Clinician Reviews

TOPLINE:

In insulin-naive people with type 2 diabetes, once-weekly icodec titrated with a dosing guide app was both noninferior and superior to daily basal analogs in reducing A1c levels, with improved treatment satisfaction and compliance scores and similarly low hypoglycemia rates.

METHODOLOGY:

• A 52-week, randomized, open-label, parallel-group, phase 3a trial with real-world elements was conducted at 176 sites in seven countries.
• A total of 1,085 insulin-naive patients with type 2 diabetes were randomly assigned to receive icodec with a dosing guide app or daily analogs (U100 glargine, U300 glargine, or icodec).

TAKEAWAY:

• A1c levels dropped from 8.96% at baseline to 7.24% at week 52 with icodec and from 8.88% to 7.61% with the daily analog, a treatment difference of 0.37 percentage point (P < .001 for noninferiority and P = .009 for superiority in favor of icodec plus the app).
• Patient-reported outcomes were more favorable with icodec plus the app vs. daily analogs, with estimated treatment differences that were significant for the Treatment Related Impact Measure for Diabetes (3.04) but not the Diabetes Treatment Satisfaction Questionnaire (0.78).
• Observed rates of combined clinically significant or severe hypoglycemia were low (0.19 event per patient-year of exposure for icodec plus the app vs. 0.14 for daily analogs; estimated rate ratio, 1.17).

IN PRACTICE:

“Once-weekly icodec with a dosing guide app could conceivably address several challenges seen in everyday practice, including inadequate dose titration and nonadherence to prescribed treatment regimens.”

SOURCE:

The study was conducted by Harpreet S. Bajaj, MD, MPH, of LMC Diabetes and Endocrinology, Brampton, Ontario, and colleagues. It was published online in Annals of Internal Medicine.

LIMITATIONS:

The research could not differentiate between the effects of icodec and those of the dosing guide app. The study had an open-label design. A 1-year duration is insufficient to assess long-term diabetes- and cardiovascular-related outcomes.

DISCLOSURES:

The study was funded by Novo Nordisk A/S.
 

A version of this article appeared on Medscape.com.

TOPLINE:

In insulin-naive people with type 2 diabetes, once-weekly icodec titrated with a dosing guide app was both noninferior and superior to daily basal analogs in reducing A1c levels, with improved treatment satisfaction and compliance scores and similarly low hypoglycemia rates.

METHODOLOGY:

• A 52-week, randomized, open-label, parallel-group, phase 3a trial with real-world elements was conducted at 176 sites in seven countries.
• A total of 1,085 insulin-naive patients with type 2 diabetes were randomly assigned to receive icodec with a dosing guide app or daily analogs (U100 glargine, U300 glargine, or icodec).

TAKEAWAY:

• A1c levels dropped from 8.96% at baseline to 7.24% at week 52 with icodec and from 8.88% to 7.61% with the daily analog, a treatment difference of 0.37 percentage point (P < .001 for noninferiority and P = .009 for superiority in favor of icodec plus the app).
• Patient-reported outcomes were more favorable with icodec plus the app vs. daily analogs, with estimated treatment differences that were significant for the Treatment Related Impact Measure for Diabetes (3.04) but not the Diabetes Treatment Satisfaction Questionnaire (0.78).
• Observed rates of combined clinically significant or severe hypoglycemia were low (0.19 event per patient-year of exposure for icodec plus the app vs. 0.14 for daily analogs; estimated rate ratio, 1.17).

IN PRACTICE:

“Once-weekly icodec with a dosing guide app could conceivably address several challenges seen in everyday practice, including inadequate dose titration and nonadherence to prescribed treatment regimens.”

SOURCE:

The study was conducted by Harpreet S. Bajaj, MD, MPH, of LMC Diabetes and Endocrinology, Brampton, Ontario, and colleagues. It was published online in Annals of Internal Medicine.

LIMITATIONS:

The research could not differentiate between the effects of icodec and those of the dosing guide app. The study had an open-label design. A 1-year duration is insufficient to assess long-term diabetes- and cardiovascular-related outcomes.

DISCLOSURES:

The study was funded by Novo Nordisk A/S.
 

A version of this article appeared on Medscape.com.

TOPLINE:

In insulin-naive people with type 2 diabetes, once-weekly icodec titrated with a dosing guide app was both noninferior and superior to daily basal analogs in reducing A1c levels, with improved treatment satisfaction and compliance scores and similarly low hypoglycemia rates.

METHODOLOGY:

• A 52-week, randomized, open-label, parallel-group, phase 3a trial with real-world elements was conducted at 176 sites in seven countries.
• A total of 1,085 insulin-naive patients with type 2 diabetes were randomly assigned to receive icodec with a dosing guide app or daily analogs (U100 glargine, U300 glargine, or icodec).

TAKEAWAY:

• A1c levels dropped from 8.96% at baseline to 7.24% at week 52 with icodec and from 8.88% to 7.61% with the daily analog, a treatment difference of 0.37 percentage point (P < .001 for noninferiority and P = .009 for superiority in favor of icodec plus the app).
• Patient-reported outcomes were more favorable with icodec plus the app vs. daily analogs, with estimated treatment differences that were significant for the Treatment Related Impact Measure for Diabetes (3.04) but not the Diabetes Treatment Satisfaction Questionnaire (0.78).
• Observed rates of combined clinically significant or severe hypoglycemia were low (0.19 event per patient-year of exposure for icodec plus the app vs. 0.14 for daily analogs; estimated rate ratio, 1.17).

IN PRACTICE:

“Once-weekly icodec with a dosing guide app could conceivably address several challenges seen in everyday practice, including inadequate dose titration and nonadherence to prescribed treatment regimens.”

SOURCE:

The study was conducted by Harpreet S. Bajaj, MD, MPH, of LMC Diabetes and Endocrinology, Brampton, Ontario, and colleagues. It was published online in Annals of Internal Medicine.

LIMITATIONS:

The research could not differentiate between the effects of icodec and those of the dosing guide app. The study had an open-label design. A 1-year duration is insufficient to assess long-term diabetes- and cardiovascular-related outcomes.

DISCLOSURES:

The study was funded by Novo Nordisk A/S.
 

A version of this article appeared on Medscape.com.

Approximately 4 in 10 cases of type 1 diabetes in adults are diagnosed at age 30 years and older, based on data from nearly 1,000 individuals.

New-onset type 1 diabetes in adults is often misdiagnosed as type 2 diabetes, which may lead to inappropriate care, wrote Michael Fang, PhD, of Johns Hopkins University, Baltimore, and colleagues.

Previous research suggests that more than half of type 1 diabetes cases develop in adults, but data on variations in clinical characteristics and age at diagnosis are limited, the researchers said. “Clarifying the burden of adult-onset type 1 diabetes in the general population may help reduce misdiagnosis.”

In a study published in Annals of Internal Medicine, the researchers identified 947 adults aged 18 years and older with newly diagnosed type 1 diabetes, by using data from the National Health Interview Survey between 2016 and 2022. The subjects’ mean age at the time of the survey was 49 years and 48% were women. The racial/ethnic distribution was 73% non-Hispanic White, 10% non-Hispanic Black, 12% Hispanic, 3%, non-Hispanic Asian, and 3% other race/ethnicity.

Overall, 37% of participants were diagnosed with type 1 diabetes after age 30 years, with an overall median age at diagnosis of 24 years.

Type 1 diabetes was diagnosed later in men than in women, at a median age of 27 years vs. 22 years, respectively, and later in racial/ethnic minorities than in non-Hispanic Whites, with a median age of 26-30 years versus 21 years, respectively.

Autoantibody and C-peptide tests are recommended to confirm type 1 diabetes in adults with a suspected diagnosis, but the best method to identify high-risk adults remains unclear, the researchers wrote in their discussion.

“Traditional markers used to differentiate type 1 and type 2 diabetes, such as body mass index, may have limited utility, especially because obesity is now common in the type 1 diabetes population,” they said. New tools combining clinical features and biomarkers may improve accuracy of diagnosis of type 1 diabetes in the adult population, but more research is needed.

The findings were limited by several factors including misclassification based on self-reports of diagnosis and age, the researchers noted. Other limitations included lack of data on diagnostic measures such as levels of autoantibodies, C-peptides, and other indicators of diabetes, as well as inexact subgroup estimates because of small sample sizes.

“We extended existing research by characterizing the age at diagnosis in a nationally representative sample and by documenting variation across race/ethnicity and clinical characteristics,” they said.

The study was supported by grants from the National Heart, Lung, and Blood Institute. The lead authors had no financial conflicts to disclose. Corresponding author Elizabeth Selvin, PhD, disclosed grants from NIH and FNIH, personal fees from Novo Nordisk, other financial relationships with Wolters Kluwer, and nonfinancial support from many pharmaceutical companies outside the current study; she also serves as deputy editor of Diabetes Care and a member of the editorial board of Diabetologia.

Approximately 4 in 10 cases of type 1 diabetes in adults are diagnosed at age 30 years and older, based on data from nearly 1,000 individuals.

New-onset type 1 diabetes in adults is often misdiagnosed as type 2 diabetes, which may lead to inappropriate care, wrote Michael Fang, PhD, of Johns Hopkins University, Baltimore, and colleagues.

Previous research suggests that more than half of type 1 diabetes cases develop in adults, but data on variations in clinical characteristics and age at diagnosis are limited, the researchers said. “Clarifying the burden of adult-onset type 1 diabetes in the general population may help reduce misdiagnosis.”

In a study published in Annals of Internal Medicine, the researchers identified 947 adults aged 18 years and older with newly diagnosed type 1 diabetes, by using data from the National Health Interview Survey between 2016 and 2022. The subjects’ mean age at the time of the survey was 49 years and 48% were women. The racial/ethnic distribution was 73% non-Hispanic White, 10% non-Hispanic Black, 12% Hispanic, 3%, non-Hispanic Asian, and 3% other race/ethnicity.

Overall, 37% of participants were diagnosed with type 1 diabetes after age 30 years, with an overall median age at diagnosis of 24 years.

Type 1 diabetes was diagnosed later in men than in women, at a median age of 27 years vs. 22 years, respectively, and later in racial/ethnic minorities than in non-Hispanic Whites, with a median age of 26-30 years versus 21 years, respectively.

Autoantibody and C-peptide tests are recommended to confirm type 1 diabetes in adults with a suspected diagnosis, but the best method to identify high-risk adults remains unclear, the researchers wrote in their discussion.

“Traditional markers used to differentiate type 1 and type 2 diabetes, such as body mass index, may have limited utility, especially because obesity is now common in the type 1 diabetes population,” they said. New tools combining clinical features and biomarkers may improve accuracy of diagnosis of type 1 diabetes in the adult population, but more research is needed.

The findings were limited by several factors including misclassification based on self-reports of diagnosis and age, the researchers noted. Other limitations included lack of data on diagnostic measures such as levels of autoantibodies, C-peptides, and other indicators of diabetes, as well as inexact subgroup estimates because of small sample sizes.

“We extended existing research by characterizing the age at diagnosis in a nationally representative sample and by documenting variation across race/ethnicity and clinical characteristics,” they said.

The study was supported by grants from the National Heart, Lung, and Blood Institute. The lead authors had no financial conflicts to disclose. Corresponding author Elizabeth Selvin, PhD, disclosed grants from NIH and FNIH, personal fees from Novo Nordisk, other financial relationships with Wolters Kluwer, and nonfinancial support from many pharmaceutical companies outside the current study; she also serves as deputy editor of Diabetes Care and a member of the editorial board of Diabetologia.

