Pharmacology

MAR DEL PLATA, ARGENTINA – Psychiatrists should prescribe metformin early to patients who experience rapid weight gain after they begin taking antipsychotic drugs, according to a new evidence-based Irish guideline for the management of this common complication in adults with psychoses who are taking medications.

The document was discussed during one of the sessions of the XXXV Argentine Congress of Psychiatry of the Association of Argentine Psychiatrists. The document also was presented by one of its authors at the European Congress on Obesity 2022.

The guideline encourages psychiatrists not to underestimate the adverse metabolic effects of their treatments and encourages them to contemplate and carry out this prevention and management strategy, commented María Delia Michat, PhD, professor of clinical psychiatry and psychopharmacology at the APSA Postgraduate Training Institute, Buenos Aires.

“Although it is always good to work as a team, it is usually we psychiatrists who coordinate the pharmacological treatment of our patients, and we have to know how to manage drugs that can prevent cardiovascular disease,” Dr. Michat said in an interview.

“The new guideline is helpful because it protocolizes the use of metformin, which is the cheapest drug and has the most evidence for antipsychotic-induced weight gain,” she added.
 

Avoiding metabolic syndrome

In patients with schizophrenia, obesity rates are 40% higher than in the general population, and 80% of patients develop weight gain after their first treatment, noted Dr. Michat. “Right away, weight gain is seen in the first month. And it is a serious problem, because patients with schizophrenia, major depression, or bipolar disorder already have an increased risk of premature mortality, especially from cardiovascular diseases, and they have an increased risk of metabolic syndrome. And we sometimes give drugs that further increase that risk,” she said.

Being overweight is a major criterion for defining metabolic syndrome. Dr. Michat noted that, among the antipsychotic drugs that increase weight the most are clozapine, olanzapine, chlorpromazine, quetiapine, and risperidone, in addition to other psychoactive drugs, such as valproic acid, lithium, mirtazapine, and tricyclic antidepressants.

Several clinical trials, such as a pioneering Chinese study from 2008, have shown the potential of metformin to mitigate the weight gain induced by this type of drug.

However, Dr. Michat noted that so far the major guidelines (for example, the Canadian Network for Mood and Anxiety Treatments [CANMAT]/International Society for Bipolar Disorders [ISBD] for bipolar disorder and the American Psychiatric Association [APA] for schizophrenia) “say very little” on how to address this complication. They propose what she defined as a “problematic” order of action in which the initial emphasis is on promoting lifestyle changes, which are difficult for these patients to carry out, as well as general proposals for changing medication (which is not simple to implement when the patient’s condition is stabilized) and eventual consultation with a clinician to start therapy with metformin or other drugs, such as liraglutide, semaglutide, and topiramate.

The new clinical practice guideline, which was published in Evidence-Based Mental Health (of the BMJ journal group), was written by a multidisciplinary team of pharmacists, psychiatrists, and mental health nurses from Ireland. It aims to fill that gap. The investigators reviewed 1,270 scientific articles and analyzed 26 of them in depth, including seven randomized clinical trials and a 2016 systematic review and meta-analysis. The authors made a “strong” recommendation, for which there was moderate-quality evidence, that for patients for whom a lifestyle intervention is unacceptable or inappropriate the use of metformin is an “alternative first-line intervention” for antipsychotic drug–induced weight gain.

Likewise, as a strong recommendation with moderate-quality evidence, the guidance encourages the use of metformin when nonpharmacologic intervention does not seem to be effective.

The guideline also says it is preferable to start metformin early for patients who gain more than 7% of their baseline weight within the first month of antipsychotic treatment. It also endorses metformin when weight gain is established.

Other recommendations include evaluating baseline kidney function before starting metformin treatment and suggest a dose adjustment when the estimated glomerular filtration rate (eGFR) is < 60 mL/min/1.73 m². The guidance says the use of metformin is contraindicated for patients in whom eGFR is <30 mL/min per 1.73 m². The proposed starting dosage is 500 mg twice per day with meals, with increments of 500 mg every 1-2 weeks until reaching a target dose of 2,000 mg/day. The guidance recommends that consideration always be given to individual tolerability and efficacy.

Treatment goals should be personalized and agreed upon with patients. In the case of early intervention, the guideline proposes initially stabilizing the weight gained or, if possible, reverse excess weight. When weight gain is established, the goal would be to lose at least 5% of the weight within the next 6 months.

The authors also recommend monitoring kidney function annually, as well as vitamin B₁₂ levels and individual tolerability and compliance. Gastrointestinal adverse effects can be managed by dose reduction or slower dose titration. The risk of lactic acidosis, which affects 4.3 per 100,000 person-years among those taking metformin, can be attenuated by adjusting the dose according to kidney function or avoiding prescribing it to patients who have a history of alcohol abuse or who are receiving treatment that may interact with the drug.
 

Validating pharmacologic management

The lead author of the new guideline, Ita Fitzgerald, a teacher in clinical pharmacy and senior pharmacist at St. Patrick’s Mental Health Services in Dublin, pointed out that there is a bias toward not using drugs for weight management and shifting the responsibility onto the patients themselves, something that is very often out of their control.

“The purpose of the guideline was to decide on a range of criteria to maximize the use of metformin, to recognize that for many people, pharmacological management is a valid and important option that could and should be more widely used and to provide precise and practical guidance to physicians to facilitate a more widespread use,” Ms. Fitzgerald said in an interview.

According to Fitzgerald, who is pursuing her doctorate at University College Cork (Ireland), one of the most outstanding results of the work is that it highlights that the main benefit of metformin is to flatten rather than reverse antipsychotic-induced weight gain and that indicating it late can nullify that effect.

“In all the recommendations, we try very hard to shift the focus from metformin’s role as a weight reversal agent to one as a weight management agent that should be used early in treatment, which is when most weight gain occurs. If metformin succeeds in flattening that increase, that’s a huge potential benefit for an inexpensive and easily accessible drug. When people have already established weight gain, metformin may not be enough and alternative treatments should be used,” she said.

In addition to its effects on weight, metformin has many other potential health benefits. Of particular importance is that it reduces hyperphagia-mediated antipsychotic-induced weight gain, Ms. Fitzgerald pointed out.

“This is subjectively very important for patients and provides a more positive experience when taking antipsychotics. Antipsychotic-induced weight gain is one of the main reasons for premature discontinuation or incomplete adherence to these drugs and therefore needs to be addressed proactively,” she concluded.

Ms. Fitzgerald and Dr. Michat have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com. This article was translated from the Medscape Spanish edition.

MAR DEL PLATA, ARGENTINA – Psychiatrists should prescribe metformin early to patients who experience rapid weight gain after they begin taking antipsychotic drugs, according to a new evidence-based Irish guideline for the management of this common complication in adults with psychoses who are taking medications.

The document was discussed during one of the sessions of the XXXV Argentine Congress of Psychiatry of the Association of Argentine Psychiatrists. The document also was presented by one of its authors at the European Congress on Obesity 2022.

The guideline encourages psychiatrists not to underestimate the adverse metabolic effects of their treatments and encourages them to contemplate and carry out this prevention and management strategy, commented María Delia Michat, PhD, professor of clinical psychiatry and psychopharmacology at the APSA Postgraduate Training Institute, Buenos Aires.

“Although it is always good to work as a team, it is usually we psychiatrists who coordinate the pharmacological treatment of our patients, and we have to know how to manage drugs that can prevent cardiovascular disease,” Dr. Michat said in an interview.

“The new guideline is helpful because it protocolizes the use of metformin, which is the cheapest drug and has the most evidence for antipsychotic-induced weight gain,” she added.
 

Avoiding metabolic syndrome

In patients with schizophrenia, obesity rates are 40% higher than in the general population, and 80% of patients develop weight gain after their first treatment, noted Dr. Michat. “Right away, weight gain is seen in the first month. And it is a serious problem, because patients with schizophrenia, major depression, or bipolar disorder already have an increased risk of premature mortality, especially from cardiovascular diseases, and they have an increased risk of metabolic syndrome. And we sometimes give drugs that further increase that risk,” she said.

Being overweight is a major criterion for defining metabolic syndrome. Dr. Michat noted that, among the antipsychotic drugs that increase weight the most are clozapine, olanzapine, chlorpromazine, quetiapine, and risperidone, in addition to other psychoactive drugs, such as valproic acid, lithium, mirtazapine, and tricyclic antidepressants.

Several clinical trials, such as a pioneering Chinese study from 2008, have shown the potential of metformin to mitigate the weight gain induced by this type of drug.

However, Dr. Michat noted that so far the major guidelines (for example, the Canadian Network for Mood and Anxiety Treatments [CANMAT]/International Society for Bipolar Disorders [ISBD] for bipolar disorder and the American Psychiatric Association [APA] for schizophrenia) “say very little” on how to address this complication. They propose what she defined as a “problematic” order of action in which the initial emphasis is on promoting lifestyle changes, which are difficult for these patients to carry out, as well as general proposals for changing medication (which is not simple to implement when the patient’s condition is stabilized) and eventual consultation with a clinician to start therapy with metformin or other drugs, such as liraglutide, semaglutide, and topiramate.

The new clinical practice guideline, which was published in Evidence-Based Mental Health (of the BMJ journal group), was written by a multidisciplinary team of pharmacists, psychiatrists, and mental health nurses from Ireland. It aims to fill that gap. The investigators reviewed 1,270 scientific articles and analyzed 26 of them in depth, including seven randomized clinical trials and a 2016 systematic review and meta-analysis. The authors made a “strong” recommendation, for which there was moderate-quality evidence, that for patients for whom a lifestyle intervention is unacceptable or inappropriate the use of metformin is an “alternative first-line intervention” for antipsychotic drug–induced weight gain.

Likewise, as a strong recommendation with moderate-quality evidence, the guidance encourages the use of metformin when nonpharmacologic intervention does not seem to be effective.

The guideline also says it is preferable to start metformin early for patients who gain more than 7% of their baseline weight within the first month of antipsychotic treatment. It also endorses metformin when weight gain is established.

Other recommendations include evaluating baseline kidney function before starting metformin treatment and suggest a dose adjustment when the estimated glomerular filtration rate (eGFR) is < 60 mL/min/1.73 m². The guidance says the use of metformin is contraindicated for patients in whom eGFR is <30 mL/min per 1.73 m². The proposed starting dosage is 500 mg twice per day with meals, with increments of 500 mg every 1-2 weeks until reaching a target dose of 2,000 mg/day. The guidance recommends that consideration always be given to individual tolerability and efficacy.

Treatment goals should be personalized and agreed upon with patients. In the case of early intervention, the guideline proposes initially stabilizing the weight gained or, if possible, reverse excess weight. When weight gain is established, the goal would be to lose at least 5% of the weight within the next 6 months.

The authors also recommend monitoring kidney function annually, as well as vitamin B₁₂ levels and individual tolerability and compliance. Gastrointestinal adverse effects can be managed by dose reduction or slower dose titration. The risk of lactic acidosis, which affects 4.3 per 100,000 person-years among those taking metformin, can be attenuated by adjusting the dose according to kidney function or avoiding prescribing it to patients who have a history of alcohol abuse or who are receiving treatment that may interact with the drug.
 

Validating pharmacologic management

The lead author of the new guideline, Ita Fitzgerald, a teacher in clinical pharmacy and senior pharmacist at St. Patrick’s Mental Health Services in Dublin, pointed out that there is a bias toward not using drugs for weight management and shifting the responsibility onto the patients themselves, something that is very often out of their control.

“The purpose of the guideline was to decide on a range of criteria to maximize the use of metformin, to recognize that for many people, pharmacological management is a valid and important option that could and should be more widely used and to provide precise and practical guidance to physicians to facilitate a more widespread use,” Ms. Fitzgerald said in an interview.

According to Fitzgerald, who is pursuing her doctorate at University College Cork (Ireland), one of the most outstanding results of the work is that it highlights that the main benefit of metformin is to flatten rather than reverse antipsychotic-induced weight gain and that indicating it late can nullify that effect.

“In all the recommendations, we try very hard to shift the focus from metformin’s role as a weight reversal agent to one as a weight management agent that should be used early in treatment, which is when most weight gain occurs. If metformin succeeds in flattening that increase, that’s a huge potential benefit for an inexpensive and easily accessible drug. When people have already established weight gain, metformin may not be enough and alternative treatments should be used,” she said.

In addition to its effects on weight, metformin has many other potential health benefits. Of particular importance is that it reduces hyperphagia-mediated antipsychotic-induced weight gain, Ms. Fitzgerald pointed out.

“This is subjectively very important for patients and provides a more positive experience when taking antipsychotics. Antipsychotic-induced weight gain is one of the main reasons for premature discontinuation or incomplete adherence to these drugs and therefore needs to be addressed proactively,” she concluded.

Ms. Fitzgerald and Dr. Michat have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com. This article was translated from the Medscape Spanish edition.

MAR DEL PLATA, ARGENTINA – Psychiatrists should prescribe metformin early to patients who experience rapid weight gain after they begin taking antipsychotic drugs, according to a new evidence-based Irish guideline for the management of this common complication in adults with psychoses who are taking medications.

The document was discussed during one of the sessions of the XXXV Argentine Congress of Psychiatry of the Association of Argentine Psychiatrists. The document also was presented by one of its authors at the European Congress on Obesity 2022.

The guideline encourages psychiatrists not to underestimate the adverse metabolic effects of their treatments and encourages them to contemplate and carry out this prevention and management strategy, commented María Delia Michat, PhD, professor of clinical psychiatry and psychopharmacology at the APSA Postgraduate Training Institute, Buenos Aires.

“Although it is always good to work as a team, it is usually we psychiatrists who coordinate the pharmacological treatment of our patients, and we have to know how to manage drugs that can prevent cardiovascular disease,” Dr. Michat said in an interview.

“The new guideline is helpful because it protocolizes the use of metformin, which is the cheapest drug and has the most evidence for antipsychotic-induced weight gain,” she added.
 

Avoiding metabolic syndrome

In patients with schizophrenia, obesity rates are 40% higher than in the general population, and 80% of patients develop weight gain after their first treatment, noted Dr. Michat. “Right away, weight gain is seen in the first month. And it is a serious problem, because patients with schizophrenia, major depression, or bipolar disorder already have an increased risk of premature mortality, especially from cardiovascular diseases, and they have an increased risk of metabolic syndrome. And we sometimes give drugs that further increase that risk,” she said.

Being overweight is a major criterion for defining metabolic syndrome. Dr. Michat noted that, among the antipsychotic drugs that increase weight the most are clozapine, olanzapine, chlorpromazine, quetiapine, and risperidone, in addition to other psychoactive drugs, such as valproic acid, lithium, mirtazapine, and tricyclic antidepressants.

Several clinical trials, such as a pioneering Chinese study from 2008, have shown the potential of metformin to mitigate the weight gain induced by this type of drug.

However, Dr. Michat noted that so far the major guidelines (for example, the Canadian Network for Mood and Anxiety Treatments [CANMAT]/International Society for Bipolar Disorders [ISBD] for bipolar disorder and the American Psychiatric Association [APA] for schizophrenia) “say very little” on how to address this complication. They propose what she defined as a “problematic” order of action in which the initial emphasis is on promoting lifestyle changes, which are difficult for these patients to carry out, as well as general proposals for changing medication (which is not simple to implement when the patient’s condition is stabilized) and eventual consultation with a clinician to start therapy with metformin or other drugs, such as liraglutide, semaglutide, and topiramate.

The new clinical practice guideline, which was published in Evidence-Based Mental Health (of the BMJ journal group), was written by a multidisciplinary team of pharmacists, psychiatrists, and mental health nurses from Ireland. It aims to fill that gap. The investigators reviewed 1,270 scientific articles and analyzed 26 of them in depth, including seven randomized clinical trials and a 2016 systematic review and meta-analysis. The authors made a “strong” recommendation, for which there was moderate-quality evidence, that for patients for whom a lifestyle intervention is unacceptable or inappropriate the use of metformin is an “alternative first-line intervention” for antipsychotic drug–induced weight gain.

Likewise, as a strong recommendation with moderate-quality evidence, the guidance encourages the use of metformin when nonpharmacologic intervention does not seem to be effective.

The guideline also says it is preferable to start metformin early for patients who gain more than 7% of their baseline weight within the first month of antipsychotic treatment. It also endorses metformin when weight gain is established.

Other recommendations include evaluating baseline kidney function before starting metformin treatment and suggest a dose adjustment when the estimated glomerular filtration rate (eGFR) is < 60 mL/min/1.73 m². The guidance says the use of metformin is contraindicated for patients in whom eGFR is <30 mL/min per 1.73 m². The proposed starting dosage is 500 mg twice per day with meals, with increments of 500 mg every 1-2 weeks until reaching a target dose of 2,000 mg/day. The guidance recommends that consideration always be given to individual tolerability and efficacy.

Treatment goals should be personalized and agreed upon with patients. In the case of early intervention, the guideline proposes initially stabilizing the weight gained or, if possible, reverse excess weight. When weight gain is established, the goal would be to lose at least 5% of the weight within the next 6 months.

The authors also recommend monitoring kidney function annually, as well as vitamin B₁₂ levels and individual tolerability and compliance. Gastrointestinal adverse effects can be managed by dose reduction or slower dose titration. The risk of lactic acidosis, which affects 4.3 per 100,000 person-years among those taking metformin, can be attenuated by adjusting the dose according to kidney function or avoiding prescribing it to patients who have a history of alcohol abuse or who are receiving treatment that may interact with the drug.
 

Validating pharmacologic management

The lead author of the new guideline, Ita Fitzgerald, a teacher in clinical pharmacy and senior pharmacist at St. Patrick’s Mental Health Services in Dublin, pointed out that there is a bias toward not using drugs for weight management and shifting the responsibility onto the patients themselves, something that is very often out of their control.

“The purpose of the guideline was to decide on a range of criteria to maximize the use of metformin, to recognize that for many people, pharmacological management is a valid and important option that could and should be more widely used and to provide precise and practical guidance to physicians to facilitate a more widespread use,” Ms. Fitzgerald said in an interview.

According to Fitzgerald, who is pursuing her doctorate at University College Cork (Ireland), one of the most outstanding results of the work is that it highlights that the main benefit of metformin is to flatten rather than reverse antipsychotic-induced weight gain and that indicating it late can nullify that effect.

“In all the recommendations, we try very hard to shift the focus from metformin’s role as a weight reversal agent to one as a weight management agent that should be used early in treatment, which is when most weight gain occurs. If metformin succeeds in flattening that increase, that’s a huge potential benefit for an inexpensive and easily accessible drug. When people have already established weight gain, metformin may not be enough and alternative treatments should be used,” she said.

In addition to its effects on weight, metformin has many other potential health benefits. Of particular importance is that it reduces hyperphagia-mediated antipsychotic-induced weight gain, Ms. Fitzgerald pointed out.

“This is subjectively very important for patients and provides a more positive experience when taking antipsychotics. Antipsychotic-induced weight gain is one of the main reasons for premature discontinuation or incomplete adherence to these drugs and therefore needs to be addressed proactively,” she concluded.

Ms. Fitzgerald and Dr. Michat have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com. This article was translated from the Medscape Spanish edition.

A wearable patch that delivers electrical stimulation to the perineum may postpone premature ejaculation, according to research presented at the annual meeting of the American Urological Association. The disposable device appears to work by helping men contract the muscles in the pelvic floor, allowing them to postpone climax.

