The Journal of Family Practice

EVIDENCE SUMMARY

PRP vs placebo. Three RCTs compared PRP with saline placebo injections and 2 found that PRP improved the Western Ontario and McMaster Universities Arthritis Index (WOMAC, a standardized scale assessing knee pain, function, and stiffness) by 40% to 70%; the third found 24% to 32% improvements in the EuroQol visual analog scale (EQ-VAS) scores at 6 months^1-3 (TABLE^1-12).

The first 2 studies enrolled patients (mean age early 60s, approximately 50% women) with clinically and radiographically evaluated knee OA of mostly moderate severity (baseline WOMAC scores about 50).^1,2 Investigators in the first RCT injected PRP once in one subgroup and twice in another subgroup, compared with a single injection of saline in a third subgroup.¹ They gave 3 weekly injections of PRP or saline in the second RCT.²

The third study enrolled mainly patients with early osteoarthritis (mean age early 50s, slightly more women). Investigators injected PRP 3 times in one subgroup and once (plus 2 saline injections) in another, compared with 3 saline injections, and evaluated patients at baseline and 6 months.³

PRP vs HA. Nine RCTs compared PRP with HA injections. Six studies (673 patients) found no significant difference; 3 studies (376 patients) found that PRP improved standardized knee assessment scores by 35% to 40% at 24-48 weeks.^7,8,10 All studies enrolled patients (mean age early 60s, approximately 50% women) with clinically and radiographically evaluated knee OA of mostly moderate severity. In 7 RCTs, ^4-6,9-12 investigators injected PRP or HA weekly for 3 weeks, in one RCT⁸ they gave 4 weekly injections, and in one⁷they gave 2 PRP injections separated by 4 weeks.

Three RCTs used the International Knee Documentation Committee (IKDC) score, considered the most reliable standardized scoring system, which quantifies subjective symptoms (pain, stiffness, swelling, giving way), activity (climbing stairs, rising from a chair, squatting, jumping), and function pre- and postintervention.^5,9,12 All 3 studies using the IKDC found no difference between PRP and HA injections. Most RCTs used the WOMAC standardized scale, scoring 5 items for pain, 2 for stiffness, and 17 for function.^1,2,4,6-8.10

Risk for bias

A systematic review¹³ that evaluated methodologic quality of the 3 studies comparing PRP with placebo rated 2^1,3 at high risk of bias and one² at moderate risk. Another meta-analysis¹⁴ performed a quality assessment including 4 of the 9 RCTs^,8-10,12 comparing PRP with HA and concluded that 3 had a high risk of bias; the fourth RCT had a moderate risk. No independent quality assessments of the other RCTs were available.^4-7,11

RECOMMENDATIONS

The American Academy of Orthopaedic Surgeons doesn’t recommend for or against PRP injections because of insufficient evidence and strongly recommends against HA injections based on multiple RCTs of moderate quality that found no difference between HA and placebo.¹⁵

EVIDENCE SUMMARY

PRP vs placebo. Three RCTs compared PRP with saline placebo injections and 2 found that PRP improved the Western Ontario and McMaster Universities Arthritis Index (WOMAC, a standardized scale assessing knee pain, function, and stiffness) by 40% to 70%; the third found 24% to 32% improvements in the EuroQol visual analog scale (EQ-VAS) scores at 6 months^1-3 (TABLE^1-12).

The first 2 studies enrolled patients (mean age early 60s, approximately 50% women) with clinically and radiographically evaluated knee OA of mostly moderate severity (baseline WOMAC scores about 50).^1,2 Investigators in the first RCT injected PRP once in one subgroup and twice in another subgroup, compared with a single injection of saline in a third subgroup.¹ They gave 3 weekly injections of PRP or saline in the second RCT.²

The third study enrolled mainly patients with early osteoarthritis (mean age early 50s, slightly more women). Investigators injected PRP 3 times in one subgroup and once (plus 2 saline injections) in another, compared with 3 saline injections, and evaluated patients at baseline and 6 months.³

PRP vs HA. Nine RCTs compared PRP with HA injections. Six studies (673 patients) found no significant difference; 3 studies (376 patients) found that PRP improved standardized knee assessment scores by 35% to 40% at 24-48 weeks.^7,8,10 All studies enrolled patients (mean age early 60s, approximately 50% women) with clinically and radiographically evaluated knee OA of mostly moderate severity. In 7 RCTs, ^4-6,9-12 investigators injected PRP or HA weekly for 3 weeks, in one RCT⁸ they gave 4 weekly injections, and in one⁷they gave 2 PRP injections separated by 4 weeks.

Three RCTs used the International Knee Documentation Committee (IKDC) score, considered the most reliable standardized scoring system, which quantifies subjective symptoms (pain, stiffness, swelling, giving way), activity (climbing stairs, rising from a chair, squatting, jumping), and function pre- and postintervention.^5,9,12 All 3 studies using the IKDC found no difference between PRP and HA injections. Most RCTs used the WOMAC standardized scale, scoring 5 items for pain, 2 for stiffness, and 17 for function.^1,2,4,6-8.10

Risk for bias

A systematic review¹³ that evaluated methodologic quality of the 3 studies comparing PRP with placebo rated 2^1,3 at high risk of bias and one² at moderate risk. Another meta-analysis¹⁴ performed a quality assessment including 4 of the 9 RCTs^,8-10,12 comparing PRP with HA and concluded that 3 had a high risk of bias; the fourth RCT had a moderate risk. No independent quality assessments of the other RCTs were available.^4-7,11

RECOMMENDATIONS

The American Academy of Orthopaedic Surgeons doesn’t recommend for or against PRP injections because of insufficient evidence and strongly recommends against HA injections based on multiple RCTs of moderate quality that found no difference between HA and placebo.¹⁵

EVIDENCE SUMMARY

PRP vs placebo. Three RCTs compared PRP with saline placebo injections and 2 found that PRP improved the Western Ontario and McMaster Universities Arthritis Index (WOMAC, a standardized scale assessing knee pain, function, and stiffness) by 40% to 70%; the third found 24% to 32% improvements in the EuroQol visual analog scale (EQ-VAS) scores at 6 months^1-3 (TABLE^1-12).

The first 2 studies enrolled patients (mean age early 60s, approximately 50% women) with clinically and radiographically evaluated knee OA of mostly moderate severity (baseline WOMAC scores about 50).^1,2 Investigators in the first RCT injected PRP once in one subgroup and twice in another subgroup, compared with a single injection of saline in a third subgroup.¹ They gave 3 weekly injections of PRP or saline in the second RCT.²

The third study enrolled mainly patients with early osteoarthritis (mean age early 50s, slightly more women). Investigators injected PRP 3 times in one subgroup and once (plus 2 saline injections) in another, compared with 3 saline injections, and evaluated patients at baseline and 6 months.³

PRP vs HA. Nine RCTs compared PRP with HA injections. Six studies (673 patients) found no significant difference; 3 studies (376 patients) found that PRP improved standardized knee assessment scores by 35% to 40% at 24-48 weeks.^7,8,10 All studies enrolled patients (mean age early 60s, approximately 50% women) with clinically and radiographically evaluated knee OA of mostly moderate severity. In 7 RCTs, ^4-6,9-12 investigators injected PRP or HA weekly for 3 weeks, in one RCT⁸ they gave 4 weekly injections, and in one⁷they gave 2 PRP injections separated by 4 weeks.

Three RCTs used the International Knee Documentation Committee (IKDC) score, considered the most reliable standardized scoring system, which quantifies subjective symptoms (pain, stiffness, swelling, giving way), activity (climbing stairs, rising from a chair, squatting, jumping), and function pre- and postintervention.^5,9,12 All 3 studies using the IKDC found no difference between PRP and HA injections. Most RCTs used the WOMAC standardized scale, scoring 5 items for pain, 2 for stiffness, and 17 for function.^1,2,4,6-8.10

Risk for bias

A systematic review¹³ that evaluated methodologic quality of the 3 studies comparing PRP with placebo rated 2^1,3 at high risk of bias and one² at moderate risk. Another meta-analysis¹⁴ performed a quality assessment including 4 of the 9 RCTs^,8-10,12 comparing PRP with HA and concluded that 3 had a high risk of bias; the fourth RCT had a moderate risk. No independent quality assessments of the other RCTs were available.^4-7,11

RECOMMENDATIONS

The American Academy of Orthopaedic Surgeons doesn’t recommend for or against PRP injections because of insufficient evidence and strongly recommends against HA injections based on multiple RCTs of moderate quality that found no difference between HA and placebo.¹⁵

THE CASE

A 37-year-old man presented with a sudden-onset, nonpruritic, nonpainful, papular rash of 1 month’s duration on his trunk and both arms and legs. Two weeks prior to the current presentation, he consulted a general practitioner, who treated the rash with a course of unknown oral antibiotics; the patient showed no improvement. He recalled that on a few occasions, he used his fingers to express a creamy discharge from some of the lesions. This temporarily reduced the size of those papules.

His medical history was unremarkable except for morbid obesity. He did not drink alcohol regularly and was not taking any medications prior to the onset of the rash. He had no family history of hyperlipidemia, but his mother had a history of diabetes mellitus.

Physical examination showed numerous discrete erythematous papules with a creamy center on his trunk and his arms and legs. The lesions were more numerous on the extensor surfaces of the arms and legs. Some of the papules coalesced to form small plaques (FIGURE). There was no scaling, and the lesions were firm in texture. The patient’s face was spared, and there was no mucosal involvement. The patient was otherwise systemically well.

THE DIAGNOSIS

Based on the morphology, distribution, and abrupt onset of the diffuse nonpruritic papules in this morbidly obese (but otherwise systemically well) middle-aged man, a clinical diagnosis of eruptive xanthoma was suspected. Subsequent blood testing revealed an elevated serum triglyceride level of 47.8 mmol/L (reference range, <1.7 mmol/L), elevated serum total cholesterol of 7.1 mmol/L (reference range, <6.2 mmol/L), and low serum high-density lipoprotein cholesterol of 0.7 mmol/L (reference range, >1 mmol/L in men). He also had an elevated fasting serum glucose level of 12.9 mmol/L (reference range, 3.9–5.6 mmol/L) and an elevated hemoglobin A1c (glycated hemoglobin) level of 10.9%.

Subsequent thyroid, liver, and renal function tests were normal, but the patient had heavy proteinuria, with an elevated urine albumin-to-creatinine ratio of 355.6 mg/mmol (reference range, ≤2.5 mg/mmol). The patient was referred to a dermatologist, who confirmed the clinical diagnosis without the need for a skin biopsy.

DISCUSSION

Xanthomas are lipid deposits in the skin and subcutaneous tissues that arise in the setting of hyperlipidemia and are caused by underlying familial or acquired disorders. Xanthomas associated with dyslipidemias include eruptive xanthoma, tendinous xanthoma, xanthoma palpebrarum, and xanthoma tuberosum (TABLE).^1-3 Other non–dyslipidemia-related xanthomas include xanthoma planum, xanthoma disseminatum, linear palmar xanthomas, and verrucous xanthoma. One retrospective cohort study reported an 8.5% (8/95) prevalence of eruptive xanthomas in patients with severe hypertriglyceridemia (ie, triglyceride levels >1770 mg/dL).⁴ Data on the prevalence of other variants of xanthoma are lacking.

Diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other conditions in the differential diagnosis can’t be ruled out or if the lesions do not resolve with treatment.