Approximately 4 in 10 cases of type 1 diabetes in adults are diagnosed at age 30 years and older, based on data from nearly 1,000 individuals.

New-onset type 1 diabetes in adults is often misdiagnosed as type 2 diabetes, which may lead to inappropriate care, wrote Michael Fang, PhD, of Johns Hopkins University, Baltimore, and colleagues.

Previous research suggests that more than half of type 1 diabetes cases develop in adults, but data on variations in clinical characteristics and age at diagnosis are limited, the researchers said. “Clarifying the burden of adult-onset type 1 diabetes in the general population may help reduce misdiagnosis.”

In a study published in Annals of Internal Medicine, the researchers identified 947 adults aged 18 years and older with newly diagnosed type 1 diabetes, by using data from the National Health Interview Survey between 2016 and 2022. The subjects’ mean age at the time of the survey was 49 years and 48% were women. The racial/ethnic distribution was 73% non-Hispanic White, 10% non-Hispanic Black, 12% Hispanic, 3%, non-Hispanic Asian, and 3% other race/ethnicity.

Overall, 37% of participants were diagnosed with type 1 diabetes after age 30 years, with an overall median age at diagnosis of 24 years.

Type 1 diabetes was diagnosed later in men than in women, at a median age of 27 years vs. 22 years, respectively, and later in racial/ethnic minorities than in non-Hispanic Whites, with a median age of 26-30 years versus 21 years, respectively.

Autoantibody and C-peptide tests are recommended to confirm type 1 diabetes in adults with a suspected diagnosis, but the best method to identify high-risk adults remains unclear, the researchers wrote in their discussion.

“Traditional markers used to differentiate type 1 and type 2 diabetes, such as body mass index, may have limited utility, especially because obesity is now common in the type 1 diabetes population,” they said. New tools combining clinical features and biomarkers may improve accuracy of diagnosis of type 1 diabetes in the adult population, but more research is needed.

The findings were limited by several factors including misclassification based on self-reports of diagnosis and age, the researchers noted. Other limitations included lack of data on diagnostic measures such as levels of autoantibodies, C-peptides, and other indicators of diabetes, as well as inexact subgroup estimates because of small sample sizes.

“We extended existing research by characterizing the age at diagnosis in a nationally representative sample and by documenting variation across race/ethnicity and clinical characteristics,” they said.

The study was supported by grants from the National Heart, Lung, and Blood Institute. The lead authors had no financial conflicts to disclose. Corresponding author Elizabeth Selvin, PhD, disclosed grants from NIH and FNIH, personal fees from Novo Nordisk, other financial relationships with Wolters Kluwer, and nonfinancial support from many pharmaceutical companies outside the current study; she also serves as deputy editor of Diabetes Care and a member of the editorial board of Diabetologia.

The complex pathophysiology of obesity requires a multidisciplinary approach that includes lifestyle and medical interventions for successful management. Antiobesity medications (AOMs) have emerged as a powerful and life-changing tool for many individuals with obesity who are unable to sustain long-term weight loss through lifestyle changes alone. As with other chronic diseases such as hypertension and hyperlipidemia, the goal of decades of research has been to develop antiobesity medications with long-term efficacy and safety. Recent groundbreaking findings from a phase 2 trial show immense potential for a new AOM.

Here are five things to know about the role of agonists in the management of obesity.

1. Gut hormone physiology informs the development of AOMs.

The three hormones associated with obesity or diabetes are glucagonlike peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon. GLP-1, a peptide released from the intestines in response to food ingestion, increases insulin production, reduces gut motility, and suppresses appetite. GIP is also an intestinal hormone that increases meal-stimulated insulin production and additionally facilitates lipolysis. Glucagon is known to increase hepatic glucose output but will also increase insulin secretion in the setting of hyperglycemia. Glucagon also promotes lipolysis.

Though these hormones are more commonly thought of as incretins, gut hormones that stimulate postprandial insulin secretion, their role in energy physiology is more diverse. Because of multiple mechanisms of action, incretins are increasingly referred to as nutrient-stimulated hormones (NuSH), a term which encompasses other peptides with therapeutic potential (e.g., amylin, oxyntomodulin, peptide tyrosine–tyrosine).

2. Studies have shown that NuSH therapies are highly effective AOMs.

In 2021 the Food and Drug Administration approved subcutaneous semaglutide 2.4 mg, a GLP-1 receptor agonist, for the treatment of obesity. Clinical trials demonstrating an average weight loss of 15% in patients taking semaglutide ushered in a new era of AOMs associated with significant weight loss that not only improve disease activity but also have the potential to achieve diabetes remission. Recent findings from the OASIS I trial demonstrated an average weight loss of 15.1% from baseline in patients treated with oral semaglutide for 68 weeks. Medical societies, including the American Diabetes Association and the American Association for the Study of Liver Diseases, recommend 10%-15% weight loss to fully treat weight-related comorbidities like type 2 diabetes and nonalcoholic fatty liver disease. In 2022, tirzepatide, a dual GLP-1 and GIP receptor agonist, demonstrated an average weight loss of 22.5% in phase 3 of the SURMOUNT-1 trial for obesity – a weight loss approaching that of some bariatric surgeries.

3. Clinical trial data show that the novel triple agonist retatrutide induces significant weight loss.

Preclinical studies on the newest NuSH therapy, triple GLP-1–GIP–glucagon receptor agonist retatrutide, showed predominant activity at the GIP receptor, with less GLP-1– and glucagon-receptor agonism than that of endogenous GLP-1 and GIP. Results from a phase 2 trial published in June 2023 showed a weight loss of 24% at 48 weeks in adults with obesity treated with retatrutide, which is the greatest weight loss reported in an obesity trial so far. Moreover, for the first time in obesity pharmacotherapy research, 100% of participants achieved clinically significant weight loss (defined as ≥ 5% of baseline weight).

4. Retatrutide may improve lipid metabolism.

In the phase 2 trial, retatrutide reduced low-density lipoprotein cholesterol levels by approximately 20%. This degree of reduced plasma LDL-C is dramatic in weight loss studies. Typically, weight loss significantly reduces triglyceride levels, increases high-density lipoprotein cholesterol levels, and has a modest effect on LDL-C reduction of about 5%.

A 20% reduction in LDL-C with retatrutide is hypothesis generating. Preclinical studies have shown glucagon to be an important regulator of proprotein convertase subtilisin/kexin type 9 degradation, with the lack of glucagon resulting in increased PCSK9 levels, decreased LDL receptors, and increased plasma LDL; conversely, treatment with glucagon decreased plasma LDL.

5. The long-term safety of retatrutide still needs to be determined.

In the 48-week phase 2 trial, retatrutide was observed to have a side-effect profile largely similar to other NuSH therapies (e.g., semaglutide 2.4 mg, tirzepatide), with a predominance of gastrointestinal symptoms including nausea, diarrhea, vomiting, and constipation. However, side effects potentially unique to retatrutide also emerged. Cutaneous hyperesthesia and skin sensitivity were reported in 7% of participants in the retatrutide group vs. 1% in the placebo group; none of these effects were associated with physical skin findings. Of note, 17 out of 198 (9%) participants in the retatrutide group developed cardiac arrhythmia vs. two out of 70 (3%) in the placebo group. There was no consistent pattern of arrhythmia type (e.g., supraventricular, ventricular) observed, and some of these events were reported as “palpitations” or “increased heart rate” without further detail. Phase 3 clinical trial data will provide further insight into the long-term safety of retatrutide.

Dr. Tchang is assistant professor of clinical medicine, division of endocrinology, Weill Cornell Medicine and physician, department of medicine, New York-Presbyterian/Weill Cornell Medical Center, both in New York. She has disclosed ties with Gelesis and Novo Nordisk.

A version of this article appeared on Medscape.com.

The complex pathophysiology of obesity requires a multidisciplinary approach that includes lifestyle and medical interventions for successful management. Antiobesity medications (AOMs) have emerged as a powerful and life-changing tool for many individuals with obesity who are unable to sustain long-term weight loss through lifestyle changes alone. As with other chronic diseases such as hypertension and hyperlipidemia, the goal of decades of research has been to develop antiobesity medications with long-term efficacy and safety. Recent groundbreaking findings from a phase 2 trial show immense potential for a new AOM.

Here are five things to know about the role of agonists in the management of obesity.

1. Gut hormone physiology informs the development of AOMs.

The three hormones associated with obesity or diabetes are glucagonlike peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon. GLP-1, a peptide released from the intestines in response to food ingestion, increases insulin production, reduces gut motility, and suppresses appetite. GIP is also an intestinal hormone that increases meal-stimulated insulin production and additionally facilitates lipolysis. Glucagon is known to increase hepatic glucose output but will also increase insulin secretion in the setting of hyperglycemia. Glucagon also promotes lipolysis.

Though these hormones are more commonly thought of as incretins, gut hormones that stimulate postprandial insulin secretion, their role in energy physiology is more diverse. Because of multiple mechanisms of action, incretins are increasingly referred to as nutrient-stimulated hormones (NuSH), a term which encompasses other peptides with therapeutic potential (e.g., amylin, oxyntomodulin, peptide tyrosine–tyrosine).

2. Studies have shown that NuSH therapies are highly effective AOMs.

In 2021 the Food and Drug Administration approved subcutaneous semaglutide 2.4 mg, a GLP-1 receptor agonist, for the treatment of obesity. Clinical trials demonstrating an average weight loss of 15% in patients taking semaglutide ushered in a new era of AOMs associated with significant weight loss that not only improve disease activity but also have the potential to achieve diabetes remission. Recent findings from the OASIS I trial demonstrated an average weight loss of 15.1% from baseline in patients treated with oral semaglutide for 68 weeks. Medical societies, including the American Diabetes Association and the American Association for the Study of Liver Diseases, recommend 10%-15% weight loss to fully treat weight-related comorbidities like type 2 diabetes and nonalcoholic fatty liver disease. In 2022, tirzepatide, a dual GLP-1 and GIP receptor agonist, demonstrated an average weight loss of 22.5% in phase 3 of the SURMOUNT-1 trial for obesity – a weight loss approaching that of some bariatric surgeries.

3. Clinical trial data show that the novel triple agonist retatrutide induces significant weight loss.

Preclinical studies on the newest NuSH therapy, triple GLP-1–GIP–glucagon receptor agonist retatrutide, showed predominant activity at the GIP receptor, with less GLP-1– and glucagon-receptor agonism than that of endogenous GLP-1 and GIP. Results from a phase 2 trial published in June 2023 showed a weight loss of 24% at 48 weeks in adults with obesity treated with retatrutide, which is the greatest weight loss reported in an obesity trial so far. Moreover, for the first time in obesity pharmacotherapy research, 100% of participants achieved clinically significant weight loss (defined as ≥ 5% of baseline weight).

4. Retatrutide may improve lipid metabolism.

In the phase 2 trial, retatrutide reduced low-density lipoprotein cholesterol levels by approximately 20%. This degree of reduced plasma LDL-C is dramatic in weight loss studies. Typically, weight loss significantly reduces triglyceride levels, increases high-density lipoprotein cholesterol levels, and has a modest effect on LDL-C reduction of about 5%.

A 20% reduction in LDL-C with retatrutide is hypothesis generating. Preclinical studies have shown glucagon to be an important regulator of proprotein convertase subtilisin/kexin type 9 degradation, with the lack of glucagon resulting in increased PCSK9 levels, decreased LDL receptors, and increased plasma LDL; conversely, treatment with glucagon decreased plasma LDL.