Among 34 men with a lifelong history of premature ejaculation, average intravaginal ejaculatory latency time – the time from vaginal penetration to ejaculation – increased from about 67 seconds at baseline to 123 seconds when they used the device.

Another 17 participants received a sham treatment – stimulation they could feel but that did not activate muscles. In this group, time to ejaculation increased from 63 seconds to 81 seconds.

The longer duration with active treatment was statistically significant (P < .0001), whereas the increase in the control group was not (P = .1653), said Ege Can Serefoglu, MD, a researcher at Biruni University, Istanbul, and editor-in-chief of the International Journal of Impotence Research.

Dr. Serefoglu is a member of the scientific advisory board for Virility Medical, a company in Hod Hasharon, Israel, that is developing the stimulator. Marketed as vPatch, the device is expected to be available in 2023, Dr. Serefoglu said. It was cleared by the Food and Drug Administration in November and has CE-mark approval in Europe, according to the company.
 

Common problem, limited options

Research shows that 20%-30% of men are not happy with their time to ejaculation, Dr. Serefoglu said.

The International Society for Sexual Medicine defines premature ejaculation as ejaculation which always or almost always occurs within about 1 minute of penetration, the patient is unable to delay this occurrence, and the condition causes personal distress.

“Unfortunately, in spite of its high prevalence we do not really have any satisfying treatment options,” Dr. Serefoglu said.

Topical anesthetics may be used to decrease the sensitivity of the glans penis, and selective serotonin reuptake inhibitors may help delay ejaculation. But these options have limited efficacy and low adherence, he said.

Preclinical studies have shown that injection of botulinum toxin into the bulbospongiosus muscles is associated with a dose-dependent increase in ejaculation latency in rats.

Data on ClinicalTrials.gov show that this approach also may increase ejaculation latency in men, Dr. Serefoglu said. Although investigators found no safety concerns, drugmaker Allergan made a strategic business decision to stop developing this treatment approach, according to the registration entry for the study.

The idea for vPatch came from researchers wondering if instead of paralyzing the muscles with botulinum toxin, they used electrical stimulation to cause contraction of those muscles, Dr. Serefoglu said. A smaller proof-of-concept study demonstrated the feasibility and safety of this technique.

To further assess the safety and efficacy of a transcutaneous perineal electrical stimulator for the treatment of premature ejaculation, investigators conducted the randomized, double-blind, sham-controlled trial at Rambam Medical Centre, Haifa, Israel, and Villa Donatello Clinic, Florence, Italy.

The trial included males with premature ejaculation aged 18-60 years. Their female partners measured IELT using a stopwatch during four sexual intercourse sessions before treatment, and four times on treatment, at home.

In addition to the increased time to ejaculation, perceived control over ejaculation, satisfaction with sexual intercourse, personal distress related to ejaculation, and interpersonal difficulty related to ejaculation all significantly improved with vPatch, the researchers found.

Of participants who received active treatment, 73.5% reported a subjective sense of improvement versus 41.2% of the control group.
 

Potential reactions

No serious adverse events were observed, Dr. Serefoglu reported. Potential adverse reactions include redness, discomfort, and localized pain, according to the company’s website.

Men should not use vPatch if they have been diagnosed with pelvic cancer, or if they have an implanted electronic device, diabetes with peripheral neuropathy, or perineal dermatologic diseases, irritations, or lesions. Other precautions include avoiding use of the vPatch in water or humid environments. The device has not been tested on use with a pregnant partner.

The disposable patches are meant for one-time use. “The miniaturized perineal stimulation device may become an on-demand, drug-free therapeutic option,” Dr. Serefoglu said.

Combining electrical stimulation with other treatment approaches may provide additional benefit, said Bradley Schwartz, DO, professor and chairman of urology at Southern Illinois University, Springfield, who moderated the session at the AUA meeting at which the results of the study were presented.

“You go from 1 to 2 minutes just with this device,” Dr. Schwartz said. “If you went from 2 to 3 minutes, you would essentially be tripling their pleasure or their time, which might make a significant difference.”

Serefoglu agreed that combining the stimulator with other treatment approaches such as topical anesthetics could increase patient satisfaction.

Comoderator Kelly Healy, MD, assistant professor of urology at Columbia University Medical Center, New York, highlighted a direction for future research: examining outcomes according to different types of relationships, as well as partner satisfaction.

“That is a perfect question that should also be considered in the future trials,” Dr. Serefoglu said. “This was mainly focused on the man’s satisfaction. But men are trying to delay their ejaculation to satisfy their partner.”

Dr. Serefoglu is on the scientific advisory board for Virility Medical, which sponsored the study. Dr. Healy had no disclosures. Dr. Schwartz disclosed ties to Cook Medical.

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

A wearable patch that delivers electrical stimulation to the perineum may postpone premature ejaculation, according to research presented at the annual meeting of the American Urological Association. The disposable device appears to work by helping men contract the muscles in the pelvic floor, allowing them to postpone climax.

Among 34 men with a lifelong history of premature ejaculation, average intravaginal ejaculatory latency time – the time from vaginal penetration to ejaculation – increased from about 67 seconds at baseline to 123 seconds when they used the device.

Another 17 participants received a sham treatment – stimulation they could feel but that did not activate muscles. In this group, time to ejaculation increased from 63 seconds to 81 seconds.

The longer duration with active treatment was statistically significant (P < .0001), whereas the increase in the control group was not (P = .1653), said Ege Can Serefoglu, MD, a researcher at Biruni University, Istanbul, and editor-in-chief of the International Journal of Impotence Research.

Dr. Serefoglu is a member of the scientific advisory board for Virility Medical, a company in Hod Hasharon, Israel, that is developing the stimulator. Marketed as vPatch, the device is expected to be available in 2023, Dr. Serefoglu said. It was cleared by the Food and Drug Administration in November and has CE-mark approval in Europe, according to the company.
 

Common problem, limited options

Research shows that 20%-30% of men are not happy with their time to ejaculation, Dr. Serefoglu said.

The International Society for Sexual Medicine defines premature ejaculation as ejaculation which always or almost always occurs within about 1 minute of penetration, the patient is unable to delay this occurrence, and the condition causes personal distress.

“Unfortunately, in spite of its high prevalence we do not really have any satisfying treatment options,” Dr. Serefoglu said.

Topical anesthetics may be used to decrease the sensitivity of the glans penis, and selective serotonin reuptake inhibitors may help delay ejaculation. But these options have limited efficacy and low adherence, he said.

Preclinical studies have shown that injection of botulinum toxin into the bulbospongiosus muscles is associated with a dose-dependent increase in ejaculation latency in rats.

Data on ClinicalTrials.gov show that this approach also may increase ejaculation latency in men, Dr. Serefoglu said. Although investigators found no safety concerns, drugmaker Allergan made a strategic business decision to stop developing this treatment approach, according to the registration entry for the study.

The idea for vPatch came from researchers wondering if instead of paralyzing the muscles with botulinum toxin, they used electrical stimulation to cause contraction of those muscles, Dr. Serefoglu said. A smaller proof-of-concept study demonstrated the feasibility and safety of this technique.

To further assess the safety and efficacy of a transcutaneous perineal electrical stimulator for the treatment of premature ejaculation, investigators conducted the randomized, double-blind, sham-controlled trial at Rambam Medical Centre, Haifa, Israel, and Villa Donatello Clinic, Florence, Italy.

The trial included males with premature ejaculation aged 18-60 years. Their female partners measured IELT using a stopwatch during four sexual intercourse sessions before treatment, and four times on treatment, at home.

In addition to the increased time to ejaculation, perceived control over ejaculation, satisfaction with sexual intercourse, personal distress related to ejaculation, and interpersonal difficulty related to ejaculation all significantly improved with vPatch, the researchers found.

Of participants who received active treatment, 73.5% reported a subjective sense of improvement versus 41.2% of the control group.
 

Potential reactions

No serious adverse events were observed, Dr. Serefoglu reported. Potential adverse reactions include redness, discomfort, and localized pain, according to the company’s website.

Men should not use vPatch if they have been diagnosed with pelvic cancer, or if they have an implanted electronic device, diabetes with peripheral neuropathy, or perineal dermatologic diseases, irritations, or lesions. Other precautions include avoiding use of the vPatch in water or humid environments. The device has not been tested on use with a pregnant partner.

The disposable patches are meant for one-time use. “The miniaturized perineal stimulation device may become an on-demand, drug-free therapeutic option,” Dr. Serefoglu said.

Combining electrical stimulation with other treatment approaches may provide additional benefit, said Bradley Schwartz, DO, professor and chairman of urology at Southern Illinois University, Springfield, who moderated the session at the AUA meeting at which the results of the study were presented.

“You go from 1 to 2 minutes just with this device,” Dr. Schwartz said. “If you went from 2 to 3 minutes, you would essentially be tripling their pleasure or their time, which might make a significant difference.”

Serefoglu agreed that combining the stimulator with other treatment approaches such as topical anesthetics could increase patient satisfaction.

Comoderator Kelly Healy, MD, assistant professor of urology at Columbia University Medical Center, New York, highlighted a direction for future research: examining outcomes according to different types of relationships, as well as partner satisfaction.

“That is a perfect question that should also be considered in the future trials,” Dr. Serefoglu said. “This was mainly focused on the man’s satisfaction. But men are trying to delay their ejaculation to satisfy their partner.”

Dr. Serefoglu is on the scientific advisory board for Virility Medical, which sponsored the study. Dr. Healy had no disclosures. Dr. Schwartz disclosed ties to Cook Medical.

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

A wearable patch that delivers electrical stimulation to the perineum may postpone premature ejaculation, according to research presented at the annual meeting of the American Urological Association. The disposable device appears to work by helping men contract the muscles in the pelvic floor, allowing them to postpone climax.

Among 34 men with a lifelong history of premature ejaculation, average intravaginal ejaculatory latency time – the time from vaginal penetration to ejaculation – increased from about 67 seconds at baseline to 123 seconds when they used the device.

Another 17 participants received a sham treatment – stimulation they could feel but that did not activate muscles. In this group, time to ejaculation increased from 63 seconds to 81 seconds.

The longer duration with active treatment was statistically significant (P < .0001), whereas the increase in the control group was not (P = .1653), said Ege Can Serefoglu, MD, a researcher at Biruni University, Istanbul, and editor-in-chief of the International Journal of Impotence Research.

Dr. Serefoglu is a member of the scientific advisory board for Virility Medical, a company in Hod Hasharon, Israel, that is developing the stimulator. Marketed as vPatch, the device is expected to be available in 2023, Dr. Serefoglu said. It was cleared by the Food and Drug Administration in November and has CE-mark approval in Europe, according to the company.
 

Common problem, limited options

Research shows that 20%-30% of men are not happy with their time to ejaculation, Dr. Serefoglu said.

The International Society for Sexual Medicine defines premature ejaculation as ejaculation which always or almost always occurs within about 1 minute of penetration, the patient is unable to delay this occurrence, and the condition causes personal distress.

“Unfortunately, in spite of its high prevalence we do not really have any satisfying treatment options,” Dr. Serefoglu said.

Topical anesthetics may be used to decrease the sensitivity of the glans penis, and selective serotonin reuptake inhibitors may help delay ejaculation. But these options have limited efficacy and low adherence, he said.

Preclinical studies have shown that injection of botulinum toxin into the bulbospongiosus muscles is associated with a dose-dependent increase in ejaculation latency in rats.

Data on ClinicalTrials.gov show that this approach also may increase ejaculation latency in men, Dr. Serefoglu said. Although investigators found no safety concerns, drugmaker Allergan made a strategic business decision to stop developing this treatment approach, according to the registration entry for the study.

The idea for vPatch came from researchers wondering if instead of paralyzing the muscles with botulinum toxin, they used electrical stimulation to cause contraction of those muscles, Dr. Serefoglu said. A smaller proof-of-concept study demonstrated the feasibility and safety of this technique.

To further assess the safety and efficacy of a transcutaneous perineal electrical stimulator for the treatment of premature ejaculation, investigators conducted the randomized, double-blind, sham-controlled trial at Rambam Medical Centre, Haifa, Israel, and Villa Donatello Clinic, Florence, Italy.

The trial included males with premature ejaculation aged 18-60 years. Their female partners measured IELT using a stopwatch during four sexual intercourse sessions before treatment, and four times on treatment, at home.

In addition to the increased time to ejaculation, perceived control over ejaculation, satisfaction with sexual intercourse, personal distress related to ejaculation, and interpersonal difficulty related to ejaculation all significantly improved with vPatch, the researchers found.

Of participants who received active treatment, 73.5% reported a subjective sense of improvement versus 41.2% of the control group.
 

Potential reactions

No serious adverse events were observed, Dr. Serefoglu reported. Potential adverse reactions include redness, discomfort, and localized pain, according to the company’s website.

Men should not use vPatch if they have been diagnosed with pelvic cancer, or if they have an implanted electronic device, diabetes with peripheral neuropathy, or perineal dermatologic diseases, irritations, or lesions. Other precautions include avoiding use of the vPatch in water or humid environments. The device has not been tested on use with a pregnant partner.

The disposable patches are meant for one-time use. “The miniaturized perineal stimulation device may become an on-demand, drug-free therapeutic option,” Dr. Serefoglu said.

Combining electrical stimulation with other treatment approaches may provide additional benefit, said Bradley Schwartz, DO, professor and chairman of urology at Southern Illinois University, Springfield, who moderated the session at the AUA meeting at which the results of the study were presented.

“You go from 1 to 2 minutes just with this device,” Dr. Schwartz said. “If you went from 2 to 3 minutes, you would essentially be tripling their pleasure or their time, which might make a significant difference.”

Serefoglu agreed that combining the stimulator with other treatment approaches such as topical anesthetics could increase patient satisfaction.

Comoderator Kelly Healy, MD, assistant professor of urology at Columbia University Medical Center, New York, highlighted a direction for future research: examining outcomes according to different types of relationships, as well as partner satisfaction.

“That is a perfect question that should also be considered in the future trials,” Dr. Serefoglu said. “This was mainly focused on the man’s satisfaction. But men are trying to delay their ejaculation to satisfy their partner.”

Dr. Serefoglu is on the scientific advisory board for Virility Medical, which sponsored the study. Dr. Healy had no disclosures. Dr. Schwartz disclosed ties to Cook Medical.

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

A limited association exists between the use of isotretinoin for severe acne and worsening of a patient’s baseline inflammatory bowel disease, results from a small retrospective study suggests.

“Early studies of isotretinoin for use in severe acne suggested the drug may serve as a trigger for new-onset inflammatory bowel disease (IBD),” researchers led by Christina G. Lopez, MD, of the Lewis Katz School of Medicine at Temple University, Philadelphia, wrote in an article published online , in the Journal of the American Academy of Dermatology. “While more recent studies have suggested no such causal relationship, little is known about the medication’s effect on patients with a preexisting IBD diagnosis.”

To investigate this topic further, the researchers identified 19 patients who were diagnosed with IBD and treated with isotretinoin between Jan. 1, 2006, and Jan. 1, 2020, at Mass General Brigham Hospitals, Boston. They determined severity of disease and degree of antecedent management of IBD by evaluating flaring two years prior to starting isotretinoin. The patients were considered to have a flare caused by isotretinoin if the IBD flare occurred during or up to 3 months following course completion.

The mean age of the 19 patients was 35 years, 26% were female, and 95% were White. Nearly half of the patients (42%) had ulcerative colitis, 37% had Crohn’s disease, and 21% had both. The researchers found that nine patients had flared two years before starting isotretinoin. Of these, five (56%) flared and four (44%) did not flare during treatment or within three months of completing the course of isotretinoin.

Of the 10 patients who did not flare two years before starting isotretinoin, seven (70%) did not flare during treatment and three (30%) flared during or within three months following completion of isotretinoin use. The researchers found no statistically significant association between isotretinoin use and flaring among patients with IBD (P = .76).

Dr. Lopez and her colleagues also assessed IBD maintenance therapy with respect to IBD flares in the study population. They observed no statistically significant association between the use of maintenance IBD therapy and the likelihood of having flares during isotretinoin treatment (P = .15).

“The results suggest limited association between isotretinoin and the worsening of a patient’s baseline IBD,” the authors concluded. They acknowledged certain limitations of the study, including its small sample size and retrospective design, and they called for larger and prospective studies to assess the relationship of IBD flaring in this population of patients.

Pooja Sodha, MD, director of the Center for Laser and Cosmetic Dermatology at George Washington University, Washington, who was asked to comment on the results, characterized the trial as “an important study highlighting how we continue to understand the safe use of isotretinoin in the IBD cohort.”

Isotretinoin, she added, “continues to be a highly important treatment for acne and in patients such as these where oral antibiotics are relatively contraindicated due to risk of exacerbating their bowel disease.” Such data are reassuring, “albeit future studies with larger patient pools are desirable,” she added. “Future studies could also help to elucidate if diet, smoking, sleep, exercise, and medication adherence are potential confounding factors along with whether the cumulative isotretinoin dose has any effect on IBD flares in those who are susceptible.”

Neither the researchers nor Dr. Sodha had financial conflicts. The other authors were from Brigham and Women’s Hospital, Harvard University, Boston, and the University of Massachusetts, Worcester.

A limited association exists between the use of isotretinoin for severe acne and worsening of a patient’s baseline inflammatory bowel disease, results from a small retrospective study suggests.

“Early studies of isotretinoin for use in severe acne suggested the drug may serve as a trigger for new-onset inflammatory bowel disease (IBD),” researchers led by Christina G. Lopez, MD, of the Lewis Katz School of Medicine at Temple University, Philadelphia, wrote in an article published online , in the Journal of the American Academy of Dermatology. “While more recent studies have suggested no such causal relationship, little is known about the medication’s effect on patients with a preexisting IBD diagnosis.”

To investigate this topic further, the researchers identified 19 patients who were diagnosed with IBD and treated with isotretinoin between Jan. 1, 2006, and Jan. 1, 2020, at Mass General Brigham Hospitals, Boston. They determined severity of disease and degree of antecedent management of IBD by evaluating flaring two years prior to starting isotretinoin. The patients were considered to have a flare caused by isotretinoin if the IBD flare occurred during or up to 3 months following course completion.

The mean age of the 19 patients was 35 years, 26% were female, and 95% were White. Nearly half of the patients (42%) had ulcerative colitis, 37% had Crohn’s disease, and 21% had both. The researchers found that nine patients had flared two years before starting isotretinoin. Of these, five (56%) flared and four (44%) did not flare during treatment or within three months of completing the course of isotretinoin.

Of the 10 patients who did not flare two years before starting isotretinoin, seven (70%) did not flare during treatment and three (30%) flared during or within three months following completion of isotretinoin use. The researchers found no statistically significant association between isotretinoin use and flaring among patients with IBD (P = .76).

Dr. Lopez and her colleagues also assessed IBD maintenance therapy with respect to IBD flares in the study population. They observed no statistically significant association between the use of maintenance IBD therapy and the likelihood of having flares during isotretinoin treatment (P = .15).

“The results suggest limited association between isotretinoin and the worsening of a patient’s baseline IBD,” the authors concluded. They acknowledged certain limitations of the study, including its small sample size and retrospective design, and they called for larger and prospective studies to assess the relationship of IBD flaring in this population of patients.