Eruptive xanthoma is characterized by an abrupt onset of crops of multiple yellowish to brownish papules that can coalesce into small plaques. The lesions can be generalized, but tend to be more densely distributed on the extensor surfaces of the arms and legs, buttocks, and thighs.⁵ Eruptive xanthoma often is associated with hypertriglyceridemia, which can be primary—as a result of a genetic defect caused by familial hypertriglyceridemia—or secondary, associated with poorly controlled diabetes mellitus, morbid obesity, excessive alcohol consumption, nephrotic syndrome, hypothyroidism, primary biliary cholangitis, and drugs like estrogen replacement therapies, corticosteroids, and isotretinoin.⁶ Pruritus and tenderness may or may not be present, and the Köbner phenomenon may occur.⁷

Continue to: The differential diagnosis

The differential diagnosis for eruptive xanthoma includes xanthoma disseminatum, non–Langerhans cell histiocytoses (eg, generalized eruptive histiocytosis), and cutaneous mastocytosis.¹

Xanthoma disseminatum is an extremely rare, but benign, disorder of non–Langerhans cell origin. The average age of onset is older than 40 years. The rash consists of multiple red-yellow papules and nodules that most commonly present in flexural areas. Forty percent to 60% of patients have mucosal involvement, and rarely the central nervous system is involved.⁸

Generalized eruptive histiocytosis is another rare non–Langerhans cell histiocytosis that occurs mainly in adults and is characterized by widespread, symmetric, red-brown papules on the trunk, arms, and legs, and rarely the mucous membranes.⁹

Cutaneous mastocytosis, especially xanthelasmoid mastocytosis, consists of multiple pruritic, yellowish, papular or nodular lesions that may mimic eruptive xanthoma. It occurs mainly in children and rarely in adults.¹⁰

Confirming the diagnosis, initiating treatment

The diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other differential diagnoses cannot be ruled out or the lesions do not resolve with treatment. Skin biopsy will reveal lipid-laden macrophages (known as foam cells) deposited in the dermis.⁷

Continue to: Treatment of eruptive xanthoma

Treatment of eruptive xanthoma involves management of the underlying causes of the condition. In most cases, dietary control, intensive triglyceride-lowering therapies, and treatment of other secondary causes of hypertriglyceridemia result in complete resolution of the lesions within several weeks.⁵

Our patient’s outcome

Our patient’s sudden-onset rash alerted us to the presence of type 2 diabetes mellitus, hypertriglyceridemia, and heavy proteinuria, which he was not aware of previously. We counselled him about stringent low-sugar, low-lipid diet control and exercise, and we started him on metformin and gemfibrozil. He was referred to an internal medicine specialist for further assessment and management of his severe hypertriglyceridemia and heavy proteinuria.

Eruptive xanthoma may be an indicator of severe hypertriglyceri- demia, which can be associated with an increased risk for acute pancreatitis.

The rash started to wane 1 month after the patient started the metformin and gemfibrozil, and his drug regimen was changed to combination therapy with metformin/glimepiride and fenofibrate/simvastatin 6 weeks later when he was seen in the medical specialty clinic. Fundus photography performed 1 month after starting oral antidiabetic therapy showed no diabetic retinopathy or lipemia retinalis.

After 3 months of treatment, his serum triglycerides and hemoglobin A1c levels dropped to 3.8 mmol/L and 8.7%, respectively. The rash also resolved considerably, with only residual papules on the abdomen. This rapid clinical response to treatment of the underlying hypertriglyceridemia and diabetes further supported the clinical diagnosis of eruptive xanthoma.

THE TAKEAWAY

Eruptive xanthoma is relatively rare, but it is important for family physicians to recognize this clinical presentation as a potential indicator of severe hypertriglyceridemia. Recognizing hypertriglyceridemia early is important, as it can be associated with an increased risk for acute pancreatitis. Moreover, eruptive xanthoma might be the sole presenting symptom of underlying diabetes mellitus or familial hyperlipidemia, both of which can lead to a significant increase in cardiovascular risk if uncontrolled.

CORRESPONDENCE
Chan Kam Sum, MBChB, FRACGP, Tseung Kwan O Jockey Club General Out-patient Clinic, 99 Po Lam Road North, G/F, Tseung Kwan O, Kowloon, Hong Kong; cks048@ha.org.hk

THE CASE

A 37-year-old man presented with a sudden-onset, nonpruritic, nonpainful, papular rash of 1 month’s duration on his trunk and both arms and legs. Two weeks prior to the current presentation, he consulted a general practitioner, who treated the rash with a course of unknown oral antibiotics; the patient showed no improvement. He recalled that on a few occasions, he used his fingers to express a creamy discharge from some of the lesions. This temporarily reduced the size of those papules.

His medical history was unremarkable except for morbid obesity. He did not drink alcohol regularly and was not taking any medications prior to the onset of the rash. He had no family history of hyperlipidemia, but his mother had a history of diabetes mellitus.

Physical examination showed numerous discrete erythematous papules with a creamy center on his trunk and his arms and legs. The lesions were more numerous on the extensor surfaces of the arms and legs. Some of the papules coalesced to form small plaques (FIGURE). There was no scaling, and the lesions were firm in texture. The patient’s face was spared, and there was no mucosal involvement. The patient was otherwise systemically well.

THE DIAGNOSIS

Based on the morphology, distribution, and abrupt onset of the diffuse nonpruritic papules in this morbidly obese (but otherwise systemically well) middle-aged man, a clinical diagnosis of eruptive xanthoma was suspected. Subsequent blood testing revealed an elevated serum triglyceride level of 47.8 mmol/L (reference range, <1.7 mmol/L), elevated serum total cholesterol of 7.1 mmol/L (reference range, <6.2 mmol/L), and low serum high-density lipoprotein cholesterol of 0.7 mmol/L (reference range, >1 mmol/L in men). He also had an elevated fasting serum glucose level of 12.9 mmol/L (reference range, 3.9–5.6 mmol/L) and an elevated hemoglobin A1c (glycated hemoglobin) level of 10.9%.

Subsequent thyroid, liver, and renal function tests were normal, but the patient had heavy proteinuria, with an elevated urine albumin-to-creatinine ratio of 355.6 mg/mmol (reference range, ≤2.5 mg/mmol). The patient was referred to a dermatologist, who confirmed the clinical diagnosis without the need for a skin biopsy.

DISCUSSION

Xanthomas are lipid deposits in the skin and subcutaneous tissues that arise in the setting of hyperlipidemia and are caused by underlying familial or acquired disorders. Xanthomas associated with dyslipidemias include eruptive xanthoma, tendinous xanthoma, xanthoma palpebrarum, and xanthoma tuberosum (TABLE).^1-3 Other non–dyslipidemia-related xanthomas include xanthoma planum, xanthoma disseminatum, linear palmar xanthomas, and verrucous xanthoma. One retrospective cohort study reported an 8.5% (8/95) prevalence of eruptive xanthomas in patients with severe hypertriglyceridemia (ie, triglyceride levels >1770 mg/dL).⁴ Data on the prevalence of other variants of xanthoma are lacking.

Diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other conditions in the differential diagnosis can’t be ruled out or if the lesions do not resolve with treatment.

Eruptive xanthoma is characterized by an abrupt onset of crops of multiple yellowish to brownish papules that can coalesce into small plaques. The lesions can be generalized, but tend to be more densely distributed on the extensor surfaces of the arms and legs, buttocks, and thighs.⁵ Eruptive xanthoma often is associated with hypertriglyceridemia, which can be primary—as a result of a genetic defect caused by familial hypertriglyceridemia—or secondary, associated with poorly controlled diabetes mellitus, morbid obesity, excessive alcohol consumption, nephrotic syndrome, hypothyroidism, primary biliary cholangitis, and drugs like estrogen replacement therapies, corticosteroids, and isotretinoin.⁶ Pruritus and tenderness may or may not be present, and the Köbner phenomenon may occur.⁷

Continue to: The differential diagnosis

The differential diagnosis for eruptive xanthoma includes xanthoma disseminatum, non–Langerhans cell histiocytoses (eg, generalized eruptive histiocytosis), and cutaneous mastocytosis.¹

Xanthoma disseminatum is an extremely rare, but benign, disorder of non–Langerhans cell origin. The average age of onset is older than 40 years. The rash consists of multiple red-yellow papules and nodules that most commonly present in flexural areas. Forty percent to 60% of patients have mucosal involvement, and rarely the central nervous system is involved.⁸

Generalized eruptive histiocytosis is another rare non–Langerhans cell histiocytosis that occurs mainly in adults and is characterized by widespread, symmetric, red-brown papules on the trunk, arms, and legs, and rarely the mucous membranes.⁹

Cutaneous mastocytosis, especially xanthelasmoid mastocytosis, consists of multiple pruritic, yellowish, papular or nodular lesions that may mimic eruptive xanthoma. It occurs mainly in children and rarely in adults.¹⁰

Confirming the diagnosis, initiating treatment

The diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other differential diagnoses cannot be ruled out or the lesions do not resolve with treatment. Skin biopsy will reveal lipid-laden macrophages (known as foam cells) deposited in the dermis.⁷

Continue to: Treatment of eruptive xanthoma

Treatment of eruptive xanthoma involves management of the underlying causes of the condition. In most cases, dietary control, intensive triglyceride-lowering therapies, and treatment of other secondary causes of hypertriglyceridemia result in complete resolution of the lesions within several weeks.⁵

Our patient’s outcome

Our patient’s sudden-onset rash alerted us to the presence of type 2 diabetes mellitus, hypertriglyceridemia, and heavy proteinuria, which he was not aware of previously. We counselled him about stringent low-sugar, low-lipid diet control and exercise, and we started him on metformin and gemfibrozil. He was referred to an internal medicine specialist for further assessment and management of his severe hypertriglyceridemia and heavy proteinuria.

Eruptive xanthoma may be an indicator of severe hypertriglyceri- demia, which can be associated with an increased risk for acute pancreatitis.

The rash started to wane 1 month after the patient started the metformin and gemfibrozil, and his drug regimen was changed to combination therapy with metformin/glimepiride and fenofibrate/simvastatin 6 weeks later when he was seen in the medical specialty clinic. Fundus photography performed 1 month after starting oral antidiabetic therapy showed no diabetic retinopathy or lipemia retinalis.

After 3 months of treatment, his serum triglycerides and hemoglobin A1c levels dropped to 3.8 mmol/L and 8.7%, respectively. The rash also resolved considerably, with only residual papules on the abdomen. This rapid clinical response to treatment of the underlying hypertriglyceridemia and diabetes further supported the clinical diagnosis of eruptive xanthoma.

THE TAKEAWAY

Eruptive xanthoma is relatively rare, but it is important for family physicians to recognize this clinical presentation as a potential indicator of severe hypertriglyceridemia. Recognizing hypertriglyceridemia early is important, as it can be associated with an increased risk for acute pancreatitis. Moreover, eruptive xanthoma might be the sole presenting symptom of underlying diabetes mellitus or familial hyperlipidemia, both of which can lead to a significant increase in cardiovascular risk if uncontrolled.

CORRESPONDENCE
Chan Kam Sum, MBChB, FRACGP, Tseung Kwan O Jockey Club General Out-patient Clinic, 99 Po Lam Road North, G/F, Tseung Kwan O, Kowloon, Hong Kong; cks048@ha.org.hk

THE CASE

A 37-year-old man presented with a sudden-onset, nonpruritic, nonpainful, papular rash of 1 month’s duration on his trunk and both arms and legs. Two weeks prior to the current presentation, he consulted a general practitioner, who treated the rash with a course of unknown oral antibiotics; the patient showed no improvement. He recalled that on a few occasions, he used his fingers to express a creamy discharge from some of the lesions. This temporarily reduced the size of those papules.

His medical history was unremarkable except for morbid obesity. He did not drink alcohol regularly and was not taking any medications prior to the onset of the rash. He had no family history of hyperlipidemia, but his mother had a history of diabetes mellitus.

Physical examination showed numerous discrete erythematous papules with a creamy center on his trunk and his arms and legs. The lesions were more numerous on the extensor surfaces of the arms and legs. Some of the papules coalesced to form small plaques (FIGURE). There was no scaling, and the lesions were firm in texture. The patient’s face was spared, and there was no mucosal involvement. The patient was otherwise systemically well.

THE DIAGNOSIS

Based on the morphology, distribution, and abrupt onset of the diffuse nonpruritic papules in this morbidly obese (but otherwise systemically well) middle-aged man, a clinical diagnosis of eruptive xanthoma was suspected. Subsequent blood testing revealed an elevated serum triglyceride level of 47.8 mmol/L (reference range, <1.7 mmol/L), elevated serum total cholesterol of 7.1 mmol/L (reference range, <6.2 mmol/L), and low serum high-density lipoprotein cholesterol of 0.7 mmol/L (reference range, >1 mmol/L in men). He also had an elevated fasting serum glucose level of 12.9 mmol/L (reference range, 3.9–5.6 mmol/L) and an elevated hemoglobin A1c (glycated hemoglobin) level of 10.9%.

Subsequent thyroid, liver, and renal function tests were normal, but the patient had heavy proteinuria, with an elevated urine albumin-to-creatinine ratio of 355.6 mg/mmol (reference range, ≤2.5 mg/mmol). The patient was referred to a dermatologist, who confirmed the clinical diagnosis without the need for a skin biopsy.

DISCUSSION

Xanthomas are lipid deposits in the skin and subcutaneous tissues that arise in the setting of hyperlipidemia and are caused by underlying familial or acquired disorders. Xanthomas associated with dyslipidemias include eruptive xanthoma, tendinous xanthoma, xanthoma palpebrarum, and xanthoma tuberosum (TABLE).^1-3 Other non–dyslipidemia-related xanthomas include xanthoma planum, xanthoma disseminatum, linear palmar xanthomas, and verrucous xanthoma. One retrospective cohort study reported an 8.5% (8/95) prevalence of eruptive xanthomas in patients with severe hypertriglyceridemia (ie, triglyceride levels >1770 mg/dL).⁴ Data on the prevalence of other variants of xanthoma are lacking.

Diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other conditions in the differential diagnosis can’t be ruled out or if the lesions do not resolve with treatment.

Eruptive xanthoma is characterized by an abrupt onset of crops of multiple yellowish to brownish papules that can coalesce into small plaques. The lesions can be generalized, but tend to be more densely distributed on the extensor surfaces of the arms and legs, buttocks, and thighs.⁵ Eruptive xanthoma often is associated with hypertriglyceridemia, which can be primary—as a result of a genetic defect caused by familial hypertriglyceridemia—or secondary, associated with poorly controlled diabetes mellitus, morbid obesity, excessive alcohol consumption, nephrotic syndrome, hypothyroidism, primary biliary cholangitis, and drugs like estrogen replacement therapies, corticosteroids, and isotretinoin.⁶ Pruritus and tenderness may or may not be present, and the Köbner phenomenon may occur.⁷

Continue to: The differential diagnosis

The differential diagnosis for eruptive xanthoma includes xanthoma disseminatum, non–Langerhans cell histiocytoses (eg, generalized eruptive histiocytosis), and cutaneous mastocytosis.¹

Xanthoma disseminatum is an extremely rare, but benign, disorder of non–Langerhans cell origin. The average age of onset is older than 40 years. The rash consists of multiple red-yellow papules and nodules that most commonly present in flexural areas. Forty percent to 60% of patients have mucosal involvement, and rarely the central nervous system is involved.⁸

Generalized eruptive histiocytosis is another rare non–Langerhans cell histiocytosis that occurs mainly in adults and is characterized by widespread, symmetric, red-brown papules on the trunk, arms, and legs, and rarely the mucous membranes.⁹

Cutaneous mastocytosis, especially xanthelasmoid mastocytosis, consists of multiple pruritic, yellowish, papular or nodular lesions that may mimic eruptive xanthoma. It occurs mainly in children and rarely in adults.¹⁰

Confirming the diagnosis, initiating treatment

The diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other differential diagnoses cannot be ruled out or the lesions do not resolve with treatment. Skin biopsy will reveal lipid-laden macrophages (known as foam cells) deposited in the dermis.⁷

Continue to: Treatment of eruptive xanthoma

Treatment of eruptive xanthoma involves management of the underlying causes of the condition. In most cases, dietary control, intensive triglyceride-lowering therapies, and treatment of other secondary causes of hypertriglyceridemia result in complete resolution of the lesions within several weeks.⁵

Our patient’s outcome

Our patient’s sudden-onset rash alerted us to the presence of type 2 diabetes mellitus, hypertriglyceridemia, and heavy proteinuria, which he was not aware of previously. We counselled him about stringent low-sugar, low-lipid diet control and exercise, and we started him on metformin and gemfibrozil. He was referred to an internal medicine specialist for further assessment and management of his severe hypertriglyceridemia and heavy proteinuria.

Eruptive xanthoma may be an indicator of severe hypertriglyceri- demia, which can be associated with an increased risk for acute pancreatitis.

The rash started to wane 1 month after the patient started the metformin and gemfibrozil, and his drug regimen was changed to combination therapy with metformin/glimepiride and fenofibrate/simvastatin 6 weeks later when he was seen in the medical specialty clinic. Fundus photography performed 1 month after starting oral antidiabetic therapy showed no diabetic retinopathy or lipemia retinalis.

After 3 months of treatment, his serum triglycerides and hemoglobin A1c levels dropped to 3.8 mmol/L and 8.7%, respectively. The rash also resolved considerably, with only residual papules on the abdomen. This rapid clinical response to treatment of the underlying hypertriglyceridemia and diabetes further supported the clinical diagnosis of eruptive xanthoma.

THE TAKEAWAY

Eruptive xanthoma is relatively rare, but it is important for family physicians to recognize this clinical presentation as a potential indicator of severe hypertriglyceridemia. Recognizing hypertriglyceridemia early is important, as it can be associated with an increased risk for acute pancreatitis. Moreover, eruptive xanthoma might be the sole presenting symptom of underlying diabetes mellitus or familial hyperlipidemia, both of which can lead to a significant increase in cardiovascular risk if uncontrolled.

CORRESPONDENCE
Chan Kam Sum, MBChB, FRACGP, Tseung Kwan O Jockey Club General Out-patient Clinic, 99 Po Lam Road North, G/F, Tseung Kwan O, Kowloon, Hong Kong; cks048@ha.org.hk

ILLUSTRATIVE CASE

A 46-year-old woman presents with a body mass index (BMI) of 28 kg/m², a 4-year history of type 2 diabetes mellitus (T2DM), and a glycated hemoglobin (HgbA1c) of 9.8%. The patient is currently being treated with intensive medical therapy (IMT), including metformin 2000 mg/d, sitagliptin 100 mg/d, and insulin glargine 12 units/d, with minimal change in HgbA1c. Should you recommend bariatric surgery as an option for the treatment of diabetes?

One in 11 Americans has diabetes and at least 95% of those have type 2.^2,3 The treatment of T2DM is generally multimodal in order to target the various mechanisms that cause hyperglycemia. Treatment strategies may include lifestyle modifications, decreasing insulin resistance, increasing secretion of insulin, insulin replacement, and targeting incretin-hormonal pathways.

The American Diabetes Association (ADA) currently recommends diet, exercise, and behavioral modifications as first-line therapy for the management of diabetes,² but these by themselves are often inadequate. In addition to various pharmacotherapeutic strategies for other populations with T2DM (see the PURL, “How do these 3 diabetes agents compare in reducing mortality?”), the ADA recommends bariatric surgery for the treatment of patients with T2DM, a BMI ≥35 kg/m², and uncontrolled hyperglycemia.^2,4 However, this recommendation from the ADA supporting bariatric surgery is based only on short-term studies.

For example, one single-center nonblinded randomized controlled trial (RCT) involving 60 patients with a BMI ≥35 kg/m² found reductions in HgbA1C levels from the average baseline of 8.65±1.45% to 7.7±0.6% in the IMT group and to 6.4±1.4% in the gastric-bypass group at 2 years.⁵ In another study, a randomized double-blind trial involving 60 moderately obese patients (BMI, 25-35 kg/m²), gastric bypass had better outcomes than sleeve gastrectomy, with 93% of patients in the gastric bypass group achieving remission of T2DM vs 47% of patients in the sleeve gastrectomy group (P=.02) over a 12-month period.⁶

The current study sought to examine the long-term outcomes of IMT alone vs bariatric surgery with IMT for the treatment of T2DM in patients who are overweight or obese.¹

STUDY SUMMARY

5-year follow-up shows surgery + intensive medical therapy works

This study by Schauer et al was a 5-year follow-up of a nonblinded, single-center RCT comparing IMT alone to IMT with Roux-en-Y gastric bypass or sleeve gastrectomy in 150 patients with T2DM.¹ Patients were included if they were 20 to 60 years of age, had a BMI of 27 to 43 kg/m², and had an HgbA1C >7%. Patients with previous bariatric surgery, complex abdominal surgery, or uncontrolled medical or psychiatric disorders were excluded.

Each patient was randomly placed in a 1:1:1 fashion into 3 groups: IMT only, IMT and gastric bypass, or IMT and sleeve gastrectomy. All patients underwent IMT as defined by the ADA. The primary outcome was the number of patients with an HgbA1c ≤6%. Secondary outcomes included weight loss, glucose control, lipid levels, blood pressure, medication use, renal function, adverse effects, ophthalmologic outcomes, and quality of life.

Continue to: Of the 150 patients...

Of the 150 patients, 1 died during the follow-up period leaving 149; 134 completed the 5-year follow-up; 8 patients in the IMT group and 1 patient in the sleeve gastrectomy group never initiated assigned treatment; an additional 6 patients were lost to follow-up. One patient from the IMT group and 1 patient from the sleeve gastrectomy group crossed over to the gastric bypass group.

Results. More patients in the bariatric surgery and sleeve gastrectomy groups achieved an HgbA1c of ≤6% compared with the IMT group (14 of 49 gastric bypass patients vs 2 of 38 IMT patients; P=.01; 11 of 47 sleeve gastrectomy patients vs 2 of 38 IMT patients; P=.03). Compared with those in the IMT group, the patients in the bariatric surgery and sleeve gastrectomy groups showed greater reductions from baseline in body weight and triglyceride levels, and greater increases from baseline in high-density lipoprotein (HDL) cholesterol levels; they also required less diabetic medication for glycemic control (see TABLE 1¹). However, when data were imputed for the intention-to-treat analysis, P-values were P=0.08 for gastric bypass and P=0.17 for sleeve gastrectomy compared with the IMT group for lowering HgbA1c.

WHAT’S NEW?

Adding surgery has big benefits with minimal adverse effects

Prior studies that evaluated the effect of gastric bypass surgery on diabetes were observational or had a shorter follow-up duration. This study demonstrates bariatric surgery plus IMT has long-term benefits with minimal adverse events compared with IMT alone.^1,5 Additionally, this study supports recommendations for bariatric surgery as treatment for T2DM for patients with a BMI ≥27 kg/m², which is below the starting BMI (35 kg/m²) recommended by the ADA.^1,4

CAVEATS

Surgery is not without risks

The risk for surgical complications, such as gastrointestinal bleeding, severe hypoglycemia requiring intervention, and ketoacidosis, in this patient population is significant.¹ Complications can include gastrointestinal leak, stroke, and infection.¹ Additionally, long-term complications from bariatric surgery are emerging and include choledocholithiasis, intestinal obstruction, and esophageal pathology.⁷ Extensive patient counseling regarding the possible complications is necessary to ensure that patients make an informed decision regarding surgery.

This study supports recommedations for bariatric surgery as treatment for T2DM for patients with a body mass index ≥27 kg/m², which is below the starting BMI recommended by the ADA.

This study utilized surrogate markers (A1c, lipid levels, and body weight) as disease-oriented outcome measures. Patient-oriented outcomes, such as morbidity and mortality, were not explored in this study.

Continue to: Due to the small sample size of the study...

Due to the small sample size of the study, it is unclear if the outcomes of the 2 surgery groups were significantly different. Patients who received gastric bypass surgery had more weight loss and used less diabetes medication at the end of follow-up compared with the patients who received sleeve gastrectomy. More information is needed to determine which gastric surgery is preferable for the treatment of T2DM while minimizing adverse effects. However, both of the procedures had outcomes superior to that with IMT, and selection of a particular type of surgery should be a joint decision between the patient and provider.

CHALLENGES TO IMPLEMENTATION

Access and cost may be barriers

The major barriers to implementation are access to, and the cost of, bariatric surgery.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 46-year-old woman presents with a body mass index (BMI) of 28 kg/m², a 4-year history of type 2 diabetes mellitus (T2DM), and a glycated hemoglobin (HgbA1c) of 9.8%. The patient is currently being treated with intensive medical therapy (IMT), including metformin 2000 mg/d, sitagliptin 100 mg/d, and insulin glargine 12 units/d, with minimal change in HgbA1c. Should you recommend bariatric surgery as an option for the treatment of diabetes?

One in 11 Americans has diabetes and at least 95% of those have type 2.^2,3 The treatment of T2DM is generally multimodal in order to target the various mechanisms that cause hyperglycemia. Treatment strategies may include lifestyle modifications, decreasing insulin resistance, increasing secretion of insulin, insulin replacement, and targeting incretin-hormonal pathways.

The American Diabetes Association (ADA) currently recommends diet, exercise, and behavioral modifications as first-line therapy for the management of diabetes,² but these by themselves are often inadequate. In addition to various pharmacotherapeutic strategies for other populations with T2DM (see the PURL, “How do these 3 diabetes agents compare in reducing mortality?”), the ADA recommends bariatric surgery for the treatment of patients with T2DM, a BMI ≥35 kg/m², and uncontrolled hyperglycemia.^2,4 However, this recommendation from the ADA supporting bariatric surgery is based only on short-term studies.

For example, one single-center nonblinded randomized controlled trial (RCT) involving 60 patients with a BMI ≥35 kg/m² found reductions in HgbA1C levels from the average baseline of 8.65±1.45% to 7.7±0.6% in the IMT group and to 6.4±1.4% in the gastric-bypass group at 2 years.⁵ In another study, a randomized double-blind trial involving 60 moderately obese patients (BMI, 25-35 kg/m²), gastric bypass had better outcomes than sleeve gastrectomy, with 93% of patients in the gastric bypass group achieving remission of T2DM vs 47% of patients in the sleeve gastrectomy group (P=.02) over a 12-month period.⁶

The current study sought to examine the long-term outcomes of IMT alone vs bariatric surgery with IMT for the treatment of T2DM in patients who are overweight or obese.¹

STUDY SUMMARY

5-year follow-up shows surgery + intensive medical therapy works

This study by Schauer et al was a 5-year follow-up of a nonblinded, single-center RCT comparing IMT alone to IMT with Roux-en-Y gastric bypass or sleeve gastrectomy in 150 patients with T2DM.¹ Patients were included if they were 20 to 60 years of age, had a BMI of 27 to 43 kg/m², and had an HgbA1C >7%. Patients with previous bariatric surgery, complex abdominal surgery, or uncontrolled medical or psychiatric disorders were excluded.

