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Heart failure drug a new treatment option for alcoholism?
(AUD), new research suggests.
Researchers at the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and Yale University, New Haven, Conn., investigated the impact of spironolactone on AUD.
Initially, they studied rodents and found that spironolactone reduced binge drinking in mice and reduced self-administration of alcohol in rats without adversely affecting food or water intake or causing motor or coordination problems.
They also analyzed electronic health records of patients drawn from the United States Veterans Affairs health care system to explore potential changes in alcohol use after spironolactone treatment was initiated for other conditions and found a significant link between spironolactone treatment and reduction in self-reported alcohol consumption, with the largest effects observed among those who reported hazardous/heavy episodic alcohol use prior to starting spironolactone treatment.
“Combining findings across three species and different types of research studies, and then seeing similarities in these data, gives us confidence that we are onto something potentially important scientifically and clinically,” senior coauthor Lorenzo Leggio, MD, PhD, senior investigator in the Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, a joint NIDA and NIAAA laboratory, said in a news release.
The study was published online in Molecular Psychiatry.
There is a “critical need to increase the armamentarium of pharmacotherapies to treat individuals with AUD,” the authors note, adding that neuroendocrine systems involved in alcohol craving and drinking “offer promising pharmacologic targets in this regard.”
“Both our team and others have observed that patients with AUD often present with changes in peripheral hormones, including aldosterone, which plays a key role in regulating blood pressure and electrolytes,” Dr. Leggio said in an interview.
Spironolactone is a nonselective mineralocorticoid receptor (MT) antagonist. In studies in animal models, investigators said they found “an inverse correlation between alcohol drinking and the expression of the MR in the amygdala, a key brain region in the development and maintenance of AUD and addiction in general.”
Taken together, this led them to hypothesize that blocking the MR, which is the mechanism of action of spironolactone, “could be a novel pharmacotherapeutic approach for AUD,” he said.
Previous research by the same group of researchers suggested spironolactone “may be a potential new medication to treat patients with AUD.” The present study expanded on those findings and consisted of a three-part investigation.
In the current study, the investigators tested different dosages of spironolactone on binge-like alcohol consumption in male and female mice and assessed food and water intake, blood alcohol levels, motor coordination, and spontaneous locomotion.
They then tested the effects of different dosages of spironolactone injections on operant alcohol self-administration in alcohol-dependent and nondependent male and female rats, also testing blood alcohol levels and motor coordination.
Finally, they analyzed health records of veterans to examine the association between at least 60 continuous days of spironolactone treatment and self-reported alcohol consumption (measured by the Alcohol Use Disorders Identification Test-Consumption [AUDIT-C]).
Each of the spironolactone-exposed patients was matched using propensity scores with up to five unexposed patients who had reported alcohol consumption in the 2 years prior to the index date.
The final analysis included a matched cohort of 10,726 spironolactone-exposed individuals who were matched to 34,461 unexposed individuals.
New targets
Spironolactone reduced alcohol intake in mice drinking a sweetened alcohol solution; a 2-way ANOVA revealed a main effect of dose (F 4,52 = 9.09; P < .0001) and sex, with female mice drinking more alcohol, compared to male mice (F 1,13 = 6.05; P = .02).
Post hoc comparisons showed that spironolactone at doses of 50, 100, and 200 mg/kg significantly reduced alcohol intake (P values = .007, .002, and .0001, respectively).
In mice drinking an unsweetened alcohol solution, the 2-way repeated measures ANOVA similarly found a main effect of dose (F 4,52 = 5.77; P = .0006), but not of sex (F 1,13 = 1.41; P = .25).
Spironolactone had no effect on the mice’s intake of a sweet solution without alcohol and had no impact on the consumption of food and water or on locomotion and coordination.
In rats, a 2-way ANOVA revealed a significant spironolactone effect of dose (F 3,66 = 43.95; P < .001), with a post hoc test indicating that spironolactone at 25, 50, and 75 mg/kg reduced alcohol self-administration in alcohol-dependent and nondependent rats (all P values = .0001).
In humans, among the exposed individuals in the matched cohort, 25%, 57%, and 18% received daily doses of spironolactone of less than 25 mg/day, 25-49 mg/day, and 50 mg/day or higher, respectively, with a median follow-up time of 542 (interquartile range, 337-730) days.
The AUDIT-C scores decreased during the study period in both treatment groups, with a larger decrease in average AUDIT-C scores among the exposed vs. unexposed individuals.
“These are very exciting times because, thanks to the progress in the addiction biomedical research field, we are increasing our understanding of the mechanisms how some people develop AUD; hence we can use this knowledge to identify new targets.” The current study “is an example of these ongoing efforts,” said Dr. Leggio.
“It is important to note that [these results] are important but preliminary.” At this juncture, “it would be too premature to think about prescribing spironolactone to treat AUD,” he added.
Exciting findings
Commenting on the study, Joyce Besheer, PhD, professor, department of psychiatry and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, called the study an “elegant demonstration of translational science.”
“While clinical trials will be needed to determine whether this medication is effective at reducing drinking in patients with AUD, these findings are exciting as they suggest that spironolactone may be a promising compound and new treatment options for AUD are much needed,” said Dr. Besheer, who was not involved with the current study.
Dr. Leggio agreed. “We now need prospective, placebo-controlled studies to assess the potential safety and efficacy of spironolactone in people with AUD,” he said.
This work was supported by the National Institutes of Health and the NIAAA. Dr. Leggio, study coauthors, and Dr. Besheer declare no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(AUD), new research suggests.
Researchers at the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and Yale University, New Haven, Conn., investigated the impact of spironolactone on AUD.
Initially, they studied rodents and found that spironolactone reduced binge drinking in mice and reduced self-administration of alcohol in rats without adversely affecting food or water intake or causing motor or coordination problems.
They also analyzed electronic health records of patients drawn from the United States Veterans Affairs health care system to explore potential changes in alcohol use after spironolactone treatment was initiated for other conditions and found a significant link between spironolactone treatment and reduction in self-reported alcohol consumption, with the largest effects observed among those who reported hazardous/heavy episodic alcohol use prior to starting spironolactone treatment.
“Combining findings across three species and different types of research studies, and then seeing similarities in these data, gives us confidence that we are onto something potentially important scientifically and clinically,” senior coauthor Lorenzo Leggio, MD, PhD, senior investigator in the Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, a joint NIDA and NIAAA laboratory, said in a news release.
The study was published online in Molecular Psychiatry.
There is a “critical need to increase the armamentarium of pharmacotherapies to treat individuals with AUD,” the authors note, adding that neuroendocrine systems involved in alcohol craving and drinking “offer promising pharmacologic targets in this regard.”
“Both our team and others have observed that patients with AUD often present with changes in peripheral hormones, including aldosterone, which plays a key role in regulating blood pressure and electrolytes,” Dr. Leggio said in an interview.
Spironolactone is a nonselective mineralocorticoid receptor (MT) antagonist. In studies in animal models, investigators said they found “an inverse correlation between alcohol drinking and the expression of the MR in the amygdala, a key brain region in the development and maintenance of AUD and addiction in general.”
Taken together, this led them to hypothesize that blocking the MR, which is the mechanism of action of spironolactone, “could be a novel pharmacotherapeutic approach for AUD,” he said.
Previous research by the same group of researchers suggested spironolactone “may be a potential new medication to treat patients with AUD.” The present study expanded on those findings and consisted of a three-part investigation.
In the current study, the investigators tested different dosages of spironolactone on binge-like alcohol consumption in male and female mice and assessed food and water intake, blood alcohol levels, motor coordination, and spontaneous locomotion.
They then tested the effects of different dosages of spironolactone injections on operant alcohol self-administration in alcohol-dependent and nondependent male and female rats, also testing blood alcohol levels and motor coordination.
Finally, they analyzed health records of veterans to examine the association between at least 60 continuous days of spironolactone treatment and self-reported alcohol consumption (measured by the Alcohol Use Disorders Identification Test-Consumption [AUDIT-C]).
Each of the spironolactone-exposed patients was matched using propensity scores with up to five unexposed patients who had reported alcohol consumption in the 2 years prior to the index date.
The final analysis included a matched cohort of 10,726 spironolactone-exposed individuals who were matched to 34,461 unexposed individuals.
New targets
Spironolactone reduced alcohol intake in mice drinking a sweetened alcohol solution; a 2-way ANOVA revealed a main effect of dose (F 4,52 = 9.09; P < .0001) and sex, with female mice drinking more alcohol, compared to male mice (F 1,13 = 6.05; P = .02).
Post hoc comparisons showed that spironolactone at doses of 50, 100, and 200 mg/kg significantly reduced alcohol intake (P values = .007, .002, and .0001, respectively).
In mice drinking an unsweetened alcohol solution, the 2-way repeated measures ANOVA similarly found a main effect of dose (F 4,52 = 5.77; P = .0006), but not of sex (F 1,13 = 1.41; P = .25).
Spironolactone had no effect on the mice’s intake of a sweet solution without alcohol and had no impact on the consumption of food and water or on locomotion and coordination.
In rats, a 2-way ANOVA revealed a significant spironolactone effect of dose (F 3,66 = 43.95; P < .001), with a post hoc test indicating that spironolactone at 25, 50, and 75 mg/kg reduced alcohol self-administration in alcohol-dependent and nondependent rats (all P values = .0001).
In humans, among the exposed individuals in the matched cohort, 25%, 57%, and 18% received daily doses of spironolactone of less than 25 mg/day, 25-49 mg/day, and 50 mg/day or higher, respectively, with a median follow-up time of 542 (interquartile range, 337-730) days.
The AUDIT-C scores decreased during the study period in both treatment groups, with a larger decrease in average AUDIT-C scores among the exposed vs. unexposed individuals.
“These are very exciting times because, thanks to the progress in the addiction biomedical research field, we are increasing our understanding of the mechanisms how some people develop AUD; hence we can use this knowledge to identify new targets.” The current study “is an example of these ongoing efforts,” said Dr. Leggio.
“It is important to note that [these results] are important but preliminary.” At this juncture, “it would be too premature to think about prescribing spironolactone to treat AUD,” he added.
Exciting findings
Commenting on the study, Joyce Besheer, PhD, professor, department of psychiatry and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, called the study an “elegant demonstration of translational science.”
“While clinical trials will be needed to determine whether this medication is effective at reducing drinking in patients with AUD, these findings are exciting as they suggest that spironolactone may be a promising compound and new treatment options for AUD are much needed,” said Dr. Besheer, who was not involved with the current study.
Dr. Leggio agreed. “We now need prospective, placebo-controlled studies to assess the potential safety and efficacy of spironolactone in people with AUD,” he said.
This work was supported by the National Institutes of Health and the NIAAA. Dr. Leggio, study coauthors, and Dr. Besheer declare no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(AUD), new research suggests.
Researchers at the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and Yale University, New Haven, Conn., investigated the impact of spironolactone on AUD.
Initially, they studied rodents and found that spironolactone reduced binge drinking in mice and reduced self-administration of alcohol in rats without adversely affecting food or water intake or causing motor or coordination problems.
They also analyzed electronic health records of patients drawn from the United States Veterans Affairs health care system to explore potential changes in alcohol use after spironolactone treatment was initiated for other conditions and found a significant link between spironolactone treatment and reduction in self-reported alcohol consumption, with the largest effects observed among those who reported hazardous/heavy episodic alcohol use prior to starting spironolactone treatment.
“Combining findings across three species and different types of research studies, and then seeing similarities in these data, gives us confidence that we are onto something potentially important scientifically and clinically,” senior coauthor Lorenzo Leggio, MD, PhD, senior investigator in the Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, a joint NIDA and NIAAA laboratory, said in a news release.
The study was published online in Molecular Psychiatry.
There is a “critical need to increase the armamentarium of pharmacotherapies to treat individuals with AUD,” the authors note, adding that neuroendocrine systems involved in alcohol craving and drinking “offer promising pharmacologic targets in this regard.”
“Both our team and others have observed that patients with AUD often present with changes in peripheral hormones, including aldosterone, which plays a key role in regulating blood pressure and electrolytes,” Dr. Leggio said in an interview.
Spironolactone is a nonselective mineralocorticoid receptor (MT) antagonist. In studies in animal models, investigators said they found “an inverse correlation between alcohol drinking and the expression of the MR in the amygdala, a key brain region in the development and maintenance of AUD and addiction in general.”
Taken together, this led them to hypothesize that blocking the MR, which is the mechanism of action of spironolactone, “could be a novel pharmacotherapeutic approach for AUD,” he said.
Previous research by the same group of researchers suggested spironolactone “may be a potential new medication to treat patients with AUD.” The present study expanded on those findings and consisted of a three-part investigation.
In the current study, the investigators tested different dosages of spironolactone on binge-like alcohol consumption in male and female mice and assessed food and water intake, blood alcohol levels, motor coordination, and spontaneous locomotion.
They then tested the effects of different dosages of spironolactone injections on operant alcohol self-administration in alcohol-dependent and nondependent male and female rats, also testing blood alcohol levels and motor coordination.
Finally, they analyzed health records of veterans to examine the association between at least 60 continuous days of spironolactone treatment and self-reported alcohol consumption (measured by the Alcohol Use Disorders Identification Test-Consumption [AUDIT-C]).
Each of the spironolactone-exposed patients was matched using propensity scores with up to five unexposed patients who had reported alcohol consumption in the 2 years prior to the index date.
The final analysis included a matched cohort of 10,726 spironolactone-exposed individuals who were matched to 34,461 unexposed individuals.
New targets
Spironolactone reduced alcohol intake in mice drinking a sweetened alcohol solution; a 2-way ANOVA revealed a main effect of dose (F 4,52 = 9.09; P < .0001) and sex, with female mice drinking more alcohol, compared to male mice (F 1,13 = 6.05; P = .02).
Post hoc comparisons showed that spironolactone at doses of 50, 100, and 200 mg/kg significantly reduced alcohol intake (P values = .007, .002, and .0001, respectively).
In mice drinking an unsweetened alcohol solution, the 2-way repeated measures ANOVA similarly found a main effect of dose (F 4,52 = 5.77; P = .0006), but not of sex (F 1,13 = 1.41; P = .25).
Spironolactone had no effect on the mice’s intake of a sweet solution without alcohol and had no impact on the consumption of food and water or on locomotion and coordination.
In rats, a 2-way ANOVA revealed a significant spironolactone effect of dose (F 3,66 = 43.95; P < .001), with a post hoc test indicating that spironolactone at 25, 50, and 75 mg/kg reduced alcohol self-administration in alcohol-dependent and nondependent rats (all P values = .0001).
In humans, among the exposed individuals in the matched cohort, 25%, 57%, and 18% received daily doses of spironolactone of less than 25 mg/day, 25-49 mg/day, and 50 mg/day or higher, respectively, with a median follow-up time of 542 (interquartile range, 337-730) days.
The AUDIT-C scores decreased during the study period in both treatment groups, with a larger decrease in average AUDIT-C scores among the exposed vs. unexposed individuals.
“These are very exciting times because, thanks to the progress in the addiction biomedical research field, we are increasing our understanding of the mechanisms how some people develop AUD; hence we can use this knowledge to identify new targets.” The current study “is an example of these ongoing efforts,” said Dr. Leggio.
“It is important to note that [these results] are important but preliminary.” At this juncture, “it would be too premature to think about prescribing spironolactone to treat AUD,” he added.
Exciting findings
Commenting on the study, Joyce Besheer, PhD, professor, department of psychiatry and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, called the study an “elegant demonstration of translational science.”
“While clinical trials will be needed to determine whether this medication is effective at reducing drinking in patients with AUD, these findings are exciting as they suggest that spironolactone may be a promising compound and new treatment options for AUD are much needed,” said Dr. Besheer, who was not involved with the current study.
Dr. Leggio agreed. “We now need prospective, placebo-controlled studies to assess the potential safety and efficacy of spironolactone in people with AUD,” he said.
This work was supported by the National Institutes of Health and the NIAAA. Dr. Leggio, study coauthors, and Dr. Besheer declare no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM MOLECULAR PSYCHIATRY
Apremilast may have some cardiometabolic benefits in patients with psoriasis
The trial, led by Joel M. Gelfand, MD, MSCE, professor of dermatology and epidemiology and vice chair of clinical research in dermatology at the University of Pennsylvania, Philadelphia, found that apremilast (Otezla) has a neutral effect on aortic vascular inflammation in patients with moderate to severe psoriasis.
It also had variable, but generally favorable, associations with 68 cardiometabolic biomarkers tested and associations with reductions in both visceral and subcutaneous fat. Findings of the study were published online in JAMA Dermatology.
Fat reductions maintained at 1-year mark
The researchers found a 5%-6% reduction in subcutaneous and visceral fat at week 16 of the study that was maintained at the 1-year mark. “The fact that it was rock stable a year later is pretty encouraging,” Dr. Gelfand told this news organization.
As for effects on vascular inflammation, Dr. Gelfand said, “The good news is we didn’t find any adverse effects on aortic vascular inflammation, but we didn’t find any beneficial effects either. That was a little disappointing.
“The most surprising thing was really the effects on visceral adiposity,” he added. “I’m not aware of any other drug having demonstrated that effect.”
