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For people with obesity or type 2 diabetes, glucagon-like peptide 1 (GLP-1) agonists (including Mounjaro, Wegovy, and Ozempic) have been labeled miracle drugs. But they aren’t miraculous for everyone. Research indicates a significant portion of people discontinue using them within a year.

The main problems with GLP-1 agonists are that they are expensive and have a fairly high rate of side effects — such as nausea, vomiting, diarrhea, or constipation. Another big one is muscle loss.

A new study, published in Nature, shows a potential alternative to GLP-1 agonists with fewer side effects, at least in mice and nonhuman primates.

This lack of side effects, particularly in how the potential drug causes no muscle loss — and in fact engages muscle for some of its effect — sets it apart and makes it a potential alternative to GLP-1s. The key is not just reducing appetite but also increasing energy expenditure.

 

How It Works

The new approach targets a protein called NK2R — a member of the neurokinin receptor family, which has a role in a variety of physiological processes, including pain sensation, anxiety, and inflammation. 

“We were looking to see genetic linkages to metabolic health, and there NK2R was,” said Zach Gerhart-Hines, PhD, a professor studying molecular metabolism at the University of Copenhagen in Denmark and principal investigator of the study. The group then created a few long-acting agonists that are selective for NK2R. So far, they’ve tested them in mice and nonhuman primates.

“The data on new medicines targeting NK2R is very promising and highlights the potential of both reducing food intake and increasing energy expenditure,” said Daniel Drucker, MD, an endocrinologist and researcher at Lunenfeld-Tanenbaum Research Institute in Toronto who was not involved in the study.

“The drug activates a certain region in the hindbrain of the animal, which is controlling food intake, and it does so by reducing appetite without increasing nausea or vomiting,” explained Frederike Sass, a research assistant at the University of Copenhagen in Copenhagen, Denmark, who led the study.

Gerhart-Hines said that even at the highest dose, there were no incidents of vomiting among the nonhuman primates. Mice can’t vomit, but there are ways to tell if they feel unwell from a drug. One way researchers test that is to start feeding the mice sweetened water at the same time they’re given a drug. Then later, when the mice are no longer on the drug, they’re given a choice between sweetened and unsweetened water. If they weren’t feeling well on the drug, they’ll choose plain water because they associate the sweet water with feeling bad, otherwise mice prefer sweet water. Sass said that with the NK2R agonist, they continued to drink sweet water after the treatment, whereas when they gave the mice semaglutide, the mice preferred plain water posttreatment.

The researchers also monitored the animals’ psychological health, as NK2R has been associated with anxiety, but they observed no behavioral changes.

 

The Key Mechanism at Work

One big question is how the NK2R agonists work. The amphetamines people used for weight loss during the 1950s and 1960s worked by making people more active. GLP-1 agonists reduce appetite and lower blood sugar. This is not that. In their studies with animals, the researchers didn’t observe that the animals were more active nor were there changes in other biomarkers like insulin. So far, the main difference they found with the NK2R agonists is an increase in thermogenesis in certain muscles.

Another benefit of the NK2R treatments is that they don’t seem to have a big impact on lean mass — the nonfat component of body weight, namely muscle, bones, and organs. Studies indicate that 25%-39% of weight loss on GLP-1 agonists is lost muscle. According to DEXA scans of the mice, Gerhart-Hines said they observed no lean mass loss. (In mice, he noted, GLP-1 agonists can cause up to 50% lean mass loss).

And for people with both diabetes and obesity, “what we found with NK2R is that obese and diabetic models, whether mice or monkeys, respond much better to that treatment in terms of glucose control and body weight loss,” Gerhart-Hines said. He explained that GLP-1 agonists don’t work quite as well for weight loss in people with diabetes because the drug stimulates insulin production in a system that already has insulin issues and can cause more sugar to be stored as fat.

Further, GLP-1 agonists are peptide drugs, which are expensive to make. The NK2R agonists are small molecules that would be cheaper to produce, Gerhart-Hines believes. One candidate they’re testing would likely be given once daily, another once weekly.

The current surge in obesity and diabetes may be a direct consequence of our bodies’ decreased energy expenditure. “Compared to 80s and 90s, the average person is more physically active, but the overarching basal resting energy expenditure has gone down,” said Gerhart-Hines, according to research by John Speakman at the University of Aberdeen, Scotland. We don’t know why, though, he said, but guesses it could be our diets or climate controlled environments.

But the NK2R agonists are among the many currently being studied for weight loss, and it may be hard to compete with the GLP-1 agonists. “As GLP-1 medicines will soon achieve 25% weight loss and have an extensively studied safety profile, the task of producing better drugs that work well in most people, are well tolerated and also reduce the complications of cardiometabolic disease, is challenging but not impossible,” said Drucker.

Gerhart-Hines said they plan to start trials in humans in the next year, but he suspects it will be another 6 or 7 years before it comes to market, if the trials are successful.

“There’s people who want [a GLP-1 agonist] and can’t even get it,” Gerhart-Hines said. As far as weight loss drugs, he noted, “we are not even saturating the market right now.”

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

For people with obesity or type 2 diabetes, glucagon-like peptide 1 (GLP-1) agonists (including Mounjaro, Wegovy, and Ozempic) have been labeled miracle drugs. But they aren’t miraculous for everyone. Research indicates a significant portion of people discontinue using them within a year.

The main problems with GLP-1 agonists are that they are expensive and have a fairly high rate of side effects — such as nausea, vomiting, diarrhea, or constipation. Another big one is muscle loss.

A new study, published in Nature, shows a potential alternative to GLP-1 agonists with fewer side effects, at least in mice and nonhuman primates.

This lack of side effects, particularly in how the potential drug causes no muscle loss — and in fact engages muscle for some of its effect — sets it apart and makes it a potential alternative to GLP-1s. The key is not just reducing appetite but also increasing energy expenditure.

 

How It Works

The new approach targets a protein called NK2R — a member of the neurokinin receptor family, which has a role in a variety of physiological processes, including pain sensation, anxiety, and inflammation. 

“We were looking to see genetic linkages to metabolic health, and there NK2R was,” said Zach Gerhart-Hines, PhD, a professor studying molecular metabolism at the University of Copenhagen in Denmark and principal investigator of the study. The group then created a few long-acting agonists that are selective for NK2R. So far, they’ve tested them in mice and nonhuman primates.

“The data on new medicines targeting NK2R is very promising and highlights the potential of both reducing food intake and increasing energy expenditure,” said Daniel Drucker, MD, an endocrinologist and researcher at Lunenfeld-Tanenbaum Research Institute in Toronto who was not involved in the study.

“The drug activates a certain region in the hindbrain of the animal, which is controlling food intake, and it does so by reducing appetite without increasing nausea or vomiting,” explained Frederike Sass, a research assistant at the University of Copenhagen in Copenhagen, Denmark, who led the study.

Gerhart-Hines said that even at the highest dose, there were no incidents of vomiting among the nonhuman primates. Mice can’t vomit, but there are ways to tell if they feel unwell from a drug. One way researchers test that is to start feeding the mice sweetened water at the same time they’re given a drug. Then later, when the mice are no longer on the drug, they’re given a choice between sweetened and unsweetened water. If they weren’t feeling well on the drug, they’ll choose plain water because they associate the sweet water with feeling bad, otherwise mice prefer sweet water. Sass said that with the NK2R agonist, they continued to drink sweet water after the treatment, whereas when they gave the mice semaglutide, the mice preferred plain water posttreatment.

The researchers also monitored the animals’ psychological health, as NK2R has been associated with anxiety, but they observed no behavioral changes.

 

The Key Mechanism at Work

One big question is how the NK2R agonists work. The amphetamines people used for weight loss during the 1950s and 1960s worked by making people more active. GLP-1 agonists reduce appetite and lower blood sugar. This is not that. In their studies with animals, the researchers didn’t observe that the animals were more active nor were there changes in other biomarkers like insulin. So far, the main difference they found with the NK2R agonists is an increase in thermogenesis in certain muscles.

Another benefit of the NK2R treatments is that they don’t seem to have a big impact on lean mass — the nonfat component of body weight, namely muscle, bones, and organs. Studies indicate that 25%-39% of weight loss on GLP-1 agonists is lost muscle. According to DEXA scans of the mice, Gerhart-Hines said they observed no lean mass loss. (In mice, he noted, GLP-1 agonists can cause up to 50% lean mass loss).

And for people with both diabetes and obesity, “what we found with NK2R is that obese and diabetic models, whether mice or monkeys, respond much better to that treatment in terms of glucose control and body weight loss,” Gerhart-Hines said. He explained that GLP-1 agonists don’t work quite as well for weight loss in people with diabetes because the drug stimulates insulin production in a system that already has insulin issues and can cause more sugar to be stored as fat.

Further, GLP-1 agonists are peptide drugs, which are expensive to make. The NK2R agonists are small molecules that would be cheaper to produce, Gerhart-Hines believes. One candidate they’re testing would likely be given once daily, another once weekly.

The current surge in obesity and diabetes may be a direct consequence of our bodies’ decreased energy expenditure. “Compared to 80s and 90s, the average person is more physically active, but the overarching basal resting energy expenditure has gone down,” said Gerhart-Hines, according to research by John Speakman at the University of Aberdeen, Scotland. We don’t know why, though, he said, but guesses it could be our diets or climate controlled environments.

But the NK2R agonists are among the many currently being studied for weight loss, and it may be hard to compete with the GLP-1 agonists. “As GLP-1 medicines will soon achieve 25% weight loss and have an extensively studied safety profile, the task of producing better drugs that work well in most people, are well tolerated and also reduce the complications of cardiometabolic disease, is challenging but not impossible,” said Drucker.

Gerhart-Hines said they plan to start trials in humans in the next year, but he suspects it will be another 6 or 7 years before it comes to market, if the trials are successful.

“There’s people who want [a GLP-1 agonist] and can’t even get it,” Gerhart-Hines said. As far as weight loss drugs, he noted, “we are not even saturating the market right now.”

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

For people with obesity or type 2 diabetes, glucagon-like peptide 1 (GLP-1) agonists (including Mounjaro, Wegovy, and Ozempic) have been labeled miracle drugs. But they aren’t miraculous for everyone. Research indicates a significant portion of people discontinue using them within a year.

The main problems with GLP-1 agonists are that they are expensive and have a fairly high rate of side effects — such as nausea, vomiting, diarrhea, or constipation. Another big one is muscle loss.

A new study, published in Nature, shows a potential alternative to GLP-1 agonists with fewer side effects, at least in mice and nonhuman primates.

This lack of side effects, particularly in how the potential drug causes no muscle loss — and in fact engages muscle for some of its effect — sets it apart and makes it a potential alternative to GLP-1s. The key is not just reducing appetite but also increasing energy expenditure.

 

How It Works

The new approach targets a protein called NK2R — a member of the neurokinin receptor family, which has a role in a variety of physiological processes, including pain sensation, anxiety, and inflammation. 

“We were looking to see genetic linkages to metabolic health, and there NK2R was,” said Zach Gerhart-Hines, PhD, a professor studying molecular metabolism at the University of Copenhagen in Denmark and principal investigator of the study. The group then created a few long-acting agonists that are selective for NK2R. So far, they’ve tested them in mice and nonhuman primates.

“The data on new medicines targeting NK2R is very promising and highlights the potential of both reducing food intake and increasing energy expenditure,” said Daniel Drucker, MD, an endocrinologist and researcher at Lunenfeld-Tanenbaum Research Institute in Toronto who was not involved in the study.

“The drug activates a certain region in the hindbrain of the animal, which is controlling food intake, and it does so by reducing appetite without increasing nausea or vomiting,” explained Frederike Sass, a research assistant at the University of Copenhagen in Copenhagen, Denmark, who led the study.

Gerhart-Hines said that even at the highest dose, there were no incidents of vomiting among the nonhuman primates. Mice can’t vomit, but there are ways to tell if they feel unwell from a drug. One way researchers test that is to start feeding the mice sweetened water at the same time they’re given a drug. Then later, when the mice are no longer on the drug, they’re given a choice between sweetened and unsweetened water. If they weren’t feeling well on the drug, they’ll choose plain water because they associate the sweet water with feeling bad, otherwise mice prefer sweet water. Sass said that with the NK2R agonist, they continued to drink sweet water after the treatment, whereas when they gave the mice semaglutide, the mice preferred plain water posttreatment.

The researchers also monitored the animals’ psychological health, as NK2R has been associated with anxiety, but they observed no behavioral changes.

 

The Key Mechanism at Work

One big question is how the NK2R agonists work. The amphetamines people used for weight loss during the 1950s and 1960s worked by making people more active. GLP-1 agonists reduce appetite and lower blood sugar. This is not that. In their studies with animals, the researchers didn’t observe that the animals were more active nor were there changes in other biomarkers like insulin. So far, the main difference they found with the NK2R agonists is an increase in thermogenesis in certain muscles.

Another benefit of the NK2R treatments is that they don’t seem to have a big impact on lean mass — the nonfat component of body weight, namely muscle, bones, and organs. Studies indicate that 25%-39% of weight loss on GLP-1 agonists is lost muscle. According to DEXA scans of the mice, Gerhart-Hines said they observed no lean mass loss. (In mice, he noted, GLP-1 agonists can cause up to 50% lean mass loss).

And for people with both diabetes and obesity, “what we found with NK2R is that obese and diabetic models, whether mice or monkeys, respond much better to that treatment in terms of glucose control and body weight loss,” Gerhart-Hines said. He explained that GLP-1 agonists don’t work quite as well for weight loss in people with diabetes because the drug stimulates insulin production in a system that already has insulin issues and can cause more sugar to be stored as fat.

Further, GLP-1 agonists are peptide drugs, which are expensive to make. The NK2R agonists are small molecules that would be cheaper to produce, Gerhart-Hines believes. One candidate they’re testing would likely be given once daily, another once weekly.

The current surge in obesity and diabetes may be a direct consequence of our bodies’ decreased energy expenditure. “Compared to 80s and 90s, the average person is more physically active, but the overarching basal resting energy expenditure has gone down,” said Gerhart-Hines, according to research by John Speakman at the University of Aberdeen, Scotland. We don’t know why, though, he said, but guesses it could be our diets or climate controlled environments.

But the NK2R agonists are among the many currently being studied for weight loss, and it may be hard to compete with the GLP-1 agonists. “As GLP-1 medicines will soon achieve 25% weight loss and have an extensively studied safety profile, the task of producing better drugs that work well in most people, are well tolerated and also reduce the complications of cardiometabolic disease, is challenging but not impossible,” said Drucker.

