Once-Weekly Semaglutide in Adults with Overweight or Obesity
Open accessAbstract
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).
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In subjects with obesity without T2D, 26 weeks of JNJ-64565111 at 10 mg resulted in placebo-corrected weight loss of about 10%, compared with −5.8% in liraglutide-treated controls.
“In subjects with obesity without T2D, 26 weeks of treatment with JNJ-64565111, at the highest tested dose of 10 mg, resulted in a placebo-corrected weight loss of ~10%, relative to −5.8% in liraglutide-treated controls101.”
From Transforming obesity: The advancement of multi-receptor drugs (2024) · cites this paper as [101]
The Abstract describes a 68-week trial of 2.4-mg semaglutide versus placebo in adults without diabetes, not a 26-week trial of 10-mg JNJ-64565111. The Discussion reports a 12.4% placebo-corrected reduction for semaglutide and cites 4.5% for liraglutide in a separate trial; it does not report liraglutide-treated controls with −5.8% weight loss. Page numbers were not provided in our copy. (LLM, conf=0.89)
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Experimental — accuracy not yet measuredGLP-1 RAs are indicated for the treatment of type 2 diabetes (all) and obesity (liraglutide and semaglutide only) and have beneficial effects on patient-important outcomes such as weight loss, cardiovascular and kidney events, hepatic steatosis, and mortality.
“Clinically, GLP-1 RAs are indicated for the treatment of type 2 diabetes (all) and obesity (liraglutide and semaglutide only) and have beneficial effects on patient-important outcomes such as weight loss, cardiovascular and kidney events, hepatic steatosis, and mortality.5,7–9,11,30”
From Glucagon-Like Peptide-1 Receptor Agonists and Thyroid Cancer: A Narrative Review (2024) · cites this paper as [11]
Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
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Experimental — accuracy not yet measuredFor semaglutide, 74.8%, 54.8%, and 34.8% of patients achieved 10%, 15%, and 20% weight reduction benchmarks, respectively.
“For semaglutide1, 74.8%, 54.8%, and 34.8% achieved those, while for tirzepatide [4] it was 90.1%, 78.2% and 62.9%.”
From New drugs for the treatment of obesity: do we need approaches to preserve muscle mass? (2025) · cites this paper as [1]
The Change in Body Weight section reports the same ≥10%, ≥15%, and ≥20% benchmarks at week 68, but gives 69.1%, 50.5%, and 32.0% for the semaglutide group, respectively. None of the three percentages attributed to this paper matches those results. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredOnce-weekly semaglutide at a dose of 2.4 mg administered subcutaneously is a potent glucagon-like peptide 1 receptor agonist that is approved for long-term weight management.
“Once weekly semaglutide at a dose of 2.4 mg administered subcutaneously is a potent glucagon-like peptide 1 receptor agonist that is approved for long-term weight management”
From Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity (2023) · cites this paper as [13]
The paper describes once-weekly subcutaneous semaglutide 2.4 mg as a GLP-1 treatment studied for weight loss (Procedures; p. 990). But its Discussion says liraglutide is the only GLP-1 receptor agonist approved for weight management, while p. 990 says semaglutide was approved at doses up to 1 mg for type 2 diabetes and cardiovascular-risk reduction—not at 2.4 mg for long-term weight management. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredIn STEP 1 and STEP 3 trials of individuals with obesity without diabetes (mean BMI 38), mean weight loss at 68 weeks was 14.9% (placebo, 2.4%; difference, 12.4%; 95% CI, 11.5%-13.4%) and 16.0% (placebo, 5.7%; difference, 10.3%; 95% CI, 8.6%-12.0%), respectively.
“In these clinical trials, mean weight loss at 68 weeks was 14.9% (placebo, 2.4%; difference, 12.4%; 95% CI, 11.5%-13.4%) and 16.0% (placebo, 5.7%; difference, 10.3%; 95% CI, 8.6%-12.0%), respectively.81,99”
From Obesity Management in Adults (2023) · cites this paper as [81]
Split into 2 atoms — 1 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
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Experimental — accuracy not yet measured
The degree of weight loss with incretin therapies is associated with a well-documented decline in lean mass and bone mineral density.
“the well-documented decline in lean mass and BMD associated with that degree of weight loss must be considered.”
From The Benefits of Exercise Training in Combination With Weight Loss Therapies (2025) · cites this paper as [42]
The Change in Body Composition section reports that total lean body mass decreased in absolute terms in the semaglutide DXA subpopulation, although its proportion of total body mass increased. The passages found do not report a decline in bone mineral density, so the BMD portion of the claim is unsupported by our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDespite inducing less weight loss than tirzepatide, semaglutide resulted in a more significant loss of lean mass, 6.9 kg, or 13.9%, over 68 weeks.