Michael S. Garshick, MD, a cardiologist with NYU Langone Health in New York, who was not involved with the trial, told this news organization that despite seemingly good epidemiologic evidence in observational studies that by treating psoriasis surrogates of cardiovascular risk can be reduced, this trial, like others before it, failed to reduce aortic vascular inflammation.
The trial does help answer the question of whether apremilast can induce weight loss, he said, something that earlier trials suggested. “This trial confirms that, which is exciting,” he said. The reduction in both visceral and subcutaneous fat “deserves a lot further study.”
Several questions remain, Dr. Garshick said. Both he and Dr. Gelfand pointed to the need for large, placebo-controlled trials. “We still don’t know which medications may be preferrable in psoriasis to reduce [cardiovascular] risk if any at all,” Dr. Garshick said.
Seventy patients enrolled
In total, 70 patients with moderate to severe psoriasis were enrolled, 60 completed week 16, and 39 completed week 52 of the single-arm, open-label trial conducted between April 2017 and August 2021 at seven dermatology sites in the United States.
Participants took 30 mg of apremilast, an oral phosphodiesterase-4 (PDE-4) inhibitor approved for treating psoriasis and psoriatic arthritis, twice daily. Participants’ average age was 47.5 years; most were male (77.1%) and White (82.9%); almost 6% were Black. Average body mass index was 30 kg/m2. Patients could not have received biologics within 90 days of study baseline (or 180 days for ustekinumab [Stelara]).
There was no change in aortic vascular inflammation at week 16 (target to background ratio, −0.02; 95% confidence interval [CI], −0.08 to 0.05; P = .61) or week 52 (target to background ratio, −0.07; 95% CI, −0.15 to 0.01; P = .09) compared with baseline.
“At week 16, there were reductions in levels of interleukin-1b, fetuin A, valine, leucine, and isoleucine,” the authors wrote, adding that at week 52, compared with baseline, “there were reductions in levels of ferritin, cholesterol efflux capacity, beta-hydroxybutyrate, acetone, and ketone bodies, and an increase in levels of apolipoprotein A-1.”
This study highlights the importance of screening, Dr. Garshick said.
He and Dr. Gelfand said people with psoriatic disease tend to be vastly underscreened for cardiovascular risk factors.
Dr. Gelfand said, “If we did what we knew worked – meaning we screened them for diabetes, we screen their cholesterol, we check their blood pressure, and we adequately treated those traditional cardiovascular risk factors, we probably could narrow the gap quite a bit” in terms of the lower life expectancy people face when they have more significant psoriasis.
Celgene was the initial funding sponsor; sponsorship was then transferred to Amgen. The authors designed, executed, analyzed, and reported the study. Celgene provided nonbinding input into study design, and Amgen provided nonbinding input into the reporting of results. Dr. Gelfand reported numerous disclosures with various pharmaceutical companies and organizations. Dr. Garshick reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The trial, led by Joel M. Gelfand, MD, MSCE, professor of dermatology and epidemiology and vice chair of clinical research in dermatology at the University of Pennsylvania, Philadelphia, found that apremilast (Otezla) has a neutral effect on aortic vascular inflammation in patients with moderate to severe psoriasis.
It also had variable, but generally favorable, associations with 68 cardiometabolic biomarkers tested and associations with reductions in both visceral and subcutaneous fat. Findings of the study were published online in JAMA Dermatology.
Fat reductions maintained at 1-year mark
The researchers found a 5%-6% reduction in subcutaneous and visceral fat at week 16 of the study that was maintained at the 1-year mark. “The fact that it was rock stable a year later is pretty encouraging,” Dr. Gelfand told this news organization.
As for effects on vascular inflammation, Dr. Gelfand said, “The good news is we didn’t find any adverse effects on aortic vascular inflammation, but we didn’t find any beneficial effects either. That was a little disappointing.
“The most surprising thing was really the effects on visceral adiposity,” he added. “I’m not aware of any other drug having demonstrated that effect.”
Michael S. Garshick, MD, a cardiologist with NYU Langone Health in New York, who was not involved with the trial, told this news organization that despite seemingly good epidemiologic evidence in observational studies that by treating psoriasis surrogates of cardiovascular risk can be reduced, this trial, like others before it, failed to reduce aortic vascular inflammation.
The trial does help answer the question of whether apremilast can induce weight loss, he said, something that earlier trials suggested. “This trial confirms that, which is exciting,” he said. The reduction in both visceral and subcutaneous fat “deserves a lot further study.”
Several questions remain, Dr. Garshick said. Both he and Dr. Gelfand pointed to the need for large, placebo-controlled trials. “We still don’t know which medications may be preferrable in psoriasis to reduce [cardiovascular] risk if any at all,” Dr. Garshick said.
Seventy patients enrolled
In total, 70 patients with moderate to severe psoriasis were enrolled, 60 completed week 16, and 39 completed week 52 of the single-arm, open-label trial conducted between April 2017 and August 2021 at seven dermatology sites in the United States.
Participants took 30 mg of apremilast, an oral phosphodiesterase-4 (PDE-4) inhibitor approved for treating psoriasis and psoriatic arthritis, twice daily. Participants’ average age was 47.5 years; most were male (77.1%) and White (82.9%); almost 6% were Black. Average body mass index was 30 kg/m2. Patients could not have received biologics within 90 days of study baseline (or 180 days for ustekinumab [Stelara]).
There was no change in aortic vascular inflammation at week 16 (target to background ratio, −0.02; 95% confidence interval [CI], −0.08 to 0.05; P = .61) or week 52 (target to background ratio, −0.07; 95% CI, −0.15 to 0.01; P = .09) compared with baseline.
“At week 16, there were reductions in levels of interleukin-1b, fetuin A, valine, leucine, and isoleucine,” the authors wrote, adding that at week 52, compared with baseline, “there were reductions in levels of ferritin, cholesterol efflux capacity, beta-hydroxybutyrate, acetone, and ketone bodies, and an increase in levels of apolipoprotein A-1.”
This study highlights the importance of screening, Dr. Garshick said.
He and Dr. Gelfand said people with psoriatic disease tend to be vastly underscreened for cardiovascular risk factors.
Dr. Gelfand said, “If we did what we knew worked – meaning we screened them for diabetes, we screen their cholesterol, we check their blood pressure, and we adequately treated those traditional cardiovascular risk factors, we probably could narrow the gap quite a bit” in terms of the lower life expectancy people face when they have more significant psoriasis.
Celgene was the initial funding sponsor; sponsorship was then transferred to Amgen. The authors designed, executed, analyzed, and reported the study. Celgene provided nonbinding input into study design, and Amgen provided nonbinding input into the reporting of results. Dr. Gelfand reported numerous disclosures with various pharmaceutical companies and organizations. Dr. Garshick reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The trial, led by Joel M. Gelfand, MD, MSCE, professor of dermatology and epidemiology and vice chair of clinical research in dermatology at the University of Pennsylvania, Philadelphia, found that apremilast (Otezla) has a neutral effect on aortic vascular inflammation in patients with moderate to severe psoriasis.
It also had variable, but generally favorable, associations with 68 cardiometabolic biomarkers tested and associations with reductions in both visceral and subcutaneous fat. Findings of the study were published online in JAMA Dermatology.
Fat reductions maintained at 1-year mark
The researchers found a 5%-6% reduction in subcutaneous and visceral fat at week 16 of the study that was maintained at the 1-year mark. “The fact that it was rock stable a year later is pretty encouraging,” Dr. Gelfand told this news organization.
As for effects on vascular inflammation, Dr. Gelfand said, “The good news is we didn’t find any adverse effects on aortic vascular inflammation, but we didn’t find any beneficial effects either. That was a little disappointing.
“The most surprising thing was really the effects on visceral adiposity,” he added. “I’m not aware of any other drug having demonstrated that effect.”
Michael S. Garshick, MD, a cardiologist with NYU Langone Health in New York, who was not involved with the trial, told this news organization that despite seemingly good epidemiologic evidence in observational studies that by treating psoriasis surrogates of cardiovascular risk can be reduced, this trial, like others before it, failed to reduce aortic vascular inflammation.
The trial does help answer the question of whether apremilast can induce weight loss, he said, something that earlier trials suggested. “This trial confirms that, which is exciting,” he said. The reduction in both visceral and subcutaneous fat “deserves a lot further study.”
Several questions remain, Dr. Garshick said. Both he and Dr. Gelfand pointed to the need for large, placebo-controlled trials. “We still don’t know which medications may be preferrable in psoriasis to reduce [cardiovascular] risk if any at all,” Dr. Garshick said.
Seventy patients enrolled
In total, 70 patients with moderate to severe psoriasis were enrolled, 60 completed week 16, and 39 completed week 52 of the single-arm, open-label trial conducted between April 2017 and August 2021 at seven dermatology sites in the United States.
Participants took 30 mg of apremilast, an oral phosphodiesterase-4 (PDE-4) inhibitor approved for treating psoriasis and psoriatic arthritis, twice daily. Participants’ average age was 47.5 years; most were male (77.1%) and White (82.9%); almost 6% were Black. Average body mass index was 30 kg/m2. Patients could not have received biologics within 90 days of study baseline (or 180 days for ustekinumab [Stelara]).
There was no change in aortic vascular inflammation at week 16 (target to background ratio, −0.02; 95% confidence interval [CI], −0.08 to 0.05; P = .61) or week 52 (target to background ratio, −0.07; 95% CI, −0.15 to 0.01; P = .09) compared with baseline.
“At week 16, there were reductions in levels of interleukin-1b, fetuin A, valine, leucine, and isoleucine,” the authors wrote, adding that at week 52, compared with baseline, “there were reductions in levels of ferritin, cholesterol efflux capacity, beta-hydroxybutyrate, acetone, and ketone bodies, and an increase in levels of apolipoprotein A-1.”
This study highlights the importance of screening, Dr. Garshick said.
He and Dr. Gelfand said people with psoriatic disease tend to be vastly underscreened for cardiovascular risk factors.
Dr. Gelfand said, “If we did what we knew worked – meaning we screened them for diabetes, we screen their cholesterol, we check their blood pressure, and we adequately treated those traditional cardiovascular risk factors, we probably could narrow the gap quite a bit” in terms of the lower life expectancy people face when they have more significant psoriasis.
Celgene was the initial funding sponsor; sponsorship was then transferred to Amgen. The authors designed, executed, analyzed, and reported the study. Celgene provided nonbinding input into study design, and Amgen provided nonbinding input into the reporting of results. Dr. Gelfand reported numerous disclosures with various pharmaceutical companies and organizations. Dr. Garshick reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA DERMATOLOGY
Add PCSK9 inhibitor to high-intensity statin at primary PCI, proposes sham-controlled EPIC-STEMI
It’s best to have patients on aggressive lipid-lowering therapy before discharge after an acute ST-segment elevation myocardial infarction (STEMI), so why not start it right away – even in the cath lab – using some of the most potent LDL cholesterol–lowering agents available?
That was a main idea behind the randomized, sham-controlled EPIC-STEMI trial, in which STEMI patients were started on a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor immediately before direct percutaneous coronary intervention (PCI) and on top of high-intensity statins.
Those in the trial getting the active agent showed a 22% drop in LDL cholesterol levels by 6 weeks, compared with the control group given a sham injection along with high-intensity statins. They were also more likely to meet LDL cholesterol goals specified in some guidelines, including reduction by at least 50%. And those outcomes were achieved regardless of baseline LDL cholesterol levels or prior statin use.
Adoption of the trial’s early, aggressive LDL cholesterolreduction strategy in practice “has the potential to substantially reduce morbidity and mortality” in such cases “by further reducing LDL beyond statins in a much greater number of high-risk patients than are currently being treated with these agents,” suggested principal investigator Shamir R. Mehta, MD, MSc, when presenting the findings at the Transcatheter Cardiovascular Therapeutics annual meeting, sponsored by the Cardiovascular Research Foundation.
Adherence to secondary prevention measures in patients with acute coronary syndromes (ACS) is much better if they are started before hospital discharge, explained Dr. Mehta, senior scientist with Population Health Research Institute and professor of medicine at McMaster University, Hamilton, Ont. But “as soon as the patient has left the hospital, it is much more difficult to get these therapies on board.”
Routine adoption of such aggressive in-hospital, lipid-lowering therapy for the vast population with ACS would likely mean far fewer deaths and cardiovascular events “across a broader patient population.”
EPIC-STEMI is among the first studies to explore the strategy. “I think that’s the point of the trial that we wanted to make, that we don’t yet have data on this. We’re treading very carefully with PCSK9 inhibitors, and it’s just inching forward in populations. And I think we need a bold trial to see whether or not this changes things.”
The PCSK9 inhibitor alirocumab (Praluent) was used in EPIC-STEMI, which was published in EuroIntervention, with Dr. Mehta as lead author, the same day as his presentation. The drug and its sham injection were given on top of either atorvastatin 40-80 mg or rosuvastatin 40 mg.
Early initiation of statins in patients with acute STEMI has become standard, but there’s good evidence from intracoronary imaging studies suggesting that the addition of PCSK9 inhibitors might promote further stabilization of plaques that could potentially cause recurrent ischemic events.
Treatment with the injectable drugs plus statins led to significant coronary lesion regression in the GLAGOV trial of patients with stable coronary disease. And initiation of PCSK9 inhibitors with high-intensity statins soon after PCI for ACS improved atheroma shrinkage in non–infarct-related arteries over 1 year in the recent, placebo-controlled PACMAN-AMI trial.
Dr. Mehta pointed out that LDL reductions on PCSK9 inhibition, compared with the sham control, weren’t necessarily as impressive as might be expected from the major trials of long-term therapy with the drugs.
“You need longer [therapy] in order to see a difference in LDL levels when you use a PCSK9 inhibitor acutely. This is shown also on measures of infarct size.” There was no difference between treatment groups in infarct size as measured by levels of the MB fraction of creatine kinase, he reported.
“What this is telling us is that the acute use of a PCSK9 inhibitor did not modify the size or the severity of the baseline STEMI event.”
And EPIC-STEMI was too small and never intended to assess clinical outcomes; it was more about feasibility and what degree of LDL cholesterol lowering might be expected.
The trial was needed, Dr. Mehta said, because the PCSK9 inhibitors haven’t been extensively adopted into clinical practice and are not getting to the patients who could most benefit. One of the reasons for that is quite clear to him. “We are missing the high-risk patients because we are not treating them acutely,” Dr. Mehta said in an interview.
The strategy “has not yet been evaluated, and there have been barriers,” he observed. “Cost has been a barrier. Access to the drug has been a barrier. But in terms of the science, in terms of reducing cardiovascular events, this is a strategy that has to be tested.”
The aggressive, early LDL cholesterol reduction strategy should be evaluated for its effect on long-term outcomes, “especially knowing that in the first 30 days to 6 months post STEMI there’s a tremendous uptick in ischemic events, including recurrent myocardial infarction,” Roxana Mehran, MD, said at a media briefing on EPIC-STEMI held before Dr. Mehta’s formal presentation.
The “fantastic reduction acutely” with a PCSK9 inhibitor on top of statins, “hopefully reducing inflammation” similarly to what’s been observed in past trials, “absolutely warrants” a STEMI clinical outcomes trial, said Dr. Mehran, Icahn School of Medicine at Mount Sinai, New York, who isn’t connected with EPIC-STEMI.
If better post-discharge medication adherence is one of the acute strategy’s goals, it will be important to consider the potential influence of prescribing a periodically injected drug, proposed Eric A. Cohen, MD, Sunnybrook Health Sciences Center, Toronto, at the press conference.
“Keep in mind that STEMI patients typically come to the hospital on zero medications and leave 2 days later on five medications,” Dr. Cohen observed. “I’m curious whether having one of those as a sub-Q injection every 2 weeks, and reducing the pill burden, will help or deter adherence to therapy. I think it’s worth studying.”
The trial originally included 97 patients undergoing PCI for STEMI who were randomly assigned to receive the PCSK9 inhibitor or a sham injection on top of high-intensity statins, without regard to LDL cholesterol levels. Randomization took place after diagnostic angiography but before PCI.
The analysis, however, subsequently excluded 29 patients who could not continue with the study, “mainly because of hospital research clinic closure due to the COVID-19 pandemic,” the published report states.
That left 68 patients who had received at least one dose of PCSK9 inhibitor, alirocumab 150 mg subcutaneously, or the sham injection, and had at least one blood draw for LDL cholesterol response which, Dr. Mehta said, still left adequate statistical power for the LDL cholesterol–based primary endpoint.
By 6 weeks, LDL cholesterol levels had fallen 72.9% in the active-therapy group and by 48.1% in the control group (P < .001). Also, 92.1% and 56.7% of patients, respectively (P = .002), had achieved levels below the 1.4 mmol/L (54 mg/dL) goal in the European guidelines, Dr. Mehta reported.
Levels fell more than 50% compared with baseline in 89.5% of alirocumab patients and 60% (P = .007) of controls, respectively.
There was no significant difference in rates of attaining LDL cholesterol levels below the 70 mg/dL (1.8 mmol/L) threshold specified in U.S. guidelines for very high-risk patients: 94.7% of alirocumab patients and 83.4% of controls (P = .26).
Nor did the groups differ significantly in natriuretic peptide levels, which reflect ventricular remodeling; or in 6-week change in the inflammatory biomarker high-sensitivity C-reactive protein.