Gerhart-Hines said they plan to start trials in humans in the next year, but he suspects it will be another 6 or 7 years before it comes to market, if the trials are successful.

“There’s people who want [a GLP-1 agonist] and can’t even get it,” Gerhart-Hines said. As far as weight loss drugs, he noted, “we are not even saturating the market right now.”

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

Of all the currently available pharmacological and nonpharmacological therapies for attention deficit and hyperactivity disorder (ADHD) in adults, only stimulants and atomoxetine are effective at reducing core symptoms, results of a large comprehensive meta-analysis showed.

The study of 113 randomized controlled trials with nearly 15,000 adults with a formal diagnosis of ADHD also revealed that atomoxetine is less acceptable to patients and that results of efficacy of nonpharmacological strategies are inconsistent.

Data on long-term efficacy of ADHD therapies are lacking, investigators noted, so these results only apply to short-term efficacy.

“There is a lot of controversy about medication, so these are quite reassuring data and certainly reinforce the role of medication as a treatment for ADHD,” study investigator Samuele Cortese, MD, PhD, with University of Southampton, England, said during a press briefing hosted by the UK Science Media Center where the findings were released.

The results also point to the “possible role of nonpharmacological interventions, which are currently not well established in current guidelines. However, there is a need for better evidence to fully understand the exact effect of these nonpharmacological interventions,” Cortese noted.

The study was published online in The Lancet Psychiatry. 

 

Bridging the Knowledge Gap

Once thought to be a childhood disorder only, ADHD is now well-known to persist into adulthood, affecting roughly 2.5% of the general adult population worldwide. The comparative benefits and harms of available interventions for ADHD in adults remain unclear.

To address this knowledge gap, researchers did a comprehensive systematic review and component network meta-analysis comparing a broad range of drug and nondrug treatments for adults with ADHD across several outcomes.

For reducing core ADHD symptoms at 12 weeks, only stimulants and atomoxetine were better than placebo in self-reported and clinician-reported rating scales, the study team found.

For stimulants, the standardized mean differences (SMDs) on the self-reported and clinician-reported scales were 0.39 and 0.61, respectively. The corresponding SMDs for atomoxetine were 0.38 and 0.51.

There was no evidence that ADHD medications were better than placebo in improving additional relevant outcomes such as quality of life.

In terms of nondrug interventions, cognitive behavioral therapy, cognitive remediation, mindfulness, psychoeducation, and transcranial direct current stimulation were better than placebo only on clinician-reported measures, with SMDs of −1.35, −0.79, −0.77, and −0.78, respectively.

However, the evidence for nondrug strategies is less conclusive overall, with “discordant results across types of raters and based on a small body of evidence,” the authors wrote in their article.

And evidence for long-term efficacy (beyond 12 weeks) for ADHD interventions is “limited and under-investigated,” they said.

Regarding acceptability, all strategies were similar to placebo except for atomoxetine and guanfacine which had lower acceptability than placebo.

“It’s very important to emphasize that we focused on the average effect, not at an individual level,” first author Edoardo Ostinelli, MD, with University of Oxford, England, said at the briefing. “Therefore, we cannot make any recommendation at an individual level. We need studies with individual participant data so that we can personalize treatment.”

Cortese said the information from this analysis may be particularly important for “psychoeducation” of the patient before actually starting with a treatment plan. Patients often ask about nonpharmacological interventions and this study provides the “best synthesis of available data to inform these discussions,” he said.

 

Experts Weigh In 

Several experts weighed in on the results in a statement from the UK Science Media Center.

Celso Arango, MD, PhD, psychiatrist with Gregorio Marañón General University Hospital, Madrid, Spain, noted that there is a “clear shortage of research on ADHD in adulthood, particularly regarding medium-term (beyond 12 weeks) and long-term treatment outcomes. Consequently, the findings are applicable only to short-term treatment.”

Another strength of the study is that it was developed with input from people with ADHD, Arango added, making it “highly relevant.”

The majority of studies available for the analysis involved pharmacological treatments, which is important to consider when interpreting the findings, noted Katya Rubia, PhD, professor of cognitive neuroscience, King’s College London, England.

“For example, for neurostimulation, only 10 studies were included and on very heterogeneous stimulation methods,” Rubia said. “The evidence on the efficacy of neurostimulation is therefore hardly conclusive and more studies are needed to establish their efficacy.”

Roi Cohen Kadosh, PhD, professor of cognitive neuroscience, University of Surrey, Guildford, England, agreed. While the study is a “valuable contribution to the literature,” it sheds light on “both the scarcity of neurostimulation research and the limited exploration of combined treatment approaches for ADHD,” he said.

“While novel neurostimulation methods linked to neuroplasticity — such as those we have demonstrated to be superior in children with ADHD — were not covered here, they have shown promising and lasting benefits. In contrast, research in adults remains relatively underdeveloped. Moving forward, greater emphasis on innovative, tolerable, personalized, and sustainable neurostimulation approaches is essential to meet the unmet clinical needs of adults with ADHD,” Kadosh added.

In a commentary in The Lancet Psychiatry, David Coghill, MD, with The University of Melbourne, Australia, cautioned that the findings do not mean that potential benefits of nonpharmacological interventions should be dismissed.

“While some of the nonpharmacological treatments (eg, cognitive behavioral therapy, cognitive remediation, mindfulness, psychoeducation, and transcranial direct current stimulation) showed effects on clinician-rated outcomes similar to, and in some cases greater than, the pharmacological treatments, they did not show the same effects on self-reported outcomes. These interventions were therefore considered less robust than the pharmacological treatments that showed changes on both measurement types,” he wrote.

This study had no commercial funding. Ostinelli had received research and consultancy fees from Angelini Pharma. Cortese received reimbursement for travel and accommodation expenses in relation to lectures delivered for the Association for Child and Adolescent Central Health, the Canadian ADHD Alliance Resource, and the British Association of Psychopharmacology; and had received honoraria from MEDICE; and is chair of the European ADHD Guidelines Group. Arango, Rubia, and Kadosh had no relevant disclosures. Coghill had received honoraria from CCM Conecta, Takeda, Novartis, Servier, and MEDICE.

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

Of all the currently available pharmacological and nonpharmacological therapies for attention deficit and hyperactivity disorder (ADHD) in adults, only stimulants and atomoxetine are effective at reducing core symptoms, results of a large comprehensive meta-analysis showed.

The study of 113 randomized controlled trials with nearly 15,000 adults with a formal diagnosis of ADHD also revealed that atomoxetine is less acceptable to patients and that results of efficacy of nonpharmacological strategies are inconsistent.

Data on long-term efficacy of ADHD therapies are lacking, investigators noted, so these results only apply to short-term efficacy.

“There is a lot of controversy about medication, so these are quite reassuring data and certainly reinforce the role of medication as a treatment for ADHD,” study investigator Samuele Cortese, MD, PhD, with University of Southampton, England, said during a press briefing hosted by the UK Science Media Center where the findings were released.

The results also point to the “possible role of nonpharmacological interventions, which are currently not well established in current guidelines. However, there is a need for better evidence to fully understand the exact effect of these nonpharmacological interventions,” Cortese noted.

The study was published online in The Lancet Psychiatry. 

 

Bridging the Knowledge Gap

Once thought to be a childhood disorder only, ADHD is now well-known to persist into adulthood, affecting roughly 2.5% of the general adult population worldwide. The comparative benefits and harms of available interventions for ADHD in adults remain unclear.

To address this knowledge gap, researchers did a comprehensive systematic review and component network meta-analysis comparing a broad range of drug and nondrug treatments for adults with ADHD across several outcomes.

For reducing core ADHD symptoms at 12 weeks, only stimulants and atomoxetine were better than placebo in self-reported and clinician-reported rating scales, the study team found.

For stimulants, the standardized mean differences (SMDs) on the self-reported and clinician-reported scales were 0.39 and 0.61, respectively. The corresponding SMDs for atomoxetine were 0.38 and 0.51.

There was no evidence that ADHD medications were better than placebo in improving additional relevant outcomes such as quality of life.

In terms of nondrug interventions, cognitive behavioral therapy, cognitive remediation, mindfulness, psychoeducation, and transcranial direct current stimulation were better than placebo only on clinician-reported measures, with SMDs of −1.35, −0.79, −0.77, and −0.78, respectively.

However, the evidence for nondrug strategies is less conclusive overall, with “discordant results across types of raters and based on a small body of evidence,” the authors wrote in their article.

And evidence for long-term efficacy (beyond 12 weeks) for ADHD interventions is “limited and under-investigated,” they said.

Regarding acceptability, all strategies were similar to placebo except for atomoxetine and guanfacine which had lower acceptability than placebo.

“It’s very important to emphasize that we focused on the average effect, not at an individual level,” first author Edoardo Ostinelli, MD, with University of Oxford, England, said at the briefing. “Therefore, we cannot make any recommendation at an individual level. We need studies with individual participant data so that we can personalize treatment.”

Cortese said the information from this analysis may be particularly important for “psychoeducation” of the patient before actually starting with a treatment plan. Patients often ask about nonpharmacological interventions and this study provides the “best synthesis of available data to inform these discussions,” he said.

 

Experts Weigh In 

Several experts weighed in on the results in a statement from the UK Science Media Center.

Celso Arango, MD, PhD, psychiatrist with Gregorio Marañón General University Hospital, Madrid, Spain, noted that there is a “clear shortage of research on ADHD in adulthood, particularly regarding medium-term (beyond 12 weeks) and long-term treatment outcomes. Consequently, the findings are applicable only to short-term treatment.”

Another strength of the study is that it was developed with input from people with ADHD, Arango added, making it “highly relevant.”

The majority of studies available for the analysis involved pharmacological treatments, which is important to consider when interpreting the findings, noted Katya Rubia, PhD, professor of cognitive neuroscience, King’s College London, England.

“For example, for neurostimulation, only 10 studies were included and on very heterogeneous stimulation methods,” Rubia said. “The evidence on the efficacy of neurostimulation is therefore hardly conclusive and more studies are needed to establish their efficacy.”

Roi Cohen Kadosh, PhD, professor of cognitive neuroscience, University of Surrey, Guildford, England, agreed. While the study is a “valuable contribution to the literature,” it sheds light on “both the scarcity of neurostimulation research and the limited exploration of combined treatment approaches for ADHD,” he said.

“While novel neurostimulation methods linked to neuroplasticity — such as those we have demonstrated to be superior in children with ADHD — were not covered here, they have shown promising and lasting benefits. In contrast, research in adults remains relatively underdeveloped. Moving forward, greater emphasis on innovative, tolerable, personalized, and sustainable neurostimulation approaches is essential to meet the unmet clinical needs of adults with ADHD,” Kadosh added.

In a commentary in The Lancet Psychiatry, David Coghill, MD, with The University of Melbourne, Australia, cautioned that the findings do not mean that potential benefits of nonpharmacological interventions should be dismissed.

“While some of the nonpharmacological treatments (eg, cognitive behavioral therapy, cognitive remediation, mindfulness, psychoeducation, and transcranial direct current stimulation) showed effects on clinician-rated outcomes similar to, and in some cases greater than, the pharmacological treatments, they did not show the same effects on self-reported outcomes. These interventions were therefore considered less robust than the pharmacological treatments that showed changes on both measurement types,” he wrote.

This study had no commercial funding. Ostinelli had received research and consultancy fees from Angelini Pharma. Cortese received reimbursement for travel and accommodation expenses in relation to lectures delivered for the Association for Child and Adolescent Central Health, the Canadian ADHD Alliance Resource, and the British Association of Psychopharmacology; and had received honoraria from MEDICE; and is chair of the European ADHD Guidelines Group. Arango, Rubia, and Kadosh had no relevant disclosures. Coghill had received honoraria from CCM Conecta, Takeda, Novartis, Servier, and MEDICE.

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

Of all the currently available pharmacological and nonpharmacological therapies for attention deficit and hyperactivity disorder (ADHD) in adults, only stimulants and atomoxetine are effective at reducing core symptoms, results of a large comprehensive meta-analysis showed.

The study of 113 randomized controlled trials with nearly 15,000 adults with a formal diagnosis of ADHD also revealed that atomoxetine is less acceptable to patients and that results of efficacy of nonpharmacological strategies are inconsistent.

Data on long-term efficacy of ADHD therapies are lacking, investigators noted, so these results only apply to short-term efficacy.

“There is a lot of controversy about medication, so these are quite reassuring data and certainly reinforce the role of medication as a treatment for ADHD,” study investigator Samuele Cortese, MD, PhD, with University of Southampton, England, said during a press briefing hosted by the UK Science Media Center where the findings were released.

The results also point to the “possible role of nonpharmacological interventions, which are currently not well established in current guidelines. However, there is a need for better evidence to fully understand the exact effect of these nonpharmacological interventions,” Cortese noted.

The study was published online in The Lancet Psychiatry. 

 

Bridging the Knowledge Gap

Once thought to be a childhood disorder only, ADHD is now well-known to persist into adulthood, affecting roughly 2.5% of the general adult population worldwide. The comparative benefits and harms of available interventions for ADHD in adults remain unclear.

To address this knowledge gap, researchers did a comprehensive systematic review and component network meta-analysis comparing a broad range of drug and nondrug treatments for adults with ADHD across several outcomes.

For reducing core ADHD symptoms at 12 weeks, only stimulants and atomoxetine were better than placebo in self-reported and clinician-reported rating scales, the study team found.

For stimulants, the standardized mean differences (SMDs) on the self-reported and clinician-reported scales were 0.39 and 0.61, respectively. The corresponding SMDs for atomoxetine were 0.38 and 0.51.

There was no evidence that ADHD medications were better than placebo in improving additional relevant outcomes such as quality of life.

In terms of nondrug interventions, cognitive behavioral therapy, cognitive remediation, mindfulness, psychoeducation, and transcranial direct current stimulation were better than placebo only on clinician-reported measures, with SMDs of −1.35, −0.79, −0.77, and −0.78, respectively.

However, the evidence for nondrug strategies is less conclusive overall, with “discordant results across types of raters and based on a small body of evidence,” the authors wrote in their article.

And evidence for long-term efficacy (beyond 12 weeks) for ADHD interventions is “limited and under-investigated,” they said.

Regarding acceptability, all strategies were similar to placebo except for atomoxetine and guanfacine which had lower acceptability than placebo.

