Computed tomography (CT) of the patient’s head revealed no acute findings. Chest CT revealed posterior right lower lobe mild ground-glass opacities, with possible ICI-induced pneumonitis. The patient received fluid resuscitation. Given concern for syndrome of inappropriate antidiuretic hormone secretion, the patient was started on 3 g salt tablets 3 times a day and urea 30 g powder daily. The etiology of the abnormal thyroid levels was unclear to endocrinology at that time. The differential diagnosis included a nonthyroidal illness or central hypothyroidism.

The patient started levothyroxine 75 mcg due to abnormal thyroid levels and persistent fatigue and fludrocortisone 0.1 mg daily to manage orthostatic hypotension. His sodium levels improved to 132 mmol/L over 6 days and he was discharged with levothyroxine 75 mcg daily, fludrocortisone 0.1 mg daily, 3 g salt tabs 3 times a day, urea 30 g powder daily, as well as oral cefpodoxime 500 mg twice daily for 3 days and azithromycin 500 mg once daily for 2 days (for a total of 10 days of antibiotic therapy) to treat potential occult pneumonia.

The patient returned to the ED 3 days after discharge following an outpatient oncology appointment with ongoing severe headaches and persistent nausea. There was concern for recurrent hyponatremia. His sodium level was within normal limits at 133 mmol/L. Repeat morning cortisol was low-normal at 9 mcg/dL. Magnetic resonance imaging (MRI) of the brain was negative for metastatic disease, but showed a slight interval increase in size of the pituitary gland compared with an MRI from 6 months prior, with mild fullness and a slightly convex superior margin near homogeneous enhancement, raising concern for infection or hypophysitis (Figure 1).

The patient was readmitted to the general medicine service and was given intravenous hydrocortisone 100 mg every 8 hours because of concern for central adrenal insufficiency due to grade 3 hypophysitis in the setting of MRI imaging and severe headaches (Table 1). He was not hypotensive at the time of hydrocortisone initiation and other vital signs were stable. A cosyntropin stimulation test—a standard diagnostic test for central adrenal insufficiency—was not performed because the patient had already started high-dose hydrocortisone. The patient’s free T4 on this admission remained low at 0.6 ng/dL.

No adjustments were made to his levothyroxine dose given that he recently began the medication and levels may lag after initiation. After a 4-day hospitalization, the decision was made to continue with the steroid taper and follow up with outpatient endocrinology to obtain a cosyntropin stimulation test to complete a full assessment of his pituitary axis (Figure 2). Repeat thyroid function testing for levothyroxine titration was arranged. The levothyroxine dosage was later increased to 88 mcg daily, but the patient discontinued the medication and remained euthyroid. Endocrinology attributed a nonthyroidal illness as the etiology of his hypothyroidism, likely euthyroid sick syndrome in the setting of illness. His hydrocortisone was tapered during outpatient care and fludrocortisone was discontinued due to hypertension.

One month after his second discharge, the patient presented to the ED with 2 weeks of dizziness, associated lightheadedness, and blurred vision when standing from a sitting position. Upon assessment, symptoms were attributed to poor oral intake. The patient’s vital signs were again positive for orthostatic hypotension, though refractory to adequate fluid replacement. Laboratory testing was significant for a low ACTH level of 3.0 pg/mL (reference range, 7.2-63.3 pg/mL). Given that the patient had not received steroids for 1 week, he underwent a cosyntropin stimulation test, which revealed a blunted response supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis (Table 2).

The patient was again readmitted to the general medicine service. A brain MRI showed interval shrinkage of the pituitary gland compared to imaging one month prior, which was attributed to hydrocortisone treatment during this month. CT of the patient’s abdomen demonstrated normal-sized adrenal glands. Positron emission tomography (PET)/CT showed no evidence of pituitary or adrenal metastases. Endocrinology recommended reinitiating oral hydrocortisone 50 mg in the morning and 50 mg around 3 pm daily with fludrocortisone 0.2 mg once daily, which resulted in near resolution of the patient’s symptoms. He was discharged after a 14-day hospitalization with home physical therapy services and endocrinology, nephrology, and oncology follow-up appointments.

The patient was readmitted twice to the general medicine service over the next 6 months for complications from hydrocortisone and fludrocortisone treatment including hypokalemia. He followed up with outpatient clinicians until his death 14 months later. He did not restart ICI therapy, and eventually joined a clinical trial for other advanced melanoma treatments at another institution. The patient’s family consented to the publication of this case report with the accompanying images.

DISCUSSION

The combination of ipilimumab (anti-CTLA-4 monoclonal antibody) and nivolumab (anti-PD-1 monoclonal antibody) is FDA-approved for treatment of advanced melanoma with the goal of harnessing complementary and synergistic mechanisms of dual therapy.^6-8 Combination therapy, however, can increase the incidence of irAEs, which are often endocrine-related and more common in patients treated with dual immunotherapy than with monotherapy.⁹ Hypophysitis has the lowest reported fatality rate among ICI-related irAEs (< 1%), compared with higher mortality rates seen in myocarditis (25%-50%) and pneumonitis (10%-20%).^4,10

The patient initially presented with ICI-related hypothyroidism, later identified as secondary (central) hypothyroidism. He was treated with levothyroxine until central hypothyroidism was confirmed. Subsequently, the patient developed headache, poor appetite, and lightheadedness, with MRI findings suggestive of hypophysitis, for which he was started on hydrocortisone. A component of primary adrenal insufficiency was initially considered, given the low ACTH level and blunted response to cosyntropin stimulation following prior high-dose steroid therapy. However, CT imaging demonstrated normal adrenal morphology without atrophy, supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis.

The estimated incidence of ICI-induced hypophysitis is 1.5% to 13.3% with anti-CTLA-4 agents, 0.3% to 3.0% with anti-PD-1 agents, and can be as high as 12.8% with combination therapy.¹ ICI-induced hypophysitis is believed to arise from the direct binding of ICI antibodies to their targets on anterior pituitary cells, such as corticotrophs, thyrotrophs, and gonadotrophs, triggering an immune response. One theory for targeting these cells is high CTLA-4 expression in the anterior pituitary gland.¹¹ PD-1 therapies tend to manifest as either hypothyroidism, hyperthyroidism, Graves’ disease, diabetes, or adrenal insufficiency.¹⁰

A concern in patients with advanced melanoma is metastasis. Melanoma has a high propensity for brain metastasis.¹² There was moderate suspicion for pituitary gland metastasis in this case, though pituitary metastasis more often manifests with symptoms of posterior pituitary gland deficiency, such as polyuria and polydipsia.¹³ The adrenal gland is the fourth-most common site for melanoma metastases, after the lung, liver, and bone.¹⁴ This patient had no evidence of pituitary or adrenal metastases on PET/CT. Therefore, his symptoms were most likely due to ICI therapy. Cases of ≥ 1 endocrine dysfunction have been reported as an ICI therapy irAE.¹⁵ In these situations, diagnosing primary and central adrenal insufficiency in the same patient is complex because hormone profiles are intertwined.

Many patients who develop hypophysitis from ICI therapy will require permanent replacement therapy. It is unclear whether low-dose replacement steroids have a significant effect on the efficacy of ICIs. Given that ICI treatment works by enhancing the immune system, medications that suppress the body’s immune system, such as steroids, could interfere with treatment efficacy. However, there are speculations that the development of irAEs is an indicator of effective treatment. In a phase 1 trial of a CTLA-4 blocker in patients with metastatic melanoma, there was a correlation between reduced CTLA-4 expression as well as low rates of melanoma recurrence and a higher incidence of irAEs.¹⁶

When assessing patients on ICI treatment, clinicians must remain vigilant for all potential irAEs, especially in patients receiving combination therapy. ICI-induced irAEs can present with vague and nonspecific symptoms. Concurrent endocrine irAEs, such as hypophysitis with thyroiditis or adrenalitis, are not uncommon in combination therapy and can complicate interpretation of hormone profiles. It is prudent for clinicians to review known risk factors. Hypophysitis is typically associated with older adult male patients.^17,18

The irAEs of ICI therapy deeply affected the quality of life of the patient in this case, as he was often experiencing many of the clinical symptoms of his hormone insufficiencies as well as the treatment modalities, thus requiring repeated hospital admissions. The risks and benefits of continuing ICI therapy should be an ongoing discussion between the physician and patient and should take into account the acuity and severity of irAEs and oncological disease burden, among other variables. Given the severity of his AEs, the patient stopped ICI therapy and instead opted to enroll in a clinical trial at another institution for continued alternative treatments.

CONCLUSIONS

This case offers a lesson in the diagnostic challenges of vague symptoms in patients with cancer who are receiving ICI therapy. ICI therapy is widely used in the treatment of solid malignancies, and as its use increases, it is expected that clinicians will likely see more cases of irAEs in hospitalized patients. The vague presentation of irAEs can often lead to treatment delays, especially when > 1 irAE presents concurrently. There are ongoing studies researching potential ways to predict the likelihood of developing these irAEs. It is imperative that clinicians are aware of these ICI-related complications and that more research be conducted to understand patient quality of life and treatment guidance based on irAE severity and disease burden.

Cannabis has a long history of use for medicinal and recreational purposes. Research illustrates the potential benefits and increased prevalence of cannabis use in patients with cancer.¹ Cannabis products have been shown to possess antineoplastic and palliative activity, improving nociceptive and neuropathic pain in addition to chemotherapy-related nausea and vomiting.^2-5 Despite these developments and changing social attitudes toward cannabis, there remains a lack of comprehensive data on patient perspectives regarding its use, especially in regions where cannabis remains illegal. This knowledge gap is notable among veterans undergoing cancer treatment in states where cannabis is prohibited. Up to 57% of veterans report lifetime marijuana use, making it crucial to understand this population’s cannabis use patterns and potential interactions with cancer treatments.⁶

This observational study sought to determine the prevalence of cannabis use among patients undergoing cancer treatment at the US Department of Veterans Affairs (VA) Memphis Healthcare System and evaluate the potential risks associated with combining cannabis products with anticancer therapies.

METHODS

This prospective observational study identified cannabis use among veterans receiving antineoplastic therapy at the Lt. Col. Luke Weathers Jr. VA Medical Center (WJVAMC) and analyzed potential interactions between cannabis products and their cancer treatments. Participants included adults aged > 18 years undergoing antineoplastic therapy at WJVAMC who consented to the study. Data collection involved a written survey approved by the WJVAMC Institutional Review Board and verbal consent from participants. The survey asked participants about their cannabis use in the previous 90 days, including details on quantity, frequency, and method of consumption (eg, inhalation, oral, topical). No incentives were offered for participation.

Surveys from 50 patients who used cannabis were analyzed and their electronic health records were reviewed for sex, age, diagnosis, and antineoplastic regimen. This information was securely stored. A literature review was conducted using PubMed and the Cochrane Library to explore potential interactions between cannabis and the antineoplastic agents that were prescribed to patients in the study, focusing on toxicity, efficacy, or synergistic effects.

Patients were categorized into 4 groups based on treatment: cytotoxic chemotherapy, immunotherapy, endocrine therapy, and targeted therapy. Patients undergoing multiple types of therapies were included in each applicable category.

RESULTS

A total of 132 patients agreed to participate. Fifty patients (38%) acknowledged using cannabis products within 90 days. The patients that used cannabis products within 90 days of the survey reported the following malignancies: 8 patients (16%) had prostate cancer, 3 patients (6%) had hepatocellular carcinoma, 7 patients (14%) had pancreatic carcinoma, 5 patients (10%) had multiple myeloma, 3 patients (6%) had chronic lymphocytic leukemia, 9 patients (18%) had non-small cell lung cancer, 3 patients (6%) had breast cancer, 3 (6%) patients had bladder cancer, 2 patients (4%) had renal cell carcinoma, 1 (2%) patient had chronic myeloid leukemia, 1 (2%) patient had renal amyloid, 1 patient (2%) had supraglottic squamous cell carcinoma, 1 patient (2%) had esophageal carcinoma, 1 (2%) patient had small cell lung cancer, 1 (2%) patient had gastric cancer, and 1 patient (2%) had follicular lymphoma.

Five (10%) of the cannabis users were female, and 45 (90%) were male. Twenty-nine patients (58%) were aged 66 to 75 years, 16 (32%) were aged 56 to 65 years, 3 (6%) were aged 46 to 55 years, and 2 (4%) were aged 76 to 85 years.

Thirty-five patients (70%) inhaled cannabis as opposed to using it via other formulations or a combination (eg, inhalation and topical). Thirty-eight percent of patients used cannabis once daily, 24% used < 1 daily, and 28% used it ≥ 2 times daily. Five patients (10%) did not report the frequency of their cannabis use. Among the patients who reported cannabis use, 21 (42%) were undergoing cytotoxic chemotherapy, 19 (38%) were undergoing immunotherapy, 12 (24%) were undergoing targeted therapy, and 10 (20%) were undergoing endocrine therapy. Some patients were treated with multiple types of antineoplastic agents and were counted in multiple categories (Table 1).

Following a literature review of cannabis and antineoplastic agents, patients were evaluated for the potential effects of cannabis on their treatment. The literature review revealed that 31% of cytotoxic chemotherapy agents received by patients in this study might have increased toxicity, and 19% could have reduced efficacy when combined with cannabis. Among immunotherapy agents received by patients in this study, 70% might have decreased efficacy when combined with cannabis use. For targeted therapies, 35% could have increased toxicity, and 70% of endocrine agents could potentially have decreased efficacy (Table 2).

DISCUSSION

This prospective study corroborates previous research by demonstrating that more than one-third of patients receiving oncology care at WJVAMC use cannabis, most often inhaled. Cannabis use was observed among patients undergoing various cancer therapies, including cytotoxic chemotherapy, immunotherapy, targeted therapy, and endocrine therapy. The most common malignancies among cannabis users at WJVAMC include patients with lung cancer, prostate cancer, pancreatic cancer, and multiple myeloma. Cannabis use in patients with pancreatic cancer and multiple myeloma was significantly out of proportion to their prevalence at WJVAMC. This could potentially be due to their drastic effect on quality of life.

Cannabis use increased the risk of toxicity in patients treated with cytotoxic chemotherapy and targeted therapy. Cannabis use potentially decreased efficacy for patients treated with cytotoxic chemotherapy and/or immunotherapy. Cannabis use did not increase the risk of toxicity or efficacy in patients treated with endocrine therapy.

Antineoplastics/Cannabis Interactions

The potential interactions between cannabis and antineoplastic therapies administered at WJVAMC are worth exploring. While this review aims to shed light on possible interactions, it is important to acknowledge that much of the data is preliminary and derived from in vitro studies. The interactions should be interpreted as potential risks rather than established facts. Additional research is needed to confirm these interactions and effectively guide clinical practices. Understanding these dynamics is essential to optimize patient care and manage the complex interplay between cannabis use and cancer treatment.

Originating from Central Asia, the cannabis plant contains > 400 medicinally relevant compounds, of which about 100 are cannabinoids (CBs). Key CBs are cannabidiol (CBD), a nonpsychoactive compound, and ?-9-tetrahydrocannabinol (THC), a psychoactive compound. THC can make up 20% to 30% of the dry weight of female cannabis flowers.⁷

CBs act through the endocannabinoid system, involving CB1 and CB2 receptors, endogenous CBs like anandamide (AEA) and 2-arachidonoylglycerol, and various enzymes. These endogenous CBs, derived from arachidonic acid, play roles in cell growth and proliferation.⁸ In some studies, AEA has induced apoptosis in neuroblastoma cells and inhibited proliferation in breast cancer cells. However, other research suggests AEA may block apoptosis under certain conditions.⁹

CB receptors are transmembrane proteins that interact with CBs differently depending on tissue type and CB structure. Synthetic CBs are designed to target specific receptors, while natural CBs may act as both agonists and antagonists.¹⁰

Cytochrome P450 Metabolism

The human cytochrome P450 (CYP) 3A subfamily affects the metabolism of many therapeutic drugs, including cancer therapeutics.¹¹ The various compositions of cannabis are primarily metabolized by the CYP450 pathway, the same as many cancer-directed pharmacologic treatments. CBs act as both CYP inducers and inhibitors. THC, for example, is a CYP inducer whereas CBD is a CYP inhibitor; both are found in the various compounds available for consumption.^12,13 Pharmacology research has suggested potential interactions and effects on established adverse symptoms, but clinical data are lacking, and current research revealing interactions are only recognized in vitro.¹⁴

The Antineoplastic Activity of Cannabis

CBs can affect various cancer-related pathways such as PKB, AMPK, CAMKK-ß, mTOR, PDHK, HIF-1 a, and PPAR-γ. Δ-9-THC can selectively induce apoptosis in tumor cells without harming normal cells, though the exact mechanism remains unclear. Promising results from early mouse studies led to a 2006 human study where intracranial Δ-9-THC in patients with recurrent glioma yielded a median survival of 24 weeks, with 2 patients surviving > 1 year.¹⁵

In a 2022 review article, Cherkasova et al highlighted potential clinical benefits of cannabis across various cancers. They found that upregulated CB1 receptors in colon cancer might enhance the effect of 5-fluorouracil. However, many studies are preliminary and therefore not definitive.¹⁰

Additional research is needed to refine these findings. Challenges include variability in cannabis formulations, the complex tumor microenvironment, and the legal and psychoactive issues surrounding cannabis use. These factors complicate the design of multicenter randomized studies and may deter patients from disclosing cannabis use, thereby hindering efforts to fully understand its therapeutic potential.

Cannabis/Cytotoxic Chemotherapy Interactions

The chemotherapy agents used in this study included carboplatin, paclitaxel, 5-fluorouracil, etoposide, irinotecan, oxaliplatin, pemetrexed, docetaxel, cabazitaxel, T-DM1, gemcitabine, and cyclophosphamide. There is a paucity of research regarding the interactions between cytotoxic chemotherapy and cannabis. Most studies focused on CBD due to its inhibition of the CYP450 pathway, which is used for metabolizing cytotoxic chemotherapies. Through this mechanism, CBD could potentially increase the concentrations of chemotherapeutic agents, enhancing their toxicity.

When combined with irinotecan, cannabis can pose risks. Δ-9-THC undergoes first-pass metabolism in the liver, mediated by the CYP450 system and CYP3A4. The glucuronidation of irinotecan is mediated by uridine diphosphate glycosyltransferase, leading to its recirculation within the hepatic system and potentially increased toxicity due to prolonged drug presence. Cannabis may also compete with drug binding to albumin, altering the plasma concentrations of irinotecan and its conversion to the metabolite SN38.¹⁶

Cannabis products can affect chemotherapy levels by interacting with cellular transporters. The MRP1 transporter family, encoded by the ABCC gene family, is expressed mainly in the lung, kidney, skeletal muscle, and hematopoietic stem cells. A 2018 study investigating the effects of THC, CBD, and CBN on MRP1 transporters found that the presence of a cannabis component increased the concentration of vincristine 3-fold. Additional studies suggest the interaction with the CB1 receptor may lead to changes in the expression of MRP1 transporters.¹⁷

CBD inhibits the BCRP transporter, which functions as an efflux pump for methotrexate. Consequently, CBD can increase methotrexate levels, potentially enhancing efficacy but also worsening adverse effects.¹⁸

In pancreatic cancer, CBD specifically interacts with gemcitabine. CB1 and CB2 receptors are upregulated, and CBD inhibits the GPR55 receptor. These interactions may enhance the antineoplastic effect of gemcitabine, reducing cell cycle progression and growth.¹⁹

CBD also interacts with temozolomide (TMZ) by affecting extracellular vesicles used by cells for pro-oncogenic signaling and immune system evasion. Experiments on patient-derived glioblastoma cells, both chemotherapy-resistant and chemotherapy-sensitive, found that CBD increases the formation of extracellular vesicles with reduced levels of miR21 (pro-oncogenic) and elevated levels of miR126 (antioncogenic).²⁰ CBD has also been found to decrease prohibitin levels, a protein associated with TMZ resistance.

