Pharmacology

Nearly half of adults prescribed metformin after a new diagnosis of type 2 diabetes have stopped taking it by 1 year, new data show.

SDI Productions/E+

The findings, from a retrospective analysis of administrative data from Alberta, Canada, during 2012-2017, also show that the fall-off in metformin adherence was most dramatic during the first 30 days, and in most cases, there was no concomitant substitution of another glucose-lowering drug.

While the majority with newly diagnosed type 2 diabetes were prescribed metformin as first-line therapy, patients started on other agents incurred far higher medication and health care costs.

The data were recently published online in Diabetic Medicine by David J. T. Campbell, MD, PhD, of the University of Calgary (Alta.), and colleagues.

“We realized that even if someone is prescribed metformin that doesn’t mean they’re staying on metformin even for a year ... the drop-off rate is really quite abrupt,” Dr. Campbell said in an interview. Most who discontinued had A1c levels above 7.5%, so it wasn’t that they no longer needed glucose-lowering medication, he noted.
 

People don’t understand chronic use; meds don’t make you feel better

One reason for the discontinuations, he said, is that patients might not realize they need to keep taking the medication.

“When a physician is seeing a person with newly diagnosed diabetes, I think it’s important to remember that they might not know the implications of having a chronic condition. A lot of times we’re quick to prescribe metformin and forget about it. ... Physicians might write a script for 3 months and three refills and not see the patient again for a year ... We may need to keep a closer eye on these folks and have more regular follow-up, and make sure they’re getting early diabetes education.”

Side effects are an issue, but not for most. “Any clinician who prescribes metformin knows there are side effects, such as upset stomach, diarrhea, and nausea. But certainly, it’s not half [who experience these]. ... A lot of people just aren’t accepting of having to take it lifelong, especially since they probably don’t feel any better on it,” Dr. Campbell said.  

James Flory, MD, an endocrinologist at Memorial Sloan Kettering Cancer Center, New York, said in an interview that about 25% of patients taking metformin experience gastrointestinal side effects.

Moreover, he noted that the drop-off in adherence is also seen with antihypertensive and lipid-lowering drugs that have fewer side effects than those of metformin. He pointed to a “striking example” of this, a 2011 randomized trial published in the New England Journal of Medicine, and as reported by this news organization, showing overall rates of adherence to these medications was around 50%, even among people who had already had a myocardial infarction.   

“People really don’t want to be on these medications. ... They have an aversion to being medicalized and taking pills. If they’re not being pretty consistently prompted and reminded and urged to take them, I think people will find rationalizations, reasons for stopping. ... I think people want to handle things through lifestyle and not be on a drug,” noted Dr. Flory, who has published on the subject of metformin adherence.

“These drugs don’t make people feel better. None of them do. At best they don’t make you feel worse. You have to really believe in the chronic condition and believe that it’s hurting you and that you can’t handle it without the drugs to motivate you to keep taking them,” Dr. Flory explained.

Communication with the patient is key, he added.

“I don’t have empirical data to support this, but I feel it’s helpful to acknowledge the downsides to patients. I tell them to let me know [if they’re having side effects] and we’ll work on it. Don’t just stop taking the drug and never circle back.” At the same time, he added, “I think it’s important to emphasize metformin’s safety and effectiveness.”

For patients experiencing gastrointestinal side effects, options including switching to extended-release metformin or lowering the dose.

Also, while patients are typically advised to take metformin with food, some experience diarrhea when they do that and prefer to take it at bedtime than with dinner. “If that’s what works for people, that’s what they should do,” Dr. Flory advised.

“It doesn’t take a lot of time to emphasize to patients the safety and this level of flexibility and control they should be able to exercise over how much they take and when. These things should really help.”  
 

Metformin usually prescribed, but not always taken

Dr. Campbell and colleagues analyzed 17,932 individuals with incident type 2 diabetes diagnosed between April 1, 2012, and March 31, 2017. Overall, 89% received metformin monotherapy as their initial diabetes prescription, 7.6% started metformin in combination with another glucose-lowering drug, and 3.3% were prescribed a nonmetformin diabetes medication. (Those prescribed insulin as their first diabetes medication were excluded.) 

The most commonly coprescribed drugs with metformin were sulfonylureas (in 47%) and DPP-4 inhibitors (28%). Of those initiated with only nonmetformin medications, sulfonylureas were also the most common (53%) and dipeptidyl peptidase-4 (DPP-4) inhibitors second (21%).

The metformin prescribing rate of 89% reflects current guidelines, Dr. Campbell noted.

“In hypertension, clinicians weren’t really following the guidelines ... they were prescribing more expensive drugs than the guidelines say. ... We showed that in diabetes, contrary to hypertension, clinicians really are generally following the clinical practice guidelines. ... The vast majority who are started on metformin are started on monotherapy. That was reassuring to us. We’re not paying for a bunch of expensive drugs when metformin would do just as well,” he said.

However, the proportion who had been dispensed metformin to cover the prescribed number of days dropped by about 10% after 30 days, by a further 10% after 90 days, and yet again after 100 days, resulting in just 54% remaining on the drug by 1 year.

Factors associated with higher adherence included older age, presence of comorbidities, and highest versus lowest neighborhood income quintile.

Those who had been prescribed nonmetformin monotherapy had about twice the total health care costs of those initially prescribed metformin monotherapy. Higher health care costs were seen among patients who were younger, had lower incomes, had higher baseline A1c, had more comorbidities, and were men.

How will the newer type 2 diabetes drugs change prescribing?

Dr. Campbell noted that “a lot has changed since 2017. ... At least in Canada, the sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists were supposed to be reserved as second-line agents in patients with cardiovascular disease, but more and more they’re being thought of as first-line agents in high-risk patients.”

“I suspect as those guidelines are transmitted to primary care colleagues who are doing the bulk of the prescribing we’ll see more and more uptake of these agents.”

Indeed, Dr. Flory said, “The metformin data at this point are very dated and the body of trials showing health benefits for it is actually very weak compared to the big trials that have been done for the newer agents, to the point where you can imagine a consensus gradually forming where people start to recommend something other than metformin for nearly everybody with type 2 diabetes. The cost implications are just huge, and I think the safety implications as well.”

According to Dr. Flory, the SGLT2 inhibitors “are fundamentally not as safe as metformin. I think they’re very safe drugs – large good studies have established that – but if you’re going to give drugs to a large number of people who are pretty healthy at baseline the safety standards have to be pretty high.”

Just the elevated risk of euglycemic diabetic ketoacidosis alone is reason for pause, Dr. Flory said. “Even though it’s manageable ... metformin just doesn’t have a safety problem like that. I’m very comfortable prescribing SGLT2 inhibitors, but If I’m going to give a drug to a million people and have nothing go wrong with any of them, that would be metformin, not an SGLT2 [inhibitor].”

Dr. Campbell and colleagues will be conducting a follow-up of prescribing data through 2019, which will of course include the newer agents. They’ll also investigate reasons for drug discontinuation and outcomes of those who discontinue versus continue metformin.

Dr. Campbell has reported no relevant financial relationships. Dr. Flory consults for a legal firm on litigation related to insulin analog pricing issues, not for or pertaining to a specific company.

A version of this article first appeared on Medscape.com.

Nearly half of adults prescribed metformin after a new diagnosis of type 2 diabetes have stopped taking it by 1 year, new data show.

SDI Productions/E+

The findings, from a retrospective analysis of administrative data from Alberta, Canada, during 2012-2017, also show that the fall-off in metformin adherence was most dramatic during the first 30 days, and in most cases, there was no concomitant substitution of another glucose-lowering drug.

While the majority with newly diagnosed type 2 diabetes were prescribed metformin as first-line therapy, patients started on other agents incurred far higher medication and health care costs.

The data were recently published online in Diabetic Medicine by David J. T. Campbell, MD, PhD, of the University of Calgary (Alta.), and colleagues.

“We realized that even if someone is prescribed metformin that doesn’t mean they’re staying on metformin even for a year ... the drop-off rate is really quite abrupt,” Dr. Campbell said in an interview. Most who discontinued had A1c levels above 7.5%, so it wasn’t that they no longer needed glucose-lowering medication, he noted.
 

People don’t understand chronic use; meds don’t make you feel better

One reason for the discontinuations, he said, is that patients might not realize they need to keep taking the medication.

“When a physician is seeing a person with newly diagnosed diabetes, I think it’s important to remember that they might not know the implications of having a chronic condition. A lot of times we’re quick to prescribe metformin and forget about it. ... Physicians might write a script for 3 months and three refills and not see the patient again for a year ... We may need to keep a closer eye on these folks and have more regular follow-up, and make sure they’re getting early diabetes education.”

Side effects are an issue, but not for most. “Any clinician who prescribes metformin knows there are side effects, such as upset stomach, diarrhea, and nausea. But certainly, it’s not half [who experience these]. ... A lot of people just aren’t accepting of having to take it lifelong, especially since they probably don’t feel any better on it,” Dr. Campbell said.  

James Flory, MD, an endocrinologist at Memorial Sloan Kettering Cancer Center, New York, said in an interview that about 25% of patients taking metformin experience gastrointestinal side effects.

Moreover, he noted that the drop-off in adherence is also seen with antihypertensive and lipid-lowering drugs that have fewer side effects than those of metformin. He pointed to a “striking example” of this, a 2011 randomized trial published in the New England Journal of Medicine, and as reported by this news organization, showing overall rates of adherence to these medications was around 50%, even among people who had already had a myocardial infarction.   

“People really don’t want to be on these medications. ... They have an aversion to being medicalized and taking pills. If they’re not being pretty consistently prompted and reminded and urged to take them, I think people will find rationalizations, reasons for stopping. ... I think people want to handle things through lifestyle and not be on a drug,” noted Dr. Flory, who has published on the subject of metformin adherence.

“These drugs don’t make people feel better. None of them do. At best they don’t make you feel worse. You have to really believe in the chronic condition and believe that it’s hurting you and that you can’t handle it without the drugs to motivate you to keep taking them,” Dr. Flory explained.

Communication with the patient is key, he added.

“I don’t have empirical data to support this, but I feel it’s helpful to acknowledge the downsides to patients. I tell them to let me know [if they’re having side effects] and we’ll work on it. Don’t just stop taking the drug and never circle back.” At the same time, he added, “I think it’s important to emphasize metformin’s safety and effectiveness.”

For patients experiencing gastrointestinal side effects, options including switching to extended-release metformin or lowering the dose.

Also, while patients are typically advised to take metformin with food, some experience diarrhea when they do that and prefer to take it at bedtime than with dinner. “If that’s what works for people, that’s what they should do,” Dr. Flory advised.

“It doesn’t take a lot of time to emphasize to patients the safety and this level of flexibility and control they should be able to exercise over how much they take and when. These things should really help.”  
 

Metformin usually prescribed, but not always taken

Dr. Campbell and colleagues analyzed 17,932 individuals with incident type 2 diabetes diagnosed between April 1, 2012, and March 31, 2017. Overall, 89% received metformin monotherapy as their initial diabetes prescription, 7.6% started metformin in combination with another glucose-lowering drug, and 3.3% were prescribed a nonmetformin diabetes medication. (Those prescribed insulin as their first diabetes medication were excluded.) 

The most commonly coprescribed drugs with metformin were sulfonylureas (in 47%) and DPP-4 inhibitors (28%). Of those initiated with only nonmetformin medications, sulfonylureas were also the most common (53%) and dipeptidyl peptidase-4 (DPP-4) inhibitors second (21%).

The metformin prescribing rate of 89% reflects current guidelines, Dr. Campbell noted.

“In hypertension, clinicians weren’t really following the guidelines ... they were prescribing more expensive drugs than the guidelines say. ... We showed that in diabetes, contrary to hypertension, clinicians really are generally following the clinical practice guidelines. ... The vast majority who are started on metformin are started on monotherapy. That was reassuring to us. We’re not paying for a bunch of expensive drugs when metformin would do just as well,” he said.

However, the proportion who had been dispensed metformin to cover the prescribed number of days dropped by about 10% after 30 days, by a further 10% after 90 days, and yet again after 100 days, resulting in just 54% remaining on the drug by 1 year.

Factors associated with higher adherence included older age, presence of comorbidities, and highest versus lowest neighborhood income quintile.

Those who had been prescribed nonmetformin monotherapy had about twice the total health care costs of those initially prescribed metformin monotherapy. Higher health care costs were seen among patients who were younger, had lower incomes, had higher baseline A1c, had more comorbidities, and were men.

How will the newer type 2 diabetes drugs change prescribing?

Dr. Campbell noted that “a lot has changed since 2017. ... At least in Canada, the sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists were supposed to be reserved as second-line agents in patients with cardiovascular disease, but more and more they’re being thought of as first-line agents in high-risk patients.”

“I suspect as those guidelines are transmitted to primary care colleagues who are doing the bulk of the prescribing we’ll see more and more uptake of these agents.”

Indeed, Dr. Flory said, “The metformin data at this point are very dated and the body of trials showing health benefits for it is actually very weak compared to the big trials that have been done for the newer agents, to the point where you can imagine a consensus gradually forming where people start to recommend something other than metformin for nearly everybody with type 2 diabetes. The cost implications are just huge, and I think the safety implications as well.”

According to Dr. Flory, the SGLT2 inhibitors “are fundamentally not as safe as metformin. I think they’re very safe drugs – large good studies have established that – but if you’re going to give drugs to a large number of people who are pretty healthy at baseline the safety standards have to be pretty high.”

Just the elevated risk of euglycemic diabetic ketoacidosis alone is reason for pause, Dr. Flory said. “Even though it’s manageable ... metformin just doesn’t have a safety problem like that. I’m very comfortable prescribing SGLT2 inhibitors, but If I’m going to give a drug to a million people and have nothing go wrong with any of them, that would be metformin, not an SGLT2 [inhibitor].”

Dr. Campbell and colleagues will be conducting a follow-up of prescribing data through 2019, which will of course include the newer agents. They’ll also investigate reasons for drug discontinuation and outcomes of those who discontinue versus continue metformin.

Dr. Campbell has reported no relevant financial relationships. Dr. Flory consults for a legal firm on litigation related to insulin analog pricing issues, not for or pertaining to a specific company.

A version of this article first appeared on Medscape.com.

Nearly half of adults prescribed metformin after a new diagnosis of type 2 diabetes have stopped taking it by 1 year, new data show.

SDI Productions/E+

The findings, from a retrospective analysis of administrative data from Alberta, Canada, during 2012-2017, also show that the fall-off in metformin adherence was most dramatic during the first 30 days, and in most cases, there was no concomitant substitution of another glucose-lowering drug.

While the majority with newly diagnosed type 2 diabetes were prescribed metformin as first-line therapy, patients started on other agents incurred far higher medication and health care costs.

The data were recently published online in Diabetic Medicine by David J. T. Campbell, MD, PhD, of the University of Calgary (Alta.), and colleagues.

“We realized that even if someone is prescribed metformin that doesn’t mean they’re staying on metformin even for a year ... the drop-off rate is really quite abrupt,” Dr. Campbell said in an interview. Most who discontinued had A1c levels above 7.5%, so it wasn’t that they no longer needed glucose-lowering medication, he noted.
 

People don’t understand chronic use; meds don’t make you feel better

One reason for the discontinuations, he said, is that patients might not realize they need to keep taking the medication.

“When a physician is seeing a person with newly diagnosed diabetes, I think it’s important to remember that they might not know the implications of having a chronic condition. A lot of times we’re quick to prescribe metformin and forget about it. ... Physicians might write a script for 3 months and three refills and not see the patient again for a year ... We may need to keep a closer eye on these folks and have more regular follow-up, and make sure they’re getting early diabetes education.”

Side effects are an issue, but not for most. “Any clinician who prescribes metformin knows there are side effects, such as upset stomach, diarrhea, and nausea. But certainly, it’s not half [who experience these]. ... A lot of people just aren’t accepting of having to take it lifelong, especially since they probably don’t feel any better on it,” Dr. Campbell said.  

James Flory, MD, an endocrinologist at Memorial Sloan Kettering Cancer Center, New York, said in an interview that about 25% of patients taking metformin experience gastrointestinal side effects.

Moreover, he noted that the drop-off in adherence is also seen with antihypertensive and lipid-lowering drugs that have fewer side effects than those of metformin. He pointed to a “striking example” of this, a 2011 randomized trial published in the New England Journal of Medicine, and as reported by this news organization, showing overall rates of adherence to these medications was around 50%, even among people who had already had a myocardial infarction.   

“People really don’t want to be on these medications. ... They have an aversion to being medicalized and taking pills. If they’re not being pretty consistently prompted and reminded and urged to take them, I think people will find rationalizations, reasons for stopping. ... I think people want to handle things through lifestyle and not be on a drug,” noted Dr. Flory, who has published on the subject of metformin adherence.

“These drugs don’t make people feel better. None of them do. At best they don’t make you feel worse. You have to really believe in the chronic condition and believe that it’s hurting you and that you can’t handle it without the drugs to motivate you to keep taking them,” Dr. Flory explained.

Communication with the patient is key, he added.

“I don’t have empirical data to support this, but I feel it’s helpful to acknowledge the downsides to patients. I tell them to let me know [if they’re having side effects] and we’ll work on it. Don’t just stop taking the drug and never circle back.” At the same time, he added, “I think it’s important to emphasize metformin’s safety and effectiveness.”

For patients experiencing gastrointestinal side effects, options including switching to extended-release metformin or lowering the dose.

Also, while patients are typically advised to take metformin with food, some experience diarrhea when they do that and prefer to take it at bedtime than with dinner. “If that’s what works for people, that’s what they should do,” Dr. Flory advised.

“It doesn’t take a lot of time to emphasize to patients the safety and this level of flexibility and control they should be able to exercise over how much they take and when. These things should really help.”  
 

Metformin usually prescribed, but not always taken

Dr. Campbell and colleagues analyzed 17,932 individuals with incident type 2 diabetes diagnosed between April 1, 2012, and March 31, 2017. Overall, 89% received metformin monotherapy as their initial diabetes prescription, 7.6% started metformin in combination with another glucose-lowering drug, and 3.3% were prescribed a nonmetformin diabetes medication. (Those prescribed insulin as their first diabetes medication were excluded.) 

The most commonly coprescribed drugs with metformin were sulfonylureas (in 47%) and DPP-4 inhibitors (28%). Of those initiated with only nonmetformin medications, sulfonylureas were also the most common (53%) and dipeptidyl peptidase-4 (DPP-4) inhibitors second (21%).

The metformin prescribing rate of 89% reflects current guidelines, Dr. Campbell noted.

“In hypertension, clinicians weren’t really following the guidelines ... they were prescribing more expensive drugs than the guidelines say. ... We showed that in diabetes, contrary to hypertension, clinicians really are generally following the clinical practice guidelines. ... The vast majority who are started on metformin are started on monotherapy. That was reassuring to us. We’re not paying for a bunch of expensive drugs when metformin would do just as well,” he said.

However, the proportion who had been dispensed metformin to cover the prescribed number of days dropped by about 10% after 30 days, by a further 10% after 90 days, and yet again after 100 days, resulting in just 54% remaining on the drug by 1 year.

Factors associated with higher adherence included older age, presence of comorbidities, and highest versus lowest neighborhood income quintile.

Those who had been prescribed nonmetformin monotherapy had about twice the total health care costs of those initially prescribed metformin monotherapy. Higher health care costs were seen among patients who were younger, had lower incomes, had higher baseline A1c, had more comorbidities, and were men.

How will the newer type 2 diabetes drugs change prescribing?