“Despite inducing a smaller magnitude of weight loss than tirzepatide, treatment with semaglutide resulted in an even more significant loss of lean mass, of 6.9 kg, or 13.9%, over its 68-week trial period (42).”
From The Benefits of Exercise Training in Combination With Weight Loss Therapies (2025) · cites this paper as [42]
The Change in Body Composition section reports that lean body mass decreased in absolute terms in the DXA subpopulation, and the Change in Body Weight section reports outcomes at week 68. Our copy does not give a lean-mass loss of 6.9 kg or 13.9%, or compare semaglutide with tirzepatide. (LLM, conf=0.88)
Experimental — accuracy not yet measuredClinical trials have shown that GLP1Ra-based therapy produces substantial weight loss, including 12-15% over one year with semaglutide and weight reductions with tirzepatide comparable to bariatric surgery.
“Indeed, clinical trials demonstrate substantial weight loss achievable with GLP1Ra-based therapy, ranging from 12-15% over a one-year period for semaglutide (6), to weight losses rivaling what is seen with bariatric surgery for tirzepatide (7).”
From <scp>G</scp> <scp>LP1Ra</scp> ‐based therapies and <scp>DXA</scp> ‐acquired musculoskeletal health outcomes: a focused meta‐analysis of placebo‐controlled trials (2025) · cites this paper as [6]
The Change in Body Weight section reports 14.9% mean weight loss with semaglutide, within the cited 12–15% range. That result was measured at week 68, not over one year. The tirzepatide comparison is attached to a different citation and is not judged here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe greatest magnitude of weight loss across body weight and composition outcomes was observed in the SURMOUNT and STEP trials.
“Across body weight and composition outcomes, the greatest magnitude of weight loss was observed in the SURMOUNT (7) and STEP (6) trials, respectively.”
From <scp>G</scp> <scp>LP1Ra</scp> ‐based therapies and <scp>DXA</scp> ‐acquired musculoskeletal health outcomes: a focused meta‐analysis of placebo‐controlled trials (2025) · cites this paper as [6]
The Change in Body Composition section (page not available) reports reduced total fat and visceral fat mass in the STEP trial’s semaglutide group. The paper does not compare STEP with other trials or establish that it had the greatest reduction across body-composition outcomes; it also provides no evidence about SURMOUNT. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn a 68-week semaglutide 2.4 mg trial in 140 individuals with overweight or obesity, body weight decreased 14.9% (15.3 kg), fat mass decreased 24.7% (10.4 kg), and lean mass decreased 13.9% (6.9 kg).
“In the context of a body weight reduction of 14.9% (À15.3 kg) and fat reduction of 24.7% (À10.4 kg), individuals also lost an average of 13.9% of their total LM (À6.9 kg) (17).”
From Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition? (2024) · cites this paper as [17]
The Abstract reports 14.9% (15.3 kg) mean weight loss at week 68 with semaglutide. “Change in Body Composition” reports reduced fat and lean mass in a 140-participant DXA subpopulation, but our copy does not give the claimed 24.7% (10.4 kg) or 13.9% (6.9 kg) reductions. The full trial enrolled 1,961 participants, not 140. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSemaglutide administration is associated with lean mass loss of 13.9% (6.9 kg) over 68 weeks, while tirzepatide induced a 10.9% (6 kg) loss over 72 weeks.
“As discussed above, Sema administration is associated with an LM loss of 13.9% ($6.9 kg) over a period of 68 weeks (17), while Tz induced a 10.9% (6 kg) loss over 72 weeks of therapy (20).”
From Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition? (2024) · cites this paper as [17]
The Change in Body Composition section (page unavailable) reports that lean body mass decreased in absolute terms in the semaglutide DXA subpopulation. Our copy does not give the claimed 13.9% or 6.9 kg lean-mass loss, although it confirms the trial’s 68-week duration. The tirzepatide result is attached to a different citation and is not assessed here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIncretin therapy decreases fat mass by about 29% on average.
“Regarding fat mass, evidence suggests a decrease of $29% after incretin therapy (17,20)”
From Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition? (2024) · cites this paper as [17]
The Change in Body Composition section reports reduced total fat mass in a 140-person DXA subpopulation treated with semaglutide, and the Discussion says fat mass fell more than lean body mass. Our copy does not report a 29% average fat-mass decrease; it studied semaglutide in adults with overweight or obesity, not incretin therapies generally. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMost patients' weight loss plateaus.
