semaglutide

Importance Metabolic dysfunction–associated steatotic liver disease (MASLD) includes a range of liver conditions, progressing from isolated steatosis (characterized by fat accumulation in the liver without inflammation) to metabolic dysfunction–associated steatohepatitis (MASH), which involves fat accumulation and inflammation in the liver. The presence of MASLD is associated with increased morbidity and mortality due to liver-related complications, hepatocellular carcinoma, cardiovascular disease, and certain extrahepatic cancers.

Observations The most common chronic liver disease worldwide, MASLD affects approximately 30% to 40% of the general adult population globally (with varying prevalence across continents), including approximately 60% to 70% of individuals with type 2 diabetes and approximately 70% to 80% of those with obesity. It is typically diagnosed based on an ultrasonographic finding of hepatic steatosis, along with at least 1 of 5 features of the metabolic syndrome (abdominal overweight or obesity, prediabetes or type 2 diabetes, hypertension, elevated level of plasma triglycerides, and low level of high-density lipoprotein cholesterol) for women who consume less than 140 g/wk of alcohol (<2 standard drinks/d) and for men who consume less than 210 g/wk (<3 standard drinks/d) and have no other known causes of steatosis such as use of a particular medication (eg, corticosteroids, tamoxifen, or methotrexate), hepatitis C, or iron overload. Other risk factors for MASLD include older age (≥50 years) and male sex (male:female ratio approximately 2). The Fibrosis-4 index (a scoring system incorporating age, serum levels of aspartate aminotransferase and alanine aminotransferase, and platelet count) and vibration-controlled transient elastography (a noninvasive imaging technique) are commonly used to stage hepatic fibrosis in patients with MASLD. Cardiovascular disease is the leading cause of death, followed by certain extrahepatic cancers (primarily gastrointestinal, breast, and gynecologic cancer) and liver-related complications, including cirrhosis, hepatic decompensation (ascites, hepatic encephalopathy, or variceal bleeding), and hepatocellular carcinoma. First-line treatment of MASLD involves behavioral modifications (including hypocaloric low-carbohydrate and low-fat diets, physical exercise, and avoidance of alcohol) and management of type 2 diabetes, obesity, hypertension, and hyperlipidemia. Bariatric surgery should be considered for patients with MASLD and a body mass index greater than 35. Resmetirom (a liver-directed, thyroid hormone receptor β-selective agonist) and subcutaneous semaglutide (a glucagon-like peptide-1 receptor agonist) are conditionally approved by the US Food and Drug Administration (FDA) for the treatment of adults with MASH who have moderate to advanced fibrosis.

Conclusions A highly prevalent condition among adults worldwide, MASLD is associated with liver-related complications, hepatocellular carcinoma, cardiovascular disease, and certain extrahepatic cancers. First-line treatment includes behavioral modifications, including a weight-reducing diet, physical exercise, and avoidance of alcohol. Resmetirom and semaglutide are conditionally FDA-approved medications for the treatment of adults with MASH and moderate to advanced fibrosis.

Author/s:

Herbert Tilg, Salvatore Petta, Norbert Stefan, Giovanni Targher

Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity

Hope Smashey — Wed, 08 Oct 2025 00:39:43 +0000

Date Added:

October 7, 2025

Journal/Publication:

New England Journal of Medicine

Publication Date:

September 18, 2025

Issue:

Volume:

393

URL:

Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity

Type:

Clinical Research Results

Format:

Article

DOI (1):

10.1056/NEJMoa2500969

Keywords

Semaglutide

overweight

PMID (1):

40934115

MeSH

Oral semaglutide 25mg daily resulted in a 14% reduction in weight in 1.4 years. James W. Mold, MD, MPH

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Background
Oral semaglutide at a dose of 25 mg may provide an alternative treatment option to injectable semaglutide (2.4 mg) and higher-dose oral semaglutide (50 mg) for persons with overweight or obesity.