Dr. Campbell noted that “a lot has changed since 2017. ... At least in Canada, the sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists were supposed to be reserved as second-line agents in patients with cardiovascular disease, but more and more they’re being thought of as first-line agents in high-risk patients.”

“I suspect as those guidelines are transmitted to primary care colleagues who are doing the bulk of the prescribing we’ll see more and more uptake of these agents.”

Indeed, Dr. Flory said, “The metformin data at this point are very dated and the body of trials showing health benefits for it is actually very weak compared to the big trials that have been done for the newer agents, to the point where you can imagine a consensus gradually forming where people start to recommend something other than metformin for nearly everybody with type 2 diabetes. The cost implications are just huge, and I think the safety implications as well.”

According to Dr. Flory, the SGLT2 inhibitors “are fundamentally not as safe as metformin. I think they’re very safe drugs – large good studies have established that – but if you’re going to give drugs to a large number of people who are pretty healthy at baseline the safety standards have to be pretty high.”

Just the elevated risk of euglycemic diabetic ketoacidosis alone is reason for pause, Dr. Flory said. “Even though it’s manageable ... metformin just doesn’t have a safety problem like that. I’m very comfortable prescribing SGLT2 inhibitors, but If I’m going to give a drug to a million people and have nothing go wrong with any of them, that would be metformin, not an SGLT2 [inhibitor].”

Dr. Campbell and colleagues will be conducting a follow-up of prescribing data through 2019, which will of course include the newer agents. They’ll also investigate reasons for drug discontinuation and outcomes of those who discontinue versus continue metformin.

Dr. Campbell has reported no relevant financial relationships. Dr. Flory consults for a legal firm on litigation related to insulin analog pricing issues, not for or pertaining to a specific company.

A version of this article first appeared on Medscape.com.

There may be a notable survival benefit for men with advanced prostate cancer and bone metastases when they are prescribed bone-protecting drugs after progressing to “castrate-resistant” status (no longer responsive to androgen deprivation therapy) and move onto first-line therapy with abiraterone acetate (Zytiga).

Results from a retrospective study show that the addition of bone resorption inhibitors (BRIs), including zoledronic acid and denosumab (Xgeva), to abiraterone plus prednisolone was associated with significantly longer overall survival (OS). The median OS was increased by nearly 9 months among recipients, compared with men who didn’t receive these drugs in this setting.

The findings were published online July 22, 2021, in JAMA Network Open.

All men with prostate cancer should receive BRIs “as the disease reaches the castration resistance with bone metastases stage, as recommended by the international guidelines,” lead author Edoardo Francini, MD, PhD, of the University of Florence (Italy) said in a comment.

While there is no evidence that BRIs – when used alone – may improve survival in metastatic castration-resistant prostate cancer (mCRPC) with bone involvement, there has been a “suggestion” of a survival benefit with BRIs when combined with other anticancer therapies in this setting, say the authors.

So Dr. Francini and a team of international coinvestigators looked at the medical records of men with mCRPC and bone metastases treated at eight institutions in Canada, Europe, and the United States and focused on patients who received abiraterone acetate (with prednisone) because it is the most common first-line therapy in this setting.

Patients were classified by receipt versus nonreceipt of concomitant BRIs and subclassified by volume of disease (high or low volume).

There were two cohorts in the study population: 529 men (71.0%) who received abiraterone alone and 216 men (29.0%) who received abiraterone plus BRIs. The median follow-up was 23.5 months.

Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone alone cohort (31.8 vs. 23.0 months; hazard ratio, 0.65; P < .001).

Notably, the OS benefit in the BRI cohort was greater for patients with high-volume versus low-volume disease (33.6 vs. 19.7 months; HR, 0.51; P < .001).

Dr. Francini hopes the new study results can effect change. “Hopefully, clinicians will be more inclined to use bone resorption inhibitors in combination with abiraterone acetate plus prednisone as soon as the disease reaches the castration-resistance with bone metastases stage, as recommended by the international guidelines.” 
 

Importance of bone-targeted drugs

“This study highlights the importance of bone-targeted therapy in current practice for men with mCRPC and bone metastases,” Samuel Takvorian, MD, and Naomi Haas, MD, of the University of Pennsylvania, Philadelphia, wrote in an accompanying editorial.

But the study also reveals that work needs to be done to get clinicians to prescribe BRIs, they said, and that clinical pathways and behavioral “nudges” could help promote adoption.

Most (71%) of the men in this study did not get bone protective drug therapy, they pointed out, even though they were being treated at major hospital systems.

So, why aren’t more men receiving BRIs?

“I think this is less likely due to poor communication from professional societies (the guidelines are clear) and more likely due to bone health being low on the list of priorities for these patients and clinician uncertainty and/or lack of appreciation of the clinical benefit of these agents,” Dr. Takvorian said in an interview.

“When prostate cancer progresses to the castration-resistant phase, clinicians (and patients) rightfully are focused on the next cancer-directed therapy. However, this may be at the expense of supportive care, like bone agents, which often gets short shrift,” he added.

As would be expected, the men who were taking BRIs had a significantly shorter time to first skeletal-related events (SREs), compared with those who were not (32.4 vs. 42.7 months; HR, 1.27; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; P < .001).

“These SREs collectively represent a clinically meaningful outcome that is often measured in clinical trials,” the editorialists observed. In the current study, SREs were comprised of pathological fractures, spinal cord compression, or the need for surgery or radiotherapy to bone.

“Up to one-half of men with mCRPC, the advanced and often fatal stage of disease, experience SREs, which are associated with considerable morbidity, decreased survival, and increased health care utilization and costs,” they wrote.
 

Costly vs. inexpensive BRI

The study found no difference in the OS benefit between the different BRIs used, that is, between that seen with zoledronic acid versus denosumab.

The editorialists suggested that this finding is important, even though it “must be considered preliminary given the limitations of a retrospective study.” These results add “to data suggesting that these agents are comparably beneficial; thus, decisions between them should focus on clinical factors, such as kidney function, patient preference, and cost.”

The two agents differ mechanistically, they added, with zoledronic acid preferentially inhibiting osteoclast proliferation and denosumab inhibiting an important factor in osteoclast maturation.

In terms of having differentiating characteristics, the editorialists say that zoledronic acid is “more often associated with acute phase reactions and required monitoring of kidney function” while “denosumab conferred a higher risk of hypocalcemia.” Rates of osteonecrosis of the jaw are comparable.

International guidelines endorse the use of either agent for the treatment of men with mCRPC. But “some argue that the marginal benefit of denosumab must be weighed against its dramatically higher cost (the annual cost of zoledronic acid is approximately $140 vs. $29,000 for denosumab),” the editorialists said.

The dramatically higher cost of denosumab versus zoledronic acid has also been noted by other oncologists treating patients with other cancers, including multiple myeloma.

In addition to drug costs, there is another issue at stake: the prescribing oncologist is reimbursed by Medicare Part D at 6% for whichever drug is chosen, which represents a “financial conflict” for oncologists, said Vincent Rajkumar, MD, professor of medicine and a hematologist/oncologist at the Mayo Clinic, Rochester, Minn.

There is also a difference in how the drugs are administered, which may influence patient preference, the myeloma experts noted. Zoledronic acid is given intravenously every 3 months and requires a 15-minute infusion at a center, while denosumab needs to be given more frequently (every month) but is administered by subcutaneous injection.

Dr. Francini reported receiving grants from Roche Italia and personal fees for research travel from Janssen-Cilag outside the submitted work. A number of other authors disclosed financial ties to Janssen or Amgen, makers of abiraterone and denosumab, respectively. The editorialists reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

There may be a notable survival benefit for men with advanced prostate cancer and bone metastases when they are prescribed bone-protecting drugs after progressing to “castrate-resistant” status (no longer responsive to androgen deprivation therapy) and move onto first-line therapy with abiraterone acetate (Zytiga).

Results from a retrospective study show that the addition of bone resorption inhibitors (BRIs), including zoledronic acid and denosumab (Xgeva), to abiraterone plus prednisolone was associated with significantly longer overall survival (OS). The median OS was increased by nearly 9 months among recipients, compared with men who didn’t receive these drugs in this setting.

The findings were published online July 22, 2021, in JAMA Network Open.

All men with prostate cancer should receive BRIs “as the disease reaches the castration resistance with bone metastases stage, as recommended by the international guidelines,” lead author Edoardo Francini, MD, PhD, of the University of Florence (Italy) said in a comment.

While there is no evidence that BRIs – when used alone – may improve survival in metastatic castration-resistant prostate cancer (mCRPC) with bone involvement, there has been a “suggestion” of a survival benefit with BRIs when combined with other anticancer therapies in this setting, say the authors.

So Dr. Francini and a team of international coinvestigators looked at the medical records of men with mCRPC and bone metastases treated at eight institutions in Canada, Europe, and the United States and focused on patients who received abiraterone acetate (with prednisone) because it is the most common first-line therapy in this setting.

Patients were classified by receipt versus nonreceipt of concomitant BRIs and subclassified by volume of disease (high or low volume).

There were two cohorts in the study population: 529 men (71.0%) who received abiraterone alone and 216 men (29.0%) who received abiraterone plus BRIs. The median follow-up was 23.5 months.

Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone alone cohort (31.8 vs. 23.0 months; hazard ratio, 0.65; P < .001).

Notably, the OS benefit in the BRI cohort was greater for patients with high-volume versus low-volume disease (33.6 vs. 19.7 months; HR, 0.51; P < .001).

Dr. Francini hopes the new study results can effect change. “Hopefully, clinicians will be more inclined to use bone resorption inhibitors in combination with abiraterone acetate plus prednisone as soon as the disease reaches the castration-resistance with bone metastases stage, as recommended by the international guidelines.” 
 

Importance of bone-targeted drugs

“This study highlights the importance of bone-targeted therapy in current practice for men with mCRPC and bone metastases,” Samuel Takvorian, MD, and Naomi Haas, MD, of the University of Pennsylvania, Philadelphia, wrote in an accompanying editorial.

But the study also reveals that work needs to be done to get clinicians to prescribe BRIs, they said, and that clinical pathways and behavioral “nudges” could help promote adoption.

Most (71%) of the men in this study did not get bone protective drug therapy, they pointed out, even though they were being treated at major hospital systems.

So, why aren’t more men receiving BRIs?

“I think this is less likely due to poor communication from professional societies (the guidelines are clear) and more likely due to bone health being low on the list of priorities for these patients and clinician uncertainty and/or lack of appreciation of the clinical benefit of these agents,” Dr. Takvorian said in an interview.

“When prostate cancer progresses to the castration-resistant phase, clinicians (and patients) rightfully are focused on the next cancer-directed therapy. However, this may be at the expense of supportive care, like bone agents, which often gets short shrift,” he added.

As would be expected, the men who were taking BRIs had a significantly shorter time to first skeletal-related events (SREs), compared with those who were not (32.4 vs. 42.7 months; HR, 1.27; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; P < .001).

“These SREs collectively represent a clinically meaningful outcome that is often measured in clinical trials,” the editorialists observed. In the current study, SREs were comprised of pathological fractures, spinal cord compression, or the need for surgery or radiotherapy to bone.

“Up to one-half of men with mCRPC, the advanced and often fatal stage of disease, experience SREs, which are associated with considerable morbidity, decreased survival, and increased health care utilization and costs,” they wrote.
 

Costly vs. inexpensive BRI

The study found no difference in the OS benefit between the different BRIs used, that is, between that seen with zoledronic acid versus denosumab.

The editorialists suggested that this finding is important, even though it “must be considered preliminary given the limitations of a retrospective study.” These results add “to data suggesting that these agents are comparably beneficial; thus, decisions between them should focus on clinical factors, such as kidney function, patient preference, and cost.”

The two agents differ mechanistically, they added, with zoledronic acid preferentially inhibiting osteoclast proliferation and denosumab inhibiting an important factor in osteoclast maturation.

In terms of having differentiating characteristics, the editorialists say that zoledronic acid is “more often associated with acute phase reactions and required monitoring of kidney function” while “denosumab conferred a higher risk of hypocalcemia.” Rates of osteonecrosis of the jaw are comparable.

International guidelines endorse the use of either agent for the treatment of men with mCRPC. But “some argue that the marginal benefit of denosumab must be weighed against its dramatically higher cost (the annual cost of zoledronic acid is approximately $140 vs. $29,000 for denosumab),” the editorialists said.

The dramatically higher cost of denosumab versus zoledronic acid has also been noted by other oncologists treating patients with other cancers, including multiple myeloma.

In addition to drug costs, there is another issue at stake: the prescribing oncologist is reimbursed by Medicare Part D at 6% for whichever drug is chosen, which represents a “financial conflict” for oncologists, said Vincent Rajkumar, MD, professor of medicine and a hematologist/oncologist at the Mayo Clinic, Rochester, Minn.

There is also a difference in how the drugs are administered, which may influence patient preference, the myeloma experts noted. Zoledronic acid is given intravenously every 3 months and requires a 15-minute infusion at a center, while denosumab needs to be given more frequently (every month) but is administered by subcutaneous injection.

Dr. Francini reported receiving grants from Roche Italia and personal fees for research travel from Janssen-Cilag outside the submitted work. A number of other authors disclosed financial ties to Janssen or Amgen, makers of abiraterone and denosumab, respectively. The editorialists reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

There may be a notable survival benefit for men with advanced prostate cancer and bone metastases when they are prescribed bone-protecting drugs after progressing to “castrate-resistant” status (no longer responsive to androgen deprivation therapy) and move onto first-line therapy with abiraterone acetate (Zytiga).

Results from a retrospective study show that the addition of bone resorption inhibitors (BRIs), including zoledronic acid and denosumab (Xgeva), to abiraterone plus prednisolone was associated with significantly longer overall survival (OS). The median OS was increased by nearly 9 months among recipients, compared with men who didn’t receive these drugs in this setting.

The findings were published online July 22, 2021, in JAMA Network Open.

All men with prostate cancer should receive BRIs “as the disease reaches the castration resistance with bone metastases stage, as recommended by the international guidelines,” lead author Edoardo Francini, MD, PhD, of the University of Florence (Italy) said in a comment.

While there is no evidence that BRIs – when used alone – may improve survival in metastatic castration-resistant prostate cancer (mCRPC) with bone involvement, there has been a “suggestion” of a survival benefit with BRIs when combined with other anticancer therapies in this setting, say the authors.

So Dr. Francini and a team of international coinvestigators looked at the medical records of men with mCRPC and bone metastases treated at eight institutions in Canada, Europe, and the United States and focused on patients who received abiraterone acetate (with prednisone) because it is the most common first-line therapy in this setting.

Patients were classified by receipt versus nonreceipt of concomitant BRIs and subclassified by volume of disease (high or low volume).

There were two cohorts in the study population: 529 men (71.0%) who received abiraterone alone and 216 men (29.0%) who received abiraterone plus BRIs. The median follow-up was 23.5 months.

Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone alone cohort (31.8 vs. 23.0 months; hazard ratio, 0.65; P < .001).

Notably, the OS benefit in the BRI cohort was greater for patients with high-volume versus low-volume disease (33.6 vs. 19.7 months; HR, 0.51; P < .001).

Dr. Francini hopes the new study results can effect change. “Hopefully, clinicians will be more inclined to use bone resorption inhibitors in combination with abiraterone acetate plus prednisone as soon as the disease reaches the castration-resistance with bone metastases stage, as recommended by the international guidelines.” 
 

Importance of bone-targeted drugs

“This study highlights the importance of bone-targeted therapy in current practice for men with mCRPC and bone metastases,” Samuel Takvorian, MD, and Naomi Haas, MD, of the University of Pennsylvania, Philadelphia, wrote in an accompanying editorial.

But the study also reveals that work needs to be done to get clinicians to prescribe BRIs, they said, and that clinical pathways and behavioral “nudges” could help promote adoption.

Most (71%) of the men in this study did not get bone protective drug therapy, they pointed out, even though they were being treated at major hospital systems.

So, why aren’t more men receiving BRIs?

“I think this is less likely due to poor communication from professional societies (the guidelines are clear) and more likely due to bone health being low on the list of priorities for these patients and clinician uncertainty and/or lack of appreciation of the clinical benefit of these agents,” Dr. Takvorian said in an interview.

“When prostate cancer progresses to the castration-resistant phase, clinicians (and patients) rightfully are focused on the next cancer-directed therapy. However, this may be at the expense of supportive care, like bone agents, which often gets short shrift,” he added.

As would be expected, the men who were taking BRIs had a significantly shorter time to first skeletal-related events (SREs), compared with those who were not (32.4 vs. 42.7 months; HR, 1.27; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; P < .001).

“These SREs collectively represent a clinically meaningful outcome that is often measured in clinical trials,” the editorialists observed. In the current study, SREs were comprised of pathological fractures, spinal cord compression, or the need for surgery or radiotherapy to bone.

“Up to one-half of men with mCRPC, the advanced and often fatal stage of disease, experience SREs, which are associated with considerable morbidity, decreased survival, and increased health care utilization and costs,” they wrote.
 

Costly vs. inexpensive BRI

The study found no difference in the OS benefit between the different BRIs used, that is, between that seen with zoledronic acid versus denosumab.

The editorialists suggested that this finding is important, even though it “must be considered preliminary given the limitations of a retrospective study.” These results add “to data suggesting that these agents are comparably beneficial; thus, decisions between them should focus on clinical factors, such as kidney function, patient preference, and cost.”

The two agents differ mechanistically, they added, with zoledronic acid preferentially inhibiting osteoclast proliferation and denosumab inhibiting an important factor in osteoclast maturation.

In terms of having differentiating characteristics, the editorialists say that zoledronic acid is “more often associated with acute phase reactions and required monitoring of kidney function” while “denosumab conferred a higher risk of hypocalcemia.” Rates of osteonecrosis of the jaw are comparable.

International guidelines endorse the use of either agent for the treatment of men with mCRPC. But “some argue that the marginal benefit of denosumab must be weighed against its dramatically higher cost (the annual cost of zoledronic acid is approximately $140 vs. $29,000 for denosumab),” the editorialists said.

The dramatically higher cost of denosumab versus zoledronic acid has also been noted by other oncologists treating patients with other cancers, including multiple myeloma.

In addition to drug costs, there is another issue at stake: the prescribing oncologist is reimbursed by Medicare Part D at 6% for whichever drug is chosen, which represents a “financial conflict” for oncologists, said Vincent Rajkumar, MD, professor of medicine and a hematologist/oncologist at the Mayo Clinic, Rochester, Minn.

There is also a difference in how the drugs are administered, which may influence patient preference, the myeloma experts noted. Zoledronic acid is given intravenously every 3 months and requires a 15-minute infusion at a center, while denosumab needs to be given more frequently (every month) but is administered by subcutaneous injection.

Dr. Francini reported receiving grants from Roche Italia and personal fees for research travel from Janssen-Cilag outside the submitted work. A number of other authors disclosed financial ties to Janssen or Amgen, makers of abiraterone and denosumab, respectively. The editorialists reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The long list of side effects that follow ads for newer expensive drugs to treat type 2 diabetes sometimes include an unusual warning: They might cause weight loss. That side effect is one that many people – especially those with type 2 diabetes, which is associated with obesity – may desperately want.

So it’s no surprise that some of the same drugs are being reformulated and renamed by manufacturers as a new obesity treatment. No longer limited to the crowded field of treatments for type 2 diabetes, which affects about 10% of Americans, they join the far smaller number of drugs for obesity, which affects 42% of Americans and is ready to be mined for profit.

One that recently hit the market – winning Food and Drug Administration approval in June – is Novo Nordisk’s Wegovy (semaglutide), a higher-dose version of the company’s injectable diabetes drug, Ozempic.