“In addition, most patients’ weight loss plateaus.5,6,13”
From Discontinuation and Reinitiation of Dual-Labeled GLP-1 Receptor Agonists Among US Adults With Overweight or Obesity (2025) · cites this paper as [6]
The Change in Body Weight section reports that mean weight loss in the semaglutide group reached its nadir at week 60, consistent with a leveling-off of the group average. It does not establish that most individual patients’ weight loss plateaued, or that this pattern applies to patients generally. (LLM, conf=0.83)
Experimental — accuracy not yet measuredSemaglutide 2.4 mg became the most-effective GLP-1 receptor agonist approved for obesity management, with 14.9% mean weight loss at 68 weeks versus 2.4% with placebo.
“In 2021, semaglutide 2.4 mg became the most-effective GLP-1 RA approved for obesity management with 14.9% mean WL at 68 weeks vs. 2.4% with placebo [8].”
From Triple Agonism Based Therapies for Obesity (2025) · cites this paper as [8]
The Abstract and Change in Body Weight section report 14.9% mean weight loss with semaglutide 2.4 mg versus 2.4% with placebo at week 68. The Discussion reports greater weight loss than with liraglutide but says liraglutide was the only GLP-1 receptor agonist then approved for weight management; it does not support the claim that semaglutide 2.4 mg had become an approved obesity treatment. (LLM, conf=0.91)
Experimental — accuracy not yet measuredOnce-weekly injection of 2.4 mg semaglutide resulted in a −14.9% reduction in body weight in adults with obesity, along with substantial improvements in glucose homeostasis and reduced risk of cardiovascular events.
“A once-weekly injection of 2.4 mg of semaglutide resulted in a remarkable reduction in body weight by − 14.9% in adults with obesity, along with substantial improvements in glucose homeostasis and reduced risk of cardiovascular events [66, 67].”
From Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes (2024) · cites this paper as [67]
The Abstract reports a 14.9% mean weight reduction at week 68 with once-weekly 2.4 mg semaglutide, and the Discussion reports improved glycated hemoglobin levels and a greater proportion of participants with normoglycemia. The Discussion does not report a reduced risk of cardiovascular events; it says an ongoing cardiovascular outcomes trial would complement these findings. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSemaglutide 2.4 mg once weekly is the latest approved GLP-1 RA for obesity management (2021) and results in 15-17% mean weight loss through appetite reduction.
“Semaglutide 2.4 mg once weekly is the latest approved GLP-1 RA for obesity management (2021) and results in 15–17% mean WL through appetite reduction [11, 12].”
From What is the pipeline for future medications for obesity? (2025) · cites this paper as [11]
The Discussion reports 14.9% mean weight loss with once-weekly 2.4-mg semaglutide and links the loss to reduced appetite, broadly supporting the efficacy and mechanism claims. It does not report a 15–17% mean, and it says liraglutide was the only GLP-1 receptor agonist approved for weight management at the time, contrary to the approval claim. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIntensive lifestyle interventions may provide small additional weight loss benefit to the new obesity pharmacotherapies.
“As the new obesity pharmacotherapies will lead up to 15–25% mean WL, intensive lifestyle interventions may provide small additional WL benefit to these treatments [11, 106].”
From What is the pipeline for future medications for obesity? (2025) · cites this paper as [11]
The Procedures section describes lifestyle counseling alongside semaglutide, and the Discussion reports 14.9% mean weight loss with that combination. The trial did not compare intensive with less-intensive lifestyle intervention alongside semaglutide, so it cannot establish that intensive intervention provides a small additional benefit. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn the STEP 1 DXA substudy of adults with obesity or overweight receiving semaglutide, there was an absolute reduction of 10.4 kg total fat mass and 6.9 kg total body lean mass, corresponding to 60% fat mass and 40% lean mass.
“For the OMM semaglutide, the DXA substudy of the STEP 1 trial of adults with obesity or overweight receiving semaglutide reported an absolute reduction of 10.4 kg total fat mass and 6.9 kg total body lean mass, corresponding to a proportional body weight reduction of 60% fat mass and 40% lean mass.”
From Body composition changes during weight reduction with tirzepatide in the <scp>SURMOUNT</scp> ‐1 study of adults with obesity or overweight (2025) · cites this paper as [31]
The Change in Body Composition section reports that both total fat mass and total lean body mass decreased in the STEP 1 DXA subpopulation, and the Discussion says fat mass fell more than lean mass. The passages in our copy do not give the claimed 10.4 kg and 6.9 kg reductions or establish the 60%–40% split. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn the STEP 1-4 trials, 68 weeks of once-weekly s.c. semaglutide 2.4 mg treatment resulted in mean weight loss of 15%-17% in adults with overweight or obesity and 10% in those who also had type 2 diabetes.