“It’s very important to emphasize that we focused on the average effect, not at an individual level,” first author Edoardo Ostinelli, MD, with University of Oxford, England, said at the briefing. “Therefore, we cannot make any recommendation at an individual level. We need studies with individual participant data so that we can personalize treatment.”

Cortese said the information from this analysis may be particularly important for “psychoeducation” of the patient before actually starting with a treatment plan. Patients often ask about nonpharmacological interventions and this study provides the “best synthesis of available data to inform these discussions,” he said.

 

Experts Weigh In 

Several experts weighed in on the results in a statement from the UK Science Media Center.

Celso Arango, MD, PhD, psychiatrist with Gregorio Marañón General University Hospital, Madrid, Spain, noted that there is a “clear shortage of research on ADHD in adulthood, particularly regarding medium-term (beyond 12 weeks) and long-term treatment outcomes. Consequently, the findings are applicable only to short-term treatment.”

Another strength of the study is that it was developed with input from people with ADHD, Arango added, making it “highly relevant.”

The majority of studies available for the analysis involved pharmacological treatments, which is important to consider when interpreting the findings, noted Katya Rubia, PhD, professor of cognitive neuroscience, King’s College London, England.

“For example, for neurostimulation, only 10 studies were included and on very heterogeneous stimulation methods,” Rubia said. “The evidence on the efficacy of neurostimulation is therefore hardly conclusive and more studies are needed to establish their efficacy.”

Roi Cohen Kadosh, PhD, professor of cognitive neuroscience, University of Surrey, Guildford, England, agreed. While the study is a “valuable contribution to the literature,” it sheds light on “both the scarcity of neurostimulation research and the limited exploration of combined treatment approaches for ADHD,” he said.

“While novel neurostimulation methods linked to neuroplasticity — such as those we have demonstrated to be superior in children with ADHD — were not covered here, they have shown promising and lasting benefits. In contrast, research in adults remains relatively underdeveloped. Moving forward, greater emphasis on innovative, tolerable, personalized, and sustainable neurostimulation approaches is essential to meet the unmet clinical needs of adults with ADHD,” Kadosh added.

In a commentary in The Lancet Psychiatry, David Coghill, MD, with The University of Melbourne, Australia, cautioned that the findings do not mean that potential benefits of nonpharmacological interventions should be dismissed.

“While some of the nonpharmacological treatments (eg, cognitive behavioral therapy, cognitive remediation, mindfulness, psychoeducation, and transcranial direct current stimulation) showed effects on clinician-rated outcomes similar to, and in some cases greater than, the pharmacological treatments, they did not show the same effects on self-reported outcomes. These interventions were therefore considered less robust than the pharmacological treatments that showed changes on both measurement types,” he wrote.

This study had no commercial funding. Ostinelli had received research and consultancy fees from Angelini Pharma. Cortese received reimbursement for travel and accommodation expenses in relation to lectures delivered for the Association for Child and Adolescent Central Health, the Canadian ADHD Alliance Resource, and the British Association of Psychopharmacology; and had received honoraria from MEDICE; and is chair of the European ADHD Guidelines Group. Arango, Rubia, and Kadosh had no relevant disclosures. Coghill had received honoraria from CCM Conecta, Takeda, Novartis, Servier, and MEDICE.

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

NEW YORK, NY — Work over the past several years has reframed hidradenitis suppurativa (HS) as a large-field inflammatory process, a recharacterization that has immediate relevance to treatment strategies and goals, according to two investigators intimately involved in much of the recent progress.

“Success is being achieved by targeting multiple inflammatory axes in HS, and therapeutics are evolving rapidly,” reported James G. Krueger, MD, PhD, head of the Laboratory of Investigative Dermatology, Rockefeller University, New York, NY.

The activity of targeted anti-inflammatory therapies — bimekizumab just joined adalimumab and secukinumab as a third approved biologic for HS — is not news, but the degree to which inflammation is upregulated systemically, not just at areas of skin involvement, has changed the conceptualization of HS.

HS Is a Systemic Inflammatory Disease

Relative to psoriasis, for which there are many parallels, “HS is hugely more inflammatory in the systemic circulation,” Krueger said at the 27th Annual Winter Symposium — Advances in Medical and Surgical Dermatology (MSWS) 2024. Yet, HS is also more complex involving additional pathways that appear to include dysbiosis. The concept of follicular occlusion, once a common explanation for HS, has been left far behind.

“Unlike psoriasis, which we can treat really well by inhibiting a single pathway target, HS is just not that simple,” Krueger said. Although largely an inflammatory process, the cascade of inflammatory factors for specific manifestations, such as tunnels, means that optimal therapy in one case might have little benefit in another.

The relatively new evidence that HS activity is not confined to lesional skin might be the most important recent step toward new strategies to target disease. These studies were performed by Kristina Navrazhina, MD, PhD, now a resident in dermatology at the Icahn School of Medicine at Mount Sinai, New York. She received her PhD while studying HS activity in non-lesional skin. Her work has led her to conclude that the best chance for better outcomes in HS is early diagnosis and treatment. Although this is generally true of any pathology, the changes in the HS phenotype once fistulae form includes a poor response to conventional therapies. 

In fact, based on her work in evaluating HS activity in non-lesional skin, Navrazhina has shown that “many patients with modest lesions already have advanced disease.” Consistent with the premise that HS is a deeply systemic inflammatory process, nodules, considered an early manifestation, turn out to be “the tip of the iceberg.”

 

Non-Lesional HS Skin Is Inflamed

When she has employed RNA sequencing based on tape strip sampling from completely normal skin away from nodules, interleukin (IL)-17 and a broad array of other inflammatory markers were found to be upregulated. When she performed ultrasound to look for disease activity under the normal skin, she has often found tunnels already formed. Doppler ultrasound showed some of these tunnels were actively draining.

This might provide a partial explanation for why therapies are not always effective even when clinical signs of disease are modest. 

“Are we missing the opportunity for intervening?” Navrazhina asked, noting that early intervention has been limited traditionally by extremely long diagnostic delays. Citing the literature, Navrazhina said the average delay is 7 years for HS versus 1 year for psoriasis. Patients often cycle through 3 or 4 providers before the diagnosis is made, she said.

Awakening first-line clinicians to the signs and symptoms of HS, whether in the emergency room or primary care, is a critical message because of the incrementally difficult task to control disease once fistulae have formed. 

Krueger made the same appeal. For the neutrophilic inflammation that characterizes nodules, targeted therapies are often effective, but he agreed that available therapies are generally far less so once tunnels form.

 

Role Seen for Bacteria in HS Pathogenesis

One reason might be an interaction between anaerobic bacteria and the keratinocytes that form the tunnel walls, according to Krueger. Although HS is not typically considered an infectious disease, he reported that the interaction of these bacteria with keratinocytes is associated with expression of approximately 1000 inflammatory gene products. The process of tunnel formation is traced to how factors recruited by upregulated inflammation, such as chemokines, coordinate.

He described recent work pursing novel strategies such as highly targeted antibiotics or inhibitors of complement factor C5a, which has been proposed as a biomarker for HS, to intervene in preventing or reversing HS tunnels. 

While this work progresses, one of the most Important unmet needs in HS is an accepted measure of clinically meaningful improvement in advanced disease, particularly the impact of therapy on HS tunnels, according to Krueger. 

“There is no measure of tunnel activity that the FDA accepts in evaluating drugs,” he noted, which will be essential for approving therapies that offer this benefit. 

A phase 3 trials program for one of the promising drugs, sonelokimab, was announced early in 2024. A nanobody that targets IL-17A/A, IL-17A/F, and IL-17F/F, the small size of this molecule permits exceptional tissue penetration while the broad anti-IL-17 activity has a high degree of theoretical potential in late-stage HS, according to Krueger. 

There are numerous pieces of the HS puzzle that are still missing, but both Krueger and Navrazhina are enthusiastic about new targets and opportunities for disease control that are stemming from a better understanding of the underlying pathophysiology. Not least, both indicated that testing for inflammatory phenotypes will allow for individualized therapeutic choices with a maximum likelihood of response, particularly if earlier diagnosis permits earlier treatment. 

“Due to the heterogeneity of HS, it is hard to know who will respond to which treatment or which treatment should be started first,” Navrazhina said. She thinks that early measures of the inflammatory profile in nodules or even non-lesional skin might provide that guidance. 

Both Krueger and Navrazhina reported no financial relationships relevant to this work. 

 

A version of this article appeared on Medscape.com.

NEW YORK, NY — Work over the past several years has reframed hidradenitis suppurativa (HS) as a large-field inflammatory process, a recharacterization that has immediate relevance to treatment strategies and goals, according to two investigators intimately involved in much of the recent progress.

“Success is being achieved by targeting multiple inflammatory axes in HS, and therapeutics are evolving rapidly,” reported James G. Krueger, MD, PhD, head of the Laboratory of Investigative Dermatology, Rockefeller University, New York, NY.

The activity of targeted anti-inflammatory therapies — bimekizumab just joined adalimumab and secukinumab as a third approved biologic for HS — is not news, but the degree to which inflammation is upregulated systemically, not just at areas of skin involvement, has changed the conceptualization of HS.

HS Is a Systemic Inflammatory Disease

Relative to psoriasis, for which there are many parallels, “HS is hugely more inflammatory in the systemic circulation,” Krueger said at the 27th Annual Winter Symposium — Advances in Medical and Surgical Dermatology (MSWS) 2024. Yet, HS is also more complex involving additional pathways that appear to include dysbiosis. The concept of follicular occlusion, once a common explanation for HS, has been left far behind.

“Unlike psoriasis, which we can treat really well by inhibiting a single pathway target, HS is just not that simple,” Krueger said. Although largely an inflammatory process, the cascade of inflammatory factors for specific manifestations, such as tunnels, means that optimal therapy in one case might have little benefit in another.

The relatively new evidence that HS activity is not confined to lesional skin might be the most important recent step toward new strategies to target disease. These studies were performed by Kristina Navrazhina, MD, PhD, now a resident in dermatology at the Icahn School of Medicine at Mount Sinai, New York. She received her PhD while studying HS activity in non-lesional skin. Her work has led her to conclude that the best chance for better outcomes in HS is early diagnosis and treatment. Although this is generally true of any pathology, the changes in the HS phenotype once fistulae form includes a poor response to conventional therapies. 

In fact, based on her work in evaluating HS activity in non-lesional skin, Navrazhina has shown that “many patients with modest lesions already have advanced disease.” Consistent with the premise that HS is a deeply systemic inflammatory process, nodules, considered an early manifestation, turn out to be “the tip of the iceberg.”

 

Non-Lesional HS Skin Is Inflamed

When she has employed RNA sequencing based on tape strip sampling from completely normal skin away from nodules, interleukin (IL)-17 and a broad array of other inflammatory markers were found to be upregulated. When she performed ultrasound to look for disease activity under the normal skin, she has often found tunnels already formed. Doppler ultrasound showed some of these tunnels were actively draining.

This might provide a partial explanation for why therapies are not always effective even when clinical signs of disease are modest. 

“Are we missing the opportunity for intervening?” Navrazhina asked, noting that early intervention has been limited traditionally by extremely long diagnostic delays. Citing the literature, Navrazhina said the average delay is 7 years for HS versus 1 year for psoriasis. Patients often cycle through 3 or 4 providers before the diagnosis is made, she said.

Awakening first-line clinicians to the signs and symptoms of HS, whether in the emergency room or primary care, is a critical message because of the incrementally difficult task to control disease once fistulae have formed. 

Krueger made the same appeal. For the neutrophilic inflammation that characterizes nodules, targeted therapies are often effective, but he agreed that available therapies are generally far less so once tunnels form.

 

Role Seen for Bacteria in HS Pathogenesis

One reason might be an interaction between anaerobic bacteria and the keratinocytes that form the tunnel walls, according to Krueger. Although HS is not typically considered an infectious disease, he reported that the interaction of these bacteria with keratinocytes is associated with expression of approximately 1000 inflammatory gene products. The process of tunnel formation is traced to how factors recruited by upregulated inflammation, such as chemokines, coordinate.

He described recent work pursing novel strategies such as highly targeted antibiotics or inhibitors of complement factor C5a, which has been proposed as a biomarker for HS, to intervene in preventing or reversing HS tunnels. 

While this work progresses, one of the most Important unmet needs in HS is an accepted measure of clinically meaningful improvement in advanced disease, particularly the impact of therapy on HS tunnels, according to Krueger. 

“There is no measure of tunnel activity that the FDA accepts in evaluating drugs,” he noted, which will be essential for approving therapies that offer this benefit. 

A phase 3 trials program for one of the promising drugs, sonelokimab, was announced early in 2024. A nanobody that targets IL-17A/A, IL-17A/F, and IL-17F/F, the small size of this molecule permits exceptional tissue penetration while the broad anti-IL-17 activity has a high degree of theoretical potential in late-stage HS, according to Krueger. 

There are numerous pieces of the HS puzzle that are still missing, but both Krueger and Navrazhina are enthusiastic about new targets and opportunities for disease control that are stemming from a better understanding of the underlying pathophysiology. Not least, both indicated that testing for inflammatory phenotypes will allow for individualized therapeutic choices with a maximum likelihood of response, particularly if earlier diagnosis permits earlier treatment. 

“Due to the heterogeneity of HS, it is hard to know who will respond to which treatment or which treatment should be started first,” Navrazhina said. She thinks that early measures of the inflammatory profile in nodules or even non-lesional skin might provide that guidance. 

Both Krueger and Navrazhina reported no financial relationships relevant to this work. 

 

A version of this article appeared on Medscape.com.

NEW YORK, NY — Work over the past several years has reframed hidradenitis suppurativa (HS) as a large-field inflammatory process, a recharacterization that has immediate relevance to treatment strategies and goals, according to two investigators intimately involved in much of the recent progress.

“Success is being achieved by targeting multiple inflammatory axes in HS, and therapeutics are evolving rapidly,” reported James G. Krueger, MD, PhD, head of the Laboratory of Investigative Dermatology, Rockefeller University, New York, NY.

The activity of targeted anti-inflammatory therapies — bimekizumab just joined adalimumab and secukinumab as a third approved biologic for HS — is not news, but the degree to which inflammation is upregulated systemically, not just at areas of skin involvement, has changed the conceptualization of HS.