Methods
In a 71-week, double-blind, randomized, placebo-controlled trial conducted at 22 sites in four countries, we enrolled persons without diabetes who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or higher or a BMI of 27 or higher with at least one obesity-related complication. The participants were randomly assigned in a 2:1 ratio to receive oral semaglutide (25 mg) or placebo once daily, plus lifestyle interventions. The coprimary end points at week 64 were the percent change in body weight and a reduction of 5% or more in body weight; confirmatory secondary end points included reductions in body weight of 10% or more, 15% or more, and 20% or more and the change in the Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL-Lite-CT) Physical Function score.

Results
A total of 205 participants were randomly assigned to receive oral semaglutide, and 102 to receive placebo. The estimated mean change in body weight from baseline to week 64 was −13.6% in the oral semaglutide group and −2.2% in the placebo group (estimated difference, −11.4 percentage points; 95% confidence interval, −13.9 to −9.0; P<0.001). Participants in the oral semaglutide group were significantly more likely than those in the placebo group to have body-weight reductions of 5% or more, 10% or more, 15% or more, and 20% or more (P<0.001 for all comparisons) and to have an improved IWQOL-Lite-CT Physical Function score (P<0.001). Gastrointestinal adverse events were more common with oral semaglutide than with placebo (74.0% vs. 42.2%).

Conclusions
Oral semaglutide at a dose of 25 mg once daily resulted in a greater mean reduction in body weight than placebo in participants with overweight or obesity. (Funded by Novo Nordisk; OASIS 4 ClinicalTrials.gov number, NCT05564117.)

Author/s:

Sean Wharton, Ildiko Lingvay, Pawel Bogdanski, Ruben Duque do Vale, Stephan Jacob, Tobias Karlsson, Chaithra Shaji, Domenica Rubino, W. Timothy Garvey

I Am Taking a GLP-1 Weight-Loss Medication—What Should I Know?

Megan George — Thu, 04 Sep 2025 19:54:15 +0000

Date Added:

September 4, 2025

Journal/Publication:

JAMA Internal Medicine

Publication Date:

July 14, 2025

URL:

I Am Taking a GLP-1 Weight-Loss Medication—What Should I Know?

Type:

Patient Education Materials

Format:

Poster

DOI (1):

10.1001/jamainternmed.2025.1133

Keywords

diet

GLP-1

weight loss

PMID (1):

40658429

MeSH

glucagon-like peptide 1

Glucagon-Like Peptide-1 Receptor Agonists

Information for patients about GLP-1 medications. James W. Mold, MD, MPH

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This JAMA Internal Medicine Patient Page describes how glucagon-like peptide-1 (GLP-1) receptor agonists work and what behaviors to adopt while using them.

Author/s:

Farhad Mehrtash, Jody Dushay, JoAnn E. Manson

Managing Adverse Effects of Incretin-Based Medications for Obesity

Megan George — Fri, 01 Aug 2025 13:22:15 +0000

Date Added:

August 1, 2025

Journal/Publication:

JAMA Insights

Publication Date:

July 29, 2025

URL:

Managing Adverse Effects of Incretin-Based Medications for Obesity

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1001/jama.2025.11153

Keywords

Cardiovascular Diseases

overweight

PMID (1):

40728833

MeSH

diabetes mellitus, type 2

Glucagon-Like Peptide-1 Receptor Agonists

cardiovascular diseases

overweight

Gastric Inhibitory Polypeptide

renal insufficiency

Information on how to deal with the side effects of obesity medications. James W. Mold, MD, MPH

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This JAMA Insights explores optimal strategies for managing the adverse effects associated with incretin-based medications for obesity, including semaglutide and tirzepatide.

Author/s:

Robert F Kushner, Jaime P Almandoz, Domenica M Rubino

What Should I Know About Injectable Weight-Loss Medications?

Erin Blanchette — Tue, 19 Mar 2024 17:42:08 +0000

Date Added:

March 19, 2024

Journal/Publication:

JAMA Internal Medicine

Publisher:

American Medical Association

Publication Date:

March 11, 2024

URL:

What Should I Know About Injectable Weight-Loss Medications?

Type:

Patient Education Materials

Format:

Article

DOI (1):

10.1001/jamainternmed.2023.7268

Keywords

Feeding and Eating Disorders

PMID (1):

38466303

MeSH

Liraglutide

diabetes mellitus

diabetes mellitus, type 2

Information for patients regarding injectable medications for weight loss. James W. Mold, MD, MPH

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How Do I Know If Injectable Weight-Loss Medications Are Right for Me?