Pooja Sodha, MD, director of the Center for Laser and Cosmetic Dermatology at George Washington University, Washington, who was asked to comment on the results, characterized the trial as “an important study highlighting how we continue to understand the safe use of isotretinoin in the IBD cohort.”

Isotretinoin, she added, “continues to be a highly important treatment for acne and in patients such as these where oral antibiotics are relatively contraindicated due to risk of exacerbating their bowel disease.” Such data are reassuring, “albeit future studies with larger patient pools are desirable,” she added. “Future studies could also help to elucidate if diet, smoking, sleep, exercise, and medication adherence are potential confounding factors along with whether the cumulative isotretinoin dose has any effect on IBD flares in those who are susceptible.”

Neither the researchers nor Dr. Sodha had financial conflicts. The other authors were from Brigham and Women’s Hospital, Harvard University, Boston, and the University of Massachusetts, Worcester.

A limited association exists between the use of isotretinoin for severe acne and worsening of a patient’s baseline inflammatory bowel disease, results from a small retrospective study suggests.

“Early studies of isotretinoin for use in severe acne suggested the drug may serve as a trigger for new-onset inflammatory bowel disease (IBD),” researchers led by Christina G. Lopez, MD, of the Lewis Katz School of Medicine at Temple University, Philadelphia, wrote in an article published online , in the Journal of the American Academy of Dermatology. “While more recent studies have suggested no such causal relationship, little is known about the medication’s effect on patients with a preexisting IBD diagnosis.”

To investigate this topic further, the researchers identified 19 patients who were diagnosed with IBD and treated with isotretinoin between Jan. 1, 2006, and Jan. 1, 2020, at Mass General Brigham Hospitals, Boston. They determined severity of disease and degree of antecedent management of IBD by evaluating flaring two years prior to starting isotretinoin. The patients were considered to have a flare caused by isotretinoin if the IBD flare occurred during or up to 3 months following course completion.

The mean age of the 19 patients was 35 years, 26% were female, and 95% were White. Nearly half of the patients (42%) had ulcerative colitis, 37% had Crohn’s disease, and 21% had both. The researchers found that nine patients had flared two years before starting isotretinoin. Of these, five (56%) flared and four (44%) did not flare during treatment or within three months of completing the course of isotretinoin.

Of the 10 patients who did not flare two years before starting isotretinoin, seven (70%) did not flare during treatment and three (30%) flared during or within three months following completion of isotretinoin use. The researchers found no statistically significant association between isotretinoin use and flaring among patients with IBD (P = .76).

Dr. Lopez and her colleagues also assessed IBD maintenance therapy with respect to IBD flares in the study population. They observed no statistically significant association between the use of maintenance IBD therapy and the likelihood of having flares during isotretinoin treatment (P = .15).

“The results suggest limited association between isotretinoin and the worsening of a patient’s baseline IBD,” the authors concluded. They acknowledged certain limitations of the study, including its small sample size and retrospective design, and they called for larger and prospective studies to assess the relationship of IBD flaring in this population of patients.

Pooja Sodha, MD, director of the Center for Laser and Cosmetic Dermatology at George Washington University, Washington, who was asked to comment on the results, characterized the trial as “an important study highlighting how we continue to understand the safe use of isotretinoin in the IBD cohort.”

Isotretinoin, she added, “continues to be a highly important treatment for acne and in patients such as these where oral antibiotics are relatively contraindicated due to risk of exacerbating their bowel disease.” Such data are reassuring, “albeit future studies with larger patient pools are desirable,” she added. “Future studies could also help to elucidate if diet, smoking, sleep, exercise, and medication adherence are potential confounding factors along with whether the cumulative isotretinoin dose has any effect on IBD flares in those who are susceptible.”

Neither the researchers nor Dr. Sodha had financial conflicts. The other authors were from Brigham and Women’s Hospital, Harvard University, Boston, and the University of Massachusetts, Worcester.

The Safer Alternatives for Emergency Response (SAFER) program provides a safe supply of substances to prevent drug overdose deaths, according to a new report.

The program has been operating in Vancouver, British Columbia, since April 2021. So far, the program has enrolled 58 participants who have reported benefits from having new options when other forms of treatment or harm reduction didn’t work. In addition, doctors who work with the program have reported increased medication adherence among the participants, as well as better chronic disease management.

Similar safe supply programs are being implemented or considered in other places across Canada. Since 2019, Health Canada has funded 18 safe supply pilot programs.

“When we look at the number of overdose deaths, it should be zero. These are preventable deaths,” author Christy Sutherland, MD, medical director at the PHS Community Services Society, Vancouver, which operates the SAFER program, told this news organization.

PHS Community Services Society

Safe supply programs

Between January 2016 and June 2021, more than 24,000 people died from opioid toxicity in Canada, according to the authors. A key driver of the ongoing public health crisis has been the introduction of illicit fentanyl and other dangerous substances into the unregulated drug supply.

In recent years, several harm-reduction options and substance use disorder treatment programs have been introduced in Canada to stem overdose deaths. However, they haven’t been sufficient, and the number of deaths continues to rise.

“In 2010, methadone worked, but now even high doses don’t keep people out of withdrawal due to the infiltration of fentanyl,” Dr. Sutherland said. “It’s clinically not working anymore. People are now going through benzodiazepine withdrawal and opiate withdrawal at the same time.”

The changes have led doctors to call for programs that provide legal and regulated sources of psychoactive substances, also known as “safe supply” programs. In particular, low-barrier and flexible options are necessary to meet the needs of various people in the community.

In Vancouver, the SAFER program provides medications that are prescribed off-label as substitutes to the illicit drug supply. A multidisciplinary team oversees the program, including doctors, nurses, pharmacists, social workers, and people who have experience living with substance use.

The program’s approach is akin to the use of medications as treatments for substance use disorder, such as opioid-agonist therapy. However, instead of promoting abstinence, the goal of SAFER is to prevent overdose deaths and other consequences by decreasing reliance on the unregulated drug market.

Enrolled participants can access medications, including opioids such as hydromorphone and fentanyl, as a substitute for the unregulated substances that they consume. A notable aspect of SAFER is the offer of fentanyl – with a known potency and without dangerous adulterants found in the local drug supply.
 

Promoting participant autonomy

Given the increasing rate of overdose deaths involving stimulants in Canada, the program also offers prescribed psychostimulants, such as methylphenidate and dextroamphetamine.

The program focuses on harm reduction and promoting participant autonomy. SAFER doesn’t have a predetermined schedule for medication access, which allows participants to return as they need.

“Creating this program has required patience to change our practices,” Dr. Sutherland said. “As you learn more and do more, you’re always growing because you care about your patients and want to help them, especially vulnerable people with a high risk for death.”

The SAFER program is integrated into health care and social services, and participants have access to on-site primary care from clinicians trained in addiction medicine. The program is located alongside a low-barrier prevention site, where supplies such as syringes, take-home naloxone kits, and drug-checking services are available.

The SAFER program will undergo a scientific evaluation, led by two of the co-authors, which will include about 200 participants. During a 2-year period, the evaluation will assess whether the program reduces the risk for overdose deaths and supports access to primary care, harm reduction, and substance use disorder treatment. In addition, the researchers will analyze other key outcomes, such as fatal versus nonfatal overdoses, medication adherence, and the qualitative lived experience of participants.
 

The end of prohibition?

“We’ve had the same challenges with people buying illegal drugs on the street for almost 30 years, but about 5 years ago, that all changed when fentanyl became a prominent drug, and overdose deaths skyrocketed,” Mark Tyndall, MD, a public health professor at the University of British Columbia, Vancouver, said in an interview.

University of British Columbia

Dr. Tyndall is also executive director of the British Columbia Centre for Disease Control and executive director of MySafe Society, a safe supply program in Canada for those with opioid addiction. He is not involved in the SAFER program.

SAFER and MySafe Society are positioned as low-barrier programs, he said, meaning that the public health response is primarily focused on preventing deaths and helping people to get access to medication that won’t kill them. The idea is to meet people where they are today.

However, these programs still face major barriers, such as limitations from federal regulators and stigmas around illicit drugs and harm-reduction programs.

“These beliefs are entrenched, and it takes a long time to help people understand that prohibition means that dangerous drugs are on the street,” he said. “I don’t think way more people are using than 10 years ago, but there was a supply of heroin that was stable in potency back then, and people weren’t dying.”

Ultimately, Dr. Tyndall said, drug policy experts would like to create a regulated supply, similar to the supply of cannabis. The political and regulatory process may take much longer to catch up, but he believes that it’s the most ethical way to reduce overdose deaths and the unregulated drug supply.

“The harshest critics of harm reduction often go to the liquor store every weekend,” he said. “It’s going to be a long process before people think this way, but having fentanyl and other dangerous drugs on the street has signaled the end stage of prohibition.”

The SAFER program is operated by PHS Community Services Society in partnership with Vancouver Coastal Health and funded through Health Canada’s Substance Use and Addiction Program. Dr. Tyndall reported no relevant disclosures.

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

The Safer Alternatives for Emergency Response (SAFER) program provides a safe supply of substances to prevent drug overdose deaths, according to a new report.

The program has been operating in Vancouver, British Columbia, since April 2021. So far, the program has enrolled 58 participants who have reported benefits from having new options when other forms of treatment or harm reduction didn’t work. In addition, doctors who work with the program have reported increased medication adherence among the participants, as well as better chronic disease management.

Similar safe supply programs are being implemented or considered in other places across Canada. Since 2019, Health Canada has funded 18 safe supply pilot programs.

“When we look at the number of overdose deaths, it should be zero. These are preventable deaths,” author Christy Sutherland, MD, medical director at the PHS Community Services Society, Vancouver, which operates the SAFER program, told this news organization.

PHS Community Services Society

Safe supply programs

Between January 2016 and June 2021, more than 24,000 people died from opioid toxicity in Canada, according to the authors. A key driver of the ongoing public health crisis has been the introduction of illicit fentanyl and other dangerous substances into the unregulated drug supply.

In recent years, several harm-reduction options and substance use disorder treatment programs have been introduced in Canada to stem overdose deaths. However, they haven’t been sufficient, and the number of deaths continues to rise.

“In 2010, methadone worked, but now even high doses don’t keep people out of withdrawal due to the infiltration of fentanyl,” Dr. Sutherland said. “It’s clinically not working anymore. People are now going through benzodiazepine withdrawal and opiate withdrawal at the same time.”

The changes have led doctors to call for programs that provide legal and regulated sources of psychoactive substances, also known as “safe supply” programs. In particular, low-barrier and flexible options are necessary to meet the needs of various people in the community.

In Vancouver, the SAFER program provides medications that are prescribed off-label as substitutes to the illicit drug supply. A multidisciplinary team oversees the program, including doctors, nurses, pharmacists, social workers, and people who have experience living with substance use.

The program’s approach is akin to the use of medications as treatments for substance use disorder, such as opioid-agonist therapy. However, instead of promoting abstinence, the goal of SAFER is to prevent overdose deaths and other consequences by decreasing reliance on the unregulated drug market.

Enrolled participants can access medications, including opioids such as hydromorphone and fentanyl, as a substitute for the unregulated substances that they consume. A notable aspect of SAFER is the offer of fentanyl – with a known potency and without dangerous adulterants found in the local drug supply.
 

Promoting participant autonomy

Given the increasing rate of overdose deaths involving stimulants in Canada, the program also offers prescribed psychostimulants, such as methylphenidate and dextroamphetamine.

The program focuses on harm reduction and promoting participant autonomy. SAFER doesn’t have a predetermined schedule for medication access, which allows participants to return as they need.

“Creating this program has required patience to change our practices,” Dr. Sutherland said. “As you learn more and do more, you’re always growing because you care about your patients and want to help them, especially vulnerable people with a high risk for death.”

The SAFER program is integrated into health care and social services, and participants have access to on-site primary care from clinicians trained in addiction medicine. The program is located alongside a low-barrier prevention site, where supplies such as syringes, take-home naloxone kits, and drug-checking services are available.

The SAFER program will undergo a scientific evaluation, led by two of the co-authors, which will include about 200 participants. During a 2-year period, the evaluation will assess whether the program reduces the risk for overdose deaths and supports access to primary care, harm reduction, and substance use disorder treatment. In addition, the researchers will analyze other key outcomes, such as fatal versus nonfatal overdoses, medication adherence, and the qualitative lived experience of participants.
 

The end of prohibition?

“We’ve had the same challenges with people buying illegal drugs on the street for almost 30 years, but about 5 years ago, that all changed when fentanyl became a prominent drug, and overdose deaths skyrocketed,” Mark Tyndall, MD, a public health professor at the University of British Columbia, Vancouver, said in an interview.

University of British Columbia

Dr. Tyndall is also executive director of the British Columbia Centre for Disease Control and executive director of MySafe Society, a safe supply program in Canada for those with opioid addiction. He is not involved in the SAFER program.

SAFER and MySafe Society are positioned as low-barrier programs, he said, meaning that the public health response is primarily focused on preventing deaths and helping people to get access to medication that won’t kill them. The idea is to meet people where they are today.

However, these programs still face major barriers, such as limitations from federal regulators and stigmas around illicit drugs and harm-reduction programs.

“These beliefs are entrenched, and it takes a long time to help people understand that prohibition means that dangerous drugs are on the street,” he said. “I don’t think way more people are using than 10 years ago, but there was a supply of heroin that was stable in potency back then, and people weren’t dying.”

Ultimately, Dr. Tyndall said, drug policy experts would like to create a regulated supply, similar to the supply of cannabis. The political and regulatory process may take much longer to catch up, but he believes that it’s the most ethical way to reduce overdose deaths and the unregulated drug supply.

“The harshest critics of harm reduction often go to the liquor store every weekend,” he said. “It’s going to be a long process before people think this way, but having fentanyl and other dangerous drugs on the street has signaled the end stage of prohibition.”

The SAFER program is operated by PHS Community Services Society in partnership with Vancouver Coastal Health and funded through Health Canada’s Substance Use and Addiction Program. Dr. Tyndall reported no relevant disclosures.

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

The Safer Alternatives for Emergency Response (SAFER) program provides a safe supply of substances to prevent drug overdose deaths, according to a new report.

The program has been operating in Vancouver, British Columbia, since April 2021. So far, the program has enrolled 58 participants who have reported benefits from having new options when other forms of treatment or harm reduction didn’t work. In addition, doctors who work with the program have reported increased medication adherence among the participants, as well as better chronic disease management.

Similar safe supply programs are being implemented or considered in other places across Canada. Since 2019, Health Canada has funded 18 safe supply pilot programs.

“When we look at the number of overdose deaths, it should be zero. These are preventable deaths,” author Christy Sutherland, MD, medical director at the PHS Community Services Society, Vancouver, which operates the SAFER program, told this news organization.

PHS Community Services Society

Safe supply programs

Between January 2016 and June 2021, more than 24,000 people died from opioid toxicity in Canada, according to the authors. A key driver of the ongoing public health crisis has been the introduction of illicit fentanyl and other dangerous substances into the unregulated drug supply.

In recent years, several harm-reduction options and substance use disorder treatment programs have been introduced in Canada to stem overdose deaths. However, they haven’t been sufficient, and the number of deaths continues to rise.

“In 2010, methadone worked, but now even high doses don’t keep people out of withdrawal due to the infiltration of fentanyl,” Dr. Sutherland said. “It’s clinically not working anymore. People are now going through benzodiazepine withdrawal and opiate withdrawal at the same time.”

The changes have led doctors to call for programs that provide legal and regulated sources of psychoactive substances, also known as “safe supply” programs. In particular, low-barrier and flexible options are necessary to meet the needs of various people in the community.

In Vancouver, the SAFER program provides medications that are prescribed off-label as substitutes to the illicit drug supply. A multidisciplinary team oversees the program, including doctors, nurses, pharmacists, social workers, and people who have experience living with substance use.

The program’s approach is akin to the use of medications as treatments for substance use disorder, such as opioid-agonist therapy. However, instead of promoting abstinence, the goal of SAFER is to prevent overdose deaths and other consequences by decreasing reliance on the unregulated drug market.

Enrolled participants can access medications, including opioids such as hydromorphone and fentanyl, as a substitute for the unregulated substances that they consume. A notable aspect of SAFER is the offer of fentanyl – with a known potency and without dangerous adulterants found in the local drug supply.
 

Promoting participant autonomy

Given the increasing rate of overdose deaths involving stimulants in Canada, the program also offers prescribed psychostimulants, such as methylphenidate and dextroamphetamine.

The program focuses on harm reduction and promoting participant autonomy. SAFER doesn’t have a predetermined schedule for medication access, which allows participants to return as they need.

“Creating this program has required patience to change our practices,” Dr. Sutherland said. “As you learn more and do more, you’re always growing because you care about your patients and want to help them, especially vulnerable people with a high risk for death.”

The SAFER program is integrated into health care and social services, and participants have access to on-site primary care from clinicians trained in addiction medicine. The program is located alongside a low-barrier prevention site, where supplies such as syringes, take-home naloxone kits, and drug-checking services are available.

The SAFER program will undergo a scientific evaluation, led by two of the co-authors, which will include about 200 participants. During a 2-year period, the evaluation will assess whether the program reduces the risk for overdose deaths and supports access to primary care, harm reduction, and substance use disorder treatment. In addition, the researchers will analyze other key outcomes, such as fatal versus nonfatal overdoses, medication adherence, and the qualitative lived experience of participants.
 

The end of prohibition?

“We’ve had the same challenges with people buying illegal drugs on the street for almost 30 years, but about 5 years ago, that all changed when fentanyl became a prominent drug, and overdose deaths skyrocketed,” Mark Tyndall, MD, a public health professor at the University of British Columbia, Vancouver, said in an interview.

University of British Columbia

Dr. Tyndall is also executive director of the British Columbia Centre for Disease Control and executive director of MySafe Society, a safe supply program in Canada for those with opioid addiction. He is not involved in the SAFER program.

SAFER and MySafe Society are positioned as low-barrier programs, he said, meaning that the public health response is primarily focused on preventing deaths and helping people to get access to medication that won’t kill them. The idea is to meet people where they are today.

However, these programs still face major barriers, such as limitations from federal regulators and stigmas around illicit drugs and harm-reduction programs.

“These beliefs are entrenched, and it takes a long time to help people understand that prohibition means that dangerous drugs are on the street,” he said. “I don’t think way more people are using than 10 years ago, but there was a supply of heroin that was stable in potency back then, and people weren’t dying.”

Ultimately, Dr. Tyndall said, drug policy experts would like to create a regulated supply, similar to the supply of cannabis. The political and regulatory process may take much longer to catch up, but he believes that it’s the most ethical way to reduce overdose deaths and the unregulated drug supply.

“The harshest critics of harm reduction often go to the liquor store every weekend,” he said. “It’s going to be a long process before people think this way, but having fentanyl and other dangerous drugs on the street has signaled the end stage of prohibition.”

The SAFER program is operated by PHS Community Services Society in partnership with Vancouver Coastal Health and funded through Health Canada’s Substance Use and Addiction Program. Dr. Tyndall reported no relevant disclosures.

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

Cariprazine (Vraylar) is a safe and effective adjunctive treatment for adults with major depressive disorder (MDD) who have an inadequate response to antidepressant monotherapy, new results from a phase 3 study show.