HS Is a Systemic Inflammatory Disease

Relative to psoriasis, for which there are many parallels, “HS is hugely more inflammatory in the systemic circulation,” Krueger said at the 27th Annual Winter Symposium — Advances in Medical and Surgical Dermatology (MSWS) 2024. Yet, HS is also more complex involving additional pathways that appear to include dysbiosis. The concept of follicular occlusion, once a common explanation for HS, has been left far behind.

“Unlike psoriasis, which we can treat really well by inhibiting a single pathway target, HS is just not that simple,” Krueger said. Although largely an inflammatory process, the cascade of inflammatory factors for specific manifestations, such as tunnels, means that optimal therapy in one case might have little benefit in another.

The relatively new evidence that HS activity is not confined to lesional skin might be the most important recent step toward new strategies to target disease. These studies were performed by Kristina Navrazhina, MD, PhD, now a resident in dermatology at the Icahn School of Medicine at Mount Sinai, New York. She received her PhD while studying HS activity in non-lesional skin. Her work has led her to conclude that the best chance for better outcomes in HS is early diagnosis and treatment. Although this is generally true of any pathology, the changes in the HS phenotype once fistulae form includes a poor response to conventional therapies. 

In fact, based on her work in evaluating HS activity in non-lesional skin, Navrazhina has shown that “many patients with modest lesions already have advanced disease.” Consistent with the premise that HS is a deeply systemic inflammatory process, nodules, considered an early manifestation, turn out to be “the tip of the iceberg.”

 

Non-Lesional HS Skin Is Inflamed

When she has employed RNA sequencing based on tape strip sampling from completely normal skin away from nodules, interleukin (IL)-17 and a broad array of other inflammatory markers were found to be upregulated. When she performed ultrasound to look for disease activity under the normal skin, she has often found tunnels already formed. Doppler ultrasound showed some of these tunnels were actively draining.

This might provide a partial explanation for why therapies are not always effective even when clinical signs of disease are modest. 

“Are we missing the opportunity for intervening?” Navrazhina asked, noting that early intervention has been limited traditionally by extremely long diagnostic delays. Citing the literature, Navrazhina said the average delay is 7 years for HS versus 1 year for psoriasis. Patients often cycle through 3 or 4 providers before the diagnosis is made, she said.

Awakening first-line clinicians to the signs and symptoms of HS, whether in the emergency room or primary care, is a critical message because of the incrementally difficult task to control disease once fistulae have formed. 

Krueger made the same appeal. For the neutrophilic inflammation that characterizes nodules, targeted therapies are often effective, but he agreed that available therapies are generally far less so once tunnels form.

 

Role Seen for Bacteria in HS Pathogenesis

One reason might be an interaction between anaerobic bacteria and the keratinocytes that form the tunnel walls, according to Krueger. Although HS is not typically considered an infectious disease, he reported that the interaction of these bacteria with keratinocytes is associated with expression of approximately 1000 inflammatory gene products. The process of tunnel formation is traced to how factors recruited by upregulated inflammation, such as chemokines, coordinate.

He described recent work pursing novel strategies such as highly targeted antibiotics or inhibitors of complement factor C5a, which has been proposed as a biomarker for HS, to intervene in preventing or reversing HS tunnels. 

While this work progresses, one of the most Important unmet needs in HS is an accepted measure of clinically meaningful improvement in advanced disease, particularly the impact of therapy on HS tunnels, according to Krueger. 

“There is no measure of tunnel activity that the FDA accepts in evaluating drugs,” he noted, which will be essential for approving therapies that offer this benefit. 

A phase 3 trials program for one of the promising drugs, sonelokimab, was announced early in 2024. A nanobody that targets IL-17A/A, IL-17A/F, and IL-17F/F, the small size of this molecule permits exceptional tissue penetration while the broad anti-IL-17 activity has a high degree of theoretical potential in late-stage HS, according to Krueger. 

There are numerous pieces of the HS puzzle that are still missing, but both Krueger and Navrazhina are enthusiastic about new targets and opportunities for disease control that are stemming from a better understanding of the underlying pathophysiology. Not least, both indicated that testing for inflammatory phenotypes will allow for individualized therapeutic choices with a maximum likelihood of response, particularly if earlier diagnosis permits earlier treatment. 

“Due to the heterogeneity of HS, it is hard to know who will respond to which treatment or which treatment should be started first,” Navrazhina said. She thinks that early measures of the inflammatory profile in nodules or even non-lesional skin might provide that guidance. 

Both Krueger and Navrazhina reported no financial relationships relevant to this work. 

 

A version of this article appeared on Medscape.com.

A new diagnostic test can accurately distinguish osteoarthritis (OA) from inflammatory arthritis using two synovial fluid biomarkers, according to research published in the Journal of Orthopaedic Research on December 18, 2024.

However, experts question whether such a test would be useful.

“The need would seem to be fairly limited, mostly those with single joint involvement and a lack of other systemic features to specify a diagnosis, which is not that common, at least in rheumatology, where there are usually features in the history and physical that can clarify the diagnosis,” said Amanda E. Nelson, MD, MSCR, professor of medicine in the Division of Rheumatology, Allergy, and Immunology at the University of North Carolina at Chapel Hill. She was not involved with the research.

The test uses an algorithm that incorporates concentrations of cartilage oligomeric matrix protein (COMP) and interleukin 8 (IL-8) in synovial fluid. The researchers hypothesized that a ratio of the two biomarkers could distinguish between primary OA and other inflammatory arthritic diagnoses.

“Primary OA is unlikely when either COMP concentration or COMP/IL‐8 ratio in the synovial fluid is low since these conditions indicate either lack of cartilage degradation or presence of high inflammation,” wrote Daniel Keter and coauthors at CD Diagnostics, Claymont, Delaware, and CD Laboratories, Towson, Maryland. “In contrast, a high COMP concentration result in combination with high COMP/IL‐8 ratio would be suggestive of low inflammation in the setting of cartilage deterioration, which is indicative of primary OA.”

In patients with OA, synovial fluid can be difficult to aspirate in sufficient amounts for testing, Nelson said.

“If synovial fluid is present and able to be aspirated, it is unclear if this test has any benefit over a simple, standard cell count and crystal assessment, which can also distinguish between osteoarthritis and more inflammatory arthritides,” she said.

 

Differentiating OA

To test this potential diagnostic algorithm, researchers obtained 171 knee synovial fluid samples from approved clinical remnant sample sources and a biovendor. All samples were annotated with an existing arthritic diagnosis, including 54 with primary OA, 57 with rheumatoid arthritis (RA), 30 with crystal arthritis (CA), and 30 with native septic arthritis (NSA).

Researchers assigned a CA diagnosis based on the presence of monosodium urate or calcium pyrophosphate dehydrate crystals in the synovial fluid, and NSA was determined via the Synovasure Alpha Defensin test. OA was confirmed via radiograph as Kellgren‐Lawrence grades 2‐4 with no other arthritic diagnoses. RA samples were purchased via a biovendor, and researchers were not provided with diagnosis‐confirming data.

All samples were randomized and blinded before testing, and researchers used enzyme-linked immunosorbent assay tests for both COMP and IL-8 biomarkers.

Of the 54 OA samples, 47 tested positive for OA using the COMP + COMP/IL-8 ratio algorithm. Of the 117 samples with inflammatory arthritis, 13 tested positive for OA. Overall, the diagnostic algorithm demonstrated a clinical sensitivity of 87.0% and specificity of 88.9%. The positive predictive value was 78.3%, while the negative predictive value was 93.7%.

 

Unclear Clinical Need

Nelson noted that while this test aims to differentiate between arthritic diagnoses, patients can also have multiple conditions.

“Many individuals with rheumatoid arthritis will develop osteoarthritis, but they can have both, so a yes/no test is of unclear utility,” she said. OA and calcium pyrophosphate deposition (CPPD) disease can often occur together, “but the driver is really the OA, and the CPPD is present but not actively inflammatory,” she continued. “Septic arthritis should be readily distinguishable by cell count alone [and again, can coexist with any of the other conditions], and a thorough history and physical should be able to differentiate in most cases.”

While these results from this study are “reasonably impressive,” more clinical information is needed to interpret these results, added C. Kent Kwoh, MD, director of the University of Arizona Arthritis Center and professor of medicine and medical imaging at the University of Arizona College of Medicine, Tucson, Arizona.

Because the study is retrospective in nature and researchers obtained specimens from different sources, it was not clear if these patients were being treated when these samples were taken and if their various conditions were controlled or flaring.

“I would say this is a reasonable first step,” Kwoh said. “We would need prospective studies, more clinical characterization, and potentially longitudinal studies to understand when this test may be useful.”

This research was internally funded by Zimmer Biomet. All authors were employees of CD Diagnostics or CD Laboratories, both of which are subsidiaries of Zimmer Biomet. Kwoh reported receiving grants or contracts with AbbVie, Artiva, Eli Lilly and Company, Bristol Myers Squibb, Cumberland, Pfizer, GSK, and Galapagos, and consulting fees from TrialSpark/Formation Bio, Express Scripts, GSK, TLC BioSciences, and AposHealth. He participates on Data Safety Monitoring or Advisory Boards of Moebius Medical, Sun Pharma, Novartis, Xalud, and Kolon TissueGene. Nelson reported no relevant disclosures.

 

A version of this article appeared on Medscape.com.

A new diagnostic test can accurately distinguish osteoarthritis (OA) from inflammatory arthritis using two synovial fluid biomarkers, according to research published in the Journal of Orthopaedic Research on December 18, 2024.

However, experts question whether such a test would be useful.

“The need would seem to be fairly limited, mostly those with single joint involvement and a lack of other systemic features to specify a diagnosis, which is not that common, at least in rheumatology, where there are usually features in the history and physical that can clarify the diagnosis,” said Amanda E. Nelson, MD, MSCR, professor of medicine in the Division of Rheumatology, Allergy, and Immunology at the University of North Carolina at Chapel Hill. She was not involved with the research.

The test uses an algorithm that incorporates concentrations of cartilage oligomeric matrix protein (COMP) and interleukin 8 (IL-8) in synovial fluid. The researchers hypothesized that a ratio of the two biomarkers could distinguish between primary OA and other inflammatory arthritic diagnoses.

“Primary OA is unlikely when either COMP concentration or COMP/IL‐8 ratio in the synovial fluid is low since these conditions indicate either lack of cartilage degradation or presence of high inflammation,” wrote Daniel Keter and coauthors at CD Diagnostics, Claymont, Delaware, and CD Laboratories, Towson, Maryland. “In contrast, a high COMP concentration result in combination with high COMP/IL‐8 ratio would be suggestive of low inflammation in the setting of cartilage deterioration, which is indicative of primary OA.”

In patients with OA, synovial fluid can be difficult to aspirate in sufficient amounts for testing, Nelson said.

“If synovial fluid is present and able to be aspirated, it is unclear if this test has any benefit over a simple, standard cell count and crystal assessment, which can also distinguish between osteoarthritis and more inflammatory arthritides,” she said.

 

Differentiating OA

To test this potential diagnostic algorithm, researchers obtained 171 knee synovial fluid samples from approved clinical remnant sample sources and a biovendor. All samples were annotated with an existing arthritic diagnosis, including 54 with primary OA, 57 with rheumatoid arthritis (RA), 30 with crystal arthritis (CA), and 30 with native septic arthritis (NSA).

Researchers assigned a CA diagnosis based on the presence of monosodium urate or calcium pyrophosphate dehydrate crystals in the synovial fluid, and NSA was determined via the Synovasure Alpha Defensin test. OA was confirmed via radiograph as Kellgren‐Lawrence grades 2‐4 with no other arthritic diagnoses. RA samples were purchased via a biovendor, and researchers were not provided with diagnosis‐confirming data.

All samples were randomized and blinded before testing, and researchers used enzyme-linked immunosorbent assay tests for both COMP and IL-8 biomarkers.

Of the 54 OA samples, 47 tested positive for OA using the COMP + COMP/IL-8 ratio algorithm. Of the 117 samples with inflammatory arthritis, 13 tested positive for OA. Overall, the diagnostic algorithm demonstrated a clinical sensitivity of 87.0% and specificity of 88.9%. The positive predictive value was 78.3%, while the negative predictive value was 93.7%.

 

Unclear Clinical Need

Nelson noted that while this test aims to differentiate between arthritic diagnoses, patients can also have multiple conditions.

“Many individuals with rheumatoid arthritis will develop osteoarthritis, but they can have both, so a yes/no test is of unclear utility,” she said. OA and calcium pyrophosphate deposition (CPPD) disease can often occur together, “but the driver is really the OA, and the CPPD is present but not actively inflammatory,” she continued. “Septic arthritis should be readily distinguishable by cell count alone [and again, can coexist with any of the other conditions], and a thorough history and physical should be able to differentiate in most cases.”

While these results from this study are “reasonably impressive,” more clinical information is needed to interpret these results, added C. Kent Kwoh, MD, director of the University of Arizona Arthritis Center and professor of medicine and medical imaging at the University of Arizona College of Medicine, Tucson, Arizona.

Because the study is retrospective in nature and researchers obtained specimens from different sources, it was not clear if these patients were being treated when these samples were taken and if their various conditions were controlled or flaring.

“I would say this is a reasonable first step,” Kwoh said. “We would need prospective studies, more clinical characterization, and potentially longitudinal studies to understand when this test may be useful.”

This research was internally funded by Zimmer Biomet. All authors were employees of CD Diagnostics or CD Laboratories, both of which are subsidiaries of Zimmer Biomet. Kwoh reported receiving grants or contracts with AbbVie, Artiva, Eli Lilly and Company, Bristol Myers Squibb, Cumberland, Pfizer, GSK, and Galapagos, and consulting fees from TrialSpark/Formation Bio, Express Scripts, GSK, TLC BioSciences, and AposHealth. He participates on Data Safety Monitoring or Advisory Boards of Moebius Medical, Sun Pharma, Novartis, Xalud, and Kolon TissueGene. Nelson reported no relevant disclosures.

 

A version of this article appeared on Medscape.com.

A new diagnostic test can accurately distinguish osteoarthritis (OA) from inflammatory arthritis using two synovial fluid biomarkers, according to research published in the Journal of Orthopaedic Research on December 18, 2024.

However, experts question whether such a test would be useful.

“The need would seem to be fairly limited, mostly those with single joint involvement and a lack of other systemic features to specify a diagnosis, which is not that common, at least in rheumatology, where there are usually features in the history and physical that can clarify the diagnosis,” said Amanda E. Nelson, MD, MSCR, professor of medicine in the Division of Rheumatology, Allergy, and Immunology at the University of North Carolina at Chapel Hill. She was not involved with the research.