In patients with glioblastoma, CBD combined with chemotherapeutic agents like TMZ, carmustine, doxorubicin, and cisplatin has shown increased sensitivity and improved tumor response. CBD is also known to inhibit NF-kB, a pathway that sustains tumor viability despite chemotherapy.²¹ Additionally, CBD inhibits the P-glycoprotein system, affecting chemotherapy efflux from neoplastic cells.¹⁴ In vitro studies have found that CBD is synergistic with bortezomib in inhibiting cancer cell viability. In another glioblastoma model, CBD enhanced the antiproliferative effects of both TMZ and carmustine.¹⁴

Different cannabis formulations may vary in how they interact with various cytotoxic chemotherapeutic agents. Some may potentiate the effects of chemotherapy and act synergistically to inhibit tumor growth, while others may lead to increased toxicity.¹⁰ More research is needed to determine which formulations, in combination with specific agents and doses, may have significant interactions that warrant adjustments in chemotherapy dosing.

Cannabis/Immunotherapy Interactions

Cannabis is an immunosuppressant. Data suggest the use of cannabis during immunotherapy worsens treatment outcomes in patients with cancer.²² Exogenous (THC) and endogenous (AEA) CBs negatively affect antitumor immunity by impairing the function of tumor-specific T cells via CB2 and by inhibiting the Jak1-STATs signaling in T cells through CNR2. Xiong et al found that THC reduces the therapeutic effect of anti-PD-1 therapy.²²

In a prospective observational clinical study, Bar-Sela et al analyzed 102 patients with advanced cancer—of which 68 were cannabis users—that were started on immune checkpoint inhibitor therapy. The study found that cannabis users on anti-PD-1 (nivolumab, pembrolizumab), anti-CTLA-4 (ipilimumab), and anti-PD-L1 (durvalumab, atezolizumab) had a significant decrease in time to treatment progression and overall survival vs cannabis non-users.²³ However, a 2023 study by Waissengrin et al found that concomitant use of medical cannabis with pembrolizumab had no harmful effect in advanced non-small cell lung cancer.²⁴ Time to treatment progression of cannabis users did not differ from cannabis nonusers.²⁵

Cannabis/Endocrine Therapy Interactions

In addition to having direct antineoplastic activity on tumor cells, data exist that show how cannabis affects the endocrine system. In animal models, cannabis has been found to suppress the whole hypothalamic-pituitary-adrenal axis as well as other hormones like thyroid, prolactin, and growth hormone. In breast cancer, cannabis competes with estrogen for the estrogen receptor and suppresses growth.²⁶

The endocrine agents used by patients with cancer in this study were antiandrogens like abiraterone, enzalutamide, tamoxifen and anastrozole. Abiraterone is metabolized by CYP450 isoenzymes and uridine diphosphate glycosyltransferases. Cannabis inhibits both processes and therefore may lead to increased toxicities.²⁷ Conversely, enzalutamide is a strong CYP3A inducer, and cannabis use during enzalutamide therapy may significantly increase the toxic effects of cannabis.

There is evidence that molecular pathways involving CB receptors and estrogens overlap, which may lead to interactions when antiestrogens are used in cannabis users with hormone receptor-positive breast cancer.²⁶ In preclinical studies, tamoxifen has been shown to act as an inverse agonist on CB1 and CB2 receptors, though the significance of this finding is unclear. There is no research evaluating the effects of CBs on tamoxifen treatment. However, CBD has been found to potentiate the effectiveness of anastrozole or exemestane in breast cancer cell lines.²⁸ Dobovišek et al demonstrated no inhibitory effect of CBD on the activity of tamoxifen, fulvestrant, or palbociclib in breast cancer cell lines.²⁹ The interactions between hormone receptor-positive breast cancer and cannabinoids are complex, and the clinical significance of these interactions remains difficult to identify.

Cannabis/Targeted Therapy Interactions

The targeted therapies used by patients in this study included zanubrutinib, ibrutinib, sorafenib, acalabrutinib, dabrafenib, trametinib, trastuzumab, bevacizumab, daratumumab, and imatinib. Compared to other classes of cancer treatments, most studies have not demonstrated decreased efficacy or increased toxicity of targeted anticancer drugs when used concomitantly with CBD.²⁹

Trastuzumab is a recombinant humanized monoclonal antibody that targets the proto-oncogene HER2/neu. It is used to treat select patients with metastatic breast cancer. Studies have shown that cannabis use does not attenuate the effectiveness of trastuzumab in HER2-positive and triple-negative breast cancer subtypes.²⁹ One study found that CBD, in combination with chemotherapeutics and Bruton tyrosine kinase inhibitors, such as ibrutinib and zanubrutinib, has synergistic potential for treating diffuse large B-cell lymphoma and mantle cell lymphoma cell lines. This synergy is attributed to the CB1 antagonist activity of cannabis against diffuse large B-cell lymphoma and mantle cell lymphoma cell lines.^30,31

Moreover, combining cannabinoids with bevacizumab (a monoclonal anti-VEGF antibody) has been shown to decrease tumor growth and intratumoral hypoxia in clinically relevant human glioblastoma models. This effect is mediated through the downregulation of HIF-1α.³² Long-term studies evaluating the potential harmful or synergistic potential of CBD on targeted anticancer therapy are needed.

CONCLUSIONS

This exploratory study of patients receiving cancer therapy at WJVAMC found a significant prevalence of concurrent cannabis use among patients undergoing antineoplastic treatments. Given that many antineoplastic agents are metabolized by the CYP450 enzyme system, the findings of this study suggest that concurrent cannabis use may pose risks of suboptimal therapeutic outcomes due to potential interactions affecting drug metabolism. These interactions could impact the efficacy and toxicity of the antineoplastic therapies, potentially leading to diminished therapeutic effects or exacerbated adverse reactions.

Patients should be informed regarding the potential decreased efficacy of immunotherapy with concurrent use of cannabis products. They should also be aware of the possibility of increased toxicity with other treatment modalities, though the exact impact on efficacy remains unclear. This highlights the necessity of caution when combining cannabis with prescribed cancer treatments.

While this study identified possible interactions, its data are preliminary and highlight the need for more rigorous research. Future studies should include larger, well-designed cohorts to compare outcomes between cannabis users and nonusers. Such research is essential to fully elucidate the clinical implications of cannabis use during cancer treatment, address the high prevalence of cannabis use among patients with cancer, and mitigate potential risks associated with combining cannabis products with antineoplastic therapies. This will ensure that treatment strategies are optimized for safety and efficacy in this complex patient population.

Cannabis has a long history of use for medicinal and recreational purposes. Research illustrates the potential benefits and increased prevalence of cannabis use in patients with cancer.¹ Cannabis products have been shown to possess antineoplastic and palliative activity, improving nociceptive and neuropathic pain in addition to chemotherapy-related nausea and vomiting.^2-5 Despite these developments and changing social attitudes toward cannabis, there remains a lack of comprehensive data on patient perspectives regarding its use, especially in regions where cannabis remains illegal. This knowledge gap is notable among veterans undergoing cancer treatment in states where cannabis is prohibited. Up to 57% of veterans report lifetime marijuana use, making it crucial to understand this population’s cannabis use patterns and potential interactions with cancer treatments.⁶

This observational study sought to determine the prevalence of cannabis use among patients undergoing cancer treatment at the US Department of Veterans Affairs (VA) Memphis Healthcare System and evaluate the potential risks associated with combining cannabis products with anticancer therapies.

METHODS

This prospective observational study identified cannabis use among veterans receiving antineoplastic therapy at the Lt. Col. Luke Weathers Jr. VA Medical Center (WJVAMC) and analyzed potential interactions between cannabis products and their cancer treatments. Participants included adults aged > 18 years undergoing antineoplastic therapy at WJVAMC who consented to the study. Data collection involved a written survey approved by the WJVAMC Institutional Review Board and verbal consent from participants. The survey asked participants about their cannabis use in the previous 90 days, including details on quantity, frequency, and method of consumption (eg, inhalation, oral, topical). No incentives were offered for participation.

Surveys from 50 patients who used cannabis were analyzed and their electronic health records were reviewed for sex, age, diagnosis, and antineoplastic regimen. This information was securely stored. A literature review was conducted using PubMed and the Cochrane Library to explore potential interactions between cannabis and the antineoplastic agents that were prescribed to patients in the study, focusing on toxicity, efficacy, or synergistic effects.

Patients were categorized into 4 groups based on treatment: cytotoxic chemotherapy, immunotherapy, endocrine therapy, and targeted therapy. Patients undergoing multiple types of therapies were included in each applicable category.

RESULTS

A total of 132 patients agreed to participate. Fifty patients (38%) acknowledged using cannabis products within 90 days. The patients that used cannabis products within 90 days of the survey reported the following malignancies: 8 patients (16%) had prostate cancer, 3 patients (6%) had hepatocellular carcinoma, 7 patients (14%) had pancreatic carcinoma, 5 patients (10%) had multiple myeloma, 3 patients (6%) had chronic lymphocytic leukemia, 9 patients (18%) had non-small cell lung cancer, 3 patients (6%) had breast cancer, 3 (6%) patients had bladder cancer, 2 patients (4%) had renal cell carcinoma, 1 (2%) patient had chronic myeloid leukemia, 1 (2%) patient had renal amyloid, 1 patient (2%) had supraglottic squamous cell carcinoma, 1 patient (2%) had esophageal carcinoma, 1 (2%) patient had small cell lung cancer, 1 (2%) patient had gastric cancer, and 1 patient (2%) had follicular lymphoma.

Five (10%) of the cannabis users were female, and 45 (90%) were male. Twenty-nine patients (58%) were aged 66 to 75 years, 16 (32%) were aged 56 to 65 years, 3 (6%) were aged 46 to 55 years, and 2 (4%) were aged 76 to 85 years.

Thirty-five patients (70%) inhaled cannabis as opposed to using it via other formulations or a combination (eg, inhalation and topical). Thirty-eight percent of patients used cannabis once daily, 24% used < 1 daily, and 28% used it ≥ 2 times daily. Five patients (10%) did not report the frequency of their cannabis use. Among the patients who reported cannabis use, 21 (42%) were undergoing cytotoxic chemotherapy, 19 (38%) were undergoing immunotherapy, 12 (24%) were undergoing targeted therapy, and 10 (20%) were undergoing endocrine therapy. Some patients were treated with multiple types of antineoplastic agents and were counted in multiple categories (Table 1).

Following a literature review of cannabis and antineoplastic agents, patients were evaluated for the potential effects of cannabis on their treatment. The literature review revealed that 31% of cytotoxic chemotherapy agents received by patients in this study might have increased toxicity, and 19% could have reduced efficacy when combined with cannabis. Among immunotherapy agents received by patients in this study, 70% might have decreased efficacy when combined with cannabis use. For targeted therapies, 35% could have increased toxicity, and 70% of endocrine agents could potentially have decreased efficacy (Table 2).

DISCUSSION

This prospective study corroborates previous research by demonstrating that more than one-third of patients receiving oncology care at WJVAMC use cannabis, most often inhaled. Cannabis use was observed among patients undergoing various cancer therapies, including cytotoxic chemotherapy, immunotherapy, targeted therapy, and endocrine therapy. The most common malignancies among cannabis users at WJVAMC include patients with lung cancer, prostate cancer, pancreatic cancer, and multiple myeloma. Cannabis use in patients with pancreatic cancer and multiple myeloma was significantly out of proportion to their prevalence at WJVAMC. This could potentially be due to their drastic effect on quality of life.

Cannabis use increased the risk of toxicity in patients treated with cytotoxic chemotherapy and targeted therapy. Cannabis use potentially decreased efficacy for patients treated with cytotoxic chemotherapy and/or immunotherapy. Cannabis use did not increase the risk of toxicity or efficacy in patients treated with endocrine therapy.

Antineoplastics/Cannabis Interactions

The potential interactions between cannabis and antineoplastic therapies administered at WJVAMC are worth exploring. While this review aims to shed light on possible interactions, it is important to acknowledge that much of the data is preliminary and derived from in vitro studies. The interactions should be interpreted as potential risks rather than established facts. Additional research is needed to confirm these interactions and effectively guide clinical practices. Understanding these dynamics is essential to optimize patient care and manage the complex interplay between cannabis use and cancer treatment.

Originating from Central Asia, the cannabis plant contains > 400 medicinally relevant compounds, of which about 100 are cannabinoids (CBs). Key CBs are cannabidiol (CBD), a nonpsychoactive compound, and ?-9-tetrahydrocannabinol (THC), a psychoactive compound. THC can make up 20% to 30% of the dry weight of female cannabis flowers.⁷

CBs act through the endocannabinoid system, involving CB1 and CB2 receptors, endogenous CBs like anandamide (AEA) and 2-arachidonoylglycerol, and various enzymes. These endogenous CBs, derived from arachidonic acid, play roles in cell growth and proliferation.⁸ In some studies, AEA has induced apoptosis in neuroblastoma cells and inhibited proliferation in breast cancer cells. However, other research suggests AEA may block apoptosis under certain conditions.⁹

CB receptors are transmembrane proteins that interact with CBs differently depending on tissue type and CB structure. Synthetic CBs are designed to target specific receptors, while natural CBs may act as both agonists and antagonists.¹⁰

Cytochrome P450 Metabolism

The human cytochrome P450 (CYP) 3A subfamily affects the metabolism of many therapeutic drugs, including cancer therapeutics.¹¹ The various compositions of cannabis are primarily metabolized by the CYP450 pathway, the same as many cancer-directed pharmacologic treatments. CBs act as both CYP inducers and inhibitors. THC, for example, is a CYP inducer whereas CBD is a CYP inhibitor; both are found in the various compounds available for consumption.^12,13 Pharmacology research has suggested potential interactions and effects on established adverse symptoms, but clinical data are lacking, and current research revealing interactions are only recognized in vitro.¹⁴

The Antineoplastic Activity of Cannabis

CBs can affect various cancer-related pathways such as PKB, AMPK, CAMKK-ß, mTOR, PDHK, HIF-1 a, and PPAR-γ. Δ-9-THC can selectively induce apoptosis in tumor cells without harming normal cells, though the exact mechanism remains unclear. Promising results from early mouse studies led to a 2006 human study where intracranial Δ-9-THC in patients with recurrent glioma yielded a median survival of 24 weeks, with 2 patients surviving > 1 year.¹⁵

In a 2022 review article, Cherkasova et al highlighted potential clinical benefits of cannabis across various cancers. They found that upregulated CB1 receptors in colon cancer might enhance the effect of 5-fluorouracil. However, many studies are preliminary and therefore not definitive.¹⁰

Additional research is needed to refine these findings. Challenges include variability in cannabis formulations, the complex tumor microenvironment, and the legal and psychoactive issues surrounding cannabis use. These factors complicate the design of multicenter randomized studies and may deter patients from disclosing cannabis use, thereby hindering efforts to fully understand its therapeutic potential.

Cannabis/Cytotoxic Chemotherapy Interactions

The chemotherapy agents used in this study included carboplatin, paclitaxel, 5-fluorouracil, etoposide, irinotecan, oxaliplatin, pemetrexed, docetaxel, cabazitaxel, T-DM1, gemcitabine, and cyclophosphamide. There is a paucity of research regarding the interactions between cytotoxic chemotherapy and cannabis. Most studies focused on CBD due to its inhibition of the CYP450 pathway, which is used for metabolizing cytotoxic chemotherapies. Through this mechanism, CBD could potentially increase the concentrations of chemotherapeutic agents, enhancing their toxicity.

When combined with irinotecan, cannabis can pose risks. Δ-9-THC undergoes first-pass metabolism in the liver, mediated by the CYP450 system and CYP3A4. The glucuronidation of irinotecan is mediated by uridine diphosphate glycosyltransferase, leading to its recirculation within the hepatic system and potentially increased toxicity due to prolonged drug presence. Cannabis may also compete with drug binding to albumin, altering the plasma concentrations of irinotecan and its conversion to the metabolite SN38.¹⁶

Cannabis products can affect chemotherapy levels by interacting with cellular transporters. The MRP1 transporter family, encoded by the ABCC gene family, is expressed mainly in the lung, kidney, skeletal muscle, and hematopoietic stem cells. A 2018 study investigating the effects of THC, CBD, and CBN on MRP1 transporters found that the presence of a cannabis component increased the concentration of vincristine 3-fold. Additional studies suggest the interaction with the CB1 receptor may lead to changes in the expression of MRP1 transporters.¹⁷

CBD inhibits the BCRP transporter, which functions as an efflux pump for methotrexate. Consequently, CBD can increase methotrexate levels, potentially enhancing efficacy but also worsening adverse effects.¹⁸

In pancreatic cancer, CBD specifically interacts with gemcitabine. CB1 and CB2 receptors are upregulated, and CBD inhibits the GPR55 receptor. These interactions may enhance the antineoplastic effect of gemcitabine, reducing cell cycle progression and growth.¹⁹

CBD also interacts with temozolomide (TMZ) by affecting extracellular vesicles used by cells for pro-oncogenic signaling and immune system evasion. Experiments on patient-derived glioblastoma cells, both chemotherapy-resistant and chemotherapy-sensitive, found that CBD increases the formation of extracellular vesicles with reduced levels of miR21 (pro-oncogenic) and elevated levels of miR126 (antioncogenic).²⁰ CBD has also been found to decrease prohibitin levels, a protein associated with TMZ resistance.

In patients with glioblastoma, CBD combined with chemotherapeutic agents like TMZ, carmustine, doxorubicin, and cisplatin has shown increased sensitivity and improved tumor response. CBD is also known to inhibit NF-kB, a pathway that sustains tumor viability despite chemotherapy.²¹ Additionally, CBD inhibits the P-glycoprotein system, affecting chemotherapy efflux from neoplastic cells.¹⁴ In vitro studies have found that CBD is synergistic with bortezomib in inhibiting cancer cell viability. In another glioblastoma model, CBD enhanced the antiproliferative effects of both TMZ and carmustine.¹⁴

Different cannabis formulations may vary in how they interact with various cytotoxic chemotherapeutic agents. Some may potentiate the effects of chemotherapy and act synergistically to inhibit tumor growth, while others may lead to increased toxicity.¹⁰ More research is needed to determine which formulations, in combination with specific agents and doses, may have significant interactions that warrant adjustments in chemotherapy dosing.

Cannabis/Immunotherapy Interactions

Cannabis is an immunosuppressant. Data suggest the use of cannabis during immunotherapy worsens treatment outcomes in patients with cancer.²² Exogenous (THC) and endogenous (AEA) CBs negatively affect antitumor immunity by impairing the function of tumor-specific T cells via CB2 and by inhibiting the Jak1-STATs signaling in T cells through CNR2. Xiong et al found that THC reduces the therapeutic effect of anti-PD-1 therapy.²²

In a prospective observational clinical study, Bar-Sela et al analyzed 102 patients with advanced cancer—of which 68 were cannabis users—that were started on immune checkpoint inhibitor therapy. The study found that cannabis users on anti-PD-1 (nivolumab, pembrolizumab), anti-CTLA-4 (ipilimumab), and anti-PD-L1 (durvalumab, atezolizumab) had a significant decrease in time to treatment progression and overall survival vs cannabis non-users.²³ However, a 2023 study by Waissengrin et al found that concomitant use of medical cannabis with pembrolizumab had no harmful effect in advanced non-small cell lung cancer.²⁴ Time to treatment progression of cannabis users did not differ from cannabis nonusers.²⁵

Cannabis/Endocrine Therapy Interactions

In addition to having direct antineoplastic activity on tumor cells, data exist that show how cannabis affects the endocrine system. In animal models, cannabis has been found to suppress the whole hypothalamic-pituitary-adrenal axis as well as other hormones like thyroid, prolactin, and growth hormone. In breast cancer, cannabis competes with estrogen for the estrogen receptor and suppresses growth.²⁶

The endocrine agents used by patients with cancer in this study were antiandrogens like abiraterone, enzalutamide, tamoxifen and anastrozole. Abiraterone is metabolized by CYP450 isoenzymes and uridine diphosphate glycosyltransferases. Cannabis inhibits both processes and therefore may lead to increased toxicities.²⁷ Conversely, enzalutamide is a strong CYP3A inducer, and cannabis use during enzalutamide therapy may significantly increase the toxic effects of cannabis.