Ozempic’s peppy ads suggest that people who use it might lose weight, but also include a disclaimer: that it “is not a weight-loss drug.” Now – with a new name – it is. And clinical trials showed using it leads to significant weight loss for many patients.

“People who go on this medication lose more weight than with any drug we’ve seen, ever,” said Fatima Cody Stanford, MD, MPH, an obesity medicine specialist at Massachusetts General Hospital and Harvard Medical School, both in Boston, who was not involved with any of the clinical trials.

But that leaves employers and insurers in the uncomfortable position of deciding if it’s worth it.

Wegovy’s monthly wholesale price tag – set at $1,349 – is about 58% more than Ozempic’s, although, the company pointed out, the drug’s injector pens contain more than twice as much of the active ingredient. Studies so far show that patients may need to take it indefinitely to maintain weight loss, translating to a tab that could top $323,000 over 20 years at the current price. Weight-loss treatments are not universally covered by insurance policies.

The arrival of this new class of weight-loss drugs – one from Lilly may soon follow – has created a thicket of issues for those who will pay for them. The decision is complicated by many unknowables concerning their long-term use and whether competition might eventually lower the price.

“The metric we try to use is value,” said James Gelfand, senior vice president for health policy at the ERISA Industry Committee, which represents large, self-insured employers. “If we pay for this drug, how much is this going to cost and how much value will it provide to the beneficiaries?”

Weight-loss treatments have had a lackluster past in this regard, with only modest results. Many employers and insurers likely remember Fen-Phen, a combination of fenfluramine and dexfenfluramine that was pulled from the market in the late 1990s for causing heart valve problems.

New drugs like Wegovy, more effective but also pricier than previous weight-loss treatments, will add more fuel to that debate.

Past treatments were shown to prompt weight loss in the range of 5%-10% of body weight. But many had relatively serious or unpleasant side effects.

Wegovy, however, helped patients lose an average of 15% of their body weight over 68 weeks in the main clinical trial that led to its approval. A comparison group that got a placebo injection lost an average of 2.5% over the same period. On the high end, nearly a third of patients in the treatment group lost 20% or more. Both groups had counseling on diet and exercise.

Side effects, generally considered mild, included nausea, diarrhea, vomiting, and constipation. A few patients developed pancreatitis, a serious inflammation of the pancreas. Like the diabetes medication, the drug carries a warning about a potential risk of a type of thyroid cancer.

Weight loss in those taking Wegovy puts it close to the 20%-25% losses seen with bariatric surgery, said Stanford, and well above the 3%-4% seen with diet and other lifestyle changes alone.

Participants also saw reductions in their waistlines and improvements in their blood pressure and blood sugar levels, which may mean they won’t develop diabetes, said Sean Wharton, MD, an internal medicine specialist and adjunct professor at York University in Toronto who was among the coauthors of the report outlining the results of the first clinical trial on Wegovy.

Since weight loss is known to reduce the risk of heart attack, high blood pressure and diabetes, might the new drug type be worth it?

Covering such treatment would be a sea change for Medicare, which specifically bars coverage for obesity medications or drugs for “anorexia, weight loss, or weight gain,” although it does pay for bariatric surgery. Pharmaceutical companies, patient advocates, and some medical professionals are backing proposed federal legislation to allow coverage. But the legislation, the Treat and Reduce Obesity Act, has not made progress despite being reintroduced every year since 2012, and sponsors are now asking federal officials instead to rewrite existing rules.

Private insurers will have to consider a cost-benefit analysis of adding Wegovy to their list of covered treatments, either broadly or with limits. Obesity was first recognized as a disease by the American Medical Association, easing the path for insurance coverage, in 2013.

“Employers are going to have a bit of a challenge” deciding whether to add the benefit to insurance offerings, said Steve Pearson, founder and president of the Institute for Clinical and Economic Review, which provides cost-benefit analyses of medical treatments but has not yet looked at Wegovy.

The trade-offs are embodied in patients like Phylander Pannell, a 49-year-old Largo, Md., woman who said she lost 65 pounds in a clinical trial of Wegovy. That study gave the drug to all participants for the first 20 weeks, then randomly assigned patients to get either the drug or a placebo for the next 48 weeks to determine what happens when the medication is stopped. Only after the trial ended did she find out she was in the treatment group the entire time.

Her weight fell slowly at first, then ramped up, eventually bringing her 190-pound frame down to about 125. Pains in her joints eased; she felt better all around.

“I definitely feel the drug was it for me,” said Ms. Pannell, who also followed the trial’s guidance on diet and exercise.

The study found that both groups lost weight in the initial 20 weeks, but those who continued to get the drug lost an additional average of 7.9% of their body weight. Those who got a placebo gained back nearly 7%.

After the trial ended, and the COVID-19 pandemic hit, Ms. Pannell regained some weight and is now at 155. She is eager to get back on the medication and hopes her job-based insurance will cover it.

Many employers do cover obesity drugs. For example, about 40% of private employer plans include Novo Nordisk’s once-daily injection called Saxenda on their health plans, said Michael Bachner, Novo Nordisk’s director of media relations.

He said the $1,349-a-month wholesale acquisition price of Wegovy was determined by making it equivalent to that of Saxenda, which is less effective.

Still, that is more than the $851 monthly wholesale price of Ozempic. But, he pointed out, the recommended dosage of Wegovy is more than twice that of Ozempic. Four milligrams come in the Ozempic injector pens for the month, while Wegovy has 9.6.

“There’s more drug in the pen,” Mr. Bachner said. “That drives the price up.”

He added: “This is not a 20-year-old drug that we now have a new indication for and are pricing it higher. It’s a whole different clinical program,” which required new trials.

Now scientists, employers, physicians, and patients will have to decide whether the new drugs are worth it.

Earlier estimates – some commissioned by Novo Nordisk – of the potential cost of adding an obesity drug benefit to Medicare showed an overall reduction in spending when better health from the resulting weight loss was factored in.

Still, those earlier estimates considered much less expensive drugs, including a range of generic and branded drugs costing as little as $7 a month to more than $300, a small fraction of Wegovy’s cost.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

The long list of side effects that follow ads for newer expensive drugs to treat type 2 diabetes sometimes include an unusual warning: They might cause weight loss. That side effect is one that many people – especially those with type 2 diabetes, which is associated with obesity – may desperately want.

So it’s no surprise that some of the same drugs are being reformulated and renamed by manufacturers as a new obesity treatment. No longer limited to the crowded field of treatments for type 2 diabetes, which affects about 10% of Americans, they join the far smaller number of drugs for obesity, which affects 42% of Americans and is ready to be mined for profit.

One that recently hit the market – winning Food and Drug Administration approval in June – is Novo Nordisk’s Wegovy (semaglutide), a higher-dose version of the company’s injectable diabetes drug, Ozempic.

Ozempic’s peppy ads suggest that people who use it might lose weight, but also include a disclaimer: that it “is not a weight-loss drug.” Now – with a new name – it is. And clinical trials showed using it leads to significant weight loss for many patients.

“People who go on this medication lose more weight than with any drug we’ve seen, ever,” said Fatima Cody Stanford, MD, MPH, an obesity medicine specialist at Massachusetts General Hospital and Harvard Medical School, both in Boston, who was not involved with any of the clinical trials.

But that leaves employers and insurers in the uncomfortable position of deciding if it’s worth it.

Wegovy’s monthly wholesale price tag – set at $1,349 – is about 58% more than Ozempic’s, although, the company pointed out, the drug’s injector pens contain more than twice as much of the active ingredient. Studies so far show that patients may need to take it indefinitely to maintain weight loss, translating to a tab that could top $323,000 over 20 years at the current price. Weight-loss treatments are not universally covered by insurance policies.

The arrival of this new class of weight-loss drugs – one from Lilly may soon follow – has created a thicket of issues for those who will pay for them. The decision is complicated by many unknowables concerning their long-term use and whether competition might eventually lower the price.

“The metric we try to use is value,” said James Gelfand, senior vice president for health policy at the ERISA Industry Committee, which represents large, self-insured employers. “If we pay for this drug, how much is this going to cost and how much value will it provide to the beneficiaries?”

Weight-loss treatments have had a lackluster past in this regard, with only modest results. Many employers and insurers likely remember Fen-Phen, a combination of fenfluramine and dexfenfluramine that was pulled from the market in the late 1990s for causing heart valve problems.

New drugs like Wegovy, more effective but also pricier than previous weight-loss treatments, will add more fuel to that debate.

Past treatments were shown to prompt weight loss in the range of 5%-10% of body weight. But many had relatively serious or unpleasant side effects.

Wegovy, however, helped patients lose an average of 15% of their body weight over 68 weeks in the main clinical trial that led to its approval. A comparison group that got a placebo injection lost an average of 2.5% over the same period. On the high end, nearly a third of patients in the treatment group lost 20% or more. Both groups had counseling on diet and exercise.

Side effects, generally considered mild, included nausea, diarrhea, vomiting, and constipation. A few patients developed pancreatitis, a serious inflammation of the pancreas. Like the diabetes medication, the drug carries a warning about a potential risk of a type of thyroid cancer.

Weight loss in those taking Wegovy puts it close to the 20%-25% losses seen with bariatric surgery, said Stanford, and well above the 3%-4% seen with diet and other lifestyle changes alone.

Participants also saw reductions in their waistlines and improvements in their blood pressure and blood sugar levels, which may mean they won’t develop diabetes, said Sean Wharton, MD, an internal medicine specialist and adjunct professor at York University in Toronto who was among the coauthors of the report outlining the results of the first clinical trial on Wegovy.

Since weight loss is known to reduce the risk of heart attack, high blood pressure and diabetes, might the new drug type be worth it?

Covering such treatment would be a sea change for Medicare, which specifically bars coverage for obesity medications or drugs for “anorexia, weight loss, or weight gain,” although it does pay for bariatric surgery. Pharmaceutical companies, patient advocates, and some medical professionals are backing proposed federal legislation to allow coverage. But the legislation, the Treat and Reduce Obesity Act, has not made progress despite being reintroduced every year since 2012, and sponsors are now asking federal officials instead to rewrite existing rules.

Private insurers will have to consider a cost-benefit analysis of adding Wegovy to their list of covered treatments, either broadly or with limits. Obesity was first recognized as a disease by the American Medical Association, easing the path for insurance coverage, in 2013.

“Employers are going to have a bit of a challenge” deciding whether to add the benefit to insurance offerings, said Steve Pearson, founder and president of the Institute for Clinical and Economic Review, which provides cost-benefit analyses of medical treatments but has not yet looked at Wegovy.

The trade-offs are embodied in patients like Phylander Pannell, a 49-year-old Largo, Md., woman who said she lost 65 pounds in a clinical trial of Wegovy. That study gave the drug to all participants for the first 20 weeks, then randomly assigned patients to get either the drug or a placebo for the next 48 weeks to determine what happens when the medication is stopped. Only after the trial ended did she find out she was in the treatment group the entire time.

Her weight fell slowly at first, then ramped up, eventually bringing her 190-pound frame down to about 125. Pains in her joints eased; she felt better all around.

“I definitely feel the drug was it for me,” said Ms. Pannell, who also followed the trial’s guidance on diet and exercise.

The study found that both groups lost weight in the initial 20 weeks, but those who continued to get the drug lost an additional average of 7.9% of their body weight. Those who got a placebo gained back nearly 7%.

After the trial ended, and the COVID-19 pandemic hit, Ms. Pannell regained some weight and is now at 155. She is eager to get back on the medication and hopes her job-based insurance will cover it.

Many employers do cover obesity drugs. For example, about 40% of private employer plans include Novo Nordisk’s once-daily injection called Saxenda on their health plans, said Michael Bachner, Novo Nordisk’s director of media relations.

He said the $1,349-a-month wholesale acquisition price of Wegovy was determined by making it equivalent to that of Saxenda, which is less effective.

Still, that is more than the $851 monthly wholesale price of Ozempic. But, he pointed out, the recommended dosage of Wegovy is more than twice that of Ozempic. Four milligrams come in the Ozempic injector pens for the month, while Wegovy has 9.6.

“There’s more drug in the pen,” Mr. Bachner said. “That drives the price up.”

He added: “This is not a 20-year-old drug that we now have a new indication for and are pricing it higher. It’s a whole different clinical program,” which required new trials.

Now scientists, employers, physicians, and patients will have to decide whether the new drugs are worth it.

Earlier estimates – some commissioned by Novo Nordisk – of the potential cost of adding an obesity drug benefit to Medicare showed an overall reduction in spending when better health from the resulting weight loss was factored in.

Still, those earlier estimates considered much less expensive drugs, including a range of generic and branded drugs costing as little as $7 a month to more than $300, a small fraction of Wegovy’s cost.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

The long list of side effects that follow ads for newer expensive drugs to treat type 2 diabetes sometimes include an unusual warning: They might cause weight loss. That side effect is one that many people – especially those with type 2 diabetes, which is associated with obesity – may desperately want.

So it’s no surprise that some of the same drugs are being reformulated and renamed by manufacturers as a new obesity treatment. No longer limited to the crowded field of treatments for type 2 diabetes, which affects about 10% of Americans, they join the far smaller number of drugs for obesity, which affects 42% of Americans and is ready to be mined for profit.

One that recently hit the market – winning Food and Drug Administration approval in June – is Novo Nordisk’s Wegovy (semaglutide), a higher-dose version of the company’s injectable diabetes drug, Ozempic.

Ozempic’s peppy ads suggest that people who use it might lose weight, but also include a disclaimer: that it “is not a weight-loss drug.” Now – with a new name – it is. And clinical trials showed using it leads to significant weight loss for many patients.

“People who go on this medication lose more weight than with any drug we’ve seen, ever,” said Fatima Cody Stanford, MD, MPH, an obesity medicine specialist at Massachusetts General Hospital and Harvard Medical School, both in Boston, who was not involved with any of the clinical trials.

But that leaves employers and insurers in the uncomfortable position of deciding if it’s worth it.

Wegovy’s monthly wholesale price tag – set at $1,349 – is about 58% more than Ozempic’s, although, the company pointed out, the drug’s injector pens contain more than twice as much of the active ingredient. Studies so far show that patients may need to take it indefinitely to maintain weight loss, translating to a tab that could top $323,000 over 20 years at the current price. Weight-loss treatments are not universally covered by insurance policies.

The arrival of this new class of weight-loss drugs – one from Lilly may soon follow – has created a thicket of issues for those who will pay for them. The decision is complicated by many unknowables concerning their long-term use and whether competition might eventually lower the price.

“The metric we try to use is value,” said James Gelfand, senior vice president for health policy at the ERISA Industry Committee, which represents large, self-insured employers. “If we pay for this drug, how much is this going to cost and how much value will it provide to the beneficiaries?”

Weight-loss treatments have had a lackluster past in this regard, with only modest results. Many employers and insurers likely remember Fen-Phen, a combination of fenfluramine and dexfenfluramine that was pulled from the market in the late 1990s for causing heart valve problems.

New drugs like Wegovy, more effective but also pricier than previous weight-loss treatments, will add more fuel to that debate.

Past treatments were shown to prompt weight loss in the range of 5%-10% of body weight. But many had relatively serious or unpleasant side effects.

Wegovy, however, helped patients lose an average of 15% of their body weight over 68 weeks in the main clinical trial that led to its approval. A comparison group that got a placebo injection lost an average of 2.5% over the same period. On the high end, nearly a third of patients in the treatment group lost 20% or more. Both groups had counseling on diet and exercise.

Side effects, generally considered mild, included nausea, diarrhea, vomiting, and constipation. A few patients developed pancreatitis, a serious inflammation of the pancreas. Like the diabetes medication, the drug carries a warning about a potential risk of a type of thyroid cancer.

Weight loss in those taking Wegovy puts it close to the 20%-25% losses seen with bariatric surgery, said Stanford, and well above the 3%-4% seen with diet and other lifestyle changes alone.

Participants also saw reductions in their waistlines and improvements in their blood pressure and blood sugar levels, which may mean they won’t develop diabetes, said Sean Wharton, MD, an internal medicine specialist and adjunct professor at York University in Toronto who was among the coauthors of the report outlining the results of the first clinical trial on Wegovy.

Since weight loss is known to reduce the risk of heart attack, high blood pressure and diabetes, might the new drug type be worth it?

Covering such treatment would be a sea change for Medicare, which specifically bars coverage for obesity medications or drugs for “anorexia, weight loss, or weight gain,” although it does pay for bariatric surgery. Pharmaceutical companies, patient advocates, and some medical professionals are backing proposed federal legislation to allow coverage. But the legislation, the Treat and Reduce Obesity Act, has not made progress despite being reintroduced every year since 2012, and sponsors are now asking federal officials instead to rewrite existing rules.

Private insurers will have to consider a cost-benefit analysis of adding Wegovy to their list of covered treatments, either broadly or with limits. Obesity was first recognized as a disease by the American Medical Association, easing the path for insurance coverage, in 2013.

“Employers are going to have a bit of a challenge” deciding whether to add the benefit to insurance offerings, said Steve Pearson, founder and president of the Institute for Clinical and Economic Review, which provides cost-benefit analyses of medical treatments but has not yet looked at Wegovy.

The trade-offs are embodied in patients like Phylander Pannell, a 49-year-old Largo, Md., woman who said she lost 65 pounds in a clinical trial of Wegovy. That study gave the drug to all participants for the first 20 weeks, then randomly assigned patients to get either the drug or a placebo for the next 48 weeks to determine what happens when the medication is stopped. Only after the trial ended did she find out she was in the treatment group the entire time.

Her weight fell slowly at first, then ramped up, eventually bringing her 190-pound frame down to about 125. Pains in her joints eased; she felt better all around.

“I definitely feel the drug was it for me,” said Ms. Pannell, who also followed the trial’s guidance on diet and exercise.

The study found that both groups lost weight in the initial 20 weeks, but those who continued to get the drug lost an additional average of 7.9% of their body weight. Those who got a placebo gained back nearly 7%.

After the trial ended, and the COVID-19 pandemic hit, Ms. Pannell regained some weight and is now at 155. She is eager to get back on the medication and hopes her job-based insurance will cover it.

Many employers do cover obesity drugs. For example, about 40% of private employer plans include Novo Nordisk’s once-daily injection called Saxenda on their health plans, said Michael Bachner, Novo Nordisk’s director of media relations.

He said the $1,349-a-month wholesale acquisition price of Wegovy was determined by making it equivalent to that of Saxenda, which is less effective.

Still, that is more than the $851 monthly wholesale price of Ozempic. But, he pointed out, the recommended dosage of Wegovy is more than twice that of Ozempic. Four milligrams come in the Ozempic injector pens for the month, while Wegovy has 9.6.

“There’s more drug in the pen,” Mr. Bachner said. “That drives the price up.”

He added: “This is not a 20-year-old drug that we now have a new indication for and are pricing it higher. It’s a whole different clinical program,” which required new trials.

Now scientists, employers, physicians, and patients will have to decide whether the new drugs are worth it.

Earlier estimates – some commissioned by Novo Nordisk – of the potential cost of adding an obesity drug benefit to Medicare showed an overall reduction in spending when better health from the resulting weight loss was factored in.

Still, those earlier estimates considered much less expensive drugs, including a range of generic and branded drugs costing as little as $7 a month to more than $300, a small fraction of Wegovy’s cost.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

A two-drug fixed-dose tablet therapy of dolutegravir/lamivudine (Dovato, ViiV Healthcare; DTG/3TC) shows noninferiority in viral suppression among people with HIV-1 who switch from any type of three- or four-drug antiretroviral (ART) regimens. But, DTG/3TC also shows feasibility as a first-line regimen in a test-and-treat setting, according to two studies presented at the virtual meeting of the International AIDS Society.