An open-label, randomized trial scheduled to launch before the end of 2022 will explore similarly early initiation of a PCSK9 inhibitor, compared with standard lipid management, in an estimated 4,000 patients hospitalized with STEMI or non-STEMI.
The EVOLVE MI trial is looking at the monoclonal antibody evolocumab (Repatha) for its effect on the primary endpoint of myocardial infarction, ischemic stroke, arterial revascularization, or death from any cause over an expected 3-4 years.
EPIC-STEMI was supported in part by Sanofi. Dr. Mehta reported an unrestricted grant from Sanofi to Hamilton Health Sciences for the present study and consulting fees from Amgen, Sanofi, and Novartis. Dr. Cohen disclosed receiving grant support from and holding research contracts with Abbott Vascular; and receiving fees for consulting, honoraria, or serving on a speaker’s bureau for Abbott Vascular, Medtronic, and Baylis. Dr. Mehran disclosed receiving grants or research support from numerous pharmaceutical companies; receiving consultant fee or honoraria or serving on a speaker’s bureau for Novartis, Abbott Vascular, Janssen, Medtronic, Medscape/WebMD, and Cine-Med Research; and holding equity, stock, or stock options with Control Rad, Applied Therapeutics, and Elixir Medical.
A version of this article first appeared on Medscape.com.
It’s best to have patients on aggressive lipid-lowering therapy before discharge after an acute ST-segment elevation myocardial infarction (STEMI), so why not start it right away – even in the cath lab – using some of the most potent LDL cholesterol–lowering agents available?
That was a main idea behind the randomized, sham-controlled EPIC-STEMI trial, in which STEMI patients were started on a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor immediately before direct percutaneous coronary intervention (PCI) and on top of high-intensity statins.
Those in the trial getting the active agent showed a 22% drop in LDL cholesterol levels by 6 weeks, compared with the control group given a sham injection along with high-intensity statins. They were also more likely to meet LDL cholesterol goals specified in some guidelines, including reduction by at least 50%. And those outcomes were achieved regardless of baseline LDL cholesterol levels or prior statin use.
Adoption of the trial’s early, aggressive LDL cholesterolreduction strategy in practice “has the potential to substantially reduce morbidity and mortality” in such cases “by further reducing LDL beyond statins in a much greater number of high-risk patients than are currently being treated with these agents,” suggested principal investigator Shamir R. Mehta, MD, MSc, when presenting the findings at the Transcatheter Cardiovascular Therapeutics annual meeting, sponsored by the Cardiovascular Research Foundation.
Adherence to secondary prevention measures in patients with acute coronary syndromes (ACS) is much better if they are started before hospital discharge, explained Dr. Mehta, senior scientist with Population Health Research Institute and professor of medicine at McMaster University, Hamilton, Ont. But “as soon as the patient has left the hospital, it is much more difficult to get these therapies on board.”
Routine adoption of such aggressive in-hospital, lipid-lowering therapy for the vast population with ACS would likely mean far fewer deaths and cardiovascular events “across a broader patient population.”
EPIC-STEMI is among the first studies to explore the strategy. “I think that’s the point of the trial that we wanted to make, that we don’t yet have data on this. We’re treading very carefully with PCSK9 inhibitors, and it’s just inching forward in populations. And I think we need a bold trial to see whether or not this changes things.”
The PCSK9 inhibitor alirocumab (Praluent) was used in EPIC-STEMI, which was published in EuroIntervention, with Dr. Mehta as lead author, the same day as his presentation. The drug and its sham injection were given on top of either atorvastatin 40-80 mg or rosuvastatin 40 mg.
Early initiation of statins in patients with acute STEMI has become standard, but there’s good evidence from intracoronary imaging studies suggesting that the addition of PCSK9 inhibitors might promote further stabilization of plaques that could potentially cause recurrent ischemic events.
Treatment with the injectable drugs plus statins led to significant coronary lesion regression in the GLAGOV trial of patients with stable coronary disease. And initiation of PCSK9 inhibitors with high-intensity statins soon after PCI for ACS improved atheroma shrinkage in non–infarct-related arteries over 1 year in the recent, placebo-controlled PACMAN-AMI trial.
Dr. Mehta pointed out that LDL reductions on PCSK9 inhibition, compared with the sham control, weren’t necessarily as impressive as might be expected from the major trials of long-term therapy with the drugs.
“You need longer [therapy] in order to see a difference in LDL levels when you use a PCSK9 inhibitor acutely. This is shown also on measures of infarct size.” There was no difference between treatment groups in infarct size as measured by levels of the MB fraction of creatine kinase, he reported.
“What this is telling us is that the acute use of a PCSK9 inhibitor did not modify the size or the severity of the baseline STEMI event.”
And EPIC-STEMI was too small and never intended to assess clinical outcomes; it was more about feasibility and what degree of LDL cholesterol lowering might be expected.
The trial was needed, Dr. Mehta said, because the PCSK9 inhibitors haven’t been extensively adopted into clinical practice and are not getting to the patients who could most benefit. One of the reasons for that is quite clear to him. “We are missing the high-risk patients because we are not treating them acutely,” Dr. Mehta said in an interview.
The strategy “has not yet been evaluated, and there have been barriers,” he observed. “Cost has been a barrier. Access to the drug has been a barrier. But in terms of the science, in terms of reducing cardiovascular events, this is a strategy that has to be tested.”
The aggressive, early LDL cholesterol reduction strategy should be evaluated for its effect on long-term outcomes, “especially knowing that in the first 30 days to 6 months post STEMI there’s a tremendous uptick in ischemic events, including recurrent myocardial infarction,” Roxana Mehran, MD, said at a media briefing on EPIC-STEMI held before Dr. Mehta’s formal presentation.
The “fantastic reduction acutely” with a PCSK9 inhibitor on top of statins, “hopefully reducing inflammation” similarly to what’s been observed in past trials, “absolutely warrants” a STEMI clinical outcomes trial, said Dr. Mehran, Icahn School of Medicine at Mount Sinai, New York, who isn’t connected with EPIC-STEMI.
If better post-discharge medication adherence is one of the acute strategy’s goals, it will be important to consider the potential influence of prescribing a periodically injected drug, proposed Eric A. Cohen, MD, Sunnybrook Health Sciences Center, Toronto, at the press conference.
“Keep in mind that STEMI patients typically come to the hospital on zero medications and leave 2 days later on five medications,” Dr. Cohen observed. “I’m curious whether having one of those as a sub-Q injection every 2 weeks, and reducing the pill burden, will help or deter adherence to therapy. I think it’s worth studying.”
The trial originally included 97 patients undergoing PCI for STEMI who were randomly assigned to receive the PCSK9 inhibitor or a sham injection on top of high-intensity statins, without regard to LDL cholesterol levels. Randomization took place after diagnostic angiography but before PCI.
The analysis, however, subsequently excluded 29 patients who could not continue with the study, “mainly because of hospital research clinic closure due to the COVID-19 pandemic,” the published report states.
That left 68 patients who had received at least one dose of PCSK9 inhibitor, alirocumab 150 mg subcutaneously, or the sham injection, and had at least one blood draw for LDL cholesterol response which, Dr. Mehta said, still left adequate statistical power for the LDL cholesterol–based primary endpoint.
By 6 weeks, LDL cholesterol levels had fallen 72.9% in the active-therapy group and by 48.1% in the control group (P < .001). Also, 92.1% and 56.7% of patients, respectively (P = .002), had achieved levels below the 1.4 mmol/L (54 mg/dL) goal in the European guidelines, Dr. Mehta reported.
Levels fell more than 50% compared with baseline in 89.5% of alirocumab patients and 60% (P = .007) of controls, respectively.
There was no significant difference in rates of attaining LDL cholesterol levels below the 70 mg/dL (1.8 mmol/L) threshold specified in U.S. guidelines for very high-risk patients: 94.7% of alirocumab patients and 83.4% of controls (P = .26).
Nor did the groups differ significantly in natriuretic peptide levels, which reflect ventricular remodeling; or in 6-week change in the inflammatory biomarker high-sensitivity C-reactive protein.
An open-label, randomized trial scheduled to launch before the end of 2022 will explore similarly early initiation of a PCSK9 inhibitor, compared with standard lipid management, in an estimated 4,000 patients hospitalized with STEMI or non-STEMI.
The EVOLVE MI trial is looking at the monoclonal antibody evolocumab (Repatha) for its effect on the primary endpoint of myocardial infarction, ischemic stroke, arterial revascularization, or death from any cause over an expected 3-4 years.
EPIC-STEMI was supported in part by Sanofi. Dr. Mehta reported an unrestricted grant from Sanofi to Hamilton Health Sciences for the present study and consulting fees from Amgen, Sanofi, and Novartis. Dr. Cohen disclosed receiving grant support from and holding research contracts with Abbott Vascular; and receiving fees for consulting, honoraria, or serving on a speaker’s bureau for Abbott Vascular, Medtronic, and Baylis. Dr. Mehran disclosed receiving grants or research support from numerous pharmaceutical companies; receiving consultant fee or honoraria or serving on a speaker’s bureau for Novartis, Abbott Vascular, Janssen, Medtronic, Medscape/WebMD, and Cine-Med Research; and holding equity, stock, or stock options with Control Rad, Applied Therapeutics, and Elixir Medical.
A version of this article first appeared on Medscape.com.
It’s best to have patients on aggressive lipid-lowering therapy before discharge after an acute ST-segment elevation myocardial infarction (STEMI), so why not start it right away – even in the cath lab – using some of the most potent LDL cholesterol–lowering agents available?
That was a main idea behind the randomized, sham-controlled EPIC-STEMI trial, in which STEMI patients were started on a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor immediately before direct percutaneous coronary intervention (PCI) and on top of high-intensity statins.
Those in the trial getting the active agent showed a 22% drop in LDL cholesterol levels by 6 weeks, compared with the control group given a sham injection along with high-intensity statins. They were also more likely to meet LDL cholesterol goals specified in some guidelines, including reduction by at least 50%. And those outcomes were achieved regardless of baseline LDL cholesterol levels or prior statin use.
Adoption of the trial’s early, aggressive LDL cholesterolreduction strategy in practice “has the potential to substantially reduce morbidity and mortality” in such cases “by further reducing LDL beyond statins in a much greater number of high-risk patients than are currently being treated with these agents,” suggested principal investigator Shamir R. Mehta, MD, MSc, when presenting the findings at the Transcatheter Cardiovascular Therapeutics annual meeting, sponsored by the Cardiovascular Research Foundation.
Adherence to secondary prevention measures in patients with acute coronary syndromes (ACS) is much better if they are started before hospital discharge, explained Dr. Mehta, senior scientist with Population Health Research Institute and professor of medicine at McMaster University, Hamilton, Ont. But “as soon as the patient has left the hospital, it is much more difficult to get these therapies on board.”
Routine adoption of such aggressive in-hospital, lipid-lowering therapy for the vast population with ACS would likely mean far fewer deaths and cardiovascular events “across a broader patient population.”
EPIC-STEMI is among the first studies to explore the strategy. “I think that’s the point of the trial that we wanted to make, that we don’t yet have data on this. We’re treading very carefully with PCSK9 inhibitors, and it’s just inching forward in populations. And I think we need a bold trial to see whether or not this changes things.”
The PCSK9 inhibitor alirocumab (Praluent) was used in EPIC-STEMI, which was published in EuroIntervention, with Dr. Mehta as lead author, the same day as his presentation. The drug and its sham injection were given on top of either atorvastatin 40-80 mg or rosuvastatin 40 mg.
Early initiation of statins in patients with acute STEMI has become standard, but there’s good evidence from intracoronary imaging studies suggesting that the addition of PCSK9 inhibitors might promote further stabilization of plaques that could potentially cause recurrent ischemic events.
Treatment with the injectable drugs plus statins led to significant coronary lesion regression in the GLAGOV trial of patients with stable coronary disease. And initiation of PCSK9 inhibitors with high-intensity statins soon after PCI for ACS improved atheroma shrinkage in non–infarct-related arteries over 1 year in the recent, placebo-controlled PACMAN-AMI trial.
Dr. Mehta pointed out that LDL reductions on PCSK9 inhibition, compared with the sham control, weren’t necessarily as impressive as might be expected from the major trials of long-term therapy with the drugs.
“You need longer [therapy] in order to see a difference in LDL levels when you use a PCSK9 inhibitor acutely. This is shown also on measures of infarct size.” There was no difference between treatment groups in infarct size as measured by levels of the MB fraction of creatine kinase, he reported.
“What this is telling us is that the acute use of a PCSK9 inhibitor did not modify the size or the severity of the baseline STEMI event.”
And EPIC-STEMI was too small and never intended to assess clinical outcomes; it was more about feasibility and what degree of LDL cholesterol lowering might be expected.
The trial was needed, Dr. Mehta said, because the PCSK9 inhibitors haven’t been extensively adopted into clinical practice and are not getting to the patients who could most benefit. One of the reasons for that is quite clear to him. “We are missing the high-risk patients because we are not treating them acutely,” Dr. Mehta said in an interview.
The strategy “has not yet been evaluated, and there have been barriers,” he observed. “Cost has been a barrier. Access to the drug has been a barrier. But in terms of the science, in terms of reducing cardiovascular events, this is a strategy that has to be tested.”
The aggressive, early LDL cholesterol reduction strategy should be evaluated for its effect on long-term outcomes, “especially knowing that in the first 30 days to 6 months post STEMI there’s a tremendous uptick in ischemic events, including recurrent myocardial infarction,” Roxana Mehran, MD, said at a media briefing on EPIC-STEMI held before Dr. Mehta’s formal presentation.
The “fantastic reduction acutely” with a PCSK9 inhibitor on top of statins, “hopefully reducing inflammation” similarly to what’s been observed in past trials, “absolutely warrants” a STEMI clinical outcomes trial, said Dr. Mehran, Icahn School of Medicine at Mount Sinai, New York, who isn’t connected with EPIC-STEMI.
If better post-discharge medication adherence is one of the acute strategy’s goals, it will be important to consider the potential influence of prescribing a periodically injected drug, proposed Eric A. Cohen, MD, Sunnybrook Health Sciences Center, Toronto, at the press conference.
“Keep in mind that STEMI patients typically come to the hospital on zero medications and leave 2 days later on five medications,” Dr. Cohen observed. “I’m curious whether having one of those as a sub-Q injection every 2 weeks, and reducing the pill burden, will help or deter adherence to therapy. I think it’s worth studying.”
The trial originally included 97 patients undergoing PCI for STEMI who were randomly assigned to receive the PCSK9 inhibitor or a sham injection on top of high-intensity statins, without regard to LDL cholesterol levels. Randomization took place after diagnostic angiography but before PCI.
The analysis, however, subsequently excluded 29 patients who could not continue with the study, “mainly because of hospital research clinic closure due to the COVID-19 pandemic,” the published report states.
That left 68 patients who had received at least one dose of PCSK9 inhibitor, alirocumab 150 mg subcutaneously, or the sham injection, and had at least one blood draw for LDL cholesterol response which, Dr. Mehta said, still left adequate statistical power for the LDL cholesterol–based primary endpoint.
By 6 weeks, LDL cholesterol levels had fallen 72.9% in the active-therapy group and by 48.1% in the control group (P < .001). Also, 92.1% and 56.7% of patients, respectively (P = .002), had achieved levels below the 1.4 mmol/L (54 mg/dL) goal in the European guidelines, Dr. Mehta reported.
Levels fell more than 50% compared with baseline in 89.5% of alirocumab patients and 60% (P = .007) of controls, respectively.
There was no significant difference in rates of attaining LDL cholesterol levels below the 70 mg/dL (1.8 mmol/L) threshold specified in U.S. guidelines for very high-risk patients: 94.7% of alirocumab patients and 83.4% of controls (P = .26).
Nor did the groups differ significantly in natriuretic peptide levels, which reflect ventricular remodeling; or in 6-week change in the inflammatory biomarker high-sensitivity C-reactive protein.
An open-label, randomized trial scheduled to launch before the end of 2022 will explore similarly early initiation of a PCSK9 inhibitor, compared with standard lipid management, in an estimated 4,000 patients hospitalized with STEMI or non-STEMI.
The EVOLVE MI trial is looking at the monoclonal antibody evolocumab (Repatha) for its effect on the primary endpoint of myocardial infarction, ischemic stroke, arterial revascularization, or death from any cause over an expected 3-4 years.
EPIC-STEMI was supported in part by Sanofi. Dr. Mehta reported an unrestricted grant from Sanofi to Hamilton Health Sciences for the present study and consulting fees from Amgen, Sanofi, and Novartis. Dr. Cohen disclosed receiving grant support from and holding research contracts with Abbott Vascular; and receiving fees for consulting, honoraria, or serving on a speaker’s bureau for Abbott Vascular, Medtronic, and Baylis. Dr. Mehran disclosed receiving grants or research support from numerous pharmaceutical companies; receiving consultant fee or honoraria or serving on a speaker’s bureau for Novartis, Abbott Vascular, Janssen, Medtronic, Medscape/WebMD, and Cine-Med Research; and holding equity, stock, or stock options with Control Rad, Applied Therapeutics, and Elixir Medical.