The test uses an algorithm that incorporates concentrations of cartilage oligomeric matrix protein (COMP) and interleukin 8 (IL-8) in synovial fluid. The researchers hypothesized that a ratio of the two biomarkers could distinguish between primary OA and other inflammatory arthritic diagnoses.

“Primary OA is unlikely when either COMP concentration or COMP/IL‐8 ratio in the synovial fluid is low since these conditions indicate either lack of cartilage degradation or presence of high inflammation,” wrote Daniel Keter and coauthors at CD Diagnostics, Claymont, Delaware, and CD Laboratories, Towson, Maryland. “In contrast, a high COMP concentration result in combination with high COMP/IL‐8 ratio would be suggestive of low inflammation in the setting of cartilage deterioration, which is indicative of primary OA.”

In patients with OA, synovial fluid can be difficult to aspirate in sufficient amounts for testing, Nelson said.

“If synovial fluid is present and able to be aspirated, it is unclear if this test has any benefit over a simple, standard cell count and crystal assessment, which can also distinguish between osteoarthritis and more inflammatory arthritides,” she said.

 

Differentiating OA

To test this potential diagnostic algorithm, researchers obtained 171 knee synovial fluid samples from approved clinical remnant sample sources and a biovendor. All samples were annotated with an existing arthritic diagnosis, including 54 with primary OA, 57 with rheumatoid arthritis (RA), 30 with crystal arthritis (CA), and 30 with native septic arthritis (NSA).

Researchers assigned a CA diagnosis based on the presence of monosodium urate or calcium pyrophosphate dehydrate crystals in the synovial fluid, and NSA was determined via the Synovasure Alpha Defensin test. OA was confirmed via radiograph as Kellgren‐Lawrence grades 2‐4 with no other arthritic diagnoses. RA samples were purchased via a biovendor, and researchers were not provided with diagnosis‐confirming data.

All samples were randomized and blinded before testing, and researchers used enzyme-linked immunosorbent assay tests for both COMP and IL-8 biomarkers.

Of the 54 OA samples, 47 tested positive for OA using the COMP + COMP/IL-8 ratio algorithm. Of the 117 samples with inflammatory arthritis, 13 tested positive for OA. Overall, the diagnostic algorithm demonstrated a clinical sensitivity of 87.0% and specificity of 88.9%. The positive predictive value was 78.3%, while the negative predictive value was 93.7%.

 

Unclear Clinical Need

Nelson noted that while this test aims to differentiate between arthritic diagnoses, patients can also have multiple conditions.

“Many individuals with rheumatoid arthritis will develop osteoarthritis, but they can have both, so a yes/no test is of unclear utility,” she said. OA and calcium pyrophosphate deposition (CPPD) disease can often occur together, “but the driver is really the OA, and the CPPD is present but not actively inflammatory,” she continued. “Septic arthritis should be readily distinguishable by cell count alone [and again, can coexist with any of the other conditions], and a thorough history and physical should be able to differentiate in most cases.”

While these results from this study are “reasonably impressive,” more clinical information is needed to interpret these results, added C. Kent Kwoh, MD, director of the University of Arizona Arthritis Center and professor of medicine and medical imaging at the University of Arizona College of Medicine, Tucson, Arizona.

Because the study is retrospective in nature and researchers obtained specimens from different sources, it was not clear if these patients were being treated when these samples were taken and if their various conditions were controlled or flaring.

“I would say this is a reasonable first step,” Kwoh said. “We would need prospective studies, more clinical characterization, and potentially longitudinal studies to understand when this test may be useful.”

This research was internally funded by Zimmer Biomet. All authors were employees of CD Diagnostics or CD Laboratories, both of which are subsidiaries of Zimmer Biomet. Kwoh reported receiving grants or contracts with AbbVie, Artiva, Eli Lilly and Company, Bristol Myers Squibb, Cumberland, Pfizer, GSK, and Galapagos, and consulting fees from TrialSpark/Formation Bio, Express Scripts, GSK, TLC BioSciences, and AposHealth. He participates on Data Safety Monitoring or Advisory Boards of Moebius Medical, Sun Pharma, Novartis, Xalud, and Kolon TissueGene. Nelson reported no relevant disclosures.

 

A version of this article appeared on Medscape.com.

TOPLINE:

Mannkind expects to submit a request for a supplemental new drug application meeting to the Food and Drug Administration (FDA) for its inhaled human insulin (Afrezza Inhalation Powder). Currently indicated to improve glycemic control in adults with diabetes, the company announced 6-month results from its phase 3 INHALE-1 study of inhaled human insulin in children and adolescents aged 4-17.

METHODOLOGY:

• INHALE-1 is a 26-week, open-label clinical trial that randomized 230 subjects aged 4-17 years with type 1 or type 2 diabetes to either inhaled pre-meal insulin or multiple daily injections (MDI) of rapid-acting insulin analog, both in combination with basal insulin.
• The primary endpoint was a noninferior change in hemoglobin A1c levels, compared with MDI after 26 weeks.
• A 26-week extension phase in which all remaining MDI patients were switched to inhaled insulin is ongoing.

TAKEAWAY:

• In the full intent-to-treat (ITT) population analysis, the between-group difference in mean A1c change over 26 weeks exceeded the prespecified non-inferiority margin of 0.4% (0.435%), but this was largely driven by the variability of a single patient who didn’t adhere to the study protocol.
• A modified ITT analysis excluding that person did not exceed the predetermined threshold of 0.4% (0.370%), thereby establishing noninferiority of inhaled insulin with MDI.
• Over 26 weeks of treatment, there were no differences in lung function parameters between the treatment groups, with mean forced expiratory volume at 1 second (FEV1) at baseline vs 26 weeks of 2.901 liters (99.6% of predicted) vs 2.934 L (96.6%) in the inhaled insulin group and 2.948 L (102.3%) vs 2.957 (98%), respectively, in the MDI group.
• There were no differences between groups or concerns in other safety measures, including hypoglycemia.

IN PRACTICE:

“It was exciting to partner with MannKind and help lead this study to potentially expand the use of inhaled insulin, which is currently used successfully by many adults with diabetes, to a population that hasn’t had a treatment option other than injectable insulin in the history of their care,” said INHALE-1 investigator Roy W. Beck, MD, PhD, founder of the Jaeb Center for Health Research, Tampa, Florida.

“The 6-month results are clinically meaningful and show Afrezza as a potential future treatment option for a growing pediatric population living with type 1 and type 2 diabetes,” Beck added.

 

SOURCE:

The results of the study were announced at a Mannkind press release on December 16, 2024.

SAFETY INFORMATION:

Inhaled insulin is not recommended for the treatment of diabetic ketoacidosis or in patients who smoke or have recently stopped smoking.

Warning: Risk for acute bronchospasm in patients with chronic lung disease

• Acute bronchospasm has been observed in Afrezza-treated patients with asthma and chronic obstructive pulmonary disease (COPD)
• Afrezza is contraindicated in patients with chronic lung disease such as asthma or COPD
• Before initiating Afrezza, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients
• Most common adverse reactions are hypoglycemia, cough, and throat pain or irritation.
•  

DISCLOSURES:

This study was funded by MannKind.

A version of this article appeared on Medscape.com.

TOPLINE:

Mannkind expects to submit a request for a supplemental new drug application meeting to the Food and Drug Administration (FDA) for its inhaled human insulin (Afrezza Inhalation Powder). Currently indicated to improve glycemic control in adults with diabetes, the company announced 6-month results from its phase 3 INHALE-1 study of inhaled human insulin in children and adolescents aged 4-17.

METHODOLOGY:

• INHALE-1 is a 26-week, open-label clinical trial that randomized 230 subjects aged 4-17 years with type 1 or type 2 diabetes to either inhaled pre-meal insulin or multiple daily injections (MDI) of rapid-acting insulin analog, both in combination with basal insulin.
• The primary endpoint was a noninferior change in hemoglobin A1c levels, compared with MDI after 26 weeks.
• A 26-week extension phase in which all remaining MDI patients were switched to inhaled insulin is ongoing.

TAKEAWAY:

• In the full intent-to-treat (ITT) population analysis, the between-group difference in mean A1c change over 26 weeks exceeded the prespecified non-inferiority margin of 0.4% (0.435%), but this was largely driven by the variability of a single patient who didn’t adhere to the study protocol.
• A modified ITT analysis excluding that person did not exceed the predetermined threshold of 0.4% (0.370%), thereby establishing noninferiority of inhaled insulin with MDI.
• Over 26 weeks of treatment, there were no differences in lung function parameters between the treatment groups, with mean forced expiratory volume at 1 second (FEV1) at baseline vs 26 weeks of 2.901 liters (99.6% of predicted) vs 2.934 L (96.6%) in the inhaled insulin group and 2.948 L (102.3%) vs 2.957 (98%), respectively, in the MDI group.
• There were no differences between groups or concerns in other safety measures, including hypoglycemia.

IN PRACTICE:

“It was exciting to partner with MannKind and help lead this study to potentially expand the use of inhaled insulin, which is currently used successfully by many adults with diabetes, to a population that hasn’t had a treatment option other than injectable insulin in the history of their care,” said INHALE-1 investigator Roy W. Beck, MD, PhD, founder of the Jaeb Center for Health Research, Tampa, Florida.

“The 6-month results are clinically meaningful and show Afrezza as a potential future treatment option for a growing pediatric population living with type 1 and type 2 diabetes,” Beck added.

 

SOURCE:

The results of the study were announced at a Mannkind press release on December 16, 2024.

SAFETY INFORMATION:

Inhaled insulin is not recommended for the treatment of diabetic ketoacidosis or in patients who smoke or have recently stopped smoking.

Warning: Risk for acute bronchospasm in patients with chronic lung disease

• Acute bronchospasm has been observed in Afrezza-treated patients with asthma and chronic obstructive pulmonary disease (COPD)
• Afrezza is contraindicated in patients with chronic lung disease such as asthma or COPD
• Before initiating Afrezza, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients
• Most common adverse reactions are hypoglycemia, cough, and throat pain or irritation.
•  

DISCLOSURES:

This study was funded by MannKind.

A version of this article appeared on Medscape.com.

TOPLINE:

Mannkind expects to submit a request for a supplemental new drug application meeting to the Food and Drug Administration (FDA) for its inhaled human insulin (Afrezza Inhalation Powder). Currently indicated to improve glycemic control in adults with diabetes, the company announced 6-month results from its phase 3 INHALE-1 study of inhaled human insulin in children and adolescents aged 4-17.

METHODOLOGY:

• INHALE-1 is a 26-week, open-label clinical trial that randomized 230 subjects aged 4-17 years with type 1 or type 2 diabetes to either inhaled pre-meal insulin or multiple daily injections (MDI) of rapid-acting insulin analog, both in combination with basal insulin.
• The primary endpoint was a noninferior change in hemoglobin A1c levels, compared with MDI after 26 weeks.
• A 26-week extension phase in which all remaining MDI patients were switched to inhaled insulin is ongoing.

TAKEAWAY:

• In the full intent-to-treat (ITT) population analysis, the between-group difference in mean A1c change over 26 weeks exceeded the prespecified non-inferiority margin of 0.4% (0.435%), but this was largely driven by the variability of a single patient who didn’t adhere to the study protocol.
• A modified ITT analysis excluding that person did not exceed the predetermined threshold of 0.4% (0.370%), thereby establishing noninferiority of inhaled insulin with MDI.
• Over 26 weeks of treatment, there were no differences in lung function parameters between the treatment groups, with mean forced expiratory volume at 1 second (FEV1) at baseline vs 26 weeks of 2.901 liters (99.6% of predicted) vs 2.934 L (96.6%) in the inhaled insulin group and 2.948 L (102.3%) vs 2.957 (98%), respectively, in the MDI group.
• There were no differences between groups or concerns in other safety measures, including hypoglycemia.

IN PRACTICE:

“It was exciting to partner with MannKind and help lead this study to potentially expand the use of inhaled insulin, which is currently used successfully by many adults with diabetes, to a population that hasn’t had a treatment option other than injectable insulin in the history of their care,” said INHALE-1 investigator Roy W. Beck, MD, PhD, founder of the Jaeb Center for Health Research, Tampa, Florida.

“The 6-month results are clinically meaningful and show Afrezza as a potential future treatment option for a growing pediatric population living with type 1 and type 2 diabetes,” Beck added.

 

SOURCE:

The results of the study were announced at a Mannkind press release on December 16, 2024.

SAFETY INFORMATION:

Inhaled insulin is not recommended for the treatment of diabetic ketoacidosis or in patients who smoke or have recently stopped smoking.

Warning: Risk for acute bronchospasm in patients with chronic lung disease

• Acute bronchospasm has been observed in Afrezza-treated patients with asthma and chronic obstructive pulmonary disease (COPD)
• Afrezza is contraindicated in patients with chronic lung disease such as asthma or COPD
• Before initiating Afrezza, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients
• Most common adverse reactions are hypoglycemia, cough, and throat pain or irritation.
•  

DISCLOSURES:

This study was funded by MannKind.

A version of this article appeared on Medscape.com.

In the latest effort to address the mental health crisis among adolescents, legislation in California would require social media platforms to come with a “black box” mental health warning label.

Despite growing evidence linking young people’s use of social media to significant health risks including depression, anxiety, and suicidal thoughts, social media companies have failed to be transparent about the risks, said Assembly member Rebecca Bauer-Kahan (D-Orinda), who introduced Assembly Bill (AB) 56.

“AB 56 ensures that families are armed with clear, actionable information to understand these dangers and make decisions that prioritizes their children’s well-being,” she said in a press release.

Bauer-Kahan noted that 95% of teens report using at least one social media platform and that more than one third say they use social media almost constantly.

“There is a powerful profit motive to keep our young people hooked online and engaged and it is exploiting the human psychology with notifications, likes, endless scrolling, and algorithmic amplification that is harming our children every day,” she said at a press conference on December 9 announcing the bill.

The warning labels are an equitable and transparent way to communicate the risks that social media poses to young users, California’s Attorney General Rob Bonta, a sponsor of AB 56, said in a press release.

Speaking at the press conference, Bonta said social media has many “incredible benefits” from giving people an outlet of expression to providing access to critical information but “there is no disputing the fact, it can have an enormously detrimental and dangerous impact on our young people. You cannot debate that. Our children are suffering.”

If AB 56 is successful, he said social media platforms would be required to display a “black box warning” for all users that would appear upon the first use of a platform and weekly thereafter.