There is evidence that molecular pathways involving CB receptors and estrogens overlap, which may lead to interactions when antiestrogens are used in cannabis users with hormone receptor-positive breast cancer.²⁶ In preclinical studies, tamoxifen has been shown to act as an inverse agonist on CB1 and CB2 receptors, though the significance of this finding is unclear. There is no research evaluating the effects of CBs on tamoxifen treatment. However, CBD has been found to potentiate the effectiveness of anastrozole or exemestane in breast cancer cell lines.²⁸ Dobovišek et al demonstrated no inhibitory effect of CBD on the activity of tamoxifen, fulvestrant, or palbociclib in breast cancer cell lines.²⁹ The interactions between hormone receptor-positive breast cancer and cannabinoids are complex, and the clinical significance of these interactions remains difficult to identify.

Cannabis/Targeted Therapy Interactions

The targeted therapies used by patients in this study included zanubrutinib, ibrutinib, sorafenib, acalabrutinib, dabrafenib, trametinib, trastuzumab, bevacizumab, daratumumab, and imatinib. Compared to other classes of cancer treatments, most studies have not demonstrated decreased efficacy or increased toxicity of targeted anticancer drugs when used concomitantly with CBD.²⁹

Trastuzumab is a recombinant humanized monoclonal antibody that targets the proto-oncogene HER2/neu. It is used to treat select patients with metastatic breast cancer. Studies have shown that cannabis use does not attenuate the effectiveness of trastuzumab in HER2-positive and triple-negative breast cancer subtypes.²⁹ One study found that CBD, in combination with chemotherapeutics and Bruton tyrosine kinase inhibitors, such as ibrutinib and zanubrutinib, has synergistic potential for treating diffuse large B-cell lymphoma and mantle cell lymphoma cell lines. This synergy is attributed to the CB1 antagonist activity of cannabis against diffuse large B-cell lymphoma and mantle cell lymphoma cell lines.^30,31

Moreover, combining cannabinoids with bevacizumab (a monoclonal anti-VEGF antibody) has been shown to decrease tumor growth and intratumoral hypoxia in clinically relevant human glioblastoma models. This effect is mediated through the downregulation of HIF-1α.³² Long-term studies evaluating the potential harmful or synergistic potential of CBD on targeted anticancer therapy are needed.

CONCLUSIONS

This exploratory study of patients receiving cancer therapy at WJVAMC found a significant prevalence of concurrent cannabis use among patients undergoing antineoplastic treatments. Given that many antineoplastic agents are metabolized by the CYP450 enzyme system, the findings of this study suggest that concurrent cannabis use may pose risks of suboptimal therapeutic outcomes due to potential interactions affecting drug metabolism. These interactions could impact the efficacy and toxicity of the antineoplastic therapies, potentially leading to diminished therapeutic effects or exacerbated adverse reactions.

Patients should be informed regarding the potential decreased efficacy of immunotherapy with concurrent use of cannabis products. They should also be aware of the possibility of increased toxicity with other treatment modalities, though the exact impact on efficacy remains unclear. This highlights the necessity of caution when combining cannabis with prescribed cancer treatments.

While this study identified possible interactions, its data are preliminary and highlight the need for more rigorous research. Future studies should include larger, well-designed cohorts to compare outcomes between cannabis users and nonusers. Such research is essential to fully elucidate the clinical implications of cannabis use during cancer treatment, address the high prevalence of cannabis use among patients with cancer, and mitigate potential risks associated with combining cannabis products with antineoplastic therapies. This will ensure that treatment strategies are optimized for safety and efficacy in this complex patient population.

Cannabis has a long history of use for medicinal and recreational purposes. Research illustrates the potential benefits and increased prevalence of cannabis use in patients with cancer.¹ Cannabis products have been shown to possess antineoplastic and palliative activity, improving nociceptive and neuropathic pain in addition to chemotherapy-related nausea and vomiting.^2-5 Despite these developments and changing social attitudes toward cannabis, there remains a lack of comprehensive data on patient perspectives regarding its use, especially in regions where cannabis remains illegal. This knowledge gap is notable among veterans undergoing cancer treatment in states where cannabis is prohibited. Up to 57% of veterans report lifetime marijuana use, making it crucial to understand this population’s cannabis use patterns and potential interactions with cancer treatments.⁶

This observational study sought to determine the prevalence of cannabis use among patients undergoing cancer treatment at the US Department of Veterans Affairs (VA) Memphis Healthcare System and evaluate the potential risks associated with combining cannabis products with anticancer therapies.

METHODS

This prospective observational study identified cannabis use among veterans receiving antineoplastic therapy at the Lt. Col. Luke Weathers Jr. VA Medical Center (WJVAMC) and analyzed potential interactions between cannabis products and their cancer treatments. Participants included adults aged > 18 years undergoing antineoplastic therapy at WJVAMC who consented to the study. Data collection involved a written survey approved by the WJVAMC Institutional Review Board and verbal consent from participants. The survey asked participants about their cannabis use in the previous 90 days, including details on quantity, frequency, and method of consumption (eg, inhalation, oral, topical). No incentives were offered for participation.

Surveys from 50 patients who used cannabis were analyzed and their electronic health records were reviewed for sex, age, diagnosis, and antineoplastic regimen. This information was securely stored. A literature review was conducted using PubMed and the Cochrane Library to explore potential interactions between cannabis and the antineoplastic agents that were prescribed to patients in the study, focusing on toxicity, efficacy, or synergistic effects.

Patients were categorized into 4 groups based on treatment: cytotoxic chemotherapy, immunotherapy, endocrine therapy, and targeted therapy. Patients undergoing multiple types of therapies were included in each applicable category.

RESULTS

A total of 132 patients agreed to participate. Fifty patients (38%) acknowledged using cannabis products within 90 days. The patients that used cannabis products within 90 days of the survey reported the following malignancies: 8 patients (16%) had prostate cancer, 3 patients (6%) had hepatocellular carcinoma, 7 patients (14%) had pancreatic carcinoma, 5 patients (10%) had multiple myeloma, 3 patients (6%) had chronic lymphocytic leukemia, 9 patients (18%) had non-small cell lung cancer, 3 patients (6%) had breast cancer, 3 (6%) patients had bladder cancer, 2 patients (4%) had renal cell carcinoma, 1 (2%) patient had chronic myeloid leukemia, 1 (2%) patient had renal amyloid, 1 patient (2%) had supraglottic squamous cell carcinoma, 1 patient (2%) had esophageal carcinoma, 1 (2%) patient had small cell lung cancer, 1 (2%) patient had gastric cancer, and 1 patient (2%) had follicular lymphoma.

Five (10%) of the cannabis users were female, and 45 (90%) were male. Twenty-nine patients (58%) were aged 66 to 75 years, 16 (32%) were aged 56 to 65 years, 3 (6%) were aged 46 to 55 years, and 2 (4%) were aged 76 to 85 years.

Thirty-five patients (70%) inhaled cannabis as opposed to using it via other formulations or a combination (eg, inhalation and topical). Thirty-eight percent of patients used cannabis once daily, 24% used < 1 daily, and 28% used it ≥ 2 times daily. Five patients (10%) did not report the frequency of their cannabis use. Among the patients who reported cannabis use, 21 (42%) were undergoing cytotoxic chemotherapy, 19 (38%) were undergoing immunotherapy, 12 (24%) were undergoing targeted therapy, and 10 (20%) were undergoing endocrine therapy. Some patients were treated with multiple types of antineoplastic agents and were counted in multiple categories (Table 1).

Following a literature review of cannabis and antineoplastic agents, patients were evaluated for the potential effects of cannabis on their treatment. The literature review revealed that 31% of cytotoxic chemotherapy agents received by patients in this study might have increased toxicity, and 19% could have reduced efficacy when combined with cannabis. Among immunotherapy agents received by patients in this study, 70% might have decreased efficacy when combined with cannabis use. For targeted therapies, 35% could have increased toxicity, and 70% of endocrine agents could potentially have decreased efficacy (Table 2).

DISCUSSION

This prospective study corroborates previous research by demonstrating that more than one-third of patients receiving oncology care at WJVAMC use cannabis, most often inhaled. Cannabis use was observed among patients undergoing various cancer therapies, including cytotoxic chemotherapy, immunotherapy, targeted therapy, and endocrine therapy. The most common malignancies among cannabis users at WJVAMC include patients with lung cancer, prostate cancer, pancreatic cancer, and multiple myeloma. Cannabis use in patients with pancreatic cancer and multiple myeloma was significantly out of proportion to their prevalence at WJVAMC. This could potentially be due to their drastic effect on quality of life.

Cannabis use increased the risk of toxicity in patients treated with cytotoxic chemotherapy and targeted therapy. Cannabis use potentially decreased efficacy for patients treated with cytotoxic chemotherapy and/or immunotherapy. Cannabis use did not increase the risk of toxicity or efficacy in patients treated with endocrine therapy.

Antineoplastics/Cannabis Interactions

The potential interactions between cannabis and antineoplastic therapies administered at WJVAMC are worth exploring. While this review aims to shed light on possible interactions, it is important to acknowledge that much of the data is preliminary and derived from in vitro studies. The interactions should be interpreted as potential risks rather than established facts. Additional research is needed to confirm these interactions and effectively guide clinical practices. Understanding these dynamics is essential to optimize patient care and manage the complex interplay between cannabis use and cancer treatment.

Originating from Central Asia, the cannabis plant contains > 400 medicinally relevant compounds, of which about 100 are cannabinoids (CBs). Key CBs are cannabidiol (CBD), a nonpsychoactive compound, and ?-9-tetrahydrocannabinol (THC), a psychoactive compound. THC can make up 20% to 30% of the dry weight of female cannabis flowers.⁷

CBs act through the endocannabinoid system, involving CB1 and CB2 receptors, endogenous CBs like anandamide (AEA) and 2-arachidonoylglycerol, and various enzymes. These endogenous CBs, derived from arachidonic acid, play roles in cell growth and proliferation.⁸ In some studies, AEA has induced apoptosis in neuroblastoma cells and inhibited proliferation in breast cancer cells. However, other research suggests AEA may block apoptosis under certain conditions.⁹

CB receptors are transmembrane proteins that interact with CBs differently depending on tissue type and CB structure. Synthetic CBs are designed to target specific receptors, while natural CBs may act as both agonists and antagonists.¹⁰

Cytochrome P450 Metabolism

The human cytochrome P450 (CYP) 3A subfamily affects the metabolism of many therapeutic drugs, including cancer therapeutics.¹¹ The various compositions of cannabis are primarily metabolized by the CYP450 pathway, the same as many cancer-directed pharmacologic treatments. CBs act as both CYP inducers and inhibitors. THC, for example, is a CYP inducer whereas CBD is a CYP inhibitor; both are found in the various compounds available for consumption.^12,13 Pharmacology research has suggested potential interactions and effects on established adverse symptoms, but clinical data are lacking, and current research revealing interactions are only recognized in vitro.¹⁴

The Antineoplastic Activity of Cannabis

CBs can affect various cancer-related pathways such as PKB, AMPK, CAMKK-ß, mTOR, PDHK, HIF-1 a, and PPAR-γ. Δ-9-THC can selectively induce apoptosis in tumor cells without harming normal cells, though the exact mechanism remains unclear. Promising results from early mouse studies led to a 2006 human study where intracranial Δ-9-THC in patients with recurrent glioma yielded a median survival of 24 weeks, with 2 patients surviving > 1 year.¹⁵

In a 2022 review article, Cherkasova et al highlighted potential clinical benefits of cannabis across various cancers. They found that upregulated CB1 receptors in colon cancer might enhance the effect of 5-fluorouracil. However, many studies are preliminary and therefore not definitive.¹⁰

Additional research is needed to refine these findings. Challenges include variability in cannabis formulations, the complex tumor microenvironment, and the legal and psychoactive issues surrounding cannabis use. These factors complicate the design of multicenter randomized studies and may deter patients from disclosing cannabis use, thereby hindering efforts to fully understand its therapeutic potential.

Cannabis/Cytotoxic Chemotherapy Interactions

The chemotherapy agents used in this study included carboplatin, paclitaxel, 5-fluorouracil, etoposide, irinotecan, oxaliplatin, pemetrexed, docetaxel, cabazitaxel, T-DM1, gemcitabine, and cyclophosphamide. There is a paucity of research regarding the interactions between cytotoxic chemotherapy and cannabis. Most studies focused on CBD due to its inhibition of the CYP450 pathway, which is used for metabolizing cytotoxic chemotherapies. Through this mechanism, CBD could potentially increase the concentrations of chemotherapeutic agents, enhancing their toxicity.

When combined with irinotecan, cannabis can pose risks. Δ-9-THC undergoes first-pass metabolism in the liver, mediated by the CYP450 system and CYP3A4. The glucuronidation of irinotecan is mediated by uridine diphosphate glycosyltransferase, leading to its recirculation within the hepatic system and potentially increased toxicity due to prolonged drug presence. Cannabis may also compete with drug binding to albumin, altering the plasma concentrations of irinotecan and its conversion to the metabolite SN38.¹⁶

Cannabis products can affect chemotherapy levels by interacting with cellular transporters. The MRP1 transporter family, encoded by the ABCC gene family, is expressed mainly in the lung, kidney, skeletal muscle, and hematopoietic stem cells. A 2018 study investigating the effects of THC, CBD, and CBN on MRP1 transporters found that the presence of a cannabis component increased the concentration of vincristine 3-fold. Additional studies suggest the interaction with the CB1 receptor may lead to changes in the expression of MRP1 transporters.¹⁷

CBD inhibits the BCRP transporter, which functions as an efflux pump for methotrexate. Consequently, CBD can increase methotrexate levels, potentially enhancing efficacy but also worsening adverse effects.¹⁸

In pancreatic cancer, CBD specifically interacts with gemcitabine. CB1 and CB2 receptors are upregulated, and CBD inhibits the GPR55 receptor. These interactions may enhance the antineoplastic effect of gemcitabine, reducing cell cycle progression and growth.¹⁹

CBD also interacts with temozolomide (TMZ) by affecting extracellular vesicles used by cells for pro-oncogenic signaling and immune system evasion. Experiments on patient-derived glioblastoma cells, both chemotherapy-resistant and chemotherapy-sensitive, found that CBD increases the formation of extracellular vesicles with reduced levels of miR21 (pro-oncogenic) and elevated levels of miR126 (antioncogenic).²⁰ CBD has also been found to decrease prohibitin levels, a protein associated with TMZ resistance.

In patients with glioblastoma, CBD combined with chemotherapeutic agents like TMZ, carmustine, doxorubicin, and cisplatin has shown increased sensitivity and improved tumor response. CBD is also known to inhibit NF-kB, a pathway that sustains tumor viability despite chemotherapy.²¹ Additionally, CBD inhibits the P-glycoprotein system, affecting chemotherapy efflux from neoplastic cells.¹⁴ In vitro studies have found that CBD is synergistic with bortezomib in inhibiting cancer cell viability. In another glioblastoma model, CBD enhanced the antiproliferative effects of both TMZ and carmustine.¹⁴

Different cannabis formulations may vary in how they interact with various cytotoxic chemotherapeutic agents. Some may potentiate the effects of chemotherapy and act synergistically to inhibit tumor growth, while others may lead to increased toxicity.¹⁰ More research is needed to determine which formulations, in combination with specific agents and doses, may have significant interactions that warrant adjustments in chemotherapy dosing.

Cannabis/Immunotherapy Interactions

Cannabis is an immunosuppressant. Data suggest the use of cannabis during immunotherapy worsens treatment outcomes in patients with cancer.²² Exogenous (THC) and endogenous (AEA) CBs negatively affect antitumor immunity by impairing the function of tumor-specific T cells via CB2 and by inhibiting the Jak1-STATs signaling in T cells through CNR2. Xiong et al found that THC reduces the therapeutic effect of anti-PD-1 therapy.²²

In a prospective observational clinical study, Bar-Sela et al analyzed 102 patients with advanced cancer—of which 68 were cannabis users—that were started on immune checkpoint inhibitor therapy. The study found that cannabis users on anti-PD-1 (nivolumab, pembrolizumab), anti-CTLA-4 (ipilimumab), and anti-PD-L1 (durvalumab, atezolizumab) had a significant decrease in time to treatment progression and overall survival vs cannabis non-users.²³ However, a 2023 study by Waissengrin et al found that concomitant use of medical cannabis with pembrolizumab had no harmful effect in advanced non-small cell lung cancer.²⁴ Time to treatment progression of cannabis users did not differ from cannabis nonusers.²⁵

Cannabis/Endocrine Therapy Interactions

In addition to having direct antineoplastic activity on tumor cells, data exist that show how cannabis affects the endocrine system. In animal models, cannabis has been found to suppress the whole hypothalamic-pituitary-adrenal axis as well as other hormones like thyroid, prolactin, and growth hormone. In breast cancer, cannabis competes with estrogen for the estrogen receptor and suppresses growth.²⁶

The endocrine agents used by patients with cancer in this study were antiandrogens like abiraterone, enzalutamide, tamoxifen and anastrozole. Abiraterone is metabolized by CYP450 isoenzymes and uridine diphosphate glycosyltransferases. Cannabis inhibits both processes and therefore may lead to increased toxicities.²⁷ Conversely, enzalutamide is a strong CYP3A inducer, and cannabis use during enzalutamide therapy may significantly increase the toxic effects of cannabis.

There is evidence that molecular pathways involving CB receptors and estrogens overlap, which may lead to interactions when antiestrogens are used in cannabis users with hormone receptor-positive breast cancer.²⁶ In preclinical studies, tamoxifen has been shown to act as an inverse agonist on CB1 and CB2 receptors, though the significance of this finding is unclear. There is no research evaluating the effects of CBs on tamoxifen treatment. However, CBD has been found to potentiate the effectiveness of anastrozole or exemestane in breast cancer cell lines.²⁸ Dobovišek et al demonstrated no inhibitory effect of CBD on the activity of tamoxifen, fulvestrant, or palbociclib in breast cancer cell lines.²⁹ The interactions between hormone receptor-positive breast cancer and cannabinoids are complex, and the clinical significance of these interactions remains difficult to identify.

Cannabis/Targeted Therapy Interactions

The targeted therapies used by patients in this study included zanubrutinib, ibrutinib, sorafenib, acalabrutinib, dabrafenib, trametinib, trastuzumab, bevacizumab, daratumumab, and imatinib. Compared to other classes of cancer treatments, most studies have not demonstrated decreased efficacy or increased toxicity of targeted anticancer drugs when used concomitantly with CBD.²⁹

Trastuzumab is a recombinant humanized monoclonal antibody that targets the proto-oncogene HER2/neu. It is used to treat select patients with metastatic breast cancer. Studies have shown that cannabis use does not attenuate the effectiveness of trastuzumab in HER2-positive and triple-negative breast cancer subtypes.²⁹ One study found that CBD, in combination with chemotherapeutics and Bruton tyrosine kinase inhibitors, such as ibrutinib and zanubrutinib, has synergistic potential for treating diffuse large B-cell lymphoma and mantle cell lymphoma cell lines. This synergy is attributed to the CB1 antagonist activity of cannabis against diffuse large B-cell lymphoma and mantle cell lymphoma cell lines.^30,31

Moreover, combining cannabinoids with bevacizumab (a monoclonal anti-VEGF antibody) has been shown to decrease tumor growth and intratumoral hypoxia in clinically relevant human glioblastoma models. This effect is mediated through the downregulation of HIF-1α.³² Long-term studies evaluating the potential harmful or synergistic potential of CBD on targeted anticancer therapy are needed.