Each patient was randomly placed in a 1:1:1 fashion into 3 groups: IMT only, IMT and gastric bypass, or IMT and sleeve gastrectomy. All patients underwent IMT as defined by the ADA. The primary outcome was the number of patients with an HgbA1c ≤6%. Secondary outcomes included weight loss, glucose control, lipid levels, blood pressure, medication use, renal function, adverse effects, ophthalmologic outcomes, and quality of life.

Continue to: Of the 150 patients...

Of the 150 patients, 1 died during the follow-up period leaving 149; 134 completed the 5-year follow-up; 8 patients in the IMT group and 1 patient in the sleeve gastrectomy group never initiated assigned treatment; an additional 6 patients were lost to follow-up. One patient from the IMT group and 1 patient from the sleeve gastrectomy group crossed over to the gastric bypass group.

Results. More patients in the bariatric surgery and sleeve gastrectomy groups achieved an HgbA1c of ≤6% compared with the IMT group (14 of 49 gastric bypass patients vs 2 of 38 IMT patients; P=.01; 11 of 47 sleeve gastrectomy patients vs 2 of 38 IMT patients; P=.03). Compared with those in the IMT group, the patients in the bariatric surgery and sleeve gastrectomy groups showed greater reductions from baseline in body weight and triglyceride levels, and greater increases from baseline in high-density lipoprotein (HDL) cholesterol levels; they also required less diabetic medication for glycemic control (see TABLE 1¹). However, when data were imputed for the intention-to-treat analysis, P-values were P=0.08 for gastric bypass and P=0.17 for sleeve gastrectomy compared with the IMT group for lowering HgbA1c.

WHAT’S NEW?

Adding surgery has big benefits with minimal adverse effects

Prior studies that evaluated the effect of gastric bypass surgery on diabetes were observational or had a shorter follow-up duration. This study demonstrates bariatric surgery plus IMT has long-term benefits with minimal adverse events compared with IMT alone.^1,5 Additionally, this study supports recommendations for bariatric surgery as treatment for T2DM for patients with a BMI ≥27 kg/m², which is below the starting BMI (35 kg/m²) recommended by the ADA.^1,4

CAVEATS

Surgery is not without risks

The risk for surgical complications, such as gastrointestinal bleeding, severe hypoglycemia requiring intervention, and ketoacidosis, in this patient population is significant.¹ Complications can include gastrointestinal leak, stroke, and infection.¹ Additionally, long-term complications from bariatric surgery are emerging and include choledocholithiasis, intestinal obstruction, and esophageal pathology.⁷ Extensive patient counseling regarding the possible complications is necessary to ensure that patients make an informed decision regarding surgery.

This study supports recommedations for bariatric surgery as treatment for T2DM for patients with a body mass index ≥27 kg/m², which is below the starting BMI recommended by the ADA.

This study utilized surrogate markers (A1c, lipid levels, and body weight) as disease-oriented outcome measures. Patient-oriented outcomes, such as morbidity and mortality, were not explored in this study.

Continue to: Due to the small sample size of the study...

Due to the small sample size of the study, it is unclear if the outcomes of the 2 surgery groups were significantly different. Patients who received gastric bypass surgery had more weight loss and used less diabetes medication at the end of follow-up compared with the patients who received sleeve gastrectomy. More information is needed to determine which gastric surgery is preferable for the treatment of T2DM while minimizing adverse effects. However, both of the procedures had outcomes superior to that with IMT, and selection of a particular type of surgery should be a joint decision between the patient and provider.

CHALLENGES TO IMPLEMENTATION

Access and cost may be barriers

The major barriers to implementation are access to, and the cost of, bariatric surgery.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 46-year-old woman presents with a body mass index (BMI) of 28 kg/m², a 4-year history of type 2 diabetes mellitus (T2DM), and a glycated hemoglobin (HgbA1c) of 9.8%. The patient is currently being treated with intensive medical therapy (IMT), including metformin 2000 mg/d, sitagliptin 100 mg/d, and insulin glargine 12 units/d, with minimal change in HgbA1c. Should you recommend bariatric surgery as an option for the treatment of diabetes?

One in 11 Americans has diabetes and at least 95% of those have type 2.^2,3 The treatment of T2DM is generally multimodal in order to target the various mechanisms that cause hyperglycemia. Treatment strategies may include lifestyle modifications, decreasing insulin resistance, increasing secretion of insulin, insulin replacement, and targeting incretin-hormonal pathways.

The American Diabetes Association (ADA) currently recommends diet, exercise, and behavioral modifications as first-line therapy for the management of diabetes,² but these by themselves are often inadequate. In addition to various pharmacotherapeutic strategies for other populations with T2DM (see the PURL, “How do these 3 diabetes agents compare in reducing mortality?”), the ADA recommends bariatric surgery for the treatment of patients with T2DM, a BMI ≥35 kg/m², and uncontrolled hyperglycemia.^2,4 However, this recommendation from the ADA supporting bariatric surgery is based only on short-term studies.

For example, one single-center nonblinded randomized controlled trial (RCT) involving 60 patients with a BMI ≥35 kg/m² found reductions in HgbA1C levels from the average baseline of 8.65±1.45% to 7.7±0.6% in the IMT group and to 6.4±1.4% in the gastric-bypass group at 2 years.⁵ In another study, a randomized double-blind trial involving 60 moderately obese patients (BMI, 25-35 kg/m²), gastric bypass had better outcomes than sleeve gastrectomy, with 93% of patients in the gastric bypass group achieving remission of T2DM vs 47% of patients in the sleeve gastrectomy group (P=.02) over a 12-month period.⁶

The current study sought to examine the long-term outcomes of IMT alone vs bariatric surgery with IMT for the treatment of T2DM in patients who are overweight or obese.¹

STUDY SUMMARY

5-year follow-up shows surgery + intensive medical therapy works

This study by Schauer et al was a 5-year follow-up of a nonblinded, single-center RCT comparing IMT alone to IMT with Roux-en-Y gastric bypass or sleeve gastrectomy in 150 patients with T2DM.¹ Patients were included if they were 20 to 60 years of age, had a BMI of 27 to 43 kg/m², and had an HgbA1C >7%. Patients with previous bariatric surgery, complex abdominal surgery, or uncontrolled medical or psychiatric disorders were excluded.

Each patient was randomly placed in a 1:1:1 fashion into 3 groups: IMT only, IMT and gastric bypass, or IMT and sleeve gastrectomy. All patients underwent IMT as defined by the ADA. The primary outcome was the number of patients with an HgbA1c ≤6%. Secondary outcomes included weight loss, glucose control, lipid levels, blood pressure, medication use, renal function, adverse effects, ophthalmologic outcomes, and quality of life.

Continue to: Of the 150 patients...

Of the 150 patients, 1 died during the follow-up period leaving 149; 134 completed the 5-year follow-up; 8 patients in the IMT group and 1 patient in the sleeve gastrectomy group never initiated assigned treatment; an additional 6 patients were lost to follow-up. One patient from the IMT group and 1 patient from the sleeve gastrectomy group crossed over to the gastric bypass group.

Results. More patients in the bariatric surgery and sleeve gastrectomy groups achieved an HgbA1c of ≤6% compared with the IMT group (14 of 49 gastric bypass patients vs 2 of 38 IMT patients; P=.01; 11 of 47 sleeve gastrectomy patients vs 2 of 38 IMT patients; P=.03). Compared with those in the IMT group, the patients in the bariatric surgery and sleeve gastrectomy groups showed greater reductions from baseline in body weight and triglyceride levels, and greater increases from baseline in high-density lipoprotein (HDL) cholesterol levels; they also required less diabetic medication for glycemic control (see TABLE 1¹). However, when data were imputed for the intention-to-treat analysis, P-values were P=0.08 for gastric bypass and P=0.17 for sleeve gastrectomy compared with the IMT group for lowering HgbA1c.

WHAT’S NEW?

Adding surgery has big benefits with minimal adverse effects

Prior studies that evaluated the effect of gastric bypass surgery on diabetes were observational or had a shorter follow-up duration. This study demonstrates bariatric surgery plus IMT has long-term benefits with minimal adverse events compared with IMT alone.^1,5 Additionally, this study supports recommendations for bariatric surgery as treatment for T2DM for patients with a BMI ≥27 kg/m², which is below the starting BMI (35 kg/m²) recommended by the ADA.^1,4

CAVEATS

Surgery is not without risks

The risk for surgical complications, such as gastrointestinal bleeding, severe hypoglycemia requiring intervention, and ketoacidosis, in this patient population is significant.¹ Complications can include gastrointestinal leak, stroke, and infection.¹ Additionally, long-term complications from bariatric surgery are emerging and include choledocholithiasis, intestinal obstruction, and esophageal pathology.⁷ Extensive patient counseling regarding the possible complications is necessary to ensure that patients make an informed decision regarding surgery.

This study supports recommedations for bariatric surgery as treatment for T2DM for patients with a body mass index ≥27 kg/m², which is below the starting BMI recommended by the ADA.

This study utilized surrogate markers (A1c, lipid levels, and body weight) as disease-oriented outcome measures. Patient-oriented outcomes, such as morbidity and mortality, were not explored in this study.

Continue to: Due to the small sample size of the study...

Due to the small sample size of the study, it is unclear if the outcomes of the 2 surgery groups were significantly different. Patients who received gastric bypass surgery had more weight loss and used less diabetes medication at the end of follow-up compared with the patients who received sleeve gastrectomy. More information is needed to determine which gastric surgery is preferable for the treatment of T2DM while minimizing adverse effects. However, both of the procedures had outcomes superior to that with IMT, and selection of a particular type of surgery should be a joint decision between the patient and provider.

CHALLENGES TO IMPLEMENTATION

Access and cost may be barriers

The major barriers to implementation are access to, and the cost of, bariatric surgery.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 64-year-old man with taype 2 diabetes mellitus (T2DM) presents for a follow-up visit. His point-of-care hemoglobin A1c is 9.5%, and he is currently taking only metformin 1000 mg bid. You are considering adding an SGLT-2 inhibitor, a GLP-1 agonist, or a dipeptidyl peptidase 4 (DPP-4) inhibitor to his treatment regimen. Which do you choose to better control his diabetes and reduce his all-cause and cardiovascular (CV) mortality risk?

Over the past several years, the number of patients with T2DM has continued to climb. In the United States, approximately 30 million people, or 1 of every 11, now struggles to reduce their blood sugar.² As prevalence of the disease has increased, so has the number of medications available that are aimed at lowering blood sugar and improving diabetes control.² In particular, the introduction of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors over the past several years has produced an area of some clinical ambiguity, due to the lack of randomized controlled trials (RCTs) comparing their efficacy.

The “American Diabetes Association Standards of Medical Care in Diabetes” points specifically to the potential roles of the SGLT-2 inhibitors empagliflozin and canagliflozin, and the GLP-1 agonist liraglutide, as agents that should be added to metformin and lifestyle modification in patients with established atherosclerotic CV disease. They cite data indicating that these drugs reduce major adverse CV events and CV mortality in this population.³ Deciding among these 3 medications, however, is left to providers and patients. For dual therapy in patients with T2DM without CV disease who remain hyperglycemic despite metformin and lifestyle modifications, SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors are recommended equally, with the choice among them to be determined by “consideration of drug-specific effects and patient factors.”³

The National Institute for Health and Care Excellence (NICE) guidelines on T2DM management list both SGLT-2 inhibitors and DPP-4 inhibitors among the potential options for intensifying therapy after metformin.⁴ The American Association of Clinical Endocrinologists and the American College of Endocrinology guidelines do include a hierarchical recommendation to try a GLP-1 agonist first, followed by an SGLT-2 inhibitor, followed by a DPP-4 inhibitor, after metformin and lifestyle modifications—although the difference in strength of recommendations for these classes is noted to be small.⁵

STUDY SUMMARY

SGLT-2s, GLP-1s are associated with better mortality outcomes than DPP-4s

Zheng and colleagues performed a network meta-analysis of 236 RCTs involving 176,310 patients to compare the clinical efficacy of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to reduce all-cause mortality and CV endpoints in patients with T2DM. The authors analyzed English-language RCTs that followed patients with T2DM for at least 12 weeks and compared SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to one another, to placebo, or to no treatment.