5. The long-term safety of retatrutide still needs to be determined.

In the 48-week phase 2 trial, retatrutide was observed to have a side-effect profile largely similar to other NuSH therapies (e.g., semaglutide 2.4 mg, tirzepatide), with a predominance of gastrointestinal symptoms including nausea, diarrhea, vomiting, and constipation. However, side effects potentially unique to retatrutide also emerged. Cutaneous hyperesthesia and skin sensitivity were reported in 7% of participants in the retatrutide group vs. 1% in the placebo group; none of these effects were associated with physical skin findings. Of note, 17 out of 198 (9%) participants in the retatrutide group developed cardiac arrhythmia vs. two out of 70 (3%) in the placebo group. There was no consistent pattern of arrhythmia type (e.g., supraventricular, ventricular) observed, and some of these events were reported as “palpitations” or “increased heart rate” without further detail. Phase 3 clinical trial data will provide further insight into the long-term safety of retatrutide.

Dr. Tchang is assistant professor of clinical medicine, division of endocrinology, Weill Cornell Medicine and physician, department of medicine, New York-Presbyterian/Weill Cornell Medical Center, both in New York. She has disclosed ties with Gelesis and Novo Nordisk.

A version of this article appeared on Medscape.com.

The complex pathophysiology of obesity requires a multidisciplinary approach that includes lifestyle and medical interventions for successful management. Antiobesity medications (AOMs) have emerged as a powerful and life-changing tool for many individuals with obesity who are unable to sustain long-term weight loss through lifestyle changes alone. As with other chronic diseases such as hypertension and hyperlipidemia, the goal of decades of research has been to develop antiobesity medications with long-term efficacy and safety. Recent groundbreaking findings from a phase 2 trial show immense potential for a new AOM.

Here are five things to know about the role of agonists in the management of obesity.

1. Gut hormone physiology informs the development of AOMs.

The three hormones associated with obesity or diabetes are glucagonlike peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon. GLP-1, a peptide released from the intestines in response to food ingestion, increases insulin production, reduces gut motility, and suppresses appetite. GIP is also an intestinal hormone that increases meal-stimulated insulin production and additionally facilitates lipolysis. Glucagon is known to increase hepatic glucose output but will also increase insulin secretion in the setting of hyperglycemia. Glucagon also promotes lipolysis.

Though these hormones are more commonly thought of as incretins, gut hormones that stimulate postprandial insulin secretion, their role in energy physiology is more diverse. Because of multiple mechanisms of action, incretins are increasingly referred to as nutrient-stimulated hormones (NuSH), a term which encompasses other peptides with therapeutic potential (e.g., amylin, oxyntomodulin, peptide tyrosine–tyrosine).

2. Studies have shown that NuSH therapies are highly effective AOMs.

In 2021 the Food and Drug Administration approved subcutaneous semaglutide 2.4 mg, a GLP-1 receptor agonist, for the treatment of obesity. Clinical trials demonstrating an average weight loss of 15% in patients taking semaglutide ushered in a new era of AOMs associated with significant weight loss that not only improve disease activity but also have the potential to achieve diabetes remission. Recent findings from the OASIS I trial demonstrated an average weight loss of 15.1% from baseline in patients treated with oral semaglutide for 68 weeks. Medical societies, including the American Diabetes Association and the American Association for the Study of Liver Diseases, recommend 10%-15% weight loss to fully treat weight-related comorbidities like type 2 diabetes and nonalcoholic fatty liver disease. In 2022, tirzepatide, a dual GLP-1 and GIP receptor agonist, demonstrated an average weight loss of 22.5% in phase 3 of the SURMOUNT-1 trial for obesity – a weight loss approaching that of some bariatric surgeries.

3. Clinical trial data show that the novel triple agonist retatrutide induces significant weight loss.

Preclinical studies on the newest NuSH therapy, triple GLP-1–GIP–glucagon receptor agonist retatrutide, showed predominant activity at the GIP receptor, with less GLP-1– and glucagon-receptor agonism than that of endogenous GLP-1 and GIP. Results from a phase 2 trial published in June 2023 showed a weight loss of 24% at 48 weeks in adults with obesity treated with retatrutide, which is the greatest weight loss reported in an obesity trial so far. Moreover, for the first time in obesity pharmacotherapy research, 100% of participants achieved clinically significant weight loss (defined as ≥ 5% of baseline weight).

4. Retatrutide may improve lipid metabolism.

In the phase 2 trial, retatrutide reduced low-density lipoprotein cholesterol levels by approximately 20%. This degree of reduced plasma LDL-C is dramatic in weight loss studies. Typically, weight loss significantly reduces triglyceride levels, increases high-density lipoprotein cholesterol levels, and has a modest effect on LDL-C reduction of about 5%.

A 20% reduction in LDL-C with retatrutide is hypothesis generating. Preclinical studies have shown glucagon to be an important regulator of proprotein convertase subtilisin/kexin type 9 degradation, with the lack of glucagon resulting in increased PCSK9 levels, decreased LDL receptors, and increased plasma LDL; conversely, treatment with glucagon decreased plasma LDL.

5. The long-term safety of retatrutide still needs to be determined.

In the 48-week phase 2 trial, retatrutide was observed to have a side-effect profile largely similar to other NuSH therapies (e.g., semaglutide 2.4 mg, tirzepatide), with a predominance of gastrointestinal symptoms including nausea, diarrhea, vomiting, and constipation. However, side effects potentially unique to retatrutide also emerged. Cutaneous hyperesthesia and skin sensitivity were reported in 7% of participants in the retatrutide group vs. 1% in the placebo group; none of these effects were associated with physical skin findings. Of note, 17 out of 198 (9%) participants in the retatrutide group developed cardiac arrhythmia vs. two out of 70 (3%) in the placebo group. There was no consistent pattern of arrhythmia type (e.g., supraventricular, ventricular) observed, and some of these events were reported as “palpitations” or “increased heart rate” without further detail. Phase 3 clinical trial data will provide further insight into the long-term safety of retatrutide.

Dr. Tchang is assistant professor of clinical medicine, division of endocrinology, Weill Cornell Medicine and physician, department of medicine, New York-Presbyterian/Weill Cornell Medical Center, both in New York. She has disclosed ties with Gelesis and Novo Nordisk.

A version of this article appeared on Medscape.com.

A real-world study published in  JAMA Open Network found that Pfizer’s COVID-19 antiviral Paxlovid is now less effective at preventing hospitalization or death in high-risk patients, compared with earlier studies. But when looking at death alone, the antiviral was still highly effective. 

Paxlovid was about 37% effective at preventing death or hospitalization in high-risk patients, compared with no treatment. The study also looked at the antiviral Lagevrio, made by Merck, and found it was about 41% effective. In preventing death alone, Paxlovid was about 84% effective, compared with no treatment, and Lagevrio was about 77% effective.

The investigators, of the University of North Carolina at Chapel Hill and the Cleveland Clinic, examined electronic health records of 68,867 patients at hospitals in Cleveland and Florida who were diagnosed with COVID from April 1, 2022, to Feb. 20, 2023.

For Paxlovid, the effectiveness against death and hospitalization was lower than the effectiveness rate of about 86% found in clinical trials in 2021, according to Bloomberg. 

The difference in effectiveness in the real-world and clinical studies may have occurred because the early studies were conducted with unvaccinated people. Also, the virus has evolved since those first studies, Bloomberg reported. 

The researchers said Paxlovid and Lagevrio are recommended for use because they reduce hospitalization and death among high-risk patients who get COVID, even taking recent Omicron subvariants into account.

“These findings suggest that the use of either nirmatrelvir (Paxlovid) or molnupiravir (Lagevrio) is associated with reductions in mortality and hospitalization in patients infected with Omicron, regardless of age, race and ethnicity, virus strain, vaccination status, previous infection status, or coexisting conditions,” the researchers wrote. “Both drugs can, therefore, be used to treat nonhospitalized patients who are at high risk of progressing to severe COVID-19.”

Both drugs should be taken within 5 days of the onset of COVID symptoms.

The study was supported by the National Institutes of Health. Three coauthors reported conflicts of interest with various companies and organizations.

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

A real-world study published in  JAMA Open Network found that Pfizer’s COVID-19 antiviral Paxlovid is now less effective at preventing hospitalization or death in high-risk patients, compared with earlier studies. But when looking at death alone, the antiviral was still highly effective. 

Paxlovid was about 37% effective at preventing death or hospitalization in high-risk patients, compared with no treatment. The study also looked at the antiviral Lagevrio, made by Merck, and found it was about 41% effective. In preventing death alone, Paxlovid was about 84% effective, compared with no treatment, and Lagevrio was about 77% effective.

The investigators, of the University of North Carolina at Chapel Hill and the Cleveland Clinic, examined electronic health records of 68,867 patients at hospitals in Cleveland and Florida who were diagnosed with COVID from April 1, 2022, to Feb. 20, 2023.

For Paxlovid, the effectiveness against death and hospitalization was lower than the effectiveness rate of about 86% found in clinical trials in 2021, according to Bloomberg. 

The difference in effectiveness in the real-world and clinical studies may have occurred because the early studies were conducted with unvaccinated people. Also, the virus has evolved since those first studies, Bloomberg reported. 

The researchers said Paxlovid and Lagevrio are recommended for use because they reduce hospitalization and death among high-risk patients who get COVID, even taking recent Omicron subvariants into account.

“These findings suggest that the use of either nirmatrelvir (Paxlovid) or molnupiravir (Lagevrio) is associated with reductions in mortality and hospitalization in patients infected with Omicron, regardless of age, race and ethnicity, virus strain, vaccination status, previous infection status, or coexisting conditions,” the researchers wrote. “Both drugs can, therefore, be used to treat nonhospitalized patients who are at high risk of progressing to severe COVID-19.”

Both drugs should be taken within 5 days of the onset of COVID symptoms.

The study was supported by the National Institutes of Health. Three coauthors reported conflicts of interest with various companies and organizations.

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

A real-world study published in  JAMA Open Network found that Pfizer’s COVID-19 antiviral Paxlovid is now less effective at preventing hospitalization or death in high-risk patients, compared with earlier studies. But when looking at death alone, the antiviral was still highly effective. 

Paxlovid was about 37% effective at preventing death or hospitalization in high-risk patients, compared with no treatment. The study also looked at the antiviral Lagevrio, made by Merck, and found it was about 41% effective. In preventing death alone, Paxlovid was about 84% effective, compared with no treatment, and Lagevrio was about 77% effective.

The investigators, of the University of North Carolina at Chapel Hill and the Cleveland Clinic, examined electronic health records of 68,867 patients at hospitals in Cleveland and Florida who were diagnosed with COVID from April 1, 2022, to Feb. 20, 2023.

For Paxlovid, the effectiveness against death and hospitalization was lower than the effectiveness rate of about 86% found in clinical trials in 2021, according to Bloomberg. 

The difference in effectiveness in the real-world and clinical studies may have occurred because the early studies were conducted with unvaccinated people. Also, the virus has evolved since those first studies, Bloomberg reported. 

The researchers said Paxlovid and Lagevrio are recommended for use because they reduce hospitalization and death among high-risk patients who get COVID, even taking recent Omicron subvariants into account.

“These findings suggest that the use of either nirmatrelvir (Paxlovid) or molnupiravir (Lagevrio) is associated with reductions in mortality and hospitalization in patients infected with Omicron, regardless of age, race and ethnicity, virus strain, vaccination status, previous infection status, or coexisting conditions,” the researchers wrote. “Both drugs can, therefore, be used to treat nonhospitalized patients who are at high risk of progressing to severe COVID-19.”

Both drugs should be taken within 5 days of the onset of COVID symptoms.