CONCLUSIONS

This exploratory study of patients receiving cancer therapy at WJVAMC found a significant prevalence of concurrent cannabis use among patients undergoing antineoplastic treatments. Given that many antineoplastic agents are metabolized by the CYP450 enzyme system, the findings of this study suggest that concurrent cannabis use may pose risks of suboptimal therapeutic outcomes due to potential interactions affecting drug metabolism. These interactions could impact the efficacy and toxicity of the antineoplastic therapies, potentially leading to diminished therapeutic effects or exacerbated adverse reactions.

Patients should be informed regarding the potential decreased efficacy of immunotherapy with concurrent use of cannabis products. They should also be aware of the possibility of increased toxicity with other treatment modalities, though the exact impact on efficacy remains unclear. This highlights the necessity of caution when combining cannabis with prescribed cancer treatments.

While this study identified possible interactions, its data are preliminary and highlight the need for more rigorous research. Future studies should include larger, well-designed cohorts to compare outcomes between cannabis users and nonusers. Such research is essential to fully elucidate the clinical implications of cannabis use during cancer treatment, address the high prevalence of cannabis use among patients with cancer, and mitigate potential risks associated with combining cannabis products with antineoplastic therapies. This will ensure that treatment strategies are optimized for safety and efficacy in this complex patient population.

Offering adjuvant therapy to patients with stage III melanoma offers no melanoma-specific or overall survival benefit, reveals extended follow-up from the first population-based national study to estimate the impact of the treatment.

Hildur Helgadottir, MD, PhD, presented the new findings at the 22nd European Association of Dermato-Oncology (EADO) Congress 2026 on April 24 and described the lead-up to the latest update on the study.

To investigate the impact of adjuvant treatment in patients with stage III melanoma, researchers initially conducted a study in which they used the Swedish Melanoma Registry (SweMR) to identify a precohort of those treated before the introduction of adjuvant therapy in 2018 and a postcohort of those treated subsequently, following both groups out to 2023, she explained.

The analysis revealed no significant difference in melanoma-specific survival between the two groups, at a hazard ratio of 0.92, nor in overall survival, at a hazard ratio of 0.93 (P = .60 for both). However, median follow-up differed between the groups, at 69 months vs 39 months for the precohort vs the postcohort.

Helgadottir, who is a senior research specialist at the Karolinska Comprehensive Cancer Center in Stockholm, Sweden, said that when the earlier results were presented at the European Society for Medical Oncology 2024, there was some criticism that the follow-up was not long enough and that there was no information on the actual adjuvant treatment received in the postcohort patients.

The researchers therefore extended their study out to 2024 to increase the median follow-up to 60 months vs 92 months in the postcohort group vs the precohort group.

They also focused patient selection on patients aged less than 75 years because exposure to adjuvant therapy in older patients was low and restricted the analysis to sentinel lymph node-positive stage IIIB-D cutaneous melanoma diagnosed between 2016 and 2020. This was because adjuvant exposure in stage IIIA disease was low, and patients with clinically detected stage III melanoma started to receive neoadjuvant therapy from 2022 onward.

The current analysis, which was recently published in the European Journal of Cancer, involved 287 patients in the precohort and 349 in the postcohort, who had a median age of 60.0 years and 61.0 years, respectively, and of whom 62.0% and 60.5%, respectively, were male. The groups were well balanced in terms of baseline disease characteristics.

Helgadottir explained that 73% of patients in the postcohort received some form of adjuvant treatment, with the majority treated with PD-1 inhibitors, and a smaller proportion given B-Raf serine-threonine kinase inhibitors. The main reasons for not giving adjuvant therapy were favorable tumor characteristics and the presence of comorbidities.

Five-year melanoma-specific survival rates in the precohorts and postcohorts were 71.4% vs 73.2%, at a hazard ratio adjusted for age, sex, and American Joint Committee on Cancer stage of 1.01 (P = .931). Five-year overall survival rates were 67.3% vs 70.1%, at an adjusted hazard ratio of 0.96 (P = .791).

Helgadottir showed that there were also no significant survival differences in any of the prespecified subgroups for neither melanoma-specific nor overall survival.

There were, again, no significant differences in survival outcomes between the two patient groups, she reported.

The latest results are similar to those from another study conducted in Netherlands and a Danish analysis, Helgadottir said.

Taken together, and “considering the side effects and the costs, it is possible that we will go back to closely following up our patients and treating only at relapse,” she said, “and optimally, of course, that will be already in the neoadjuvant setting.”

“And of course we will need biomarkers because there could be some patients that really need adjuvant treatment, but we need to identify these patients,” continued Helgadottir. Overall survival results from KEYNOTE-054, which compares pembrolizumab with placebo after resection of high-risk stage III melanoma, are awaited, she continued.

Helgadottir explained that adjuvant treatment for stage III melanoma was approved in Sweden in 2018, with treatments freely available to all Swedish residents.

The SweMR is a population-based national register that has near-complete and detailed data on primary cutaneous melanomas, including nodal status and satellite and in-transit disease, and is linked to the national Cause of Death Registry. Helgadottir noted, however, that the SweMR does not contain any information on relapses or the nature of the oncologic treatment received by patients with melanoma.

Following her presentation, she was challenged by an audience member as to whether, on the basis of her findings, she would go back to following up with patients and treating at relapses.

“Maybe we should do that and believe in our own data, and we do. But still, the gold standard must always be the randomized clinical trial,” Helgadottir responded. “So I think, although that we believe in this data, we also want to see the results of the randomized studies.”

The audience member commented that she can see in the data from her own institution that they treat fewer and fewer patients with melanoma with adjuvant therapy by discussing it more thoroughly and being stricter on who should receive it.

Helgadottir agreed, adding that “based on this experience, we did not introduce it to stage II patients because it’s always harder to go back” once a group of patients has started to receive a treatment.

The research was supported by Regional Cancer Centres in Sweden and with grants from the Swedish Cancer Society, Region Stockholm, and the Cancer Research Funds of Radiumhemmet. Helgadottir declared having relationships with Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, and Novartis.

The trial was supported by SkinVision. The researchers declared having no relevant financial relationships.

This article was previously published by Medscape.

Offering adjuvant therapy to patients with stage III melanoma offers no melanoma-specific or overall survival benefit, reveals extended follow-up from the first population-based national study to estimate the impact of the treatment.

Hildur Helgadottir, MD, PhD, presented the new findings at the 22nd European Association of Dermato-Oncology (EADO) Congress 2026 on April 24 and described the lead-up to the latest update on the study.

To investigate the impact of adjuvant treatment in patients with stage III melanoma, researchers initially conducted a study in which they used the Swedish Melanoma Registry (SweMR) to identify a precohort of those treated before the introduction of adjuvant therapy in 2018 and a postcohort of those treated subsequently, following both groups out to 2023, she explained.

The analysis revealed no significant difference in melanoma-specific survival between the two groups, at a hazard ratio of 0.92, nor in overall survival, at a hazard ratio of 0.93 (P = .60 for both). However, median follow-up differed between the groups, at 69 months vs 39 months for the precohort vs the postcohort.

Helgadottir, who is a senior research specialist at the Karolinska Comprehensive Cancer Center in Stockholm, Sweden, said that when the earlier results were presented at the European Society for Medical Oncology 2024, there was some criticism that the follow-up was not long enough and that there was no information on the actual adjuvant treatment received in the postcohort patients.

The researchers therefore extended their study out to 2024 to increase the median follow-up to 60 months vs 92 months in the postcohort group vs the precohort group.

They also focused patient selection on patients aged less than 75 years because exposure to adjuvant therapy in older patients was low and restricted the analysis to sentinel lymph node-positive stage IIIB-D cutaneous melanoma diagnosed between 2016 and 2020. This was because adjuvant exposure in stage IIIA disease was low, and patients with clinically detected stage III melanoma started to receive neoadjuvant therapy from 2022 onward.

The current analysis, which was recently published in the European Journal of Cancer, involved 287 patients in the precohort and 349 in the postcohort, who had a median age of 60.0 years and 61.0 years, respectively, and of whom 62.0% and 60.5%, respectively, were male. The groups were well balanced in terms of baseline disease characteristics.

Helgadottir explained that 73% of patients in the postcohort received some form of adjuvant treatment, with the majority treated with PD-1 inhibitors, and a smaller proportion given B-Raf serine-threonine kinase inhibitors. The main reasons for not giving adjuvant therapy were favorable tumor characteristics and the presence of comorbidities.

Five-year melanoma-specific survival rates in the precohorts and postcohorts were 71.4% vs 73.2%, at a hazard ratio adjusted for age, sex, and American Joint Committee on Cancer stage of 1.01 (P = .931). Five-year overall survival rates were 67.3% vs 70.1%, at an adjusted hazard ratio of 0.96 (P = .791).

Helgadottir showed that there were also no significant survival differences in any of the prespecified subgroups for neither melanoma-specific nor overall survival.

There were, again, no significant differences in survival outcomes between the two patient groups, she reported.

The latest results are similar to those from another study conducted in Netherlands and a Danish analysis, Helgadottir said.

Taken together, and “considering the side effects and the costs, it is possible that we will go back to closely following up our patients and treating only at relapse,” she said, “and optimally, of course, that will be already in the neoadjuvant setting.”

“And of course we will need biomarkers because there could be some patients that really need adjuvant treatment, but we need to identify these patients,” continued Helgadottir. Overall survival results from KEYNOTE-054, which compares pembrolizumab with placebo after resection of high-risk stage III melanoma, are awaited, she continued.

Helgadottir explained that adjuvant treatment for stage III melanoma was approved in Sweden in 2018, with treatments freely available to all Swedish residents.

The SweMR is a population-based national register that has near-complete and detailed data on primary cutaneous melanomas, including nodal status and satellite and in-transit disease, and is linked to the national Cause of Death Registry. Helgadottir noted, however, that the SweMR does not contain any information on relapses or the nature of the oncologic treatment received by patients with melanoma.

Following her presentation, she was challenged by an audience member as to whether, on the basis of her findings, she would go back to following up with patients and treating at relapses.

“Maybe we should do that and believe in our own data, and we do. But still, the gold standard must always be the randomized clinical trial,” Helgadottir responded. “So I think, although that we believe in this data, we also want to see the results of the randomized studies.”

The audience member commented that she can see in the data from her own institution that they treat fewer and fewer patients with melanoma with adjuvant therapy by discussing it more thoroughly and being stricter on who should receive it.

Helgadottir agreed, adding that “based on this experience, we did not introduce it to stage II patients because it’s always harder to go back” once a group of patients has started to receive a treatment.

The research was supported by Regional Cancer Centres in Sweden and with grants from the Swedish Cancer Society, Region Stockholm, and the Cancer Research Funds of Radiumhemmet. Helgadottir declared having relationships with Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, and Novartis.

The trial was supported by SkinVision. The researchers declared having no relevant financial relationships.

This article was previously published by Medscape.

Offering adjuvant therapy to patients with stage III melanoma offers no melanoma-specific or overall survival benefit, reveals extended follow-up from the first population-based national study to estimate the impact of the treatment.

Hildur Helgadottir, MD, PhD, presented the new findings at the 22nd European Association of Dermato-Oncology (EADO) Congress 2026 on April 24 and described the lead-up to the latest update on the study.

To investigate the impact of adjuvant treatment in patients with stage III melanoma, researchers initially conducted a study in which they used the Swedish Melanoma Registry (SweMR) to identify a precohort of those treated before the introduction of adjuvant therapy in 2018 and a postcohort of those treated subsequently, following both groups out to 2023, she explained.

The analysis revealed no significant difference in melanoma-specific survival between the two groups, at a hazard ratio of 0.92, nor in overall survival, at a hazard ratio of 0.93 (P = .60 for both). However, median follow-up differed between the groups, at 69 months vs 39 months for the precohort vs the postcohort.

Helgadottir, who is a senior research specialist at the Karolinska Comprehensive Cancer Center in Stockholm, Sweden, said that when the earlier results were presented at the European Society for Medical Oncology 2024, there was some criticism that the follow-up was not long enough and that there was no information on the actual adjuvant treatment received in the postcohort patients.

The researchers therefore extended their study out to 2024 to increase the median follow-up to 60 months vs 92 months in the postcohort group vs the precohort group.

They also focused patient selection on patients aged less than 75 years because exposure to adjuvant therapy in older patients was low and restricted the analysis to sentinel lymph node-positive stage IIIB-D cutaneous melanoma diagnosed between 2016 and 2020. This was because adjuvant exposure in stage IIIA disease was low, and patients with clinically detected stage III melanoma started to receive neoadjuvant therapy from 2022 onward.

The current analysis, which was recently published in the European Journal of Cancer, involved 287 patients in the precohort and 349 in the postcohort, who had a median age of 60.0 years and 61.0 years, respectively, and of whom 62.0% and 60.5%, respectively, were male. The groups were well balanced in terms of baseline disease characteristics.

Helgadottir explained that 73% of patients in the postcohort received some form of adjuvant treatment, with the majority treated with PD-1 inhibitors, and a smaller proportion given B-Raf serine-threonine kinase inhibitors. The main reasons for not giving adjuvant therapy were favorable tumor characteristics and the presence of comorbidities.

Five-year melanoma-specific survival rates in the precohorts and postcohorts were 71.4% vs 73.2%, at a hazard ratio adjusted for age, sex, and American Joint Committee on Cancer stage of 1.01 (P = .931). Five-year overall survival rates were 67.3% vs 70.1%, at an adjusted hazard ratio of 0.96 (P = .791).

Helgadottir showed that there were also no significant survival differences in any of the prespecified subgroups for neither melanoma-specific nor overall survival.

There were, again, no significant differences in survival outcomes between the two patient groups, she reported.

The latest results are similar to those from another study conducted in Netherlands and a Danish analysis, Helgadottir said.

Taken together, and “considering the side effects and the costs, it is possible that we will go back to closely following up our patients and treating only at relapse,” she said, “and optimally, of course, that will be already in the neoadjuvant setting.”

“And of course we will need biomarkers because there could be some patients that really need adjuvant treatment, but we need to identify these patients,” continued Helgadottir. Overall survival results from KEYNOTE-054, which compares pembrolizumab with placebo after resection of high-risk stage III melanoma, are awaited, she continued.

Helgadottir explained that adjuvant treatment for stage III melanoma was approved in Sweden in 2018, with treatments freely available to all Swedish residents.

The SweMR is a population-based national register that has near-complete and detailed data on primary cutaneous melanomas, including nodal status and satellite and in-transit disease, and is linked to the national Cause of Death Registry. Helgadottir noted, however, that the SweMR does not contain any information on relapses or the nature of the oncologic treatment received by patients with melanoma.

Following her presentation, she was challenged by an audience member as to whether, on the basis of her findings, she would go back to following up with patients and treating at relapses.

“Maybe we should do that and believe in our own data, and we do. But still, the gold standard must always be the randomized clinical trial,” Helgadottir responded. “So I think, although that we believe in this data, we also want to see the results of the randomized studies.”

The audience member commented that she can see in the data from her own institution that they treat fewer and fewer patients with melanoma with adjuvant therapy by discussing it more thoroughly and being stricter on who should receive it.

Helgadottir agreed, adding that “based on this experience, we did not introduce it to stage II patients because it’s always harder to go back” once a group of patients has started to receive a treatment.

The research was supported by Regional Cancer Centres in Sweden and with grants from the Swedish Cancer Society, Region Stockholm, and the Cancer Research Funds of Radiumhemmet. Helgadottir declared having relationships with Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, and Novartis.

The trial was supported by SkinVision. The researchers declared having no relevant financial relationships.

This article was previously published by Medscape.

Two studies published in March by researchers at the Veterans Affairs Saint Louis Healthcare System highlight the clinical significance of glucagon-like peptide 1 receptor agonists (GLP-1s) and their impact on reducing substance use disorder (SUD) risks. The studies also explore the impact of GLP-1 discontinuation or interruption on their effectiveness in protection against the cardiovascular events.

In one study, Al-Aly et al assigned 606,434 veterans with type 2 diabetes to 1 of 2 protocols, comparing GLP-1s with sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and followed the patients for up to 3 years. Al-Aly et al found that GLP-1s were “consistently associated” with a lower risk of developing SUDs, including those involving alcohol, cannabis, cocaine, nicotine, and opioids. The findings suggested “potential preventive effects across a broad range of addictive substances.”

In participants with pre-existing SUDs, GLP-1s were also associated with reduced risks of SUD-related emergency department visits, hospital admissions, and mortality, in addition to drug overdoses and suicidal behaviors. A study published in 2025 from the same research group reported that GLP-1s could have a variety of health benefits, including reducing the risk of incident alcohol and cannabis disorders, neurocognitive disorders (such as Alzheimer's disease and dementia), coagulation disorders, cardiometabolic disorders, infectious illnesses and several respiratory conditions, but less was known about the potential for preventing development of opioid use disorder and other SUDs. 

GLP-1s target the brain’s reward pathways and have recently made attention-grabbing headlines regarding celebrity weight loss, with social media boosting public interest. One study, for example, found 100 videos on TikTok with the #Ozempic viewed nearly 70 million times.

Al-Aly et al used SGLT-2 inhibitors as active comparators because “they have no established direct actions on mesolimbic reward circuits in the brain, whereas GLP-1 receptors are present in areas of the brain involved in impulse control and reward signaling.”

The second study found that quitting or pausing GLP-1 treatment for 6 months could have a rebound effect and possibly reverse any progress. Discontinuing GLP-1 treatment is common, with rates ranging from 36% to 81% in the first year. Stopping or interrupting the treatment is often followed by weight regain and a rebound in inflammation, both major drivers in cardiovascular disease risk. 

The study followed 132,551 VA patients using GLP-1s and 201,136 using sulfonylureas from 2017 through 2023. About two-thirds of participants took semaglutide, prescribed as Ozempic to treat diabetes and Wegovy to reduce obesity. A total of 26% of the participants stopped GLP-1 treatment during the follow-up period, with 64% occurring during the first year. Most (67%) treatment interruptions also came in the first year.

Compared with incident use of sulfonylureas, incident use of GLP-1s was associated with a reduced risk of heart attack, stroke, or death. Patients who took the GLP-1s without interruption > 3 years experienced an 18% lower risk for heart attack or stroke.  

Cardiovascular benefits accumulated with continuous use over 3 years, but even brief periods of discontinuations or interruptions could progressively erode and ultimately reverse this protection, the researchers found. Discontinuing treatment for half a year was associated with an increased risk of major adverse cardiovascular events (incidence risk ratio [IRR], 1.04), while longer gaps were progressively associated with a higher risk of disease (IRR, 1.12 for 1 year; IRR, 1.16 for 2 years of interrupted use, respectively).

Dr. Ziyad Al-Aly, a study author and Chief of the Research and Education Service at the Veterans Affairs Saint Louis Healthcare System, called it “metabolic whiplash.” In an interview, he said it was important to caution patients that these medications “need to be taken for the long haul. This is not something (patients) can take for a month or 2 or 3 and get off of it. It's not going to work like that.”