Already approved by the U.S. Food and Drug Administration to treat adults with schizophrenia and manic, mixed, or depressive episodes of bipolar I disorder, cariprazine is under investigation as an add-on therapy for MDD.

“Even patients who appear to be nonresponsive to standard antidepressant drugs have a very good chance of responding” to cariprazine, lead study author Gary Sachs, MD, associate clinical professor of psychiatry at Massachusetts General Hospital, Boston, told this news organization.

He noted that cariprazine, which is a partial agonist at D2 and D3, as well as 5-HT1A, “is an entirely different class” of drugs.

“It’s worth understanding how to use drugs like cariprazine and expanding our nomenclature; instead of referring to these drugs as atypical antipsychotics, perhaps referring to them as atypical antidepressants makes more sense,” Dr. Sachs said.

The findings were presented at the annual meeting of the American Psychiatric Association.
 

More options critical

MDD is among the most common psychiatric disorders in the United States. In 2020, an estimated 21 million adults had at least one major depressive episode.

Previous research has shown almost half of patients with MDD do not experience satisfactory results from their current treatment regimen. Therefore, research on more options for patients is critical, Dr. Sachs said.

Results from a previously published placebo-controlled study showed adjunctive treatment with cariprazine at 2-mg to 4.5-mg per day doses was more effective than placebo in improving depressive symptoms in adults with MDD.

The new analysis included patients with MDD and an inadequate response to antidepressant therapy, including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants. They were recruited from 116 centers in the United States and Europe.

Dr. Sachs noted that a nonresponse to an adequate dose of an antidepressant typically means having less than a 50% improvement over 6 weeks or more.

Researchers randomly assigned the patients to oral cariprazine 1.5 mg/day, cariprazine 3 mg/day, or placebo. All continued to take their antidepressant monotherapy.

The analysis included 757 mostly White participants (mean age, 44.8 years; 73.4% women). All had experienced depression for a “huge” part of their life (average, about 14 years), “not to mention their adult life,” said Dr. Sachs.

In addition, at the start of the study, the participants had been depressed for almost 8 months on average.

The primary endpoint was change at week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. The mean baseline MADRS total score was 32.5.

Less is sometimes more

Results showed a significantly greater mean reduction in MADRS total score for cariprazine 1.5 mg/day vs. placebo at week 6 (P = .005). Significant differences from placebo were observed as early as week 2 and were maintained at week 4, as well as week 6.

“I can say with great confidence that the 1.5-mg dose met all the standards for efficacy,” Dr. Sachs said.

However, this was not the case for the 3-mg/day dose. Although there was a numerically greater reduction in MADRS total score for this dosage of the drug vs. placebo at week 6, the difference was not statistically significant (P = .07).

At week 6, more patients taking the active drug at 1.5 mg/day than placebo responded to treatment, defined as 50% or greater reduction in MADRS total score (44% vs. 34.9%, respectively; P < .05).

Researchers also assessed scores on the Clinical Global Impressions, finding significantly greater score improvement for both the 1.5-mg/day (P = .0026) and 3-mg/day (P =.0076) groups vs. the placebo group.

Improvement at week 6 in mean total score on the Hamilton Depression Rating Scale (HAM-17) reached nominal significance for cariprazine 1.5 mg/day vs. placebo – but not for 3 mg/day.

The results of this “high-quality” double-blind, randomized, controlled, parallel group study provide “what I regard as proven efficacy,” Dr. Sachs said.

He added that the investigational drug was also relatively safe. “The vast majority of patients tolerated it quite well,” he stressed. In addition, the drop-out rate because of adverse events was “quite low overall.”

The only adverse events (AEs) that occurred with the active treatment at a frequency of 5% or more and double that of placebo were akathisia and nausea. Changes in weight were relatively small, at less than 1 kg, in all treatment groups.

There was one serious AE in each active drug group, one of which was a kidney infection. There were two serious AEs reported in the placebo group, including one patient with multiple sclerosis. There were no deaths.

Dr. Sachs noted an advantage of cariprazine is its long half-life, which makes it more user-friendly because “it forgives you if you miss a dose or two.”

Drug manufacturer AbbVie’s supplemental New Drug Application for cariprazine is currently under review by the FDA for expanded use as adjunctive treatment of MDD. A decision by the agency is expected by the end of this year.

Another potential treatment option

Commenting on the findings, James Murrough, MD, PhD, associate professor of psychiatry and of neuroscience and director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai, New York, said he welcomes research into additional treatments for MDD.

“Each medicine in a particular class has a unique pharmacology, so a larger number of medication options may help the clinician find a good match for a particular patient,” said Dr. Murrough, who was not involved with the research.

He noted cariprazine is “somewhat unique” among the dopamine modulators in “preferring interactions with the D3 receptor, one of many types of dopamine receptors.”

Although the study results showed cariprazine was effective in MDD, it “does not entirely break new ground” because previous research has already established the drug’s efficacy as adjunctive therapy for patients with depression not responding to a standard antidepressant, said Dr. Murrough.

He also noted that the lower dose, but not the higher dose, of the drug was found to be significantly beneficial for patients, compared with placebo.

“This is a good reminder that higher doses of a medication are not always better,” Dr. Murrough said.

The study was funded by AbbVie. Dr. Sachs is a full-time employee of Signant Health, which conducted the training and quality control for this study. Dr. Murrough has reported no relevant financial relationships.

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

Cariprazine (Vraylar) is a safe and effective adjunctive treatment for adults with major depressive disorder (MDD) who have an inadequate response to antidepressant monotherapy, new results from a phase 3 study show.

Already approved by the U.S. Food and Drug Administration to treat adults with schizophrenia and manic, mixed, or depressive episodes of bipolar I disorder, cariprazine is under investigation as an add-on therapy for MDD.

“Even patients who appear to be nonresponsive to standard antidepressant drugs have a very good chance of responding” to cariprazine, lead study author Gary Sachs, MD, associate clinical professor of psychiatry at Massachusetts General Hospital, Boston, told this news organization.

He noted that cariprazine, which is a partial agonist at D2 and D3, as well as 5-HT1A, “is an entirely different class” of drugs.

“It’s worth understanding how to use drugs like cariprazine and expanding our nomenclature; instead of referring to these drugs as atypical antipsychotics, perhaps referring to them as atypical antidepressants makes more sense,” Dr. Sachs said.

The findings were presented at the annual meeting of the American Psychiatric Association.
 

More options critical

MDD is among the most common psychiatric disorders in the United States. In 2020, an estimated 21 million adults had at least one major depressive episode.

Previous research has shown almost half of patients with MDD do not experience satisfactory results from their current treatment regimen. Therefore, research on more options for patients is critical, Dr. Sachs said.

Results from a previously published placebo-controlled study showed adjunctive treatment with cariprazine at 2-mg to 4.5-mg per day doses was more effective than placebo in improving depressive symptoms in adults with MDD.

The new analysis included patients with MDD and an inadequate response to antidepressant therapy, including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants. They were recruited from 116 centers in the United States and Europe.

Dr. Sachs noted that a nonresponse to an adequate dose of an antidepressant typically means having less than a 50% improvement over 6 weeks or more.

Researchers randomly assigned the patients to oral cariprazine 1.5 mg/day, cariprazine 3 mg/day, or placebo. All continued to take their antidepressant monotherapy.

The analysis included 757 mostly White participants (mean age, 44.8 years; 73.4% women). All had experienced depression for a “huge” part of their life (average, about 14 years), “not to mention their adult life,” said Dr. Sachs.

In addition, at the start of the study, the participants had been depressed for almost 8 months on average.

The primary endpoint was change at week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. The mean baseline MADRS total score was 32.5.

Less is sometimes more

Results showed a significantly greater mean reduction in MADRS total score for cariprazine 1.5 mg/day vs. placebo at week 6 (P = .005). Significant differences from placebo were observed as early as week 2 and were maintained at week 4, as well as week 6.

“I can say with great confidence that the 1.5-mg dose met all the standards for efficacy,” Dr. Sachs said.

However, this was not the case for the 3-mg/day dose. Although there was a numerically greater reduction in MADRS total score for this dosage of the drug vs. placebo at week 6, the difference was not statistically significant (P = .07).

At week 6, more patients taking the active drug at 1.5 mg/day than placebo responded to treatment, defined as 50% or greater reduction in MADRS total score (44% vs. 34.9%, respectively; P < .05).

Researchers also assessed scores on the Clinical Global Impressions, finding significantly greater score improvement for both the 1.5-mg/day (P = .0026) and 3-mg/day (P =.0076) groups vs. the placebo group.

Improvement at week 6 in mean total score on the Hamilton Depression Rating Scale (HAM-17) reached nominal significance for cariprazine 1.5 mg/day vs. placebo – but not for 3 mg/day.

The results of this “high-quality” double-blind, randomized, controlled, parallel group study provide “what I regard as proven efficacy,” Dr. Sachs said.

He added that the investigational drug was also relatively safe. “The vast majority of patients tolerated it quite well,” he stressed. In addition, the drop-out rate because of adverse events was “quite low overall.”

The only adverse events (AEs) that occurred with the active treatment at a frequency of 5% or more and double that of placebo were akathisia and nausea. Changes in weight were relatively small, at less than 1 kg, in all treatment groups.

There was one serious AE in each active drug group, one of which was a kidney infection. There were two serious AEs reported in the placebo group, including one patient with multiple sclerosis. There were no deaths.

Dr. Sachs noted an advantage of cariprazine is its long half-life, which makes it more user-friendly because “it forgives you if you miss a dose or two.”

Drug manufacturer AbbVie’s supplemental New Drug Application for cariprazine is currently under review by the FDA for expanded use as adjunctive treatment of MDD. A decision by the agency is expected by the end of this year.

Another potential treatment option

Commenting on the findings, James Murrough, MD, PhD, associate professor of psychiatry and of neuroscience and director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai, New York, said he welcomes research into additional treatments for MDD.

“Each medicine in a particular class has a unique pharmacology, so a larger number of medication options may help the clinician find a good match for a particular patient,” said Dr. Murrough, who was not involved with the research.

He noted cariprazine is “somewhat unique” among the dopamine modulators in “preferring interactions with the D3 receptor, one of many types of dopamine receptors.”

Although the study results showed cariprazine was effective in MDD, it “does not entirely break new ground” because previous research has already established the drug’s efficacy as adjunctive therapy for patients with depression not responding to a standard antidepressant, said Dr. Murrough.

He also noted that the lower dose, but not the higher dose, of the drug was found to be significantly beneficial for patients, compared with placebo.

“This is a good reminder that higher doses of a medication are not always better,” Dr. Murrough said.

The study was funded by AbbVie. Dr. Sachs is a full-time employee of Signant Health, which conducted the training and quality control for this study. Dr. Murrough has reported no relevant financial relationships.

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

Cariprazine (Vraylar) is a safe and effective adjunctive treatment for adults with major depressive disorder (MDD) who have an inadequate response to antidepressant monotherapy, new results from a phase 3 study show.

Already approved by the U.S. Food and Drug Administration to treat adults with schizophrenia and manic, mixed, or depressive episodes of bipolar I disorder, cariprazine is under investigation as an add-on therapy for MDD.

“Even patients who appear to be nonresponsive to standard antidepressant drugs have a very good chance of responding” to cariprazine, lead study author Gary Sachs, MD, associate clinical professor of psychiatry at Massachusetts General Hospital, Boston, told this news organization.

He noted that cariprazine, which is a partial agonist at D2 and D3, as well as 5-HT1A, “is an entirely different class” of drugs.

“It’s worth understanding how to use drugs like cariprazine and expanding our nomenclature; instead of referring to these drugs as atypical antipsychotics, perhaps referring to them as atypical antidepressants makes more sense,” Dr. Sachs said.

The findings were presented at the annual meeting of the American Psychiatric Association.
 

More options critical

MDD is among the most common psychiatric disorders in the United States. In 2020, an estimated 21 million adults had at least one major depressive episode.

Previous research has shown almost half of patients with MDD do not experience satisfactory results from their current treatment regimen. Therefore, research on more options for patients is critical, Dr. Sachs said.

Results from a previously published placebo-controlled study showed adjunctive treatment with cariprazine at 2-mg to 4.5-mg per day doses was more effective than placebo in improving depressive symptoms in adults with MDD.

The new analysis included patients with MDD and an inadequate response to antidepressant therapy, including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants. They were recruited from 116 centers in the United States and Europe.

Dr. Sachs noted that a nonresponse to an adequate dose of an antidepressant typically means having less than a 50% improvement over 6 weeks or more.

Researchers randomly assigned the patients to oral cariprazine 1.5 mg/day, cariprazine 3 mg/day, or placebo. All continued to take their antidepressant monotherapy.

The analysis included 757 mostly White participants (mean age, 44.8 years; 73.4% women). All had experienced depression for a “huge” part of their life (average, about 14 years), “not to mention their adult life,” said Dr. Sachs.

In addition, at the start of the study, the participants had been depressed for almost 8 months on average.

The primary endpoint was change at week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. The mean baseline MADRS total score was 32.5.

Less is sometimes more

Results showed a significantly greater mean reduction in MADRS total score for cariprazine 1.5 mg/day vs. placebo at week 6 (P = .005). Significant differences from placebo were observed as early as week 2 and were maintained at week 4, as well as week 6.

“I can say with great confidence that the 1.5-mg dose met all the standards for efficacy,” Dr. Sachs said.

However, this was not the case for the 3-mg/day dose. Although there was a numerically greater reduction in MADRS total score for this dosage of the drug vs. placebo at week 6, the difference was not statistically significant (P = .07).

At week 6, more patients taking the active drug at 1.5 mg/day than placebo responded to treatment, defined as 50% or greater reduction in MADRS total score (44% vs. 34.9%, respectively; P < .05).

Researchers also assessed scores on the Clinical Global Impressions, finding significantly greater score improvement for both the 1.5-mg/day (P = .0026) and 3-mg/day (P =.0076) groups vs. the placebo group.

Improvement at week 6 in mean total score on the Hamilton Depression Rating Scale (HAM-17) reached nominal significance for cariprazine 1.5 mg/day vs. placebo – but not for 3 mg/day.

The results of this “high-quality” double-blind, randomized, controlled, parallel group study provide “what I regard as proven efficacy,” Dr. Sachs said.

He added that the investigational drug was also relatively safe. “The vast majority of patients tolerated it quite well,” he stressed. In addition, the drop-out rate because of adverse events was “quite low overall.”

The only adverse events (AEs) that occurred with the active treatment at a frequency of 5% or more and double that of placebo were akathisia and nausea. Changes in weight were relatively small, at less than 1 kg, in all treatment groups.

There was one serious AE in each active drug group, one of which was a kidney infection. There were two serious AEs reported in the placebo group, including one patient with multiple sclerosis. There were no deaths.

Dr. Sachs noted an advantage of cariprazine is its long half-life, which makes it more user-friendly because “it forgives you if you miss a dose or two.”

Drug manufacturer AbbVie’s supplemental New Drug Application for cariprazine is currently under review by the FDA for expanded use as adjunctive treatment of MDD. A decision by the agency is expected by the end of this year.

Another potential treatment option

Commenting on the findings, James Murrough, MD, PhD, associate professor of psychiatry and of neuroscience and director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai, New York, said he welcomes research into additional treatments for MDD.

“Each medicine in a particular class has a unique pharmacology, so a larger number of medication options may help the clinician find a good match for a particular patient,” said Dr. Murrough, who was not involved with the research.

He noted cariprazine is “somewhat unique” among the dopamine modulators in “preferring interactions with the D3 receptor, one of many types of dopamine receptors.”

Although the study results showed cariprazine was effective in MDD, it “does not entirely break new ground” because previous research has already established the drug’s efficacy as adjunctive therapy for patients with depression not responding to a standard antidepressant, said Dr. Murrough.

He also noted that the lower dose, but not the higher dose, of the drug was found to be significantly beneficial for patients, compared with placebo.

“This is a good reminder that higher doses of a medication are not always better,” Dr. Murrough said.

The study was funded by AbbVie. Dr. Sachs is a full-time employee of Signant Health, which conducted the training and quality control for this study. Dr. Murrough has reported no relevant financial relationships.

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

Use of sodium–glucose cotransporter-2 (SGLT-2) inhibitors rather than metformin as first-line treatment for type 2 diabetes appears to cut the risk for heart failure hospitalization but not myocardial infarction, stroke, or all-cause mortality, a new analysis of real-world data suggests.

Safety findings were similar, except for the fact that genital infections were more common with SGLT-2 inhibitors.

The study was conducted using claims data from two large U.S. insurance databases and Medicare. Propensity score matching was used to account for baseline differences.

The study was conducted by HoJin Shin, BPharm, PhD, a postdoctoral research fellow at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and colleagues. The findings were published online in Annals of Internal Medicine.

“Those who start SGLT-2 inhibitors as first line show similar risks, compared with metformin in MI, stroke, and all-cause mortality outcomes. Strikingly and consistently, SGLT-2 inhibitors show lower risk for hospitalization for heart failure, which is consistent with the findings from cardiovascular outcomes trials,” Dr. Shin said in an interview.
 

Just a beginning step, although trial probably wasn’t long enough

However, she added, “I don’t want to overstate anything. ... We aren’t powered enough to investigate who would benefit the most. ... As a pharmacoepidemiologist, I think it’s my duty to provide high-quality evidence so we can actually help physicians and patients make better decisions on their medication. Our current research is just a beginning step.”

Asked to comment, Simeon I. Taylor, MD, PhD, professor of medicine at the University of Maryland, Baltimore, told this news organization, “This study generally confirmed conclusions from published RCTs [randomized clinical trials]. No real surprises, albeit the conclusions may not fully support some of the most enthusiastic claims for SGLT-2 inhibitors with respect to MI, stroke, and cardiovascular death.”

Indeed, Dr. Taylor noted that only two SGLT-2 inhibitors, canagliflozin and empagliflozin, were shown to have a statistically significant association with decreased major adverse cardiovascular events.

In contrast, neither dapagliflozin nor ertugliflozin showed significant benefit regarding those outcomes.

He also pointed out that those four major SLGT-2 inhibitor cardiovascular outcomes trials were placebo-controlled rather than head-to-head trials in which they were compared to an active comparator such as metformin.

“Viewed in this light, it’s probably not surprising that the present study did not demonstrate a robust benefit for SGLT-2 inhibitors to decrease [major adverse CV events].”

The duration of follow-up in the current study is also a limitation, he added.

“The majority of patients were followed for a year or less. This is probably sufficient to assess the impact of some pharmacological mechanisms, for example, the beneficial impact to decrease risk of heart failure by promoting urinary sodium excretion. However, it’s probably insufficient time to observe a beneficial impact on atherosclerosis. For example, there is typically a lag of several years before statins demonstrate efficacy with respect to adverse cardiovascular events.”

Nevertheless, he said, “it provides strong support for benefit with respect to decreasing risk of hospitalization for heart failure.”

He noted that while metformin is currently significantly cheaper than any SGLT-2 inhibitors, once the latter become available as generics, they will be cheaper, and this will likely have a bearing on prescribing decisions.

“Availability of generic SGLT-2 inhibitors offers potential to transform prescribing patterns for type 2 diabetes,” he noted.