The study was supported by the National Institutes of Health. Three coauthors reported conflicts of interest with various companies and organizations.

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

Vitamin D deficiency appears to render people more vulnerable to canagliflozin’s adverse effects on bone health, whereas vitamin D3 supplementation appears protective of individuals with vitamin D deficiency.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are beneficial for treating type 2 diabetes and reducing cardiovascular and kidney disease risk. However, some, but not all, trial data have linked the SLGT2 inhibitor canagliflozin to increased fracture risk. That particular agent has been reported to accelerate loss of bone mineral density, which could contribute to fracture risk. Other drugs in the class have also been implicated in worsening markers of bone health.

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

Vitamin D deficiency appears to render people more vulnerable to canagliflozin’s adverse effects on bone health, whereas vitamin D3 supplementation appears protective of individuals with vitamin D deficiency.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are beneficial for treating type 2 diabetes and reducing cardiovascular and kidney disease risk. However, some, but not all, trial data have linked the SLGT2 inhibitor canagliflozin to increased fracture risk. That particular agent has been reported to accelerate loss of bone mineral density, which could contribute to fracture risk. Other drugs in the class have also been implicated in worsening markers of bone health.

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

Vitamin D deficiency appears to render people more vulnerable to canagliflozin’s adverse effects on bone health, whereas vitamin D3 supplementation appears protective of individuals with vitamin D deficiency.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are beneficial for treating type 2 diabetes and reducing cardiovascular and kidney disease risk. However, some, but not all, trial data have linked the SLGT2 inhibitor canagliflozin to increased fracture risk. That particular agent has been reported to accelerate loss of bone mineral density, which could contribute to fracture risk. Other drugs in the class have also been implicated in worsening markers of bone health.

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

Antidiabetic drug tirzepatide (Mounjaro) shows superiority over semaglutide (Ozempic, Wegovy, and Rybelsus) in controlling blood glucose as well as in the amount of weight lost, results from a meta-analysis of 22 randomized controlled trials show.

“The results indicate tirzepatide’s superior performance over subcutaneous semaglutide in managing blood sugar and achieving weight loss, making it a promising option in the pharmaceutical management of type 2 diabetes,” first author Thomas Karagiannis, MD, PhD, Aristotle University of Thessaloniki, Greece, said in an interview.

“In clinical context, the most potent doses of each drug revealed a clear difference regarding weight loss, with tirzepatide resulting in an average weight reduction that exceeded that of semaglutide by 5.7 kg (12.6 pounds),” he said.

The study is scheduled to be presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in early October.

While a multitude of studies have been conducted for tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist, and semaglutide, a selective GLP-1 agonist, studies comparing the two drugs directly are lacking.

For a more comprehensive understanding of how the drugs compare, Dr. Karagiannis and colleagues conducted the meta-analysis of 22 trials, including two direct comparisons, the SURPASS-2 trial and a smaller trial, and 20 other studies comparing either semaglutide or tirzepatide with a common comparator, such as placebo, basal insulin, or other GLP-RA-1 drugs.

Overall, 18,472 participants were included in the studies.

All included studies had assessed a maintenance dose of tirzepatide of either 5, 10, or 15 mg once weekly or semaglutide at doses of 0.5, 1.0, or 2.0 mg once weekly for at least 12 weeks. All comparisons were for subcutaneous injection formulations (semaglutide can also be taken orally).
 

Blood glucose reduction

Tirzepatide at 15 mg was found to have the highest efficacy in the reduction of A1c compared with placebo, with a mean difference of –2.00%, followed by tirzepatide 10 mg (–1.86%) and semaglutide 2.0 mg (–1.62%).

All three of the tirzepatide doses had greater reductions in A1c compared with the respective low, medium, and high doses of semaglutide.

Dr. Karagiannis noted that the differences are significant: “An A1c reduction even by 0.5% is often deemed clinically important,” he said.
 

Body weight reduction comparisons

The reductions in body weight across the three drug doses were greater with tirzepatide (–10.96 kg [24.2 pounds], –8.75 kg [19.3 pounds], and –6.16 kg [13.6 pounds] for 15, 10, and 5 mg, respectively) compared with semaglutide (–5.24 kg [11.6 pounds], –4.44 kg [9.8 pounds], and –2.72 kg [6 pounds] for semaglutide 2.0, 1.0, and 0.5 mg, respectively).

In terms of drug-to-drug comparisons, tirzepatide 15 mg had a mean of 5.72 kg (12.6 pounds) greater reduction in body weight vs. semaglutide 2.0 mg; tirzepatide 10 mg had a mean of 3.52 kg (7.8 pounds) reduction vs. semaglutide 2.0 mg; and tirzepatide 5 mg had a mean of a 1.72 kg (3.8 pounds) greater reduction vs. semaglutide 1.0 mg.
 

Adverse events: Increased GI events with highest tirzepatide dose

Regarding the gastrointestinal adverse events associated with the drugs, tirzepatide 15 mg had the highest rate of the two drugs at their various doses, with a risk ratio (RR) of 3.57 compared with placebo for nausea, an RR of 4.35 for vomiting, and 2.04 for diarrhea.

There were no significant differences between the two drugs for the gastrointestinal events, with the exception of the highest dose of tirzepatide, 15 mg, which had a higher risk of vomiting vs. semaglutide 1.0 (RR 1.39) and semaglutide 0.5 mg (RR 1.85).

In addition, tirzepatide 15 mg had a higher risk vs. semaglutide 0.5 mg for nausea (RR 1.45).

There were no significant differences between the two drugs and placebo in the risk of serious adverse events.
 

Real-world applications, comparisons

Dr. Karagiannis noted that the results indicate that benefits of the efficacy of the higher tirzepatide dose need to be balanced with those potential side effects.

“Although the efficacy of the high tirzepatide dose might make it a favorable choice, its real-world application can be affected on an individual’s ability to tolerate these side effects in case they occur,” he explained.

Ultimately, “some patients may prioritize tolerability over enhanced efficacy,” he added.

Furthermore, while all three maintenance doses of tirzepatide analyzed have received marketing authorization, “to get a clearer picture of the real-world tolerance to these doses outside the context of randomized controlled trials, well-designed observational studies would be necessary,” Dr. Karagiannis said.

Among other issues of comparison with the two drugs is cost.

In a recent analysis, the cost per 1% of body weight reduction was reported to be $1,197 for high-dose tirzepatide (15 mg) vs. $1,511 for semaglutide 2.4 mg, with an overall cost of 72 weeks of therapy with tirzepatide at $17,527 compared with $22,878 for semaglutide.

Overall, patients and clinicians should consider the full range of differences and similarities between the medications, “from [their] efficacy and side effects to cost-effectiveness, long-term safety, and cardiovascular profile,” Dr. Karagiannis said.

Semaglutide is currently approved by the Food and Drug Administration for treatment of type 2 diabetes and obesity/weight loss management.

Tirzepatide has also received approval for the treatment of type 2 diabetes and its manufacturers have submitted applications for its approval for obesity/weight loss management.

Dr. Karagiannis reports no relevant financial relationships.

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

Antidiabetic drug tirzepatide (Mounjaro) shows superiority over semaglutide (Ozempic, Wegovy, and Rybelsus) in controlling blood glucose as well as in the amount of weight lost, results from a meta-analysis of 22 randomized controlled trials show.

“The results indicate tirzepatide’s superior performance over subcutaneous semaglutide in managing blood sugar and achieving weight loss, making it a promising option in the pharmaceutical management of type 2 diabetes,” first author Thomas Karagiannis, MD, PhD, Aristotle University of Thessaloniki, Greece, said in an interview.

“In clinical context, the most potent doses of each drug revealed a clear difference regarding weight loss, with tirzepatide resulting in an average weight reduction that exceeded that of semaglutide by 5.7 kg (12.6 pounds),” he said.

The study is scheduled to be presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in early October.

While a multitude of studies have been conducted for tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist, and semaglutide, a selective GLP-1 agonist, studies comparing the two drugs directly are lacking.

For a more comprehensive understanding of how the drugs compare, Dr. Karagiannis and colleagues conducted the meta-analysis of 22 trials, including two direct comparisons, the SURPASS-2 trial and a smaller trial, and 20 other studies comparing either semaglutide or tirzepatide with a common comparator, such as placebo, basal insulin, or other GLP-RA-1 drugs.

Overall, 18,472 participants were included in the studies.

All included studies had assessed a maintenance dose of tirzepatide of either 5, 10, or 15 mg once weekly or semaglutide at doses of 0.5, 1.0, or 2.0 mg once weekly for at least 12 weeks. All comparisons were for subcutaneous injection formulations (semaglutide can also be taken orally).
 

Blood glucose reduction

Tirzepatide at 15 mg was found to have the highest efficacy in the reduction of A1c compared with placebo, with a mean difference of –2.00%, followed by tirzepatide 10 mg (–1.86%) and semaglutide 2.0 mg (–1.62%).

All three of the tirzepatide doses had greater reductions in A1c compared with the respective low, medium, and high doses of semaglutide.

Dr. Karagiannis noted that the differences are significant: “An A1c reduction even by 0.5% is often deemed clinically important,” he said.
 

Body weight reduction comparisons

The reductions in body weight across the three drug doses were greater with tirzepatide (–10.96 kg [24.2 pounds], –8.75 kg [19.3 pounds], and –6.16 kg [13.6 pounds] for 15, 10, and 5 mg, respectively) compared with semaglutide (–5.24 kg [11.6 pounds], –4.44 kg [9.8 pounds], and –2.72 kg [6 pounds] for semaglutide 2.0, 1.0, and 0.5 mg, respectively).

In terms of drug-to-drug comparisons, tirzepatide 15 mg had a mean of 5.72 kg (12.6 pounds) greater reduction in body weight vs. semaglutide 2.0 mg; tirzepatide 10 mg had a mean of 3.52 kg (7.8 pounds) reduction vs. semaglutide 2.0 mg; and tirzepatide 5 mg had a mean of a 1.72 kg (3.8 pounds) greater reduction vs. semaglutide 1.0 mg.
 

Adverse events: Increased GI events with highest tirzepatide dose

Regarding the gastrointestinal adverse events associated with the drugs, tirzepatide 15 mg had the highest rate of the two drugs at their various doses, with a risk ratio (RR) of 3.57 compared with placebo for nausea, an RR of 4.35 for vomiting, and 2.04 for diarrhea.

There were no significant differences between the two drugs for the gastrointestinal events, with the exception of the highest dose of tirzepatide, 15 mg, which had a higher risk of vomiting vs. semaglutide 1.0 (RR 1.39) and semaglutide 0.5 mg (RR 1.85).

In addition, tirzepatide 15 mg had a higher risk vs. semaglutide 0.5 mg for nausea (RR 1.45).

There were no significant differences between the two drugs and placebo in the risk of serious adverse events.
 

Real-world applications, comparisons

Dr. Karagiannis noted that the results indicate that benefits of the efficacy of the higher tirzepatide dose need to be balanced with those potential side effects.

“Although the efficacy of the high tirzepatide dose might make it a favorable choice, its real-world application can be affected on an individual’s ability to tolerate these side effects in case they occur,” he explained.

Ultimately, “some patients may prioritize tolerability over enhanced efficacy,” he added.

Furthermore, while all three maintenance doses of tirzepatide analyzed have received marketing authorization, “to get a clearer picture of the real-world tolerance to these doses outside the context of randomized controlled trials, well-designed observational studies would be necessary,” Dr. Karagiannis said.

Among other issues of comparison with the two drugs is cost.