Two studies published in March by researchers at the Veterans Affairs Saint Louis Healthcare System highlight the clinical significance of glucagon-like peptide 1 receptor agonists (GLP-1s) and their impact on reducing substance use disorder (SUD) risks. The studies also explore the impact of GLP-1 discontinuation or interruption on their effectiveness in protection against the cardiovascular events.

In one study, Al-Aly et al assigned 606,434 veterans with type 2 diabetes to 1 of 2 protocols, comparing GLP-1s with sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and followed the patients for up to 3 years. Al-Aly et al found that GLP-1s were “consistently associated” with a lower risk of developing SUDs, including those involving alcohol, cannabis, cocaine, nicotine, and opioids. The findings suggested “potential preventive effects across a broad range of addictive substances.”

In participants with pre-existing SUDs, GLP-1s were also associated with reduced risks of SUD-related emergency department visits, hospital admissions, and mortality, in addition to drug overdoses and suicidal behaviors. A study published in 2025 from the same research group reported that GLP-1s could have a variety of health benefits, including reducing the risk of incident alcohol and cannabis disorders, neurocognitive disorders (such as Alzheimer's disease and dementia), coagulation disorders, cardiometabolic disorders, infectious illnesses and several respiratory conditions, but less was known about the potential for preventing development of opioid use disorder and other SUDs. 

GLP-1s target the brain’s reward pathways and have recently made attention-grabbing headlines regarding celebrity weight loss, with social media boosting public interest. One study, for example, found 100 videos on TikTok with the #Ozempic viewed nearly 70 million times.

Al-Aly et al used SGLT-2 inhibitors as active comparators because “they have no established direct actions on mesolimbic reward circuits in the brain, whereas GLP-1 receptors are present in areas of the brain involved in impulse control and reward signaling.”

The second study found that quitting or pausing GLP-1 treatment for 6 months could have a rebound effect and possibly reverse any progress. Discontinuing GLP-1 treatment is common, with rates ranging from 36% to 81% in the first year. Stopping or interrupting the treatment is often followed by weight regain and a rebound in inflammation, both major drivers in cardiovascular disease risk. 

The study followed 132,551 VA patients using GLP-1s and 201,136 using sulfonylureas from 2017 through 2023. About two-thirds of participants took semaglutide, prescribed as Ozempic to treat diabetes and Wegovy to reduce obesity. A total of 26% of the participants stopped GLP-1 treatment during the follow-up period, with 64% occurring during the first year. Most (67%) treatment interruptions also came in the first year.

Compared with incident use of sulfonylureas, incident use of GLP-1s was associated with a reduced risk of heart attack, stroke, or death. Patients who took the GLP-1s without interruption > 3 years experienced an 18% lower risk for heart attack or stroke.  

Cardiovascular benefits accumulated with continuous use over 3 years, but even brief periods of discontinuations or interruptions could progressively erode and ultimately reverse this protection, the researchers found. Discontinuing treatment for half a year was associated with an increased risk of major adverse cardiovascular events (incidence risk ratio [IRR], 1.04), while longer gaps were progressively associated with a higher risk of disease (IRR, 1.12 for 1 year; IRR, 1.16 for 2 years of interrupted use, respectively).

Dr. Ziyad Al-Aly, a study author and Chief of the Research and Education Service at the Veterans Affairs Saint Louis Healthcare System, called it “metabolic whiplash.” In an interview, he said it was important to caution patients that these medications “need to be taken for the long haul. This is not something (patients) can take for a month or 2 or 3 and get off of it. It's not going to work like that.”

Two studies published in March by researchers at the Veterans Affairs Saint Louis Healthcare System highlight the clinical significance of glucagon-like peptide 1 receptor agonists (GLP-1s) and their impact on reducing substance use disorder (SUD) risks. The studies also explore the impact of GLP-1 discontinuation or interruption on their effectiveness in protection against the cardiovascular events.

In one study, Al-Aly et al assigned 606,434 veterans with type 2 diabetes to 1 of 2 protocols, comparing GLP-1s with sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and followed the patients for up to 3 years. Al-Aly et al found that GLP-1s were “consistently associated” with a lower risk of developing SUDs, including those involving alcohol, cannabis, cocaine, nicotine, and opioids. The findings suggested “potential preventive effects across a broad range of addictive substances.”

In participants with pre-existing SUDs, GLP-1s were also associated with reduced risks of SUD-related emergency department visits, hospital admissions, and mortality, in addition to drug overdoses and suicidal behaviors. A study published in 2025 from the same research group reported that GLP-1s could have a variety of health benefits, including reducing the risk of incident alcohol and cannabis disorders, neurocognitive disorders (such as Alzheimer's disease and dementia), coagulation disorders, cardiometabolic disorders, infectious illnesses and several respiratory conditions, but less was known about the potential for preventing development of opioid use disorder and other SUDs. 

GLP-1s target the brain’s reward pathways and have recently made attention-grabbing headlines regarding celebrity weight loss, with social media boosting public interest. One study, for example, found 100 videos on TikTok with the #Ozempic viewed nearly 70 million times.

Al-Aly et al used SGLT-2 inhibitors as active comparators because “they have no established direct actions on mesolimbic reward circuits in the brain, whereas GLP-1 receptors are present in areas of the brain involved in impulse control and reward signaling.”

The second study found that quitting or pausing GLP-1 treatment for 6 months could have a rebound effect and possibly reverse any progress. Discontinuing GLP-1 treatment is common, with rates ranging from 36% to 81% in the first year. Stopping or interrupting the treatment is often followed by weight regain and a rebound in inflammation, both major drivers in cardiovascular disease risk. 

The study followed 132,551 VA patients using GLP-1s and 201,136 using sulfonylureas from 2017 through 2023. About two-thirds of participants took semaglutide, prescribed as Ozempic to treat diabetes and Wegovy to reduce obesity. A total of 26% of the participants stopped GLP-1 treatment during the follow-up period, with 64% occurring during the first year. Most (67%) treatment interruptions also came in the first year.

Compared with incident use of sulfonylureas, incident use of GLP-1s was associated with a reduced risk of heart attack, stroke, or death. Patients who took the GLP-1s without interruption > 3 years experienced an 18% lower risk for heart attack or stroke.  

Cardiovascular benefits accumulated with continuous use over 3 years, but even brief periods of discontinuations or interruptions could progressively erode and ultimately reverse this protection, the researchers found. Discontinuing treatment for half a year was associated with an increased risk of major adverse cardiovascular events (incidence risk ratio [IRR], 1.04), while longer gaps were progressively associated with a higher risk of disease (IRR, 1.12 for 1 year; IRR, 1.16 for 2 years of interrupted use, respectively).

Dr. Ziyad Al-Aly, a study author and Chief of the Research and Education Service at the Veterans Affairs Saint Louis Healthcare System, called it “metabolic whiplash.” In an interview, he said it was important to caution patients that these medications “need to be taken for the long haul. This is not something (patients) can take for a month or 2 or 3 and get off of it. It's not going to work like that.”

More than 38 million people in the United States (12%) have diabetes mellitus (DM), though 1 in 5 are unaware they have DM.¹ The prevalence among veterans is even more substantial, impacting nearly 25% of those who received care from the US Department of Veterans Affairs (VA).² DM can lead to increased health care costs in addition to various complications (eg, cardiovascular, renal), especially if left uncontrolled.^1,3 similar impact is found in the perioperative period (defined as at or around the time of an operation), as multiple studies have found that uncontrolled preoperative DM can result in worsened surgical outcomes, including longer hospital stays, more infectious complications, and higher perioperative mortality.^4-6

In contrast, adequate glycemic control assessed with blood glucose levels has been shown to decrease the incidence of postoperative infections.⁷ Optimizing glycemic control during hospital stays, especially postsurgery, has become the standard of care, with most health systems establishing specific protocols. In current literature, most studies examining DM management in the perioperative period are focused on postoperative care, with little attention to the preoperative period.^4,6,7

One study found that patients with poor presurgery glycemic control assessed by hemoglobin A_1c (HbA_1c) levels were more likely to remain hyperglycemic during and after surgery. 8 Blood glucose levels < 200 mg/dL can lead to an increased risk of infection and impaired wound healing, meaning a well-controlled HbA_1c before a procedure serves as a potential factor for success.⁹ The 2025 American Diabetes Association (ADA) Standards of Care (SOC) recommendation is to target HbA_1c < 8% whenever possible, and some health systems require lower levels (eg, < 7% or 7.5%).¹⁰ With that goal in mind and knowing that preoperative hyperglycemia has been shown to be a contributing factor in the delay or cancellation of surgical cases, an argument can be made that attention to preoperative DM management also should be a focus for health care systems performing surgeries.^8,9,11

Attention to glucose control during preoperative care offers an opportunity to screen for DM in patients who may not have been screened otherwise and to standardize perioperative DM management. Since DM disproportionately impacts veterans, this is a pertinent issue to the VA. Veterans can be more susceptible to complications if DM is left uncontrolled prior to surgery. To determine readiness for surgery and control of comorbid conditions such as DM before a planned surgery, facilities often perform a preoperative clinic assessment, often in a multidisciplinary clinic.

At Veteran Health Indiana (VHI), a presurgery clinic visit involving the primary surgery service (physician, nurse practitioner, and/or a physician assistant) is conducted 1 to 2 months prior to the planned procedure to determine whether a patient is ready for surgery. During this visit, patients receive a packet with instructions for various tasks and medications, such as applying topical antibiotic prophylaxis on the anticipated surgical site. This is documented in the form of a note in the VHI Computerized Patient Record System (CPRS). The medication instructions are provided according to the preferences of the surgical team. These may be templated notes that contain general directions on the timing and dosing of specific medications, in addition to instructions for holding or reducing doses when appropriate. The instructions can be tailored by the team conducting the preoperative visit (eg, “Take 20 units of insulin glargine the day before surgery” vs “Take half of your long-acting insulin the night before surgery”). Specific to DM, VHI has a nurse-driven day of surgery glucose assessment where point-of-care blood glucose is collected during preoperative holding for most patients.

There is limited research assessing the level of preoperative glycemic control and the incidence of complications in a veteran population. The objective of this study was to gain a baseline understanding of what, if any, standardization exists for preoperative instructions for DM medications and to assess the level of preoperative glycemic control and postoperative complications in patients with DM undergoing major elective surgical procedures.

Methods

This retrospective, single-center chart review was conducted at VHI. The Indiana University and VHI institutional review boards determined that this quality improvement project was exempt from review.

The primary outcome was the number of patients with surgical procedures delayed or canceled due to hyperglycemia or hypoglycemia. Hyperglycemia was defined as blood glucose > 180 mg/dL and hypoglycemia was defined as < 70 mg/dL, slight variations from the current ADA SOC preoperative specific recommendation of a blood glucose reading of 100 to 180 mg/dL within 4 hours of surgery.¹⁰ The standard outpatient hypoglycemia definition of blood glucose < 70 mg/dL was chosen because the current goal (< 100 mg/dL) was not the standard in previous ADA SOCs that were in place during the study period. Specifically, the 2018 ADA SOC did not provide preoperative recommendations and the 2019-2021 ADA SOC recommended 80 to 180 mg/dL.^10,12-18 For patients who had multiple preoperative blood glucose measurements, the first recorded glucose on the day of the procedure was used.

The secondary outcomes of this study were focused on the preoperative process/care at VHI and postoperative glycemic control. The preoperative process included examining whether medication instructions were given and their quality. Additionally, the number of interventions for hyperglycemia and hypoglycemia were required immediately prior to surgery and the average preoperative HbA_1c (measured within 3 months prior to surgery) were collected and analyzed. For postoperative glycemic control, average blood glucose measurements and number of hypoglycemic (< 70 mg/dL) and hyperglycemic (> 180 mg/dL) events were measured in addition to the frequency of changes made at discharge to patients’ DM medication regimens.

The safety outcome of this study assessed commonly observed postoperative complications and was examined up to 30 days postsurgery. These included acute kidney injury (defined using Kidney Disease: Improving Global Outcomes 2012, the standard during the study period), nonfatal myocardial infarction, nonfatal stroke, and surgical site infections, which were identified from the discharge summary written by the primary surgery service.¹⁹ All-cause mortality also was collected.

Patients were included if they were admitted for major elective surgeries and had a diagnosis of either type 1 or type 2 DM on their problem list, determined by International Classification of Diseases, Tenth Revision codes. Major elective surgery was defined as a procedure that would likely result in a hospital admission of > 24 hours. Of note, patients may have been included in this study more than once if they had > 1 procedure at least 30 days apart and met inclusion criteria within the time frame. Patients were excluded if they were taking no DM medications or chronic steroids (at any dose), residing in a long-term care facility, being managed by a non-VA clinician prior to surgery, or missing a preoperative blood glucose measurement.

All data were collected from the CPRS. A list of surgical cases involving patients with DM who were scheduled to undergo major elective surgeries from January 1, 2018, to December 31, 2021, at VHI was generated. The list was randomized to a smaller number (N = 394) for data collection due to the time and resource constraints for a pharmacy residency project. All data were deidentified and stored in a secured VA server to protect patient confidentiality. Descriptive statistics were used for all results.

Results

Initially, 2362 surgeries were identified. A randomized sample of 394 charts were reviewed and 131 cases met inclusion criteria. Each case involved a unique patient (Figure). The most common reasons for exclusion were 143 patients with diet-controlled DM and 78 nonelective surgeries. The mean (SD) age of patients was 68 (8) years, and the most were male (98.5%) and White (76.3%) (Table 1). 

At baseline, 45 of 131 patients (34.4%) had coronary artery disease and 29 (22.1%) each had autonomic neuropathy and chronic kidney disease. Most surgeries were conducted by orthopedic (32.1%) and peripheral vascular (21.4%) specialties. The mean (SD) length of surgery was 4.6 (2.6) hours and of hospital length of stay was 4 (4) days. No patients stayed longer than the 30-day safety outcome follow-up period. All patients had type 2 DM and took a mean 2 DM medications. The 63 patients taking insulin had a mean (SD) total daily dose of 99 (77) U (Table 2). A preoperative HbA1c was collected in 116 patients within 3 months of surgery, with a mean HbA_1c of 7.0% (range, 5.3-10.7).

No patients had surgeries delayed or canceled because of uncontrolled DM on the day of surgery. The mean preoperative blood glucose level was 146 mg/dL (range, 73-365) (Table 3). No patients had a preoperative blood glucose level of < 70 mg/dL and 19 (14.5%) had a blood glucose level > 180 mg/dL. Among patients with hyperglycemia immediately prior to surgery, 6 (31.6%) had documentation of insulin being provided.

For this sample of patients, the preoperative clinic visit was conducted a mean 22 days prior to the planned surgery date. Among the 131 included patients, 122 (93.1%) had documentation of receiving instructions for DM medications. Among patients who had documented receipt of instructions, only 30 (24.6%) had instructions specifically tailored to their regimen rather than a generic templated form. The mean (SD) preoperative blood glucose was similar for those who received specific perioperative DM instructions at 146 (50) mg/dL when compared with those who did not at 147 (45) mg/dL. The mean (SD) preoperative blood glucose reading for those who had no documentation of receipt of perioperative instructions was 126 (54) mg/dL compared with 147 (46) mg/dL for those who did.

The mean number of postoperative blood glucose events per day was negligible for hypoglycemia and more frequent for hyperglycemia with a mean of 2 events per day. The mean postoperative blood glucose range was 121 to 247 mg/dL with most readings < 180 mg/dL. Upon discharge, most patients continued their home DM regimen with 5 patients (3.8%) having changes made to their regimen upon discharge.

Very few postoperative complications were identified from chart review. The most frequently observed postoperative complications were acute kidney injury, surgical site infections, and nonfatal stroke. There were no documented nonfatal myocardial infarctions. Two patients (1.5%) died within 30 days of the surgery; neither death was deemed to have been related to poor perioperative glycemic control.

Discussion

To our knowledge, this retrospective chart review was the first study to assess preoperative DM management and postoperative complications in a veteran population. VHI is a large, tertiary, level 1a, academic medical center that serves approximately 62,000 veterans annually and performs about 5000 to 6000 surgeries annually, a total that is increasing following the COVID-19 pandemic.²⁰ This study found that the current process of a presurgery clinic visit and day of surgery glucose assessment has prevented surgical delays or cancellations.

Most patients included in this study were well controlled at baseline in accordance with the 2025 ADA SOC HbA_1c recommendation of a preoperative HbA1c of < 8%, which may have contributed to no surgical delays or cancellations.¹⁰ However, not all patients had HbA1c collected within 3 months of surgery or even had one collected at all. Despite the ADA SOC providing no explicit recommendation for universal HbA_1c screening prior to elective procedures, its importance cannot be understated given the body of evidence demonstrating poor outcomes with uncontrolled preoperative DM.^8,10 The glycemic control at baseline may have contributed to the very few postsurgical complications observed in this study.

Although the current process at VHI prevented surgical delays and cancellations in this sample, there are still identified areas for improvement. One area is the instructions the patients received. Patients with DM are often prescribed ≥ 1 medication or a combination of insulins, noninsulin injectables, and oral DM medications, and this study population was no different. Because these medications may influence the anesthesia and perioperative periods, the ADA has specific guidance for altering administration schedules in the days leading up to surgery.¹⁰

Inappropriate administration of DM medications could lead to perioperative hypoglycemia or hyperglycemia, possibly causing surgical delays, case cancellations, and/or postoperative complications.21 Although these data reveal the specificity and documented receipt that the preoperative DM instructions did not impact the first recorded preoperative blood glucose, future studies should examine patient confidence in how to properly administer their DM medications prior to surgery. It is vital that patients receive clear instructions in accordance with the ADA SOC on whether to continue, hold, or adjust the dose of their medications to prevent fluctuations in blood glucose levels in the perioperative period, ensure safety with anesthesia, and prevent postoperative complications such as acute kidney injury. Of note, compliance with guideline recommendations for medication instructions was not examined because the data collection time frame expanded over multiple years and the recommendations have evolved each year as new data emerge.

Preoperative DM Management

The first key takeaway from this study is to ensure patients are ready for surgery with a formal assessment (typically in the form of a clinic visit) prior to the surgery. One private sector health system published their approach to this by administering an automatic preoperative HbA_1c screening for those with a DM diagnosis and all patients with a random plasma glucose ≥ 200 mg/dL.²² Additionally, if the patient's HbA_1c level was not at goal prior to surgery (≥ 8% for those with known DM and ≥ 6.5% with no known DM), patients were referred to endocrinology for further management. Increasing attention to the preoperative visit and extending HbA_1c testing to all patients regardless of DM status also provides an opportunity to identify individuals living with undiagnosed DM.¹

Even though there was no difference in the mean preoperative blood glucose level based on receipt or specificity of preoperative DM instructions, a second takeaway from this study is the importance of ensuring patients receive clear instructions on their DM medication schedule in the perioperative period. A practical first step may be updating the templates used by the primary surgery teams and providing education to the clinicians in the clinic on how to personalize the visits. Because the current preoperative DM process at VHI is managed by the primary surgical team in a clinic visit, there is an opportunity to shift this responsibility to other health care professionals, such as pharmacists—a change shown to reduce unintended omission of home medications following surgery during hospitalization and reduce costs.^23,24

Limitations

This study relied on data included in the patient chart. These data include medication interventions made immediately prior to surgery, which can sometimes be inaccurately charted or difficult to find as they are not documented in the typical medication administration record. Also, the safety outcomes were collected from a discharge summary written by different clinicians, which may lead to information bias. Special attention was taken to ensure these data points were collected as accurately as possible, but it is possible some data may be inaccurate from unintentional human error. Additionally, the safety outcome was limited to a 30-day follow-up, but encompassed the entire length of postoperative stay for all included patients. Finally, given this study was retrospective with no comparison group and the intent was to improve processes at VHI, only hypotheses and potential interventions can be generated from this study. Future prospective studies with larger sample sizes and comparator groups are needed to draw further conclusions.