First-line SGLT2 inhibitors versus metformin: Most outcomes similar

The study data came from two commercial U.S. health insurance databases, Optum Clinfomatics Data Mart and IBM Marketscan, and from Medicare fee-for-service enrollees.

From April 2013 through March 2020, a total of 9,334 patients began treatment with first-line SGLT-2 inhibitors; 819,973 patients began taking metformin. After 1:2 propensity score matching for confounders, there were 8,613 participants in the SGLT-2 inhibitor group and 17,226 in the group that began treatment with metformin.

The mean follow-up times were 10.7 months for patients taking SGLT-2 inhibitors and 12.2 months for patients taking metformin.

Incidence rates per 1,000 person-years for the composite of hospitalization for MI, hospitalization for ischemic or hemorrhagic stroke, or all-cause mortality (MI/stroke/mortality) were 15.0 versus 16.2 for SLGT-2 inhibitors versus metformin, not a significant difference (hazard ratio, 0.96).

However, for the composite of heart failure hospitalization or all-cause mortality, the rates were 18.3 versus 23.5, a significant difference, with an HR of 0.80. The benefit was seen beginning at about 6 months.

Compared with metformin, SGLT-2 inhibitors showed a significantly lower risk for heart failure hospitalization (HR, 0.78), a numerically (but not significantly) lower risk for MI (HR, 0.70), and similar risks for stroke, mortality, and MI/stroke/HHF/mortality.

Genital infections were significantly more common with SGLT-2 inhibitors (54.1 vs. 23.7 per 1,000 person-years; HR, 2.19). Other safety measures were similar, including acute kidney injury, bone fractures, severe hypoglycemia, diabetic ketoacidosis, and lower-limb amputations.
 

How does cost factor in?

A sensitivity analysis aimed at examining the possible effect of unmeasured socioeconomic status showed no difference in cardiovascular benefit for first-line SGLT-2 inhibitors and metformin, compared with first-line dipeptidyl peptidase–4 (DPP-4) inhibitors, which cost more than metformin; it is not known what effect DPP-4 inhibitors have on the cardiovascular outcomes of interest.

Cost and insurance coverage factor into the benefit/risk calculation. Metformin is far less costly than any of the SGLT-2 inhibitors – roughly $10 to $20 per month, compared with more than $500 a month.

However, “for some fortunate patients with the most generous pharmacy benefit insurance coverage, the out-of-pocket cost of brand name drugs like SGLT-2 inhibitors is substantially lower,” Dr. Taylor noted.

He said that the current study “raises questions about whether the clinical benefits of SGLT-2 inhibitors as initial monotherapy justify the higher price relative to metformin. The data in this paper suggest that the value case for SGLT-2 inhibitors is strongest for patients with the greatest risk to be hospitalized for heart failure.”

Indeed, Dr. Shin said, “Once we get more information, it may just help in extending the coverage from insurance companies and Medicare/Medicaid, to lower the barrier to access.”

Dr. Taylor reiterated that patents on some of the early SGLT-2 inhibitors are expected to expire in the next few years, which would make it possible for generic versions to be approved. “At that point, prices would likely fall, possibly to levels similar to metformin.”

The study was funded by grant support from the Division of Pharmacoepidemiology and Pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, and Harvard Medical School, the National Institute on Aging, and the Patient-Centered Outcomes Research Institute. Dr. Shin has disclosed no relevant financial relationships. Dr. Taylor is a consultant for Ionis Pharmaceuticals.

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

Use of sodium–glucose cotransporter-2 (SGLT-2) inhibitors rather than metformin as first-line treatment for type 2 diabetes appears to cut the risk for heart failure hospitalization but not myocardial infarction, stroke, or all-cause mortality, a new analysis of real-world data suggests.

Safety findings were similar, except for the fact that genital infections were more common with SGLT-2 inhibitors.

The study was conducted using claims data from two large U.S. insurance databases and Medicare. Propensity score matching was used to account for baseline differences.

The study was conducted by HoJin Shin, BPharm, PhD, a postdoctoral research fellow at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and colleagues. The findings were published online in Annals of Internal Medicine.

“Those who start SGLT-2 inhibitors as first line show similar risks, compared with metformin in MI, stroke, and all-cause mortality outcomes. Strikingly and consistently, SGLT-2 inhibitors show lower risk for hospitalization for heart failure, which is consistent with the findings from cardiovascular outcomes trials,” Dr. Shin said in an interview.
 

Just a beginning step, although trial probably wasn’t long enough

However, she added, “I don’t want to overstate anything. ... We aren’t powered enough to investigate who would benefit the most. ... As a pharmacoepidemiologist, I think it’s my duty to provide high-quality evidence so we can actually help physicians and patients make better decisions on their medication. Our current research is just a beginning step.”

Asked to comment, Simeon I. Taylor, MD, PhD, professor of medicine at the University of Maryland, Baltimore, told this news organization, “This study generally confirmed conclusions from published RCTs [randomized clinical trials]. No real surprises, albeit the conclusions may not fully support some of the most enthusiastic claims for SGLT-2 inhibitors with respect to MI, stroke, and cardiovascular death.”

Indeed, Dr. Taylor noted that only two SGLT-2 inhibitors, canagliflozin and empagliflozin, were shown to have a statistically significant association with decreased major adverse cardiovascular events.

In contrast, neither dapagliflozin nor ertugliflozin showed significant benefit regarding those outcomes.

He also pointed out that those four major SLGT-2 inhibitor cardiovascular outcomes trials were placebo-controlled rather than head-to-head trials in which they were compared to an active comparator such as metformin.

“Viewed in this light, it’s probably not surprising that the present study did not demonstrate a robust benefit for SGLT-2 inhibitors to decrease [major adverse CV events].”

The duration of follow-up in the current study is also a limitation, he added.

“The majority of patients were followed for a year or less. This is probably sufficient to assess the impact of some pharmacological mechanisms, for example, the beneficial impact to decrease risk of heart failure by promoting urinary sodium excretion. However, it’s probably insufficient time to observe a beneficial impact on atherosclerosis. For example, there is typically a lag of several years before statins demonstrate efficacy with respect to adverse cardiovascular events.”

Nevertheless, he said, “it provides strong support for benefit with respect to decreasing risk of hospitalization for heart failure.”

He noted that while metformin is currently significantly cheaper than any SGLT-2 inhibitors, once the latter become available as generics, they will be cheaper, and this will likely have a bearing on prescribing decisions.

“Availability of generic SGLT-2 inhibitors offers potential to transform prescribing patterns for type 2 diabetes,” he noted.

First-line SGLT2 inhibitors versus metformin: Most outcomes similar

The study data came from two commercial U.S. health insurance databases, Optum Clinfomatics Data Mart and IBM Marketscan, and from Medicare fee-for-service enrollees.

From April 2013 through March 2020, a total of 9,334 patients began treatment with first-line SGLT-2 inhibitors; 819,973 patients began taking metformin. After 1:2 propensity score matching for confounders, there were 8,613 participants in the SGLT-2 inhibitor group and 17,226 in the group that began treatment with metformin.

The mean follow-up times were 10.7 months for patients taking SGLT-2 inhibitors and 12.2 months for patients taking metformin.

Incidence rates per 1,000 person-years for the composite of hospitalization for MI, hospitalization for ischemic or hemorrhagic stroke, or all-cause mortality (MI/stroke/mortality) were 15.0 versus 16.2 for SLGT-2 inhibitors versus metformin, not a significant difference (hazard ratio, 0.96).

However, for the composite of heart failure hospitalization or all-cause mortality, the rates were 18.3 versus 23.5, a significant difference, with an HR of 0.80. The benefit was seen beginning at about 6 months.

Compared with metformin, SGLT-2 inhibitors showed a significantly lower risk for heart failure hospitalization (HR, 0.78), a numerically (but not significantly) lower risk for MI (HR, 0.70), and similar risks for stroke, mortality, and MI/stroke/HHF/mortality.

Genital infections were significantly more common with SGLT-2 inhibitors (54.1 vs. 23.7 per 1,000 person-years; HR, 2.19). Other safety measures were similar, including acute kidney injury, bone fractures, severe hypoglycemia, diabetic ketoacidosis, and lower-limb amputations.
 

How does cost factor in?

A sensitivity analysis aimed at examining the possible effect of unmeasured socioeconomic status showed no difference in cardiovascular benefit for first-line SGLT-2 inhibitors and metformin, compared with first-line dipeptidyl peptidase–4 (DPP-4) inhibitors, which cost more than metformin; it is not known what effect DPP-4 inhibitors have on the cardiovascular outcomes of interest.

Cost and insurance coverage factor into the benefit/risk calculation. Metformin is far less costly than any of the SGLT-2 inhibitors – roughly $10 to $20 per month, compared with more than $500 a month.

However, “for some fortunate patients with the most generous pharmacy benefit insurance coverage, the out-of-pocket cost of brand name drugs like SGLT-2 inhibitors is substantially lower,” Dr. Taylor noted.

He said that the current study “raises questions about whether the clinical benefits of SGLT-2 inhibitors as initial monotherapy justify the higher price relative to metformin. The data in this paper suggest that the value case for SGLT-2 inhibitors is strongest for patients with the greatest risk to be hospitalized for heart failure.”

Indeed, Dr. Shin said, “Once we get more information, it may just help in extending the coverage from insurance companies and Medicare/Medicaid, to lower the barrier to access.”

Dr. Taylor reiterated that patents on some of the early SGLT-2 inhibitors are expected to expire in the next few years, which would make it possible for generic versions to be approved. “At that point, prices would likely fall, possibly to levels similar to metformin.”

The study was funded by grant support from the Division of Pharmacoepidemiology and Pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, and Harvard Medical School, the National Institute on Aging, and the Patient-Centered Outcomes Research Institute. Dr. Shin has disclosed no relevant financial relationships. Dr. Taylor is a consultant for Ionis Pharmaceuticals.

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

Use of sodium–glucose cotransporter-2 (SGLT-2) inhibitors rather than metformin as first-line treatment for type 2 diabetes appears to cut the risk for heart failure hospitalization but not myocardial infarction, stroke, or all-cause mortality, a new analysis of real-world data suggests.

Safety findings were similar, except for the fact that genital infections were more common with SGLT-2 inhibitors.

The study was conducted using claims data from two large U.S. insurance databases and Medicare. Propensity score matching was used to account for baseline differences.

The study was conducted by HoJin Shin, BPharm, PhD, a postdoctoral research fellow at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and colleagues. The findings were published online in Annals of Internal Medicine.

“Those who start SGLT-2 inhibitors as first line show similar risks, compared with metformin in MI, stroke, and all-cause mortality outcomes. Strikingly and consistently, SGLT-2 inhibitors show lower risk for hospitalization for heart failure, which is consistent with the findings from cardiovascular outcomes trials,” Dr. Shin said in an interview.
 

Just a beginning step, although trial probably wasn’t long enough

However, she added, “I don’t want to overstate anything. ... We aren’t powered enough to investigate who would benefit the most. ... As a pharmacoepidemiologist, I think it’s my duty to provide high-quality evidence so we can actually help physicians and patients make better decisions on their medication. Our current research is just a beginning step.”

Asked to comment, Simeon I. Taylor, MD, PhD, professor of medicine at the University of Maryland, Baltimore, told this news organization, “This study generally confirmed conclusions from published RCTs [randomized clinical trials]. No real surprises, albeit the conclusions may not fully support some of the most enthusiastic claims for SGLT-2 inhibitors with respect to MI, stroke, and cardiovascular death.”

Indeed, Dr. Taylor noted that only two SGLT-2 inhibitors, canagliflozin and empagliflozin, were shown to have a statistically significant association with decreased major adverse cardiovascular events.

In contrast, neither dapagliflozin nor ertugliflozin showed significant benefit regarding those outcomes.

He also pointed out that those four major SLGT-2 inhibitor cardiovascular outcomes trials were placebo-controlled rather than head-to-head trials in which they were compared to an active comparator such as metformin.

“Viewed in this light, it’s probably not surprising that the present study did not demonstrate a robust benefit for SGLT-2 inhibitors to decrease [major adverse CV events].”

The duration of follow-up in the current study is also a limitation, he added.

“The majority of patients were followed for a year or less. This is probably sufficient to assess the impact of some pharmacological mechanisms, for example, the beneficial impact to decrease risk of heart failure by promoting urinary sodium excretion. However, it’s probably insufficient time to observe a beneficial impact on atherosclerosis. For example, there is typically a lag of several years before statins demonstrate efficacy with respect to adverse cardiovascular events.”

Nevertheless, he said, “it provides strong support for benefit with respect to decreasing risk of hospitalization for heart failure.”

He noted that while metformin is currently significantly cheaper than any SGLT-2 inhibitors, once the latter become available as generics, they will be cheaper, and this will likely have a bearing on prescribing decisions.

“Availability of generic SGLT-2 inhibitors offers potential to transform prescribing patterns for type 2 diabetes,” he noted.

First-line SGLT2 inhibitors versus metformin: Most outcomes similar

The study data came from two commercial U.S. health insurance databases, Optum Clinfomatics Data Mart and IBM Marketscan, and from Medicare fee-for-service enrollees.

From April 2013 through March 2020, a total of 9,334 patients began treatment with first-line SGLT-2 inhibitors; 819,973 patients began taking metformin. After 1:2 propensity score matching for confounders, there were 8,613 participants in the SGLT-2 inhibitor group and 17,226 in the group that began treatment with metformin.

The mean follow-up times were 10.7 months for patients taking SGLT-2 inhibitors and 12.2 months for patients taking metformin.

Incidence rates per 1,000 person-years for the composite of hospitalization for MI, hospitalization for ischemic or hemorrhagic stroke, or all-cause mortality (MI/stroke/mortality) were 15.0 versus 16.2 for SLGT-2 inhibitors versus metformin, not a significant difference (hazard ratio, 0.96).

However, for the composite of heart failure hospitalization or all-cause mortality, the rates were 18.3 versus 23.5, a significant difference, with an HR of 0.80. The benefit was seen beginning at about 6 months.

Compared with metformin, SGLT-2 inhibitors showed a significantly lower risk for heart failure hospitalization (HR, 0.78), a numerically (but not significantly) lower risk for MI (HR, 0.70), and similar risks for stroke, mortality, and MI/stroke/HHF/mortality.

Genital infections were significantly more common with SGLT-2 inhibitors (54.1 vs. 23.7 per 1,000 person-years; HR, 2.19). Other safety measures were similar, including acute kidney injury, bone fractures, severe hypoglycemia, diabetic ketoacidosis, and lower-limb amputations.
 

How does cost factor in?

A sensitivity analysis aimed at examining the possible effect of unmeasured socioeconomic status showed no difference in cardiovascular benefit for first-line SGLT-2 inhibitors and metformin, compared with first-line dipeptidyl peptidase–4 (DPP-4) inhibitors, which cost more than metformin; it is not known what effect DPP-4 inhibitors have on the cardiovascular outcomes of interest.

Cost and insurance coverage factor into the benefit/risk calculation. Metformin is far less costly than any of the SGLT-2 inhibitors – roughly $10 to $20 per month, compared with more than $500 a month.

However, “for some fortunate patients with the most generous pharmacy benefit insurance coverage, the out-of-pocket cost of brand name drugs like SGLT-2 inhibitors is substantially lower,” Dr. Taylor noted.

He said that the current study “raises questions about whether the clinical benefits of SGLT-2 inhibitors as initial monotherapy justify the higher price relative to metformin. The data in this paper suggest that the value case for SGLT-2 inhibitors is strongest for patients with the greatest risk to be hospitalized for heart failure.”

Indeed, Dr. Shin said, “Once we get more information, it may just help in extending the coverage from insurance companies and Medicare/Medicaid, to lower the barrier to access.”

Dr. Taylor reiterated that patents on some of the early SGLT-2 inhibitors are expected to expire in the next few years, which would make it possible for generic versions to be approved. “At that point, prices would likely fall, possibly to levels similar to metformin.”

The study was funded by grant support from the Division of Pharmacoepidemiology and Pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, and Harvard Medical School, the National Institute on Aging, and the Patient-Centered Outcomes Research Institute. Dr. Shin has disclosed no relevant financial relationships. Dr. Taylor is a consultant for Ionis Pharmaceuticals.

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

Yet another study has found that vitamin D supplementation doesn’t reduce the risk of developing type 2 diabetes in the general population with prediabetes, but it does leave the door open for benefit in those with low insulin secretion.

The new findings come from the prospective Diabetes Prevention With Active Vitamin D (DPVD) trial of more than 1,200 Japanese participants with impaired glucose tolerance.

The data were published online in The BMJ by Tetsuya Kawahara, MD, PhD, of Shin Komonji Hospital, Kitakyushu, Japan, and colleagues.

Treatment with 0.75 μg/day of eldecalcitol, an active vitamin D analogue, for 3 years did not prevent progression from prediabetes to type 2 diabetes, nor did it improve the rate of regression to normoglycemia, compared with placebo.

However, “we showed a preventive effect of eldecalcitol after adjusting for covariables ... The preventive effect of eldecalcitol on development of type 2 diabetes in a prediabetic population was seen especially among participants with insulin insufficiency,” wrote Dr. Kawahara and colleagues.
 

‘Remarkably similar’ results in several trials

The new trial is “well conducted, with rigorously defined and tested diagnostic criteria, and of sufficient duration, but it may have been underpowered to detect a small effect,” Tatiana Christides, MD, PhD, of Queen Mary University of London, wrote in an accompanying editorial.

Dr. Christides notes that a recent meta-analysis of intervention trials did find a significant 10% reduction in risk of type 2 diabetes with vitamin D supplementation, “a difference too small to be detected by the new trial ... Although a 10% risk reduction is modest, it may be valuable at the population level and justifies further study.”

The new finding, a nonsignificant 13% relative reduction in risk, is similar to the 13% relative risk reduction found in the Vitamin D and Type 2 Diabetes (D2d) trial reported in 2019.

But in that study as in this one, there was a suggested benefit in a subset of people. In D2d, it was in those who were vitamin D deficient.  

Asked to comment, D2d lead investigator Anastassios G. Pittas, MD, chief of the division of diabetes, endocrinology, and metabolism at Tufts University, Boston, pointed out that the results were also “remarkably similar” to those of a third study from Norway published in 2014, which also found a 13% relative risk reduction.

“The nearly identical results from the three trials that were specifically designed and conducted to test whether vitamin D supplementation lowers diabetes clearly points to a beneficial effect of vitamin D for diabetes risk reduction. However, the overall effect in people not selected for vitamin D insufficiency seems to be less than hypothesized in each trial,” Dr. Pittas said in an interview.  

He added, “there will be no more specific vitamin D and diabetes prevention trials, so we need to continue gaining insights from these three trials.”

Some patients with prediabetes may benefit from vitamin D

Dr. Pittas advised that although the overall effect is modest in people with prediabetes who aren’t selected for vitamin D deficiency, “given how prevalent prediabetes and type 2 diabetes are, clinicians and patients should consider vitamin D supplementation as an adjunct to weight loss for diabetes prevention. Based on analyses from the D2d study, people with prediabetes who have low levels of vitamin D and are nonobese derive the most benefit.”

He noted that secondary analyses from D2d also suggest greater benefit among those achieving higher blood levels of vitamin D, but that high supplemental doses could cause adverse musculoskeletal outcomes in older adults, “so the benefit–harm ratio needs to be ascertained individually.”