The results on the switch to DTG/3TC are from the phase 3 SALSA trial, which compared patients with HIV-1 who either remained on any current three- or four-drug ART regimen or who switched to the two-drug dolutegravir option.

For the primary endpoint, rates of virologic failure at 48 weeks were noninferior in the DTG/3TC group versus the three- or four-drug regimen (.4% vs. 1.2; adjusted difference: –.8% [95% confidence interval, –2.4%, .8%]).

In addition, rates of virologic suppression at week 48 were noninferior, with 94.3% of patients achieving HIV-1 RNA < 50 c/mL in the DTG/3TC group versus 92.7% in the three- or four-drug regimen (adjusted difference: 1.6% [95% CI, –2.8%, 5.9%).

“These data build upon the previous TANGO study and support DTG/3TC as a robust switch option with high levels of efficacy, good safety and tolerability, and a high barrier of resistance,” first author Josep M. Llibre, MD, PhD, consultant, infectious diseases department, Germans Trias i Pujol University Hospital, Barcelona, said in presenting the findings.

The two-drug dolutegravir-based regimen had previously been shown in the phase 3 GEMINI-1 and GEMINI-2 trials to have virologic noninferiority and safety compared with three- or four-drug DTG plus tenofovir/emtricitabine (TDF/FTC) ART regimens in treatment-naive individuals, and, in the subsequent TANGO trial, the regimen was also noninferior versus tenofovir alafenamide–based regimens among treatment-experienced patients, at 144 weeks in both studies.


 

Trial details

The new SALSA trial, designed to broaden the comparison to treatment with any current three- or four-drug ART regimen, involved 493 patients at 120 study sites in 17 countries.

All patients were initially on a three- or four-drug regimen, with HIV-1 RNA of less than 50 c/mL for more than 6 months, and without prior virologic failure or nucleoside reverse transcriptase inhibitors or dolutegravir resistance-associated mutations.

The participants were randomized 1:1 to remain on their current regimen (n = 247) or to switch to the once-daily, fixed-dose tablet two-drug combination of dolutegravir 50 mg/lamivudine 300 mg (n = 246) for 52 weeks.

In addition to the noninferior virologic outcomes, there were no serious drug-related adverse events, no confirmed virologic withdrawals, and no resistance mutations in either group.

Of note, weight increase was higher in the DTG/3TC group (8%; n = 20) versus the current ART arm (2%; n = 5), as has been observed in previous studies. The adjusted mean change in weight from baseline to week 48 in the DTG arm was 2.1 kg versus 0.6 kg in the current ART arm.

Dr. Llibre pointed out that many of the participants who switched were discontinuing regimens such as TDF and efavirenz that are associated with weight loss, “so discontinuation could be more related to weight gain than the introduction of dolutegravir, but this deserves further study,” he noted.

There were no significant differences in changes in eGFR and fasting lipids, or in changes in inflammatory biomarkers between the groups.

Bone and renal biomarkers were more favorable in the dolutegravir two-drug arm, suggesting that bone and renal function was either maintained or even improved with the drug switch, Dr. Llibre noted.

STAT trial: Feasibility of two-drug DTG/3TC as first-line treatment

In further findings presented at the meeting on the STAT trial, researchers evaluated the feasibility not of switching to, but of initiating patients on, the two-drug DTG treatment as a first-line therapy, within 14 days of HIV-1 diagnosis.

The “test-and-treat” approach counters common belief that the regimen should be started only after the traditional three-drug regimens, because of the potential of transmitted resistance and baseline hepatitis B virus coinfection.

In the study of 131 patients, at week 48, 82% (107/131) of all participants and 97% (107/110) of those with available data achieved HIV-1 RNA levels of < 50 c/mL.

While two participants had confirmed virologic failure in the study, there were no treatment-emergent resistance-associated mutations, and neither patient discontinued the two-drug DTG treatment. There were low rates of drug-related adverse events (8%) and they were not serious.

A two-drug fixed-dose tablet therapy of dolutegravir/lamivudine (Dovato, ViiV Healthcare; DTG/3TC) shows noninferiority in viral suppression among people with HIV-1 who switch from any type of three- or four-drug antiretroviral (ART) regimens. But, DTG/3TC also shows feasibility as a first-line regimen in a test-and-treat setting, according to two studies presented at the virtual meeting of the International AIDS Society.

The results on the switch to DTG/3TC are from the phase 3 SALSA trial, which compared patients with HIV-1 who either remained on any current three- or four-drug ART regimen or who switched to the two-drug dolutegravir option.

For the primary endpoint, rates of virologic failure at 48 weeks were noninferior in the DTG/3TC group versus the three- or four-drug regimen (.4% vs. 1.2; adjusted difference: –.8% [95% confidence interval, –2.4%, .8%]).

In addition, rates of virologic suppression at week 48 were noninferior, with 94.3% of patients achieving HIV-1 RNA < 50 c/mL in the DTG/3TC group versus 92.7% in the three- or four-drug regimen (adjusted difference: 1.6% [95% CI, –2.8%, 5.9%).

“These data build upon the previous TANGO study and support DTG/3TC as a robust switch option with high levels of efficacy, good safety and tolerability, and a high barrier of resistance,” first author Josep M. Llibre, MD, PhD, consultant, infectious diseases department, Germans Trias i Pujol University Hospital, Barcelona, said in presenting the findings.

The two-drug dolutegravir-based regimen had previously been shown in the phase 3 GEMINI-1 and GEMINI-2 trials to have virologic noninferiority and safety compared with three- or four-drug DTG plus tenofovir/emtricitabine (TDF/FTC) ART regimens in treatment-naive individuals, and, in the subsequent TANGO trial, the regimen was also noninferior versus tenofovir alafenamide–based regimens among treatment-experienced patients, at 144 weeks in both studies.


 

Trial details

The new SALSA trial, designed to broaden the comparison to treatment with any current three- or four-drug ART regimen, involved 493 patients at 120 study sites in 17 countries.

All patients were initially on a three- or four-drug regimen, with HIV-1 RNA of less than 50 c/mL for more than 6 months, and without prior virologic failure or nucleoside reverse transcriptase inhibitors or dolutegravir resistance-associated mutations.

The participants were randomized 1:1 to remain on their current regimen (n = 247) or to switch to the once-daily, fixed-dose tablet two-drug combination of dolutegravir 50 mg/lamivudine 300 mg (n = 246) for 52 weeks.

In addition to the noninferior virologic outcomes, there were no serious drug-related adverse events, no confirmed virologic withdrawals, and no resistance mutations in either group.

Of note, weight increase was higher in the DTG/3TC group (8%; n = 20) versus the current ART arm (2%; n = 5), as has been observed in previous studies. The adjusted mean change in weight from baseline to week 48 in the DTG arm was 2.1 kg versus 0.6 kg in the current ART arm.

Dr. Llibre pointed out that many of the participants who switched were discontinuing regimens such as TDF and efavirenz that are associated with weight loss, “so discontinuation could be more related to weight gain than the introduction of dolutegravir, but this deserves further study,” he noted.

There were no significant differences in changes in eGFR and fasting lipids, or in changes in inflammatory biomarkers between the groups.

Bone and renal biomarkers were more favorable in the dolutegravir two-drug arm, suggesting that bone and renal function was either maintained or even improved with the drug switch, Dr. Llibre noted.

STAT trial: Feasibility of two-drug DTG/3TC as first-line treatment

In further findings presented at the meeting on the STAT trial, researchers evaluated the feasibility not of switching to, but of initiating patients on, the two-drug DTG treatment as a first-line therapy, within 14 days of HIV-1 diagnosis.

The “test-and-treat” approach counters common belief that the regimen should be started only after the traditional three-drug regimens, because of the potential of transmitted resistance and baseline hepatitis B virus coinfection.

In the study of 131 patients, at week 48, 82% (107/131) of all participants and 97% (107/110) of those with available data achieved HIV-1 RNA levels of < 50 c/mL.

While two participants had confirmed virologic failure in the study, there were no treatment-emergent resistance-associated mutations, and neither patient discontinued the two-drug DTG treatment. There were low rates of drug-related adverse events (8%) and they were not serious.

A two-drug fixed-dose tablet therapy of dolutegravir/lamivudine (Dovato, ViiV Healthcare; DTG/3TC) shows noninferiority in viral suppression among people with HIV-1 who switch from any type of three- or four-drug antiretroviral (ART) regimens. But, DTG/3TC also shows feasibility as a first-line regimen in a test-and-treat setting, according to two studies presented at the virtual meeting of the International AIDS Society.

The results on the switch to DTG/3TC are from the phase 3 SALSA trial, which compared patients with HIV-1 who either remained on any current three- or four-drug ART regimen or who switched to the two-drug dolutegravir option.

For the primary endpoint, rates of virologic failure at 48 weeks were noninferior in the DTG/3TC group versus the three- or four-drug regimen (.4% vs. 1.2; adjusted difference: –.8% [95% confidence interval, –2.4%, .8%]).

In addition, rates of virologic suppression at week 48 were noninferior, with 94.3% of patients achieving HIV-1 RNA < 50 c/mL in the DTG/3TC group versus 92.7% in the three- or four-drug regimen (adjusted difference: 1.6% [95% CI, –2.8%, 5.9%).

“These data build upon the previous TANGO study and support DTG/3TC as a robust switch option with high levels of efficacy, good safety and tolerability, and a high barrier of resistance,” first author Josep M. Llibre, MD, PhD, consultant, infectious diseases department, Germans Trias i Pujol University Hospital, Barcelona, said in presenting the findings.

The two-drug dolutegravir-based regimen had previously been shown in the phase 3 GEMINI-1 and GEMINI-2 trials to have virologic noninferiority and safety compared with three- or four-drug DTG plus tenofovir/emtricitabine (TDF/FTC) ART regimens in treatment-naive individuals, and, in the subsequent TANGO trial, the regimen was also noninferior versus tenofovir alafenamide–based regimens among treatment-experienced patients, at 144 weeks in both studies.


 

Trial details

The new SALSA trial, designed to broaden the comparison to treatment with any current three- or four-drug ART regimen, involved 493 patients at 120 study sites in 17 countries.

All patients were initially on a three- or four-drug regimen, with HIV-1 RNA of less than 50 c/mL for more than 6 months, and without prior virologic failure or nucleoside reverse transcriptase inhibitors or dolutegravir resistance-associated mutations.

The participants were randomized 1:1 to remain on their current regimen (n = 247) or to switch to the once-daily, fixed-dose tablet two-drug combination of dolutegravir 50 mg/lamivudine 300 mg (n = 246) for 52 weeks.

In addition to the noninferior virologic outcomes, there were no serious drug-related adverse events, no confirmed virologic withdrawals, and no resistance mutations in either group.

Of note, weight increase was higher in the DTG/3TC group (8%; n = 20) versus the current ART arm (2%; n = 5), as has been observed in previous studies. The adjusted mean change in weight from baseline to week 48 in the DTG arm was 2.1 kg versus 0.6 kg in the current ART arm.

Dr. Llibre pointed out that many of the participants who switched were discontinuing regimens such as TDF and efavirenz that are associated with weight loss, “so discontinuation could be more related to weight gain than the introduction of dolutegravir, but this deserves further study,” he noted.

There were no significant differences in changes in eGFR and fasting lipids, or in changes in inflammatory biomarkers between the groups.

Bone and renal biomarkers were more favorable in the dolutegravir two-drug arm, suggesting that bone and renal function was either maintained or even improved with the drug switch, Dr. Llibre noted.

STAT trial: Feasibility of two-drug DTG/3TC as first-line treatment

In further findings presented at the meeting on the STAT trial, researchers evaluated the feasibility not of switching to, but of initiating patients on, the two-drug DTG treatment as a first-line therapy, within 14 days of HIV-1 diagnosis.

The “test-and-treat” approach counters common belief that the regimen should be started only after the traditional three-drug regimens, because of the potential of transmitted resistance and baseline hepatitis B virus coinfection.

In the study of 131 patients, at week 48, 82% (107/131) of all participants and 97% (107/110) of those with available data achieved HIV-1 RNA levels of < 50 c/mL.

While two participants had confirmed virologic failure in the study, there were no treatment-emergent resistance-associated mutations, and neither patient discontinued the two-drug DTG treatment. There were low rates of drug-related adverse events (8%) and they were not serious.

Patients with rheumatoid arthritis currently being treated with low doses of oral glucocorticoids (GCs) had a 59% increased risk of sustaining a vertebral fracture when compared with past users, results of a retrospective cohort study have shown.

izusek/Getty Images

Although the overall risk of an osteoporotic fracture was not increased when comparing current and past GC users, with a hazard ratio of 1.14 (95% confidence interval, 0.98-1.33), the HR for sustaining a spinal fracture was 1.59 (95% CI, 1.11-2.29).

“Clinicians should be aware that, even in RA patients who receive low daily glucocorticoid doses, the risk of clinical vertebral fracture is increased,” Shahab Abtahi, MD, of Maastricht (the Netherlands) University and coauthors reported in Rheumatology.

This is important considering around a quarter of RA patients are treated with GCs in the United Kingdom in accordance with European recommendations, they observed.

Conflicting randomized and observational findings on whether or not osteoporotic fractures might be linked to the use of low-dose GCs prompted Dr. Abtahi and associates to see if there were any signals in real-world data. To do so, they used data one of the world’s largest primary care databases – the Clinical Practice Research Datalink (CPRD), which consists of anonymized patient data from a network of primary care practices across the United Kingdom.

Altogether, the records of more than 15,000 patients with RA aged 50 years and older who were held in the CRPD between 1997 and 2017 were pulled for analysis, and just half (n = 7,039) were receiving or had received GC therapy. Low-dose GC therapy was defined as a prednisolone equivalent dose (PED) of 7.5 mg or less per day.

The use of low-dose GCs use during three key time periods was considered: within the past 6 months (current users), within the past 7-12 months (recent users), and within the past year (past users).

The analyses involved time-dependent Cox proportional-hazards models to look for associations between GC use and all types of osteoporotic fracture, including the risk for incident hip, vertebral, humeral, forearm, pelvis, and rib fractures. They were adjusted for various lifestyle parameters, comorbidities, and the use of other medications.

“Current GC use was further broken down into subcategories based on average daily and cumulative dose,” Dr. Abtahi observed. As might be expected, doses even lower than 7.5 mg or less PED did not increase the chance of any osteoporotic fracture but there was an increased risk for some types with higher average daily doses, notably at the hip and pelvis, as well as the spine.

“Low-dose oral GC therapy was associated with an increased risk of clinical vertebral fracture, while the risk of other individual OP fracture sites was not increased,” said the team, adding that the main results remained unchanged regardless of short- or long-term use.

“We know that vertebral fracture risk is markedly increased in RA, and it is well known that GC therapy in particular affects trabecular bone, which is abundantly present in lumbar vertebrae,” Dr. Abtahi wrote.

“Therefore, we can hypothesize that the beneficial effect of low-dose GC therapy on suppressing the background inflammation of RA could probably be enough to offset its negative effect on bone synthesis in most fracture sites but not in vertebrae,” they suggested.

One of the limitations of the study is that the researchers lacked data on the disease activity of the patients or if they were being treated with biologic therapy. This means that confounding by disease severity might be an issue with only those with higher disease activity being treated with GCs and thus were at higher risk for fractures.

“Another limitation was a potential misclassification of exposure with oral GCs, as we had only prescribing information from CPRD, which is roughly two steps behind actual drug use by patients,” the researchers conceded. The average duration of GC use was estimated at 3.7 years, which is an indication of actual use.

A detection bias may also be involved with regard to vertebral fractures, with complaints of back pain maybe being discussed more often when prescribing GCs, leading to more referrals for possible fracture assessment.

Dr. Abtahi and a fellow coauthor disclosed receiving research and other funding from several pharmaceutical companies unrelated to this study. All other coauthors had no conflicts of interest.

Patients with rheumatoid arthritis currently being treated with low doses of oral glucocorticoids (GCs) had a 59% increased risk of sustaining a vertebral fracture when compared with past users, results of a retrospective cohort study have shown.

izusek/Getty Images

Although the overall risk of an osteoporotic fracture was not increased when comparing current and past GC users, with a hazard ratio of 1.14 (95% confidence interval, 0.98-1.33), the HR for sustaining a spinal fracture was 1.59 (95% CI, 1.11-2.29).

“Clinicians should be aware that, even in RA patients who receive low daily glucocorticoid doses, the risk of clinical vertebral fracture is increased,” Shahab Abtahi, MD, of Maastricht (the Netherlands) University and coauthors reported in Rheumatology.

This is important considering around a quarter of RA patients are treated with GCs in the United Kingdom in accordance with European recommendations, they observed.

Conflicting randomized and observational findings on whether or not osteoporotic fractures might be linked to the use of low-dose GCs prompted Dr. Abtahi and associates to see if there were any signals in real-world data. To do so, they used data one of the world’s largest primary care databases – the Clinical Practice Research Datalink (CPRD), which consists of anonymized patient data from a network of primary care practices across the United Kingdom.

Altogether, the records of more than 15,000 patients with RA aged 50 years and older who were held in the CRPD between 1997 and 2017 were pulled for analysis, and just half (n = 7,039) were receiving or had received GC therapy. Low-dose GC therapy was defined as a prednisolone equivalent dose (PED) of 7.5 mg or less per day.

The use of low-dose GCs use during three key time periods was considered: within the past 6 months (current users), within the past 7-12 months (recent users), and within the past year (past users).

The analyses involved time-dependent Cox proportional-hazards models to look for associations between GC use and all types of osteoporotic fracture, including the risk for incident hip, vertebral, humeral, forearm, pelvis, and rib fractures. They were adjusted for various lifestyle parameters, comorbidities, and the use of other medications.

“Current GC use was further broken down into subcategories based on average daily and cumulative dose,” Dr. Abtahi observed. As might be expected, doses even lower than 7.5 mg or less PED did not increase the chance of any osteoporotic fracture but there was an increased risk for some types with higher average daily doses, notably at the hip and pelvis, as well as the spine.

“Low-dose oral GC therapy was associated with an increased risk of clinical vertebral fracture, while the risk of other individual OP fracture sites was not increased,” said the team, adding that the main results remained unchanged regardless of short- or long-term use.

“We know that vertebral fracture risk is markedly increased in RA, and it is well known that GC therapy in particular affects trabecular bone, which is abundantly present in lumbar vertebrae,” Dr. Abtahi wrote.

“Therefore, we can hypothesize that the beneficial effect of low-dose GC therapy on suppressing the background inflammation of RA could probably be enough to offset its negative effect on bone synthesis in most fracture sites but not in vertebrae,” they suggested.

One of the limitations of the study is that the researchers lacked data on the disease activity of the patients or if they were being treated with biologic therapy. This means that confounding by disease severity might be an issue with only those with higher disease activity being treated with GCs and thus were at higher risk for fractures.

“Another limitation was a potential misclassification of exposure with oral GCs, as we had only prescribing information from CPRD, which is roughly two steps behind actual drug use by patients,” the researchers conceded. The average duration of GC use was estimated at 3.7 years, which is an indication of actual use.

A detection bias may also be involved with regard to vertebral fractures, with complaints of back pain maybe being discussed more often when prescribing GCs, leading to more referrals for possible fracture assessment.

Dr. Abtahi and a fellow coauthor disclosed receiving research and other funding from several pharmaceutical companies unrelated to this study. All other coauthors had no conflicts of interest.