Conclusions

This study found that the current presurgery process at VHI appears to be successful in preventing surgical delays or cancellations due to hyperglycemia or hypoglycemia. Optimizing DM management can improve surgical outcomes by decreasing rates of postoperative complications, and this study added additional evidence in support of that in a unique population: veterans. Insight on the awareness of preoperative blood glucose management should be gleaned from this study, and based on this sample and site, the preadmission screening process and instructions provided to patients can serve as 2 starting points for optimizing elective surgery.

More than 38 million people in the United States (12%) have diabetes mellitus (DM), though 1 in 5 are unaware they have DM.¹ The prevalence among veterans is even more substantial, impacting nearly 25% of those who received care from the US Department of Veterans Affairs (VA).² DM can lead to increased health care costs in addition to various complications (eg, cardiovascular, renal), especially if left uncontrolled.^1,3 similar impact is found in the perioperative period (defined as at or around the time of an operation), as multiple studies have found that uncontrolled preoperative DM can result in worsened surgical outcomes, including longer hospital stays, more infectious complications, and higher perioperative mortality.^4-6

In contrast, adequate glycemic control assessed with blood glucose levels has been shown to decrease the incidence of postoperative infections.⁷ Optimizing glycemic control during hospital stays, especially postsurgery, has become the standard of care, with most health systems establishing specific protocols. In current literature, most studies examining DM management in the perioperative period are focused on postoperative care, with little attention to the preoperative period.^4,6,7

One study found that patients with poor presurgery glycemic control assessed by hemoglobin A_1c (HbA_1c) levels were more likely to remain hyperglycemic during and after surgery. 8 Blood glucose levels < 200 mg/dL can lead to an increased risk of infection and impaired wound healing, meaning a well-controlled HbA_1c before a procedure serves as a potential factor for success.⁹ The 2025 American Diabetes Association (ADA) Standards of Care (SOC) recommendation is to target HbA_1c < 8% whenever possible, and some health systems require lower levels (eg, < 7% or 7.5%).¹⁰ With that goal in mind and knowing that preoperative hyperglycemia has been shown to be a contributing factor in the delay or cancellation of surgical cases, an argument can be made that attention to preoperative DM management also should be a focus for health care systems performing surgeries.^8,9,11

Attention to glucose control during preoperative care offers an opportunity to screen for DM in patients who may not have been screened otherwise and to standardize perioperative DM management. Since DM disproportionately impacts veterans, this is a pertinent issue to the VA. Veterans can be more susceptible to complications if DM is left uncontrolled prior to surgery. To determine readiness for surgery and control of comorbid conditions such as DM before a planned surgery, facilities often perform a preoperative clinic assessment, often in a multidisciplinary clinic.

At Veteran Health Indiana (VHI), a presurgery clinic visit involving the primary surgery service (physician, nurse practitioner, and/or a physician assistant) is conducted 1 to 2 months prior to the planned procedure to determine whether a patient is ready for surgery. During this visit, patients receive a packet with instructions for various tasks and medications, such as applying topical antibiotic prophylaxis on the anticipated surgical site. This is documented in the form of a note in the VHI Computerized Patient Record System (CPRS). The medication instructions are provided according to the preferences of the surgical team. These may be templated notes that contain general directions on the timing and dosing of specific medications, in addition to instructions for holding or reducing doses when appropriate. The instructions can be tailored by the team conducting the preoperative visit (eg, “Take 20 units of insulin glargine the day before surgery” vs “Take half of your long-acting insulin the night before surgery”). Specific to DM, VHI has a nurse-driven day of surgery glucose assessment where point-of-care blood glucose is collected during preoperative holding for most patients.

There is limited research assessing the level of preoperative glycemic control and the incidence of complications in a veteran population. The objective of this study was to gain a baseline understanding of what, if any, standardization exists for preoperative instructions for DM medications and to assess the level of preoperative glycemic control and postoperative complications in patients with DM undergoing major elective surgical procedures.

Methods

This retrospective, single-center chart review was conducted at VHI. The Indiana University and VHI institutional review boards determined that this quality improvement project was exempt from review.

The primary outcome was the number of patients with surgical procedures delayed or canceled due to hyperglycemia or hypoglycemia. Hyperglycemia was defined as blood glucose > 180 mg/dL and hypoglycemia was defined as < 70 mg/dL, slight variations from the current ADA SOC preoperative specific recommendation of a blood glucose reading of 100 to 180 mg/dL within 4 hours of surgery.¹⁰ The standard outpatient hypoglycemia definition of blood glucose < 70 mg/dL was chosen because the current goal (< 100 mg/dL) was not the standard in previous ADA SOCs that were in place during the study period. Specifically, the 2018 ADA SOC did not provide preoperative recommendations and the 2019-2021 ADA SOC recommended 80 to 180 mg/dL.^10,12-18 For patients who had multiple preoperative blood glucose measurements, the first recorded glucose on the day of the procedure was used.

The secondary outcomes of this study were focused on the preoperative process/care at VHI and postoperative glycemic control. The preoperative process included examining whether medication instructions were given and their quality. Additionally, the number of interventions for hyperglycemia and hypoglycemia were required immediately prior to surgery and the average preoperative HbA_1c (measured within 3 months prior to surgery) were collected and analyzed. For postoperative glycemic control, average blood glucose measurements and number of hypoglycemic (< 70 mg/dL) and hyperglycemic (> 180 mg/dL) events were measured in addition to the frequency of changes made at discharge to patients’ DM medication regimens.

The safety outcome of this study assessed commonly observed postoperative complications and was examined up to 30 days postsurgery. These included acute kidney injury (defined using Kidney Disease: Improving Global Outcomes 2012, the standard during the study period), nonfatal myocardial infarction, nonfatal stroke, and surgical site infections, which were identified from the discharge summary written by the primary surgery service.¹⁹ All-cause mortality also was collected.

Patients were included if they were admitted for major elective surgeries and had a diagnosis of either type 1 or type 2 DM on their problem list, determined by International Classification of Diseases, Tenth Revision codes. Major elective surgery was defined as a procedure that would likely result in a hospital admission of > 24 hours. Of note, patients may have been included in this study more than once if they had > 1 procedure at least 30 days apart and met inclusion criteria within the time frame. Patients were excluded if they were taking no DM medications or chronic steroids (at any dose), residing in a long-term care facility, being managed by a non-VA clinician prior to surgery, or missing a preoperative blood glucose measurement.

All data were collected from the CPRS. A list of surgical cases involving patients with DM who were scheduled to undergo major elective surgeries from January 1, 2018, to December 31, 2021, at VHI was generated. The list was randomized to a smaller number (N = 394) for data collection due to the time and resource constraints for a pharmacy residency project. All data were deidentified and stored in a secured VA server to protect patient confidentiality. Descriptive statistics were used for all results.

Results

Initially, 2362 surgeries were identified. A randomized sample of 394 charts were reviewed and 131 cases met inclusion criteria. Each case involved a unique patient (Figure). The most common reasons for exclusion were 143 patients with diet-controlled DM and 78 nonelective surgeries. The mean (SD) age of patients was 68 (8) years, and the most were male (98.5%) and White (76.3%) (Table 1). 

At baseline, 45 of 131 patients (34.4%) had coronary artery disease and 29 (22.1%) each had autonomic neuropathy and chronic kidney disease. Most surgeries were conducted by orthopedic (32.1%) and peripheral vascular (21.4%) specialties. The mean (SD) length of surgery was 4.6 (2.6) hours and of hospital length of stay was 4 (4) days. No patients stayed longer than the 30-day safety outcome follow-up period. All patients had type 2 DM and took a mean 2 DM medications. The 63 patients taking insulin had a mean (SD) total daily dose of 99 (77) U (Table 2). A preoperative HbA1c was collected in 116 patients within 3 months of surgery, with a mean HbA_1c of 7.0% (range, 5.3-10.7).

No patients had surgeries delayed or canceled because of uncontrolled DM on the day of surgery. The mean preoperative blood glucose level was 146 mg/dL (range, 73-365) (Table 3). No patients had a preoperative blood glucose level of < 70 mg/dL and 19 (14.5%) had a blood glucose level > 180 mg/dL. Among patients with hyperglycemia immediately prior to surgery, 6 (31.6%) had documentation of insulin being provided.

For this sample of patients, the preoperative clinic visit was conducted a mean 22 days prior to the planned surgery date. Among the 131 included patients, 122 (93.1%) had documentation of receiving instructions for DM medications. Among patients who had documented receipt of instructions, only 30 (24.6%) had instructions specifically tailored to their regimen rather than a generic templated form. The mean (SD) preoperative blood glucose was similar for those who received specific perioperative DM instructions at 146 (50) mg/dL when compared with those who did not at 147 (45) mg/dL. The mean (SD) preoperative blood glucose reading for those who had no documentation of receipt of perioperative instructions was 126 (54) mg/dL compared with 147 (46) mg/dL for those who did.

The mean number of postoperative blood glucose events per day was negligible for hypoglycemia and more frequent for hyperglycemia with a mean of 2 events per day. The mean postoperative blood glucose range was 121 to 247 mg/dL with most readings < 180 mg/dL. Upon discharge, most patients continued their home DM regimen with 5 patients (3.8%) having changes made to their regimen upon discharge.

Very few postoperative complications were identified from chart review. The most frequently observed postoperative complications were acute kidney injury, surgical site infections, and nonfatal stroke. There were no documented nonfatal myocardial infarctions. Two patients (1.5%) died within 30 days of the surgery; neither death was deemed to have been related to poor perioperative glycemic control.

Discussion

To our knowledge, this retrospective chart review was the first study to assess preoperative DM management and postoperative complications in a veteran population. VHI is a large, tertiary, level 1a, academic medical center that serves approximately 62,000 veterans annually and performs about 5000 to 6000 surgeries annually, a total that is increasing following the COVID-19 pandemic.²⁰ This study found that the current process of a presurgery clinic visit and day of surgery glucose assessment has prevented surgical delays or cancellations.

Most patients included in this study were well controlled at baseline in accordance with the 2025 ADA SOC HbA_1c recommendation of a preoperative HbA1c of < 8%, which may have contributed to no surgical delays or cancellations.¹⁰ However, not all patients had HbA1c collected within 3 months of surgery or even had one collected at all. Despite the ADA SOC providing no explicit recommendation for universal HbA_1c screening prior to elective procedures, its importance cannot be understated given the body of evidence demonstrating poor outcomes with uncontrolled preoperative DM.^8,10 The glycemic control at baseline may have contributed to the very few postsurgical complications observed in this study.

Although the current process at VHI prevented surgical delays and cancellations in this sample, there are still identified areas for improvement. One area is the instructions the patients received. Patients with DM are often prescribed ≥ 1 medication or a combination of insulins, noninsulin injectables, and oral DM medications, and this study population was no different. Because these medications may influence the anesthesia and perioperative periods, the ADA has specific guidance for altering administration schedules in the days leading up to surgery.¹⁰

Inappropriate administration of DM medications could lead to perioperative hypoglycemia or hyperglycemia, possibly causing surgical delays, case cancellations, and/or postoperative complications.21 Although these data reveal the specificity and documented receipt that the preoperative DM instructions did not impact the first recorded preoperative blood glucose, future studies should examine patient confidence in how to properly administer their DM medications prior to surgery. It is vital that patients receive clear instructions in accordance with the ADA SOC on whether to continue, hold, or adjust the dose of their medications to prevent fluctuations in blood glucose levels in the perioperative period, ensure safety with anesthesia, and prevent postoperative complications such as acute kidney injury. Of note, compliance with guideline recommendations for medication instructions was not examined because the data collection time frame expanded over multiple years and the recommendations have evolved each year as new data emerge.

Preoperative DM Management

The first key takeaway from this study is to ensure patients are ready for surgery with a formal assessment (typically in the form of a clinic visit) prior to the surgery. One private sector health system published their approach to this by administering an automatic preoperative HbA_1c screening for those with a DM diagnosis and all patients with a random plasma glucose ≥ 200 mg/dL.²² Additionally, if the patient's HbA_1c level was not at goal prior to surgery (≥ 8% for those with known DM and ≥ 6.5% with no known DM), patients were referred to endocrinology for further management. Increasing attention to the preoperative visit and extending HbA_1c testing to all patients regardless of DM status also provides an opportunity to identify individuals living with undiagnosed DM.¹

Even though there was no difference in the mean preoperative blood glucose level based on receipt or specificity of preoperative DM instructions, a second takeaway from this study is the importance of ensuring patients receive clear instructions on their DM medication schedule in the perioperative period. A practical first step may be updating the templates used by the primary surgery teams and providing education to the clinicians in the clinic on how to personalize the visits. Because the current preoperative DM process at VHI is managed by the primary surgical team in a clinic visit, there is an opportunity to shift this responsibility to other health care professionals, such as pharmacists—a change shown to reduce unintended omission of home medications following surgery during hospitalization and reduce costs.^23,24

Limitations

This study relied on data included in the patient chart. These data include medication interventions made immediately prior to surgery, which can sometimes be inaccurately charted or difficult to find as they are not documented in the typical medication administration record. Also, the safety outcomes were collected from a discharge summary written by different clinicians, which may lead to information bias. Special attention was taken to ensure these data points were collected as accurately as possible, but it is possible some data may be inaccurate from unintentional human error. Additionally, the safety outcome was limited to a 30-day follow-up, but encompassed the entire length of postoperative stay for all included patients. Finally, given this study was retrospective with no comparison group and the intent was to improve processes at VHI, only hypotheses and potential interventions can be generated from this study. Future prospective studies with larger sample sizes and comparator groups are needed to draw further conclusions.

Conclusions

This study found that the current presurgery process at VHI appears to be successful in preventing surgical delays or cancellations due to hyperglycemia or hypoglycemia. Optimizing DM management can improve surgical outcomes by decreasing rates of postoperative complications, and this study added additional evidence in support of that in a unique population: veterans. Insight on the awareness of preoperative blood glucose management should be gleaned from this study, and based on this sample and site, the preadmission screening process and instructions provided to patients can serve as 2 starting points for optimizing elective surgery.

More than 38 million people in the United States (12%) have diabetes mellitus (DM), though 1 in 5 are unaware they have DM.¹ The prevalence among veterans is even more substantial, impacting nearly 25% of those who received care from the US Department of Veterans Affairs (VA).² DM can lead to increased health care costs in addition to various complications (eg, cardiovascular, renal), especially if left uncontrolled.^1,3 similar impact is found in the perioperative period (defined as at or around the time of an operation), as multiple studies have found that uncontrolled preoperative DM can result in worsened surgical outcomes, including longer hospital stays, more infectious complications, and higher perioperative mortality.^4-6

In contrast, adequate glycemic control assessed with blood glucose levels has been shown to decrease the incidence of postoperative infections.⁷ Optimizing glycemic control during hospital stays, especially postsurgery, has become the standard of care, with most health systems establishing specific protocols. In current literature, most studies examining DM management in the perioperative period are focused on postoperative care, with little attention to the preoperative period.^4,6,7

One study found that patients with poor presurgery glycemic control assessed by hemoglobin A_1c (HbA_1c) levels were more likely to remain hyperglycemic during and after surgery. 8 Blood glucose levels < 200 mg/dL can lead to an increased risk of infection and impaired wound healing, meaning a well-controlled HbA_1c before a procedure serves as a potential factor for success.⁹ The 2025 American Diabetes Association (ADA) Standards of Care (SOC) recommendation is to target HbA_1c < 8% whenever possible, and some health systems require lower levels (eg, < 7% or 7.5%).¹⁰ With that goal in mind and knowing that preoperative hyperglycemia has been shown to be a contributing factor in the delay or cancellation of surgical cases, an argument can be made that attention to preoperative DM management also should be a focus for health care systems performing surgeries.^8,9,11

Attention to glucose control during preoperative care offers an opportunity to screen for DM in patients who may not have been screened otherwise and to standardize perioperative DM management. Since DM disproportionately impacts veterans, this is a pertinent issue to the VA. Veterans can be more susceptible to complications if DM is left uncontrolled prior to surgery. To determine readiness for surgery and control of comorbid conditions such as DM before a planned surgery, facilities often perform a preoperative clinic assessment, often in a multidisciplinary clinic.

At Veteran Health Indiana (VHI), a presurgery clinic visit involving the primary surgery service (physician, nurse practitioner, and/or a physician assistant) is conducted 1 to 2 months prior to the planned procedure to determine whether a patient is ready for surgery. During this visit, patients receive a packet with instructions for various tasks and medications, such as applying topical antibiotic prophylaxis on the anticipated surgical site. This is documented in the form of a note in the VHI Computerized Patient Record System (CPRS). The medication instructions are provided according to the preferences of the surgical team. These may be templated notes that contain general directions on the timing and dosing of specific medications, in addition to instructions for holding or reducing doses when appropriate. The instructions can be tailored by the team conducting the preoperative visit (eg, “Take 20 units of insulin glargine the day before surgery” vs “Take half of your long-acting insulin the night before surgery”). Specific to DM, VHI has a nurse-driven day of surgery glucose assessment where point-of-care blood glucose is collected during preoperative holding for most patients.

There is limited research assessing the level of preoperative glycemic control and the incidence of complications in a veteran population. The objective of this study was to gain a baseline understanding of what, if any, standardization exists for preoperative instructions for DM medications and to assess the level of preoperative glycemic control and postoperative complications in patients with DM undergoing major elective surgical procedures.

Methods

This retrospective, single-center chart review was conducted at VHI. The Indiana University and VHI institutional review boards determined that this quality improvement project was exempt from review.

The primary outcome was the number of patients with surgical procedures delayed or canceled due to hyperglycemia or hypoglycemia. Hyperglycemia was defined as blood glucose > 180 mg/dL and hypoglycemia was defined as < 70 mg/dL, slight variations from the current ADA SOC preoperative specific recommendation of a blood glucose reading of 100 to 180 mg/dL within 4 hours of surgery.¹⁰ The standard outpatient hypoglycemia definition of blood glucose < 70 mg/dL was chosen because the current goal (< 100 mg/dL) was not the standard in previous ADA SOCs that were in place during the study period. Specifically, the 2018 ADA SOC did not provide preoperative recommendations and the 2019-2021 ADA SOC recommended 80 to 180 mg/dL.^10,12-18 For patients who had multiple preoperative blood glucose measurements, the first recorded glucose on the day of the procedure was used.

The secondary outcomes of this study were focused on the preoperative process/care at VHI and postoperative glycemic control. The preoperative process included examining whether medication instructions were given and their quality. Additionally, the number of interventions for hyperglycemia and hypoglycemia were required immediately prior to surgery and the average preoperative HbA_1c (measured within 3 months prior to surgery) were collected and analyzed. For postoperative glycemic control, average blood glucose measurements and number of hypoglycemic (< 70 mg/dL) and hyperglycemic (> 180 mg/dL) events were measured in addition to the frequency of changes made at discharge to patients’ DM medication regimens.

The safety outcome of this study assessed commonly observed postoperative complications and was examined up to 30 days postsurgery. These included acute kidney injury (defined using Kidney Disease: Improving Global Outcomes 2012, the standard during the study period), nonfatal myocardial infarction, nonfatal stroke, and surgical site infections, which were identified from the discharge summary written by the primary surgery service.¹⁹ All-cause mortality also was collected.

Patients were included if they were admitted for major elective surgeries and had a diagnosis of either type 1 or type 2 DM on their problem list, determined by International Classification of Diseases, Tenth Revision codes. Major elective surgery was defined as a procedure that would likely result in a hospital admission of > 24 hours. Of note, patients may have been included in this study more than once if they had > 1 procedure at least 30 days apart and met inclusion criteria within the time frame. Patients were excluded if they were taking no DM medications or chronic steroids (at any dose), residing in a long-term care facility, being managed by a non-VA clinician prior to surgery, or missing a preoperative blood glucose measurement.