A version of this article first appeared on Medscape.com.
FROM TCT 2022
Limiting antibiotic overprescription in pandemics: New guidelines
A statement by the Society for Healthcare Epidemiology of America, published online in Infection Control & Hospital Epidemiology, offers health care providers guidelines on how to prevent inappropriate antibiotic use in future pandemics and to avoid some of the negative scenarios that have been seen with COVID-19.
According to the U.S. Centers of Disease Control and Prevention,
The culprit might be the widespread antibiotic overprescription during the current pandemic. A 2022 meta-analysis revealed that in high-income countries, 58% of patients with COVID-19 were given antibiotics, whereas in lower- and middle-income countries, 89% of patients were put on such drugs. Some hospitals in Europe and the United States reported similarly elevated numbers, sometimes approaching 100%.
“We’ve lost control,” Natasha Pettit, PharmD, pharmacy director at University of Chicago Medicine, told this news organization. Dr. Pettit was not involved in the SHEA study. “Even if CDC didn’t come out with that data, I can tell you right now more of my time is spent trying to figure out how to manage these multi-drug–resistant infections, and we are running out of options for these patients,”
“Dealing with uncertainty, exhaustion, [and] critical illness in often young, otherwise healthy patients meant doctors wanted to do something for their patients,” said Tamar Barlam, MD, an infectious diseases expert at the Boston Medical Center who led the development of the SHEA white paper, in an interview.
That something often was a prescription for antibiotics, even without a clear indication that they were actually needed. A British study revealed that in times of pandemic uncertainty, clinicians often reached for antibiotics “just in case” and referred to conservative prescribing as “bravery.”
Studies have shown, however, that bacterial co-infections in COVID-19 are rare. A 2020 meta-analysis of 24 studies concluded that only 3.5% of patients had a bacterial co-infection on presentation, and 14.3% had a secondary infection. Similar patterns had previously been observed in other viral outbreaks. Research on MERS-CoV, for example, documented only 1% of patients with a bacterial co-infection on admission. During the 2009 H1N1 influenza pandemic, that number was 12% of non–ICU hospitalized patients.
Yet, according to Dr. Pettit, even when such data became available, it didn’t necessarily change prescribing patterns. “Information was coming at us so quickly, I think the providers didn’t have a moment to see the data, to understand what it meant for their prescribing. Having external guidance earlier on would have been hugely helpful,” she told this news organization.
That’s where the newly published SHEA statement comes in: It outlines recommendations on when to prescribe antibiotics during a respiratory viral pandemic, what tests to order, and when to de-escalate or discontinue the treatment. These recommendations include, for instance, advice to not trust inflammatory markers as reliable indicators of bacterial or fungal infection and to not use procalcitonin routinely to aid in the decision to initiate antibiotics.
According to Dr. Barlam, one of the crucial lessons here is that if clinicians see patients with symptoms that are consistent with the current pandemic, they should trust their own impressions and avoid reaching for antimicrobials “just in case.”
Another important lesson is that antibiotic stewardship programs have a huge role to play during pandemics. They should not only monitor prescribing but also compile new information on bacterial co-infections as it gets released and make sure it reaches the clinicians in a clear form.
Evidence suggests that such programs and guidelines do work to limit unnecessary antibiotic use. In one medical center in Chicago, for example, before recommendations on when to initiate and discontinue antimicrobials were released, over 74% of COVID-19 patients received antibiotics. After guidelines were put in place, the use of such drugs fell to 42%.
Dr. Pettit believes, however, that it’s important not to leave each medical center to its own devices. “Hindsight is always twenty-twenty,” she said, “but I think it would be great that, if we start hearing about a pathogen that might lead to another pandemic, we should have a mechanism in place to call together an expert body to get guidance for how antimicrobial stewardship programs should get involved.”
One of the authors of the SHEA statement, Susan Seo, reports an investigator-initiated Merck grant on cost-effectiveness of letermovir in hematopoietic stem cell transplant patients. Another author, Graeme Forrest, reports a clinical study grant from Regeneron for inpatient monoclonals against SARS-CoV-2. All other authors report no conflicts of interest. The study was independently supported.
A version of this article first appeared on Medscape.com.
A statement by the Society for Healthcare Epidemiology of America, published online in Infection Control & Hospital Epidemiology, offers health care providers guidelines on how to prevent inappropriate antibiotic use in future pandemics and to avoid some of the negative scenarios that have been seen with COVID-19.
According to the U.S. Centers of Disease Control and Prevention,
The culprit might be the widespread antibiotic overprescription during the current pandemic. A 2022 meta-analysis revealed that in high-income countries, 58% of patients with COVID-19 were given antibiotics, whereas in lower- and middle-income countries, 89% of patients were put on such drugs. Some hospitals in Europe and the United States reported similarly elevated numbers, sometimes approaching 100%.
“We’ve lost control,” Natasha Pettit, PharmD, pharmacy director at University of Chicago Medicine, told this news organization. Dr. Pettit was not involved in the SHEA study. “Even if CDC didn’t come out with that data, I can tell you right now more of my time is spent trying to figure out how to manage these multi-drug–resistant infections, and we are running out of options for these patients,”
“Dealing with uncertainty, exhaustion, [and] critical illness in often young, otherwise healthy patients meant doctors wanted to do something for their patients,” said Tamar Barlam, MD, an infectious diseases expert at the Boston Medical Center who led the development of the SHEA white paper, in an interview.
That something often was a prescription for antibiotics, even without a clear indication that they were actually needed. A British study revealed that in times of pandemic uncertainty, clinicians often reached for antibiotics “just in case” and referred to conservative prescribing as “bravery.”
Studies have shown, however, that bacterial co-infections in COVID-19 are rare. A 2020 meta-analysis of 24 studies concluded that only 3.5% of patients had a bacterial co-infection on presentation, and 14.3% had a secondary infection. Similar patterns had previously been observed in other viral outbreaks. Research on MERS-CoV, for example, documented only 1% of patients with a bacterial co-infection on admission. During the 2009 H1N1 influenza pandemic, that number was 12% of non–ICU hospitalized patients.
Yet, according to Dr. Pettit, even when such data became available, it didn’t necessarily change prescribing patterns. “Information was coming at us so quickly, I think the providers didn’t have a moment to see the data, to understand what it meant for their prescribing. Having external guidance earlier on would have been hugely helpful,” she told this news organization.
That’s where the newly published SHEA statement comes in: It outlines recommendations on when to prescribe antibiotics during a respiratory viral pandemic, what tests to order, and when to de-escalate or discontinue the treatment. These recommendations include, for instance, advice to not trust inflammatory markers as reliable indicators of bacterial or fungal infection and to not use procalcitonin routinely to aid in the decision to initiate antibiotics.
According to Dr. Barlam, one of the crucial lessons here is that if clinicians see patients with symptoms that are consistent with the current pandemic, they should trust their own impressions and avoid reaching for antimicrobials “just in case.”
Another important lesson is that antibiotic stewardship programs have a huge role to play during pandemics. They should not only monitor prescribing but also compile new information on bacterial co-infections as it gets released and make sure it reaches the clinicians in a clear form.
Evidence suggests that such programs and guidelines do work to limit unnecessary antibiotic use. In one medical center in Chicago, for example, before recommendations on when to initiate and discontinue antimicrobials were released, over 74% of COVID-19 patients received antibiotics. After guidelines were put in place, the use of such drugs fell to 42%.
Dr. Pettit believes, however, that it’s important not to leave each medical center to its own devices. “Hindsight is always twenty-twenty,” she said, “but I think it would be great that, if we start hearing about a pathogen that might lead to another pandemic, we should have a mechanism in place to call together an expert body to get guidance for how antimicrobial stewardship programs should get involved.”
One of the authors of the SHEA statement, Susan Seo, reports an investigator-initiated Merck grant on cost-effectiveness of letermovir in hematopoietic stem cell transplant patients. Another author, Graeme Forrest, reports a clinical study grant from Regeneron for inpatient monoclonals against SARS-CoV-2. All other authors report no conflicts of interest. The study was independently supported.
A version of this article first appeared on Medscape.com.
A statement by the Society for Healthcare Epidemiology of America, published online in Infection Control & Hospital Epidemiology, offers health care providers guidelines on how to prevent inappropriate antibiotic use in future pandemics and to avoid some of the negative scenarios that have been seen with COVID-19.
According to the U.S. Centers of Disease Control and Prevention,
The culprit might be the widespread antibiotic overprescription during the current pandemic. A 2022 meta-analysis revealed that in high-income countries, 58% of patients with COVID-19 were given antibiotics, whereas in lower- and middle-income countries, 89% of patients were put on such drugs. Some hospitals in Europe and the United States reported similarly elevated numbers, sometimes approaching 100%.
“We’ve lost control,” Natasha Pettit, PharmD, pharmacy director at University of Chicago Medicine, told this news organization. Dr. Pettit was not involved in the SHEA study. “Even if CDC didn’t come out with that data, I can tell you right now more of my time is spent trying to figure out how to manage these multi-drug–resistant infections, and we are running out of options for these patients,”
“Dealing with uncertainty, exhaustion, [and] critical illness in often young, otherwise healthy patients meant doctors wanted to do something for their patients,” said Tamar Barlam, MD, an infectious diseases expert at the Boston Medical Center who led the development of the SHEA white paper, in an interview.
That something often was a prescription for antibiotics, even without a clear indication that they were actually needed. A British study revealed that in times of pandemic uncertainty, clinicians often reached for antibiotics “just in case” and referred to conservative prescribing as “bravery.”
Studies have shown, however, that bacterial co-infections in COVID-19 are rare. A 2020 meta-analysis of 24 studies concluded that only 3.5% of patients had a bacterial co-infection on presentation, and 14.3% had a secondary infection. Similar patterns had previously been observed in other viral outbreaks. Research on MERS-CoV, for example, documented only 1% of patients with a bacterial co-infection on admission. During the 2009 H1N1 influenza pandemic, that number was 12% of non–ICU hospitalized patients.
Yet, according to Dr. Pettit, even when such data became available, it didn’t necessarily change prescribing patterns. “Information was coming at us so quickly, I think the providers didn’t have a moment to see the data, to understand what it meant for their prescribing. Having external guidance earlier on would have been hugely helpful,” she told this news organization.
That’s where the newly published SHEA statement comes in: It outlines recommendations on when to prescribe antibiotics during a respiratory viral pandemic, what tests to order, and when to de-escalate or discontinue the treatment. These recommendations include, for instance, advice to not trust inflammatory markers as reliable indicators of bacterial or fungal infection and to not use procalcitonin routinely to aid in the decision to initiate antibiotics.
According to Dr. Barlam, one of the crucial lessons here is that if clinicians see patients with symptoms that are consistent with the current pandemic, they should trust their own impressions and avoid reaching for antimicrobials “just in case.”
Another important lesson is that antibiotic stewardship programs have a huge role to play during pandemics. They should not only monitor prescribing but also compile new information on bacterial co-infections as it gets released and make sure it reaches the clinicians in a clear form.
Evidence suggests that such programs and guidelines do work to limit unnecessary antibiotic use. In one medical center in Chicago, for example, before recommendations on when to initiate and discontinue antimicrobials were released, over 74% of COVID-19 patients received antibiotics. After guidelines were put in place, the use of such drugs fell to 42%.
Dr. Pettit believes, however, that it’s important not to leave each medical center to its own devices. “Hindsight is always twenty-twenty,” she said, “but I think it would be great that, if we start hearing about a pathogen that might lead to another pandemic, we should have a mechanism in place to call together an expert body to get guidance for how antimicrobial stewardship programs should get involved.”
One of the authors of the SHEA statement, Susan Seo, reports an investigator-initiated Merck grant on cost-effectiveness of letermovir in hematopoietic stem cell transplant patients. Another author, Graeme Forrest, reports a clinical study grant from Regeneron for inpatient monoclonals against SARS-CoV-2. All other authors report no conflicts of interest. The study was independently supported.
A version of this article first appeared on Medscape.com.
FROM INFECTION CONTROL & HOSPITAL EPIDEMIOLOGY
FDA okays terlipressin (Terlivaz) injection for hepatorenal syndrome
The Food and Drug Administration has approved terlipressin (Terlivaz), the first and only drug approved for patients with hepatorenal syndrome (HRS).
HRS is characterized by progressive deterioration in kidney function in people with advanced liver disease.
Terlipressin is an injectable synthetic vasopressin analogue indicated for patients with HRS who are experiencing rapid deterioration of kidney function (type 1 HRS). The condition affects an estimated 35,000 Americans annually.
The safety and efficacy of terlipressin for type 1 HRS was assessed in the phase 3 CONFIRM trial, which involved 300 patients in the United States and Canada.
Patients received an injection of terlipressin (0.85 mg) or placebo every 6 hours for a maximum of 14 days. The dose was adjusted on the basis of changes in kidney function.
Twenty-nine percent of patients in the terlipressin group experienced improvement in kidney function, vs. 16% in the placebo group.
The CONFIRM trial met its primary endpoint of verified HRS reversal, defined as renal function improvement, avoidance of dialysis, and short-term survival (P = .012).
To achieve this endpoint, patients had to have two consecutive serum creatinine (SCr) values of ≤ 1.5 mg/dL at least 2 hours apart by day 14 or be discharged from the hospital.
The most commonly observed adverse reactions that occurred in at least 4% of patients treated with terlipressin were abdominal pain (19.5%), nausea (16%), respiratory failure (15.5%), diarrhea (13%), and dyspnea (12.5%).
Results of the CONFIRM trial were published in The New England Journal of Medicine.
“Diagnosing and treating HRS can be challenging, and every minute counts when managing patients who have it,” said Steven Romano, MD, executive vice president and chief scientific officer at Mallinckrodt, which makes the drug.
“Terlivaz gives physicians the first FDA-approved option for treating HRS patients with rapid reduction in kidney function that may help them improve kidney function and lessen the associated need for renal replacement therapy, such as dialysis,” Dr. Romano said.
The company plans to launch the product in the coming weeks.
The application for terlipressin for HRS was granted priority review and fast-track status, as well as orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved terlipressin (Terlivaz), the first and only drug approved for patients with hepatorenal syndrome (HRS).
HRS is characterized by progressive deterioration in kidney function in people with advanced liver disease.
Terlipressin is an injectable synthetic vasopressin analogue indicated for patients with HRS who are experiencing rapid deterioration of kidney function (type 1 HRS). The condition affects an estimated 35,000 Americans annually.
The safety and efficacy of terlipressin for type 1 HRS was assessed in the phase 3 CONFIRM trial, which involved 300 patients in the United States and Canada.
Patients received an injection of terlipressin (0.85 mg) or placebo every 6 hours for a maximum of 14 days. The dose was adjusted on the basis of changes in kidney function.
Twenty-nine percent of patients in the terlipressin group experienced improvement in kidney function, vs. 16% in the placebo group.
The CONFIRM trial met its primary endpoint of verified HRS reversal, defined as renal function improvement, avoidance of dialysis, and short-term survival (P = .012).
To achieve this endpoint, patients had to have two consecutive serum creatinine (SCr) values of ≤ 1.5 mg/dL at least 2 hours apart by day 14 or be discharged from the hospital.
The most commonly observed adverse reactions that occurred in at least 4% of patients treated with terlipressin were abdominal pain (19.5%), nausea (16%), respiratory failure (15.5%), diarrhea (13%), and dyspnea (12.5%).
Results of the CONFIRM trial were published in The New England Journal of Medicine.
“Diagnosing and treating HRS can be challenging, and every minute counts when managing patients who have it,” said Steven Romano, MD, executive vice president and chief scientific officer at Mallinckrodt, which makes the drug.
“Terlivaz gives physicians the first FDA-approved option for treating HRS patients with rapid reduction in kidney function that may help them improve kidney function and lessen the associated need for renal replacement therapy, such as dialysis,” Dr. Romano said.
The company plans to launch the product in the coming weeks.
The application for terlipressin for HRS was granted priority review and fast-track status, as well as orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved terlipressin (Terlivaz), the first and only drug approved for patients with hepatorenal syndrome (HRS).
HRS is characterized by progressive deterioration in kidney function in people with advanced liver disease.
Terlipressin is an injectable synthetic vasopressin analogue indicated for patients with HRS who are experiencing rapid deterioration of kidney function (type 1 HRS). The condition affects an estimated 35,000 Americans annually.
The safety and efficacy of terlipressin for type 1 HRS was assessed in the phase 3 CONFIRM trial, which involved 300 patients in the United States and Canada.
Patients received an injection of terlipressin (0.85 mg) or placebo every 6 hours for a maximum of 14 days. The dose was adjusted on the basis of changes in kidney function.
Twenty-nine percent of patients in the terlipressin group experienced improvement in kidney function, vs. 16% in the placebo group.
The CONFIRM trial met its primary endpoint of verified HRS reversal, defined as renal function improvement, avoidance of dialysis, and short-term survival (P = .012).
To achieve this endpoint, patients had to have two consecutive serum creatinine (SCr) values of ≤ 1.5 mg/dL at least 2 hours apart by day 14 or be discharged from the hospital.
The most commonly observed adverse reactions that occurred in at least 4% of patients treated with terlipressin were abdominal pain (19.5%), nausea (16%), respiratory failure (15.5%), diarrhea (13%), and dyspnea (12.5%).