The proposed language for the warning label is: “The Surgeon General has advised that there are ample indicators that social media can have a profound risk of harm to the mental health and well-being of children and adolescents.”

“This warning label isn’t a panacea, we know that, but it is another tool in our toolbox. It’s one prong in what has to be a multi-pronged continued, coordinated effort to address this public health crisis,” Bonta said.

Reached for comment, Bonta’s office said sponsorship of the bill was informed by their ongoing work to create a safer online space for children and teens and by the US Surgeon General’s call to Congress to add warning labels to social media.

In June, US Surgeon General Vivek Murthy, MD, said a Surgeon General’s warning label is needed to address the mental health emergency among adolescents and noted that evidence from tobacco studies shows warning labels can increase awareness and change behavior. In September, the attorneys general of 42 states announced their support of the proposal.

Also in September, US Senators John Fetterman (D-PA) and Katie Britt (R-AL) introduced the Stop the Scroll Act to create a mental health warning label requirement for social media platforms.

In a controversial move in November, Australia passed the world’s first law banning social media for children younger than 16 years. The law gives platforms such as TikTok, Facebook, X, Snapchat, and Instagram 1 year to figure out how to implement the ban before facing fines of up 50 million Australian dollars ($33 million) for systemic failures to prevent children younger than 16 years from holding accounts.

 

‘A Broken Fire Alarm’

“Slapping a warning label on social media is like a broken fire alarm going off with no evidence of smoke. It ignores the reality that most teens view social media as an important outlet for social connection,” Todd O’Boyle, with the tech industry policy group Chamber of Progress, said in a statement on AB 56.

He highlighted a 2022 Pew Research Center survey reporting that most teens credit social media with deepening connections and providing a support network and a 2020 study reporting that social media is not a strong or consistent risk factor for depressive symptoms in US adolescents.

O’Boyle predicted that, without strong evidence, AB 56 will run into the same “First Amendment buzzsaw” that has doomed other California kids’ bills.

Pediatrician Jason Nagata, MD, University of California San Francisco, points out in Bonta’s press release that social media can displace time for other healthful activities including sleep, exercise, and in-person socialization.

“While social media can provide educational content, it can also provide misinformation about health and expose children to content that damages their mental well-being. These are risks that adolescents and their parents should be aware of,” Nagata said.

Indeed, a tearful Victoria Hinks of Larkspur, California, spoke at the press conference of her 16-year-old daughter, Alexandra, who committed suicide 4 months ago after being sucked into social media and served content on self-harm, eating disorders, suicidal ideation, and glamorization of suicide.

“She was led down dark rabbit holes she had no hope of escaping,” Hinks said. “There is not a bone in my body that doubts social media played a role leading her to that final irreversible decision.”

Jim Steyer, CEO and founder of Common Sense Media, applauded California for being the first state to introduce social media warning label legislation. The group plans to lobby for similar proposals in other states he said at the press conference, noting that there are “tens of thousands of Alexandras out there.”

“We have seat belt laws, we have warning labels on cigarettes and alcohol, and that’s what we’re doing here,” Steyer said. “It’s a straightforward simple proposition, which is put your kids and teenagers first, put their self-interest first and hold the largest, most powerful, and wealthy companies in all of our lifetimes accountable for the harms that have happened on their platforms.”

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

In the latest effort to address the mental health crisis among adolescents, legislation in California would require social media platforms to come with a “black box” mental health warning label.

Despite growing evidence linking young people’s use of social media to significant health risks including depression, anxiety, and suicidal thoughts, social media companies have failed to be transparent about the risks, said Assembly member Rebecca Bauer-Kahan (D-Orinda), who introduced Assembly Bill (AB) 56.

“AB 56 ensures that families are armed with clear, actionable information to understand these dangers and make decisions that prioritizes their children’s well-being,” she said in a press release.

Bauer-Kahan noted that 95% of teens report using at least one social media platform and that more than one third say they use social media almost constantly.

“There is a powerful profit motive to keep our young people hooked online and engaged and it is exploiting the human psychology with notifications, likes, endless scrolling, and algorithmic amplification that is harming our children every day,” she said at a press conference on December 9 announcing the bill.

The warning labels are an equitable and transparent way to communicate the risks that social media poses to young users, California’s Attorney General Rob Bonta, a sponsor of AB 56, said in a press release.

Speaking at the press conference, Bonta said social media has many “incredible benefits” from giving people an outlet of expression to providing access to critical information but “there is no disputing the fact, it can have an enormously detrimental and dangerous impact on our young people. You cannot debate that. Our children are suffering.”

If AB 56 is successful, he said social media platforms would be required to display a “black box warning” for all users that would appear upon the first use of a platform and weekly thereafter.

The proposed language for the warning label is: “The Surgeon General has advised that there are ample indicators that social media can have a profound risk of harm to the mental health and well-being of children and adolescents.”

“This warning label isn’t a panacea, we know that, but it is another tool in our toolbox. It’s one prong in what has to be a multi-pronged continued, coordinated effort to address this public health crisis,” Bonta said.

Reached for comment, Bonta’s office said sponsorship of the bill was informed by their ongoing work to create a safer online space for children and teens and by the US Surgeon General’s call to Congress to add warning labels to social media.

In June, US Surgeon General Vivek Murthy, MD, said a Surgeon General’s warning label is needed to address the mental health emergency among adolescents and noted that evidence from tobacco studies shows warning labels can increase awareness and change behavior. In September, the attorneys general of 42 states announced their support of the proposal.

Also in September, US Senators John Fetterman (D-PA) and Katie Britt (R-AL) introduced the Stop the Scroll Act to create a mental health warning label requirement for social media platforms.

In a controversial move in November, Australia passed the world’s first law banning social media for children younger than 16 years. The law gives platforms such as TikTok, Facebook, X, Snapchat, and Instagram 1 year to figure out how to implement the ban before facing fines of up 50 million Australian dollars ($33 million) for systemic failures to prevent children younger than 16 years from holding accounts.

 

‘A Broken Fire Alarm’

“Slapping a warning label on social media is like a broken fire alarm going off with no evidence of smoke. It ignores the reality that most teens view social media as an important outlet for social connection,” Todd O’Boyle, with the tech industry policy group Chamber of Progress, said in a statement on AB 56.

He highlighted a 2022 Pew Research Center survey reporting that most teens credit social media with deepening connections and providing a support network and a 2020 study reporting that social media is not a strong or consistent risk factor for depressive symptoms in US adolescents.

O’Boyle predicted that, without strong evidence, AB 56 will run into the same “First Amendment buzzsaw” that has doomed other California kids’ bills.

Pediatrician Jason Nagata, MD, University of California San Francisco, points out in Bonta’s press release that social media can displace time for other healthful activities including sleep, exercise, and in-person socialization.

“While social media can provide educational content, it can also provide misinformation about health and expose children to content that damages their mental well-being. These are risks that adolescents and their parents should be aware of,” Nagata said.

Indeed, a tearful Victoria Hinks of Larkspur, California, spoke at the press conference of her 16-year-old daughter, Alexandra, who committed suicide 4 months ago after being sucked into social media and served content on self-harm, eating disorders, suicidal ideation, and glamorization of suicide.

“She was led down dark rabbit holes she had no hope of escaping,” Hinks said. “There is not a bone in my body that doubts social media played a role leading her to that final irreversible decision.”

Jim Steyer, CEO and founder of Common Sense Media, applauded California for being the first state to introduce social media warning label legislation. The group plans to lobby for similar proposals in other states he said at the press conference, noting that there are “tens of thousands of Alexandras out there.”

“We have seat belt laws, we have warning labels on cigarettes and alcohol, and that’s what we’re doing here,” Steyer said. “It’s a straightforward simple proposition, which is put your kids and teenagers first, put their self-interest first and hold the largest, most powerful, and wealthy companies in all of our lifetimes accountable for the harms that have happened on their platforms.”

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

In the latest effort to address the mental health crisis among adolescents, legislation in California would require social media platforms to come with a “black box” mental health warning label.

Despite growing evidence linking young people’s use of social media to significant health risks including depression, anxiety, and suicidal thoughts, social media companies have failed to be transparent about the risks, said Assembly member Rebecca Bauer-Kahan (D-Orinda), who introduced Assembly Bill (AB) 56.

“AB 56 ensures that families are armed with clear, actionable information to understand these dangers and make decisions that prioritizes their children’s well-being,” she said in a press release.

Bauer-Kahan noted that 95% of teens report using at least one social media platform and that more than one third say they use social media almost constantly.

“There is a powerful profit motive to keep our young people hooked online and engaged and it is exploiting the human psychology with notifications, likes, endless scrolling, and algorithmic amplification that is harming our children every day,” she said at a press conference on December 9 announcing the bill.

The warning labels are an equitable and transparent way to communicate the risks that social media poses to young users, California’s Attorney General Rob Bonta, a sponsor of AB 56, said in a press release.

Speaking at the press conference, Bonta said social media has many “incredible benefits” from giving people an outlet of expression to providing access to critical information but “there is no disputing the fact, it can have an enormously detrimental and dangerous impact on our young people. You cannot debate that. Our children are suffering.”

If AB 56 is successful, he said social media platforms would be required to display a “black box warning” for all users that would appear upon the first use of a platform and weekly thereafter.

The proposed language for the warning label is: “The Surgeon General has advised that there are ample indicators that social media can have a profound risk of harm to the mental health and well-being of children and adolescents.”

“This warning label isn’t a panacea, we know that, but it is another tool in our toolbox. It’s one prong in what has to be a multi-pronged continued, coordinated effort to address this public health crisis,” Bonta said.

Reached for comment, Bonta’s office said sponsorship of the bill was informed by their ongoing work to create a safer online space for children and teens and by the US Surgeon General’s call to Congress to add warning labels to social media.

In June, US Surgeon General Vivek Murthy, MD, said a Surgeon General’s warning label is needed to address the mental health emergency among adolescents and noted that evidence from tobacco studies shows warning labels can increase awareness and change behavior. In September, the attorneys general of 42 states announced their support of the proposal.

Also in September, US Senators John Fetterman (D-PA) and Katie Britt (R-AL) introduced the Stop the Scroll Act to create a mental health warning label requirement for social media platforms.

In a controversial move in November, Australia passed the world’s first law banning social media for children younger than 16 years. The law gives platforms such as TikTok, Facebook, X, Snapchat, and Instagram 1 year to figure out how to implement the ban before facing fines of up 50 million Australian dollars ($33 million) for systemic failures to prevent children younger than 16 years from holding accounts.

 

‘A Broken Fire Alarm’

“Slapping a warning label on social media is like a broken fire alarm going off with no evidence of smoke. It ignores the reality that most teens view social media as an important outlet for social connection,” Todd O’Boyle, with the tech industry policy group Chamber of Progress, said in a statement on AB 56.

He highlighted a 2022 Pew Research Center survey reporting that most teens credit social media with deepening connections and providing a support network and a 2020 study reporting that social media is not a strong or consistent risk factor for depressive symptoms in US adolescents.

O’Boyle predicted that, without strong evidence, AB 56 will run into the same “First Amendment buzzsaw” that has doomed other California kids’ bills.

Pediatrician Jason Nagata, MD, University of California San Francisco, points out in Bonta’s press release that social media can displace time for other healthful activities including sleep, exercise, and in-person socialization.

“While social media can provide educational content, it can also provide misinformation about health and expose children to content that damages their mental well-being. These are risks that adolescents and their parents should be aware of,” Nagata said.

Indeed, a tearful Victoria Hinks of Larkspur, California, spoke at the press conference of her 16-year-old daughter, Alexandra, who committed suicide 4 months ago after being sucked into social media and served content on self-harm, eating disorders, suicidal ideation, and glamorization of suicide.

“She was led down dark rabbit holes she had no hope of escaping,” Hinks said. “There is not a bone in my body that doubts social media played a role leading her to that final irreversible decision.”

Jim Steyer, CEO and founder of Common Sense Media, applauded California for being the first state to introduce social media warning label legislation. The group plans to lobby for similar proposals in other states he said at the press conference, noting that there are “tens of thousands of Alexandras out there.”

“We have seat belt laws, we have warning labels on cigarettes and alcohol, and that’s what we’re doing here,” Steyer said. “It’s a straightforward simple proposition, which is put your kids and teenagers first, put their self-interest first and hold the largest, most powerful, and wealthy companies in all of our lifetimes accountable for the harms that have happened on their platforms.”

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

Adults with high cholesterol taking statins may have a significantly higher risk of developing glaucoma than those not taking the cholesterol-lowering drugs, an observational study of a large research database found.

The study, published in Ophthalmology Glaucoma, analyzed electronic health records of 79,742 adults with hyperlipidemia in the All of Us Research Program database from 2017 to 2022. The repository is maintained by the National Institutes of Health and provides data for research into precision medicine.

The 6365 statin users in the study population had a 47% greater unadjusted prevalence of glaucoma than nonusers of the drugs (P < .001) and a 13% greater prevalence in models that adjusted for potential confounding variables (P = .02). The researchers also found statin users had significantly higher levels of low-density lipoprotein cholesterol (LDL-C), but even patients with optimal levels of LDL-C had higher rates of glaucoma.

 

‘A Little Unusual’

Drawing any clinically relevant conclusions from this latest study would be premature, said Victoria Tseng, MD, PhD, an assistant professor at UCLA Stein Eye Institute and Doheny Eye Centers UCLA, and the senior author of the study. “I certainly would not be telling my patients on statins to stop their statins.”

Tseng acknowledged her group’s finding runs counter to previous studies that found statins may help prevent glaucoma or at least have no effect on the eye disease, although the association between cholesterol and glaucoma has been well established.

A 2019 analysis of nearly 137,000 participants in three population studies found no connection between statin use and the risk for primary open-angle glaucoma. A 2012 study of more than 500,000 people with high cholesterol found statin use was associated with a significant reduction in the risk for open-angle glaucoma.

“It’s a little unusual that we found the opposite,” Tseng said in an interview.

One explanation is the observational nature of the AoU analysis Tseng’s group conducted. “We don’t know what these people look like or how well the data were collected, so we’re going off of what’s there in the database,” she said.

Another explanation could be the nature of hyperlipidemia itself, she said. “There have definitely been studies that suggest increased cholesterol levels are associated with an increased risk of glaucoma. Presumably, you’re not going to be taking a statin unless your cholesterol is a little worse.”

While the study analysis attempted to control for cholesterol levels, Tseng noted, “there could be some residual confounding from that.”