All data were collected from the CPRS. A list of surgical cases involving patients with DM who were scheduled to undergo major elective surgeries from January 1, 2018, to December 31, 2021, at VHI was generated. The list was randomized to a smaller number (N = 394) for data collection due to the time and resource constraints for a pharmacy residency project. All data were deidentified and stored in a secured VA server to protect patient confidentiality. Descriptive statistics were used for all results.

Results

Initially, 2362 surgeries were identified. A randomized sample of 394 charts were reviewed and 131 cases met inclusion criteria. Each case involved a unique patient (Figure). The most common reasons for exclusion were 143 patients with diet-controlled DM and 78 nonelective surgeries. The mean (SD) age of patients was 68 (8) years, and the most were male (98.5%) and White (76.3%) (Table 1). 

At baseline, 45 of 131 patients (34.4%) had coronary artery disease and 29 (22.1%) each had autonomic neuropathy and chronic kidney disease. Most surgeries were conducted by orthopedic (32.1%) and peripheral vascular (21.4%) specialties. The mean (SD) length of surgery was 4.6 (2.6) hours and of hospital length of stay was 4 (4) days. No patients stayed longer than the 30-day safety outcome follow-up period. All patients had type 2 DM and took a mean 2 DM medications. The 63 patients taking insulin had a mean (SD) total daily dose of 99 (77) U (Table 2). A preoperative HbA1c was collected in 116 patients within 3 months of surgery, with a mean HbA_1c of 7.0% (range, 5.3-10.7).

No patients had surgeries delayed or canceled because of uncontrolled DM on the day of surgery. The mean preoperative blood glucose level was 146 mg/dL (range, 73-365) (Table 3). No patients had a preoperative blood glucose level of < 70 mg/dL and 19 (14.5%) had a blood glucose level > 180 mg/dL. Among patients with hyperglycemia immediately prior to surgery, 6 (31.6%) had documentation of insulin being provided.

For this sample of patients, the preoperative clinic visit was conducted a mean 22 days prior to the planned surgery date. Among the 131 included patients, 122 (93.1%) had documentation of receiving instructions for DM medications. Among patients who had documented receipt of instructions, only 30 (24.6%) had instructions specifically tailored to their regimen rather than a generic templated form. The mean (SD) preoperative blood glucose was similar for those who received specific perioperative DM instructions at 146 (50) mg/dL when compared with those who did not at 147 (45) mg/dL. The mean (SD) preoperative blood glucose reading for those who had no documentation of receipt of perioperative instructions was 126 (54) mg/dL compared with 147 (46) mg/dL for those who did.

The mean number of postoperative blood glucose events per day was negligible for hypoglycemia and more frequent for hyperglycemia with a mean of 2 events per day. The mean postoperative blood glucose range was 121 to 247 mg/dL with most readings < 180 mg/dL. Upon discharge, most patients continued their home DM regimen with 5 patients (3.8%) having changes made to their regimen upon discharge.

Very few postoperative complications were identified from chart review. The most frequently observed postoperative complications were acute kidney injury, surgical site infections, and nonfatal stroke. There were no documented nonfatal myocardial infarctions. Two patients (1.5%) died within 30 days of the surgery; neither death was deemed to have been related to poor perioperative glycemic control.

Discussion

To our knowledge, this retrospective chart review was the first study to assess preoperative DM management and postoperative complications in a veteran population. VHI is a large, tertiary, level 1a, academic medical center that serves approximately 62,000 veterans annually and performs about 5000 to 6000 surgeries annually, a total that is increasing following the COVID-19 pandemic.²⁰ This study found that the current process of a presurgery clinic visit and day of surgery glucose assessment has prevented surgical delays or cancellations.

Most patients included in this study were well controlled at baseline in accordance with the 2025 ADA SOC HbA_1c recommendation of a preoperative HbA1c of < 8%, which may have contributed to no surgical delays or cancellations.¹⁰ However, not all patients had HbA1c collected within 3 months of surgery or even had one collected at all. Despite the ADA SOC providing no explicit recommendation for universal HbA_1c screening prior to elective procedures, its importance cannot be understated given the body of evidence demonstrating poor outcomes with uncontrolled preoperative DM.^8,10 The glycemic control at baseline may have contributed to the very few postsurgical complications observed in this study.

Although the current process at VHI prevented surgical delays and cancellations in this sample, there are still identified areas for improvement. One area is the instructions the patients received. Patients with DM are often prescribed ≥ 1 medication or a combination of insulins, noninsulin injectables, and oral DM medications, and this study population was no different. Because these medications may influence the anesthesia and perioperative periods, the ADA has specific guidance for altering administration schedules in the days leading up to surgery.¹⁰

Inappropriate administration of DM medications could lead to perioperative hypoglycemia or hyperglycemia, possibly causing surgical delays, case cancellations, and/or postoperative complications.21 Although these data reveal the specificity and documented receipt that the preoperative DM instructions did not impact the first recorded preoperative blood glucose, future studies should examine patient confidence in how to properly administer their DM medications prior to surgery. It is vital that patients receive clear instructions in accordance with the ADA SOC on whether to continue, hold, or adjust the dose of their medications to prevent fluctuations in blood glucose levels in the perioperative period, ensure safety with anesthesia, and prevent postoperative complications such as acute kidney injury. Of note, compliance with guideline recommendations for medication instructions was not examined because the data collection time frame expanded over multiple years and the recommendations have evolved each year as new data emerge.

Preoperative DM Management

The first key takeaway from this study is to ensure patients are ready for surgery with a formal assessment (typically in the form of a clinic visit) prior to the surgery. One private sector health system published their approach to this by administering an automatic preoperative HbA_1c screening for those with a DM diagnosis and all patients with a random plasma glucose ≥ 200 mg/dL.²² Additionally, if the patient's HbA_1c level was not at goal prior to surgery (≥ 8% for those with known DM and ≥ 6.5% with no known DM), patients were referred to endocrinology for further management. Increasing attention to the preoperative visit and extending HbA_1c testing to all patients regardless of DM status also provides an opportunity to identify individuals living with undiagnosed DM.¹

Even though there was no difference in the mean preoperative blood glucose level based on receipt or specificity of preoperative DM instructions, a second takeaway from this study is the importance of ensuring patients receive clear instructions on their DM medication schedule in the perioperative period. A practical first step may be updating the templates used by the primary surgery teams and providing education to the clinicians in the clinic on how to personalize the visits. Because the current preoperative DM process at VHI is managed by the primary surgical team in a clinic visit, there is an opportunity to shift this responsibility to other health care professionals, such as pharmacists—a change shown to reduce unintended omission of home medications following surgery during hospitalization and reduce costs.^23,24

Limitations

This study relied on data included in the patient chart. These data include medication interventions made immediately prior to surgery, which can sometimes be inaccurately charted or difficult to find as they are not documented in the typical medication administration record. Also, the safety outcomes were collected from a discharge summary written by different clinicians, which may lead to information bias. Special attention was taken to ensure these data points were collected as accurately as possible, but it is possible some data may be inaccurate from unintentional human error. Additionally, the safety outcome was limited to a 30-day follow-up, but encompassed the entire length of postoperative stay for all included patients. Finally, given this study was retrospective with no comparison group and the intent was to improve processes at VHI, only hypotheses and potential interventions can be generated from this study. Future prospective studies with larger sample sizes and comparator groups are needed to draw further conclusions.

Conclusions

This study found that the current presurgery process at VHI appears to be successful in preventing surgical delays or cancellations due to hyperglycemia or hypoglycemia. Optimizing DM management can improve surgical outcomes by decreasing rates of postoperative complications, and this study added additional evidence in support of that in a unique population: veterans. Insight on the awareness of preoperative blood glucose management should be gleaned from this study, and based on this sample and site, the preadmission screening process and instructions provided to patients can serve as 2 starting points for optimizing elective surgery.

Type 2 diabetes mellitus (T2DM) is a chronic disease becoming more prevalent each year and is the seventh-leading cause of death in the United States.¹ The most common reason for hospitalization for patients with T2DM is uncontrolled glycemic levels.² Nearly 25% of the US Department of Veterans Affairs (VA) patient population has T2DM.³ T2DM is the leading cause of blindness, end-stage renal disease, and amputation for VA patients.⁴

According to the 2023 American Diabetes Association (ADA) guidelines, treatment goals of T2DM include eliminating symptoms, preventing or delaying complications, and attaining glycemic goals. A typical hemoglobin A_1c (HbA_1c) goal range is < 7%, but individual goals can vary up to < 9% due to a multitude of factors, including patient comorbidities and clinical status.⁵

Initial treatment recommendations are nonpharmacologic and include comprehensive lifestyle interventions such as optimizing nutrition, physical activity, and behavioral therapy. When pharmacologic therapy is required, metformin is the preferred first-line treatment for the majority of newly diagnosed patients with T2DM and should be added to continued lifestyle management.⁵ If HbA_1c levels remains above goal, the 2023 ADA guidelines recommend adding a second medication, including but not limited to insulin, a glucagonlike peptide-1 receptor agonist (GLP-1RA), or a sodium-glucose cotransporter 2 inhibitor. Medication choice is largely based on the patient’s concomitant conditions (eg, atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease). The 2023 ADA guidelines suggest initiating insulin therapy when a patient's blood glucose ≥ 300 mg/dL, HbA_1c > 10%, or if the patient has symptoms of hyperglycemia, even at initial diagnosis. Initiating medications to minimize or avoid hypoglycemia is a priority, especially in high-risk individuals.⁵

Clinical evidence shows that GLP-1RAs may provide similar glycemic control to insulin with lower risk of hypoglycemia.⁶ Other reported benefits of GLP-1RAs include weight loss, blood pressure reduction, and improved lipid levels. The most common adverse events (AEs) with GLP-1RAs are gastrointestinal. Including GLP-1RAs in T2DM pharmacotherapy may lower the risk of hypoglycemia, especially in patients at high risk of hypoglycemia.

The 2023 ADA guidelines indicate that it is appropriate to initiate GLP-]1RAs in patients on insulin.⁵ However, while GLP-1RAs do not increase the risk of hypoglycemia independently, combination treatment with GLP-1RAs and insulin can still result in hypoglycemia.⁶ Insulin is the key suspect of this hypoglycemic risk.⁷ Thus, if insulin dosage can be reduced or discontinued, this might reduce the risk of hypoglycemia.

The literature is limited on how the addition of a GLP-1RA to insulin treatment will affect the patient's daily insulin doses, particularly for the veteran population. The goal of this study is to examine this gap in current research by examining semaglutide, which is the current formulary preferred GLP-1RA at the VA.

Semaglutide is subcutaneously initiated at a dose of 0.25 mg once weekly for 4 weeks to reduce gastrointestinal symptoms, then increased to 0.5 mg weekly. Additional increases to a maintenance dose of 1 mg or 2 mg weekly can occur to achieve glycemic goals. The SUSTAIN-FORTE randomized controlled trial sought to determine whether there was a difference in HbA_1c level reduction and significant weight loss with the 2-mg vs 1-mg dose.⁸ Patients in the trial were taking metformin but needed additional medication to control their HbA_1c. They were not using insulin and may or may not have been taking sulfonylureas prior to semaglutide initiation. Semaglutide 2 mg was found to significantly improve HbA_1c control and promote weight loss compared with semaglutide 1 mg, while maintaining a similar safety profile.

Because this study involved patients who required additional HbA_1c control, although semaglutide reduced HbA_1c, not all patients were able to reduce their other diabetes medications, which depended on the baseline HbA_1c level and the level upon completion of semaglutide titration. Dose reductions for the patients’ other T2DM medications were not reported at trial end. SUSTAIN-FORTE established titration up to semaglutide 2 mg as effective for HbA_1c reduction, although it did not study patients also on insulin.⁸

Insulin is associated with hypoglycemic risk, weight gain, and other AEs.^7,8 This study analyzed whether increasing semaglutide could reduce insulin doses and therefore reduce risk of AEs in patients with T2DM.

Methods

A retrospective, single-center, chart review was conducted at VA Sioux Falls Health Care System (VASFHCS). Data were collected through manual review of VASFHCS electronic medical records. Patients aged ≥ 18 years with active prescriptions for at least once-daily insulin who were initiated on 2-mg weekly dose of semaglutide at the VASFHCS clinical pharmacy practitioner medication management clinic between January 1, 2021, and September 1, 2023, were included. VASFHCS clinical pharmacy practitioners have a scope of practice that allows them to initiate, modify, or discontinue medication therapy within medication management clinics.

The most frequently used prandial insulin at VASFHCS is insulin aspart, and the most frequently used basal insulin is insulin glargine. Patients were retrospectively monitored as they progressed from baseline (the point in time where semaglutide 0.5 mg was initiated) to ≥ 3 months on semaglutide 2-mg therapy. Patients were excluded if they previously used a GLP-1RA or if they were on sliding scale insulin without an exact daily dosage.

The primary endpoint was the percent change in total daily insulin dose from baseline to each dose increase after receiving semaglutide 2 mg for ≥ 3 months. Secondary endpoints included changes in daily prandial insulin dose, daily basal insulin dose, HbA_1c, and number of hypoglycemic events reported. Data collected included age, race, weight, body mass index, total daily prandial insulin dose, total daily basal insulin dose, HbA_1c, and hypoglycemic events reported at the visit when semaglutide was initiated.

Statistical Analysis

The sample size was calculated prior to data collection, and it was determined that for α = .05, 47 patients were needed to achieve 95% power. The primary endpoint was assessed using a paired t test, as were each secondary endpoint. Results with P < .05 were considered statistically significant.

Results

Sixty-two patients were included. The mean HbA_1c level at baseline was 7.7%, the baseline mean prandial and insulin daily doses were 41.5 units and 85.1 units, respectively (Table 1) From baseline to initiation of a semaglutide 1-mg dose, the daily insulin dose changed –5.6% (95% CI, 2.2-14.0; P = .008). From baseline to 2-mg dose initiation daily insulin changed -22.2% (95% CI, 22.0-35.1; P < .001) and for patients receiving semaglutide 2 mg for ≥ 3 months it changed -36.9% (95% CI, 37.4-56.5; P < .001) (Figure).

After receiving the 2-mg dose for ≥ 3 months, the mean daily dose of prandial insulin decreased from 41.5 units to 24.6 units (95% CI, 12.6-21.2; P < .001); mean daily dose of basal insulin decreased from 85.1 units to 52.1 units (95% CI, 23.9-42.0; P < .001); and mean HbA_1c level decreased from 7.7% to 7.1% (95% CI, 0.3-0.8; P < .001). Mean number of hypoglycemic events reported was not statistically significant, changing from 3.6 to 3.2 (95% CI, –0.6 to 0.1; P = .21) (Table 2).

Discussion

This study investigated the effect of subcutaneous semaglutide dose escalation on total daily insulin dose for patients with T2DM. There was a statistically significant decrease in total daily insulin dose from baseline to 1 mg initiation; this decrease continued with further insulin dose reduction seen at the 2-mg dose initiation and additional insulin dose reduction at ≥ 3 months at this dose. It was hypothesized there would be a significant total daily insulin dose reduction at some point, especially when transitioning from the semaglutide 1-mg to the 2-mg dose, based on previous research. ^9,10 The additional reduction in daily insulin dose when continuing on semaglutide 2 mg for ≥ 3 months was an unanticipated but added benefit, showing that if tolerated, maintaining the 2-mg dose will help patients reduce their insulin doses.

In terms of secondary endpoints, there was a statistically significant decrease in mean total daily dose individually for prandial and basal insulin from baseline to ≥ 3 months after semaglutide 2 mg initiation. The change in HbA_1c level was also statistically significant and decreased from baseline, even as insulin doses were reduced. This change in HbA_1c level was expected; previous literature has shown a significant link between improving HbA_1c control when semaglutide doses are increased to 2 mg weekly.¹⁰ Due to having been shown in previous trials, it was expected that HbA_1c levels would decrease even when the insulin doses were being reduced.¹⁰ Insulin dose reduction can potentially be added to the growing evidence of semaglutide benefits. The change in the number of hypoglycemic events was not statistically significant, which was unexpected since previous research show a trend in patients taking GLP-1RAs having fewer hypoglycemic events than those taking insulin.⁶ Further investigation with a larger sample size and prospective trial could determine whether this result is an outlier. In this study, there was no increase in HbA_1c or hypoglycemic events reported with increasing semaglutide doses, which provides further evidence of the safety of semaglutide even at higher doses.

These data suggest that for a patient with T2DM who is already taking insulin, the recommended titration of semaglutide is to start with 0.5 mg and titrate up to a 2-mg subcutaneous weekly dose and to then continue at that dose. As long as the 2-mg dose is tolerated, it will provide patients with the most HbA_1c control and lead to a reduction of their total daily insulin doses according to these results.

Strengths and Limitations

This study compared patient data at different points. This method did not require a second distinct control group, which would potentially introduce confounding factors, such as different baseline characteristics. Another strength is that documentation was available for all patients throughout the study so no one was lost to follow-up. This allowed comprehensive data collection and provided a stronger conclusion given the completeness of the data from baseline to follow-up.

Limitations include the retrospective design and small sample size. In addition, the study design did not allow for randomization. There is no documentation of adherence to medication regimen, which was difficult to determine due to the retrospective nature. Other changes to the patients’ medication regimen were not collected in aggregate and thus, it is possible the total daily insulin dose was impacted by other medication changes. There is also potential for inconsistent documentation of the patients’ true total daily insulin dose in the medical record, thus leading to inaccuracy of recorded data.

Conclusions

A small sample of veterans with T2DM had statistically significant reductions in total daily insulin dose when subcutaneous semaglutide was initiated, as well as after each dose increase. There was also a statistically significant reduction in HbA_1c levels from baseline even as patient insulin doses were reduced. These results support the current practice of using semaglutide to treat T2DM, suggesting it may be safe and effective at reducing HbA_1c levels as the dose is titrated up to 2 mg. There was no statistically significant change in the number of hypoglycemic events reported as semaglutide was titrated up. Thus, when semaglutide is increased to the maximum recommended dose of 2 mg for T2DM, patients may experience a reduction of their total daily dose of insulin and HbA_1c levels. These benefits may reduce the risk of insulin-related AEs while maintaining appropriate glycemic control.

Type 2 diabetes mellitus (T2DM) is a chronic disease becoming more prevalent each year and is the seventh-leading cause of death in the United States.¹ The most common reason for hospitalization for patients with T2DM is uncontrolled glycemic levels.² Nearly 25% of the US Department of Veterans Affairs (VA) patient population has T2DM.³ T2DM is the leading cause of blindness, end-stage renal disease, and amputation for VA patients.⁴

According to the 2023 American Diabetes Association (ADA) guidelines, treatment goals of T2DM include eliminating symptoms, preventing or delaying complications, and attaining glycemic goals. A typical hemoglobin A_1c (HbA_1c) goal range is < 7%, but individual goals can vary up to < 9% due to a multitude of factors, including patient comorbidities and clinical status.⁵

Initial treatment recommendations are nonpharmacologic and include comprehensive lifestyle interventions such as optimizing nutrition, physical activity, and behavioral therapy. When pharmacologic therapy is required, metformin is the preferred first-line treatment for the majority of newly diagnosed patients with T2DM and should be added to continued lifestyle management.⁵ If HbA_1c levels remains above goal, the 2023 ADA guidelines recommend adding a second medication, including but not limited to insulin, a glucagonlike peptide-1 receptor agonist (GLP-1RA), or a sodium-glucose cotransporter 2 inhibitor. Medication choice is largely based on the patient’s concomitant conditions (eg, atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease). The 2023 ADA guidelines suggest initiating insulin therapy when a patient's blood glucose ≥ 300 mg/dL, HbA_1c > 10%, or if the patient has symptoms of hyperglycemia, even at initial diagnosis. Initiating medications to minimize or avoid hypoglycemia is a priority, especially in high-risk individuals.⁵

Clinical evidence shows that GLP-1RAs may provide similar glycemic control to insulin with lower risk of hypoglycemia.⁶ Other reported benefits of GLP-1RAs include weight loss, blood pressure reduction, and improved lipid levels. The most common adverse events (AEs) with GLP-1RAs are gastrointestinal. Including GLP-1RAs in T2DM pharmacotherapy may lower the risk of hypoglycemia, especially in patients at high risk of hypoglycemia.