When compared to placebo or no treatment, the use of SGLT-2 inhibitors or GLP-1 agonists is associated with lower all- cause mortality and lower CV mortality than is the use of DPP-4 inhibitors.

A majority of the patients in both the intervention and control groups were taking additional diabetes medications, such as metformin, prior to enrollment and during the trials. About half of the patients analyzed were enrolled in trials that specifically evaluated patients at elevated CV risk, which is notable because patients with higher CV risk ultimately derived the most benefit from the treatments studied.

The primary outcome was all-cause mortality. Secondary outcomes were CV mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke, as well as the safety outcomes of hypoglycemia and adverse events (any events, serious events, and those leading to study withdrawal).

Continue to: Results

Results. Compared with the patients in the control groups (placebo or no treatment), patients in both the SGLT-2 inhibitor and GLP-1 agonist groups had decreased all-cause mortality (SGLT-2 inhibitor group, hazard ratio [HR]=0.80; 95% credible interval [CrI], 0.71-0.89; absolute risk difference [RD]= –1%; number needed to treat [NNT]=100; GLP-1 agonist group, HR=0.88; 95% CrI, 0.81-0.94; absolute RD= -0.6%; NNT=167). Patients in the DPP-4 inhibitor group did not have a difference in mortality compared with the control groups (HR=1.02; 95% CrI, 0.94-1.11; absolute RD=0.1%). Both the SGLT-2 inhibitor (HR=0.78; 95% CrI, 0.68-0.90; absolute RD= –0.9%; NNT=111) and GLP-1 agonist (HR=0.86; 95% CrI, 0.77-0.96; absolute RD= –0.5%; NNT=200) groups had reduced all-cause mortality when compared with the DPP-4 inhibitor group.

CV endpoints. Similarly, the SGLT-2 inhibitor (HR=0.79; 95% Crl, 0.69-0.91; absolute RD= –0.8%; NNT=125) and GLP-1 agonist (HR=0.85; Crl, 95% 0.77-0.94; absolute RD= –0.5%; NNT=200) groups had a reduction in CV mortality compared with the control groups, while those in the DPP-4 inhibitor group experienced no effect. Additionally, those taking SGLT-2 inhibitors had lower rates of HF events (HR=0.62; 95% CrI, 0.54-0.72; absolute RD= –1.1%; NNT=91) and MIs (HR=0.86; 95% CrI, 0.77–0.97; absolute RD= –0.6%; NNT=167) than those in the control groups. They also had lower rates of HF than those taking GLP-1 agonists (HR=0.67; 95% CrI, 0.57 to 0.80; absolute RD= –0.9; NNT=111) or DPP-4 inhibitors (HR=0.55; 95% CrI, 0.46-0.67; absolute RD= –1.1%; NNT=91). Neither the GLP-1 agonist groups nor the DPP-4 inhibitor groups saw lower rates of HF or MI than the control groups.

Adverse effects. DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors were all associated with a small increased risk for hypoglycemia compared with the control groups, but there were no significant differences between drug classes. All agents resulted in an increased risk for adverse events leading to trial withdrawal compared with the control groups (GPL-1 agonists, HR=2; 95% CrI, 1.70-2.37; absolute RD=4.7%; number needed to harm [NNH]=21; SGLT-2 inhibitors, HR=1.8; 95% CrI, 1.44-2.25; absolute RD=5.8%; NNH=17; and DPP-4 inhibitors, HR=1.93; 95% CrI, 1.59-2.35; absolute RD=3.1%; NNH=32).

When compared with the control groups, the SGLT-2 inhibitor group was associated with an increased risk for genital infection (relative risk [RR]=4.19; 95% confidence interval [CI], 3.45-5.09; absolute RD=6%; NNH=16), but not of urinary tract infection or lower limb amputation, although the authors noted high heterogeneity among studies with regard to the limb amputation outcome. DPP-4 inhibitors were associated with an increased risk for acute pancreatitis (RR=1.58; 95% CI, 1.04-2.39; absolute RD=0.1%; NNH=1000) compared with control groups.

WHAT’S NEW

SGLT-2s: Lower mortality, fewer heart failure events

This meta-analysis concludes that when compared with placebo or no treatment, the use of SGLT-2 inhibitors or GLP-1 agonists is associated with lower all-cause mortality and lower CV mortality than is the use of DPP-4 inhibitors. Additionally, SGLT-2 inhibitors are associated with lower rates of HF events than GLP-1 agonists or DPP-4 inhibitors.

Continue to: CAVEATS

A lack of head-to-head RCTs

This study was a network meta-analysis that included many trials, the majority of which compared SGLT-1 inhibitors, GLP-1 agonists, and DPP-4 inhibitors with controls rather than to one another. Thus, the findings are not derived from a robust base of head-to-head RCTs involving the 3 classes of medication.

For another diabetes-related PURL, see “Bariatric surgery + medical therapy: Effective Tx for T2DM?"

However, there was relatively low heterogeneity among the studies included (I2=12), which lends strength to the meta-analysis.⁶ Patients with the highest baseline CV risk likely gleaned the greatest benefits from these treatments and may have driven much of the observed mortality reduction. This may limit the generalizability of the results to people with low CV risk. The comparative effectiveness and risk for adverse effects among individual medications within each class is unknown because the analysis was completed by drug class in order to adequately power the study to detect treatment effects.

CHALLENGES TO IMPLEMENTATION

Cost, adverse effects, and formulation may represent challenges

The cost of SGLT-2 inhibitors and GLP-1 agonists may present challenges to patients wishing to use these options. Additionally, the increased risk for genital infections with SGLT-2 inhibitors, and of overall adverse effects (many of which were gastrointestinal) with GLP-1 agonists, must be considered. Lastly, the injectable formulation of GLP-1 agonists may present a barrier to patients’ ability and willingness to effectively administer these agents.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 64-year-old man with taype 2 diabetes mellitus (T2DM) presents for a follow-up visit. His point-of-care hemoglobin A1c is 9.5%, and he is currently taking only metformin 1000 mg bid. You are considering adding an SGLT-2 inhibitor, a GLP-1 agonist, or a dipeptidyl peptidase 4 (DPP-4) inhibitor to his treatment regimen. Which do you choose to better control his diabetes and reduce his all-cause and cardiovascular (CV) mortality risk?

Over the past several years, the number of patients with T2DM has continued to climb. In the United States, approximately 30 million people, or 1 of every 11, now struggles to reduce their blood sugar.² As prevalence of the disease has increased, so has the number of medications available that are aimed at lowering blood sugar and improving diabetes control.² In particular, the introduction of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors over the past several years has produced an area of some clinical ambiguity, due to the lack of randomized controlled trials (RCTs) comparing their efficacy.

The “American Diabetes Association Standards of Medical Care in Diabetes” points specifically to the potential roles of the SGLT-2 inhibitors empagliflozin and canagliflozin, and the GLP-1 agonist liraglutide, as agents that should be added to metformin and lifestyle modification in patients with established atherosclerotic CV disease. They cite data indicating that these drugs reduce major adverse CV events and CV mortality in this population.³ Deciding among these 3 medications, however, is left to providers and patients. For dual therapy in patients with T2DM without CV disease who remain hyperglycemic despite metformin and lifestyle modifications, SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors are recommended equally, with the choice among them to be determined by “consideration of drug-specific effects and patient factors.”³

The National Institute for Health and Care Excellence (NICE) guidelines on T2DM management list both SGLT-2 inhibitors and DPP-4 inhibitors among the potential options for intensifying therapy after metformin.⁴ The American Association of Clinical Endocrinologists and the American College of Endocrinology guidelines do include a hierarchical recommendation to try a GLP-1 agonist first, followed by an SGLT-2 inhibitor, followed by a DPP-4 inhibitor, after metformin and lifestyle modifications—although the difference in strength of recommendations for these classes is noted to be small.⁵

STUDY SUMMARY

SGLT-2s, GLP-1s are associated with better mortality outcomes than DPP-4s

Zheng and colleagues performed a network meta-analysis of 236 RCTs involving 176,310 patients to compare the clinical efficacy of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to reduce all-cause mortality and CV endpoints in patients with T2DM. The authors analyzed English-language RCTs that followed patients with T2DM for at least 12 weeks and compared SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to one another, to placebo, or to no treatment.

When compared to placebo or no treatment, the use of SGLT-2 inhibitors or GLP-1 agonists is associated with lower all- cause mortality and lower CV mortality than is the use of DPP-4 inhibitors.

A majority of the patients in both the intervention and control groups were taking additional diabetes medications, such as metformin, prior to enrollment and during the trials. About half of the patients analyzed were enrolled in trials that specifically evaluated patients at elevated CV risk, which is notable because patients with higher CV risk ultimately derived the most benefit from the treatments studied.

The primary outcome was all-cause mortality. Secondary outcomes were CV mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke, as well as the safety outcomes of hypoglycemia and adverse events (any events, serious events, and those leading to study withdrawal).

Continue to: Results

Results. Compared with the patients in the control groups (placebo or no treatment), patients in both the SGLT-2 inhibitor and GLP-1 agonist groups had decreased all-cause mortality (SGLT-2 inhibitor group, hazard ratio [HR]=0.80; 95% credible interval [CrI], 0.71-0.89; absolute risk difference [RD]= –1%; number needed to treat [NNT]=100; GLP-1 agonist group, HR=0.88; 95% CrI, 0.81-0.94; absolute RD= -0.6%; NNT=167). Patients in the DPP-4 inhibitor group did not have a difference in mortality compared with the control groups (HR=1.02; 95% CrI, 0.94-1.11; absolute RD=0.1%). Both the SGLT-2 inhibitor (HR=0.78; 95% CrI, 0.68-0.90; absolute RD= –0.9%; NNT=111) and GLP-1 agonist (HR=0.86; 95% CrI, 0.77-0.96; absolute RD= –0.5%; NNT=200) groups had reduced all-cause mortality when compared with the DPP-4 inhibitor group.

CV endpoints. Similarly, the SGLT-2 inhibitor (HR=0.79; 95% Crl, 0.69-0.91; absolute RD= –0.8%; NNT=125) and GLP-1 agonist (HR=0.85; Crl, 95% 0.77-0.94; absolute RD= –0.5%; NNT=200) groups had a reduction in CV mortality compared with the control groups, while those in the DPP-4 inhibitor group experienced no effect. Additionally, those taking SGLT-2 inhibitors had lower rates of HF events (HR=0.62; 95% CrI, 0.54-0.72; absolute RD= –1.1%; NNT=91) and MIs (HR=0.86; 95% CrI, 0.77–0.97; absolute RD= –0.6%; NNT=167) than those in the control groups. They also had lower rates of HF than those taking GLP-1 agonists (HR=0.67; 95% CrI, 0.57 to 0.80; absolute RD= –0.9; NNT=111) or DPP-4 inhibitors (HR=0.55; 95% CrI, 0.46-0.67; absolute RD= –1.1%; NNT=91). Neither the GLP-1 agonist groups nor the DPP-4 inhibitor groups saw lower rates of HF or MI than the control groups.

Adverse effects. DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors were all associated with a small increased risk for hypoglycemia compared with the control groups, but there were no significant differences between drug classes. All agents resulted in an increased risk for adverse events leading to trial withdrawal compared with the control groups (GPL-1 agonists, HR=2; 95% CrI, 1.70-2.37; absolute RD=4.7%; number needed to harm [NNH]=21; SGLT-2 inhibitors, HR=1.8; 95% CrI, 1.44-2.25; absolute RD=5.8%; NNH=17; and DPP-4 inhibitors, HR=1.93; 95% CrI, 1.59-2.35; absolute RD=3.1%; NNH=32).

When compared with the control groups, the SGLT-2 inhibitor group was associated with an increased risk for genital infection (relative risk [RR]=4.19; 95% confidence interval [CI], 3.45-5.09; absolute RD=6%; NNH=16), but not of urinary tract infection or lower limb amputation, although the authors noted high heterogeneity among studies with regard to the limb amputation outcome. DPP-4 inhibitors were associated with an increased risk for acute pancreatitis (RR=1.58; 95% CI, 1.04-2.39; absolute RD=0.1%; NNH=1000) compared with control groups.

WHAT’S NEW

SGLT-2s: Lower mortality, fewer heart failure events

This meta-analysis concludes that when compared with placebo or no treatment, the use of SGLT-2 inhibitors or GLP-1 agonists is associated with lower all-cause mortality and lower CV mortality than is the use of DPP-4 inhibitors. Additionally, SGLT-2 inhibitors are associated with lower rates of HF events than GLP-1 agonists or DPP-4 inhibitors.