In a recent analysis, the cost per 1% of body weight reduction was reported to be $1,197 for high-dose tirzepatide (15 mg) vs. $1,511 for semaglutide 2.4 mg, with an overall cost of 72 weeks of therapy with tirzepatide at $17,527 compared with $22,878 for semaglutide.

Overall, patients and clinicians should consider the full range of differences and similarities between the medications, “from [their] efficacy and side effects to cost-effectiveness, long-term safety, and cardiovascular profile,” Dr. Karagiannis said.

Semaglutide is currently approved by the Food and Drug Administration for treatment of type 2 diabetes and obesity/weight loss management.

Tirzepatide has also received approval for the treatment of type 2 diabetes and its manufacturers have submitted applications for its approval for obesity/weight loss management.

Dr. Karagiannis reports no relevant financial relationships.

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

Antidiabetic drug tirzepatide (Mounjaro) shows superiority over semaglutide (Ozempic, Wegovy, and Rybelsus) in controlling blood glucose as well as in the amount of weight lost, results from a meta-analysis of 22 randomized controlled trials show.

“The results indicate tirzepatide’s superior performance over subcutaneous semaglutide in managing blood sugar and achieving weight loss, making it a promising option in the pharmaceutical management of type 2 diabetes,” first author Thomas Karagiannis, MD, PhD, Aristotle University of Thessaloniki, Greece, said in an interview.

“In clinical context, the most potent doses of each drug revealed a clear difference regarding weight loss, with tirzepatide resulting in an average weight reduction that exceeded that of semaglutide by 5.7 kg (12.6 pounds),” he said.

The study is scheduled to be presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in early October.

While a multitude of studies have been conducted for tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist, and semaglutide, a selective GLP-1 agonist, studies comparing the two drugs directly are lacking.

For a more comprehensive understanding of how the drugs compare, Dr. Karagiannis and colleagues conducted the meta-analysis of 22 trials, including two direct comparisons, the SURPASS-2 trial and a smaller trial, and 20 other studies comparing either semaglutide or tirzepatide with a common comparator, such as placebo, basal insulin, or other GLP-RA-1 drugs.

Overall, 18,472 participants were included in the studies.

All included studies had assessed a maintenance dose of tirzepatide of either 5, 10, or 15 mg once weekly or semaglutide at doses of 0.5, 1.0, or 2.0 mg once weekly for at least 12 weeks. All comparisons were for subcutaneous injection formulations (semaglutide can also be taken orally).
 

Blood glucose reduction

Tirzepatide at 15 mg was found to have the highest efficacy in the reduction of A1c compared with placebo, with a mean difference of –2.00%, followed by tirzepatide 10 mg (–1.86%) and semaglutide 2.0 mg (–1.62%).

All three of the tirzepatide doses had greater reductions in A1c compared with the respective low, medium, and high doses of semaglutide.

Dr. Karagiannis noted that the differences are significant: “An A1c reduction even by 0.5% is often deemed clinically important,” he said.
 

Body weight reduction comparisons

The reductions in body weight across the three drug doses were greater with tirzepatide (–10.96 kg [24.2 pounds], –8.75 kg [19.3 pounds], and –6.16 kg [13.6 pounds] for 15, 10, and 5 mg, respectively) compared with semaglutide (–5.24 kg [11.6 pounds], –4.44 kg [9.8 pounds], and –2.72 kg [6 pounds] for semaglutide 2.0, 1.0, and 0.5 mg, respectively).

In terms of drug-to-drug comparisons, tirzepatide 15 mg had a mean of 5.72 kg (12.6 pounds) greater reduction in body weight vs. semaglutide 2.0 mg; tirzepatide 10 mg had a mean of 3.52 kg (7.8 pounds) reduction vs. semaglutide 2.0 mg; and tirzepatide 5 mg had a mean of a 1.72 kg (3.8 pounds) greater reduction vs. semaglutide 1.0 mg.
 

Adverse events: Increased GI events with highest tirzepatide dose

Regarding the gastrointestinal adverse events associated with the drugs, tirzepatide 15 mg had the highest rate of the two drugs at their various doses, with a risk ratio (RR) of 3.57 compared with placebo for nausea, an RR of 4.35 for vomiting, and 2.04 for diarrhea.

There were no significant differences between the two drugs for the gastrointestinal events, with the exception of the highest dose of tirzepatide, 15 mg, which had a higher risk of vomiting vs. semaglutide 1.0 (RR 1.39) and semaglutide 0.5 mg (RR 1.85).

In addition, tirzepatide 15 mg had a higher risk vs. semaglutide 0.5 mg for nausea (RR 1.45).

There were no significant differences between the two drugs and placebo in the risk of serious adverse events.
 

Real-world applications, comparisons

Dr. Karagiannis noted that the results indicate that benefits of the efficacy of the higher tirzepatide dose need to be balanced with those potential side effects.

“Although the efficacy of the high tirzepatide dose might make it a favorable choice, its real-world application can be affected on an individual’s ability to tolerate these side effects in case they occur,” he explained.

Ultimately, “some patients may prioritize tolerability over enhanced efficacy,” he added.

Furthermore, while all three maintenance doses of tirzepatide analyzed have received marketing authorization, “to get a clearer picture of the real-world tolerance to these doses outside the context of randomized controlled trials, well-designed observational studies would be necessary,” Dr. Karagiannis said.

Among other issues of comparison with the two drugs is cost.

In a recent analysis, the cost per 1% of body weight reduction was reported to be $1,197 for high-dose tirzepatide (15 mg) vs. $1,511 for semaglutide 2.4 mg, with an overall cost of 72 weeks of therapy with tirzepatide at $17,527 compared with $22,878 for semaglutide.

Overall, patients and clinicians should consider the full range of differences and similarities between the medications, “from [their] efficacy and side effects to cost-effectiveness, long-term safety, and cardiovascular profile,” Dr. Karagiannis said.

Semaglutide is currently approved by the Food and Drug Administration for treatment of type 2 diabetes and obesity/weight loss management.

Tirzepatide has also received approval for the treatment of type 2 diabetes and its manufacturers have submitted applications for its approval for obesity/weight loss management.

Dr. Karagiannis reports no relevant financial relationships.

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

When patients seek primary care, it’s becoming more likely that they’ll see a nurse practitioner or physician assistant.

Health care visits to NPs and PAs, also known as advanced practice providers, have been rising in recent years compared with doctor visits, according to the latest studies. The proportion of Medicare visits that NPs and PAs delivered nearly doubled in the 7-year period 2013-2019 (14% in 2013 to 26% in 2019), according to research published this month in the BMJ. Among study participants, 42% had at least one visit with an NP or PA. Meanwhile, primary care visits with a physician decreased by 18%, the study showed.

Medicare accounts for roughly 20% of the U.S. population and 23% of health care spending, according to 2023 data cited in the report. Study authors surveyed a random sample, 20% of Medicare recipients who sought care through in-person and telemedicine visits to outpatient and nursing facilities before the COVID-19 pandemic.

Medical clinics have turned to NPs and PAs to offset a shortage of primary care doctors, with the United States having fewer physicians per capita than other industrialized nations, according to Ateev Mehrotra, MD, MPH, professor of health care policy at Harvard Medical School and one of the authors of the BMJ report.

Nursing schools also struggle to meet the growing demand for NPs. In more than half of U.S. states, NPs can work independently without physician supervision, while PAs face more restrictions.

Another study earlier this year also found a rise in APP care. FAIR Health reported that nearly one in three patients received care between 2016 and 2022 from someone other than a physician, with NPs providing 27% of primary care visits and PAs, 15%.

The trend isn’t new. But for many years, claims data from Medicare or commercial payers masked the impact of advanced practitioners because their care was billed under a supervising physician, explained Michael L. Powe, vice president of reimbursement and professional advocacy for the American Academy of Physician Assistants, which represents PAs.

NPs and PAs are more likely to see patients with lower incomes, those who live in rural communities, or those who have disabilities, according to the BMJ study, suggesting that these providers may improve access to health care.

They already comprise about half of the primary care professionals in rural areas, said Stephen Ferrara, DNP, president of the American Association of Nurse Practitioners, citing a 2022 report by the Medicare Payment Advisory Commission.

The BMJ study also found that NPs and PAs were more likely to see patients for certain conditions. For example, they handled 42% of visits for respiratory infections and 37% of visits for anxiety, compared with only 13% of visits for eye problems and 20% of visits for hypertension.

Dr. Mehrotra said patients, in general, are still unlikely to see only an NP for many conditions, particularly chronic illness. “You might see the physician one time and then the nurse practitioner, and then the PA. And you might see another physician in the practice.”

He said health care leaders need to decide how to set up teams to best serve patients. From a health policy perspective, they should also consider whether to boost funding for NP and PA education or primary care residencies.

Meanwhile, the growth of advanced practitioners continues. The Bureau of Labor Statistics estimates that the number of NPs will increase to 359,000 in 2031 (80% growth from 2019) and the number of PAs will increase to 178,000 (48% growth).
 

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

When patients seek primary care, it’s becoming more likely that they’ll see a nurse practitioner or physician assistant.

Health care visits to NPs and PAs, also known as advanced practice providers, have been rising in recent years compared with doctor visits, according to the latest studies. The proportion of Medicare visits that NPs and PAs delivered nearly doubled in the 7-year period 2013-2019 (14% in 2013 to 26% in 2019), according to research published this month in the BMJ. Among study participants, 42% had at least one visit with an NP or PA. Meanwhile, primary care visits with a physician decreased by 18%, the study showed.

Medicare accounts for roughly 20% of the U.S. population and 23% of health care spending, according to 2023 data cited in the report. Study authors surveyed a random sample, 20% of Medicare recipients who sought care through in-person and telemedicine visits to outpatient and nursing facilities before the COVID-19 pandemic.

Medical clinics have turned to NPs and PAs to offset a shortage of primary care doctors, with the United States having fewer physicians per capita than other industrialized nations, according to Ateev Mehrotra, MD, MPH, professor of health care policy at Harvard Medical School and one of the authors of the BMJ report.

Nursing schools also struggle to meet the growing demand for NPs. In more than half of U.S. states, NPs can work independently without physician supervision, while PAs face more restrictions.

Another study earlier this year also found a rise in APP care. FAIR Health reported that nearly one in three patients received care between 2016 and 2022 from someone other than a physician, with NPs providing 27% of primary care visits and PAs, 15%.

The trend isn’t new. But for many years, claims data from Medicare or commercial payers masked the impact of advanced practitioners because their care was billed under a supervising physician, explained Michael L. Powe, vice president of reimbursement and professional advocacy for the American Academy of Physician Assistants, which represents PAs.

NPs and PAs are more likely to see patients with lower incomes, those who live in rural communities, or those who have disabilities, according to the BMJ study, suggesting that these providers may improve access to health care.

They already comprise about half of the primary care professionals in rural areas, said Stephen Ferrara, DNP, president of the American Association of Nurse Practitioners, citing a 2022 report by the Medicare Payment Advisory Commission.

The BMJ study also found that NPs and PAs were more likely to see patients for certain conditions. For example, they handled 42% of visits for respiratory infections and 37% of visits for anxiety, compared with only 13% of visits for eye problems and 20% of visits for hypertension.

Dr. Mehrotra said patients, in general, are still unlikely to see only an NP for many conditions, particularly chronic illness. “You might see the physician one time and then the nurse practitioner, and then the PA. And you might see another physician in the practice.”

He said health care leaders need to decide how to set up teams to best serve patients. From a health policy perspective, they should also consider whether to boost funding for NP and PA education or primary care residencies.