The 2023 ADA guidelines indicate that it is appropriate to initiate GLP-]1RAs in patients on insulin.⁵ However, while GLP-1RAs do not increase the risk of hypoglycemia independently, combination treatment with GLP-1RAs and insulin can still result in hypoglycemia.⁶ Insulin is the key suspect of this hypoglycemic risk.⁷ Thus, if insulin dosage can be reduced or discontinued, this might reduce the risk of hypoglycemia.

The literature is limited on how the addition of a GLP-1RA to insulin treatment will affect the patient's daily insulin doses, particularly for the veteran population. The goal of this study is to examine this gap in current research by examining semaglutide, which is the current formulary preferred GLP-1RA at the VA.

Semaglutide is subcutaneously initiated at a dose of 0.25 mg once weekly for 4 weeks to reduce gastrointestinal symptoms, then increased to 0.5 mg weekly. Additional increases to a maintenance dose of 1 mg or 2 mg weekly can occur to achieve glycemic goals. The SUSTAIN-FORTE randomized controlled trial sought to determine whether there was a difference in HbA_1c level reduction and significant weight loss with the 2-mg vs 1-mg dose.⁸ Patients in the trial were taking metformin but needed additional medication to control their HbA_1c. They were not using insulin and may or may not have been taking sulfonylureas prior to semaglutide initiation. Semaglutide 2 mg was found to significantly improve HbA_1c control and promote weight loss compared with semaglutide 1 mg, while maintaining a similar safety profile.

Because this study involved patients who required additional HbA_1c control, although semaglutide reduced HbA_1c, not all patients were able to reduce their other diabetes medications, which depended on the baseline HbA_1c level and the level upon completion of semaglutide titration. Dose reductions for the patients’ other T2DM medications were not reported at trial end. SUSTAIN-FORTE established titration up to semaglutide 2 mg as effective for HbA_1c reduction, although it did not study patients also on insulin.⁸

Insulin is associated with hypoglycemic risk, weight gain, and other AEs.^7,8 This study analyzed whether increasing semaglutide could reduce insulin doses and therefore reduce risk of AEs in patients with T2DM.

Methods

A retrospective, single-center, chart review was conducted at VA Sioux Falls Health Care System (VASFHCS). Data were collected through manual review of VASFHCS electronic medical records. Patients aged ≥ 18 years with active prescriptions for at least once-daily insulin who were initiated on 2-mg weekly dose of semaglutide at the VASFHCS clinical pharmacy practitioner medication management clinic between January 1, 2021, and September 1, 2023, were included. VASFHCS clinical pharmacy practitioners have a scope of practice that allows them to initiate, modify, or discontinue medication therapy within medication management clinics.

The most frequently used prandial insulin at VASFHCS is insulin aspart, and the most frequently used basal insulin is insulin glargine. Patients were retrospectively monitored as they progressed from baseline (the point in time where semaglutide 0.5 mg was initiated) to ≥ 3 months on semaglutide 2-mg therapy. Patients were excluded if they previously used a GLP-1RA or if they were on sliding scale insulin without an exact daily dosage.

The primary endpoint was the percent change in total daily insulin dose from baseline to each dose increase after receiving semaglutide 2 mg for ≥ 3 months. Secondary endpoints included changes in daily prandial insulin dose, daily basal insulin dose, HbA_1c, and number of hypoglycemic events reported. Data collected included age, race, weight, body mass index, total daily prandial insulin dose, total daily basal insulin dose, HbA_1c, and hypoglycemic events reported at the visit when semaglutide was initiated.

Statistical Analysis

The sample size was calculated prior to data collection, and it was determined that for α = .05, 47 patients were needed to achieve 95% power. The primary endpoint was assessed using a paired t test, as were each secondary endpoint. Results with P < .05 were considered statistically significant.

Results

Sixty-two patients were included. The mean HbA_1c level at baseline was 7.7%, the baseline mean prandial and insulin daily doses were 41.5 units and 85.1 units, respectively (Table 1) From baseline to initiation of a semaglutide 1-mg dose, the daily insulin dose changed –5.6% (95% CI, 2.2-14.0; P = .008). From baseline to 2-mg dose initiation daily insulin changed -22.2% (95% CI, 22.0-35.1; P < .001) and for patients receiving semaglutide 2 mg for ≥ 3 months it changed -36.9% (95% CI, 37.4-56.5; P < .001) (Figure).

After receiving the 2-mg dose for ≥ 3 months, the mean daily dose of prandial insulin decreased from 41.5 units to 24.6 units (95% CI, 12.6-21.2; P < .001); mean daily dose of basal insulin decreased from 85.1 units to 52.1 units (95% CI, 23.9-42.0; P < .001); and mean HbA_1c level decreased from 7.7% to 7.1% (95% CI, 0.3-0.8; P < .001). Mean number of hypoglycemic events reported was not statistically significant, changing from 3.6 to 3.2 (95% CI, –0.6 to 0.1; P = .21) (Table 2).

Discussion

This study investigated the effect of subcutaneous semaglutide dose escalation on total daily insulin dose for patients with T2DM. There was a statistically significant decrease in total daily insulin dose from baseline to 1 mg initiation; this decrease continued with further insulin dose reduction seen at the 2-mg dose initiation and additional insulin dose reduction at ≥ 3 months at this dose. It was hypothesized there would be a significant total daily insulin dose reduction at some point, especially when transitioning from the semaglutide 1-mg to the 2-mg dose, based on previous research. ^9,10 The additional reduction in daily insulin dose when continuing on semaglutide 2 mg for ≥ 3 months was an unanticipated but added benefit, showing that if tolerated, maintaining the 2-mg dose will help patients reduce their insulin doses.

In terms of secondary endpoints, there was a statistically significant decrease in mean total daily dose individually for prandial and basal insulin from baseline to ≥ 3 months after semaglutide 2 mg initiation. The change in HbA_1c level was also statistically significant and decreased from baseline, even as insulin doses were reduced. This change in HbA_1c level was expected; previous literature has shown a significant link between improving HbA_1c control when semaglutide doses are increased to 2 mg weekly.¹⁰ Due to having been shown in previous trials, it was expected that HbA_1c levels would decrease even when the insulin doses were being reduced.¹⁰ Insulin dose reduction can potentially be added to the growing evidence of semaglutide benefits. The change in the number of hypoglycemic events was not statistically significant, which was unexpected since previous research show a trend in patients taking GLP-1RAs having fewer hypoglycemic events than those taking insulin.⁶ Further investigation with a larger sample size and prospective trial could determine whether this result is an outlier. In this study, there was no increase in HbA_1c or hypoglycemic events reported with increasing semaglutide doses, which provides further evidence of the safety of semaglutide even at higher doses.

These data suggest that for a patient with T2DM who is already taking insulin, the recommended titration of semaglutide is to start with 0.5 mg and titrate up to a 2-mg subcutaneous weekly dose and to then continue at that dose. As long as the 2-mg dose is tolerated, it will provide patients with the most HbA_1c control and lead to a reduction of their total daily insulin doses according to these results.

Strengths and Limitations

This study compared patient data at different points. This method did not require a second distinct control group, which would potentially introduce confounding factors, such as different baseline characteristics. Another strength is that documentation was available for all patients throughout the study so no one was lost to follow-up. This allowed comprehensive data collection and provided a stronger conclusion given the completeness of the data from baseline to follow-up.

Limitations include the retrospective design and small sample size. In addition, the study design did not allow for randomization. There is no documentation of adherence to medication regimen, which was difficult to determine due to the retrospective nature. Other changes to the patients’ medication regimen were not collected in aggregate and thus, it is possible the total daily insulin dose was impacted by other medication changes. There is also potential for inconsistent documentation of the patients’ true total daily insulin dose in the medical record, thus leading to inaccuracy of recorded data.

Conclusions

A small sample of veterans with T2DM had statistically significant reductions in total daily insulin dose when subcutaneous semaglutide was initiated, as well as after each dose increase. There was also a statistically significant reduction in HbA_1c levels from baseline even as patient insulin doses were reduced. These results support the current practice of using semaglutide to treat T2DM, suggesting it may be safe and effective at reducing HbA_1c levels as the dose is titrated up to 2 mg. There was no statistically significant change in the number of hypoglycemic events reported as semaglutide was titrated up. Thus, when semaglutide is increased to the maximum recommended dose of 2 mg for T2DM, patients may experience a reduction of their total daily dose of insulin and HbA_1c levels. These benefits may reduce the risk of insulin-related AEs while maintaining appropriate glycemic control.

Type 2 diabetes mellitus (T2DM) is a chronic disease becoming more prevalent each year and is the seventh-leading cause of death in the United States.¹ The most common reason for hospitalization for patients with T2DM is uncontrolled glycemic levels.² Nearly 25% of the US Department of Veterans Affairs (VA) patient population has T2DM.³ T2DM is the leading cause of blindness, end-stage renal disease, and amputation for VA patients.⁴

According to the 2023 American Diabetes Association (ADA) guidelines, treatment goals of T2DM include eliminating symptoms, preventing or delaying complications, and attaining glycemic goals. A typical hemoglobin A_1c (HbA_1c) goal range is < 7%, but individual goals can vary up to < 9% due to a multitude of factors, including patient comorbidities and clinical status.⁵

Initial treatment recommendations are nonpharmacologic and include comprehensive lifestyle interventions such as optimizing nutrition, physical activity, and behavioral therapy. When pharmacologic therapy is required, metformin is the preferred first-line treatment for the majority of newly diagnosed patients with T2DM and should be added to continued lifestyle management.⁵ If HbA_1c levels remains above goal, the 2023 ADA guidelines recommend adding a second medication, including but not limited to insulin, a glucagonlike peptide-1 receptor agonist (GLP-1RA), or a sodium-glucose cotransporter 2 inhibitor. Medication choice is largely based on the patient’s concomitant conditions (eg, atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease). The 2023 ADA guidelines suggest initiating insulin therapy when a patient's blood glucose ≥ 300 mg/dL, HbA_1c > 10%, or if the patient has symptoms of hyperglycemia, even at initial diagnosis. Initiating medications to minimize or avoid hypoglycemia is a priority, especially in high-risk individuals.⁵

Clinical evidence shows that GLP-1RAs may provide similar glycemic control to insulin with lower risk of hypoglycemia.⁶ Other reported benefits of GLP-1RAs include weight loss, blood pressure reduction, and improved lipid levels. The most common adverse events (AEs) with GLP-1RAs are gastrointestinal. Including GLP-1RAs in T2DM pharmacotherapy may lower the risk of hypoglycemia, especially in patients at high risk of hypoglycemia.

The 2023 ADA guidelines indicate that it is appropriate to initiate GLP-]1RAs in patients on insulin.⁵ However, while GLP-1RAs do not increase the risk of hypoglycemia independently, combination treatment with GLP-1RAs and insulin can still result in hypoglycemia.⁶ Insulin is the key suspect of this hypoglycemic risk.⁷ Thus, if insulin dosage can be reduced or discontinued, this might reduce the risk of hypoglycemia.

The literature is limited on how the addition of a GLP-1RA to insulin treatment will affect the patient's daily insulin doses, particularly for the veteran population. The goal of this study is to examine this gap in current research by examining semaglutide, which is the current formulary preferred GLP-1RA at the VA.

Semaglutide is subcutaneously initiated at a dose of 0.25 mg once weekly for 4 weeks to reduce gastrointestinal symptoms, then increased to 0.5 mg weekly. Additional increases to a maintenance dose of 1 mg or 2 mg weekly can occur to achieve glycemic goals. The SUSTAIN-FORTE randomized controlled trial sought to determine whether there was a difference in HbA_1c level reduction and significant weight loss with the 2-mg vs 1-mg dose.⁸ Patients in the trial were taking metformin but needed additional medication to control their HbA_1c. They were not using insulin and may or may not have been taking sulfonylureas prior to semaglutide initiation. Semaglutide 2 mg was found to significantly improve HbA_1c control and promote weight loss compared with semaglutide 1 mg, while maintaining a similar safety profile.

Because this study involved patients who required additional HbA_1c control, although semaglutide reduced HbA_1c, not all patients were able to reduce their other diabetes medications, which depended on the baseline HbA_1c level and the level upon completion of semaglutide titration. Dose reductions for the patients’ other T2DM medications were not reported at trial end. SUSTAIN-FORTE established titration up to semaglutide 2 mg as effective for HbA_1c reduction, although it did not study patients also on insulin.⁸

Insulin is associated with hypoglycemic risk, weight gain, and other AEs.^7,8 This study analyzed whether increasing semaglutide could reduce insulin doses and therefore reduce risk of AEs in patients with T2DM.

Methods

A retrospective, single-center, chart review was conducted at VA Sioux Falls Health Care System (VASFHCS). Data were collected through manual review of VASFHCS electronic medical records. Patients aged ≥ 18 years with active prescriptions for at least once-daily insulin who were initiated on 2-mg weekly dose of semaglutide at the VASFHCS clinical pharmacy practitioner medication management clinic between January 1, 2021, and September 1, 2023, were included. VASFHCS clinical pharmacy practitioners have a scope of practice that allows them to initiate, modify, or discontinue medication therapy within medication management clinics.

The most frequently used prandial insulin at VASFHCS is insulin aspart, and the most frequently used basal insulin is insulin glargine. Patients were retrospectively monitored as they progressed from baseline (the point in time where semaglutide 0.5 mg was initiated) to ≥ 3 months on semaglutide 2-mg therapy. Patients were excluded if they previously used a GLP-1RA or if they were on sliding scale insulin without an exact daily dosage.

The primary endpoint was the percent change in total daily insulin dose from baseline to each dose increase after receiving semaglutide 2 mg for ≥ 3 months. Secondary endpoints included changes in daily prandial insulin dose, daily basal insulin dose, HbA_1c, and number of hypoglycemic events reported. Data collected included age, race, weight, body mass index, total daily prandial insulin dose, total daily basal insulin dose, HbA_1c, and hypoglycemic events reported at the visit when semaglutide was initiated.

Statistical Analysis

The sample size was calculated prior to data collection, and it was determined that for α = .05, 47 patients were needed to achieve 95% power. The primary endpoint was assessed using a paired t test, as were each secondary endpoint. Results with P < .05 were considered statistically significant.

Results

Sixty-two patients were included. The mean HbA_1c level at baseline was 7.7%, the baseline mean prandial and insulin daily doses were 41.5 units and 85.1 units, respectively (Table 1) From baseline to initiation of a semaglutide 1-mg dose, the daily insulin dose changed –5.6% (95% CI, 2.2-14.0; P = .008). From baseline to 2-mg dose initiation daily insulin changed -22.2% (95% CI, 22.0-35.1; P < .001) and for patients receiving semaglutide 2 mg for ≥ 3 months it changed -36.9% (95% CI, 37.4-56.5; P < .001) (Figure).

After receiving the 2-mg dose for ≥ 3 months, the mean daily dose of prandial insulin decreased from 41.5 units to 24.6 units (95% CI, 12.6-21.2; P < .001); mean daily dose of basal insulin decreased from 85.1 units to 52.1 units (95% CI, 23.9-42.0; P < .001); and mean HbA_1c level decreased from 7.7% to 7.1% (95% CI, 0.3-0.8; P < .001). Mean number of hypoglycemic events reported was not statistically significant, changing from 3.6 to 3.2 (95% CI, –0.6 to 0.1; P = .21) (Table 2).

Discussion

This study investigated the effect of subcutaneous semaglutide dose escalation on total daily insulin dose for patients with T2DM. There was a statistically significant decrease in total daily insulin dose from baseline to 1 mg initiation; this decrease continued with further insulin dose reduction seen at the 2-mg dose initiation and additional insulin dose reduction at ≥ 3 months at this dose. It was hypothesized there would be a significant total daily insulin dose reduction at some point, especially when transitioning from the semaglutide 1-mg to the 2-mg dose, based on previous research. ^9,10 The additional reduction in daily insulin dose when continuing on semaglutide 2 mg for ≥ 3 months was an unanticipated but added benefit, showing that if tolerated, maintaining the 2-mg dose will help patients reduce their insulin doses.

In terms of secondary endpoints, there was a statistically significant decrease in mean total daily dose individually for prandial and basal insulin from baseline to ≥ 3 months after semaglutide 2 mg initiation. The change in HbA_1c level was also statistically significant and decreased from baseline, even as insulin doses were reduced. This change in HbA_1c level was expected; previous literature has shown a significant link between improving HbA_1c control when semaglutide doses are increased to 2 mg weekly.¹⁰ Due to having been shown in previous trials, it was expected that HbA_1c levels would decrease even when the insulin doses were being reduced.¹⁰ Insulin dose reduction can potentially be added to the growing evidence of semaglutide benefits. The change in the number of hypoglycemic events was not statistically significant, which was unexpected since previous research show a trend in patients taking GLP-1RAs having fewer hypoglycemic events than those taking insulin.⁶ Further investigation with a larger sample size and prospective trial could determine whether this result is an outlier. In this study, there was no increase in HbA_1c or hypoglycemic events reported with increasing semaglutide doses, which provides further evidence of the safety of semaglutide even at higher doses.

These data suggest that for a patient with T2DM who is already taking insulin, the recommended titration of semaglutide is to start with 0.5 mg and titrate up to a 2-mg subcutaneous weekly dose and to then continue at that dose. As long as the 2-mg dose is tolerated, it will provide patients with the most HbA_1c control and lead to a reduction of their total daily insulin doses according to these results.

Strengths and Limitations

This study compared patient data at different points. This method did not require a second distinct control group, which would potentially introduce confounding factors, such as different baseline characteristics. Another strength is that documentation was available for all patients throughout the study so no one was lost to follow-up. This allowed comprehensive data collection and provided a stronger conclusion given the completeness of the data from baseline to follow-up.

Limitations include the retrospective design and small sample size. In addition, the study design did not allow for randomization. There is no documentation of adherence to medication regimen, which was difficult to determine due to the retrospective nature. Other changes to the patients’ medication regimen were not collected in aggregate and thus, it is possible the total daily insulin dose was impacted by other medication changes. There is also potential for inconsistent documentation of the patients’ true total daily insulin dose in the medical record, thus leading to inaccuracy of recorded data.

Conclusions

A small sample of veterans with T2DM had statistically significant reductions in total daily insulin dose when subcutaneous semaglutide was initiated, as well as after each dose increase. There was also a statistically significant reduction in HbA_1c levels from baseline even as patient insulin doses were reduced. These results support the current practice of using semaglutide to treat T2DM, suggesting it may be safe and effective at reducing HbA_1c levels as the dose is titrated up to 2 mg. There was no statistically significant change in the number of hypoglycemic events reported as semaglutide was titrated up. Thus, when semaglutide is increased to the maximum recommended dose of 2 mg for T2DM, patients may experience a reduction of their total daily dose of insulin and HbA_1c levels. These benefits may reduce the risk of insulin-related AEs while maintaining appropriate glycemic control.