Continue to: CAVEATS

A lack of head-to-head RCTs

This study was a network meta-analysis that included many trials, the majority of which compared SGLT-1 inhibitors, GLP-1 agonists, and DPP-4 inhibitors with controls rather than to one another. Thus, the findings are not derived from a robust base of head-to-head RCTs involving the 3 classes of medication.

For another diabetes-related PURL, see “Bariatric surgery + medical therapy: Effective Tx for T2DM?"

However, there was relatively low heterogeneity among the studies included (I2=12), which lends strength to the meta-analysis.⁶ Patients with the highest baseline CV risk likely gleaned the greatest benefits from these treatments and may have driven much of the observed mortality reduction. This may limit the generalizability of the results to people with low CV risk. The comparative effectiveness and risk for adverse effects among individual medications within each class is unknown because the analysis was completed by drug class in order to adequately power the study to detect treatment effects.

CHALLENGES TO IMPLEMENTATION

Cost, adverse effects, and formulation may represent challenges

The cost of SGLT-2 inhibitors and GLP-1 agonists may present challenges to patients wishing to use these options. Additionally, the increased risk for genital infections with SGLT-2 inhibitors, and of overall adverse effects (many of which were gastrointestinal) with GLP-1 agonists, must be considered. Lastly, the injectable formulation of GLP-1 agonists may present a barrier to patients’ ability and willingness to effectively administer these agents.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 64-year-old man with taype 2 diabetes mellitus (T2DM) presents for a follow-up visit. His point-of-care hemoglobin A1c is 9.5%, and he is currently taking only metformin 1000 mg bid. You are considering adding an SGLT-2 inhibitor, a GLP-1 agonist, or a dipeptidyl peptidase 4 (DPP-4) inhibitor to his treatment regimen. Which do you choose to better control his diabetes and reduce his all-cause and cardiovascular (CV) mortality risk?

Over the past several years, the number of patients with T2DM has continued to climb. In the United States, approximately 30 million people, or 1 of every 11, now struggles to reduce their blood sugar.² As prevalence of the disease has increased, so has the number of medications available that are aimed at lowering blood sugar and improving diabetes control.² In particular, the introduction of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors over the past several years has produced an area of some clinical ambiguity, due to the lack of randomized controlled trials (RCTs) comparing their efficacy.

The “American Diabetes Association Standards of Medical Care in Diabetes” points specifically to the potential roles of the SGLT-2 inhibitors empagliflozin and canagliflozin, and the GLP-1 agonist liraglutide, as agents that should be added to metformin and lifestyle modification in patients with established atherosclerotic CV disease. They cite data indicating that these drugs reduce major adverse CV events and CV mortality in this population.³ Deciding among these 3 medications, however, is left to providers and patients. For dual therapy in patients with T2DM without CV disease who remain hyperglycemic despite metformin and lifestyle modifications, SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors are recommended equally, with the choice among them to be determined by “consideration of drug-specific effects and patient factors.”³

The National Institute for Health and Care Excellence (NICE) guidelines on T2DM management list both SGLT-2 inhibitors and DPP-4 inhibitors among the potential options for intensifying therapy after metformin.⁴ The American Association of Clinical Endocrinologists and the American College of Endocrinology guidelines do include a hierarchical recommendation to try a GLP-1 agonist first, followed by an SGLT-2 inhibitor, followed by a DPP-4 inhibitor, after metformin and lifestyle modifications—although the difference in strength of recommendations for these classes is noted to be small.⁵

STUDY SUMMARY

SGLT-2s, GLP-1s are associated with better mortality outcomes than DPP-4s

Zheng and colleagues performed a network meta-analysis of 236 RCTs involving 176,310 patients to compare the clinical efficacy of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to reduce all-cause mortality and CV endpoints in patients with T2DM. The authors analyzed English-language RCTs that followed patients with T2DM for at least 12 weeks and compared SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors to one another, to placebo, or to no treatment.

When compared to placebo or no treatment, the use of SGLT-2 inhibitors or GLP-1 agonists is associated with lower all- cause mortality and lower CV mortality than is the use of DPP-4 inhibitors.

A majority of the patients in both the intervention and control groups were taking additional diabetes medications, such as metformin, prior to enrollment and during the trials. About half of the patients analyzed were enrolled in trials that specifically evaluated patients at elevated CV risk, which is notable because patients with higher CV risk ultimately derived the most benefit from the treatments studied.

The primary outcome was all-cause mortality. Secondary outcomes were CV mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke, as well as the safety outcomes of hypoglycemia and adverse events (any events, serious events, and those leading to study withdrawal).

Continue to: Results

Results. Compared with the patients in the control groups (placebo or no treatment), patients in both the SGLT-2 inhibitor and GLP-1 agonist groups had decreased all-cause mortality (SGLT-2 inhibitor group, hazard ratio [HR]=0.80; 95% credible interval [CrI], 0.71-0.89; absolute risk difference [RD]= –1%; number needed to treat [NNT]=100; GLP-1 agonist group, HR=0.88; 95% CrI, 0.81-0.94; absolute RD= -0.6%; NNT=167). Patients in the DPP-4 inhibitor group did not have a difference in mortality compared with the control groups (HR=1.02; 95% CrI, 0.94-1.11; absolute RD=0.1%). Both the SGLT-2 inhibitor (HR=0.78; 95% CrI, 0.68-0.90; absolute RD= –0.9%; NNT=111) and GLP-1 agonist (HR=0.86; 95% CrI, 0.77-0.96; absolute RD= –0.5%; NNT=200) groups had reduced all-cause mortality when compared with the DPP-4 inhibitor group.

CV endpoints. Similarly, the SGLT-2 inhibitor (HR=0.79; 95% Crl, 0.69-0.91; absolute RD= –0.8%; NNT=125) and GLP-1 agonist (HR=0.85; Crl, 95% 0.77-0.94; absolute RD= –0.5%; NNT=200) groups had a reduction in CV mortality compared with the control groups, while those in the DPP-4 inhibitor group experienced no effect. Additionally, those taking SGLT-2 inhibitors had lower rates of HF events (HR=0.62; 95% CrI, 0.54-0.72; absolute RD= –1.1%; NNT=91) and MIs (HR=0.86; 95% CrI, 0.77–0.97; absolute RD= –0.6%; NNT=167) than those in the control groups. They also had lower rates of HF than those taking GLP-1 agonists (HR=0.67; 95% CrI, 0.57 to 0.80; absolute RD= –0.9; NNT=111) or DPP-4 inhibitors (HR=0.55; 95% CrI, 0.46-0.67; absolute RD= –1.1%; NNT=91). Neither the GLP-1 agonist groups nor the DPP-4 inhibitor groups saw lower rates of HF or MI than the control groups.

Adverse effects. DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors were all associated with a small increased risk for hypoglycemia compared with the control groups, but there were no significant differences between drug classes. All agents resulted in an increased risk for adverse events leading to trial withdrawal compared with the control groups (GPL-1 agonists, HR=2; 95% CrI, 1.70-2.37; absolute RD=4.7%; number needed to harm [NNH]=21; SGLT-2 inhibitors, HR=1.8; 95% CrI, 1.44-2.25; absolute RD=5.8%; NNH=17; and DPP-4 inhibitors, HR=1.93; 95% CrI, 1.59-2.35; absolute RD=3.1%; NNH=32).

When compared with the control groups, the SGLT-2 inhibitor group was associated with an increased risk for genital infection (relative risk [RR]=4.19; 95% confidence interval [CI], 3.45-5.09; absolute RD=6%; NNH=16), but not of urinary tract infection or lower limb amputation, although the authors noted high heterogeneity among studies with regard to the limb amputation outcome. DPP-4 inhibitors were associated with an increased risk for acute pancreatitis (RR=1.58; 95% CI, 1.04-2.39; absolute RD=0.1%; NNH=1000) compared with control groups.

WHAT’S NEW

SGLT-2s: Lower mortality, fewer heart failure events

This meta-analysis concludes that when compared with placebo or no treatment, the use of SGLT-2 inhibitors or GLP-1 agonists is associated with lower all-cause mortality and lower CV mortality than is the use of DPP-4 inhibitors. Additionally, SGLT-2 inhibitors are associated with lower rates of HF events than GLP-1 agonists or DPP-4 inhibitors.

Continue to: CAVEATS

A lack of head-to-head RCTs

This study was a network meta-analysis that included many trials, the majority of which compared SGLT-1 inhibitors, GLP-1 agonists, and DPP-4 inhibitors with controls rather than to one another. Thus, the findings are not derived from a robust base of head-to-head RCTs involving the 3 classes of medication.

For another diabetes-related PURL, see “Bariatric surgery + medical therapy: Effective Tx for T2DM?"

However, there was relatively low heterogeneity among the studies included (I2=12), which lends strength to the meta-analysis.⁶ Patients with the highest baseline CV risk likely gleaned the greatest benefits from these treatments and may have driven much of the observed mortality reduction. This may limit the generalizability of the results to people with low CV risk. The comparative effectiveness and risk for adverse effects among individual medications within each class is unknown because the analysis was completed by drug class in order to adequately power the study to detect treatment effects.

CHALLENGES TO IMPLEMENTATION

Cost, adverse effects, and formulation may represent challenges

The cost of SGLT-2 inhibitors and GLP-1 agonists may present challenges to patients wishing to use these options. Additionally, the increased risk for genital infections with SGLT-2 inhibitors, and of overall adverse effects (many of which were gastrointestinal) with GLP-1 agonists, must be considered. Lastly, the injectable formulation of GLP-1 agonists may present a barrier to patients’ ability and willingness to effectively administer these agents.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

One of the most important commitments family physicians can undertake in protecting the health of their patients and communities is to ensure that their patients are fully vaccinated. This task is increasingly complicated as new vaccines are approved every year and recommendations change regarding new and established vaccines. To assist primary care providers, the Centers for Disease Control and Prevention (CDC) annually updates 2 immunization schedules—one for children and adolescents, and one for adults. These schedules are available on the CDC Web site (https://www.cdc.gov/vaccines/schedules/index.html).

These updates originate from the Advisory Committee on Immunization Practices (ACIP), which meets 3 times a year to consider and adopt changes to the schedules. During 2018, relatively few new recommendations were adopted. The September 2018 Practice Alert¹ in this journal covered the updated recommendations for influenza immunization, which included reinstating live attenuated influenza vaccine (LAIV) to the active list of influenza vaccines.

This current Practice Alert reviews 3 additional updates: 1) a new hepatitis B (HepB) vaccine; 2) updated recommendations for the use of hepatitis A (HepA) vaccine for post-exposure prevention and before travel; and 3) inclusion of the homeless among those who should be routinely vaccinated with HepA vaccine.

Hepatitis B: New 2-dose product

As of 2015, the annual incidence of new hepatitis B cases had declined by 88.5% since the first HepB vaccine was licensed in 1981 and recommendations for its routine use were issued in 1982.² The HepB vaccine products available in the United States are 2 single-antigen products, Engerix-B (GlaxoSmithKline) and Recombivax HB (Merck & Co.). Both can be used in all age groups, starting at birth, in a 3-dose series. HepB vaccine is also available in 2 combination products: Pediarix, containing HepB, diphtheria and tetanus toxoids, acellular pertussis, and inactivated poliovirus (GlaxoSmithKline), approved for use in children 6 weeks to 6 years old; and Twinrix (GlaxoSmithKline), which contains both HepB and HepA and is approved for use in adults 18 years and older.

The HepB vaccine is recommended for all children and unvaccinated adolescents as part of the routine vaccination schedule. It is also recommended for unvaccinated adults with specific risks (TABLE 1²). However, the rate of HepB vaccination in adults for whom it is recommended is suboptimal (FIGURE),³ and just a little more than half of adults who start a 3-dose series of HepB complete it.⁴A new vaccine against hepatitis B, HEPLISAV-B (Dynavax Technologies), was licensed by the US Food and Drug Administration in late 2017. ACIP now recommends it as an option along with other available HepB products. HEPLISAV-B is given in 2 doses separated by 1 month. It is hoped that this shortened 2-dose series will increase the number of adults who achieve full vaccination. In addition, it appears that HEPLISAV-B provides higher levels of protection in some high-risk groups—those with type 2 diabetes or chronic kidney disease.³ However, initial safety studies have shown a small absolute increase in cardiac events after vaccination with HEPLISAV-B. Post-marketing surveillance will be needed to show whether this is causal or coincidental.³

If a HepB series must be completed with different products, just be sure 3 doses are given—even if HEPLISAV-B is one of the agents.

As with other HepB products, use of HEPLISAV-B should follow the latest CDC directives on who to test serologically for prior immunity, and on post-vaccination testing to ensure protective antibody levels were achieved.² It is best to complete a HepB series with the same product, but, if necessary, a combination of products at different doses can be used to complete the HepB series. Any such combination should include 3 doses, even if one of the doses is HEPLISAV-B.