Dr. Christides advised, “Until further data are available from high-quality randomized trials, health care professionals should continue to discuss with patients the musculoskeletal health benefits of vitamin D and support them to achieve and maintain lifestyle changes that, although challenging to sustain, are known to decrease development of [type 2 diabetes].”
 

DPVD: Hint of benefit in those with greater insulin resistance

The double-blind, multicenter, randomized, placebo-controlled DPVD trial took place from June 1, 2013, through Aug. 31, 2015, and involved 1,256 participants with impaired glucose tolerance (with or without impaired fasting glucose) from 32 institutions in Japan. They were randomized 1:1 to receive eldecalcitol or placebo for 3 years.

During the 3-year period, 12.5% of the 630 patients in the eldecalcitol group and 14.2% of the 626 patients in the placebo group developed diabetes. The difference was not significant, with a hazard ratio (HR) of 0.87 (P = .39). There was no difference in regression to normoglycemia, which had occurred in 23.0% with eldecalcitol versus 20.1% with placebo by the end of the study (P = .21).

However, eldecalcitol was effective for preventing the development of type 2 diabetes after adjustment for prespecified variables, including age, sex, hypertension, body mass index, family history of diabetes, 2-hour plasma glucose, 25-hydroxyvitamin D, and insulin resistance (HR, 0.69; P = .02).

In a post hoc analysis, eldecalcitol significantly prevented the development of type 2 diabetes among those with the lowest divisions of homeostatic model assessment (HOMA)-β (HR, 0.35; P < .001), HOMA-insulin resistance (HR, 0.37; P = .001), and fasting immunoreactive insulin (HR, 0.41; P = .001).

“These results indicate that eldecalcitol had a beneficial effect on insufficient basal insulin secretion,” Dr. Kawahara and colleagues wrote.

Discontinuations due to adverse events occurred in 4.1% with eldecalcitol and 3.4% in the placebo group (HR, 1.23; P = .47). Rates and types of adverse events didn’t differ significantly between the two groups.

The study was supported by a grant from the Kitakyushu Medical Association. The authors had no further disclosures. Dr. Christides had no disclosures. Dr. Pittas has reported receiving funding from the National Institutes of Health.

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

Yet another study has found that vitamin D supplementation doesn’t reduce the risk of developing type 2 diabetes in the general population with prediabetes, but it does leave the door open for benefit in those with low insulin secretion.

The new findings come from the prospective Diabetes Prevention With Active Vitamin D (DPVD) trial of more than 1,200 Japanese participants with impaired glucose tolerance.

The data were published online in The BMJ by Tetsuya Kawahara, MD, PhD, of Shin Komonji Hospital, Kitakyushu, Japan, and colleagues.

Treatment with 0.75 μg/day of eldecalcitol, an active vitamin D analogue, for 3 years did not prevent progression from prediabetes to type 2 diabetes, nor did it improve the rate of regression to normoglycemia, compared with placebo.

However, “we showed a preventive effect of eldecalcitol after adjusting for covariables ... The preventive effect of eldecalcitol on development of type 2 diabetes in a prediabetic population was seen especially among participants with insulin insufficiency,” wrote Dr. Kawahara and colleagues.
 

‘Remarkably similar’ results in several trials

The new trial is “well conducted, with rigorously defined and tested diagnostic criteria, and of sufficient duration, but it may have been underpowered to detect a small effect,” Tatiana Christides, MD, PhD, of Queen Mary University of London, wrote in an accompanying editorial.

Dr. Christides notes that a recent meta-analysis of intervention trials did find a significant 10% reduction in risk of type 2 diabetes with vitamin D supplementation, “a difference too small to be detected by the new trial ... Although a 10% risk reduction is modest, it may be valuable at the population level and justifies further study.”

The new finding, a nonsignificant 13% relative reduction in risk, is similar to the 13% relative risk reduction found in the Vitamin D and Type 2 Diabetes (D2d) trial reported in 2019.

But in that study as in this one, there was a suggested benefit in a subset of people. In D2d, it was in those who were vitamin D deficient.  

Asked to comment, D2d lead investigator Anastassios G. Pittas, MD, chief of the division of diabetes, endocrinology, and metabolism at Tufts University, Boston, pointed out that the results were also “remarkably similar” to those of a third study from Norway published in 2014, which also found a 13% relative risk reduction.

“The nearly identical results from the three trials that were specifically designed and conducted to test whether vitamin D supplementation lowers diabetes clearly points to a beneficial effect of vitamin D for diabetes risk reduction. However, the overall effect in people not selected for vitamin D insufficiency seems to be less than hypothesized in each trial,” Dr. Pittas said in an interview.  

He added, “there will be no more specific vitamin D and diabetes prevention trials, so we need to continue gaining insights from these three trials.”

Some patients with prediabetes may benefit from vitamin D

Dr. Pittas advised that although the overall effect is modest in people with prediabetes who aren’t selected for vitamin D deficiency, “given how prevalent prediabetes and type 2 diabetes are, clinicians and patients should consider vitamin D supplementation as an adjunct to weight loss for diabetes prevention. Based on analyses from the D2d study, people with prediabetes who have low levels of vitamin D and are nonobese derive the most benefit.”

He noted that secondary analyses from D2d also suggest greater benefit among those achieving higher blood levels of vitamin D, but that high supplemental doses could cause adverse musculoskeletal outcomes in older adults, “so the benefit–harm ratio needs to be ascertained individually.”

Dr. Christides advised, “Until further data are available from high-quality randomized trials, health care professionals should continue to discuss with patients the musculoskeletal health benefits of vitamin D and support them to achieve and maintain lifestyle changes that, although challenging to sustain, are known to decrease development of [type 2 diabetes].”
 

DPVD: Hint of benefit in those with greater insulin resistance

The double-blind, multicenter, randomized, placebo-controlled DPVD trial took place from June 1, 2013, through Aug. 31, 2015, and involved 1,256 participants with impaired glucose tolerance (with or without impaired fasting glucose) from 32 institutions in Japan. They were randomized 1:1 to receive eldecalcitol or placebo for 3 years.

During the 3-year period, 12.5% of the 630 patients in the eldecalcitol group and 14.2% of the 626 patients in the placebo group developed diabetes. The difference was not significant, with a hazard ratio (HR) of 0.87 (P = .39). There was no difference in regression to normoglycemia, which had occurred in 23.0% with eldecalcitol versus 20.1% with placebo by the end of the study (P = .21).

However, eldecalcitol was effective for preventing the development of type 2 diabetes after adjustment for prespecified variables, including age, sex, hypertension, body mass index, family history of diabetes, 2-hour plasma glucose, 25-hydroxyvitamin D, and insulin resistance (HR, 0.69; P = .02).

In a post hoc analysis, eldecalcitol significantly prevented the development of type 2 diabetes among those with the lowest divisions of homeostatic model assessment (HOMA)-β (HR, 0.35; P < .001), HOMA-insulin resistance (HR, 0.37; P = .001), and fasting immunoreactive insulin (HR, 0.41; P = .001).

“These results indicate that eldecalcitol had a beneficial effect on insufficient basal insulin secretion,” Dr. Kawahara and colleagues wrote.

Discontinuations due to adverse events occurred in 4.1% with eldecalcitol and 3.4% in the placebo group (HR, 1.23; P = .47). Rates and types of adverse events didn’t differ significantly between the two groups.

The study was supported by a grant from the Kitakyushu Medical Association. The authors had no further disclosures. Dr. Christides had no disclosures. Dr. Pittas has reported receiving funding from the National Institutes of Health.

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

Yet another study has found that vitamin D supplementation doesn’t reduce the risk of developing type 2 diabetes in the general population with prediabetes, but it does leave the door open for benefit in those with low insulin secretion.

The new findings come from the prospective Diabetes Prevention With Active Vitamin D (DPVD) trial of more than 1,200 Japanese participants with impaired glucose tolerance.

The data were published online in The BMJ by Tetsuya Kawahara, MD, PhD, of Shin Komonji Hospital, Kitakyushu, Japan, and colleagues.

Treatment with 0.75 μg/day of eldecalcitol, an active vitamin D analogue, for 3 years did not prevent progression from prediabetes to type 2 diabetes, nor did it improve the rate of regression to normoglycemia, compared with placebo.

However, “we showed a preventive effect of eldecalcitol after adjusting for covariables ... The preventive effect of eldecalcitol on development of type 2 diabetes in a prediabetic population was seen especially among participants with insulin insufficiency,” wrote Dr. Kawahara and colleagues.
 

‘Remarkably similar’ results in several trials

The new trial is “well conducted, with rigorously defined and tested diagnostic criteria, and of sufficient duration, but it may have been underpowered to detect a small effect,” Tatiana Christides, MD, PhD, of Queen Mary University of London, wrote in an accompanying editorial.

Dr. Christides notes that a recent meta-analysis of intervention trials did find a significant 10% reduction in risk of type 2 diabetes with vitamin D supplementation, “a difference too small to be detected by the new trial ... Although a 10% risk reduction is modest, it may be valuable at the population level and justifies further study.”

The new finding, a nonsignificant 13% relative reduction in risk, is similar to the 13% relative risk reduction found in the Vitamin D and Type 2 Diabetes (D2d) trial reported in 2019.

But in that study as in this one, there was a suggested benefit in a subset of people. In D2d, it was in those who were vitamin D deficient.  

Asked to comment, D2d lead investigator Anastassios G. Pittas, MD, chief of the division of diabetes, endocrinology, and metabolism at Tufts University, Boston, pointed out that the results were also “remarkably similar” to those of a third study from Norway published in 2014, which also found a 13% relative risk reduction.

“The nearly identical results from the three trials that were specifically designed and conducted to test whether vitamin D supplementation lowers diabetes clearly points to a beneficial effect of vitamin D for diabetes risk reduction. However, the overall effect in people not selected for vitamin D insufficiency seems to be less than hypothesized in each trial,” Dr. Pittas said in an interview.  

He added, “there will be no more specific vitamin D and diabetes prevention trials, so we need to continue gaining insights from these three trials.”

Some patients with prediabetes may benefit from vitamin D

Dr. Pittas advised that although the overall effect is modest in people with prediabetes who aren’t selected for vitamin D deficiency, “given how prevalent prediabetes and type 2 diabetes are, clinicians and patients should consider vitamin D supplementation as an adjunct to weight loss for diabetes prevention. Based on analyses from the D2d study, people with prediabetes who have low levels of vitamin D and are nonobese derive the most benefit.”

He noted that secondary analyses from D2d also suggest greater benefit among those achieving higher blood levels of vitamin D, but that high supplemental doses could cause adverse musculoskeletal outcomes in older adults, “so the benefit–harm ratio needs to be ascertained individually.”

Dr. Christides advised, “Until further data are available from high-quality randomized trials, health care professionals should continue to discuss with patients the musculoskeletal health benefits of vitamin D and support them to achieve and maintain lifestyle changes that, although challenging to sustain, are known to decrease development of [type 2 diabetes].”
 

DPVD: Hint of benefit in those with greater insulin resistance

The double-blind, multicenter, randomized, placebo-controlled DPVD trial took place from June 1, 2013, through Aug. 31, 2015, and involved 1,256 participants with impaired glucose tolerance (with or without impaired fasting glucose) from 32 institutions in Japan. They were randomized 1:1 to receive eldecalcitol or placebo for 3 years.

During the 3-year period, 12.5% of the 630 patients in the eldecalcitol group and 14.2% of the 626 patients in the placebo group developed diabetes. The difference was not significant, with a hazard ratio (HR) of 0.87 (P = .39). There was no difference in regression to normoglycemia, which had occurred in 23.0% with eldecalcitol versus 20.1% with placebo by the end of the study (P = .21).

However, eldecalcitol was effective for preventing the development of type 2 diabetes after adjustment for prespecified variables, including age, sex, hypertension, body mass index, family history of diabetes, 2-hour plasma glucose, 25-hydroxyvitamin D, and insulin resistance (HR, 0.69; P = .02).

In a post hoc analysis, eldecalcitol significantly prevented the development of type 2 diabetes among those with the lowest divisions of homeostatic model assessment (HOMA)-β (HR, 0.35; P < .001), HOMA-insulin resistance (HR, 0.37; P = .001), and fasting immunoreactive insulin (HR, 0.41; P = .001).

“These results indicate that eldecalcitol had a beneficial effect on insufficient basal insulin secretion,” Dr. Kawahara and colleagues wrote.

Discontinuations due to adverse events occurred in 4.1% with eldecalcitol and 3.4% in the placebo group (HR, 1.23; P = .47). Rates and types of adverse events didn’t differ significantly between the two groups.

The study was supported by a grant from the Kitakyushu Medical Association. The authors had no further disclosures. Dr. Christides had no disclosures. Dr. Pittas has reported receiving funding from the National Institutes of Health.

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

NEW ORLEANS – New research reveals that patients with treatment-resistant depression who were treated with repeated intravenous ketamine show no significant differences in achieving response or remission, compared with those receiving the intranasal formulation of the drug, esketamine – although fewer treatments appear necessary with the intravenous formulation.

“This is one of the first studies to compare the efficacy of IV and intranasal ketamine, and the results give us some indication that, if you treat with IV, you might get a faster response, although at the end, the responses are similar,” said first author Balwinder Singh, MD, of the department of psychiatry and psychology, Mayo Clinic, in Rochester, Minn.

courtesy Balwinder Singh

The findings were presented at the annual meeting of the American Psychiatric Association.

Commenting on the study, Roger S. McIntyre, MD, underscored that “this is an important study that addresses the priority questions that everyone wants to know – not only for clinical reasons, but economic reasons.” Dr. McIntyre, a professor of psychiatry and pharmacology at the University of Toronto, and head of the university’s mood disorders psychopharmacology unit, said that “there are implications not only for clinical outcomes and cost, but also implementation because IV is obviously more demanding and complicated.”

As intravenous ketamine increasingly gained interest as a rapid-acting treatment for patients with severe, treatment-resistant depression, the introduction of a more convenient intranasal formulation was seen as a welcome improvement and received approval from the Food and Drug Administration in 2019. However, while the approval ushered in more coverage by insurance companies, the treatment can still be expensive. Intravenous ketamine does not have FDA approval.

With a lack of studies in the real-world setting comparing efficacy of the two formulations, Dr. Singh and his colleagues conducted the observational study, evaluating the responses of 62 adults with treatment-resistant depression who had received either up to six IV ketamine infusions of 0.5 mg/kg, infused over 40 minutes, or up to eight intranasal esketamine treatments of 56/84 mg, as approved by the FDA, at the Mayo Clinic Depression Center.

Of the patients, who had a mean age of 47 years, 59 had major depression and 3 had bipolar depression. Among them, 76% (47) received intravenous ketamine and 24% (15) received esketamine, which Dr. Singh noted reflected the higher number of patients included before esketamine received FDA approval. The patients had similar comorbidity profiles, with the intravenous ketamine group having a higher body mass index at baseline.

Overall, the patients all had significant improvement in their depression at the end of the acute phase of 4 weeks, with a mean change in on the 16-Item Quick Inventory of Depressive Symptomatology (QIDS-SR) scale of –8.6 from baseline (P < .001).

The overall remission rate was 38.7% and overall response rate was 58.1%. Those receiving intravenous ketamine had response and remission rates of 57.4% and 42.6%, versus response and remission rates of 60.0% and 26.7% among the esketamine group, which Dr. Singh said were not significant differences (P > .05).

However, the mean number of treatments necessary to achieve response in the intravenous ketamine group was just 2.3 versus 4.6 with esketamine, and the mean number of treatments to achieve remission were 2.5 versus 6.3, respectively (P = .008).

After a multivariate adjustment, the time to response was determined to be faster with intravenous ketamine versus esketamine (hazard ratio, 2.61; P = .05) and the time to remission was also faster (HR, 5.0; P = .02).

“What this means is you would need fewer treatments to achieve a response or remission with IV ketamine, so there could be an acceleration of patients’ antidepressant response,” Dr. Singh explained.

There were no significant differences between the groups in terms of side effects, and most patients tolerated the treatments well.

Dr. Singh noted the limitation of the study is that it was observational and included a small sample size. Nevertheless, when asked which he would choose if starting treatment when insurance was not an issue, Dr. Singh replied: “I would take patient preference into account, but certainly IV seems to have an advantage.”

Dr. McIntyre noted that, though small, the study’s setting in a real world clinical environment is important.

“Obviously this is observational and not controlled, but the strength is that this involved a real-world cohort of patients and real world applications,” he said. “It’s difficult to have a true comparator head-to-head trial, so that makes this all the more important because it takes into consideration all of the complexities of real world patients.”

Dr. McIntyre emphasized that the study is not “the last word on the story because we need to see a larger sample and replication. But certainly they make an argument that IV ketamine may have an advantage over the speed of onset with intranasal ketamine, which will need to be either replicated or refuted, but it’s a great starting point in the conversation.”
 

Navigating patient preference

Robert Meisner, MD, founding medical director of the McLean Ketamine Service, Division of Psychiatric Neurotherapeutics, McLean Hospital, Harvard Medical School, in Boston, noted that wide-ranging factors may influence patient as well as clinician decisions about which ketamine treatment approach to use.

“When a patient appears to be equally well-suited for both interventions, I continue to be surprised by why one patient will indicate a preference for intranasal esketamine, while another will lean toward IV racemic ketamine,” he said in an interview.

“Some patients find esketamine’s clear and consistent protocol optimal for scheduling and navigating the logistics of daily life; others value the flexibility offered by certain evidence-based, racemic (IV) protocols,” he said. “Predicting who will prefer each treatment, even with the apparent temporal advantage with IV ketamine, is extremely difficult.”

Likewise, in terms of clinician preference, Dr. Meisner notes that key concerns may sway decisions.

“If I’m concerned with labile pressures or hypertension, for example, or if I have a patient with, say, Erlos Danlos Syndrome without a clear subtype, and hence, some risk of undiscovered aneurysmal vascular disease, I may lean toward racemic IV ketamine.”

On the other hand, “some patients find the simplicity and predictability of the maintenance esketamine protocol comforting and psychologically stabilizing,” he added. “Yet others find that their work or family’s erratic demands on their time make one of the evidence-based racemic regimens preferable – inasmuch as it integrates more flexibility and allows them to remain more fully engaged in the basic activities or work and family.”

Dr. Meisner noted the caveat that efforts to decide which method to use are often complicated by substantial misinformation.

“I can’t emphasize how much misinformation continues to abound regarding appropriate (evidence-based) and safe use of ketamine and esketamine,” he said. “Especially on the IV racemic side, there simply is no substantive evidence base for many of the claims that some providers are preaching.”

The confusion, driven in part by social media, “has diffused into sectors of the field and industry that one might assume are relatively immune (i.e., allied physicians, sophisticated payers, etc),” he added.

“In short, two mantra continue to apply,” Dr. Meisner said. “One – if it sounds too good to be true, it probably is; and two – in pharmacology and interventional psychiatry, we see remarkable progress and potential, but there simply is no such thing as a magic bullet.”

Dr. Singh and Dr. Meisner had no disclosures to report. Dr. McIntyre has received research grant support from Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/National Natural Science Foundation of China, and speaker/consultation fees from Lundbeck, Janssen, Alkermes,Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie, and Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific.