The decision to start an injectable weight-loss medication is based on several factors. These include weight, medical history, personal preference, and medication cost. Talk with your health care professional about whether these medications are right for you.

Author/s:

Andrew Kraftson, Dina Griauzde

Once-Weekly Semaglutide in Adolescents with Obesity

Aubrey Delammermore — Sun, 06 Nov 2022 05:00:00 +0000

Date Added:

November 6, 2022

Journal/Publication:

New England Journal of Medicine

Publisher:

Massachusetts Medical Society

Publication Date:

November 2, 2022

URL:

Once-Weekly Semaglutide in Adolescents with Obesity

Type:

Clinical Research Results

Format:

Article

DOI (1):

10.1056/NEJMoa2208601

Keywords

Cardiometabolic Risk Factors

Confidence Intervals

Glycated Hemoglobin A

Waist Circumference

Lipoproteins, HDL

PMID (1):

36322838

MeSH

body mass index

Glucagon-Like Peptide-1 Receptor

Alanine Transaminase

semaglutide

pediatric obesity

In overweight adolescents, weekly semaglutide injections plus “lifestyle intervention” resulted in an average reduction in BMI of 16% compared to a reduction of 0.6% with the lifestyle intervention alone at 68 weeks. GI side effects occurred in 62% of the semaglutide group and 42% of the lifestyle alone group. James W. Mold, MD, MPH

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BACKGROUND
A once-weekly, 2.4-mg dose of subcutaneous semaglutide, a glucagon-like peptide-1 receptor agonist, is used to treat obesity in adults, but assessment of the drug in adolescents has been lacking.

METHODS
In this double-blind, parallel-group, randomized, placebo-controlled trial, we enrolled adolescents (12 to <18 years of age) with obesity (a body-mass index [BMI] in the 95th percentile or higher) or with overweight (a BMI in the 85th percentile or higher) and at least one weight-related coexisting condition. Participants were randomly assigned in a 2:1 ratio to receive once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo for 68 weeks, plus lifestyle intervention. The primary end point was the percentage change in BMI from baseline to week 68; the secondary confirmatory end point was weight loss of at least 5% at week 68.

RESULTS
A total of 201 participants underwent randomization, and 180 (90%) completed treatment. All but one of the participants had obesity. The mean change in BMI from baseline to week 68 was −16.1% with semaglutide and 0.6% with placebo (estimated difference, −16.7 percentage points; 95% confidence interval [CI], −20.3 to −13.2; P<0.001). At week 68, a total of 95 of 131 participants (73%) in the semaglutide group had weight loss of 5% or more, as compared with 11 of 62 participants (18%) in the placebo group (estimated odds ratio, 14.0; 95% CI, 6.3 to 31.0; P<0.001). Reductions in body weight and improvement with respect to cardiometabolic risk factors (waist circumference and levels of glycated hemoglobin, lipids [except high-density lipoprotein cholesterol], and alanine aminotransferase) were greater with semaglutide than with placebo. The incidence of gastrointestinal adverse events was greater with semaglutide than with placebo (62% vs. 42%). Five participants (4%) in the semaglutide group and no participants in the placebo group had cholelithiasis. Serious adverse events were reported in 15 of 133 participants (11%) in the semaglutide group and in 6 of 67 participants (9%) in the placebo group.

CONCLUSIONS
Among adolescents with obesity, once-weekly treatment with a 2.4-mg dose of semaglutide plus lifestyle intervention resulted in a greater reduction in BMI than lifestyle intervention alone. (Funded by Novo Nordisk; STEP TEENS ClinicalTrials.gov number, NCT04102189. opens in new tab.)

Author/s:

Weghuber, D., Barrett, T.