Results of the CONFIRM trial were published in The New England Journal of Medicine.
“Diagnosing and treating HRS can be challenging, and every minute counts when managing patients who have it,” said Steven Romano, MD, executive vice president and chief scientific officer at Mallinckrodt, which makes the drug.
“Terlivaz gives physicians the first FDA-approved option for treating HRS patients with rapid reduction in kidney function that may help them improve kidney function and lessen the associated need for renal replacement therapy, such as dialysis,” Dr. Romano said.
The company plans to launch the product in the coming weeks.
The application for terlipressin for HRS was granted priority review and fast-track status, as well as orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
A version of this article first appeared on Medscape.com.
Ketamine linked to reduced suicidal thoughts, depression, anxiety
, new research suggests.
Results from a retrospective chart review analysis, which included more than 400 participants with TRD, illustrate that ketamine is a safe and rapid treatment in a real-world patient population, lead author Patrick A. Oliver, MD, founder and medical director, MindPeace Clinics, Richmond, Va., told this news organization.
The effect was perhaps most notable for reducing suicidal ideation, he said.
“In 2 weeks, we can take somebody from being suicidal to nonsuicidal. It’s a total game changer,” Dr. Oliver added.
Every year in the United States, about 12 million individuals think about suicide, 3.2 million make a plan to kill themselves, and more than 46,000 succeed, the investigators note.
The findings were published online in the Journal of Clinical Psychiatry.
Molecule mixture
Primarily used as an anesthetic in hospitals, ketamine is also taken illegally as a recreational drug. Users may aim for an intense high or feeling of dissociation, or an out-of-body–type experience.
Ketamine is a mixture of two mirror-image molecules. An intranasal version of one of these molecules (esketamine) is approved by the U.S. Food and Drug Administration for TRD. Both esketamine and ketamine are believed to increase neurotrophic signaling that affects synaptic function.
The study included 424 patients (mean age, 41.7 years) with major depressive disorder or another mood disorder and who received at least one ketamine infusion at a specialty clinic. Most participants had failed prior medication trials.
Patients in the study were typically started on 0.5 mg/kg of ketamine, with the dose titrated to achieve symptoms of partial dissociation. The median dose administered after titration was 0.93 mg/kg over 40 minutes.
The main treatment course of at least six infusions within 21 days was completed by 70% of the patients.
At each clinic visit, all participants completed the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7).
The primary outcome was PHQ-9 total scores, for which researchers looked at seven time periods: 1 week, 2-3 weeks, 4-6 weeks, 7-12 weeks, 13-24 weeks, 25-51 weeks, and 52+ weeks.
‘Blows it out of the water’
Results showed PHQ-9 total scores declined by 50% throughout the course of treatment, with much of the improvement gained within 4-6 weeks. There was a significant difference between week 1 and all later time periods (all P values < .001) and between weeks 2 and 3 and all later periods (all P values < .001).
Other measures included treatment response, defined as at least a 50% improvement on the PHQ-9, and depression remission, defined as a PHQ-9 score of less than 5. After three infusions, 14% of the patients responded and 7% were in remission. After 10 infusions, 72% responded and 38% were in remission.
These results compare favorably to other depression treatments, said Dr. Oliver. “Truthfully, with the exception of ECT [electroconvulsive therapy], this blows it all out of the water,” he added.
Dr. Oliver noted that the success rate for repetitive transcranial magnetic stimulation is 40%-60% depending on the modality; and for selective serotonin reuptake inhibitors, the success rate “is somewhere between the mid-20s and low-30s percent range.”
Another outcome measure was the self-harm/suicidal ideation item of the PHQ-9 questionnaire, which asks about “thoughts that you would be better off dead, or of hurting yourself in some way.” About 22% of the study participants no longer reported suicidal ideation after 3 infusions, 50% by 6 infusions, and 75% by 10 infusions.
By 15 infusions, 85% no longer reported these thoughts. “Nothing else has shown that, ever,” said Dr. Oliver.
Symptoms of generalized anxiety were also substantially improved. There was about a 30% reduction in the GAD-7 score during treatment and, again, most of the response occurred by 4-6 weeks.
Study limitations
Sex, age, and other demographic characteristics did not predict response or remission, but suicide planning trended toward higher response rates (P = .083). This suggests that a more depressed subgroup can achieve greater benefit from the treatment than can less symptomatic patients, the investigators note.
A history of psychosis also trended toward better response to treatment (P = .086) but not remission.
The researchers note that study limitations include that it was retrospective, lacked a control group, and did not require patients to be hospitalized – so the study sample may have been less severely ill than in other studies.
In addition, most patients paid out of pocket for the treatment at $495 per infusion, and they self-reported their symptoms.
As well, the researchers did not assess adverse events, although nurses made follow-up calls to patients. Dr. Oliver noted the most common side effects of ketamine are nausea, vomiting, and anxiety.
Previous research has suggested that ketamine therapy is not linked to long-term side effects, such as sexual dysfunction, weight gain, lethargy, or cognitive issues, said Dr. Oliver.
The investigators point out another study limitation was lack of detailed demographic information, such as race, income, and education, which might affect its generalizability.
Concerns and questions
Pouya Movahed Rad, MD, PhD, senior consultant and researcher in psychiatry, Lund (Sweden) University, noted several concerns, including that the clinics treating the study participants with ketamine profited from it.
He also speculated about who can afford the treatment because only a few patients in the study were reimbursed through insurance.
Dr. Movahed Rad was not involved with the current research but was principal investigator for a recent study that compared intravenous ketamine to ECT.
He questioned whether the patient population in the new study really was “real world.” Well-designed randomized controlled trials have been carried out in a “naturalistic setting, [which] get closer to real-life patients,” he said.
He also noted that the median dose after clinician titration (0.93 mg/kg over 40 minutes) “may be considered very high.”
With regard to doses being titrated to achieve symptoms of partial dissociation, “there is no obvious evidence to my knowledge that patients need to develop dissociative symptoms in order to have antidepressant effect,” said Dr. Movahed Rad.
Finally, he noted that the finding that 28% of the participants were using illegal drugs “is worrying” and wondered what drugs they were taking; he also questioned why 81% of the study population needed to take antidepressants.
The study did not receive outside funding. Dr. Oliver is the founder of MindPeace Clinics, which specialize in ketamine therapeutics. Dr. Movahed Rad has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests.
Results from a retrospective chart review analysis, which included more than 400 participants with TRD, illustrate that ketamine is a safe and rapid treatment in a real-world patient population, lead author Patrick A. Oliver, MD, founder and medical director, MindPeace Clinics, Richmond, Va., told this news organization.
The effect was perhaps most notable for reducing suicidal ideation, he said.
“In 2 weeks, we can take somebody from being suicidal to nonsuicidal. It’s a total game changer,” Dr. Oliver added.
Every year in the United States, about 12 million individuals think about suicide, 3.2 million make a plan to kill themselves, and more than 46,000 succeed, the investigators note.
The findings were published online in the Journal of Clinical Psychiatry.
Molecule mixture
Primarily used as an anesthetic in hospitals, ketamine is also taken illegally as a recreational drug. Users may aim for an intense high or feeling of dissociation, or an out-of-body–type experience.
Ketamine is a mixture of two mirror-image molecules. An intranasal version of one of these molecules (esketamine) is approved by the U.S. Food and Drug Administration for TRD. Both esketamine and ketamine are believed to increase neurotrophic signaling that affects synaptic function.
The study included 424 patients (mean age, 41.7 years) with major depressive disorder or another mood disorder and who received at least one ketamine infusion at a specialty clinic. Most participants had failed prior medication trials.
Patients in the study were typically started on 0.5 mg/kg of ketamine, with the dose titrated to achieve symptoms of partial dissociation. The median dose administered after titration was 0.93 mg/kg over 40 minutes.
The main treatment course of at least six infusions within 21 days was completed by 70% of the patients.
At each clinic visit, all participants completed the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7).
The primary outcome was PHQ-9 total scores, for which researchers looked at seven time periods: 1 week, 2-3 weeks, 4-6 weeks, 7-12 weeks, 13-24 weeks, 25-51 weeks, and 52+ weeks.
‘Blows it out of the water’
Results showed PHQ-9 total scores declined by 50% throughout the course of treatment, with much of the improvement gained within 4-6 weeks. There was a significant difference between week 1 and all later time periods (all P values < .001) and between weeks 2 and 3 and all later periods (all P values < .001).
Other measures included treatment response, defined as at least a 50% improvement on the PHQ-9, and depression remission, defined as a PHQ-9 score of less than 5. After three infusions, 14% of the patients responded and 7% were in remission. After 10 infusions, 72% responded and 38% were in remission.
These results compare favorably to other depression treatments, said Dr. Oliver. “Truthfully, with the exception of ECT [electroconvulsive therapy], this blows it all out of the water,” he added.
Dr. Oliver noted that the success rate for repetitive transcranial magnetic stimulation is 40%-60% depending on the modality; and for selective serotonin reuptake inhibitors, the success rate “is somewhere between the mid-20s and low-30s percent range.”
Another outcome measure was the self-harm/suicidal ideation item of the PHQ-9 questionnaire, which asks about “thoughts that you would be better off dead, or of hurting yourself in some way.” About 22% of the study participants no longer reported suicidal ideation after 3 infusions, 50% by 6 infusions, and 75% by 10 infusions.
By 15 infusions, 85% no longer reported these thoughts. “Nothing else has shown that, ever,” said Dr. Oliver.
Symptoms of generalized anxiety were also substantially improved. There was about a 30% reduction in the GAD-7 score during treatment and, again, most of the response occurred by 4-6 weeks.
Study limitations
Sex, age, and other demographic characteristics did not predict response or remission, but suicide planning trended toward higher response rates (P = .083). This suggests that a more depressed subgroup can achieve greater benefit from the treatment than can less symptomatic patients, the investigators note.
A history of psychosis also trended toward better response to treatment (P = .086) but not remission.
The researchers note that study limitations include that it was retrospective, lacked a control group, and did not require patients to be hospitalized – so the study sample may have been less severely ill than in other studies.
In addition, most patients paid out of pocket for the treatment at $495 per infusion, and they self-reported their symptoms.
As well, the researchers did not assess adverse events, although nurses made follow-up calls to patients. Dr. Oliver noted the most common side effects of ketamine are nausea, vomiting, and anxiety.
Previous research has suggested that ketamine therapy is not linked to long-term side effects, such as sexual dysfunction, weight gain, lethargy, or cognitive issues, said Dr. Oliver.
The investigators point out another study limitation was lack of detailed demographic information, such as race, income, and education, which might affect its generalizability.
Concerns and questions
Pouya Movahed Rad, MD, PhD, senior consultant and researcher in psychiatry, Lund (Sweden) University, noted several concerns, including that the clinics treating the study participants with ketamine profited from it.
He also speculated about who can afford the treatment because only a few patients in the study were reimbursed through insurance.
Dr. Movahed Rad was not involved with the current research but was principal investigator for a recent study that compared intravenous ketamine to ECT.
He questioned whether the patient population in the new study really was “real world.” Well-designed randomized controlled trials have been carried out in a “naturalistic setting, [which] get closer to real-life patients,” he said.
He also noted that the median dose after clinician titration (0.93 mg/kg over 40 minutes) “may be considered very high.”
With regard to doses being titrated to achieve symptoms of partial dissociation, “there is no obvious evidence to my knowledge that patients need to develop dissociative symptoms in order to have antidepressant effect,” said Dr. Movahed Rad.
Finally, he noted that the finding that 28% of the participants were using illegal drugs “is worrying” and wondered what drugs they were taking; he also questioned why 81% of the study population needed to take antidepressants.
The study did not receive outside funding. Dr. Oliver is the founder of MindPeace Clinics, which specialize in ketamine therapeutics. Dr. Movahed Rad has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests.
Results from a retrospective chart review analysis, which included more than 400 participants with TRD, illustrate that ketamine is a safe and rapid treatment in a real-world patient population, lead author Patrick A. Oliver, MD, founder and medical director, MindPeace Clinics, Richmond, Va., told this news organization.
The effect was perhaps most notable for reducing suicidal ideation, he said.
“In 2 weeks, we can take somebody from being suicidal to nonsuicidal. It’s a total game changer,” Dr. Oliver added.
Every year in the United States, about 12 million individuals think about suicide, 3.2 million make a plan to kill themselves, and more than 46,000 succeed, the investigators note.
The findings were published online in the Journal of Clinical Psychiatry.
Molecule mixture
Primarily used as an anesthetic in hospitals, ketamine is also taken illegally as a recreational drug. Users may aim for an intense high or feeling of dissociation, or an out-of-body–type experience.
Ketamine is a mixture of two mirror-image molecules. An intranasal version of one of these molecules (esketamine) is approved by the U.S. Food and Drug Administration for TRD. Both esketamine and ketamine are believed to increase neurotrophic signaling that affects synaptic function.
The study included 424 patients (mean age, 41.7 years) with major depressive disorder or another mood disorder and who received at least one ketamine infusion at a specialty clinic. Most participants had failed prior medication trials.
Patients in the study were typically started on 0.5 mg/kg of ketamine, with the dose titrated to achieve symptoms of partial dissociation. The median dose administered after titration was 0.93 mg/kg over 40 minutes.
The main treatment course of at least six infusions within 21 days was completed by 70% of the patients.
At each clinic visit, all participants completed the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7).
The primary outcome was PHQ-9 total scores, for which researchers looked at seven time periods: 1 week, 2-3 weeks, 4-6 weeks, 7-12 weeks, 13-24 weeks, 25-51 weeks, and 52+ weeks.
‘Blows it out of the water’
Results showed PHQ-9 total scores declined by 50% throughout the course of treatment, with much of the improvement gained within 4-6 weeks. There was a significant difference between week 1 and all later time periods (all P values < .001) and between weeks 2 and 3 and all later periods (all P values < .001).
Other measures included treatment response, defined as at least a 50% improvement on the PHQ-9, and depression remission, defined as a PHQ-9 score of less than 5. After three infusions, 14% of the patients responded and 7% were in remission. After 10 infusions, 72% responded and 38% were in remission.
These results compare favorably to other depression treatments, said Dr. Oliver. “Truthfully, with the exception of ECT [electroconvulsive therapy], this blows it all out of the water,” he added.
Dr. Oliver noted that the success rate for repetitive transcranial magnetic stimulation is 40%-60% depending on the modality; and for selective serotonin reuptake inhibitors, the success rate “is somewhere between the mid-20s and low-30s percent range.”
Another outcome measure was the self-harm/suicidal ideation item of the PHQ-9 questionnaire, which asks about “thoughts that you would be better off dead, or of hurting yourself in some way.” About 22% of the study participants no longer reported suicidal ideation after 3 infusions, 50% by 6 infusions, and 75% by 10 infusions.
By 15 infusions, 85% no longer reported these thoughts. “Nothing else has shown that, ever,” said Dr. Oliver.
Symptoms of generalized anxiety were also substantially improved. There was about a 30% reduction in the GAD-7 score during treatment and, again, most of the response occurred by 4-6 weeks.
Study limitations
Sex, age, and other demographic characteristics did not predict response or remission, but suicide planning trended toward higher response rates (P = .083). This suggests that a more depressed subgroup can achieve greater benefit from the treatment than can less symptomatic patients, the investigators note.
A history of psychosis also trended toward better response to treatment (P = .086) but not remission.
The researchers note that study limitations include that it was retrospective, lacked a control group, and did not require patients to be hospitalized – so the study sample may have been less severely ill than in other studies.
In addition, most patients paid out of pocket for the treatment at $495 per infusion, and they self-reported their symptoms.
As well, the researchers did not assess adverse events, although nurses made follow-up calls to patients. Dr. Oliver noted the most common side effects of ketamine are nausea, vomiting, and anxiety.
Previous research has suggested that ketamine therapy is not linked to long-term side effects, such as sexual dysfunction, weight gain, lethargy, or cognitive issues, said Dr. Oliver.
The investigators point out another study limitation was lack of detailed demographic information, such as race, income, and education, which might affect its generalizability.
Concerns and questions
Pouya Movahed Rad, MD, PhD, senior consultant and researcher in psychiatry, Lund (Sweden) University, noted several concerns, including that the clinics treating the study participants with ketamine profited from it.
He also speculated about who can afford the treatment because only a few patients in the study were reimbursed through insurance.
Dr. Movahed Rad was not involved with the current research but was principal investigator for a recent study that compared intravenous ketamine to ECT.
He questioned whether the patient population in the new study really was “real world.” Well-designed randomized controlled trials have been carried out in a “naturalistic setting, [which] get closer to real-life patients,” he said.
He also noted that the median dose after clinician titration (0.93 mg/kg over 40 minutes) “may be considered very high.”
With regard to doses being titrated to achieve symptoms of partial dissociation, “there is no obvious evidence to my knowledge that patients need to develop dissociative symptoms in order to have antidepressant effect,” said Dr. Movahed Rad.
Finally, he noted that the finding that 28% of the participants were using illegal drugs “is worrying” and wondered what drugs they were taking; he also questioned why 81% of the study population needed to take antidepressants.