NEW ORLEANS – New research reveals that patients with treatment-resistant depression who were treated with repeated intravenous ketamine show no significant differences in achieving response or remission, compared with those receiving the intranasal formulation of the drug, esketamine – although fewer treatments appear necessary with the intravenous formulation.

“This is one of the first studies to compare the efficacy of IV and intranasal ketamine, and the results give us some indication that, if you treat with IV, you might get a faster response, although at the end, the responses are similar,” said first author Balwinder Singh, MD, of the department of psychiatry and psychology, Mayo Clinic, in Rochester, Minn.

courtesy Balwinder Singh

The findings were presented at the annual meeting of the American Psychiatric Association.

Commenting on the study, Roger S. McIntyre, MD, underscored that “this is an important study that addresses the priority questions that everyone wants to know – not only for clinical reasons, but economic reasons.” Dr. McIntyre, a professor of psychiatry and pharmacology at the University of Toronto, and head of the university’s mood disorders psychopharmacology unit, said that “there are implications not only for clinical outcomes and cost, but also implementation because IV is obviously more demanding and complicated.”

As intravenous ketamine increasingly gained interest as a rapid-acting treatment for patients with severe, treatment-resistant depression, the introduction of a more convenient intranasal formulation was seen as a welcome improvement and received approval from the Food and Drug Administration in 2019. However, while the approval ushered in more coverage by insurance companies, the treatment can still be expensive. Intravenous ketamine does not have FDA approval.

With a lack of studies in the real-world setting comparing efficacy of the two formulations, Dr. Singh and his colleagues conducted the observational study, evaluating the responses of 62 adults with treatment-resistant depression who had received either up to six IV ketamine infusions of 0.5 mg/kg, infused over 40 minutes, or up to eight intranasal esketamine treatments of 56/84 mg, as approved by the FDA, at the Mayo Clinic Depression Center.

Of the patients, who had a mean age of 47 years, 59 had major depression and 3 had bipolar depression. Among them, 76% (47) received intravenous ketamine and 24% (15) received esketamine, which Dr. Singh noted reflected the higher number of patients included before esketamine received FDA approval. The patients had similar comorbidity profiles, with the intravenous ketamine group having a higher body mass index at baseline.

Overall, the patients all had significant improvement in their depression at the end of the acute phase of 4 weeks, with a mean change in on the 16-Item Quick Inventory of Depressive Symptomatology (QIDS-SR) scale of –8.6 from baseline (P < .001).

The overall remission rate was 38.7% and overall response rate was 58.1%. Those receiving intravenous ketamine had response and remission rates of 57.4% and 42.6%, versus response and remission rates of 60.0% and 26.7% among the esketamine group, which Dr. Singh said were not significant differences (P > .05).

However, the mean number of treatments necessary to achieve response in the intravenous ketamine group was just 2.3 versus 4.6 with esketamine, and the mean number of treatments to achieve remission were 2.5 versus 6.3, respectively (P = .008).

After a multivariate adjustment, the time to response was determined to be faster with intravenous ketamine versus esketamine (hazard ratio, 2.61; P = .05) and the time to remission was also faster (HR, 5.0; P = .02).

“What this means is you would need fewer treatments to achieve a response or remission with IV ketamine, so there could be an acceleration of patients’ antidepressant response,” Dr. Singh explained.

There were no significant differences between the groups in terms of side effects, and most patients tolerated the treatments well.

Dr. Singh noted the limitation of the study is that it was observational and included a small sample size. Nevertheless, when asked which he would choose if starting treatment when insurance was not an issue, Dr. Singh replied: “I would take patient preference into account, but certainly IV seems to have an advantage.”

Dr. McIntyre noted that, though small, the study’s setting in a real world clinical environment is important.

“Obviously this is observational and not controlled, but the strength is that this involved a real-world cohort of patients and real world applications,” he said. “It’s difficult to have a true comparator head-to-head trial, so that makes this all the more important because it takes into consideration all of the complexities of real world patients.”

Dr. McIntyre emphasized that the study is not “the last word on the story because we need to see a larger sample and replication. But certainly they make an argument that IV ketamine may have an advantage over the speed of onset with intranasal ketamine, which will need to be either replicated or refuted, but it’s a great starting point in the conversation.”
 

Navigating patient preference

Robert Meisner, MD, founding medical director of the McLean Ketamine Service, Division of Psychiatric Neurotherapeutics, McLean Hospital, Harvard Medical School, in Boston, noted that wide-ranging factors may influence patient as well as clinician decisions about which ketamine treatment approach to use.

“When a patient appears to be equally well-suited for both interventions, I continue to be surprised by why one patient will indicate a preference for intranasal esketamine, while another will lean toward IV racemic ketamine,” he said in an interview.

“Some patients find esketamine’s clear and consistent protocol optimal for scheduling and navigating the logistics of daily life; others value the flexibility offered by certain evidence-based, racemic (IV) protocols,” he said. “Predicting who will prefer each treatment, even with the apparent temporal advantage with IV ketamine, is extremely difficult.”

Likewise, in terms of clinician preference, Dr. Meisner notes that key concerns may sway decisions.

“If I’m concerned with labile pressures or hypertension, for example, or if I have a patient with, say, Erlos Danlos Syndrome without a clear subtype, and hence, some risk of undiscovered aneurysmal vascular disease, I may lean toward racemic IV ketamine.”

On the other hand, “some patients find the simplicity and predictability of the maintenance esketamine protocol comforting and psychologically stabilizing,” he added. “Yet others find that their work or family’s erratic demands on their time make one of the evidence-based racemic regimens preferable – inasmuch as it integrates more flexibility and allows them to remain more fully engaged in the basic activities or work and family.”

Dr. Meisner noted the caveat that efforts to decide which method to use are often complicated by substantial misinformation.

“I can’t emphasize how much misinformation continues to abound regarding appropriate (evidence-based) and safe use of ketamine and esketamine,” he said. “Especially on the IV racemic side, there simply is no substantive evidence base for many of the claims that some providers are preaching.”

The confusion, driven in part by social media, “has diffused into sectors of the field and industry that one might assume are relatively immune (i.e., allied physicians, sophisticated payers, etc),” he added.

“In short, two mantra continue to apply,” Dr. Meisner said. “One – if it sounds too good to be true, it probably is; and two – in pharmacology and interventional psychiatry, we see remarkable progress and potential, but there simply is no such thing as a magic bullet.”

Dr. Singh and Dr. Meisner had no disclosures to report. Dr. McIntyre has received research grant support from Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/National Natural Science Foundation of China, and speaker/consultation fees from Lundbeck, Janssen, Alkermes,Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie, and Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific.

NEW ORLEANS – New research reveals that patients with treatment-resistant depression who were treated with repeated intravenous ketamine show no significant differences in achieving response or remission, compared with those receiving the intranasal formulation of the drug, esketamine – although fewer treatments appear necessary with the intravenous formulation.

“This is one of the first studies to compare the efficacy of IV and intranasal ketamine, and the results give us some indication that, if you treat with IV, you might get a faster response, although at the end, the responses are similar,” said first author Balwinder Singh, MD, of the department of psychiatry and psychology, Mayo Clinic, in Rochester, Minn.

courtesy Balwinder Singh

The findings were presented at the annual meeting of the American Psychiatric Association.

Commenting on the study, Roger S. McIntyre, MD, underscored that “this is an important study that addresses the priority questions that everyone wants to know – not only for clinical reasons, but economic reasons.” Dr. McIntyre, a professor of psychiatry and pharmacology at the University of Toronto, and head of the university’s mood disorders psychopharmacology unit, said that “there are implications not only for clinical outcomes and cost, but also implementation because IV is obviously more demanding and complicated.”

As intravenous ketamine increasingly gained interest as a rapid-acting treatment for patients with severe, treatment-resistant depression, the introduction of a more convenient intranasal formulation was seen as a welcome improvement and received approval from the Food and Drug Administration in 2019. However, while the approval ushered in more coverage by insurance companies, the treatment can still be expensive. Intravenous ketamine does not have FDA approval.

With a lack of studies in the real-world setting comparing efficacy of the two formulations, Dr. Singh and his colleagues conducted the observational study, evaluating the responses of 62 adults with treatment-resistant depression who had received either up to six IV ketamine infusions of 0.5 mg/kg, infused over 40 minutes, or up to eight intranasal esketamine treatments of 56/84 mg, as approved by the FDA, at the Mayo Clinic Depression Center.

Of the patients, who had a mean age of 47 years, 59 had major depression and 3 had bipolar depression. Among them, 76% (47) received intravenous ketamine and 24% (15) received esketamine, which Dr. Singh noted reflected the higher number of patients included before esketamine received FDA approval. The patients had similar comorbidity profiles, with the intravenous ketamine group having a higher body mass index at baseline.

Overall, the patients all had significant improvement in their depression at the end of the acute phase of 4 weeks, with a mean change in on the 16-Item Quick Inventory of Depressive Symptomatology (QIDS-SR) scale of –8.6 from baseline (P < .001).

The overall remission rate was 38.7% and overall response rate was 58.1%. Those receiving intravenous ketamine had response and remission rates of 57.4% and 42.6%, versus response and remission rates of 60.0% and 26.7% among the esketamine group, which Dr. Singh said were not significant differences (P > .05).

However, the mean number of treatments necessary to achieve response in the intravenous ketamine group was just 2.3 versus 4.6 with esketamine, and the mean number of treatments to achieve remission were 2.5 versus 6.3, respectively (P = .008).

After a multivariate adjustment, the time to response was determined to be faster with intravenous ketamine versus esketamine (hazard ratio, 2.61; P = .05) and the time to remission was also faster (HR, 5.0; P = .02).

“What this means is you would need fewer treatments to achieve a response or remission with IV ketamine, so there could be an acceleration of patients’ antidepressant response,” Dr. Singh explained.

There were no significant differences between the groups in terms of side effects, and most patients tolerated the treatments well.

Dr. Singh noted the limitation of the study is that it was observational and included a small sample size. Nevertheless, when asked which he would choose if starting treatment when insurance was not an issue, Dr. Singh replied: “I would take patient preference into account, but certainly IV seems to have an advantage.”

Dr. McIntyre noted that, though small, the study’s setting in a real world clinical environment is important.

“Obviously this is observational and not controlled, but the strength is that this involved a real-world cohort of patients and real world applications,” he said. “It’s difficult to have a true comparator head-to-head trial, so that makes this all the more important because it takes into consideration all of the complexities of real world patients.”

Dr. McIntyre emphasized that the study is not “the last word on the story because we need to see a larger sample and replication. But certainly they make an argument that IV ketamine may have an advantage over the speed of onset with intranasal ketamine, which will need to be either replicated or refuted, but it’s a great starting point in the conversation.”
 

Navigating patient preference

Robert Meisner, MD, founding medical director of the McLean Ketamine Service, Division of Psychiatric Neurotherapeutics, McLean Hospital, Harvard Medical School, in Boston, noted that wide-ranging factors may influence patient as well as clinician decisions about which ketamine treatment approach to use.

“When a patient appears to be equally well-suited for both interventions, I continue to be surprised by why one patient will indicate a preference for intranasal esketamine, while another will lean toward IV racemic ketamine,” he said in an interview.

“Some patients find esketamine’s clear and consistent protocol optimal for scheduling and navigating the logistics of daily life; others value the flexibility offered by certain evidence-based, racemic (IV) protocols,” he said. “Predicting who will prefer each treatment, even with the apparent temporal advantage with IV ketamine, is extremely difficult.”

Likewise, in terms of clinician preference, Dr. Meisner notes that key concerns may sway decisions.

“If I’m concerned with labile pressures or hypertension, for example, or if I have a patient with, say, Erlos Danlos Syndrome without a clear subtype, and hence, some risk of undiscovered aneurysmal vascular disease, I may lean toward racemic IV ketamine.”

On the other hand, “some patients find the simplicity and predictability of the maintenance esketamine protocol comforting and psychologically stabilizing,” he added. “Yet others find that their work or family’s erratic demands on their time make one of the evidence-based racemic regimens preferable – inasmuch as it integrates more flexibility and allows them to remain more fully engaged in the basic activities or work and family.”

Dr. Meisner noted the caveat that efforts to decide which method to use are often complicated by substantial misinformation.

“I can’t emphasize how much misinformation continues to abound regarding appropriate (evidence-based) and safe use of ketamine and esketamine,” he said. “Especially on the IV racemic side, there simply is no substantive evidence base for many of the claims that some providers are preaching.”

The confusion, driven in part by social media, “has diffused into sectors of the field and industry that one might assume are relatively immune (i.e., allied physicians, sophisticated payers, etc),” he added.

“In short, two mantra continue to apply,” Dr. Meisner said. “One – if it sounds too good to be true, it probably is; and two – in pharmacology and interventional psychiatry, we see remarkable progress and potential, but there simply is no such thing as a magic bullet.”

Dr. Singh and Dr. Meisner had no disclosures to report. Dr. McIntyre has received research grant support from Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/National Natural Science Foundation of China, and speaker/consultation fees from Lundbeck, Janssen, Alkermes,Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie, and Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific.

Controversy regarding the purported link between the use of proton pump inhibitors (PPIs) or histamine H₂ receptor antagonists (H2RAs) and risk for dementia continues.

Adding to the “no link” column comes new evidence from a study presented at the annual Digestive Disease Week^® (DDW) .

Among almost 19,000 people, no association was found between the use of these agents and a greater likelihood of incident dementia, Alzheimer’s disease, or cognitive decline in people older than 65 years.

“We found that baseline PPI or H2RA use in older adults was not associated with dementia, with mild cognitive impairment, or declines in cognitive scores over time,” said lead author Raaj Shishir Mehta, MD, a gastroenterology fellow at Massachusetts General Hospital in Boston.

“While deprescribing efforts are important, especially when medications are not indicated, these data provide reassurance about the cognitive impacts of long-term use of PPIs in older adults,” he added.
 

Growing use, growing concern

As PPI use has increased worldwide, so too have concerns over the adverse effects from their long-term use, Dr. Mehta said.

“One particular area of concern, especially among older adults, is the link between long-term PPI use and risk for dementia,” he said.

Igniting the controversy was a February 2016 study published in JAMA Neurology that showed a positive association between PPI use and dementia in residents of Germany aged 75 years and older. Researchers linked PPI use to a 44% increased risk of dementia over 5 years.

The 2016 study was based on claims data, which can introduce “inaccuracy or bias in defining dementia cases,” Dr. Mehta said. He noted that it and other previous studies also were limited by an inability to account for concomitant medications or comorbidities.

To overcome these limitations in their study, Dr. Mehta and colleagues analyzed medication data collected during in-person visits and asked experts to confirm dementia outcomes. The research data come from ASPREE, a large aspirin study of 18,846 people older than 65 years in the United States and Australia. Participants were enrolled from 2010 to 2014. A total of 566 people developed incident dementia during follow-up.

The researchers had data on alcohol consumption and other lifestyle factors, as well as information on comorbidities, hospitalizations, and overall well-being.

“Perhaps the biggest strength of our study is our rigorous neurocognitive assessments,” Dr. Mehta said.

They assessed cognition at baseline and at years 1, 3, 5, and 7 using a battery of tests. An expert panel of neurologists, neuropsychologists, and geriatricians adjudicated cases of dementia, in accordance with DSM-IV criteria. If the diagnosis was unclear, they referred people for additional workup, including neuroimaging.

Cox proportional hazards, regression, and/or mixed effects modeling were used to relate medication use with cognitive scores.

All analyses were adjusted for age, sex, body mass index, alcohol use, family history of dementia, medications, and other medical comorbidities.

At baseline, PPI users were more likely to be White, have fewer years of education, and have higher rates of hypertension, diabetes, and kidney disease. This group also was more likely to be taking five or more medications.
 

Key points

During 80,976 person-years of follow-up, there were 566 incident cases of dementia, including 235 probable cases of Alzheimer’s disease and 331 other dementias.

Baseline PPI use, in comparison with nonuse, was not associated with incident dementia (hazard ratio, 0.86; 95% confidence interval, 0.70-1.05).

“Similarly, when we look specifically at Alzheimer’s disease or mixed types of dementia, we find no association between baseline PPI use and dementia,” Dr. Mehta said.

When they excluded people already taking PPIs at baseline, they found no association between starting PPIs and developing dementia over time.

Secondary aims of the study included looking for a link between PPI use and mild cognitive impairment or significant changes in cognition over time. In both cases, no association emerged. PPI use at baseline also was not associated with cognitive impairment/no dementia (also known as mild cognitive impairment) or with changes in overall cognitive test scores over time.

To determine whether any association could be a class effect of acid suppression medication, they assessed use of H2RA medications and development of incident dementia. Again, the researchers found no link.

A diverse multinational population from urban and rural areas was a strength of the study, as was the “very rigorous cognitive testing with expert adjudication of our endpoints,” Dr. Mehta said. In addition, fewer than 5% of patients were lost to follow-up.

In terms of limitations, this was an observational study “so residual confounding is always possible,” he added. “But I’ll emphasize that we are among the largest studies to date with wealth of covariates.”
 

Why the different findings?

The study was “really well done,” session moderator Paul Moayyedi, MD, said during the Q&A session at DDW 2022.

Dr. Moayyedi, a professor of medicine at McMaster University, Hamilton, Ont., asked Dr. Mehta why he “found absolutely no signal, whereas the German study did.”

“It’s a good question,” Dr. Mehta responded. “If you look across the board, there have been conflicting results.”

The disparity could be related to how researchers conducting claims data studies classify dementia, he noted.

“If you look at the nitty-gritty details over 5 years, almost 40% of participants [in those studies] end up with a diagnosis of dementia, which is quite high,” Dr. Mehta said. “That raises questions about whether the diagnosis of dementia is truly accurate.”

Dr. Mehta and Dr. Moayyedi reported no relevant financial relationships.

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

Controversy regarding the purported link between the use of proton pump inhibitors (PPIs) or histamine H₂ receptor antagonists (H2RAs) and risk for dementia continues.

Adding to the “no link” column comes new evidence from a study presented at the annual Digestive Disease Week^® (DDW) .

Among almost 19,000 people, no association was found between the use of these agents and a greater likelihood of incident dementia, Alzheimer’s disease, or cognitive decline in people older than 65 years.

“We found that baseline PPI or H2RA use in older adults was not associated with dementia, with mild cognitive impairment, or declines in cognitive scores over time,” said lead author Raaj Shishir Mehta, MD, a gastroenterology fellow at Massachusetts General Hospital in Boston.

“While deprescribing efforts are important, especially when medications are not indicated, these data provide reassurance about the cognitive impacts of long-term use of PPIs in older adults,” he added.
 

Growing use, growing concern

As PPI use has increased worldwide, so too have concerns over the adverse effects from their long-term use, Dr. Mehta said.

“One particular area of concern, especially among older adults, is the link between long-term PPI use and risk for dementia,” he said.

Igniting the controversy was a February 2016 study published in JAMA Neurology that showed a positive association between PPI use and dementia in residents of Germany aged 75 years and older. Researchers linked PPI use to a 44% increased risk of dementia over 5 years.

The 2016 study was based on claims data, which can introduce “inaccuracy or bias in defining dementia cases,” Dr. Mehta said. He noted that it and other previous studies also were limited by an inability to account for concomitant medications or comorbidities.