Once-Weekly Semaglutide in Adults with Overweight or Obesity

Devin Evans — Wed, 24 Mar 2021 05:00:00 +0000

Date Added:

March 24, 2021

Journal/Publication:

New England Journal of Medicine

Publication Date:

March 18, 2021

Issue:

Volume:

384

Pages:

989

URL:

Once-Weekly Semaglutide in Adults with Overweight or Obesity

Type:

Clinical Research Results

Format:

Article

DOI (1):

10.1056/NEJMoa2032183

Keywords

PMID (1):

33567185

MeSH

Once weekly Semaglutide plus lifestyle counseling was much more effective for helping non-diabetic patients lose weight than placebo plus lifestyle counseling at 68 weeks. The results were clinically significant. James W. Mold, MD, MPH

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Background: Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

Methods: In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.

Results: The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).

Conclusions: In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

Author/s:

Wilding, John P.H., Batterham, Rachel L., Calanna, Salvatore, Davies, Melanie, Van Gaal, Luc F., Lingvay, Ildiko, McGowan, Barbara M., Rosenstock, Julio, Tran, Marie T.D., Wadden, Thomas A.,, Sean, Yokote, Koutaro, Zeuthen, Niels, Kushner, Robert F., STEP 1 Study Group

Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial

Devin Evans — Fri, 26 Feb 2021 06:00:00 +0000

Date Added:

February 26, 2021

Journal/Publication:

Journal of the American Medical Association

Publication Date:

February 24, 2021

URL:

Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial

Type:

Clinical Research Results

Format:

Article

DOI (1):

10.1001/jama.2021.1831

Keywords

PMID (1):

33625476

MeSH

Once weekly SC injections of Semaglutide in addition to intensive behavior change assistance was twice as effective as the behavior change interventions alone after 68 weeks. James W. Mold, MD, MPH

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Importance: Weight loss improves cardiometabolic risk factors in people with overweight or obesity. Intensive lifestyle intervention and pharmacotherapy are the most effective noninvasive weight loss approaches.

Objective: To compare the effects of once-weekly subcutaneous semaglutide, 2.4 mg vs placebo for weight management as an adjunct to intensive behavioral therapy with initial low-calorie diet in adults with overweight or obesity.

Design, setting, and participants: Randomized, double-blind, parallel-group, 68-week, phase 3a study (STEP 3) conducted at 41 sites in the US from August 2018 to April 2020 in adults without diabetes (N = 611) and with either overweight (body mass index ≥27) plus at least 1 comorbidity or obesity (body mass index ≥30).

Interventions: Participants were randomized (2:1) to semaglutide, 2.4 mg (n = 407) or placebo (n = 204), both combined with a low-calorie diet for the first 8 weeks and intensive behavioral therapy (ie, 30 counseling visits) during 68 weeks.

Main outcomes and measures: The co-primary end points were percentage change in body weight and the loss of 5% or more of baseline weight by week 68. Confirmatory secondary end points included losses of at least 10% or 15% of baseline weight.

Results: Of 611 randomized participants (495 women [81.0%], mean age 46 years [SD, 13], body weight 105.8 kg [SD, 22.9], and body mass index 38.0 [SD, 6.7]), 567 (92.8%) completed the trial, and 505 (82.7%) were receiving treatment at trial end. At week 68, the estimated mean body weight change from baseline was -16.0% for semaglutide vs -5.7% for placebo (difference, -10.3 percentage points [95% CI, -12.0 to -8.6]; P < .001). More participants treated with semaglutide vs placebo lost at least 5% of baseline body weight (86.6% vs 47.6%, respectively; P < .001). A higher proportion of participants in the semaglutide vs placebo group achieved weight losses of at least 10% or 15% (75.3% vs 27.0% and 55.8% vs 13.2%, respectively; P < .001). Gastrointestinal adverse events were more frequent with semaglutide (82.8%) vs placebo (63.2%). Treatment was discontinued owing to these events in 3.4% of semaglutide participants vs 0% of placebo participants.

Conclusions and relevance: Among adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in significantly greater weight loss during 68 weeks. Further research is needed to assess the durability of these findings.

Author/s:

Wadden, Thomas A., Bailey, Timothy S., Billings, Liana K., Davies, Melanie, Frias, Juan P., Koroleva, Anna, Lingvay, Ildiko, O'Neil, Patrick M., Runino, Domenica M., Skovgaard, Dorthe, Wallenstein, Signe O.R., Garvey, W. TImothy, STEP 3 Investigators