Statin users in the study had an average LDL-C level of 144.9 mg/dL vs 136.3 mg/dL in the population not taking any cholesterol medication (P < .001). Statin users with optimal LDL-C, defined as less than 100 mg/dL, had a 39% greater adjusted prevalence of glaucoma (P = .02), while those with high LDL-C (160-189 mg/dL) had a 37% greater adjusted prevalence (P = .005).

Age was another factor in the risk for glaucoma, the study found. Statin users aged 60-69 years had an adjusted rate of glaucoma 28% greater than that for nonusers (P = .05).

Laboratory studies may help clarify the relationships between statins and glaucoma, Tseng said. That could include putting statins directly on the optic nerve of laboratory mice and further investigating how statins affect the mechanisms that influence eye pressure, a key driver of glaucoma. From a population study perspective, a randomized trial of glaucoma patients comparing the effect of statins and other cholesterol-lowering medications with nonuse may provide answers.

 

Database Strengths and Limitations

The study “adds to the somewhat mixed literature on the potential association between statins and glaucoma,” Sophia Wang, MD, MS, a glaucoma specialist at Stanford Byers Eye Institute in Palo Alto, California, said in an interview.

The AoU research cohort is a “notable strength” of the new paper, added Wang, who has used the AoU database to study the relationship between blood pressure, blood pressure medications, and glaucoma.

“The population is especially large and diverse, with a large proportion of participants from backgrounds that are traditionally underrepresented in research,” she said. And The inclusion of both medical records and survey data means the health information on the cohort is detailed and longitudinal.

“The authors make excellent use here of the data by including in their analyses results of laboratory investigations — LDL-C, notably — which wouldn’t be readily available in other types of datasets such as claims datasets,” she said.

However, the database has limitations as well, including its reliance on coding, which is prone to errors, to determine glaucoma diagnosis and missing information on eye examinations. In addition, the study used one LDL-C measurement rather than multiple measurements, Wang pointed out, “and we know that LDL-C can vary over time.”

The study was funded by Research to Prevent Blindness. Tseng and Wang reported no relevant financial relationships to disclose.

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

Adults with high cholesterol taking statins may have a significantly higher risk of developing glaucoma than those not taking the cholesterol-lowering drugs, an observational study of a large research database found.

The study, published in Ophthalmology Glaucoma, analyzed electronic health records of 79,742 adults with hyperlipidemia in the All of Us Research Program database from 2017 to 2022. The repository is maintained by the National Institutes of Health and provides data for research into precision medicine.

The 6365 statin users in the study population had a 47% greater unadjusted prevalence of glaucoma than nonusers of the drugs (P < .001) and a 13% greater prevalence in models that adjusted for potential confounding variables (P = .02). The researchers also found statin users had significantly higher levels of low-density lipoprotein cholesterol (LDL-C), but even patients with optimal levels of LDL-C had higher rates of glaucoma.

 

‘A Little Unusual’

Drawing any clinically relevant conclusions from this latest study would be premature, said Victoria Tseng, MD, PhD, an assistant professor at UCLA Stein Eye Institute and Doheny Eye Centers UCLA, and the senior author of the study. “I certainly would not be telling my patients on statins to stop their statins.”

Tseng acknowledged her group’s finding runs counter to previous studies that found statins may help prevent glaucoma or at least have no effect on the eye disease, although the association between cholesterol and glaucoma has been well established.

A 2019 analysis of nearly 137,000 participants in three population studies found no connection between statin use and the risk for primary open-angle glaucoma. A 2012 study of more than 500,000 people with high cholesterol found statin use was associated with a significant reduction in the risk for open-angle glaucoma.

“It’s a little unusual that we found the opposite,” Tseng said in an interview.

One explanation is the observational nature of the AoU analysis Tseng’s group conducted. “We don’t know what these people look like or how well the data were collected, so we’re going off of what’s there in the database,” she said.

Another explanation could be the nature of hyperlipidemia itself, she said. “There have definitely been studies that suggest increased cholesterol levels are associated with an increased risk of glaucoma. Presumably, you’re not going to be taking a statin unless your cholesterol is a little worse.”

While the study analysis attempted to control for cholesterol levels, Tseng noted, “there could be some residual confounding from that.”

Statin users in the study had an average LDL-C level of 144.9 mg/dL vs 136.3 mg/dL in the population not taking any cholesterol medication (P < .001). Statin users with optimal LDL-C, defined as less than 100 mg/dL, had a 39% greater adjusted prevalence of glaucoma (P = .02), while those with high LDL-C (160-189 mg/dL) had a 37% greater adjusted prevalence (P = .005).

Age was another factor in the risk for glaucoma, the study found. Statin users aged 60-69 years had an adjusted rate of glaucoma 28% greater than that for nonusers (P = .05).

Laboratory studies may help clarify the relationships between statins and glaucoma, Tseng said. That could include putting statins directly on the optic nerve of laboratory mice and further investigating how statins affect the mechanisms that influence eye pressure, a key driver of glaucoma. From a population study perspective, a randomized trial of glaucoma patients comparing the effect of statins and other cholesterol-lowering medications with nonuse may provide answers.

 

Database Strengths and Limitations

The study “adds to the somewhat mixed literature on the potential association between statins and glaucoma,” Sophia Wang, MD, MS, a glaucoma specialist at Stanford Byers Eye Institute in Palo Alto, California, said in an interview.

The AoU research cohort is a “notable strength” of the new paper, added Wang, who has used the AoU database to study the relationship between blood pressure, blood pressure medications, and glaucoma.

“The population is especially large and diverse, with a large proportion of participants from backgrounds that are traditionally underrepresented in research,” she said. And The inclusion of both medical records and survey data means the health information on the cohort is detailed and longitudinal.

“The authors make excellent use here of the data by including in their analyses results of laboratory investigations — LDL-C, notably — which wouldn’t be readily available in other types of datasets such as claims datasets,” she said.

However, the database has limitations as well, including its reliance on coding, which is prone to errors, to determine glaucoma diagnosis and missing information on eye examinations. In addition, the study used one LDL-C measurement rather than multiple measurements, Wang pointed out, “and we know that LDL-C can vary over time.”

The study was funded by Research to Prevent Blindness. Tseng and Wang reported no relevant financial relationships to disclose.

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

Adults with high cholesterol taking statins may have a significantly higher risk of developing glaucoma than those not taking the cholesterol-lowering drugs, an observational study of a large research database found.

The study, published in Ophthalmology Glaucoma, analyzed electronic health records of 79,742 adults with hyperlipidemia in the All of Us Research Program database from 2017 to 2022. The repository is maintained by the National Institutes of Health and provides data for research into precision medicine.

The 6365 statin users in the study population had a 47% greater unadjusted prevalence of glaucoma than nonusers of the drugs (P < .001) and a 13% greater prevalence in models that adjusted for potential confounding variables (P = .02). The researchers also found statin users had significantly higher levels of low-density lipoprotein cholesterol (LDL-C), but even patients with optimal levels of LDL-C had higher rates of glaucoma.

 

‘A Little Unusual’

Drawing any clinically relevant conclusions from this latest study would be premature, said Victoria Tseng, MD, PhD, an assistant professor at UCLA Stein Eye Institute and Doheny Eye Centers UCLA, and the senior author of the study. “I certainly would not be telling my patients on statins to stop their statins.”

Tseng acknowledged her group’s finding runs counter to previous studies that found statins may help prevent glaucoma or at least have no effect on the eye disease, although the association between cholesterol and glaucoma has been well established.

A 2019 analysis of nearly 137,000 participants in three population studies found no connection between statin use and the risk for primary open-angle glaucoma. A 2012 study of more than 500,000 people with high cholesterol found statin use was associated with a significant reduction in the risk for open-angle glaucoma.

“It’s a little unusual that we found the opposite,” Tseng said in an interview.

One explanation is the observational nature of the AoU analysis Tseng’s group conducted. “We don’t know what these people look like or how well the data were collected, so we’re going off of what’s there in the database,” she said.

Another explanation could be the nature of hyperlipidemia itself, she said. “There have definitely been studies that suggest increased cholesterol levels are associated with an increased risk of glaucoma. Presumably, you’re not going to be taking a statin unless your cholesterol is a little worse.”

While the study analysis attempted to control for cholesterol levels, Tseng noted, “there could be some residual confounding from that.”

Statin users in the study had an average LDL-C level of 144.9 mg/dL vs 136.3 mg/dL in the population not taking any cholesterol medication (P < .001). Statin users with optimal LDL-C, defined as less than 100 mg/dL, had a 39% greater adjusted prevalence of glaucoma (P = .02), while those with high LDL-C (160-189 mg/dL) had a 37% greater adjusted prevalence (P = .005).

Age was another factor in the risk for glaucoma, the study found. Statin users aged 60-69 years had an adjusted rate of glaucoma 28% greater than that for nonusers (P = .05).

Laboratory studies may help clarify the relationships between statins and glaucoma, Tseng said. That could include putting statins directly on the optic nerve of laboratory mice and further investigating how statins affect the mechanisms that influence eye pressure, a key driver of glaucoma. From a population study perspective, a randomized trial of glaucoma patients comparing the effect of statins and other cholesterol-lowering medications with nonuse may provide answers.

 

Database Strengths and Limitations

The study “adds to the somewhat mixed literature on the potential association between statins and glaucoma,” Sophia Wang, MD, MS, a glaucoma specialist at Stanford Byers Eye Institute in Palo Alto, California, said in an interview.

The AoU research cohort is a “notable strength” of the new paper, added Wang, who has used the AoU database to study the relationship between blood pressure, blood pressure medications, and glaucoma.

“The population is especially large and diverse, with a large proportion of participants from backgrounds that are traditionally underrepresented in research,” she said. And The inclusion of both medical records and survey data means the health information on the cohort is detailed and longitudinal.

“The authors make excellent use here of the data by including in their analyses results of laboratory investigations — LDL-C, notably — which wouldn’t be readily available in other types of datasets such as claims datasets,” she said.

However, the database has limitations as well, including its reliance on coding, which is prone to errors, to determine glaucoma diagnosis and missing information on eye examinations. In addition, the study used one LDL-C measurement rather than multiple measurements, Wang pointed out, “and we know that LDL-C can vary over time.”

The study was funded by Research to Prevent Blindness. Tseng and Wang reported no relevant financial relationships to disclose.

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

TOPLINE:

Muscle-building dietary supplement (MBS) use among young men substantially increases the odds of subsequent anabolic-androgenic steroid (AAS) initiation. Users of MBS showed elevated odds of incident AAS use within 1-5 years, supporting the gateway hypothesis for escalating risk-taking behaviors to increase muscularity.

METHODOLOGY:

• Analysis included data from two Growing Up Today Study prospective cohorts spanning 14 years (2007-2021).
• Participants included 4073 cisgender boys and young men aged 10-27 years at baseline (mean age, 20.3 years).
• Demographics showed 92.8% White participants and 7.2% other races or ethnicities.
• Researchers assessed past-year substance use for muscle building, including protein supplements, creatine, amino acids, hydroxymethylbutyrate, and dehydroepiandrosterone.

TAKEAWAY:

• Initial survey results showed 11.1% of respondents reported past-year muscle-building supplement use, and 0.4% reported AAS use.
• Over the study period, 37.7% of respondents reported any past-year muscle-building supplement use, while 0.5% reported any past-year AAS use.
• Analysis revealed muscle-building supplement users had (odds ratio [OR], 8.31; 95% CI, 2.59-26.73) higher odds of initiating AAS use by the next survey wave than nonusers.
• Age (adjusted OR [AOR], 0.98; 95% CI, 0.85-1.12) and cohort (AOR, 0.83; 95% CI, 0.30-2.32) were not statistically significant factors.

IN PRACTICE:

“The health risks of MBS use are well documented, as inadequate federal regulation has resulted in a US MBS marketplace rife with inaccurate labeling and adulteration with toxic ingredients. Clinicians, coaches, and parents should counsel against MBS use. Future studies with larger and more diverse samples are needed,” wrote the authors of the study.

SOURCE:

The study was led by Abigail Bulens, Division of Adolescent and Young Adult Medicine, Boston Children’s Hospital in Boston. It was published online in JAMA Network Open.

LIMITATIONS:

The study had a wide CI around the OR, potentially affecting the precision of the risk estimates. Additionally, the sample lacked diversity, with 92.8% of participants being White, which may limit the generalizability of findings to other racial and ethnic groups.

DISCLOSURES:

One coauthor received support from grant 1F32MDO17452-01 from the National Institute on Minority Health and Health Disparities. Another coauthor received support from training grant T76-MC-00001 from the Maternal and Child Health Bureau, Health Resources and Services Administration, Department of Health and Human Services. The cohorts were supported by National Institutes of Health grants HD045763, HD057368, DK46834, and HLO3533. The funders had no role in the study design, data collection, analysis, interpretation, manuscript preparation, or publication decision.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

TOPLINE:

Muscle-building dietary supplement (MBS) use among young men substantially increases the odds of subsequent anabolic-androgenic steroid (AAS) initiation. Users of MBS showed elevated odds of incident AAS use within 1-5 years, supporting the gateway hypothesis for escalating risk-taking behaviors to increase muscularity.

METHODOLOGY:

• Analysis included data from two Growing Up Today Study prospective cohorts spanning 14 years (2007-2021).
• Participants included 4073 cisgender boys and young men aged 10-27 years at baseline (mean age, 20.3 years).
• Demographics showed 92.8% White participants and 7.2% other races or ethnicities.
• Researchers assessed past-year substance use for muscle building, including protein supplements, creatine, amino acids, hydroxymethylbutyrate, and dehydroepiandrosterone.

TAKEAWAY:

• Initial survey results showed 11.1% of respondents reported past-year muscle-building supplement use, and 0.4% reported AAS use.
• Over the study period, 37.7% of respondents reported any past-year muscle-building supplement use, while 0.5% reported any past-year AAS use.
• Analysis revealed muscle-building supplement users had (odds ratio [OR], 8.31; 95% CI, 2.59-26.73) higher odds of initiating AAS use by the next survey wave than nonusers.
• Age (adjusted OR [AOR], 0.98; 95% CI, 0.85-1.12) and cohort (AOR, 0.83; 95% CI, 0.30-2.32) were not statistically significant factors.