The study did not receive outside funding. Dr. Oliver is the founder of MindPeace Clinics, which specialize in ketamine therapeutics. Dr. Movahed Rad has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JOURNAL OF CLINICAL PSYCHIATRY
Is acetaminophen really safer than NSAIDs in heart disease?
New research calls into question the assumption that acetaminophen is safer than NSAIDs for patients with known cardiovascular disease (CVD) or CVD risk factors.
The analysis found a significant correlation between the use of acetaminophen and elevated systolic blood pressure.
While acetaminophen may still be safer than NSAIDs from a bleeding risk standpoint, or in patients with known kidney disease, “the gap may not be as large as once thought,” Rahul Gupta, MD, cardiologist with Lehigh Valley Health Network, Allentown, Pa., said in an interview.
“Cautious use is recommended over the long term, especially in patients with pre-existing hypertension or cardiovascular risk factors,” Dr. Gupta said.
The study was presented at the Hypertension Scientific Sessions, San Diego, sponsored by the American Heart Association.
Acetaminophen is one of the most widely used over-the-counter medications, as it is considered a safer medication for long-term use since it lacks the anti-inflammatory effects of NSAIDs, Dr. Gupta explained.
NSAIDs have been known to raise blood pressure, but the effect of acetaminophen in this regard has not been well studied. Observational studies have shown contradictory results in terms of its effect on blood pressure, he noted.
To investigate further, Dr. Gupta and colleagues did a meta-analysis of three studies that compared the effect of acetaminophen (3-4 g/day) versus placebo on systolic and diastolic ambulatory blood pressure in patients with heart disease or hypertension. Together, the studies included 172 adults (mean age, 60 years; 73% male).
They found that patients receiving acetaminophen had significantly higher systolic blood pressure, compared with those receiving placebo (standard mean difference [SMD] = 0.35; 95% confidence interval, 0.08-0.63; P = .01).
Subgroup analysis of the effect on hypertensive patients showed significant change in systolic blood pressure as well (SMD = 0.38; 95% CI, 0.05-0.71; P = .02).
“Interestingly, there was no significant difference in the effect on diastolic blood pressure,” Dr. Gupta commented.
Reached for comment, Timothy S. Anderson, MD, clinical investigator in the Division of General Medicine at Beth Israel Deaconess Medical Center and assistant professor of medicine at the Harvard Medical School, both in Boston, said this is “an interesting and not particularly well-known issue.”
“However, most of the trials look at very high doses of acetaminophen use (for example, six to eight of the 500 mg pills each day) so we don’t really know whether the more common patterns of using one to two acetaminophen pills every once in a while is problematic,” Dr. Anderson told this news organization.
“We also don’t have data showing a direct harm from these medications with regards to strokes or heart attacks or other downstream consequences of high blood pressure. Ideally we would need a head-to-head trial comparing ibuprofen-type medications to acetaminophen-type medications,” Dr. Anderson said.
The study had no specific funding. Dr. Gupta and Dr. Anderson reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
New research calls into question the assumption that acetaminophen is safer than NSAIDs for patients with known cardiovascular disease (CVD) or CVD risk factors.
The analysis found a significant correlation between the use of acetaminophen and elevated systolic blood pressure.
While acetaminophen may still be safer than NSAIDs from a bleeding risk standpoint, or in patients with known kidney disease, “the gap may not be as large as once thought,” Rahul Gupta, MD, cardiologist with Lehigh Valley Health Network, Allentown, Pa., said in an interview.
“Cautious use is recommended over the long term, especially in patients with pre-existing hypertension or cardiovascular risk factors,” Dr. Gupta said.
The study was presented at the Hypertension Scientific Sessions, San Diego, sponsored by the American Heart Association.
Acetaminophen is one of the most widely used over-the-counter medications, as it is considered a safer medication for long-term use since it lacks the anti-inflammatory effects of NSAIDs, Dr. Gupta explained.
NSAIDs have been known to raise blood pressure, but the effect of acetaminophen in this regard has not been well studied. Observational studies have shown contradictory results in terms of its effect on blood pressure, he noted.
To investigate further, Dr. Gupta and colleagues did a meta-analysis of three studies that compared the effect of acetaminophen (3-4 g/day) versus placebo on systolic and diastolic ambulatory blood pressure in patients with heart disease or hypertension. Together, the studies included 172 adults (mean age, 60 years; 73% male).
They found that patients receiving acetaminophen had significantly higher systolic blood pressure, compared with those receiving placebo (standard mean difference [SMD] = 0.35; 95% confidence interval, 0.08-0.63; P = .01).
Subgroup analysis of the effect on hypertensive patients showed significant change in systolic blood pressure as well (SMD = 0.38; 95% CI, 0.05-0.71; P = .02).
“Interestingly, there was no significant difference in the effect on diastolic blood pressure,” Dr. Gupta commented.
Reached for comment, Timothy S. Anderson, MD, clinical investigator in the Division of General Medicine at Beth Israel Deaconess Medical Center and assistant professor of medicine at the Harvard Medical School, both in Boston, said this is “an interesting and not particularly well-known issue.”
“However, most of the trials look at very high doses of acetaminophen use (for example, six to eight of the 500 mg pills each day) so we don’t really know whether the more common patterns of using one to two acetaminophen pills every once in a while is problematic,” Dr. Anderson told this news organization.
“We also don’t have data showing a direct harm from these medications with regards to strokes or heart attacks or other downstream consequences of high blood pressure. Ideally we would need a head-to-head trial comparing ibuprofen-type medications to acetaminophen-type medications,” Dr. Anderson said.
The study had no specific funding. Dr. Gupta and Dr. Anderson reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
New research calls into question the assumption that acetaminophen is safer than NSAIDs for patients with known cardiovascular disease (CVD) or CVD risk factors.
The analysis found a significant correlation between the use of acetaminophen and elevated systolic blood pressure.
While acetaminophen may still be safer than NSAIDs from a bleeding risk standpoint, or in patients with known kidney disease, “the gap may not be as large as once thought,” Rahul Gupta, MD, cardiologist with Lehigh Valley Health Network, Allentown, Pa., said in an interview.
“Cautious use is recommended over the long term, especially in patients with pre-existing hypertension or cardiovascular risk factors,” Dr. Gupta said.
The study was presented at the Hypertension Scientific Sessions, San Diego, sponsored by the American Heart Association.
Acetaminophen is one of the most widely used over-the-counter medications, as it is considered a safer medication for long-term use since it lacks the anti-inflammatory effects of NSAIDs, Dr. Gupta explained.
NSAIDs have been known to raise blood pressure, but the effect of acetaminophen in this regard has not been well studied. Observational studies have shown contradictory results in terms of its effect on blood pressure, he noted.
To investigate further, Dr. Gupta and colleagues did a meta-analysis of three studies that compared the effect of acetaminophen (3-4 g/day) versus placebo on systolic and diastolic ambulatory blood pressure in patients with heart disease or hypertension. Together, the studies included 172 adults (mean age, 60 years; 73% male).
They found that patients receiving acetaminophen had significantly higher systolic blood pressure, compared with those receiving placebo (standard mean difference [SMD] = 0.35; 95% confidence interval, 0.08-0.63; P = .01).
Subgroup analysis of the effect on hypertensive patients showed significant change in systolic blood pressure as well (SMD = 0.38; 95% CI, 0.05-0.71; P = .02).
“Interestingly, there was no significant difference in the effect on diastolic blood pressure,” Dr. Gupta commented.
Reached for comment, Timothy S. Anderson, MD, clinical investigator in the Division of General Medicine at Beth Israel Deaconess Medical Center and assistant professor of medicine at the Harvard Medical School, both in Boston, said this is “an interesting and not particularly well-known issue.”
“However, most of the trials look at very high doses of acetaminophen use (for example, six to eight of the 500 mg pills each day) so we don’t really know whether the more common patterns of using one to two acetaminophen pills every once in a while is problematic,” Dr. Anderson told this news organization.
“We also don’t have data showing a direct harm from these medications with regards to strokes or heart attacks or other downstream consequences of high blood pressure. Ideally we would need a head-to-head trial comparing ibuprofen-type medications to acetaminophen-type medications,” Dr. Anderson said.
The study had no specific funding. Dr. Gupta and Dr. Anderson reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM HYPERTENSION 2022
‘Game changer’ semaglutide halves diabetes risk from obesity
Treatment of people with obesity but without diabetes with the glucagon-like peptide-1 (GLP-1) agonist semaglutide (Wegovy) – hailed at its approval in 2021 as a “game changer” for the treatment of obesity – led to beneficial changes in body mass index (BMI), glycemic control, and other clinical measures.
This collectively cut the calculated risk for possible future development of type 2 diabetes in study participants by more than half, based on post-hoc analysis of data from two pivotal trials that compared semaglutide with placebo.
The findings “suggest that semaglutide could help prevent type 2 diabetes in people with overweight or obesity,” said W. Timothy Garvey, MD, in a presentation at the annual meeting of the European Association for the Study of Diabetes.
Asked to comment, Rodolfo J. Galindo, MD, said: “We devote a significant amount of effort to treating people with diabetes but very little effort for diabetes prevention. We hope that further scientific findings showing the benefits of weight loss, as illustrated by [Dr.] Garvey [and colleagues], for diabetes prevention will change the pandemic of adiposity-based chronic disease.”
GLP-1 agonists as complication-reducing agents
Finding a link between treatment with semaglutide and a reduced future risk of developing type 2 diabetes is important because it shows that this regimen is not just a BMI-centric approach to treating people with obesity but is also a way to potentially reduce complications of obesity such as diabetes onset, explained Dr. Garvey, a professor and director of the Diabetes Research Center at the University of Alabama at Birmingham.
Recent obesity-management recommendations have focused on interventions aimed at avoiding complications, as in 2016 guidelines from the American Association of Clinical Endocrinologists and the American College of Endocrinology, he noted.
Having evidence that treatment with a GLP-1 agonist such as semaglutide can reduce the incidence of diabetes in people with obesity might also help convince payers to more uniformly reimburse for this type of obesity intervention, which up to now has commonly faced coverage limitations, especially in the United States, he said in an interview.
Dr. Garvey added that evidence for a reduction in the incidence of cardiovascular disease complications such as myocardial infarction and stroke may need to join diabetes prevention as proven effects from obesity intervention before coverage decisions change.
He cited the SELECT trial, which is testing the hypothesis that semaglutide treatment of people with overweight or obesity can reduce the incidence of cardiovascular events in about 17,500 participants and with expected completion toward the end of 2023.
“A complication-centric approach to management of people with obesity needs prediction tools that allow a focus on prevention strategies for people with obesity who are at increased risk of developing diabetes,” commented Dr. Galindo, an endocrinologist at Emory University, Atlanta, in an interview.
Combined analysis of STEP 1 and STEP 4 data
The analysis conducted by Dr. Garvey and colleagues used data from the STEP 1 trial, which compared semaglutide 2.4 mg subcutaneous once weekly with placebo for weight loss in more than 1,500 people predominantly with obesity (about 6% were overweight) and showed that after 68 weeks semaglutide cut the calculated risk of developing type 2 diabetes over the subsequent 10 years from 18% at baseline to 7%, compared with a drop from 18% at baseline to 16% among those who received placebo.
A second, similar analysis of data from people predominantly with obesity in the STEP 4 trial – which treated around 800 people with semaglutide 2.4 mg for 20 weeks and then randomized them to placebo or continued semaglutide treatment – showed that semaglutide treatment cut their calculated 10-year risk for incident type 2 diabetes from 20% at baseline to about 11% after 20 weeks. The risk rebounded in the study participants who then switched from semaglutide to placebo. Among those randomized to remain on semaglutide for a total of 68 weeks, the 10-year risk fell further to 8%.
Dr. Garvey and associates used a validated prognostic formula, the cardiometabolic disease staging (CMDS) tool, they had previously developed and reported to calculate 10-year risk for development of type 2 diabetes based on three unmodifiable factors (age, sex, and race) and five modifiable factors (BMI, blood pressure, glucose level, HDL cholesterol, and triglycerides). They applied the analysis to data from 1,561 of the STEP 1 participants and 766 participants in the STEP 4 study.
“There is no better tool I know of to predict diabetes incidence,” commented Michael A. Nauck, MD, professor and chief of clinical research, diabetes division, St. Josef Hospital, Bochum, Germany.
In his opinion, the CMDS tool is appropriate for estimating the risk of developing incident type 2 diabetes in populations but not in specific individuals.
The new analyses also showed that, in STEP 1, the impact of semaglutide on reducing future risk of developing type 2 diabetes was roughly the same regardless of whether participants entered the study with prediabetes or were normoglycemic at entry.
Blood glucose changes confer the biggest effect
The biggest contributor among the five modifiable components of the CMDS tool for altering the predicted risk for incident diabetes was the reduction in blood glucose produced by semaglutide treatment, which influenced just under half of the change in predicted risk, Dr. Garvey said. The four other modifiable components had roughly similar individual effects on predicted risk, with change in BMI influencing about 15% of the observed effect.
“Our analysis shows that semaglutide treatment is preventing diabetes via several mechanisms. It’s not just a reduction in glucose,” Dr. Garvey said.
Dr. Nauck cautioned, however, that it is hard to judge the efficacy of an intervention like semaglutide for preventing incident diabetes when one of its effects is to dampen down hyperglycemia, the signal indicator of diabetes onset.
Indeed, semaglutide was first approved as a treatment for type 2 diabetes (known as Ozempic, Novo Nordisk) at slightly lower doses than it is approved for obesity. It is also available as an oral agent to treat diabetes (Rybelsus).
Dr. Nauck also noted that the results from at least one previously reported study had already shown the same relationship between treatment with the GLP-1 agonist liraglutide as an anti-obesity agent (3.0 mg dose daily, known as Saxenda) and a reduced subsequent incidence of type 2 diabetes but using actual clinical outcomes during 3 years of follow-up rather than a calculated projection of diabetes likelihood.
The SCALE Obesity and Prediabetes trial randomized 2,254 people with prediabetes and overweight or obesity to weekly treatment with 3.0 mg of liraglutide or placebo. After 160 weeks on treatment, the cumulative incidence of type 2 diabetes was 2% in those who received liraglutide and 6% among those on placebo, with a significant hazard ratio reduction of 79% in the incidence of diabetes on liraglutide treatment.
The STEP 1 and STEP 4 trials were sponsored by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Garvey has reported serving as an advisor without compensation to Novo Nordisk as well as Boehringer Ingelheim, Eli Lilly, Jazz, and Pfizer. He is also a site principal investigator for multicentered clinical trials sponsored by the University of Alabama at Birmingham and funded by Novo Nordisk, Eli Lilly, Epitomee, and Pfizer. Dr .Galindo has reported being a consultant or advisor for Boehringer Ingelheim, Eli Lilly, Pfizer, Sanofi, and Weight Watchers and receiving research funding from Dexcom, Eli Lilly, and Novo Nordisk. Dr. Nauck has reported being an advisor or consultant to Novo Nordisk as well as to Boehringer Ingelheim, Eli Lilly, Menarini/Berlin Chemie, MSD, Regor, and ShouTi/Gasherbrum, receiving research funding from MSD, being a member of a data monitoring and safety board for Inventiva, and being a speaker on behalf of Novo Nordisk as well as for Eli Lilly, Menarini/Berlin Chemie, MSD, and Sun Pharmaceuticals.
A version of this article first appeared on Medscape.com.
Treatment of people with obesity but without diabetes with the glucagon-like peptide-1 (GLP-1) agonist semaglutide (Wegovy) – hailed at its approval in 2021 as a “game changer” for the treatment of obesity – led to beneficial changes in body mass index (BMI), glycemic control, and other clinical measures.
This collectively cut the calculated risk for possible future development of type 2 diabetes in study participants by more than half, based on post-hoc analysis of data from two pivotal trials that compared semaglutide with placebo.
The findings “suggest that semaglutide could help prevent type 2 diabetes in people with overweight or obesity,” said W. Timothy Garvey, MD, in a presentation at the annual meeting of the European Association for the Study of Diabetes.
Asked to comment, Rodolfo J. Galindo, MD, said: “We devote a significant amount of effort to treating people with diabetes but very little effort for diabetes prevention. We hope that further scientific findings showing the benefits of weight loss, as illustrated by [Dr.] Garvey [and colleagues], for diabetes prevention will change the pandemic of adiposity-based chronic disease.”
GLP-1 agonists as complication-reducing agents
Finding a link between treatment with semaglutide and a reduced future risk of developing type 2 diabetes is important because it shows that this regimen is not just a BMI-centric approach to treating people with obesity but is also a way to potentially reduce complications of obesity such as diabetes onset, explained Dr. Garvey, a professor and director of the Diabetes Research Center at the University of Alabama at Birmingham.
Recent obesity-management recommendations have focused on interventions aimed at avoiding complications, as in 2016 guidelines from the American Association of Clinical Endocrinologists and the American College of Endocrinology, he noted.
Having evidence that treatment with a GLP-1 agonist such as semaglutide can reduce the incidence of diabetes in people with obesity might also help convince payers to more uniformly reimburse for this type of obesity intervention, which up to now has commonly faced coverage limitations, especially in the United States, he said in an interview.
Dr. Garvey added that evidence for a reduction in the incidence of cardiovascular disease complications such as myocardial infarction and stroke may need to join diabetes prevention as proven effects from obesity intervention before coverage decisions change.