Patients with rheumatoid arthritis currently being treated with low doses of oral glucocorticoids (GCs) had a 59% increased risk of sustaining a vertebral fracture when compared with past users, results of a retrospective cohort study have shown.

izusek/Getty Images

Although the overall risk of an osteoporotic fracture was not increased when comparing current and past GC users, with a hazard ratio of 1.14 (95% confidence interval, 0.98-1.33), the HR for sustaining a spinal fracture was 1.59 (95% CI, 1.11-2.29).

“Clinicians should be aware that, even in RA patients who receive low daily glucocorticoid doses, the risk of clinical vertebral fracture is increased,” Shahab Abtahi, MD, of Maastricht (the Netherlands) University and coauthors reported in Rheumatology.

This is important considering around a quarter of RA patients are treated with GCs in the United Kingdom in accordance with European recommendations, they observed.

Conflicting randomized and observational findings on whether or not osteoporotic fractures might be linked to the use of low-dose GCs prompted Dr. Abtahi and associates to see if there were any signals in real-world data. To do so, they used data one of the world’s largest primary care databases – the Clinical Practice Research Datalink (CPRD), which consists of anonymized patient data from a network of primary care practices across the United Kingdom.

Altogether, the records of more than 15,000 patients with RA aged 50 years and older who were held in the CRPD between 1997 and 2017 were pulled for analysis, and just half (n = 7,039) were receiving or had received GC therapy. Low-dose GC therapy was defined as a prednisolone equivalent dose (PED) of 7.5 mg or less per day.

The use of low-dose GCs use during three key time periods was considered: within the past 6 months (current users), within the past 7-12 months (recent users), and within the past year (past users).

The analyses involved time-dependent Cox proportional-hazards models to look for associations between GC use and all types of osteoporotic fracture, including the risk for incident hip, vertebral, humeral, forearm, pelvis, and rib fractures. They were adjusted for various lifestyle parameters, comorbidities, and the use of other medications.

“Current GC use was further broken down into subcategories based on average daily and cumulative dose,” Dr. Abtahi observed. As might be expected, doses even lower than 7.5 mg or less PED did not increase the chance of any osteoporotic fracture but there was an increased risk for some types with higher average daily doses, notably at the hip and pelvis, as well as the spine.

“Low-dose oral GC therapy was associated with an increased risk of clinical vertebral fracture, while the risk of other individual OP fracture sites was not increased,” said the team, adding that the main results remained unchanged regardless of short- or long-term use.

“We know that vertebral fracture risk is markedly increased in RA, and it is well known that GC therapy in particular affects trabecular bone, which is abundantly present in lumbar vertebrae,” Dr. Abtahi wrote.

“Therefore, we can hypothesize that the beneficial effect of low-dose GC therapy on suppressing the background inflammation of RA could probably be enough to offset its negative effect on bone synthesis in most fracture sites but not in vertebrae,” they suggested.

One of the limitations of the study is that the researchers lacked data on the disease activity of the patients or if they were being treated with biologic therapy. This means that confounding by disease severity might be an issue with only those with higher disease activity being treated with GCs and thus were at higher risk for fractures.

“Another limitation was a potential misclassification of exposure with oral GCs, as we had only prescribing information from CPRD, which is roughly two steps behind actual drug use by patients,” the researchers conceded. The average duration of GC use was estimated at 3.7 years, which is an indication of actual use.

A detection bias may also be involved with regard to vertebral fractures, with complaints of back pain maybe being discussed more often when prescribing GCs, leading to more referrals for possible fracture assessment.

Dr. Abtahi and a fellow coauthor disclosed receiving research and other funding from several pharmaceutical companies unrelated to this study. All other coauthors had no conflicts of interest.

Lower doses of linezolid in the BPaL drug regimen (bedaquiline, pretomanid, and linezolid) significantly reduce the adverse events associated with the treatment for patients with highly drug-resistant tuberculosis (TB) without compromising its high efficacy, new research shows.

“The ZeNix trial shows that reduced doses and/or shorter durations of linezolid appear to have high efficacy and improved safety,” said first author Francesca Conradie, MB, BCh, of the clinical HIV research unit, faculty of health sciences, University of Witwatersrand, Johannesburg, South Africa, in presenting the findings at the virtual meeting of the International AIDS Society conference.

As recently reported in the pivotal Nix-TB trial, the BPaL regimen yielded a 90% treatment success rate among people with highly drug-resistant forms of TB.

However, a 6-month regimen that included linezolid 1,200 mg resulted in toxic effects: 81% of patients in the study experienced peripheral neuropathy, and myelosuppression occurred in 48%. These effects often led to dose reductions or treatment interruption.

Adjustments in the dose of linezolid in the new ZeNix trial substantially reduced peripheral neuropathy to 13% and myelosuppression to 7%, with no significant reduction in the treatment response.

Importantly, the results were similar among patients with and those without HIV. This is of note because TB is the leading cause of death among patients with HIV.

“In the ZeNix trial, only 20% of patients were HIV infected, but in the [previous] Nix-TB trial, 30% were infected, so we have experience now in about 70 patients who were infected, and the outcomes were no different,” Dr. Conradie said in an interview.

Experts say the findings represent an important turn in the steep challenge of tackling highly resistant TB.

“In our opinion, these are exciting results that could change treatment guidelines for highly drug-resistant tuberculosis, with real benefits for the patients,” said Hendrik Streeck, MD, International AIDS Society cochair and director of the Institute of Virology and the Institute for HIV Research at the University Bonn (Germany), in a press conference.

Payam Nahid, MD, MPH, director of the Center for Tuberculosis at theUniversity of California, San Francisco, agreed.

“The results of this trial will impact global practices in treating drug-resistant TB as well as the design and conduct of future TB clinical trials,” Dr. Nahid said in an interview.
 

ZeNix trial

The phase 3 ZeNix trial included 181 patients with highly resistant TB in South Africa, Russia, Georgia, and Moldova. The mean age of the patients was 37 years; 67.4% were men, 63.5% were White, and 19.9% were HIV positive.

All patients were treated for 6 months with bedaquiline 200 mg daily for 8 weeks followed by 100 mg daily for 18 weeks, as well as pretomanid 200 mg daily.

The patients were randomly assigned to receive one of four daily doses of linezolid: 1,200 mg for 6 months (the original dose from the Nix-TB trial; n = 45) or 2 months (n = 46), or 600 mg for 6 or 2 months (45 patients each).

Percentages of patients with HIV were equal among the four groups, at about 20% each.

The primary outcomes – resolution of clinical disease and a negative culture status after 6 months – were observed across all linezolid dose groups. The success rate was 93% for those receiving 1,200 mg for 6 months, 89% for those receiving 1,200 mg for 2 months, 91% for those receiving 600 mg for 6 months, and 84% for those receiving 600 mg for 2 months.

With regard to the key adverse events of peripheral neuropathy and myelosuppression, manifested as anemia, the highest rates were among those who received linezolid 1,200 mg for 6 month, at 38% and 22%, respectively, compared with 24% and 17.4% among those who received 1,200 mg for 2 months, 24% and 2% among those who received 600 mg for 6 months, and 13% and 6.7% among those who received 600 mg for 2 months.

Four cases of optic neuropathy occurred among those who received 1,200 mg for 6 months; all cases resolved.

Patients who received 1,200 mg for 6 months required the highest number of linezolid dose modifications; 51% required changes that included reduction, interruption, or discontinuation, compared with 28% among those who received 1,200 mg for 2 months and 13% each in the other two groups.

On the basis of these results, “my personal opinion is that 600 mg at 6 months [of linezolid] is most likely the best strategy for the treatment of this highly resistant treatment population group,” Dr. Conradie told this news organization.
 

Findings represent ‘great news’ in addressing concerns

Dr. Nahid further commented that the results are highly encouraging in light of the ongoing concerns about the effects of linezolid in the BPaL regimen.

“This is great news,” he said. “The ZeNix trial addresses a key concern that providers and patients have had regarding the safety and tolerability of taking 6 months of linezolid at 1200 mg/d as part of the BPaL regimen.

“The findings that doses lower and durations shorter than the current 1,200 mg linezolid daily for 6 months will significantly expand the usability of the BPaL regimen worldwide.”

The inclusion of patients with HIV was essential in the trial, he noted.

“There are drug-drug interactions to be considered, among other factors that impact drug exposure,” Dr. Nahid said.

“Inclusion of patients living with HIV in this study means that any modifications to the BPaL regimen considered by the WHO [World Health Organization] and other policy decision makers will include data from this key population,” he said. “Of course, more data are needed on safety, tolerability, and efficacy on BPaL in general, and there are international cohorts and demonstration projects underway that will enhance our understanding of the regimen in HIV and in other special populations.”

The authors, Dr. Streeck, and Dr. Nahid have disclosed no relevant financial relationships.

This article was updated 7/21/21.

Lower doses of linezolid in the BPaL drug regimen (bedaquiline, pretomanid, and linezolid) significantly reduce the adverse events associated with the treatment for patients with highly drug-resistant tuberculosis (TB) without compromising its high efficacy, new research shows.

“The ZeNix trial shows that reduced doses and/or shorter durations of linezolid appear to have high efficacy and improved safety,” said first author Francesca Conradie, MB, BCh, of the clinical HIV research unit, faculty of health sciences, University of Witwatersrand, Johannesburg, South Africa, in presenting the findings at the virtual meeting of the International AIDS Society conference.

As recently reported in the pivotal Nix-TB trial, the BPaL regimen yielded a 90% treatment success rate among people with highly drug-resistant forms of TB.

However, a 6-month regimen that included linezolid 1,200 mg resulted in toxic effects: 81% of patients in the study experienced peripheral neuropathy, and myelosuppression occurred in 48%. These effects often led to dose reductions or treatment interruption.

Adjustments in the dose of linezolid in the new ZeNix trial substantially reduced peripheral neuropathy to 13% and myelosuppression to 7%, with no significant reduction in the treatment response.

Importantly, the results were similar among patients with and those without HIV. This is of note because TB is the leading cause of death among patients with HIV.

“In the ZeNix trial, only 20% of patients were HIV infected, but in the [previous] Nix-TB trial, 30% were infected, so we have experience now in about 70 patients who were infected, and the outcomes were no different,” Dr. Conradie said in an interview.

Experts say the findings represent an important turn in the steep challenge of tackling highly resistant TB.

“In our opinion, these are exciting results that could change treatment guidelines for highly drug-resistant tuberculosis, with real benefits for the patients,” said Hendrik Streeck, MD, International AIDS Society cochair and director of the Institute of Virology and the Institute for HIV Research at the University Bonn (Germany), in a press conference.

Payam Nahid, MD, MPH, director of the Center for Tuberculosis at theUniversity of California, San Francisco, agreed.

“The results of this trial will impact global practices in treating drug-resistant TB as well as the design and conduct of future TB clinical trials,” Dr. Nahid said in an interview.
 

ZeNix trial

The phase 3 ZeNix trial included 181 patients with highly resistant TB in South Africa, Russia, Georgia, and Moldova. The mean age of the patients was 37 years; 67.4% were men, 63.5% were White, and 19.9% were HIV positive.

All patients were treated for 6 months with bedaquiline 200 mg daily for 8 weeks followed by 100 mg daily for 18 weeks, as well as pretomanid 200 mg daily.

The patients were randomly assigned to receive one of four daily doses of linezolid: 1,200 mg for 6 months (the original dose from the Nix-TB trial; n = 45) or 2 months (n = 46), or 600 mg for 6 or 2 months (45 patients each).

Percentages of patients with HIV were equal among the four groups, at about 20% each.

The primary outcomes – resolution of clinical disease and a negative culture status after 6 months – were observed across all linezolid dose groups. The success rate was 93% for those receiving 1,200 mg for 6 months, 89% for those receiving 1,200 mg for 2 months, 91% for those receiving 600 mg for 6 months, and 84% for those receiving 600 mg for 2 months.

With regard to the key adverse events of peripheral neuropathy and myelosuppression, manifested as anemia, the highest rates were among those who received linezolid 1,200 mg for 6 month, at 38% and 22%, respectively, compared with 24% and 17.4% among those who received 1,200 mg for 2 months, 24% and 2% among those who received 600 mg for 6 months, and 13% and 6.7% among those who received 600 mg for 2 months.

Four cases of optic neuropathy occurred among those who received 1,200 mg for 6 months; all cases resolved.

Patients who received 1,200 mg for 6 months required the highest number of linezolid dose modifications; 51% required changes that included reduction, interruption, or discontinuation, compared with 28% among those who received 1,200 mg for 2 months and 13% each in the other two groups.

On the basis of these results, “my personal opinion is that 600 mg at 6 months [of linezolid] is most likely the best strategy for the treatment of this highly resistant treatment population group,” Dr. Conradie told this news organization.
 

Findings represent ‘great news’ in addressing concerns

Dr. Nahid further commented that the results are highly encouraging in light of the ongoing concerns about the effects of linezolid in the BPaL regimen.

“This is great news,” he said. “The ZeNix trial addresses a key concern that providers and patients have had regarding the safety and tolerability of taking 6 months of linezolid at 1200 mg/d as part of the BPaL regimen.

“The findings that doses lower and durations shorter than the current 1,200 mg linezolid daily for 6 months will significantly expand the usability of the BPaL regimen worldwide.”

The inclusion of patients with HIV was essential in the trial, he noted.

“There are drug-drug interactions to be considered, among other factors that impact drug exposure,” Dr. Nahid said.

“Inclusion of patients living with HIV in this study means that any modifications to the BPaL regimen considered by the WHO [World Health Organization] and other policy decision makers will include data from this key population,” he said. “Of course, more data are needed on safety, tolerability, and efficacy on BPaL in general, and there are international cohorts and demonstration projects underway that will enhance our understanding of the regimen in HIV and in other special populations.”

The authors, Dr. Streeck, and Dr. Nahid have disclosed no relevant financial relationships.

This article was updated 7/21/21.

Lower doses of linezolid in the BPaL drug regimen (bedaquiline, pretomanid, and linezolid) significantly reduce the adverse events associated with the treatment for patients with highly drug-resistant tuberculosis (TB) without compromising its high efficacy, new research shows.

“The ZeNix trial shows that reduced doses and/or shorter durations of linezolid appear to have high efficacy and improved safety,” said first author Francesca Conradie, MB, BCh, of the clinical HIV research unit, faculty of health sciences, University of Witwatersrand, Johannesburg, South Africa, in presenting the findings at the virtual meeting of the International AIDS Society conference.

As recently reported in the pivotal Nix-TB trial, the BPaL regimen yielded a 90% treatment success rate among people with highly drug-resistant forms of TB.

However, a 6-month regimen that included linezolid 1,200 mg resulted in toxic effects: 81% of patients in the study experienced peripheral neuropathy, and myelosuppression occurred in 48%. These effects often led to dose reductions or treatment interruption.

Adjustments in the dose of linezolid in the new ZeNix trial substantially reduced peripheral neuropathy to 13% and myelosuppression to 7%, with no significant reduction in the treatment response.

Importantly, the results were similar among patients with and those without HIV. This is of note because TB is the leading cause of death among patients with HIV.

“In the ZeNix trial, only 20% of patients were HIV infected, but in the [previous] Nix-TB trial, 30% were infected, so we have experience now in about 70 patients who were infected, and the outcomes were no different,” Dr. Conradie said in an interview.

Experts say the findings represent an important turn in the steep challenge of tackling highly resistant TB.

“In our opinion, these are exciting results that could change treatment guidelines for highly drug-resistant tuberculosis, with real benefits for the patients,” said Hendrik Streeck, MD, International AIDS Society cochair and director of the Institute of Virology and the Institute for HIV Research at the University Bonn (Germany), in a press conference.

Payam Nahid, MD, MPH, director of the Center for Tuberculosis at theUniversity of California, San Francisco, agreed.

“The results of this trial will impact global practices in treating drug-resistant TB as well as the design and conduct of future TB clinical trials,” Dr. Nahid said in an interview.
 

ZeNix trial

The phase 3 ZeNix trial included 181 patients with highly resistant TB in South Africa, Russia, Georgia, and Moldova. The mean age of the patients was 37 years; 67.4% were men, 63.5% were White, and 19.9% were HIV positive.

All patients were treated for 6 months with bedaquiline 200 mg daily for 8 weeks followed by 100 mg daily for 18 weeks, as well as pretomanid 200 mg daily.

The patients were randomly assigned to receive one of four daily doses of linezolid: 1,200 mg for 6 months (the original dose from the Nix-TB trial; n = 45) or 2 months (n = 46), or 600 mg for 6 or 2 months (45 patients each).

Percentages of patients with HIV were equal among the four groups, at about 20% each.

The primary outcomes – resolution of clinical disease and a negative culture status after 6 months – were observed across all linezolid dose groups. The success rate was 93% for those receiving 1,200 mg for 6 months, 89% for those receiving 1,200 mg for 2 months, 91% for those receiving 600 mg for 6 months, and 84% for those receiving 600 mg for 2 months.

With regard to the key adverse events of peripheral neuropathy and myelosuppression, manifested as anemia, the highest rates were among those who received linezolid 1,200 mg for 6 month, at 38% and 22%, respectively, compared with 24% and 17.4% among those who received 1,200 mg for 2 months, 24% and 2% among those who received 600 mg for 6 months, and 13% and 6.7% among those who received 600 mg for 2 months.

Four cases of optic neuropathy occurred among those who received 1,200 mg for 6 months; all cases resolved.

Patients who received 1,200 mg for 6 months required the highest number of linezolid dose modifications; 51% required changes that included reduction, interruption, or discontinuation, compared with 28% among those who received 1,200 mg for 2 months and 13% each in the other two groups.

On the basis of these results, “my personal opinion is that 600 mg at 6 months [of linezolid] is most likely the best strategy for the treatment of this highly resistant treatment population group,” Dr. Conradie told this news organization.
 

Findings represent ‘great news’ in addressing concerns

Dr. Nahid further commented that the results are highly encouraging in light of the ongoing concerns about the effects of linezolid in the BPaL regimen.

“This is great news,” he said. “The ZeNix trial addresses a key concern that providers and patients have had regarding the safety and tolerability of taking 6 months of linezolid at 1200 mg/d as part of the BPaL regimen.

“The findings that doses lower and durations shorter than the current 1,200 mg linezolid daily for 6 months will significantly expand the usability of the BPaL regimen worldwide.”

The inclusion of patients with HIV was essential in the trial, he noted.

“There are drug-drug interactions to be considered, among other factors that impact drug exposure,” Dr. Nahid said.

“Inclusion of patients living with HIV in this study means that any modifications to the BPaL regimen considered by the WHO [World Health Organization] and other policy decision makers will include data from this key population,” he said. “Of course, more data are needed on safety, tolerability, and efficacy on BPaL in general, and there are international cohorts and demonstration projects underway that will enhance our understanding of the regimen in HIV and in other special populations.”

The authors, Dr. Streeck, and Dr. Nahid have disclosed no relevant financial relationships.

This article was updated 7/21/21.

A lack of consensus in the evidence regarding the antiviral remdesivir (Veklury) to treat people with COVID-19 continues, leaving clinicians without clear direction on one of the few treatments for the illness approved under U.S. Food and Drug Administration emergency use authorization.

The latest research comes from Michael Ohl, MD, MSPH, and colleagues, who studied a large group of VA patients hospitalized with COVID-19. Compared with a matched group of veterans who did not receive the antiviral, remdesivir did not significantly improve survival.

The percentages were close: 12.2% of patients in the remdesivir group died within 30 days compared with 10.6% of those in the control group.