Meanwhile, the growth of advanced practitioners continues. The Bureau of Labor Statistics estimates that the number of NPs will increase to 359,000 in 2031 (80% growth from 2019) and the number of PAs will increase to 178,000 (48% growth).
 

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

When patients seek primary care, it’s becoming more likely that they’ll see a nurse practitioner or physician assistant.

Health care visits to NPs and PAs, also known as advanced practice providers, have been rising in recent years compared with doctor visits, according to the latest studies. The proportion of Medicare visits that NPs and PAs delivered nearly doubled in the 7-year period 2013-2019 (14% in 2013 to 26% in 2019), according to research published this month in the BMJ. Among study participants, 42% had at least one visit with an NP or PA. Meanwhile, primary care visits with a physician decreased by 18%, the study showed.

Medicare accounts for roughly 20% of the U.S. population and 23% of health care spending, according to 2023 data cited in the report. Study authors surveyed a random sample, 20% of Medicare recipients who sought care through in-person and telemedicine visits to outpatient and nursing facilities before the COVID-19 pandemic.

Medical clinics have turned to NPs and PAs to offset a shortage of primary care doctors, with the United States having fewer physicians per capita than other industrialized nations, according to Ateev Mehrotra, MD, MPH, professor of health care policy at Harvard Medical School and one of the authors of the BMJ report.

Nursing schools also struggle to meet the growing demand for NPs. In more than half of U.S. states, NPs can work independently without physician supervision, while PAs face more restrictions.

Another study earlier this year also found a rise in APP care. FAIR Health reported that nearly one in three patients received care between 2016 and 2022 from someone other than a physician, with NPs providing 27% of primary care visits and PAs, 15%.

The trend isn’t new. But for many years, claims data from Medicare or commercial payers masked the impact of advanced practitioners because their care was billed under a supervising physician, explained Michael L. Powe, vice president of reimbursement and professional advocacy for the American Academy of Physician Assistants, which represents PAs.

NPs and PAs are more likely to see patients with lower incomes, those who live in rural communities, or those who have disabilities, according to the BMJ study, suggesting that these providers may improve access to health care.

They already comprise about half of the primary care professionals in rural areas, said Stephen Ferrara, DNP, president of the American Association of Nurse Practitioners, citing a 2022 report by the Medicare Payment Advisory Commission.

The BMJ study also found that NPs and PAs were more likely to see patients for certain conditions. For example, they handled 42% of visits for respiratory infections and 37% of visits for anxiety, compared with only 13% of visits for eye problems and 20% of visits for hypertension.

Dr. Mehrotra said patients, in general, are still unlikely to see only an NP for many conditions, particularly chronic illness. “You might see the physician one time and then the nurse practitioner, and then the PA. And you might see another physician in the practice.”

He said health care leaders need to decide how to set up teams to best serve patients. From a health policy perspective, they should also consider whether to boost funding for NP and PA education or primary care residencies.

Meanwhile, the growth of advanced practitioners continues. The Bureau of Labor Statistics estimates that the number of NPs will increase to 359,000 in 2031 (80% growth from 2019) and the number of PAs will increase to 178,000 (48% growth).
 

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

Women with premenstrual disorders may be more likely go through menopause before they are 45 years old, a new study suggests. 

Women with premenstrual disorders, or PMDs, were also more likely to have moderate or severe night sweats or hot flashes during menopause, the researchers found.

Published in JAMA Network Open, the new findings stem from data from more than 3,600 nurses who contributed their health information to a database between 1991 and 2017. Women with PMDs were more than twice as likely as women without PMDs to have early menopause.

Most women have menopause between the ages of 45 and 55 years old, according to the World Health Organization. 

There are numerous PMDs, including the well-known premenstrual syndrome, which is considered a mild disorder affecting up to 30% of women that causes symptoms like crankiness and bloating. A less common PMD is premenstrual dysphoric disorder, which can severely impact a woman’s life through psychological, gastrointestinal, skin, and neurological problems.

Previous research has linked PMDs during the reproductive years and postmenopausal issues like hot flashes and night sweats to increased risks of health problems like high blood pressure, heart conditions, and diabetes.

“It is important to identify women at risk for early menopause because of its link with poorer heart, brain, and bone health,” Stephanie Faubion, MD, MBA, a doctor at the Mayo Clinic and medical director of the North American Menopause Society, told CNN. Dr. Faubion was not involved in the study.

That said, it’s important to note that the study was observational – meaning researchers can’t say for certain that PMDs will cause early menopause. Rather, the study shows there may be a correlation between the two, Donghao Lu, MD, an associate professor in the department of medical epidemiology and biostatistics at the Karolinska Institute, told CNN.

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

Women with premenstrual disorders may be more likely go through menopause before they are 45 years old, a new study suggests. 

Women with premenstrual disorders, or PMDs, were also more likely to have moderate or severe night sweats or hot flashes during menopause, the researchers found.

Published in JAMA Network Open, the new findings stem from data from more than 3,600 nurses who contributed their health information to a database between 1991 and 2017. Women with PMDs were more than twice as likely as women without PMDs to have early menopause.

Most women have menopause between the ages of 45 and 55 years old, according to the World Health Organization. 

There are numerous PMDs, including the well-known premenstrual syndrome, which is considered a mild disorder affecting up to 30% of women that causes symptoms like crankiness and bloating. A less common PMD is premenstrual dysphoric disorder, which can severely impact a woman’s life through psychological, gastrointestinal, skin, and neurological problems.

Previous research has linked PMDs during the reproductive years and postmenopausal issues like hot flashes and night sweats to increased risks of health problems like high blood pressure, heart conditions, and diabetes.

“It is important to identify women at risk for early menopause because of its link with poorer heart, brain, and bone health,” Stephanie Faubion, MD, MBA, a doctor at the Mayo Clinic and medical director of the North American Menopause Society, told CNN. Dr. Faubion was not involved in the study.

That said, it’s important to note that the study was observational – meaning researchers can’t say for certain that PMDs will cause early menopause. Rather, the study shows there may be a correlation between the two, Donghao Lu, MD, an associate professor in the department of medical epidemiology and biostatistics at the Karolinska Institute, told CNN.

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

Women with premenstrual disorders may be more likely go through menopause before they are 45 years old, a new study suggests. 

Women with premenstrual disorders, or PMDs, were also more likely to have moderate or severe night sweats or hot flashes during menopause, the researchers found.

Published in JAMA Network Open, the new findings stem from data from more than 3,600 nurses who contributed their health information to a database between 1991 and 2017. Women with PMDs were more than twice as likely as women without PMDs to have early menopause.

Most women have menopause between the ages of 45 and 55 years old, according to the World Health Organization. 

There are numerous PMDs, including the well-known premenstrual syndrome, which is considered a mild disorder affecting up to 30% of women that causes symptoms like crankiness and bloating. A less common PMD is premenstrual dysphoric disorder, which can severely impact a woman’s life through psychological, gastrointestinal, skin, and neurological problems.

Previous research has linked PMDs during the reproductive years and postmenopausal issues like hot flashes and night sweats to increased risks of health problems like high blood pressure, heart conditions, and diabetes.

“It is important to identify women at risk for early menopause because of its link with poorer heart, brain, and bone health,” Stephanie Faubion, MD, MBA, a doctor at the Mayo Clinic and medical director of the North American Menopause Society, told CNN. Dr. Faubion was not involved in the study.

That said, it’s important to note that the study was observational – meaning researchers can’t say for certain that PMDs will cause early menopause. Rather, the study shows there may be a correlation between the two, Donghao Lu, MD, an associate professor in the department of medical epidemiology and biostatistics at the Karolinska Institute, told CNN.

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

Taking creatine as a supplement for 6 months appears to significantly improve clinical features of post–COVID-19 fatigue syndrome (PVFS or long COVID), a small randomized, placebo-controlled, double-blinded study suggests.

Researchers, led by Jelena Slankamenac, with Applied Bioenergetics Lab, Faculty of Sport and PE, University of Novi Sad, Serbia, published their findings in Food, Science & Nutrition .

“This is the first human study known to the authors that evaluated the efficacy and safety of supplemental creatine for fatigue, tissue bioenergetics, and patient-reported outcomes in patients with post–COVID-19 fatigue syndrome,” the authors write.

They say the findings may be attributed to creatine’s “energy-replenishing and neuroprotective activity.”
 

Significant reductions in symptoms

Researchers randomized the 12 participants into two groups of 6 each. The creatine group received 4 g creatine monohydrate per day, while the placebo group received the same amount of inulin.

At 3 months, dietary creatine supplements produced a significant reduction in fatigue, compared with baseline values ( P = .04) and significantly improved scores for several long COVID–related symptoms, including loss of taste, breathing difficulties, body aches, headache, and difficulties concentrating) ( P < .05), the researchers report.

Intervention effect sizes were assessed by Cohen statistics, with a d of at least 0.8 indicating a large effect.

Among highlights of the results were that patients reported a significant 77.8% drop in scores for concentration difficulties at the 3-month follow-up (Cohen’s effect, d = 1.19) and no concentration difficulties at the 6-month follow-up (Cohen’s effect, d = 2.46).

Total creatine levels increased in several locations across the brain (as much as 33% for right parietal white matter). No changes in tissue creatine levels were found in the placebo group during the trial.

“Since PVFS is characterized by impaired tissue bioenergetics ..., supplemental creatine might be an effective dietary intervention to uphold brain creatine in post–COVID-19 fatigue syndrome,” the authors write.

The authors add that creatine supplements for long COVID patients could benefit organs beyond the brain as participants saw “a significant drop in lung and body pain after the intervention.”
 

Unanswered questions

Some experts said the results should be interpreted with caution.

“This research paper is very interesting,” says Nisha Viswanathan, MD, director of the long COVID program at University of California, Los Angeles, “but the limited number of patients makes the results difficult to generalize.”

Dr. Viswanathan, who was not part of the study, pointed out that the patients included in this study had a recent COVID infection (under 3 months).

“Acute COVID infection can take up to 3 months to resolve,” she says. “We define patients with long COVID as those with symptoms lasting greater than 3 months. Therefore, these patients could have had improvements in their fatigue due to the natural course of the illness rather than creatine supplementation.”

Alba Azola, MD, assistant professor in the department of physical medicine and rehabilitation at Johns Hopkins University, Baltimore, said she also was troubled by the window of 3 months for recent COVID infection.

She said she would like to see results for patients who have ongoing symptoms for at least 6 months after infection, especially given creatine supplements’ history in research.

Creatine supplements for other conditions, such as fibromyalgia and chronic fatigue syndrome, have been tested for nearly 2 decades, she pointed out, with conflicting findings, something the authors acknowledge in the paper.

“I think it’s premature to say (creatine) is the key,” she says. She added that the small sample size is important to consider given the heterogeneity of patients with long COVID.

That said, Dr. Azola says, she applauds all efforts to find treatments for long COVID, especially randomized, controlled studies like this one.
 

No major side effects

No major side effects were reported for either intervention, except for transient mild nausea reported by one patient after taking creatine.

Compliance with the intervention was 90.6% ± 3.5% in the creatine group and 95.3% ± 5.0% in the control group (P = .04).

Participants were eligible for inclusion if they were 18-65 years old, had a positive COVID test within the last 3 months (documented by a valid polymerase chain reaction [PCR] or antigen test performed in a COVID-19–certified lab); had moderate to severe fatigue; and at least one additional COVID-related symptom, including loss of taste or smell, breathing trouble, lung pain, body aches, headaches, or difficulties concentrating.

The authors acknowledge that they selected a sample of young to middle-aged adults experiencing moderate long COVID symptoms, and it’s unknown whether creatine is equally effective in other PVFS populations, such as elderly people, children, or patients with less or more severe disease.