He cited the SELECT trial, which is testing the hypothesis that semaglutide treatment of people with overweight or obesity can reduce the incidence of cardiovascular events in about 17,500 participants and with expected completion toward the end of 2023.
“A complication-centric approach to management of people with obesity needs prediction tools that allow a focus on prevention strategies for people with obesity who are at increased risk of developing diabetes,” commented Dr. Galindo, an endocrinologist at Emory University, Atlanta, in an interview.
Combined analysis of STEP 1 and STEP 4 data
The analysis conducted by Dr. Garvey and colleagues used data from the STEP 1 trial, which compared semaglutide 2.4 mg subcutaneous once weekly with placebo for weight loss in more than 1,500 people predominantly with obesity (about 6% were overweight) and showed that after 68 weeks semaglutide cut the calculated risk of developing type 2 diabetes over the subsequent 10 years from 18% at baseline to 7%, compared with a drop from 18% at baseline to 16% among those who received placebo.
A second, similar analysis of data from people predominantly with obesity in the STEP 4 trial – which treated around 800 people with semaglutide 2.4 mg for 20 weeks and then randomized them to placebo or continued semaglutide treatment – showed that semaglutide treatment cut their calculated 10-year risk for incident type 2 diabetes from 20% at baseline to about 11% after 20 weeks. The risk rebounded in the study participants who then switched from semaglutide to placebo. Among those randomized to remain on semaglutide for a total of 68 weeks, the 10-year risk fell further to 8%.
Dr. Garvey and associates used a validated prognostic formula, the cardiometabolic disease staging (CMDS) tool, they had previously developed and reported to calculate 10-year risk for development of type 2 diabetes based on three unmodifiable factors (age, sex, and race) and five modifiable factors (BMI, blood pressure, glucose level, HDL cholesterol, and triglycerides). They applied the analysis to data from 1,561 of the STEP 1 participants and 766 participants in the STEP 4 study.
“There is no better tool I know of to predict diabetes incidence,” commented Michael A. Nauck, MD, professor and chief of clinical research, diabetes division, St. Josef Hospital, Bochum, Germany.
In his opinion, the CMDS tool is appropriate for estimating the risk of developing incident type 2 diabetes in populations but not in specific individuals.
The new analyses also showed that, in STEP 1, the impact of semaglutide on reducing future risk of developing type 2 diabetes was roughly the same regardless of whether participants entered the study with prediabetes or were normoglycemic at entry.
Blood glucose changes confer the biggest effect
The biggest contributor among the five modifiable components of the CMDS tool for altering the predicted risk for incident diabetes was the reduction in blood glucose produced by semaglutide treatment, which influenced just under half of the change in predicted risk, Dr. Garvey said. The four other modifiable components had roughly similar individual effects on predicted risk, with change in BMI influencing about 15% of the observed effect.
“Our analysis shows that semaglutide treatment is preventing diabetes via several mechanisms. It’s not just a reduction in glucose,” Dr. Garvey said.
Dr. Nauck cautioned, however, that it is hard to judge the efficacy of an intervention like semaglutide for preventing incident diabetes when one of its effects is to dampen down hyperglycemia, the signal indicator of diabetes onset.
Indeed, semaglutide was first approved as a treatment for type 2 diabetes (known as Ozempic, Novo Nordisk) at slightly lower doses than it is approved for obesity. It is also available as an oral agent to treat diabetes (Rybelsus).
Dr. Nauck also noted that the results from at least one previously reported study had already shown the same relationship between treatment with the GLP-1 agonist liraglutide as an anti-obesity agent (3.0 mg dose daily, known as Saxenda) and a reduced subsequent incidence of type 2 diabetes but using actual clinical outcomes during 3 years of follow-up rather than a calculated projection of diabetes likelihood.
The SCALE Obesity and Prediabetes trial randomized 2,254 people with prediabetes and overweight or obesity to weekly treatment with 3.0 mg of liraglutide or placebo. After 160 weeks on treatment, the cumulative incidence of type 2 diabetes was 2% in those who received liraglutide and 6% among those on placebo, with a significant hazard ratio reduction of 79% in the incidence of diabetes on liraglutide treatment.
The STEP 1 and STEP 4 trials were sponsored by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Garvey has reported serving as an advisor without compensation to Novo Nordisk as well as Boehringer Ingelheim, Eli Lilly, Jazz, and Pfizer. He is also a site principal investigator for multicentered clinical trials sponsored by the University of Alabama at Birmingham and funded by Novo Nordisk, Eli Lilly, Epitomee, and Pfizer. Dr .Galindo has reported being a consultant or advisor for Boehringer Ingelheim, Eli Lilly, Pfizer, Sanofi, and Weight Watchers and receiving research funding from Dexcom, Eli Lilly, and Novo Nordisk. Dr. Nauck has reported being an advisor or consultant to Novo Nordisk as well as to Boehringer Ingelheim, Eli Lilly, Menarini/Berlin Chemie, MSD, Regor, and ShouTi/Gasherbrum, receiving research funding from MSD, being a member of a data monitoring and safety board for Inventiva, and being a speaker on behalf of Novo Nordisk as well as for Eli Lilly, Menarini/Berlin Chemie, MSD, and Sun Pharmaceuticals.
A version of this article first appeared on Medscape.com.
Treatment of people with obesity but without diabetes with the glucagon-like peptide-1 (GLP-1) agonist semaglutide (Wegovy) – hailed at its approval in 2021 as a “game changer” for the treatment of obesity – led to beneficial changes in body mass index (BMI), glycemic control, and other clinical measures.
This collectively cut the calculated risk for possible future development of type 2 diabetes in study participants by more than half, based on post-hoc analysis of data from two pivotal trials that compared semaglutide with placebo.
The findings “suggest that semaglutide could help prevent type 2 diabetes in people with overweight or obesity,” said W. Timothy Garvey, MD, in a presentation at the annual meeting of the European Association for the Study of Diabetes.
Asked to comment, Rodolfo J. Galindo, MD, said: “We devote a significant amount of effort to treating people with diabetes but very little effort for diabetes prevention. We hope that further scientific findings showing the benefits of weight loss, as illustrated by [Dr.] Garvey [and colleagues], for diabetes prevention will change the pandemic of adiposity-based chronic disease.”
GLP-1 agonists as complication-reducing agents
Finding a link between treatment with semaglutide and a reduced future risk of developing type 2 diabetes is important because it shows that this regimen is not just a BMI-centric approach to treating people with obesity but is also a way to potentially reduce complications of obesity such as diabetes onset, explained Dr. Garvey, a professor and director of the Diabetes Research Center at the University of Alabama at Birmingham.
Recent obesity-management recommendations have focused on interventions aimed at avoiding complications, as in 2016 guidelines from the American Association of Clinical Endocrinologists and the American College of Endocrinology, he noted.
Having evidence that treatment with a GLP-1 agonist such as semaglutide can reduce the incidence of diabetes in people with obesity might also help convince payers to more uniformly reimburse for this type of obesity intervention, which up to now has commonly faced coverage limitations, especially in the United States, he said in an interview.
Dr. Garvey added that evidence for a reduction in the incidence of cardiovascular disease complications such as myocardial infarction and stroke may need to join diabetes prevention as proven effects from obesity intervention before coverage decisions change.
He cited the SELECT trial, which is testing the hypothesis that semaglutide treatment of people with overweight or obesity can reduce the incidence of cardiovascular events in about 17,500 participants and with expected completion toward the end of 2023.
“A complication-centric approach to management of people with obesity needs prediction tools that allow a focus on prevention strategies for people with obesity who are at increased risk of developing diabetes,” commented Dr. Galindo, an endocrinologist at Emory University, Atlanta, in an interview.
Combined analysis of STEP 1 and STEP 4 data
The analysis conducted by Dr. Garvey and colleagues used data from the STEP 1 trial, which compared semaglutide 2.4 mg subcutaneous once weekly with placebo for weight loss in more than 1,500 people predominantly with obesity (about 6% were overweight) and showed that after 68 weeks semaglutide cut the calculated risk of developing type 2 diabetes over the subsequent 10 years from 18% at baseline to 7%, compared with a drop from 18% at baseline to 16% among those who received placebo.
A second, similar analysis of data from people predominantly with obesity in the STEP 4 trial – which treated around 800 people with semaglutide 2.4 mg for 20 weeks and then randomized them to placebo or continued semaglutide treatment – showed that semaglutide treatment cut their calculated 10-year risk for incident type 2 diabetes from 20% at baseline to about 11% after 20 weeks. The risk rebounded in the study participants who then switched from semaglutide to placebo. Among those randomized to remain on semaglutide for a total of 68 weeks, the 10-year risk fell further to 8%.
Dr. Garvey and associates used a validated prognostic formula, the cardiometabolic disease staging (CMDS) tool, they had previously developed and reported to calculate 10-year risk for development of type 2 diabetes based on three unmodifiable factors (age, sex, and race) and five modifiable factors (BMI, blood pressure, glucose level, HDL cholesterol, and triglycerides). They applied the analysis to data from 1,561 of the STEP 1 participants and 766 participants in the STEP 4 study.
“There is no better tool I know of to predict diabetes incidence,” commented Michael A. Nauck, MD, professor and chief of clinical research, diabetes division, St. Josef Hospital, Bochum, Germany.
In his opinion, the CMDS tool is appropriate for estimating the risk of developing incident type 2 diabetes in populations but not in specific individuals.
The new analyses also showed that, in STEP 1, the impact of semaglutide on reducing future risk of developing type 2 diabetes was roughly the same regardless of whether participants entered the study with prediabetes or were normoglycemic at entry.
Blood glucose changes confer the biggest effect
The biggest contributor among the five modifiable components of the CMDS tool for altering the predicted risk for incident diabetes was the reduction in blood glucose produced by semaglutide treatment, which influenced just under half of the change in predicted risk, Dr. Garvey said. The four other modifiable components had roughly similar individual effects on predicted risk, with change in BMI influencing about 15% of the observed effect.
“Our analysis shows that semaglutide treatment is preventing diabetes via several mechanisms. It’s not just a reduction in glucose,” Dr. Garvey said.
Dr. Nauck cautioned, however, that it is hard to judge the efficacy of an intervention like semaglutide for preventing incident diabetes when one of its effects is to dampen down hyperglycemia, the signal indicator of diabetes onset.
Indeed, semaglutide was first approved as a treatment for type 2 diabetes (known as Ozempic, Novo Nordisk) at slightly lower doses than it is approved for obesity. It is also available as an oral agent to treat diabetes (Rybelsus).
Dr. Nauck also noted that the results from at least one previously reported study had already shown the same relationship between treatment with the GLP-1 agonist liraglutide as an anti-obesity agent (3.0 mg dose daily, known as Saxenda) and a reduced subsequent incidence of type 2 diabetes but using actual clinical outcomes during 3 years of follow-up rather than a calculated projection of diabetes likelihood.
The SCALE Obesity and Prediabetes trial randomized 2,254 people with prediabetes and overweight or obesity to weekly treatment with 3.0 mg of liraglutide or placebo. After 160 weeks on treatment, the cumulative incidence of type 2 diabetes was 2% in those who received liraglutide and 6% among those on placebo, with a significant hazard ratio reduction of 79% in the incidence of diabetes on liraglutide treatment.
The STEP 1 and STEP 4 trials were sponsored by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Garvey has reported serving as an advisor without compensation to Novo Nordisk as well as Boehringer Ingelheim, Eli Lilly, Jazz, and Pfizer. He is also a site principal investigator for multicentered clinical trials sponsored by the University of Alabama at Birmingham and funded by Novo Nordisk, Eli Lilly, Epitomee, and Pfizer. Dr .Galindo has reported being a consultant or advisor for Boehringer Ingelheim, Eli Lilly, Pfizer, Sanofi, and Weight Watchers and receiving research funding from Dexcom, Eli Lilly, and Novo Nordisk. Dr. Nauck has reported being an advisor or consultant to Novo Nordisk as well as to Boehringer Ingelheim, Eli Lilly, Menarini/Berlin Chemie, MSD, Regor, and ShouTi/Gasherbrum, receiving research funding from MSD, being a member of a data monitoring and safety board for Inventiva, and being a speaker on behalf of Novo Nordisk as well as for Eli Lilly, Menarini/Berlin Chemie, MSD, and Sun Pharmaceuticals.
A version of this article first appeared on Medscape.com.
Adderall shortage reported by pharmacies, patients
Half a dozen people told Bloomberg that pharmacies told them in August and September that the drug was out of stock. The patients were told the drug might not be available for weeks, though it’s supposed to be taken daily. BuzzFeed News said 20 people across the nation said that their pharmacies didn’t have Adderall in stock.
“It’s so frustrating that getting my meds requires me to be organized, focused, and motivated – all the things I’m on these meds to help with,” Irene Kelly, who has been using Adderall for 14 years, told BuzzFeed News.
Two pharmacy chains told Bloomberg that Adderall has not always been available to sell. Walgreens spokesperson Rebekah Pajak said there were “supply chain challenges” affecting instant-release and extended-release versions of the drug. CVS pharmacies can fill Adderall prescriptions “in most cases,” CVS spokesperson Matthew Blanchette said.
Several drugmakers have had brand-name and generic versions of Adderall on back order for months, Bloomberg reported. The problem started with a labor shortage at Teva Pharmaceutical, the top seller of Adderall in the United States, that created a limited supply of brand-name and generic instant-release Adderall, according to the outlet.
That said, the Food and Drug Administration is not reporting an Adderall shortage on its drug shortages database. The federal agency says it lists a drug as being in short supply when “overall market demand is not being met by the manufacturers of the product,” Bloomberg said.
“Manufacturers continue to release product,” FDA spokesperson Cherie Duvall-Jones said, according to Bloomberg.
Demand for Adderall is growing, possibly because of rising ADHD diagnoses that occurred during telehealth medical appointments amid the COVID-19 pandemic, Bloomberg reported, noting that some of those telehealth companies have come under scrutiny by the Drug Enforcement Administration and other government agencies.
NBC News, citing IQVIA, an analytics provider for the life sciences industry, reported that 41.4 million Adderall prescriptions were issued last year, up 10.4% from 2020.
A version of this article first appeared on WebMD.com.
Half a dozen people told Bloomberg that pharmacies told them in August and September that the drug was out of stock. The patients were told the drug might not be available for weeks, though it’s supposed to be taken daily. BuzzFeed News said 20 people across the nation said that their pharmacies didn’t have Adderall in stock.
“It’s so frustrating that getting my meds requires me to be organized, focused, and motivated – all the things I’m on these meds to help with,” Irene Kelly, who has been using Adderall for 14 years, told BuzzFeed News.
Two pharmacy chains told Bloomberg that Adderall has not always been available to sell. Walgreens spokesperson Rebekah Pajak said there were “supply chain challenges” affecting instant-release and extended-release versions of the drug. CVS pharmacies can fill Adderall prescriptions “in most cases,” CVS spokesperson Matthew Blanchette said.
Several drugmakers have had brand-name and generic versions of Adderall on back order for months, Bloomberg reported. The problem started with a labor shortage at Teva Pharmaceutical, the top seller of Adderall in the United States, that created a limited supply of brand-name and generic instant-release Adderall, according to the outlet.
That said, the Food and Drug Administration is not reporting an Adderall shortage on its drug shortages database. The federal agency says it lists a drug as being in short supply when “overall market demand is not being met by the manufacturers of the product,” Bloomberg said.
“Manufacturers continue to release product,” FDA spokesperson Cherie Duvall-Jones said, according to Bloomberg.
Demand for Adderall is growing, possibly because of rising ADHD diagnoses that occurred during telehealth medical appointments amid the COVID-19 pandemic, Bloomberg reported, noting that some of those telehealth companies have come under scrutiny by the Drug Enforcement Administration and other government agencies.
NBC News, citing IQVIA, an analytics provider for the life sciences industry, reported that 41.4 million Adderall prescriptions were issued last year, up 10.4% from 2020.
A version of this article first appeared on WebMD.com.
Half a dozen people told Bloomberg that pharmacies told them in August and September that the drug was out of stock. The patients were told the drug might not be available for weeks, though it’s supposed to be taken daily. BuzzFeed News said 20 people across the nation said that their pharmacies didn’t have Adderall in stock.
“It’s so frustrating that getting my meds requires me to be organized, focused, and motivated – all the things I’m on these meds to help with,” Irene Kelly, who has been using Adderall for 14 years, told BuzzFeed News.
Two pharmacy chains told Bloomberg that Adderall has not always been available to sell. Walgreens spokesperson Rebekah Pajak said there were “supply chain challenges” affecting instant-release and extended-release versions of the drug. CVS pharmacies can fill Adderall prescriptions “in most cases,” CVS spokesperson Matthew Blanchette said.
Several drugmakers have had brand-name and generic versions of Adderall on back order for months, Bloomberg reported. The problem started with a labor shortage at Teva Pharmaceutical, the top seller of Adderall in the United States, that created a limited supply of brand-name and generic instant-release Adderall, according to the outlet.
That said, the Food and Drug Administration is not reporting an Adderall shortage on its drug shortages database. The federal agency says it lists a drug as being in short supply when “overall market demand is not being met by the manufacturers of the product,” Bloomberg said.