Hepatitis A: Vaccination assumes greater importance for more people

A Practice Alert in early 2018 described a series of outbreaks of hepatitis A around the country and the high rates of associated hospitalizations.⁵ These outbreaks have occurred primarily among the homeless and their contacts and those who use illicit drugs. This nationwide outbreak has now spread, resulting in more than 7500 cases since July 1, 2016.⁶ The progress of this epidemic can be viewed on the CDC Web site (https://www.cdc.gov/hepatitis/outbreaks/2017March-HepatitisA.htm).⁷ At its October 2018 meeting, ACIP added homelessness to the list of those (previously unvaccinated) who should receive the HepA vaccine (TABLE 2).⁶

Continue to: Remember that the current recommendation...

Remember that the current recommendation is to vaccinate all children 12 to 23 months old with HepA, in 2 separate doses. Two single-antigen HepA products are available: Havrix (GSK) and Vaqta (Merck). For the 2-dose sequence, Havrix is given at 0 and 6 to 12 months; Vaqta at 0 and 6 to 18 months. Even a single dose will provide protection for up to 11 years. In addition to these vaccines, there is the combination HepA and HepB vaccine (Twinrix) mentioned earlier.

Previous recommendations for preventing hepatitis A after exposure, made in 2007, stated that HepA vaccine was preferred for healthy individuals ages 12 months through 40 years, while immune globulin (IG) was preferred for adults older than 40, infants before their first birthday, immunocompromised individuals, those with chronic liver disease, and those for whom HepA vaccine is contraindicated.⁸ The 2007 recommendations also advised vaccinating individuals traveling to countries with intermediate to high hepatitis A endemicity.

A single dose of HepA vaccine was recommended for all those 12 months or older, although older adults, immunocompromised individuals, and those with chronic liver disease or other chronic medical conditions planning to visit an endemic area in ≤ 2 weeks were supposed to receive the initial dose of vaccine and could also receive IG (0.02 mL/kg) if their provider advised it. Travelers who declined vaccination, those younger than 12 months, or those allergic to a vaccine component could receive a single dose of IG (0.02 mL/kg), which provides protection up to 3 months.

Consider prescribing daily pre-exposure prophylaxis for men and women at risk from sexual exposure to HIV or who inject illicit drugs.

Several factors influenced ACIP to reconsider both the pre- and post-exposure recommendations. Regarding IG, evidence of its decreased potency over time led the committee to increase the recommended dose (see below). IG also must be re-administered every 2 months, the supply of the product is questionable, and many health care facilities do not stock it. By comparison, HepA vaccine offers the advantages of easier administration, inducing active immunity, and providing longer protection. Another issue involved infants ages 6 to 11 months traveling to an area with endemic measles transmission and who must therefore receive the measles, mumps, and rubella (MMR) vaccine. MMR and IG should not be co-administered, and, for infants, the health risk from measles outweighs that from hepatitis A.

Updated recommendations. After considering all this information, ACIP made the following changes to its hepatitis A virus (HAV) prevention recommendations (in addition to adding homeless people to the list of HepA vaccine recipients)⁹:

• Administer HepA vaccine as post-exposure prophylaxis to all individuals 12 months and older.
• IG may be administered, in addition to HepA vaccine, to those older than 40 years, depending on the provider’s risk assessment (degree of exposure and medical conditions that might lead to severe complications from HAV infection). The recommended IG dose is now 0.1 mL/kg for post-exposure prevention; it is 0.1 to 0.2 mL/kg for pre-exposure prophylaxis for travelers, depending on the length of planned travel.
• Administer HepA vaccine alone to infants ages 6 to 11 months traveling outside the United States when protection against hepatitis A is recommended.

These recommendations have been published in the Morbidity and Mortality Weekly Report.⁹

One of the most important commitments family physicians can undertake in protecting the health of their patients and communities is to ensure that their patients are fully vaccinated. This task is increasingly complicated as new vaccines are approved every year and recommendations change regarding new and established vaccines. To assist primary care providers, the Centers for Disease Control and Prevention (CDC) annually updates 2 immunization schedules—one for children and adolescents, and one for adults. These schedules are available on the CDC Web site (https://www.cdc.gov/vaccines/schedules/index.html).

These updates originate from the Advisory Committee on Immunization Practices (ACIP), which meets 3 times a year to consider and adopt changes to the schedules. During 2018, relatively few new recommendations were adopted. The September 2018 Practice Alert¹ in this journal covered the updated recommendations for influenza immunization, which included reinstating live attenuated influenza vaccine (LAIV) to the active list of influenza vaccines.

This current Practice Alert reviews 3 additional updates: 1) a new hepatitis B (HepB) vaccine; 2) updated recommendations for the use of hepatitis A (HepA) vaccine for post-exposure prevention and before travel; and 3) inclusion of the homeless among those who should be routinely vaccinated with HepA vaccine.

Hepatitis B: New 2-dose product

As of 2015, the annual incidence of new hepatitis B cases had declined by 88.5% since the first HepB vaccine was licensed in 1981 and recommendations for its routine use were issued in 1982.² The HepB vaccine products available in the United States are 2 single-antigen products, Engerix-B (GlaxoSmithKline) and Recombivax HB (Merck & Co.). Both can be used in all age groups, starting at birth, in a 3-dose series. HepB vaccine is also available in 2 combination products: Pediarix, containing HepB, diphtheria and tetanus toxoids, acellular pertussis, and inactivated poliovirus (GlaxoSmithKline), approved for use in children 6 weeks to 6 years old; and Twinrix (GlaxoSmithKline), which contains both HepB and HepA and is approved for use in adults 18 years and older.

The HepB vaccine is recommended for all children and unvaccinated adolescents as part of the routine vaccination schedule. It is also recommended for unvaccinated adults with specific risks (TABLE 1²). However, the rate of HepB vaccination in adults for whom it is recommended is suboptimal (FIGURE),³ and just a little more than half of adults who start a 3-dose series of HepB complete it.⁴A new vaccine against hepatitis B, HEPLISAV-B (Dynavax Technologies), was licensed by the US Food and Drug Administration in late 2017. ACIP now recommends it as an option along with other available HepB products. HEPLISAV-B is given in 2 doses separated by 1 month. It is hoped that this shortened 2-dose series will increase the number of adults who achieve full vaccination. In addition, it appears that HEPLISAV-B provides higher levels of protection in some high-risk groups—those with type 2 diabetes or chronic kidney disease.³ However, initial safety studies have shown a small absolute increase in cardiac events after vaccination with HEPLISAV-B. Post-marketing surveillance will be needed to show whether this is causal or coincidental.³

If a HepB series must be completed with different products, just be sure 3 doses are given—even if HEPLISAV-B is one of the agents.

As with other HepB products, use of HEPLISAV-B should follow the latest CDC directives on who to test serologically for prior immunity, and on post-vaccination testing to ensure protective antibody levels were achieved.² It is best to complete a HepB series with the same product, but, if necessary, a combination of products at different doses can be used to complete the HepB series. Any such combination should include 3 doses, even if one of the doses is HEPLISAV-B.

Hepatitis A: Vaccination assumes greater importance for more people

A Practice Alert in early 2018 described a series of outbreaks of hepatitis A around the country and the high rates of associated hospitalizations.⁵ These outbreaks have occurred primarily among the homeless and their contacts and those who use illicit drugs. This nationwide outbreak has now spread, resulting in more than 7500 cases since July 1, 2016.⁶ The progress of this epidemic can be viewed on the CDC Web site (https://www.cdc.gov/hepatitis/outbreaks/2017March-HepatitisA.htm).⁷ At its October 2018 meeting, ACIP added homelessness to the list of those (previously unvaccinated) who should receive the HepA vaccine (TABLE 2).⁶

Continue to: Remember that the current recommendation...

Remember that the current recommendation is to vaccinate all children 12 to 23 months old with HepA, in 2 separate doses. Two single-antigen HepA products are available: Havrix (GSK) and Vaqta (Merck). For the 2-dose sequence, Havrix is given at 0 and 6 to 12 months; Vaqta at 0 and 6 to 18 months. Even a single dose will provide protection for up to 11 years. In addition to these vaccines, there is the combination HepA and HepB vaccine (Twinrix) mentioned earlier.

Previous recommendations for preventing hepatitis A after exposure, made in 2007, stated that HepA vaccine was preferred for healthy individuals ages 12 months through 40 years, while immune globulin (IG) was preferred for adults older than 40, infants before their first birthday, immunocompromised individuals, those with chronic liver disease, and those for whom HepA vaccine is contraindicated.⁸ The 2007 recommendations also advised vaccinating individuals traveling to countries with intermediate to high hepatitis A endemicity.

A single dose of HepA vaccine was recommended for all those 12 months or older, although older adults, immunocompromised individuals, and those with chronic liver disease or other chronic medical conditions planning to visit an endemic area in ≤ 2 weeks were supposed to receive the initial dose of vaccine and could also receive IG (0.02 mL/kg) if their provider advised it. Travelers who declined vaccination, those younger than 12 months, or those allergic to a vaccine component could receive a single dose of IG (0.02 mL/kg), which provides protection up to 3 months.

Consider prescribing daily pre-exposure prophylaxis for men and women at risk from sexual exposure to HIV or who inject illicit drugs.

Several factors influenced ACIP to reconsider both the pre- and post-exposure recommendations. Regarding IG, evidence of its decreased potency over time led the committee to increase the recommended dose (see below). IG also must be re-administered every 2 months, the supply of the product is questionable, and many health care facilities do not stock it. By comparison, HepA vaccine offers the advantages of easier administration, inducing active immunity, and providing longer protection. Another issue involved infants ages 6 to 11 months traveling to an area with endemic measles transmission and who must therefore receive the measles, mumps, and rubella (MMR) vaccine. MMR and IG should not be co-administered, and, for infants, the health risk from measles outweighs that from hepatitis A.

Updated recommendations. After considering all this information, ACIP made the following changes to its hepatitis A virus (HAV) prevention recommendations (in addition to adding homeless people to the list of HepA vaccine recipients)⁹:

• Administer HepA vaccine as post-exposure prophylaxis to all individuals 12 months and older.
• IG may be administered, in addition to HepA vaccine, to those older than 40 years, depending on the provider’s risk assessment (degree of exposure and medical conditions that might lead to severe complications from HAV infection). The recommended IG dose is now 0.1 mL/kg for post-exposure prevention; it is 0.1 to 0.2 mL/kg for pre-exposure prophylaxis for travelers, depending on the length of planned travel.
• Administer HepA vaccine alone to infants ages 6 to 11 months traveling outside the United States when protection against hepatitis A is recommended.

These recommendations have been published in the Morbidity and Mortality Weekly Report.⁹

One of the most important commitments family physicians can undertake in protecting the health of their patients and communities is to ensure that their patients are fully vaccinated. This task is increasingly complicated as new vaccines are approved every year and recommendations change regarding new and established vaccines. To assist primary care providers, the Centers for Disease Control and Prevention (CDC) annually updates 2 immunization schedules—one for children and adolescents, and one for adults. These schedules are available on the CDC Web site (https://www.cdc.gov/vaccines/schedules/index.html).

These updates originate from the Advisory Committee on Immunization Practices (ACIP), which meets 3 times a year to consider and adopt changes to the schedules. During 2018, relatively few new recommendations were adopted. The September 2018 Practice Alert¹ in this journal covered the updated recommendations for influenza immunization, which included reinstating live attenuated influenza vaccine (LAIV) to the active list of influenza vaccines.

This current Practice Alert reviews 3 additional updates: 1) a new hepatitis B (HepB) vaccine; 2) updated recommendations for the use of hepatitis A (HepA) vaccine for post-exposure prevention and before travel; and 3) inclusion of the homeless among those who should be routinely vaccinated with HepA vaccine.

Hepatitis B: New 2-dose product

As of 2015, the annual incidence of new hepatitis B cases had declined by 88.5% since the first HepB vaccine was licensed in 1981 and recommendations for its routine use were issued in 1982.² The HepB vaccine products available in the United States are 2 single-antigen products, Engerix-B (GlaxoSmithKline) and Recombivax HB (Merck & Co.). Both can be used in all age groups, starting at birth, in a 3-dose series. HepB vaccine is also available in 2 combination products: Pediarix, containing HepB, diphtheria and tetanus toxoids, acellular pertussis, and inactivated poliovirus (GlaxoSmithKline), approved for use in children 6 weeks to 6 years old; and Twinrix (GlaxoSmithKline), which contains both HepB and HepA and is approved for use in adults 18 years and older.