Senior author Dr. Sergei Ostojic serves as a member of the Scientific Advisory Board on creatine in health and medicine (AlzChem LLC). He co-owns a patent for “Supplements Based on Liquid Creatine” at the European Patent Office. He has received research support related to creatine during the past 36 months from the Serbian Ministry of Education, Science, and Technological Development; Provincial Secretariat for Higher Education and Scientific Research; Alzchem GmbH; ThermoLife International; and Hueston Hennigan LLP. He does not own stocks and shares in any organization. Other authors declare no known relevant financial interests. Dr. Viswanathan and Dr. Azola report no relevant financial relationships.
 

Taking creatine as a supplement for 6 months appears to significantly improve clinical features of post–COVID-19 fatigue syndrome (PVFS or long COVID), a small randomized, placebo-controlled, double-blinded study suggests.

Researchers, led by Jelena Slankamenac, with Applied Bioenergetics Lab, Faculty of Sport and PE, University of Novi Sad, Serbia, published their findings in Food, Science & Nutrition .

“This is the first human study known to the authors that evaluated the efficacy and safety of supplemental creatine for fatigue, tissue bioenergetics, and patient-reported outcomes in patients with post–COVID-19 fatigue syndrome,” the authors write.

They say the findings may be attributed to creatine’s “energy-replenishing and neuroprotective activity.”
 

Significant reductions in symptoms

Researchers randomized the 12 participants into two groups of 6 each. The creatine group received 4 g creatine monohydrate per day, while the placebo group received the same amount of inulin.

At 3 months, dietary creatine supplements produced a significant reduction in fatigue, compared with baseline values ( P = .04) and significantly improved scores for several long COVID–related symptoms, including loss of taste, breathing difficulties, body aches, headache, and difficulties concentrating) ( P < .05), the researchers report.

Intervention effect sizes were assessed by Cohen statistics, with a d of at least 0.8 indicating a large effect.

Among highlights of the results were that patients reported a significant 77.8% drop in scores for concentration difficulties at the 3-month follow-up (Cohen’s effect, d = 1.19) and no concentration difficulties at the 6-month follow-up (Cohen’s effect, d = 2.46).

Total creatine levels increased in several locations across the brain (as much as 33% for right parietal white matter). No changes in tissue creatine levels were found in the placebo group during the trial.

“Since PVFS is characterized by impaired tissue bioenergetics ..., supplemental creatine might be an effective dietary intervention to uphold brain creatine in post–COVID-19 fatigue syndrome,” the authors write.

The authors add that creatine supplements for long COVID patients could benefit organs beyond the brain as participants saw “a significant drop in lung and body pain after the intervention.”
 

Unanswered questions

Some experts said the results should be interpreted with caution.

“This research paper is very interesting,” says Nisha Viswanathan, MD, director of the long COVID program at University of California, Los Angeles, “but the limited number of patients makes the results difficult to generalize.”

Dr. Viswanathan, who was not part of the study, pointed out that the patients included in this study had a recent COVID infection (under 3 months).

“Acute COVID infection can take up to 3 months to resolve,” she says. “We define patients with long COVID as those with symptoms lasting greater than 3 months. Therefore, these patients could have had improvements in their fatigue due to the natural course of the illness rather than creatine supplementation.”

Alba Azola, MD, assistant professor in the department of physical medicine and rehabilitation at Johns Hopkins University, Baltimore, said she also was troubled by the window of 3 months for recent COVID infection.

She said she would like to see results for patients who have ongoing symptoms for at least 6 months after infection, especially given creatine supplements’ history in research.

Creatine supplements for other conditions, such as fibromyalgia and chronic fatigue syndrome, have been tested for nearly 2 decades, she pointed out, with conflicting findings, something the authors acknowledge in the paper.

“I think it’s premature to say (creatine) is the key,” she says. She added that the small sample size is important to consider given the heterogeneity of patients with long COVID.

That said, Dr. Azola says, she applauds all efforts to find treatments for long COVID, especially randomized, controlled studies like this one.
 

No major side effects

No major side effects were reported for either intervention, except for transient mild nausea reported by one patient after taking creatine.

Compliance with the intervention was 90.6% ± 3.5% in the creatine group and 95.3% ± 5.0% in the control group (P = .04).

Participants were eligible for inclusion if they were 18-65 years old, had a positive COVID test within the last 3 months (documented by a valid polymerase chain reaction [PCR] or antigen test performed in a COVID-19–certified lab); had moderate to severe fatigue; and at least one additional COVID-related symptom, including loss of taste or smell, breathing trouble, lung pain, body aches, headaches, or difficulties concentrating.

The authors acknowledge that they selected a sample of young to middle-aged adults experiencing moderate long COVID symptoms, and it’s unknown whether creatine is equally effective in other PVFS populations, such as elderly people, children, or patients with less or more severe disease.

Senior author Dr. Sergei Ostojic serves as a member of the Scientific Advisory Board on creatine in health and medicine (AlzChem LLC). He co-owns a patent for “Supplements Based on Liquid Creatine” at the European Patent Office. He has received research support related to creatine during the past 36 months from the Serbian Ministry of Education, Science, and Technological Development; Provincial Secretariat for Higher Education and Scientific Research; Alzchem GmbH; ThermoLife International; and Hueston Hennigan LLP. He does not own stocks and shares in any organization. Other authors declare no known relevant financial interests. Dr. Viswanathan and Dr. Azola report no relevant financial relationships.
 

Taking creatine as a supplement for 6 months appears to significantly improve clinical features of post–COVID-19 fatigue syndrome (PVFS or long COVID), a small randomized, placebo-controlled, double-blinded study suggests.

Researchers, led by Jelena Slankamenac, with Applied Bioenergetics Lab, Faculty of Sport and PE, University of Novi Sad, Serbia, published their findings in Food, Science & Nutrition .

“This is the first human study known to the authors that evaluated the efficacy and safety of supplemental creatine for fatigue, tissue bioenergetics, and patient-reported outcomes in patients with post–COVID-19 fatigue syndrome,” the authors write.

They say the findings may be attributed to creatine’s “energy-replenishing and neuroprotective activity.”
 

Significant reductions in symptoms

Researchers randomized the 12 participants into two groups of 6 each. The creatine group received 4 g creatine monohydrate per day, while the placebo group received the same amount of inulin.

At 3 months, dietary creatine supplements produced a significant reduction in fatigue, compared with baseline values ( P = .04) and significantly improved scores for several long COVID–related symptoms, including loss of taste, breathing difficulties, body aches, headache, and difficulties concentrating) ( P < .05), the researchers report.

Intervention effect sizes were assessed by Cohen statistics, with a d of at least 0.8 indicating a large effect.

Among highlights of the results were that patients reported a significant 77.8% drop in scores for concentration difficulties at the 3-month follow-up (Cohen’s effect, d = 1.19) and no concentration difficulties at the 6-month follow-up (Cohen’s effect, d = 2.46).

Total creatine levels increased in several locations across the brain (as much as 33% for right parietal white matter). No changes in tissue creatine levels were found in the placebo group during the trial.

“Since PVFS is characterized by impaired tissue bioenergetics ..., supplemental creatine might be an effective dietary intervention to uphold brain creatine in post–COVID-19 fatigue syndrome,” the authors write.

The authors add that creatine supplements for long COVID patients could benefit organs beyond the brain as participants saw “a significant drop in lung and body pain after the intervention.”
 

Unanswered questions

Some experts said the results should be interpreted with caution.

“This research paper is very interesting,” says Nisha Viswanathan, MD, director of the long COVID program at University of California, Los Angeles, “but the limited number of patients makes the results difficult to generalize.”

Dr. Viswanathan, who was not part of the study, pointed out that the patients included in this study had a recent COVID infection (under 3 months).

“Acute COVID infection can take up to 3 months to resolve,” she says. “We define patients with long COVID as those with symptoms lasting greater than 3 months. Therefore, these patients could have had improvements in their fatigue due to the natural course of the illness rather than creatine supplementation.”

Alba Azola, MD, assistant professor in the department of physical medicine and rehabilitation at Johns Hopkins University, Baltimore, said she also was troubled by the window of 3 months for recent COVID infection.

She said she would like to see results for patients who have ongoing symptoms for at least 6 months after infection, especially given creatine supplements’ history in research.

Creatine supplements for other conditions, such as fibromyalgia and chronic fatigue syndrome, have been tested for nearly 2 decades, she pointed out, with conflicting findings, something the authors acknowledge in the paper.

“I think it’s premature to say (creatine) is the key,” she says. She added that the small sample size is important to consider given the heterogeneity of patients with long COVID.

That said, Dr. Azola says, she applauds all efforts to find treatments for long COVID, especially randomized, controlled studies like this one.
 

No major side effects

No major side effects were reported for either intervention, except for transient mild nausea reported by one patient after taking creatine.

Compliance with the intervention was 90.6% ± 3.5% in the creatine group and 95.3% ± 5.0% in the control group (P = .04).

Participants were eligible for inclusion if they were 18-65 years old, had a positive COVID test within the last 3 months (documented by a valid polymerase chain reaction [PCR] or antigen test performed in a COVID-19–certified lab); had moderate to severe fatigue; and at least one additional COVID-related symptom, including loss of taste or smell, breathing trouble, lung pain, body aches, headaches, or difficulties concentrating.

The authors acknowledge that they selected a sample of young to middle-aged adults experiencing moderate long COVID symptoms, and it’s unknown whether creatine is equally effective in other PVFS populations, such as elderly people, children, or patients with less or more severe disease.

Senior author Dr. Sergei Ostojic serves as a member of the Scientific Advisory Board on creatine in health and medicine (AlzChem LLC). He co-owns a patent for “Supplements Based on Liquid Creatine” at the European Patent Office. He has received research support related to creatine during the past 36 months from the Serbian Ministry of Education, Science, and Technological Development; Provincial Secretariat for Higher Education and Scientific Research; Alzchem GmbH; ThermoLife International; and Hueston Hennigan LLP. He does not own stocks and shares in any organization. Other authors declare no known relevant financial interests. Dr. Viswanathan and Dr. Azola report no relevant financial relationships.
 

Exercising in the morning may have the biggest impact on the likelihood of having obesity, whereas morning and afternoon exercise appear to reduce the risk of developing type 2 diabetes, suggest two studies.

Tongyu Ma, PhD, research assistant professor with the Health Sciences Department, Franklin Pierce University, Rindge, N.H., and colleagues studied data on almost 5,300 individuals, finding a strong association between moderate to vigorous physical activity (MVPA) and obesity.

The research, published in Obesity, showed that people who exercised in the morning had a lower body mass index than that of those who exercised at other times, even though they were more sedentary.

For the second study, Chirag J. Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, and colleagues examined more than 93,000 individuals and found that morning and afternoon, but not evening, exercise reduced the risk for type 2 diabetes.

However, the results, published in Diabetologia, also indicated that people who undertook at least MVPA were protected against developing type 2 diabetes no matter what time of day they exercised.

Along with considering the timing of exercise, the authors suggest that it is “helpful to include some higher intensity activity to help reduce the risk of developing diabetes and other cardiovascular disease.”
 

Morning exercisers perform less physical activity

Dr. Ma and colleagues noted that “although a beneficial association among the levels of physical activity with obesity has been frequently reported, the optimal timing of physical activity for decreasing obesity remains controversial.”

The researchers analyzed data from the National Health and Nutrition Examination Survey for the 2003-2004 and 2005-2006 cycles, because accelerometry was implemented in those periods.