“Manufacturers continue to release product,” FDA spokesperson Cherie Duvall-Jones said, according to Bloomberg.
Demand for Adderall is growing, possibly because of rising ADHD diagnoses that occurred during telehealth medical appointments amid the COVID-19 pandemic, Bloomberg reported, noting that some of those telehealth companies have come under scrutiny by the Drug Enforcement Administration and other government agencies.
NBC News, citing IQVIA, an analytics provider for the life sciences industry, reported that 41.4 million Adderall prescriptions were issued last year, up 10.4% from 2020.
A version of this article first appeared on WebMD.com.
Atezolizumab doubles survival of NSCLC patients with poor performance status
PARIS – Patients with untreated non–small cell lung cancer (NSCLC) who could not withstand the rigors of platinum-based chemotherapy regimens had significantly better overall survival when treated with the immune checkpoint inhibitor atezolizumab (Tecentriq), compared with their counterparts treated with either vinorelbine or gemcitabine in a phase 3 randomized trial.
Among 353 patients with treatment-naive stage 3B to 4 NSCLC who were not candidates for platinum-based chemotherapy because of poor performance status (PS), advanced age, or significant comorbidities, the median overall survival (OS) was 10.3 months for patients treated with atezolizumab vs. 9.2 months for patients assigned to receive the investigator’s choice of single-agent chemotherapy.
This difference translated into a hazard ratio for death with atezolizumab of 0.78 (P = .028), Siow Ming Lee, MD, PhD, of University College London, reported at the ESMO Congress.
The 2-year OS rate with atezolizumab was 24.3%, compared with 12.4% for single-agent chemotherapy.
“When I saw the data, I was amazed. One of four patients survived for 2 years!” he said in an interview.
, those with Eastern Cooperative Oncology Group PS scores of 2 or greater, or who have substantial comorbidities that preclude their ability to receive platinum doublet or single platinum agent chemotherapy, he said.
Invited discussant Natasha Leighl, MD, MMSc, of the Princess Margaret Cancer Center, Toronto, called the study “really extraordinary. This study enrolls patients that historically are excluded or underrepresented in trials, and yet really represent the majority of patients that we diagnose and treat around the world.”
Excluded from clinical trials
“Cancer chemotherapy has changed the treatment landscape for the metastatic NSCLC population, but these treatments are mainly recommended for fit patients,” Dr. Lee said during his presentation of the data in a presidential symposium.
First-line pivotal trials for lung cancer patients comparing either single-agent immunotherapy or an immunotherapy/chemotherapy combination have all been conducted in fit patients, with ECOG PS of 0 or 1, he noted.
“In reality, we still have a large population of unfit NSCLC patients, of at least 40%, many of which we cannot treat with standard platinum chemotherapy. There are many elderly patients with poor performance status, and the elderly with many comorbidities, and they are frequently on many drug medications, which we see frequently in our clinic,” he said.
Study details
To see whether immunotherapy could improve outcomes for unfit patients, investigators designed the IPSOS trial, a phase 3 multicenter open-label study of efficacy, safety, and patient-reported outcomes with atezolizumab compared with single-agent chemotherapy.
Patients from 23 centers in North America, South America, Europe, and Asia who were ineligible for platinum-based chemotherapy because of ECOG performance status of 2 or 3, or who were aged 70 or older with performance status 0 or 1 but with multiple comorbidities or other contraindications to platinum were stratified by histology, programmed death-ligand-1 (PD-L1) expression, and brain metastases, and were then randomly assigned to receive either atezolizumab 1,200 mg intravenously every 3 weeks (302 patients), or to investigator’s choice of either vinorelbine delivered orally or intravenously, according to local practice, or intravenous gemcitabine given intravenously per local practice (151 patients).
As noted before, overall survival, the primary endpoint, was significantly better with atezolizumab, translating into a 22% reduction in risk of death compared with chemotherapy.
The 1-year OS rates were 43.7% with atezolizumab vs. 36.6% with chemotherapy, and the 2-year rates were 24.3% vs. 12.4%, respectively.
A subgroup analysis showed trends toward better benefit for immunotherapy regardless of age, sex, race, performance status, history of tobacco use, tumor histology, stage, presence of liver metastases, number of metastatic sites, or PD-L1 expression levels. The benefit of atezolizumab was also significantly better among patients without brain metastases.
The median duration of response was 14 months with ateziluzmab vs. 7.8 months with chemotherapy. Respective objective response rates were 16.9% vs. 15.5%. Median progression-free survival, a secondary endpoint, was 4.2 months with atezolizumab and 4 months with chemotherapy, a difference that was not statistically significant. Median treatment duration was 3.5 months with atezolizumab, 2.3 months with gemcitabine, and 1.8 months with vinorelbine. Treatment-related adverse events of any grade occurred in 57% of patients on immunotherapy vs. 80.3% of those on chemotherapy. Grade 3 or 4 adverse events related to therapy occurred in 16.3% vs. 33.3%, respectively. About 13% of patients in each arm had an adverse event leading to drug discontinuation. There were three treatment-related deaths among patients on atezolizumab, and four among patients on chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilizing of health-related quality-of-life domains of functioning, and significant improvement in delaying the time to deterioration of chest pain.
Age is not prognostic
“I think it’s important though to remember that in this study there are very distinct populations of patients. Poor performance status and comorbidities are prognostic, but age is not,” Dr. Leighl said in her discussion.
“In terms of current standards, performance status 3 patients are currently recommended to have best supportive care unless a targeted therapy is available for them, and while PS 2 patients have been excluded from checkpoint inhibitor trials, we treat most of these patients the same way. In this study in particular, patients had to be ineligible for platinum doublet therapy, but of course this definition was subjective,” she said.
She also commented that “if we’re now going to treat everyone with atezolizumab, I think the budget impact of this is going to be huge.”
It will be important to identify more clearly those patients aged 80 and older who might benefit from atezolizumab in this setting by better incorporating biomarkers such as PD-L1 levels to determine who can benefit from therapy and who might be spared the necessity of coming into the hospital or clinic for regular intravenous infusions, she added.
The study was supported by F. Hoffman-La Roche. Dr. Lee disclosed research funding from the company to his institution. Dr. Leighl disclosed institutional grant funding and personal fees from Roche and others.
PARIS – Patients with untreated non–small cell lung cancer (NSCLC) who could not withstand the rigors of platinum-based chemotherapy regimens had significantly better overall survival when treated with the immune checkpoint inhibitor atezolizumab (Tecentriq), compared with their counterparts treated with either vinorelbine or gemcitabine in a phase 3 randomized trial.
Among 353 patients with treatment-naive stage 3B to 4 NSCLC who were not candidates for platinum-based chemotherapy because of poor performance status (PS), advanced age, or significant comorbidities, the median overall survival (OS) was 10.3 months for patients treated with atezolizumab vs. 9.2 months for patients assigned to receive the investigator’s choice of single-agent chemotherapy.
This difference translated into a hazard ratio for death with atezolizumab of 0.78 (P = .028), Siow Ming Lee, MD, PhD, of University College London, reported at the ESMO Congress.
The 2-year OS rate with atezolizumab was 24.3%, compared with 12.4% for single-agent chemotherapy.
“When I saw the data, I was amazed. One of four patients survived for 2 years!” he said in an interview.
, those with Eastern Cooperative Oncology Group PS scores of 2 or greater, or who have substantial comorbidities that preclude their ability to receive platinum doublet or single platinum agent chemotherapy, he said.
Invited discussant Natasha Leighl, MD, MMSc, of the Princess Margaret Cancer Center, Toronto, called the study “really extraordinary. This study enrolls patients that historically are excluded or underrepresented in trials, and yet really represent the majority of patients that we diagnose and treat around the world.”
Excluded from clinical trials
“Cancer chemotherapy has changed the treatment landscape for the metastatic NSCLC population, but these treatments are mainly recommended for fit patients,” Dr. Lee said during his presentation of the data in a presidential symposium.
First-line pivotal trials for lung cancer patients comparing either single-agent immunotherapy or an immunotherapy/chemotherapy combination have all been conducted in fit patients, with ECOG PS of 0 or 1, he noted.
“In reality, we still have a large population of unfit NSCLC patients, of at least 40%, many of which we cannot treat with standard platinum chemotherapy. There are many elderly patients with poor performance status, and the elderly with many comorbidities, and they are frequently on many drug medications, which we see frequently in our clinic,” he said.
Study details
To see whether immunotherapy could improve outcomes for unfit patients, investigators designed the IPSOS trial, a phase 3 multicenter open-label study of efficacy, safety, and patient-reported outcomes with atezolizumab compared with single-agent chemotherapy.
Patients from 23 centers in North America, South America, Europe, and Asia who were ineligible for platinum-based chemotherapy because of ECOG performance status of 2 or 3, or who were aged 70 or older with performance status 0 or 1 but with multiple comorbidities or other contraindications to platinum were stratified by histology, programmed death-ligand-1 (PD-L1) expression, and brain metastases, and were then randomly assigned to receive either atezolizumab 1,200 mg intravenously every 3 weeks (302 patients), or to investigator’s choice of either vinorelbine delivered orally or intravenously, according to local practice, or intravenous gemcitabine given intravenously per local practice (151 patients).
As noted before, overall survival, the primary endpoint, was significantly better with atezolizumab, translating into a 22% reduction in risk of death compared with chemotherapy.
The 1-year OS rates were 43.7% with atezolizumab vs. 36.6% with chemotherapy, and the 2-year rates were 24.3% vs. 12.4%, respectively.
A subgroup analysis showed trends toward better benefit for immunotherapy regardless of age, sex, race, performance status, history of tobacco use, tumor histology, stage, presence of liver metastases, number of metastatic sites, or PD-L1 expression levels. The benefit of atezolizumab was also significantly better among patients without brain metastases.
The median duration of response was 14 months with ateziluzmab vs. 7.8 months with chemotherapy. Respective objective response rates were 16.9% vs. 15.5%. Median progression-free survival, a secondary endpoint, was 4.2 months with atezolizumab and 4 months with chemotherapy, a difference that was not statistically significant. Median treatment duration was 3.5 months with atezolizumab, 2.3 months with gemcitabine, and 1.8 months with vinorelbine. Treatment-related adverse events of any grade occurred in 57% of patients on immunotherapy vs. 80.3% of those on chemotherapy. Grade 3 or 4 adverse events related to therapy occurred in 16.3% vs. 33.3%, respectively. About 13% of patients in each arm had an adverse event leading to drug discontinuation. There were three treatment-related deaths among patients on atezolizumab, and four among patients on chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilizing of health-related quality-of-life domains of functioning, and significant improvement in delaying the time to deterioration of chest pain.
Age is not prognostic
“I think it’s important though to remember that in this study there are very distinct populations of patients. Poor performance status and comorbidities are prognostic, but age is not,” Dr. Leighl said in her discussion.
“In terms of current standards, performance status 3 patients are currently recommended to have best supportive care unless a targeted therapy is available for them, and while PS 2 patients have been excluded from checkpoint inhibitor trials, we treat most of these patients the same way. In this study in particular, patients had to be ineligible for platinum doublet therapy, but of course this definition was subjective,” she said.
She also commented that “if we’re now going to treat everyone with atezolizumab, I think the budget impact of this is going to be huge.”
It will be important to identify more clearly those patients aged 80 and older who might benefit from atezolizumab in this setting by better incorporating biomarkers such as PD-L1 levels to determine who can benefit from therapy and who might be spared the necessity of coming into the hospital or clinic for regular intravenous infusions, she added.
The study was supported by F. Hoffman-La Roche. Dr. Lee disclosed research funding from the company to his institution. Dr. Leighl disclosed institutional grant funding and personal fees from Roche and others.
PARIS – Patients with untreated non–small cell lung cancer (NSCLC) who could not withstand the rigors of platinum-based chemotherapy regimens had significantly better overall survival when treated with the immune checkpoint inhibitor atezolizumab (Tecentriq), compared with their counterparts treated with either vinorelbine or gemcitabine in a phase 3 randomized trial.
Among 353 patients with treatment-naive stage 3B to 4 NSCLC who were not candidates for platinum-based chemotherapy because of poor performance status (PS), advanced age, or significant comorbidities, the median overall survival (OS) was 10.3 months for patients treated with atezolizumab vs. 9.2 months for patients assigned to receive the investigator’s choice of single-agent chemotherapy.
This difference translated into a hazard ratio for death with atezolizumab of 0.78 (P = .028), Siow Ming Lee, MD, PhD, of University College London, reported at the ESMO Congress.
The 2-year OS rate with atezolizumab was 24.3%, compared with 12.4% for single-agent chemotherapy.
“When I saw the data, I was amazed. One of four patients survived for 2 years!” he said in an interview.
, those with Eastern Cooperative Oncology Group PS scores of 2 or greater, or who have substantial comorbidities that preclude their ability to receive platinum doublet or single platinum agent chemotherapy, he said.
Invited discussant Natasha Leighl, MD, MMSc, of the Princess Margaret Cancer Center, Toronto, called the study “really extraordinary. This study enrolls patients that historically are excluded or underrepresented in trials, and yet really represent the majority of patients that we diagnose and treat around the world.”
Excluded from clinical trials
“Cancer chemotherapy has changed the treatment landscape for the metastatic NSCLC population, but these treatments are mainly recommended for fit patients,” Dr. Lee said during his presentation of the data in a presidential symposium.
First-line pivotal trials for lung cancer patients comparing either single-agent immunotherapy or an immunotherapy/chemotherapy combination have all been conducted in fit patients, with ECOG PS of 0 or 1, he noted.
“In reality, we still have a large population of unfit NSCLC patients, of at least 40%, many of which we cannot treat with standard platinum chemotherapy. There are many elderly patients with poor performance status, and the elderly with many comorbidities, and they are frequently on many drug medications, which we see frequently in our clinic,” he said.
Study details
To see whether immunotherapy could improve outcomes for unfit patients, investigators designed the IPSOS trial, a phase 3 multicenter open-label study of efficacy, safety, and patient-reported outcomes with atezolizumab compared with single-agent chemotherapy.
Patients from 23 centers in North America, South America, Europe, and Asia who were ineligible for platinum-based chemotherapy because of ECOG performance status of 2 or 3, or who were aged 70 or older with performance status 0 or 1 but with multiple comorbidities or other contraindications to platinum were stratified by histology, programmed death-ligand-1 (PD-L1) expression, and brain metastases, and were then randomly assigned to receive either atezolizumab 1,200 mg intravenously every 3 weeks (302 patients), or to investigator’s choice of either vinorelbine delivered orally or intravenously, according to local practice, or intravenous gemcitabine given intravenously per local practice (151 patients).
As noted before, overall survival, the primary endpoint, was significantly better with atezolizumab, translating into a 22% reduction in risk of death compared with chemotherapy.
The 1-year OS rates were 43.7% with atezolizumab vs. 36.6% with chemotherapy, and the 2-year rates were 24.3% vs. 12.4%, respectively.
A subgroup analysis showed trends toward better benefit for immunotherapy regardless of age, sex, race, performance status, history of tobacco use, tumor histology, stage, presence of liver metastases, number of metastatic sites, or PD-L1 expression levels. The benefit of atezolizumab was also significantly better among patients without brain metastases.
The median duration of response was 14 months with ateziluzmab vs. 7.8 months with chemotherapy. Respective objective response rates were 16.9% vs. 15.5%. Median progression-free survival, a secondary endpoint, was 4.2 months with atezolizumab and 4 months with chemotherapy, a difference that was not statistically significant. Median treatment duration was 3.5 months with atezolizumab, 2.3 months with gemcitabine, and 1.8 months with vinorelbine. Treatment-related adverse events of any grade occurred in 57% of patients on immunotherapy vs. 80.3% of those on chemotherapy. Grade 3 or 4 adverse events related to therapy occurred in 16.3% vs. 33.3%, respectively. About 13% of patients in each arm had an adverse event leading to drug discontinuation. There were three treatment-related deaths among patients on atezolizumab, and four among patients on chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilizing of health-related quality-of-life domains of functioning, and significant improvement in delaying the time to deterioration of chest pain.
Age is not prognostic
“I think it’s important though to remember that in this study there are very distinct populations of patients. Poor performance status and comorbidities are prognostic, but age is not,” Dr. Leighl said in her discussion.
“In terms of current standards, performance status 3 patients are currently recommended to have best supportive care unless a targeted therapy is available for them, and while PS 2 patients have been excluded from checkpoint inhibitor trials, we treat most of these patients the same way. In this study in particular, patients had to be ineligible for platinum doublet therapy, but of course this definition was subjective,” she said.
She also commented that “if we’re now going to treat everyone with atezolizumab, I think the budget impact of this is going to be huge.”
It will be important to identify more clearly those patients aged 80 and older who might benefit from atezolizumab in this setting by better incorporating biomarkers such as PD-L1 levels to determine who can benefit from therapy and who might be spared the necessity of coming into the hospital or clinic for regular intravenous infusions, she added.
The study was supported by F. Hoffman-La Roche. Dr. Lee disclosed research funding from the company to his institution. Dr. Leighl disclosed institutional grant funding and personal fees from Roche and others.
AT ESMO CONGRESS 2022