At the same time, the retrospective cohort study showed remdesivir was associated with more days in the hospital.

“There is still uncertainty about the role of remdesivir in treatment for people hospitalized with COVID-19,” Dr. Ohl told this news organization.

“It is reasonable to follow the CDC and Infectious Diseases Society of America guidelines for remdesivir use, “but clinicians should avoid admitting people or keeping people in the hospital solely to receive remdesivir if they do not meet other criteria for hospitalization,” said Dr. Ohl, lead author and an infectious disease specialist at the Center for Access & Delivery Research and Evaluation, Iowa City Veterans Affairs (VA) Health Care System.

The study was published online July 15 in JAMA Network Open.
 

Sticking with the official protocol?

The longer a hospital stays associated with remdesivir, a median 6 days versus 3 days, could be a result of treating people for 5 or 10 days with the antiviral agent. In other words, it is “possible that clinicians were not discharging patients who otherwise met the criteria for hospital discharge until the remdesivir course was completed,” Dr. Ohl and colleagues note.

Not doing so, they add, could have resulted in “increased used of scarce hospital beds during the pandemic.”

“The recommended remdesivir treatment course is a somewhat arbitrary 5 or 10 days depending on illness severity, and remdesivir is currently available only as an intravenous formulation for use in health care settings,” they add.

This is the “most likely explanation,” notes Gio J. Baracco, MD, in an invited commentary accompanying the study.

At the time of the study, use of remdesivir also required patient consent, close adverse event monitoring, and ongoing testing, Dr. Baracco notes.

He added that an option to discharge patients earlier if they responded to treatment might have been lost in translation from clinical trial protocol to real-world use in the VA system.

While a large clinical trial protocol called for the remdesivir infusions to be stopped early if the patient met the primary outcome and was ready to be discharged, “this detail was not adequately translated to the clinicians treating these patients,” added Dr. Baracco, who’s with the Division of Infectious Diseases at the University of Miami Miller School of Medicine and the Miami VA Healthcare System.
 

Conflicting evidence

Another large study, the World Health Organization Solidarity Trial, found remdesivir was not associated with shorter hospital stays or improved survival compared with standard of care. For this reason, the WHO recommends against use of remdesivir.

In contrast, the double-blind, randomized Adaptive COVID-19 Treatment Trial (ACTT-1) linked remdesivir treatment to shorter stays in the hospital, a median 10 days versus 15 days in a placebo group.

The FDA included the 2020 ACTT-1 in its consideration for remdesivir emergency use authorization. The FDA issued the EUA in May 2020, followed by full approval as the first treatment indicated for COVID-19 in October.

ACTT-1 lead author John H. Beigel, MD, and colleagues also looked at the death rates for remdesivir versus placebo.

By day 15, the proportion of people who died was 6.7% in the remdesivir group versus 11%. By day 29, the rate was 11.4% among those who received the antiviral versus 15.2% among those who did not.

When asked why the VA and ACTT-1 studies yielded different results, Dr. Beigel cited two reasons. The timing was different, with the VA study starting after the remdesivir EUA was issued, and ACTT-1 findings were announced.

“So at that point, clinicians understood those populations most likely to benefit from remdesivir. The use of remdesivir likely did not occur at random; it was likely to be more commonly used in those who were sicker or at higher risk for poor outcomes,” said Dr. Beigel, associate director for clinical research in the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases (NIAID).

In addition, the studies evaluated very different populations, he said. The differences in median duration of hospitalization between the trials reflects this, Dr. Beigel added.

Furthermore, when asked if he thinks the new evidence should affect clinical use of remdesivir, Dr. Beigel replied, “No. Observational studies, even with adjustments such as propensity score matching, are not equivalent levels of proof compared to randomized trials.”
 

Study details

Dr. Ohl and colleagues identified patients admitted to one of 123 VA hospitals for the first time for COVID-19 from May 1 to Oct. 8, 2020. Each had a PCR-confirmed SARS-CoV-2 infection. The researchers then compared 1,172 patients receiving remdesivir to another 1,172 patients not receiving the agent.

Those receiving remdesivir were more likely to be older, White, have chronic obstructive pulmonary disease and have more severe COVID-19. A total 94% of the remdesivir group were men.

“Over 90% of the people included in VA study were men, mostly over the age of 60,” Dr. Ohl said when asked how generalizable the findings would be to a non-VA population.

“There is no obvious biological reason that remdesivir should have different effects in men and women, but we should be cautious about extrapolating study findings to women and younger individuals,” he added.

Limitations of the study include its observational design, which makes unadjusted confounding based on illness severity a possibility. In addition, the investigators were unable to identify specific subgroups that might benefit from remdesivir treatment.

The data did suggest that remdesivir was more effective earlier in the course of disease when patients required supplemental oxygen and before need for mechanical ventilation.

Dr. Baracco pointed out the contradictory findings in his commentary: “The real-life application of a drug promising to hasten discharge from the hospital as its primary beneficial outcome must include an assessment of how easy it is to do so and make it clear that once a patient reaches that point, they can discontinue the drug.”

“The paradoxical findings in the study by Dr. Ohl et al. compared with the study used for its authorization illustrate this point very clearly,” he adds.

Dr. Ohl reported receiving grants from Veterans Affairs Health Services Research and Development during the conduct of the study and consulting for Gilead Pharmaceuticals outside the submitted work. Dr. Baracco reported receiving salary support from the U.S. Department of Veterans Affairs. Dr. Beigel has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A lack of consensus in the evidence regarding the antiviral remdesivir (Veklury) to treat people with COVID-19 continues, leaving clinicians without clear direction on one of the few treatments for the illness approved under U.S. Food and Drug Administration emergency use authorization.

The latest research comes from Michael Ohl, MD, MSPH, and colleagues, who studied a large group of VA patients hospitalized with COVID-19. Compared with a matched group of veterans who did not receive the antiviral, remdesivir did not significantly improve survival.

The percentages were close: 12.2% of patients in the remdesivir group died within 30 days compared with 10.6% of those in the control group.

At the same time, the retrospective cohort study showed remdesivir was associated with more days in the hospital.

“There is still uncertainty about the role of remdesivir in treatment for people hospitalized with COVID-19,” Dr. Ohl told this news organization.

“It is reasonable to follow the CDC and Infectious Diseases Society of America guidelines for remdesivir use, “but clinicians should avoid admitting people or keeping people in the hospital solely to receive remdesivir if they do not meet other criteria for hospitalization,” said Dr. Ohl, lead author and an infectious disease specialist at the Center for Access & Delivery Research and Evaluation, Iowa City Veterans Affairs (VA) Health Care System.

The study was published online July 15 in JAMA Network Open.
 

Sticking with the official protocol?

The longer a hospital stays associated with remdesivir, a median 6 days versus 3 days, could be a result of treating people for 5 or 10 days with the antiviral agent. In other words, it is “possible that clinicians were not discharging patients who otherwise met the criteria for hospital discharge until the remdesivir course was completed,” Dr. Ohl and colleagues note.

Not doing so, they add, could have resulted in “increased used of scarce hospital beds during the pandemic.”

“The recommended remdesivir treatment course is a somewhat arbitrary 5 or 10 days depending on illness severity, and remdesivir is currently available only as an intravenous formulation for use in health care settings,” they add.

This is the “most likely explanation,” notes Gio J. Baracco, MD, in an invited commentary accompanying the study.

At the time of the study, use of remdesivir also required patient consent, close adverse event monitoring, and ongoing testing, Dr. Baracco notes.

He added that an option to discharge patients earlier if they responded to treatment might have been lost in translation from clinical trial protocol to real-world use in the VA system.

While a large clinical trial protocol called for the remdesivir infusions to be stopped early if the patient met the primary outcome and was ready to be discharged, “this detail was not adequately translated to the clinicians treating these patients,” added Dr. Baracco, who’s with the Division of Infectious Diseases at the University of Miami Miller School of Medicine and the Miami VA Healthcare System.
 

Conflicting evidence

Another large study, the World Health Organization Solidarity Trial, found remdesivir was not associated with shorter hospital stays or improved survival compared with standard of care. For this reason, the WHO recommends against use of remdesivir.

In contrast, the double-blind, randomized Adaptive COVID-19 Treatment Trial (ACTT-1) linked remdesivir treatment to shorter stays in the hospital, a median 10 days versus 15 days in a placebo group.

The FDA included the 2020 ACTT-1 in its consideration for remdesivir emergency use authorization. The FDA issued the EUA in May 2020, followed by full approval as the first treatment indicated for COVID-19 in October.

ACTT-1 lead author John H. Beigel, MD, and colleagues also looked at the death rates for remdesivir versus placebo.

By day 15, the proportion of people who died was 6.7% in the remdesivir group versus 11%. By day 29, the rate was 11.4% among those who received the antiviral versus 15.2% among those who did not.

When asked why the VA and ACTT-1 studies yielded different results, Dr. Beigel cited two reasons. The timing was different, with the VA study starting after the remdesivir EUA was issued, and ACTT-1 findings were announced.

“So at that point, clinicians understood those populations most likely to benefit from remdesivir. The use of remdesivir likely did not occur at random; it was likely to be more commonly used in those who were sicker or at higher risk for poor outcomes,” said Dr. Beigel, associate director for clinical research in the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases (NIAID).

In addition, the studies evaluated very different populations, he said. The differences in median duration of hospitalization between the trials reflects this, Dr. Beigel added.

Furthermore, when asked if he thinks the new evidence should affect clinical use of remdesivir, Dr. Beigel replied, “No. Observational studies, even with adjustments such as propensity score matching, are not equivalent levels of proof compared to randomized trials.”
 

Study details

Dr. Ohl and colleagues identified patients admitted to one of 123 VA hospitals for the first time for COVID-19 from May 1 to Oct. 8, 2020. Each had a PCR-confirmed SARS-CoV-2 infection. The researchers then compared 1,172 patients receiving remdesivir to another 1,172 patients not receiving the agent.

Those receiving remdesivir were more likely to be older, White, have chronic obstructive pulmonary disease and have more severe COVID-19. A total 94% of the remdesivir group were men.

“Over 90% of the people included in VA study were men, mostly over the age of 60,” Dr. Ohl said when asked how generalizable the findings would be to a non-VA population.

“There is no obvious biological reason that remdesivir should have different effects in men and women, but we should be cautious about extrapolating study findings to women and younger individuals,” he added.

Limitations of the study include its observational design, which makes unadjusted confounding based on illness severity a possibility. In addition, the investigators were unable to identify specific subgroups that might benefit from remdesivir treatment.

The data did suggest that remdesivir was more effective earlier in the course of disease when patients required supplemental oxygen and before need for mechanical ventilation.

Dr. Baracco pointed out the contradictory findings in his commentary: “The real-life application of a drug promising to hasten discharge from the hospital as its primary beneficial outcome must include an assessment of how easy it is to do so and make it clear that once a patient reaches that point, they can discontinue the drug.”

“The paradoxical findings in the study by Dr. Ohl et al. compared with the study used for its authorization illustrate this point very clearly,” he adds.

Dr. Ohl reported receiving grants from Veterans Affairs Health Services Research and Development during the conduct of the study and consulting for Gilead Pharmaceuticals outside the submitted work. Dr. Baracco reported receiving salary support from the U.S. Department of Veterans Affairs. Dr. Beigel has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A lack of consensus in the evidence regarding the antiviral remdesivir (Veklury) to treat people with COVID-19 continues, leaving clinicians without clear direction on one of the few treatments for the illness approved under U.S. Food and Drug Administration emergency use authorization.

The latest research comes from Michael Ohl, MD, MSPH, and colleagues, who studied a large group of VA patients hospitalized with COVID-19. Compared with a matched group of veterans who did not receive the antiviral, remdesivir did not significantly improve survival.

The percentages were close: 12.2% of patients in the remdesivir group died within 30 days compared with 10.6% of those in the control group.

At the same time, the retrospective cohort study showed remdesivir was associated with more days in the hospital.

“There is still uncertainty about the role of remdesivir in treatment for people hospitalized with COVID-19,” Dr. Ohl told this news organization.

“It is reasonable to follow the CDC and Infectious Diseases Society of America guidelines for remdesivir use, “but clinicians should avoid admitting people or keeping people in the hospital solely to receive remdesivir if they do not meet other criteria for hospitalization,” said Dr. Ohl, lead author and an infectious disease specialist at the Center for Access & Delivery Research and Evaluation, Iowa City Veterans Affairs (VA) Health Care System.

The study was published online July 15 in JAMA Network Open.
 

Sticking with the official protocol?

The longer a hospital stays associated with remdesivir, a median 6 days versus 3 days, could be a result of treating people for 5 or 10 days with the antiviral agent. In other words, it is “possible that clinicians were not discharging patients who otherwise met the criteria for hospital discharge until the remdesivir course was completed,” Dr. Ohl and colleagues note.

Not doing so, they add, could have resulted in “increased used of scarce hospital beds during the pandemic.”

“The recommended remdesivir treatment course is a somewhat arbitrary 5 or 10 days depending on illness severity, and remdesivir is currently available only as an intravenous formulation for use in health care settings,” they add.

This is the “most likely explanation,” notes Gio J. Baracco, MD, in an invited commentary accompanying the study.

At the time of the study, use of remdesivir also required patient consent, close adverse event monitoring, and ongoing testing, Dr. Baracco notes.

He added that an option to discharge patients earlier if they responded to treatment might have been lost in translation from clinical trial protocol to real-world use in the VA system.

While a large clinical trial protocol called for the remdesivir infusions to be stopped early if the patient met the primary outcome and was ready to be discharged, “this detail was not adequately translated to the clinicians treating these patients,” added Dr. Baracco, who’s with the Division of Infectious Diseases at the University of Miami Miller School of Medicine and the Miami VA Healthcare System.
 

Conflicting evidence

Another large study, the World Health Organization Solidarity Trial, found remdesivir was not associated with shorter hospital stays or improved survival compared with standard of care. For this reason, the WHO recommends against use of remdesivir.

In contrast, the double-blind, randomized Adaptive COVID-19 Treatment Trial (ACTT-1) linked remdesivir treatment to shorter stays in the hospital, a median 10 days versus 15 days in a placebo group.

The FDA included the 2020 ACTT-1 in its consideration for remdesivir emergency use authorization. The FDA issued the EUA in May 2020, followed by full approval as the first treatment indicated for COVID-19 in October.

ACTT-1 lead author John H. Beigel, MD, and colleagues also looked at the death rates for remdesivir versus placebo.

By day 15, the proportion of people who died was 6.7% in the remdesivir group versus 11%. By day 29, the rate was 11.4% among those who received the antiviral versus 15.2% among those who did not.

When asked why the VA and ACTT-1 studies yielded different results, Dr. Beigel cited two reasons. The timing was different, with the VA study starting after the remdesivir EUA was issued, and ACTT-1 findings were announced.

“So at that point, clinicians understood those populations most likely to benefit from remdesivir. The use of remdesivir likely did not occur at random; it was likely to be more commonly used in those who were sicker or at higher risk for poor outcomes,” said Dr. Beigel, associate director for clinical research in the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases (NIAID).

In addition, the studies evaluated very different populations, he said. The differences in median duration of hospitalization between the trials reflects this, Dr. Beigel added.

Furthermore, when asked if he thinks the new evidence should affect clinical use of remdesivir, Dr. Beigel replied, “No. Observational studies, even with adjustments such as propensity score matching, are not equivalent levels of proof compared to randomized trials.”
 

Study details

Dr. Ohl and colleagues identified patients admitted to one of 123 VA hospitals for the first time for COVID-19 from May 1 to Oct. 8, 2020. Each had a PCR-confirmed SARS-CoV-2 infection. The researchers then compared 1,172 patients receiving remdesivir to another 1,172 patients not receiving the agent.

Those receiving remdesivir were more likely to be older, White, have chronic obstructive pulmonary disease and have more severe COVID-19. A total 94% of the remdesivir group were men.

“Over 90% of the people included in VA study were men, mostly over the age of 60,” Dr. Ohl said when asked how generalizable the findings would be to a non-VA population.

“There is no obvious biological reason that remdesivir should have different effects in men and women, but we should be cautious about extrapolating study findings to women and younger individuals,” he added.

Limitations of the study include its observational design, which makes unadjusted confounding based on illness severity a possibility. In addition, the investigators were unable to identify specific subgroups that might benefit from remdesivir treatment.

The data did suggest that remdesivir was more effective earlier in the course of disease when patients required supplemental oxygen and before need for mechanical ventilation.

Dr. Baracco pointed out the contradictory findings in his commentary: “The real-life application of a drug promising to hasten discharge from the hospital as its primary beneficial outcome must include an assessment of how easy it is to do so and make it clear that once a patient reaches that point, they can discontinue the drug.”

“The paradoxical findings in the study by Dr. Ohl et al. compared with the study used for its authorization illustrate this point very clearly,” he adds.

Dr. Ohl reported receiving grants from Veterans Affairs Health Services Research and Development during the conduct of the study and consulting for Gilead Pharmaceuticals outside the submitted work. Dr. Baracco reported receiving salary support from the U.S. Department of Veterans Affairs. Dr. Beigel has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Use of metformin was associated with a significant reduction in the risk of developing basal cell carcinoma (BCC), based on data from a population case-control study in Iceland.

“In addition to general anticarcinogenic effects, metformin has also been shown to directly inhibit the sonic hedgehog pathway, a key pathway in basal cell carcinoma (BCC) pathogenesis,” Jonas A. Adalsteinsson, MD, of the University of Iceland, Reykjavik, and colleagues wrote. “The relationship between metformin and keratinocyte carcinoma has not been well-characterized but is of importance considering that metformin is a commonly prescribed medication.”

They added that the hedgehog pathway inhibitors vismodegib (Erivedge) and sonidegib (Odomzo), approved for treating BCC, “are highly effective for BCC prevention, but their broad use for BCC prophylaxis is limited due to numerous side effects.”

In the study, published in the Journal of the American Academy of Dermatology, the researchers identified 6,880 first-time cancer patients with BCC, squamous cell carcinoma in situ (SCCis), or invasive SCC, and 69,620 population controls using data from the Icelandic Cancer Registry and the Icelandic Prescription Medicine Register between 2003 and 2017. Metformin exposure was defined as having filled at least one prescription of metformin more than 2 years prior to cancer diagnosis. They used grams and daily dose units of metformin in their analysis; one DDU of metformin, “or its average daily maintenance dose when used for its primary indication, is 2 grams,” they noted.

Overall, metformin use was associated with a significantly lower risk of developing BCC, compared with nonuse (adjusted odds ratio, 0.71; 95% confidence interval, 0.61-0.83).

The reduced risk occurred similarly across age and gender subgroups, with the exception of individuals younger than 60 years, the researchers said. “This might signify that metformin has less of a protective effect in younger individuals, but we might also have lacked power in this category.” The association with reduced BCC risk remained significant at all three cumulative dose levels measured: 1-500 DDUs, 501-1,500 DDUs, and more than 1,500 DDUs.

Metformin use was not significantly associated with reduced risk of invasive SCC (aOR, 1.01) and in most cases of SCCis. However, the 501-1,500 DDU dose category was associated with a slight increase in risk of SCCis (aOR, 1.40; 95% CI, 1.00-1.96), “showing a possible increased risk of SCCis,” the authors wrote.

The decrease in BCC risk was seen across all metformin dosing levels, but the reason for this remains unclear, and might be related to a confounding factor that was not considered in this study, the researchers said. “It could also be that metformin’s BCC risk-lowering effect is immediate, with only a low dose being needed to see a clinical benefit.”