The HepB vaccine is recommended for all children and unvaccinated adolescents as part of the routine vaccination schedule. It is also recommended for unvaccinated adults with specific risks (TABLE 1²). However, the rate of HepB vaccination in adults for whom it is recommended is suboptimal (FIGURE),³ and just a little more than half of adults who start a 3-dose series of HepB complete it.⁴A new vaccine against hepatitis B, HEPLISAV-B (Dynavax Technologies), was licensed by the US Food and Drug Administration in late 2017. ACIP now recommends it as an option along with other available HepB products. HEPLISAV-B is given in 2 doses separated by 1 month. It is hoped that this shortened 2-dose series will increase the number of adults who achieve full vaccination. In addition, it appears that HEPLISAV-B provides higher levels of protection in some high-risk groups—those with type 2 diabetes or chronic kidney disease.³ However, initial safety studies have shown a small absolute increase in cardiac events after vaccination with HEPLISAV-B. Post-marketing surveillance will be needed to show whether this is causal or coincidental.³

If a HepB series must be completed with different products, just be sure 3 doses are given—even if HEPLISAV-B is one of the agents.

As with other HepB products, use of HEPLISAV-B should follow the latest CDC directives on who to test serologically for prior immunity, and on post-vaccination testing to ensure protective antibody levels were achieved.² It is best to complete a HepB series with the same product, but, if necessary, a combination of products at different doses can be used to complete the HepB series. Any such combination should include 3 doses, even if one of the doses is HEPLISAV-B.

Hepatitis A: Vaccination assumes greater importance for more people

A Practice Alert in early 2018 described a series of outbreaks of hepatitis A around the country and the high rates of associated hospitalizations.⁵ These outbreaks have occurred primarily among the homeless and their contacts and those who use illicit drugs. This nationwide outbreak has now spread, resulting in more than 7500 cases since July 1, 2016.⁶ The progress of this epidemic can be viewed on the CDC Web site (https://www.cdc.gov/hepatitis/outbreaks/2017March-HepatitisA.htm).⁷ At its October 2018 meeting, ACIP added homelessness to the list of those (previously unvaccinated) who should receive the HepA vaccine (TABLE 2).⁶

Continue to: Remember that the current recommendation...

Remember that the current recommendation is to vaccinate all children 12 to 23 months old with HepA, in 2 separate doses. Two single-antigen HepA products are available: Havrix (GSK) and Vaqta (Merck). For the 2-dose sequence, Havrix is given at 0 and 6 to 12 months; Vaqta at 0 and 6 to 18 months. Even a single dose will provide protection for up to 11 years. In addition to these vaccines, there is the combination HepA and HepB vaccine (Twinrix) mentioned earlier.

Previous recommendations for preventing hepatitis A after exposure, made in 2007, stated that HepA vaccine was preferred for healthy individuals ages 12 months through 40 years, while immune globulin (IG) was preferred for adults older than 40, infants before their first birthday, immunocompromised individuals, those with chronic liver disease, and those for whom HepA vaccine is contraindicated.⁸ The 2007 recommendations also advised vaccinating individuals traveling to countries with intermediate to high hepatitis A endemicity.

A single dose of HepA vaccine was recommended for all those 12 months or older, although older adults, immunocompromised individuals, and those with chronic liver disease or other chronic medical conditions planning to visit an endemic area in ≤ 2 weeks were supposed to receive the initial dose of vaccine and could also receive IG (0.02 mL/kg) if their provider advised it. Travelers who declined vaccination, those younger than 12 months, or those allergic to a vaccine component could receive a single dose of IG (0.02 mL/kg), which provides protection up to 3 months.

Consider prescribing daily pre-exposure prophylaxis for men and women at risk from sexual exposure to HIV or who inject illicit drugs.

Several factors influenced ACIP to reconsider both the pre- and post-exposure recommendations. Regarding IG, evidence of its decreased potency over time led the committee to increase the recommended dose (see below). IG also must be re-administered every 2 months, the supply of the product is questionable, and many health care facilities do not stock it. By comparison, HepA vaccine offers the advantages of easier administration, inducing active immunity, and providing longer protection. Another issue involved infants ages 6 to 11 months traveling to an area with endemic measles transmission and who must therefore receive the measles, mumps, and rubella (MMR) vaccine. MMR and IG should not be co-administered, and, for infants, the health risk from measles outweighs that from hepatitis A.

Updated recommendations. After considering all this information, ACIP made the following changes to its hepatitis A virus (HAV) prevention recommendations (in addition to adding homeless people to the list of HepA vaccine recipients)⁹:

• Administer HepA vaccine as post-exposure prophylaxis to all individuals 12 months and older.
• IG may be administered, in addition to HepA vaccine, to those older than 40 years, depending on the provider’s risk assessment (degree of exposure and medical conditions that might lead to severe complications from HAV infection). The recommended IG dose is now 0.1 mL/kg for post-exposure prevention; it is 0.1 to 0.2 mL/kg for pre-exposure prophylaxis for travelers, depending on the length of planned travel.
• Administer HepA vaccine alone to infants ages 6 to 11 months traveling outside the United States when protection against hepatitis A is recommended.

These recommendations have been published in the Morbidity and Mortality Weekly Report.⁹

The FP suspected that this was a skin cancer with ulceration and pigmentation. The differential diagnosis included pigmented basal cell carcinoma, melanoma, and squamous cell carcinoma. If this were a melanoma, there would appear to be areas of regression between the islands of pigmentation. The FP explained that a biopsy was needed and suggested a broad shave biopsy because this technique would provide adequate tissue to the pathologist. (See the Watch & Learn video on “Shave biopsy.”)

The FP performed the broad shave biopsy and saw some remaining pigment at the base of the initial cut. He performed a second pass with the DermaBlade and explained this in the pathology requisition. (It is acceptable to send a deeper section of tissue if it appears that there is some remaining tumor below the initial biopsy.)

The biopsy report revealed lentigo maligna melanoma, which was approximately 2 mm thick—much deeper than the clinical appearance suggested. The pathologist combined the depths from the 2 specimens to get an approximate Breslow level. In this case, the most important information was that this was >1 mm in depth, which suggested that a sentinel lymph node biopsy would be needed for prognostic information. The patient was referred to Surgical Oncology for wide excision and sentinel lymph node biopsy.

Fortunately, the nodes were negative for metastasis. The wide excision was closed with a graft that healed well over time. The patient was followed with regular skin exams and careful lymph node exams of the neck and supraclavicular areas. He now wears a hat whenever he is outdoors.

‌

Photo courtesy of Jonathan Karnes, MD and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Squamous cell carcinoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1103-1111.

To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

The FP suspected that this was a skin cancer with ulceration and pigmentation. The differential diagnosis included pigmented basal cell carcinoma, melanoma, and squamous cell carcinoma. If this were a melanoma, there would appear to be areas of regression between the islands of pigmentation. The FP explained that a biopsy was needed and suggested a broad shave biopsy because this technique would provide adequate tissue to the pathologist. (See the Watch & Learn video on “Shave biopsy.”)

The FP performed the broad shave biopsy and saw some remaining pigment at the base of the initial cut. He performed a second pass with the DermaBlade and explained this in the pathology requisition. (It is acceptable to send a deeper section of tissue if it appears that there is some remaining tumor below the initial biopsy.)

The biopsy report revealed lentigo maligna melanoma, which was approximately 2 mm thick—much deeper than the clinical appearance suggested. The pathologist combined the depths from the 2 specimens to get an approximate Breslow level. In this case, the most important information was that this was >1 mm in depth, which suggested that a sentinel lymph node biopsy would be needed for prognostic information. The patient was referred to Surgical Oncology for wide excision and sentinel lymph node biopsy.

Fortunately, the nodes were negative for metastasis. The wide excision was closed with a graft that healed well over time. The patient was followed with regular skin exams and careful lymph node exams of the neck and supraclavicular areas. He now wears a hat whenever he is outdoors.

‌

Photo courtesy of Jonathan Karnes, MD and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Squamous cell carcinoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1103-1111.

To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

The FP suspected that this was a skin cancer with ulceration and pigmentation. The differential diagnosis included pigmented basal cell carcinoma, melanoma, and squamous cell carcinoma. If this were a melanoma, there would appear to be areas of regression between the islands of pigmentation. The FP explained that a biopsy was needed and suggested a broad shave biopsy because this technique would provide adequate tissue to the pathologist. (See the Watch & Learn video on “Shave biopsy.”)

The FP performed the broad shave biopsy and saw some remaining pigment at the base of the initial cut. He performed a second pass with the DermaBlade and explained this in the pathology requisition. (It is acceptable to send a deeper section of tissue if it appears that there is some remaining tumor below the initial biopsy.)

The biopsy report revealed lentigo maligna melanoma, which was approximately 2 mm thick—much deeper than the clinical appearance suggested. The pathologist combined the depths from the 2 specimens to get an approximate Breslow level. In this case, the most important information was that this was >1 mm in depth, which suggested that a sentinel lymph node biopsy would be needed for prognostic information. The patient was referred to Surgical Oncology for wide excision and sentinel lymph node biopsy.

Fortunately, the nodes were negative for metastasis. The wide excision was closed with a graft that healed well over time. The patient was followed with regular skin exams and careful lymph node exams of the neck and supraclavicular areas. He now wears a hat whenever he is outdoors.

‌

Photo courtesy of Jonathan Karnes, MD and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Squamous cell carcinoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1103-1111.

To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

Menstrual bleeding is considered normal when it occurs regularly (every 21-35 days), lasts 4 to 8 days, and is not associated with heavy bleeding.¹ During the first few years after menarche, it is normal for girls to experience irregular menstrual cycles but, by the third year, 60% to 80% of girls have an adult pattern of menstrual bleeding.²

Menstrual flow without normal volume, duration, regularity, or frequency is considered abnormal uterine bleeding (AUB). The condition is considered acute if there is need for immediate intervention. In the absence of the need for immediate intervention, recurrent AUB is classified as chronic.³ Chronic AUB is the focus of this article.

Invaluable tool: The FIGO classification

In 2011, the International Federation of Gynecology and Obstetrics (FIGO) proposed what is known as the PALM–COEIN AUB classification system (TABLE 1).³ This mnemonic system divides AUB into 2 broad types:

• structural causes, recalled by “PALM” (Polyps, Adenomyosis, Leiomyoma, and Malignancy/hyperplasia)
• nonstructural causes, recalled by “COEIN” (Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, and Not yet classified).

The PALM–COEIN system also uses descriptive terminology (heavy bleeding, intermenstrual bleeding) to characterize the bleeding pattern.³ The American College of Obstetricians and Gynecologists has adopted this classification system and recommends that such historically used terminology as “dysfunctional uterine bleeding,” “menorrhagia,” and “metrorrhagia” be abandoned.¹

The initial workup of all causes of chronic uterine bleeding begins with a history; physical examination, including pelvic exam; and laboratory testing, including a urine pregnancy test, complete blood count, and a test of thyroid-stimulating hormone (TABLE 2). The need for additional laboratory testing, imaging, or endometrial biopsy depends on the suspected cause of AUB, detailed stepwise in FIGURE 1 (women <18 years) and FIGURE 2 (≥18 years).

We first briefly review the 9 categories of AUB in the PALM–COEIN system; discuss the most common causes in more detail; and review common treatment options (TABLE 3).

CASE 1

Marsha R, a 41-year-old-woman, complains of heavy menstrual bleeding for the past year that has become worse over the past 2 months. Her menstrual cycles have occurred every 28 days and last 10 days; she uses 10 to 12 pads a day.

Continue to: Recently, Ms. R reports...

Recently, Ms. R reports, she has been bleeding continuously for 14 days, with episodes of lighter bleeding followed by heavier bleeding. She also complains of fatigue.

Bimanual examination is notable for an enlarged uterus.

How would you proceed with the workup of this patient, to determine the cause of her bleeding and tailor management accordingly?

Structural AUB: The “PALM” mnemonic

A structural cause of AUB must be considered when you encounter an abnormality on physical exam (TABLE 1).³ In obese women or other patients in whom the physical exam is difficult, historical clues—including postcoital bleeding, intermenstrual bleeding, or pelvic pain or pressure—also suggest a structural abnormality.⁴

Transvaginal ultrasonography (TVUS) is the initial method of evaluation when a structural abnormality is suspected.^1,4 However, although TVUS is excellent at visualizing the myometrium, lesions within the uterine cavity can be missed. If intracavitary pathology, such as submucosal fibroids or endometrial polyps, is suspected, additional imaging with saline infusion sonohysterography (SIS) should be performed. If a cavitary abnormality is confirmed, hysteroscopy is indicated.¹ Magnetic resonance imaging (MRI) is reserved for cases in which a uterine cavity abnormality is found on TVUS but cannot be further characterized by SIS or hysteroscopy.¹