IN PRACTICE:

“The health risks of MBS use are well documented, as inadequate federal regulation has resulted in a US MBS marketplace rife with inaccurate labeling and adulteration with toxic ingredients. Clinicians, coaches, and parents should counsel against MBS use. Future studies with larger and more diverse samples are needed,” wrote the authors of the study.

SOURCE:

The study was led by Abigail Bulens, Division of Adolescent and Young Adult Medicine, Boston Children’s Hospital in Boston. It was published online in JAMA Network Open.

LIMITATIONS:

The study had a wide CI around the OR, potentially affecting the precision of the risk estimates. Additionally, the sample lacked diversity, with 92.8% of participants being White, which may limit the generalizability of findings to other racial and ethnic groups.

DISCLOSURES:

One coauthor received support from grant 1F32MDO17452-01 from the National Institute on Minority Health and Health Disparities. Another coauthor received support from training grant T76-MC-00001 from the Maternal and Child Health Bureau, Health Resources and Services Administration, Department of Health and Human Services. The cohorts were supported by National Institutes of Health grants HD045763, HD057368, DK46834, and HLO3533. The funders had no role in the study design, data collection, analysis, interpretation, manuscript preparation, or publication decision.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

TOPLINE:

Muscle-building dietary supplement (MBS) use among young men substantially increases the odds of subsequent anabolic-androgenic steroid (AAS) initiation. Users of MBS showed elevated odds of incident AAS use within 1-5 years, supporting the gateway hypothesis for escalating risk-taking behaviors to increase muscularity.

METHODOLOGY:

• Analysis included data from two Growing Up Today Study prospective cohorts spanning 14 years (2007-2021).
• Participants included 4073 cisgender boys and young men aged 10-27 years at baseline (mean age, 20.3 years).
• Demographics showed 92.8% White participants and 7.2% other races or ethnicities.
• Researchers assessed past-year substance use for muscle building, including protein supplements, creatine, amino acids, hydroxymethylbutyrate, and dehydroepiandrosterone.

TAKEAWAY:

• Initial survey results showed 11.1% of respondents reported past-year muscle-building supplement use, and 0.4% reported AAS use.
• Over the study period, 37.7% of respondents reported any past-year muscle-building supplement use, while 0.5% reported any past-year AAS use.
• Analysis revealed muscle-building supplement users had (odds ratio [OR], 8.31; 95% CI, 2.59-26.73) higher odds of initiating AAS use by the next survey wave than nonusers.
• Age (adjusted OR [AOR], 0.98; 95% CI, 0.85-1.12) and cohort (AOR, 0.83; 95% CI, 0.30-2.32) were not statistically significant factors.

IN PRACTICE:

“The health risks of MBS use are well documented, as inadequate federal regulation has resulted in a US MBS marketplace rife with inaccurate labeling and adulteration with toxic ingredients. Clinicians, coaches, and parents should counsel against MBS use. Future studies with larger and more diverse samples are needed,” wrote the authors of the study.

SOURCE:

The study was led by Abigail Bulens, Division of Adolescent and Young Adult Medicine, Boston Children’s Hospital in Boston. It was published online in JAMA Network Open.

LIMITATIONS:

The study had a wide CI around the OR, potentially affecting the precision of the risk estimates. Additionally, the sample lacked diversity, with 92.8% of participants being White, which may limit the generalizability of findings to other racial and ethnic groups.

DISCLOSURES:

One coauthor received support from grant 1F32MDO17452-01 from the National Institute on Minority Health and Health Disparities. Another coauthor received support from training grant T76-MC-00001 from the Maternal and Child Health Bureau, Health Resources and Services Administration, Department of Health and Human Services. The cohorts were supported by National Institutes of Health grants HD045763, HD057368, DK46834, and HLO3533. The funders had no role in the study design, data collection, analysis, interpretation, manuscript preparation, or publication decision.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

This transcript has been edited for clarity. 

Michelle L. O’Donoghue, MD, MPH: I’m here at the American Heart Association Scientific Sessions. It’s a very exciting meeting, but one of the interesting topics that we’re going to be talking about is lipoprotein(a) [Lp(a)] . It’s definitely one of the hottest sessions of the meeting.

Joining me to discuss this topic is Dr Steve Nicholls, who is arguably one of the leading experts in the world on lipids. He’s a professor of medicine at Monash University in Australia. Welcome. Thanks, Steve. 

Stephen J. Nicholls, MBBS, PhD: Thanks for having me. 

O’Donoghue: There are two phase 2 studies that we’ll circle back to that are being presented here at the American Heart Association meeting. These are for novel therapeutics that lower Lp(a). Perhaps taking a step back, we know that there’s a large body of evidence to support the concept that Lp(a) plays a causal role in heart disease and atherogenesis, but to date we haven’t had any effective therapies to really lower it.

Thinking about the therapeutics specifically that are on the horizon, perhaps we could start there. Which one is furthest along in development, and how does that look in terms of its ability to lower Lp(a)?

 

Pelacarsen, an ASO

Nicholls: Most of the therapies are injectable. Most of them are nucleic acid–based therapies, and the one that’s most advanced is an agent called pelacarsen. Pelacarsen is an antisense oligonucleotide (ASO), and it has gone all the way through its early phase 2 studies. It has a fully enrolled cardiovascular outcome trial.

We’re all eagerly awaiting the results of that study sometime in the next year or so. That will be the first large-scale clinical trial that will give us some clinical validation to ask the question of whether substantive lowering of Lp(a) will lower cardiovascular risk, with an agent that in early studies looks like it lowers Lp(a) about 80%.

O’Donoghue: Which is tremendous, because again, we really don’t have any effective therapies right now. I guess one of the big questions is, how much do we need to lower Lp(a) for that to translate into meaningful clinical benefit? What’s your sense there? 

Nicholls: Well, we simply don’t know. We’ve tried to look to genetics to try and give us some sort of sense in terms of what that looks like. Lp(a) is a little tricky because the assays and the numbers that get spit out can be tricky in terms of trying to compare apples and apples in different studies. 

We think that it’s probably at least a 50- to 75-mg/dL lowering of Lp(a) using the old units. We think that pelacarsen would hit that, and so our hope is that that would translate to a 15%-20% reduction in major cardiovascular events, but again, we’ve never asked this question before. 

We have data from PCSK9 inhibitor trials showing that lesser reductions in Lp(a) of 25%-30% with both evolocumab and alirocumab contributed to the clinical benefit that we saw in those studies. Those agents were really good at lowering low-density lipoprotein (LDL) cholesterol, but Lp(a) lowering seemed to matter. One would be very hopeful that if a 25%-30% lowering of Lp(a) is useful, then an 80% or greater lowering of Lp(a) should be really useful. 

 

The siRNAs

O’Donoghue: In addition to the ASO pelacarsen that you mentioned, there are several therapeutics in the pipeline, including three small interfering (si) RNAs that are at least in phase 2 and phase 3 testing at this point in time. There’s olpasiran, which in phase 2 testing led to more than a 95% reduction in Lp(a), and then lepodisiran , which has now moved into phase 3  testing, albeit we haven’t seen yet the phase 2  results. 

What is your sense of lepodisiran and its efficacy? 

Nicholls: What’s been really quite striking about the siRNAs is the even more profound degree of lowering of Lp(a) that we’re seeing. We’re seeing 90% and greater lowering of Lp(a) in all of those programs. We’re seeing some differences between the programs in terms of the durability of that effect. 

I think it would be fair to say that with zerlasiran we’re starting to see perhaps that lowering effect starts to taper off a little bit more quickly than the other two. I think that may have some implications in terms of what dosing regimens may look like in the future. 

Even so, we’re talking about therapies that may be dosed 3- to 6-monthly, or even with the potential for being less frequent than that with lepodisiran. Again, I think the phase 2 data will be really important in terms of giving us more information.

O’Donoghue: For the lepodisiran results, I was really quite struck that even though it was small numbers, single dose administered, it really looked like the duration of effect persisted at the higher doses up to about a year. 

Nicholls: It looks pretty promising. We’ve launched the ACCLAIM study, the large cardiovascular outcome trial of lepodisiran, with a 6-monthly regimen. We are hopeful that more information may be able to give us the opportunity for even less frequent administration. 

That has really important implications for patients where adherence is a particular issue. They may just simply want to come into the clinic. You know, once or twice a year, very much like we’re seeing with inclisiran, and that may be a really effective approach for many patients. 

O’Donoghue: You alluded to the zerlasiran results, which were presented here at the American Heart Association meeting, and that even though it led to a robust reduction in Lp(a), it looked like the durability component was maybe a little bit shorter than for some of the other siRNAs that are currently being evaluated.

What’s your sense of that? 

Nicholls: It probably is. The implications clinically, at least in an outcome trial when they ultimately get to that point, probably aren’t that important. They’ll probably just have slightly more frequent administration. That may become a bigger issue when it gets out into the clinic.

The nice thing is that if all of these agents appear to be effective, are well tolerated, and get out to the clinic, then clinicians and patients are going to have a lot of choice. 

O’Donoghue: I think more competition is always good news for the field, ultimately. I think to your point, especially for a drug that might be self-administered, ultimately, whether it’s once a month or once every 3 months, it doesn’t probably make much difference. I think different choices are needed for different patients. 

Perhaps that’s a perfect segue to talk about the oral Lp(a) inhibitor that is also being developed. You presented these results for muvalaplin. 

 

Muvalaplin, an Oral Small Molecule

Nicholls: In terms of frequency of administration, we’re talking about a daily oral therapeutic. For patients who don’t want an injectable and are happy to take a tablet every day, muvalaplin has the potential to be a really good option for them. 

Muvalaplin is an oral small-molecule inhibitor. It essentially prevents apolipoprotein(a) [apo(a)] from binding to apolipoprotein B (apo B). We presented phase 1 data  at the European Society of Cardiology meeting last year, showing probably Lp(a) lowering on the order of about 65%. Here, we’re going to show that that’s a little bit more. It looks like it’s probably at least 70% lowering using a standard Lp(a) assay. Using an assay that looks specifically at intact Lp(a) particles, it’s probably well in excess of 80%.

Those are really good results. The safety and tolerability with muvalaplin look really good. Again, we’ll need to see that agent move forward into a large outcome trial and we’ve yet to hear about that, at least for now. 

O’Donoghue: It’s an interesting challenge that you faced in terms of the assay because, as you say, it really disrupts the apo(a) from binding to the apo B particle, and hence, a traditional assay that just measures apo(a), regardless of whether or not it’s bound to an apo B particle, may be a conservative estimate.

Nicholls: It may, in particular, because we know that apo(a) ultimately then binds to the drug. That assay is measuring what we think is nonfunctional apo(a) in addition to functional apo(a). It’s measuring functional apo(a) that’s still on an actual Lp(a) particle, but if it’s bound to muvalaplin, we think to some degree that’s probably unfair to count that. That’s why trying to develop other assays to try and understand the full effect of the drug is really important in terms of trying to understand how we develop that and move that forward.

O’Donoghue: Is there any evidence yet that the apo(a) particle that is not bound to apo B is in fact nonfunctional as you described it? 

Nicholls: We think that’s likely to be the case, but I think there continues to be research in that space to try and settle that question once and for all. 

O’Donoghue: Again, I think it’s a really exciting time in this field. Right now, we have three ongoing phase 3 trials. We have the pelacarsen trial that is still in follow-up, and fingers crossed, maybe will report out next year. Olpasiran is also in phase 3 testing, completed enrollment, and also is in the follow-up period. We also have lepodisiran, the ACCLAIM trial, as you mentioned. For people who are perhaps watching and looking to enroll their patients, this trial is still ongoing right now in terms of enrollment. 

Nicholls: It is, and what’s nice about the ACCLAIM study is that it includes both primary and secondary prevention patients. For the first time in a big outcome trial, patients with high Lp(a) levels but who have yet to have a clinical event can actually get into a clinical trial.

I’m sure, like you, my clinic is full of patients with high Lp(a) who are really desperate to get into these trials. Many of those primary prevention patients just simply haven’t qualified, so that’s really good news. 

The step beyond that, if we’re talking about even less frequent administration, is gene editing. We’re seeing those studies with CRISPR move forward to try to evaluate whether a single gene-editing approach at Lp(a) will be all that you need, which is even a more amazing concept, but that’s a study that needs more work. 

O’Donoghue: An exciting space though, for sure. As a final thought, you mentioned the patients in your clinic who you have identified as having high Lp(a). What are you doing right now in your practice for managing those patients? I think there are many practitioners out there who struggle with whether they should really measure their patients’ Lp(a), and whether they want to know that information.

Nicholls: Yeah, it’s really hard. The answer is yes, we do want to know it. We know it’s a great risk enhancer. We know that a patient with a high Lp(a) is somebody whom I want to more intensively treat their other risk factors. I’m aiming for a lower LDL. I’m being much tighter with blood pressure control.

I think there’s some argument from observational data at least that aspirin remains a consideration, particularly in patients where you think there’s a particularly high risk associated with that high Lp(a). I think there are things we absolutely can do today, but we can’t do anything if you don’t know the numbers.

It starts with testing, and then we can move on to what we can do today, and then hopefully in the not-too-distant future, we’ll have specific therapies that really enable for us to address Lp(a) quite definitively. 

O’Donoghue: Thanks again for taking the time. This was a very helpful discussion.

 

Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates. Dr O’Donoghue, Senior Investigator, TIMI Study Group; Associate Professor of Medicine, Harvard Medical School; Associate Physician, Brigham and Women’s Hospital, Boston, Massachusetts, disclosed ties to Janssen; Novartis; CVS Minute Clinic; Merck & Co.; GlaxoSmithKline; Eisai Inc.; AstraZeneca Pharmaceuticals LP; Janssen Pharmaceuticals; Medicines Company; and Amgen. The opinions expressed in this article do not necessarily reflect the views and opinions of Brigham and Women’s Hospital. Stephen J. Nicholls, MBBS, PhD, Director, Victorian Heart Institute, Monash University; Director, Victorian Heart Hospital, Monash Health, Melbourne, Australia, has disclosed ties with Akcea Therapeutics; Amgen; AstraZeneca; Boehringer Ingelheim; CSL Behring; Eli Lilly and Company; Esperion Therapeutics; Kowa Pharmaceuticals; Merck; Novo Nordisk; Pfizer; Sanofi Regeneron; Daichii Sankyo; Vaxxinity; Cyclarity; CSL Sequirus; Takeda; Anthera Pharmaceuticals; Cerenis Therapeutics; Infraredx; New Amsterdam Pharma; Novartis; and Resverlogix.

A version of this article appeared on Medscape.com.