To overcome these limitations in their study, Dr. Mehta and colleagues analyzed medication data collected during in-person visits and asked experts to confirm dementia outcomes. The research data come from ASPREE, a large aspirin study of 18,846 people older than 65 years in the United States and Australia. Participants were enrolled from 2010 to 2014. A total of 566 people developed incident dementia during follow-up.

The researchers had data on alcohol consumption and other lifestyle factors, as well as information on comorbidities, hospitalizations, and overall well-being.

“Perhaps the biggest strength of our study is our rigorous neurocognitive assessments,” Dr. Mehta said.

They assessed cognition at baseline and at years 1, 3, 5, and 7 using a battery of tests. An expert panel of neurologists, neuropsychologists, and geriatricians adjudicated cases of dementia, in accordance with DSM-IV criteria. If the diagnosis was unclear, they referred people for additional workup, including neuroimaging.

Cox proportional hazards, regression, and/or mixed effects modeling were used to relate medication use with cognitive scores.

All analyses were adjusted for age, sex, body mass index, alcohol use, family history of dementia, medications, and other medical comorbidities.

At baseline, PPI users were more likely to be White, have fewer years of education, and have higher rates of hypertension, diabetes, and kidney disease. This group also was more likely to be taking five or more medications.
 

Key points

During 80,976 person-years of follow-up, there were 566 incident cases of dementia, including 235 probable cases of Alzheimer’s disease and 331 other dementias.

Baseline PPI use, in comparison with nonuse, was not associated with incident dementia (hazard ratio, 0.86; 95% confidence interval, 0.70-1.05).

“Similarly, when we look specifically at Alzheimer’s disease or mixed types of dementia, we find no association between baseline PPI use and dementia,” Dr. Mehta said.

When they excluded people already taking PPIs at baseline, they found no association between starting PPIs and developing dementia over time.

Secondary aims of the study included looking for a link between PPI use and mild cognitive impairment or significant changes in cognition over time. In both cases, no association emerged. PPI use at baseline also was not associated with cognitive impairment/no dementia (also known as mild cognitive impairment) or with changes in overall cognitive test scores over time.

To determine whether any association could be a class effect of acid suppression medication, they assessed use of H2RA medications and development of incident dementia. Again, the researchers found no link.

A diverse multinational population from urban and rural areas was a strength of the study, as was the “very rigorous cognitive testing with expert adjudication of our endpoints,” Dr. Mehta said. In addition, fewer than 5% of patients were lost to follow-up.

In terms of limitations, this was an observational study “so residual confounding is always possible,” he added. “But I’ll emphasize that we are among the largest studies to date with wealth of covariates.”
 

Why the different findings?

The study was “really well done,” session moderator Paul Moayyedi, MD, said during the Q&A session at DDW 2022.

Dr. Moayyedi, a professor of medicine at McMaster University, Hamilton, Ont., asked Dr. Mehta why he “found absolutely no signal, whereas the German study did.”

“It’s a good question,” Dr. Mehta responded. “If you look across the board, there have been conflicting results.”

The disparity could be related to how researchers conducting claims data studies classify dementia, he noted.

“If you look at the nitty-gritty details over 5 years, almost 40% of participants [in those studies] end up with a diagnosis of dementia, which is quite high,” Dr. Mehta said. “That raises questions about whether the diagnosis of dementia is truly accurate.”

Dr. Mehta and Dr. Moayyedi reported no relevant financial relationships.

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

Controversy regarding the purported link between the use of proton pump inhibitors (PPIs) or histamine H₂ receptor antagonists (H2RAs) and risk for dementia continues.

Adding to the “no link” column comes new evidence from a study presented at the annual Digestive Disease Week^® (DDW) .

Among almost 19,000 people, no association was found between the use of these agents and a greater likelihood of incident dementia, Alzheimer’s disease, or cognitive decline in people older than 65 years.

“We found that baseline PPI or H2RA use in older adults was not associated with dementia, with mild cognitive impairment, or declines in cognitive scores over time,” said lead author Raaj Shishir Mehta, MD, a gastroenterology fellow at Massachusetts General Hospital in Boston.

“While deprescribing efforts are important, especially when medications are not indicated, these data provide reassurance about the cognitive impacts of long-term use of PPIs in older adults,” he added.
 

Growing use, growing concern

As PPI use has increased worldwide, so too have concerns over the adverse effects from their long-term use, Dr. Mehta said.

“One particular area of concern, especially among older adults, is the link between long-term PPI use and risk for dementia,” he said.

Igniting the controversy was a February 2016 study published in JAMA Neurology that showed a positive association between PPI use and dementia in residents of Germany aged 75 years and older. Researchers linked PPI use to a 44% increased risk of dementia over 5 years.

The 2016 study was based on claims data, which can introduce “inaccuracy or bias in defining dementia cases,” Dr. Mehta said. He noted that it and other previous studies also were limited by an inability to account for concomitant medications or comorbidities.

To overcome these limitations in their study, Dr. Mehta and colleagues analyzed medication data collected during in-person visits and asked experts to confirm dementia outcomes. The research data come from ASPREE, a large aspirin study of 18,846 people older than 65 years in the United States and Australia. Participants were enrolled from 2010 to 2014. A total of 566 people developed incident dementia during follow-up.

The researchers had data on alcohol consumption and other lifestyle factors, as well as information on comorbidities, hospitalizations, and overall well-being.

“Perhaps the biggest strength of our study is our rigorous neurocognitive assessments,” Dr. Mehta said.

They assessed cognition at baseline and at years 1, 3, 5, and 7 using a battery of tests. An expert panel of neurologists, neuropsychologists, and geriatricians adjudicated cases of dementia, in accordance with DSM-IV criteria. If the diagnosis was unclear, they referred people for additional workup, including neuroimaging.

Cox proportional hazards, regression, and/or mixed effects modeling were used to relate medication use with cognitive scores.

All analyses were adjusted for age, sex, body mass index, alcohol use, family history of dementia, medications, and other medical comorbidities.

At baseline, PPI users were more likely to be White, have fewer years of education, and have higher rates of hypertension, diabetes, and kidney disease. This group also was more likely to be taking five or more medications.
 

Key points

During 80,976 person-years of follow-up, there were 566 incident cases of dementia, including 235 probable cases of Alzheimer’s disease and 331 other dementias.

Baseline PPI use, in comparison with nonuse, was not associated with incident dementia (hazard ratio, 0.86; 95% confidence interval, 0.70-1.05).

“Similarly, when we look specifically at Alzheimer’s disease or mixed types of dementia, we find no association between baseline PPI use and dementia,” Dr. Mehta said.

When they excluded people already taking PPIs at baseline, they found no association between starting PPIs and developing dementia over time.

Secondary aims of the study included looking for a link between PPI use and mild cognitive impairment or significant changes in cognition over time. In both cases, no association emerged. PPI use at baseline also was not associated with cognitive impairment/no dementia (also known as mild cognitive impairment) or with changes in overall cognitive test scores over time.

To determine whether any association could be a class effect of acid suppression medication, they assessed use of H2RA medications and development of incident dementia. Again, the researchers found no link.

A diverse multinational population from urban and rural areas was a strength of the study, as was the “very rigorous cognitive testing with expert adjudication of our endpoints,” Dr. Mehta said. In addition, fewer than 5% of patients were lost to follow-up.

In terms of limitations, this was an observational study “so residual confounding is always possible,” he added. “But I’ll emphasize that we are among the largest studies to date with wealth of covariates.”
 

Why the different findings?

The study was “really well done,” session moderator Paul Moayyedi, MD, said during the Q&A session at DDW 2022.

Dr. Moayyedi, a professor of medicine at McMaster University, Hamilton, Ont., asked Dr. Mehta why he “found absolutely no signal, whereas the German study did.”

“It’s a good question,” Dr. Mehta responded. “If you look across the board, there have been conflicting results.”

The disparity could be related to how researchers conducting claims data studies classify dementia, he noted.

“If you look at the nitty-gritty details over 5 years, almost 40% of participants [in those studies] end up with a diagnosis of dementia, which is quite high,” Dr. Mehta said. “That raises questions about whether the diagnosis of dementia is truly accurate.”

Dr. Mehta and Dr. Moayyedi reported no relevant financial relationships.

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

In the largest investigation into the issue to date, metformin did not improve survival of patients with high-risk, operable breast cancer when added to standard adjuvant treatments.

Metformin, a common option for patients with type 2 diabetes, had previously been shown in observational studies to be associated with improved survival of cancer patients. Those studies mostly involved older patients with cancer who also had diabetes.

These findings have led to trials of the use of metformin for patients with cancer who do not have diabetes, but two lung cancer trials found no effect on survival.

Now this latest trial in breast cancer, which included 3,649 patients with hormone receptor–positive or –negative disease – who did not have diabetes – also found that metformin had no effect on survival.

These results “tell us that metformin is not effective against the most common types of breast cancer and any off-label use [of] this drug for the treatment of these common types of breast cancer should be stopped,” lead investigator and medical oncologist Pamela Goodwin, MD, a breast cancer researcher at the Lunenfeld-Tanenbaum Research Institute in Toronto, said in a press release.

The negative results “underscore the need for well-conducted randomized trials” before observational studies are put into practice, Dr. Goodwin and her team said.

However, the investigators cautioned against extrapolating their results to patients with diabetes, noting that “because metformin is effective in type 2 diabetes, the results ... should not affect the use of metformin” in breast cancer patients who have diabetes.

The study was published online in JAMA.

Patients were enrolled from 2010 to 2013 while undergoing adjuvant treatment – chemotherapy, radiotherapy, hormone therapy, and/or others – following complete resection of T1-3, N0-3 tumors. They were almost exclusively women (mean age, 52.4 years), and almost 90% were non-Hispanic White. They were primarily from the United States and Canada, with some patients from the United Kingdom and Switzerland.

Patients were randomly assigned equally to receive either metformin 850 mg twice daily or placebo for 5 years. Median follow-up was about 8 years.

Among 2,533 patients with estrogen receptor– and/or progesterone receptor–positive disease, the incidence of invasive disease–free survival events was 2.78 per 100 patient-years in the metformin group, vs. 2.74 per 100 patient-years in the placebo arm (hazard ratio [HR], 1.01, P = .93). There were 1.46 deaths per 100 patient-years with metformin, vs. 1.32 with placebo (HR, 1.10, P = .47).

Metformin was stopped early at about 3 years for the 1,116 hormone receptor–negative patients after futility was declared on interim analysis. The incidence of invasive disease–free survival events was 3.58 with metformin, vs. 3.60 with placebo per 100 patient-years (HR, 1.01, P = .92). There were 1.91 deaths per 100 patient-years in the metformin arm, vs. 2.15 in the group that received placebo (HR, 0.89, P = .46).

However, the findings were different and suggested a signal among the small subset of patients (17% of the total) who had HER2-positive disease. There were 1.93 disease-free survival events with metformin per 100 patient-years, vs. 3.05 events with placebo (HR, 0.64, P = .03), and 0.78 deaths in the metformin arm, vs. 1.43 deaths per 100 patient-years in the placebo arm (HR, 0.54, P = .04).

The benefit seen in this HER2-postive subgroup was limited to patients with any C allele of the rs11212617 single-nucleotide variant.

This was an exploratory analysis, so the results need to be confirmed in a randomized trial, but it’s possible that metformin “could provide an additional treatment option for HER2-positive breast cancer,” Dr. Goodwin said.

Grade 3 or higher adverse events were more common with metformin (21.5% vs. 17.5%). The most common such events were hypertension (2.4% vs. 1.9%), irregular menses (1.5% vs. 1.4%), and diarrhea (1.9% vs. 0.8%).

The study was conducted by the Canadian Cancer Trials Group and was funded by the Canadian Cancer Society, the National Cancer Institute, and others. Dr. Goodwin has disclosed no relevant financial relationships. Several coauthors reported ties to Pfizer, Eli Lilly, Roche, and a number of other companies. One coauthor is an AstraZeneca employee.

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

In the largest investigation into the issue to date, metformin did not improve survival of patients with high-risk, operable breast cancer when added to standard adjuvant treatments.

Metformin, a common option for patients with type 2 diabetes, had previously been shown in observational studies to be associated with improved survival of cancer patients. Those studies mostly involved older patients with cancer who also had diabetes.

These findings have led to trials of the use of metformin for patients with cancer who do not have diabetes, but two lung cancer trials found no effect on survival.

Now this latest trial in breast cancer, which included 3,649 patients with hormone receptor–positive or –negative disease – who did not have diabetes – also found that metformin had no effect on survival.

These results “tell us that metformin is not effective against the most common types of breast cancer and any off-label use [of] this drug for the treatment of these common types of breast cancer should be stopped,” lead investigator and medical oncologist Pamela Goodwin, MD, a breast cancer researcher at the Lunenfeld-Tanenbaum Research Institute in Toronto, said in a press release.

The negative results “underscore the need for well-conducted randomized trials” before observational studies are put into practice, Dr. Goodwin and her team said.

However, the investigators cautioned against extrapolating their results to patients with diabetes, noting that “because metformin is effective in type 2 diabetes, the results ... should not affect the use of metformin” in breast cancer patients who have diabetes.

The study was published online in JAMA.

Patients were enrolled from 2010 to 2013 while undergoing adjuvant treatment – chemotherapy, radiotherapy, hormone therapy, and/or others – following complete resection of T1-3, N0-3 tumors. They were almost exclusively women (mean age, 52.4 years), and almost 90% were non-Hispanic White. They were primarily from the United States and Canada, with some patients from the United Kingdom and Switzerland.

Patients were randomly assigned equally to receive either metformin 850 mg twice daily or placebo for 5 years. Median follow-up was about 8 years.

Among 2,533 patients with estrogen receptor– and/or progesterone receptor–positive disease, the incidence of invasive disease–free survival events was 2.78 per 100 patient-years in the metformin group, vs. 2.74 per 100 patient-years in the placebo arm (hazard ratio [HR], 1.01, P = .93). There were 1.46 deaths per 100 patient-years with metformin, vs. 1.32 with placebo (HR, 1.10, P = .47).

Metformin was stopped early at about 3 years for the 1,116 hormone receptor–negative patients after futility was declared on interim analysis. The incidence of invasive disease–free survival events was 3.58 with metformin, vs. 3.60 with placebo per 100 patient-years (HR, 1.01, P = .92). There were 1.91 deaths per 100 patient-years in the metformin arm, vs. 2.15 in the group that received placebo (HR, 0.89, P = .46).

However, the findings were different and suggested a signal among the small subset of patients (17% of the total) who had HER2-positive disease. There were 1.93 disease-free survival events with metformin per 100 patient-years, vs. 3.05 events with placebo (HR, 0.64, P = .03), and 0.78 deaths in the metformin arm, vs. 1.43 deaths per 100 patient-years in the placebo arm (HR, 0.54, P = .04).

The benefit seen in this HER2-postive subgroup was limited to patients with any C allele of the rs11212617 single-nucleotide variant.

This was an exploratory analysis, so the results need to be confirmed in a randomized trial, but it’s possible that metformin “could provide an additional treatment option for HER2-positive breast cancer,” Dr. Goodwin said.

Grade 3 or higher adverse events were more common with metformin (21.5% vs. 17.5%). The most common such events were hypertension (2.4% vs. 1.9%), irregular menses (1.5% vs. 1.4%), and diarrhea (1.9% vs. 0.8%).

The study was conducted by the Canadian Cancer Trials Group and was funded by the Canadian Cancer Society, the National Cancer Institute, and others. Dr. Goodwin has disclosed no relevant financial relationships. Several coauthors reported ties to Pfizer, Eli Lilly, Roche, and a number of other companies. One coauthor is an AstraZeneca employee.

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

In the largest investigation into the issue to date, metformin did not improve survival of patients with high-risk, operable breast cancer when added to standard adjuvant treatments.

Metformin, a common option for patients with type 2 diabetes, had previously been shown in observational studies to be associated with improved survival of cancer patients. Those studies mostly involved older patients with cancer who also had diabetes.

These findings have led to trials of the use of metformin for patients with cancer who do not have diabetes, but two lung cancer trials found no effect on survival.

Now this latest trial in breast cancer, which included 3,649 patients with hormone receptor–positive or –negative disease – who did not have diabetes – also found that metformin had no effect on survival.

These results “tell us that metformin is not effective against the most common types of breast cancer and any off-label use [of] this drug for the treatment of these common types of breast cancer should be stopped,” lead investigator and medical oncologist Pamela Goodwin, MD, a breast cancer researcher at the Lunenfeld-Tanenbaum Research Institute in Toronto, said in a press release.

The negative results “underscore the need for well-conducted randomized trials” before observational studies are put into practice, Dr. Goodwin and her team said.

However, the investigators cautioned against extrapolating their results to patients with diabetes, noting that “because metformin is effective in type 2 diabetes, the results ... should not affect the use of metformin” in breast cancer patients who have diabetes.

The study was published online in JAMA.

Patients were enrolled from 2010 to 2013 while undergoing adjuvant treatment – chemotherapy, radiotherapy, hormone therapy, and/or others – following complete resection of T1-3, N0-3 tumors. They were almost exclusively women (mean age, 52.4 years), and almost 90% were non-Hispanic White. They were primarily from the United States and Canada, with some patients from the United Kingdom and Switzerland.

Patients were randomly assigned equally to receive either metformin 850 mg twice daily or placebo for 5 years. Median follow-up was about 8 years.

Among 2,533 patients with estrogen receptor– and/or progesterone receptor–positive disease, the incidence of invasive disease–free survival events was 2.78 per 100 patient-years in the metformin group, vs. 2.74 per 100 patient-years in the placebo arm (hazard ratio [HR], 1.01, P = .93). There were 1.46 deaths per 100 patient-years with metformin, vs. 1.32 with placebo (HR, 1.10, P = .47).

Metformin was stopped early at about 3 years for the 1,116 hormone receptor–negative patients after futility was declared on interim analysis. The incidence of invasive disease–free survival events was 3.58 with metformin, vs. 3.60 with placebo per 100 patient-years (HR, 1.01, P = .92). There were 1.91 deaths per 100 patient-years in the metformin arm, vs. 2.15 in the group that received placebo (HR, 0.89, P = .46).

However, the findings were different and suggested a signal among the small subset of patients (17% of the total) who had HER2-positive disease. There were 1.93 disease-free survival events with metformin per 100 patient-years, vs. 3.05 events with placebo (HR, 0.64, P = .03), and 0.78 deaths in the metformin arm, vs. 1.43 deaths per 100 patient-years in the placebo arm (HR, 0.54, P = .04).

The benefit seen in this HER2-postive subgroup was limited to patients with any C allele of the rs11212617 single-nucleotide variant.

This was an exploratory analysis, so the results need to be confirmed in a randomized trial, but it’s possible that metformin “could provide an additional treatment option for HER2-positive breast cancer,” Dr. Goodwin said.

Grade 3 or higher adverse events were more common with metformin (21.5% vs. 17.5%). The most common such events were hypertension (2.4% vs. 1.9%), irregular menses (1.5% vs. 1.4%), and diarrhea (1.9% vs. 0.8%).

The study was conducted by the Canadian Cancer Trials Group and was funded by the Canadian Cancer Society, the National Cancer Institute, and others. Dr. Goodwin has disclosed no relevant financial relationships. Several coauthors reported ties to Pfizer, Eli Lilly, Roche, and a number of other companies. One coauthor is an AstraZeneca employee.

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