They included 5,285 individuals aged ≥ 20 years who had physical activity measured via an accelerometer worn on the right hip during waking hours for 7 consecutive days.

The diurnal pattern of MVPA was classified into three clusters by the established technique of K-means clustering analysis: morning (n = 642), midday (n = 2,456), and evening (n = 2,187).

The association between MVPA, diurnal pattern, and obesity was then assessed in linear regression models taking into account a range of potential confounding factors.

Overall, participants in the morning cluster were older and more likely to be female than those in the other clusters (P < .001 for both). They were also more likely to be nonsmokers (P = .007) and to have less than high school education (P = .0041).

Morning cluster individuals performed less physical activity and were more sedentary than those in the midday and evening groups (P < .001 for both), although they were more likely to be healthy eaters (P = .004), with a lower calorie intake (P < .001).

Individuals in the morning cluster had, on average, a lower body mass index than those in other clusters, at 27.4 vs. 28.4 in the midday cluster and 28.2 in the evening cluster (P for interaction = .02).

Morning cluster participants also had a lower waist circumference than participants in the midday or evening cluster: 95.9 cm, 97.9 cm, and 97.3 cm, respectively (P for interaction = .06).

The team reported that there was a strong linear association between MVPA and obesity in the morning cluster, whereas there was a weaker curvilinear association in the midday and evening clusters.

“This is exciting new research that is consistent with a common tip for meeting exercise goals – that is, schedule exercise in the morning before emails, phone calls, or meetings that might distract you,” Rebecca Krukowski, PhD, professor, public health sciences, University of Virginia, Charlottesville, said in a release.

However, she noted that the cross-sectional nature of the study means that it is “not known whether people who exercise consistently in the morning may be systematically different from those who exercise at other times, in ways that were not measured in this study.

“For example, people who exercise regularly in the morning could have more predictable schedules, such as being less likely to be shift workers or less likely to have caregiving responsibilities that impede morning exercise,” said Dr. Krukowski, who was not involved in the study.
 

No association between evening activity and type 2 diabetes risk

In the second study, the team studied 93,095 persons in the UK Biobank, with a mean age of 62 years and no history of type 2 diabetes, who wore a wrist accelerometer for 1 week.

The movement data were used to estimate the metabolic equivalent of task, which was then summed into the total physical activity completed in the morning, afternoon, and evening and linked to the development of incident type 2 diabetes.

After adjustment for potential confounding factors, both morning and afternoon physical activity were associated with a reduced risk of developing type 2 diabetes, at hazard ratios of 0.90 (P = 7 × 10-8) and 0.91 (P = 1 × 10-5), respectively.

However, there was no association between evening activity and the risk for type 2 diabetes, at a hazard ratio of 0.95 (P = .07).

The team found, however, that MVPA and vigorous physical activity were associated with a reduced risk for type 2 diabetes at all times of day.

Dr. Patel’s study was supported in part by National Institutes of Health grants. No other funding was declared. No relevant financial relationships were declared.

A version of this article appeared on Medscape.com.

Exercising in the morning may have the biggest impact on the likelihood of having obesity, whereas morning and afternoon exercise appear to reduce the risk of developing type 2 diabetes, suggest two studies.

Tongyu Ma, PhD, research assistant professor with the Health Sciences Department, Franklin Pierce University, Rindge, N.H., and colleagues studied data on almost 5,300 individuals, finding a strong association between moderate to vigorous physical activity (MVPA) and obesity.

The research, published in Obesity, showed that people who exercised in the morning had a lower body mass index than that of those who exercised at other times, even though they were more sedentary.

For the second study, Chirag J. Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, and colleagues examined more than 93,000 individuals and found that morning and afternoon, but not evening, exercise reduced the risk for type 2 diabetes.

However, the results, published in Diabetologia, also indicated that people who undertook at least MVPA were protected against developing type 2 diabetes no matter what time of day they exercised.

Along with considering the timing of exercise, the authors suggest that it is “helpful to include some higher intensity activity to help reduce the risk of developing diabetes and other cardiovascular disease.”
 

Morning exercisers perform less physical activity

Dr. Ma and colleagues noted that “although a beneficial association among the levels of physical activity with obesity has been frequently reported, the optimal timing of physical activity for decreasing obesity remains controversial.”

The researchers analyzed data from the National Health and Nutrition Examination Survey for the 2003-2004 and 2005-2006 cycles, because accelerometry was implemented in those periods.

They included 5,285 individuals aged ≥ 20 years who had physical activity measured via an accelerometer worn on the right hip during waking hours for 7 consecutive days.

The diurnal pattern of MVPA was classified into three clusters by the established technique of K-means clustering analysis: morning (n = 642), midday (n = 2,456), and evening (n = 2,187).

The association between MVPA, diurnal pattern, and obesity was then assessed in linear regression models taking into account a range of potential confounding factors.

Overall, participants in the morning cluster were older and more likely to be female than those in the other clusters (P < .001 for both). They were also more likely to be nonsmokers (P = .007) and to have less than high school education (P = .0041).

Morning cluster individuals performed less physical activity and were more sedentary than those in the midday and evening groups (P < .001 for both), although they were more likely to be healthy eaters (P = .004), with a lower calorie intake (P < .001).

Individuals in the morning cluster had, on average, a lower body mass index than those in other clusters, at 27.4 vs. 28.4 in the midday cluster and 28.2 in the evening cluster (P for interaction = .02).

Morning cluster participants also had a lower waist circumference than participants in the midday or evening cluster: 95.9 cm, 97.9 cm, and 97.3 cm, respectively (P for interaction = .06).

The team reported that there was a strong linear association between MVPA and obesity in the morning cluster, whereas there was a weaker curvilinear association in the midday and evening clusters.

“This is exciting new research that is consistent with a common tip for meeting exercise goals – that is, schedule exercise in the morning before emails, phone calls, or meetings that might distract you,” Rebecca Krukowski, PhD, professor, public health sciences, University of Virginia, Charlottesville, said in a release.

However, she noted that the cross-sectional nature of the study means that it is “not known whether people who exercise consistently in the morning may be systematically different from those who exercise at other times, in ways that were not measured in this study.

“For example, people who exercise regularly in the morning could have more predictable schedules, such as being less likely to be shift workers or less likely to have caregiving responsibilities that impede morning exercise,” said Dr. Krukowski, who was not involved in the study.
 

No association between evening activity and type 2 diabetes risk

In the second study, the team studied 93,095 persons in the UK Biobank, with a mean age of 62 years and no history of type 2 diabetes, who wore a wrist accelerometer for 1 week.

The movement data were used to estimate the metabolic equivalent of task, which was then summed into the total physical activity completed in the morning, afternoon, and evening and linked to the development of incident type 2 diabetes.

After adjustment for potential confounding factors, both morning and afternoon physical activity were associated with a reduced risk of developing type 2 diabetes, at hazard ratios of 0.90 (P = 7 × 10-8) and 0.91 (P = 1 × 10-5), respectively.

However, there was no association between evening activity and the risk for type 2 diabetes, at a hazard ratio of 0.95 (P = .07).

The team found, however, that MVPA and vigorous physical activity were associated with a reduced risk for type 2 diabetes at all times of day.

Dr. Patel’s study was supported in part by National Institutes of Health grants. No other funding was declared. No relevant financial relationships were declared.

A version of this article appeared on Medscape.com.

Exercising in the morning may have the biggest impact on the likelihood of having obesity, whereas morning and afternoon exercise appear to reduce the risk of developing type 2 diabetes, suggest two studies.

Tongyu Ma, PhD, research assistant professor with the Health Sciences Department, Franklin Pierce University, Rindge, N.H., and colleagues studied data on almost 5,300 individuals, finding a strong association between moderate to vigorous physical activity (MVPA) and obesity.

The research, published in Obesity, showed that people who exercised in the morning had a lower body mass index than that of those who exercised at other times, even though they were more sedentary.

For the second study, Chirag J. Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, and colleagues examined more than 93,000 individuals and found that morning and afternoon, but not evening, exercise reduced the risk for type 2 diabetes.

However, the results, published in Diabetologia, also indicated that people who undertook at least MVPA were protected against developing type 2 diabetes no matter what time of day they exercised.

Along with considering the timing of exercise, the authors suggest that it is “helpful to include some higher intensity activity to help reduce the risk of developing diabetes and other cardiovascular disease.”
 

Morning exercisers perform less physical activity

Dr. Ma and colleagues noted that “although a beneficial association among the levels of physical activity with obesity has been frequently reported, the optimal timing of physical activity for decreasing obesity remains controversial.”

The researchers analyzed data from the National Health and Nutrition Examination Survey for the 2003-2004 and 2005-2006 cycles, because accelerometry was implemented in those periods.

They included 5,285 individuals aged ≥ 20 years who had physical activity measured via an accelerometer worn on the right hip during waking hours for 7 consecutive days.

The diurnal pattern of MVPA was classified into three clusters by the established technique of K-means clustering analysis: morning (n = 642), midday (n = 2,456), and evening (n = 2,187).

The association between MVPA, diurnal pattern, and obesity was then assessed in linear regression models taking into account a range of potential confounding factors.

Overall, participants in the morning cluster were older and more likely to be female than those in the other clusters (P < .001 for both). They were also more likely to be nonsmokers (P = .007) and to have less than high school education (P = .0041).

Morning cluster individuals performed less physical activity and were more sedentary than those in the midday and evening groups (P < .001 for both), although they were more likely to be healthy eaters (P = .004), with a lower calorie intake (P < .001).

Individuals in the morning cluster had, on average, a lower body mass index than those in other clusters, at 27.4 vs. 28.4 in the midday cluster and 28.2 in the evening cluster (P for interaction = .02).

Morning cluster participants also had a lower waist circumference than participants in the midday or evening cluster: 95.9 cm, 97.9 cm, and 97.3 cm, respectively (P for interaction = .06).

The team reported that there was a strong linear association between MVPA and obesity in the morning cluster, whereas there was a weaker curvilinear association in the midday and evening clusters.

“This is exciting new research that is consistent with a common tip for meeting exercise goals – that is, schedule exercise in the morning before emails, phone calls, or meetings that might distract you,” Rebecca Krukowski, PhD, professor, public health sciences, University of Virginia, Charlottesville, said in a release.

However, she noted that the cross-sectional nature of the study means that it is “not known whether people who exercise consistently in the morning may be systematically different from those who exercise at other times, in ways that were not measured in this study.

“For example, people who exercise regularly in the morning could have more predictable schedules, such as being less likely to be shift workers or less likely to have caregiving responsibilities that impede morning exercise,” said Dr. Krukowski, who was not involved in the study.
 

No association between evening activity and type 2 diabetes risk

In the second study, the team studied 93,095 persons in the UK Biobank, with a mean age of 62 years and no history of type 2 diabetes, who wore a wrist accelerometer for 1 week.

The movement data were used to estimate the metabolic equivalent of task, which was then summed into the total physical activity completed in the morning, afternoon, and evening and linked to the development of incident type 2 diabetes.

After adjustment for potential confounding factors, both morning and afternoon physical activity were associated with a reduced risk of developing type 2 diabetes, at hazard ratios of 0.90 (P = 7 × 10-8) and 0.91 (P = 1 × 10-5), respectively.

However, there was no association between evening activity and the risk for type 2 diabetes, at a hazard ratio of 0.95 (P = .07).

The team found, however, that MVPA and vigorous physical activity were associated with a reduced risk for type 2 diabetes at all times of day.

Dr. Patel’s study was supported in part by National Institutes of Health grants. No other funding was declared. No relevant financial relationships were declared.

A version of this article appeared on Medscape.com.