The study findings were limited by several factors, including the retrospective design and the inability to adjust for factors including ultraviolet exposure, Fitzpatrick skin type, and comorbidities. The frequent use of metformin by people with type 2 diabetes suggests diabetes itself or other diabetes medications could be possible confounding factors, the researchers wrote.

However, the results were strengthened by the large study population, and the data suggest an association between reduced risk of first-time BCC and metformin use, they added.

“Randomized, prospective trials are required to fully understand the effect metformin has on BCC and SCC risk,” the researchers concluded.

“There is a dire need to reduce incidence of skin cancers in general, and consequently a need for new non-surgical treatment options for keratinocytic nonmelanoma skin cancers,” Amor Khachemoune, MD, a dermatologist at the State University of New York, Brooklyn, and the department of dermatology of the Veteran Affairs NY Harbor Healthcare System, also in Brooklyn, said in an interview.

Dr. Khachemoune, who was not involved with the study, said that he was not surprised by the findings. “Like other well-studied sonic hedgehog inhibitors, vismodegib and sonidegib, metformin has a demonstrated effect on this pathway. The medical community outside of dermatology has extensive experience with the use of metformin for a host of other indications, including its role as anticarcinogenic, so it seemed natural that one would consider widening its use to quell the ever-expanding cases of basal cell carcinomas.”

However, complications from long-term use, though likely rare, could be a limitation in using metformin as a chemoprotective agent, Dr. Khachemoune said. Metformin-associated lactic acidosis is one example of a rare, but potentially life-threatening adverse event.

“Finding the right dosage and having an algorithm for follow up monitoring of side effects would certainly need to be put in place in a standardized way,” he emphasized. “As stated by the authors of this study, more inclusive research involving other groups with nonkeratinocytic malignancies in larger cohorts is needed.”

The study received no outside funding. The researchers and Dr. Khachemoune had no financial conflicts to disclose.

Use of metformin was associated with a significant reduction in the risk of developing basal cell carcinoma (BCC), based on data from a population case-control study in Iceland.

“In addition to general anticarcinogenic effects, metformin has also been shown to directly inhibit the sonic hedgehog pathway, a key pathway in basal cell carcinoma (BCC) pathogenesis,” Jonas A. Adalsteinsson, MD, of the University of Iceland, Reykjavik, and colleagues wrote. “The relationship between metformin and keratinocyte carcinoma has not been well-characterized but is of importance considering that metformin is a commonly prescribed medication.”

They added that the hedgehog pathway inhibitors vismodegib (Erivedge) and sonidegib (Odomzo), approved for treating BCC, “are highly effective for BCC prevention, but their broad use for BCC prophylaxis is limited due to numerous side effects.”

In the study, published in the Journal of the American Academy of Dermatology, the researchers identified 6,880 first-time cancer patients with BCC, squamous cell carcinoma in situ (SCCis), or invasive SCC, and 69,620 population controls using data from the Icelandic Cancer Registry and the Icelandic Prescription Medicine Register between 2003 and 2017. Metformin exposure was defined as having filled at least one prescription of metformin more than 2 years prior to cancer diagnosis. They used grams and daily dose units of metformin in their analysis; one DDU of metformin, “or its average daily maintenance dose when used for its primary indication, is 2 grams,” they noted.

Overall, metformin use was associated with a significantly lower risk of developing BCC, compared with nonuse (adjusted odds ratio, 0.71; 95% confidence interval, 0.61-0.83).

The reduced risk occurred similarly across age and gender subgroups, with the exception of individuals younger than 60 years, the researchers said. “This might signify that metformin has less of a protective effect in younger individuals, but we might also have lacked power in this category.” The association with reduced BCC risk remained significant at all three cumulative dose levels measured: 1-500 DDUs, 501-1,500 DDUs, and more than 1,500 DDUs.

Metformin use was not significantly associated with reduced risk of invasive SCC (aOR, 1.01) and in most cases of SCCis. However, the 501-1,500 DDU dose category was associated with a slight increase in risk of SCCis (aOR, 1.40; 95% CI, 1.00-1.96), “showing a possible increased risk of SCCis,” the authors wrote.

The decrease in BCC risk was seen across all metformin dosing levels, but the reason for this remains unclear, and might be related to a confounding factor that was not considered in this study, the researchers said. “It could also be that metformin’s BCC risk-lowering effect is immediate, with only a low dose being needed to see a clinical benefit.”

The study findings were limited by several factors, including the retrospective design and the inability to adjust for factors including ultraviolet exposure, Fitzpatrick skin type, and comorbidities. The frequent use of metformin by people with type 2 diabetes suggests diabetes itself or other diabetes medications could be possible confounding factors, the researchers wrote.

However, the results were strengthened by the large study population, and the data suggest an association between reduced risk of first-time BCC and metformin use, they added.

“Randomized, prospective trials are required to fully understand the effect metformin has on BCC and SCC risk,” the researchers concluded.

“There is a dire need to reduce incidence of skin cancers in general, and consequently a need for new non-surgical treatment options for keratinocytic nonmelanoma skin cancers,” Amor Khachemoune, MD, a dermatologist at the State University of New York, Brooklyn, and the department of dermatology of the Veteran Affairs NY Harbor Healthcare System, also in Brooklyn, said in an interview.

Dr. Khachemoune, who was not involved with the study, said that he was not surprised by the findings. “Like other well-studied sonic hedgehog inhibitors, vismodegib and sonidegib, metformin has a demonstrated effect on this pathway. The medical community outside of dermatology has extensive experience with the use of metformin for a host of other indications, including its role as anticarcinogenic, so it seemed natural that one would consider widening its use to quell the ever-expanding cases of basal cell carcinomas.”

However, complications from long-term use, though likely rare, could be a limitation in using metformin as a chemoprotective agent, Dr. Khachemoune said. Metformin-associated lactic acidosis is one example of a rare, but potentially life-threatening adverse event.

“Finding the right dosage and having an algorithm for follow up monitoring of side effects would certainly need to be put in place in a standardized way,” he emphasized. “As stated by the authors of this study, more inclusive research involving other groups with nonkeratinocytic malignancies in larger cohorts is needed.”

The study received no outside funding. The researchers and Dr. Khachemoune had no financial conflicts to disclose.

Use of metformin was associated with a significant reduction in the risk of developing basal cell carcinoma (BCC), based on data from a population case-control study in Iceland.

“In addition to general anticarcinogenic effects, metformin has also been shown to directly inhibit the sonic hedgehog pathway, a key pathway in basal cell carcinoma (BCC) pathogenesis,” Jonas A. Adalsteinsson, MD, of the University of Iceland, Reykjavik, and colleagues wrote. “The relationship between metformin and keratinocyte carcinoma has not been well-characterized but is of importance considering that metformin is a commonly prescribed medication.”

They added that the hedgehog pathway inhibitors vismodegib (Erivedge) and sonidegib (Odomzo), approved for treating BCC, “are highly effective for BCC prevention, but their broad use for BCC prophylaxis is limited due to numerous side effects.”

In the study, published in the Journal of the American Academy of Dermatology, the researchers identified 6,880 first-time cancer patients with BCC, squamous cell carcinoma in situ (SCCis), or invasive SCC, and 69,620 population controls using data from the Icelandic Cancer Registry and the Icelandic Prescription Medicine Register between 2003 and 2017. Metformin exposure was defined as having filled at least one prescription of metformin more than 2 years prior to cancer diagnosis. They used grams and daily dose units of metformin in their analysis; one DDU of metformin, “or its average daily maintenance dose when used for its primary indication, is 2 grams,” they noted.

Overall, metformin use was associated with a significantly lower risk of developing BCC, compared with nonuse (adjusted odds ratio, 0.71; 95% confidence interval, 0.61-0.83).

The reduced risk occurred similarly across age and gender subgroups, with the exception of individuals younger than 60 years, the researchers said. “This might signify that metformin has less of a protective effect in younger individuals, but we might also have lacked power in this category.” The association with reduced BCC risk remained significant at all three cumulative dose levels measured: 1-500 DDUs, 501-1,500 DDUs, and more than 1,500 DDUs.

Metformin use was not significantly associated with reduced risk of invasive SCC (aOR, 1.01) and in most cases of SCCis. However, the 501-1,500 DDU dose category was associated with a slight increase in risk of SCCis (aOR, 1.40; 95% CI, 1.00-1.96), “showing a possible increased risk of SCCis,” the authors wrote.

The decrease in BCC risk was seen across all metformin dosing levels, but the reason for this remains unclear, and might be related to a confounding factor that was not considered in this study, the researchers said. “It could also be that metformin’s BCC risk-lowering effect is immediate, with only a low dose being needed to see a clinical benefit.”

The study findings were limited by several factors, including the retrospective design and the inability to adjust for factors including ultraviolet exposure, Fitzpatrick skin type, and comorbidities. The frequent use of metformin by people with type 2 diabetes suggests diabetes itself or other diabetes medications could be possible confounding factors, the researchers wrote.

However, the results were strengthened by the large study population, and the data suggest an association between reduced risk of first-time BCC and metformin use, they added.

“Randomized, prospective trials are required to fully understand the effect metformin has on BCC and SCC risk,” the researchers concluded.

“There is a dire need to reduce incidence of skin cancers in general, and consequently a need for new non-surgical treatment options for keratinocytic nonmelanoma skin cancers,” Amor Khachemoune, MD, a dermatologist at the State University of New York, Brooklyn, and the department of dermatology of the Veteran Affairs NY Harbor Healthcare System, also in Brooklyn, said in an interview.

Dr. Khachemoune, who was not involved with the study, said that he was not surprised by the findings. “Like other well-studied sonic hedgehog inhibitors, vismodegib and sonidegib, metformin has a demonstrated effect on this pathway. The medical community outside of dermatology has extensive experience with the use of metformin for a host of other indications, including its role as anticarcinogenic, so it seemed natural that one would consider widening its use to quell the ever-expanding cases of basal cell carcinomas.”

However, complications from long-term use, though likely rare, could be a limitation in using metformin as a chemoprotective agent, Dr. Khachemoune said. Metformin-associated lactic acidosis is one example of a rare, but potentially life-threatening adverse event.

“Finding the right dosage and having an algorithm for follow up monitoring of side effects would certainly need to be put in place in a standardized way,” he emphasized. “As stated by the authors of this study, more inclusive research involving other groups with nonkeratinocytic malignancies in larger cohorts is needed.”

The study received no outside funding. The researchers and Dr. Khachemoune had no financial conflicts to disclose.

Patients with cancer have shown varying responses to COVID-19 vaccination, with good responses in patients with solid tumors (even while on systemic therapy) and poor responses in patients with blood cancers, particularly those on immunosuppressive therapies.

The data are evolving to show factors associated with a poor response but are not strong enough yet to recommend booster shots, say researchers.

The work is defining who will likely need a COVID vaccine booster when they become available. “It’s definitely not all cancer patients,” said Dimpy Shah, MD, PhD, a cancer epidemiologist at the Mays Cancer Center, University of Texas, San Antonio.
 

Public anxiously awaiting boosters

Boosters aren’t recommended in the United States at the moment, in large part because the Emergency Use Authorization under which the vaccines are being administered allows for only two shots of the Pfizer and Moderna vaccines and one shot of the Johnson & Johnson vaccine.

Even so, regulators and policymakers are “keenly aware that physicians and patients alike are anxious to get going and start doing boosters,” Dr. Shah said. There’s concern that antibody response might wane over time, perhaps even more quickly in patients with cancer.

Pfizer is already in talks with the U.S. Food and Drug Administration to authorize a third dose of its vaccine in the United States. Guidelines could very well change in coming months, said Ghady Haidar, MD, a specialist in infectious diseases and cancer at the University of Pittsburgh.

However, it’s still early in the game, and it’s not clear yet if boosters are necessary in cancer, Dr. Haidar said in an interview.

For one thing, it’s unknown if poor antibody response really means that patients aren’t protected, he explained. The vaccines elicit T-cell responses that could protect patients regardless of antibody levels. It’s also unclear if antibody titer levels are clinically relevant, and there hasn’t been much indication yet that less-than-robust vaccine responses translate to worse COVID outcomes in patients with cancer.

Those and other questions are areas of active investigation by Dr. Shah, Dr. Haidar, and others. Dozens of clinical trials are investigating vaccine response in patients with cancer, including the use of boosters.

Meanwhile, some cancer patients aren’t waiting around for more study results. “I get many, many emails a day” about booster shots, Dr. Haidar said. “We recommend against” them for now but some people bend the rules and get an extra shot anyway. “I get it. People are apprehensive.”
 

Three COVID deaths despite full vaccination

The vaccine clinical trials had fewer patients with cancer, so researchers are moving fast to backfill the data. Although there is some variation in what’s being reported, an overall picture is slowly emerging.

Dr. Shah and her team reported on responses to the mRNA COVID vaccines from Pfizer and Moderna and found a 94% seroconversion rate in 131 patients with cancer 3-4 weeks after their second dose of vaccine. They also found good responses among patients on cytotoxic chemotherapy within 6 months of their first vaccine dose, although their antibody titer levels were significantly lower than seen in other patients with cancer.

Investigators from Montefiore Medical Center in New York City also recently reported a 94% seroconversion rate among 200 patients with cancer, including 98% seroconversion in patients with solid tumors. Rates were lower in patients with blood cancers but were still 85% overall, with 70% conversion among patients on anti-CD20 therapies and 73% among stem cell transplant patients. 

Dr. Haidar’s group reported a seroconversion rate of 82.4% among patients with solid tumors but only 54.7% among those with blood cancer. Risk factors for poor response included treatment with antimetabolites and anti-CD20 therapies, and, in the solid tumor group, radiation therapy, likely because of its overall toxicity and impact on lymphocyte function.   

Israeli investigators reported in May a 90% seroconversion rate after two doses of the Pfizer vaccine among 102 patients with solid tumors on active treatment, which compared favorably to the 100% conversion rate in healthy controls, but they noted that antibody titers were considerably lower in patients with cancer.

The only variable associated with lower titer levels was combined use of chemotherapy and immunotherapy, they noted. There were also three women on dose-dense chemotherapy for breast cancer who did not produce any antibodies.

In a study limited to patients with blood cancers, a Lithuanian team recently reported that among 885 patients, those on Bruton tyrosine kinase inhibitors, ruxolitinib (Jakafi), venetoclax (Venclexta), or anti-CD20 therapies mounted almost no antibody response to the Pfizer vaccine.

The Lithuanian group also reported nine breakthrough COVID infections among their fully vaccinated blood cancer patients, including three deaths.  

A team from the Icahn School of Medicine at Mount Sinai, New York reported that more than 15% of 260 patients with multiple myeloma also had no response to the Pfizer or Moderna vaccine; they were on BCMA-targeted therapy or anti-CD38 monoclonal antibody therapy at the time of vaccination, but a few had undergone CAR-T cell therapy more than 3 months beforehand.
 

Heated debate about antibody testing

Despite these reports of some patients with cancer having poorer responses, there’s some uncertainty over the benefit of giving a third (booster) shot.

There’s the question about the clinical relevance of antibody titer levels, and very little work has been done to date on cellular T-cell immunity from the vaccines.  

“Right now, we are using titer levels like they actually mean something when they might not,” said Ravi Parikh, MD, a genitourinary and thoracic oncologist at the University of Pennsylvania, Philadelphia, who co-wrote an editorial that accompanies the Israeli report.

That’s one of the reasons why the FDA and others do not currently recommend antibody tests for COVID vaccine decisions outside of a clinical trial, but not everyone agrees with that position.

There’s been “a lot of heated debate in the medical community” over the issue, Dr. Haidar said.

The Icahn team, for instance, said that their results “underscore the need for routine serological monitoring of [multiple myeloma] patients following COVID-19 vaccination” to see if they might still need to mask-up and socially distance. 

There is precedence, too, for vaccine boosters in cancer. As Dr. Parikh noted in his editorial, guidelines recommend revaccination after stem cell transplant for meningococcus, tetanus, and varicella, and other infections.

In France, COVID booster shots are already standard care for patients on dialysis and those on anti-CD20 agents, as well as for solid organ transplant recipients, for whom the literature supporting the benefit of COVID boosters is much more evolved than in cancer.

Israel has also authorized vaccine boosters for immunocompromised patients, including those with cancer, according to news reports.

It is also almost certain that the FDA will grant a formal approval for the COVID vaccines, at which point doctors will be free to administer boosters as they see fit.

“People are going to have to think really hard about what to do with them” if guidance hasn’t changed by then, Dr. Haidar said.

As the story unfolds, Dr. Haidar and others said in an interview that the take-home message for oncologists remains largely what it has been – namely to get patients vaccinated but also to consider masks and social distancing afterward for those at risk of a poor response. 

Dr. Shah, Dr. Haidar, and Dr. Parikh have disclosed no relevant financial relationships. Dr. Parikh is a regular contributor to Medscape Oncology.

A version of this article first appeared on Medscape.com.

Patients with cancer have shown varying responses to COVID-19 vaccination, with good responses in patients with solid tumors (even while on systemic therapy) and poor responses in patients with blood cancers, particularly those on immunosuppressive therapies.

The data are evolving to show factors associated with a poor response but are not strong enough yet to recommend booster shots, say researchers.

The work is defining who will likely need a COVID vaccine booster when they become available. “It’s definitely not all cancer patients,” said Dimpy Shah, MD, PhD, a cancer epidemiologist at the Mays Cancer Center, University of Texas, San Antonio.
 

Public anxiously awaiting boosters

Boosters aren’t recommended in the United States at the moment, in large part because the Emergency Use Authorization under which the vaccines are being administered allows for only two shots of the Pfizer and Moderna vaccines and one shot of the Johnson & Johnson vaccine.

Even so, regulators and policymakers are “keenly aware that physicians and patients alike are anxious to get going and start doing boosters,” Dr. Shah said. There’s concern that antibody response might wane over time, perhaps even more quickly in patients with cancer.

Pfizer is already in talks with the U.S. Food and Drug Administration to authorize a third dose of its vaccine in the United States. Guidelines could very well change in coming months, said Ghady Haidar, MD, a specialist in infectious diseases and cancer at the University of Pittsburgh.

However, it’s still early in the game, and it’s not clear yet if boosters are necessary in cancer, Dr. Haidar said in an interview.

For one thing, it’s unknown if poor antibody response really means that patients aren’t protected, he explained. The vaccines elicit T-cell responses that could protect patients regardless of antibody levels. It’s also unclear if antibody titer levels are clinically relevant, and there hasn’t been much indication yet that less-than-robust vaccine responses translate to worse COVID outcomes in patients with cancer.

Those and other questions are areas of active investigation by Dr. Shah, Dr. Haidar, and others. Dozens of clinical trials are investigating vaccine response in patients with cancer, including the use of boosters.

Meanwhile, some cancer patients aren’t waiting around for more study results. “I get many, many emails a day” about booster shots, Dr. Haidar said. “We recommend against” them for now but some people bend the rules and get an extra shot anyway. “I get it. People are apprehensive.”
 

Three COVID deaths despite full vaccination

The vaccine clinical trials had fewer patients with cancer, so researchers are moving fast to backfill the data. Although there is some variation in what’s being reported, an overall picture is slowly emerging.

Dr. Shah and her team reported on responses to the mRNA COVID vaccines from Pfizer and Moderna and found a 94% seroconversion rate in 131 patients with cancer 3-4 weeks after their second dose of vaccine. They also found good responses among patients on cytotoxic chemotherapy within 6 months of their first vaccine dose, although their antibody titer levels were significantly lower than seen in other patients with cancer.

Investigators from Montefiore Medical Center in New York City also recently reported a 94% seroconversion rate among 200 patients with cancer, including 98% seroconversion in patients with solid tumors. Rates were lower in patients with blood cancers but were still 85% overall, with 70% conversion among patients on anti-CD20 therapies and 73% among stem cell transplant patients. 

Dr. Haidar’s group reported a seroconversion rate of 82.4% among patients with solid tumors but only 54.7% among those with blood cancer. Risk factors for poor response included treatment with antimetabolites and anti-CD20 therapies, and, in the solid tumor group, radiation therapy, likely because of its overall toxicity and impact on lymphocyte function.   

Israeli investigators reported in May a 90% seroconversion rate after two doses of the Pfizer vaccine among 102 patients with solid tumors on active treatment, which compared favorably to the 100% conversion rate in healthy controls, but they noted that antibody titers were considerably lower in patients with cancer.

The only variable associated with lower titer levels was combined use of chemotherapy and immunotherapy, they noted. There were also three women on dose-dense chemotherapy for breast cancer who did not produce any antibodies.

In a study limited to patients with blood cancers, a Lithuanian team recently reported that among 885 patients, those on Bruton tyrosine kinase inhibitors, ruxolitinib (Jakafi), venetoclax (Venclexta), or anti-CD20 therapies mounted almost no antibody response to the Pfizer vaccine.

The Lithuanian group also reported nine breakthrough COVID infections among their fully vaccinated blood cancer patients, including three deaths.  

A team from the Icahn School of Medicine at Mount Sinai, New York reported that more than 15% of 260 patients with multiple myeloma also had no response to the Pfizer or Moderna vaccine; they were on BCMA-targeted therapy or anti-CD38 monoclonal antibody therapy at the time of vaccination, but a few had undergone CAR-T cell therapy more than 3 months beforehand.
 

Heated debate about antibody testing

Despite these reports of some patients with cancer having poorer responses, there’s some uncertainty over the benefit of giving a third (booster) shot.

There’s the question about the clinical relevance of antibody titer levels, and very little work has been done to date on cellular T-cell immunity from the vaccines.  

“Right now, we are using titer levels like they actually mean something when they might not,” said Ravi Parikh, MD, a genitourinary and thoracic oncologist at the University of Pennsylvania, Philadelphia, who co-wrote an editorial that accompanies the Israeli report.

That’s one of the reasons why the FDA and others do not currently recommend antibody tests for COVID vaccine decisions outside of a clinical trial, but not everyone agrees with that position.

There’s been “a lot of heated debate in the medical community” over the issue, Dr. Haidar said.

The Icahn team, for instance, said that their results “underscore the need for routine serological monitoring of [multiple myeloma] patients following COVID-19 vaccination” to see if they might still need to mask-up and socially distance. 

There is precedence, too, for vaccine boosters in cancer. As Dr. Parikh noted in his editorial, guidelines recommend revaccination after stem cell transplant for meningococcus, tetanus, and varicella, and other infections.

In France, COVID booster shots are already standard care for patients on dialysis and those on anti-CD20 agents, as well as for solid organ transplant recipients, for whom the literature supporting the benefit of COVID boosters is much more evolved than in cancer.

Israel has also authorized vaccine boosters for immunocompromised patients, including those with cancer, according to news reports.

It is also almost certain that the FDA will grant a formal approval for the COVID vaccines, at which point doctors will be free to administer boosters as they see fit.

“People are going to have to think really hard about what to do with them” if guidance hasn’t changed by then, Dr. Haidar said.

As the story unfolds, Dr. Haidar and others said in an interview that the take-home message for oncologists remains largely what it has been – namely to get patients vaccinated but also to consider masks and social distancing afterward for those at risk of a poor response. 

Dr. Shah, Dr. Haidar, and Dr. Parikh have disclosed no relevant financial relationships. Dr. Parikh is a regular contributor to Medscape Oncology.

A version of this article first appeared on Medscape.com.

Patients with cancer have shown varying responses to COVID-19 vaccination, with good responses in patients with solid tumors (even while on systemic therapy) and poor responses in patients with blood cancers, particularly those on immunosuppressive therapies.

The data are evolving to show factors associated with a poor response but are not strong enough yet to recommend booster shots, say researchers.

The work is defining who will likely need a COVID vaccine booster when they become available. “It’s definitely not all cancer patients,” said Dimpy Shah, MD, PhD, a cancer epidemiologist at the Mays Cancer Center, University of Texas, San Antonio.
 

Public anxiously awaiting boosters

Boosters aren’t recommended in the United States at the moment, in large part because the Emergency Use Authorization under which the vaccines are being administered allows for only two shots of the Pfizer and Moderna vaccines and one shot of the Johnson & Johnson vaccine.

Even so, regulators and policymakers are “keenly aware that physicians and patients alike are anxious to get going and start doing boosters,” Dr. Shah said. There’s concern that antibody response might wane over time, perhaps even more quickly in patients with cancer.

Pfizer is already in talks with the U.S. Food and Drug Administration to authorize a third dose of its vaccine in the United States. Guidelines could very well change in coming months, said Ghady Haidar, MD, a specialist in infectious diseases and cancer at the University of Pittsburgh.

However, it’s still early in the game, and it’s not clear yet if boosters are necessary in cancer, Dr. Haidar said in an interview.

For one thing, it’s unknown if poor antibody response really means that patients aren’t protected, he explained. The vaccines elicit T-cell responses that could protect patients regardless of antibody levels. It’s also unclear if antibody titer levels are clinically relevant, and there hasn’t been much indication yet that less-than-robust vaccine responses translate to worse COVID outcomes in patients with cancer.

Those and other questions are areas of active investigation by Dr. Shah, Dr. Haidar, and others. Dozens of clinical trials are investigating vaccine response in patients with cancer, including the use of boosters.

Meanwhile, some cancer patients aren’t waiting around for more study results. “I get many, many emails a day” about booster shots, Dr. Haidar said. “We recommend against” them for now but some people bend the rules and get an extra shot anyway. “I get it. People are apprehensive.”
 

Three COVID deaths despite full vaccination

The vaccine clinical trials had fewer patients with cancer, so researchers are moving fast to backfill the data. Although there is some variation in what’s being reported, an overall picture is slowly emerging.

Dr. Shah and her team reported on responses to the mRNA COVID vaccines from Pfizer and Moderna and found a 94% seroconversion rate in 131 patients with cancer 3-4 weeks after their second dose of vaccine. They also found good responses among patients on cytotoxic chemotherapy within 6 months of their first vaccine dose, although their antibody titer levels were significantly lower than seen in other patients with cancer.

Investigators from Montefiore Medical Center in New York City also recently reported a 94% seroconversion rate among 200 patients with cancer, including 98% seroconversion in patients with solid tumors. Rates were lower in patients with blood cancers but were still 85% overall, with 70% conversion among patients on anti-CD20 therapies and 73% among stem cell transplant patients. 

Dr. Haidar’s group reported a seroconversion rate of 82.4% among patients with solid tumors but only 54.7% among those with blood cancer. Risk factors for poor response included treatment with antimetabolites and anti-CD20 therapies, and, in the solid tumor group, radiation therapy, likely because of its overall toxicity and impact on lymphocyte function.   

Israeli investigators reported in May a 90% seroconversion rate after two doses of the Pfizer vaccine among 102 patients with solid tumors on active treatment, which compared favorably to the 100% conversion rate in healthy controls, but they noted that antibody titers were considerably lower in patients with cancer.

The only variable associated with lower titer levels was combined use of chemotherapy and immunotherapy, they noted. There were also three women on dose-dense chemotherapy for breast cancer who did not produce any antibodies.

In a study limited to patients with blood cancers, a Lithuanian team recently reported that among 885 patients, those on Bruton tyrosine kinase inhibitors, ruxolitinib (Jakafi), venetoclax (Venclexta), or anti-CD20 therapies mounted almost no antibody response to the Pfizer vaccine.

The Lithuanian group also reported nine breakthrough COVID infections among their fully vaccinated blood cancer patients, including three deaths.  

A team from the Icahn School of Medicine at Mount Sinai, New York reported that more than 15% of 260 patients with multiple myeloma also had no response to the Pfizer or Moderna vaccine; they were on BCMA-targeted therapy or anti-CD38 monoclonal antibody therapy at the time of vaccination, but a few had undergone CAR-T cell therapy more than 3 months beforehand.
 

Heated debate about antibody testing

Despite these reports of some patients with cancer having poorer responses, there’s some uncertainty over the benefit of giving a third (booster) shot.

There’s the question about the clinical relevance of antibody titer levels, and very little work has been done to date on cellular T-cell immunity from the vaccines.  

“Right now, we are using titer levels like they actually mean something when they might not,” said Ravi Parikh, MD, a genitourinary and thoracic oncologist at the University of Pennsylvania, Philadelphia, who co-wrote an editorial that accompanies the Israeli report.

That’s one of the reasons why the FDA and others do not currently recommend antibody tests for COVID vaccine decisions outside of a clinical trial, but not everyone agrees with that position.

There’s been “a lot of heated debate in the medical community” over the issue, Dr. Haidar said.

The Icahn team, for instance, said that their results “underscore the need for routine serological monitoring of [multiple myeloma] patients following COVID-19 vaccination” to see if they might still need to mask-up and socially distance. 

There is precedence, too, for vaccine boosters in cancer. As Dr. Parikh noted in his editorial, guidelines recommend revaccination after stem cell transplant for meningococcus, tetanus, and varicella, and other infections.

In France, COVID booster shots are already standard care for patients on dialysis and those on anti-CD20 agents, as well as for solid organ transplant recipients, for whom the literature supporting the benefit of COVID boosters is much more evolved than in cancer.

Israel has also authorized vaccine boosters for immunocompromised patients, including those with cancer, according to news reports.

It is also almost certain that the FDA will grant a formal approval for the COVID vaccines, at which point doctors will be free to administer boosters as they see fit.

“People are going to have to think really hard about what to do with them” if guidance hasn’t changed by then, Dr. Haidar said.

As the story unfolds, Dr. Haidar and others said in an interview that the take-home message for oncologists remains largely what it has been – namely to get patients vaccinated but also to consider masks and social distancing afterward for those at risk of a poor response. 

Dr. Shah, Dr. Haidar, and Dr. Parikh have disclosed no relevant financial relationships. Dr. Parikh is a regular contributor to Medscape Oncology.

A version of this article first appeared on Medscape.com.

Data from a long-term study suggest that testosterone replacement therapy (TRT) for men with hypogonadism may reduce the risk for major adverse cardiovascular events. Previous studies have yielded conflicting results on whether there is a benefit.

The latest results come from a study of 805 men with hypogonadism from Germany and Qatar who were followed for nearly a decade. For those who received parenteral testosterone 1,000 mg every 12 weeks, there were improvements in classical cardiovascular risk factors, such as obesity, lipid level, and inflammatory markers, whereas among those who chose not to take testosterone (control patients), all of these factors worsened.

In addition, there were only 16 deaths among patients in the TRT group, and none of the deaths were from myocardial infarction or stroke. In contrast, there were 74 deaths among the control patients, as well as 70 cases of MI and 59 strokes.

The men in the study were all at relatively high risk for cardiovascular adverse events. In the TRT group, the mean Framingham Risk score was 15.5; in the control group, it was 15.8. This translates into mean 10-year risks of 22.7% and 23.5%, respectively.

“Given that all these men would normally have been expected to suffer a heart attack or stroke in the next 5-10 years with no other intervention, it was a real surprise to see no cardiovascular events at all in the group on testosterone therapy. It’s clear that this treatment can significantly reduce the risks in this particular group,” commented lead investigator Omar Aboumarzouk, MD, from Hamad Medical in Doha, Qatar.

He presented the new data at the 2021 annual congress of the European Association of Urology.

Dr. Aboumarzouk emphasized, however, that, “while men need testosterone for certain psychological and biological functions, only those with low levels who display other symptoms are likely to benefit from testosterone therapy.”

Maarten Albersen, MD, a urologist at the University of Leuven (Belgium), who was not involved in the study, noted that, although the study showed a reduction in major adverse cardiovascular events and mortality among the men who received TRT, the risk scores were in the intermediate range, and the men in the TRT group were slightly younger and were at slightly lower risk at baseline.

“The study was long enough to see differences in the rate of cardiovascular events. However, the numbers involved and the fact that the trial was not randomized mean it’s still difficult to draw any hard conclusions,” he said.
 

Registry study

The data came from a cumulative registry study begun in 2004 to assess the long-term efficacy and safety of TRT every 3 months in men with hypogonadism. The study, conducted in Bremen, Dresden, and Muenster in Germany, as well as in Doha, Qatar, is ongoing.

At total of 805 men were enrolled; 412 received TRT, and 393 declined testosterone replacement and served as control patients.

The investigators reported 10-year data. Statistical models controlled for age, body mass index, smoking, alcohol, total and HDL cholesterol level, systolic blood pressure, and type 2 diabetes.

The median age at baseline was lower among those in the TRT arm, at 57.7 years versus 63.7 years for control patients (P < .001).

All classical cardiovascular risk factors, including obesity, glycemic control, lipid pattern, and C-reactive protein, improved in the TRT group and worsened in the control group.

Dr. Albersen noted that “a new trial is now underway, aiming to recruit 6,000 participants, and this should provide definitive answers on the cardiovascular risks or even benefits of hormone therapy in men with low testosterone.”

No funding source for the study was reported. Dr. Aboumarzouk and Dr. Albersen have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Data from a long-term study suggest that testosterone replacement therapy (TRT) for men with hypogonadism may reduce the risk for major adverse cardiovascular events. Previous studies have yielded conflicting results on whether there is a benefit.

The latest results come from a study of 805 men with hypogonadism from Germany and Qatar who were followed for nearly a decade. For those who received parenteral testosterone 1,000 mg every 12 weeks, there were improvements in classical cardiovascular risk factors, such as obesity, lipid level, and inflammatory markers, whereas among those who chose not to take testosterone (control patients), all of these factors worsened.

In addition, there were only 16 deaths among patients in the TRT group, and none of the deaths were from myocardial infarction or stroke. In contrast, there were 74 deaths among the control patients, as well as 70 cases of MI and 59 strokes.

The men in the study were all at relatively high risk for cardiovascular adverse events. In the TRT group, the mean Framingham Risk score was 15.5; in the control group, it was 15.8. This translates into mean 10-year risks of 22.7% and 23.5%, respectively.

“Given that all these men would normally have been expected to suffer a heart attack or stroke in the next 5-10 years with no other intervention, it was a real surprise to see no cardiovascular events at all in the group on testosterone therapy. It’s clear that this treatment can significantly reduce the risks in this particular group,” commented lead investigator Omar Aboumarzouk, MD, from Hamad Medical in Doha, Qatar.

He presented the new data at the 2021 annual congress of the European Association of Urology.

Dr. Aboumarzouk emphasized, however, that, “while men need testosterone for certain psychological and biological functions, only those with low levels who display other symptoms are likely to benefit from testosterone therapy.”

Maarten Albersen, MD, a urologist at the University of Leuven (Belgium), who was not involved in the study, noted that, although the study showed a reduction in major adverse cardiovascular events and mortality among the men who received TRT, the risk scores were in the intermediate range, and the men in the TRT group were slightly younger and were at slightly lower risk at baseline.

“The study was long enough to see differences in the rate of cardiovascular events. However, the numbers involved and the fact that the trial was not randomized mean it’s still difficult to draw any hard conclusions,” he said.
 

Registry study

The data came from a cumulative registry study begun in 2004 to assess the long-term efficacy and safety of TRT every 3 months in men with hypogonadism. The study, conducted in Bremen, Dresden, and Muenster in Germany, as well as in Doha, Qatar, is ongoing.

At total of 805 men were enrolled; 412 received TRT, and 393 declined testosterone replacement and served as control patients.

The investigators reported 10-year data. Statistical models controlled for age, body mass index, smoking, alcohol, total and HDL cholesterol level, systolic blood pressure, and type 2 diabetes.

The median age at baseline was lower among those in the TRT arm, at 57.7 years versus 63.7 years for control patients (P < .001).

All classical cardiovascular risk factors, including obesity, glycemic control, lipid pattern, and C-reactive protein, improved in the TRT group and worsened in the control group.

Dr. Albersen noted that “a new trial is now underway, aiming to recruit 6,000 participants, and this should provide definitive answers on the cardiovascular risks or even benefits of hormone therapy in men with low testosterone.”

No funding source for the study was reported. Dr. Aboumarzouk and Dr. Albersen have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Data from a long-term study suggest that testosterone replacement therapy (TRT) for men with hypogonadism may reduce the risk for major adverse cardiovascular events. Previous studies have yielded conflicting results on whether there is a benefit.

The latest results come from a study of 805 men with hypogonadism from Germany and Qatar who were followed for nearly a decade. For those who received parenteral testosterone 1,000 mg every 12 weeks, there were improvements in classical cardiovascular risk factors, such as obesity, lipid level, and inflammatory markers, whereas among those who chose not to take testosterone (control patients), all of these factors worsened.

In addition, there were only 16 deaths among patients in the TRT group, and none of the deaths were from myocardial infarction or stroke. In contrast, there were 74 deaths among the control patients, as well as 70 cases of MI and 59 strokes.

The men in the study were all at relatively high risk for cardiovascular adverse events. In the TRT group, the mean Framingham Risk score was 15.5; in the control group, it was 15.8. This translates into mean 10-year risks of 22.7% and 23.5%, respectively.

“Given that all these men would normally have been expected to suffer a heart attack or stroke in the next 5-10 years with no other intervention, it was a real surprise to see no cardiovascular events at all in the group on testosterone therapy. It’s clear that this treatment can significantly reduce the risks in this particular group,” commented lead investigator Omar Aboumarzouk, MD, from Hamad Medical in Doha, Qatar.

He presented the new data at the 2021 annual congress of the European Association of Urology.

Dr. Aboumarzouk emphasized, however, that, “while men need testosterone for certain psychological and biological functions, only those with low levels who display other symptoms are likely to benefit from testosterone therapy.”

Maarten Albersen, MD, a urologist at the University of Leuven (Belgium), who was not involved in the study, noted that, although the study showed a reduction in major adverse cardiovascular events and mortality among the men who received TRT, the risk scores were in the intermediate range, and the men in the TRT group were slightly younger and were at slightly lower risk at baseline.

“The study was long enough to see differences in the rate of cardiovascular events. However, the numbers involved and the fact that the trial was not randomized mean it’s still difficult to draw any hard conclusions,” he said.
 

Registry study

The data came from a cumulative registry study begun in 2004 to assess the long-term efficacy and safety of TRT every 3 months in men with hypogonadism. The study, conducted in Bremen, Dresden, and Muenster in Germany, as well as in Doha, Qatar, is ongoing.

At total of 805 men were enrolled; 412 received TRT, and 393 declined testosterone replacement and served as control patients.

The investigators reported 10-year data. Statistical models controlled for age, body mass index, smoking, alcohol, total and HDL cholesterol level, systolic blood pressure, and type 2 diabetes.

The median age at baseline was lower among those in the TRT arm, at 57.7 years versus 63.7 years for control patients (P < .001).

All classical cardiovascular risk factors, including obesity, glycemic control, lipid pattern, and C-reactive protein, improved in the TRT group and worsened in the control group.

Dr. Albersen noted that “a new trial is now underway, aiming to recruit 6,000 participants, and this should provide definitive answers on the cardiovascular risks or even benefits of hormone therapy in men with low testosterone.”

No funding source for the study was reported. Dr. Aboumarzouk and Dr. Albersen have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.