“In the first of the STEP trials (STEP 1–4), 68 weeks of once-weekly s.c. semaglutide 2.4 mg treatment resulted in mean weight loss of 15%–17% in adults with overweight or obesity and 10% in those who also had type 2 diabetes.13, 14, 15, 16”
From Effects of once-weekly semaglutide 2.4 mg on C-reactive protein in adults with overweight or obesity (STEP 1, 2, and 3): exploratory analyses of three randomised, double-blind, placebo-controlled, phase 3 trials (2023) · cites this paper as [15]
The Abstract and p. 1000 report that STEP 1 participants without diabetes lost a mean 14.9% of body weight after 68 weeks of once-weekly subcutaneous semaglutide 2.4 mg plus lifestyle intervention, supporting the approximately 15% figure. This paper does not report the 15%–17% range across STEP 1–4 or the 10% figure for participants with type 2 diabetes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredWeight loss has an anti-inflammatory effect.
“as it is well-known that weight loss has an anti-inflammatory effect [30–32]”
From Impact of semaglutide on high-sensitivity C-reactive protein: exploratory patient-level analyses of SUSTAIN and PIONEER randomized clinical trials (2022) · cites this paper as [30]
The Discussion (page not specified) reports that weight loss with semaglutide was accompanied by a greater decrease in C-reactive protein, a marker of inflammation, than with placebo. This supports an association in the trial, but does not establish that weight loss itself caused the decrease or that the effect applies to weight loss generally. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSemaglutide mimics endogenous GLP-1 and acts centrally on hypothalamic GLP-1 receptors to suppress appetite, enhance satiety, and reduce food intake.
“Semaglutide mimics the effects of endogenous GLP-1, a gut-derived incretin hormone. It acts centrally on hypothalamic GLP-1 receptors to suppress appetite, enhance satiety, and reduce food intake.”
From Obesity: Clinical Impact, Pathophysiology, Complications, and Modern Innovations in Therapeutic Strategies (2025) · cites this paper as [6]
The introduction (p. 990) identifies semaglutide as a GLP-1 analogue. The Discussion says reduced energy intake stems from decreased appetite, thought to result from effects on the brain. It does not specify hypothalamic GLP-1 receptors, establish enhanced satiety, or describe endogenous GLP-1 as a gut-derived incretin hormone. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn STEP trials, semaglutide 2.4 mg weekly produced a mean placebo-adjusted weight loss of 14.9% over 68 weeks in STEP 1 and up to 16.0% in STEP 4 with continued use.
“In the semaglutide treatment effect in people (STEP) with obesity trials, semaglutide 2.4 mg weekly produced a mean placebo-adjusted weight loss of 14.9% over 68 weeks in STEP 1, and up to 16.0% in STEP 4 with continued use [6,8].”
From Obesity: Clinical Impact, Pathophysiology, Complications, and Modern Innovations in Therapeutic Strategies (2025) · cites this paper as [6]
The Abstract reports 14.9% mean weight loss with semaglutide in STEP 1 at week 68, but the placebo-adjusted difference was 12.4 percentage points, not 14.9%. The STEP 4 result appears to be attributed to the sentence’s other citation; this paper reports STEP 1. (LLM, conf=0.91)
Experimental — accuracy not yet measuredSemaglutide peripherally slows gastric emptying and improves insulin secretion in a glucose-dependent manner, indirectly promoting weight loss.
“Peripherally, it slows gastric emptying and improves insulin secretion in a glucose-dependent manner, indirectly promoting weight loss [6].”
From Obesity: Clinical Impact, Pathophysiology, Complications, and Modern Innovations in Therapeutic Strategies (2025) · cites this paper as [6]
The Discussion reports weight loss with semaglutide and attributes it to reduced energy intake from decreased appetite, thought to involve effects on the brain. It does not state that slowed gastric emptying or glucose-dependent insulin secretion promotes that weight loss; gastric emptying appears only in a cited study’s title in the References. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIt is common in obesity pharmacotherapy trials that more people in the placebo group are lost to follow-up than in the active treatment group.
“It is common in obesity pharmacotherapy trials that more people in the placebo group are lost to follow-up than in the active treatment group.8,10,35”
From Healthy weight loss maintenance with exercise, GLP-1 receptor agonist, or both combined followed by one year without treatment: a post-treatment analysis of a randomised placebo-controlled trial (2024) · cites this paper as [8]
The Study Participants and Change in Body Weight sections report that 1212 of 1306 semaglutide participants and 577 of 655 placebo participants had week-68 body-weight data, indicating a higher proportion without that assessment in the placebo group. Missing an assessment is not necessarily being lost to follow-up, and this single trial does not establish that the pattern is common across obesity pharmacotherapy trials. The absolute number without an assessment was also higher in the semaglutide group. (LLM, conf=0.78)
Experimental — accuracy not yet measuredBimagrumab effects in patients with obesity are preferable to those of semaglutide because the fat loss is not associated with muscle atrophy, as is the case with semaglutide treatment.
“In an opinion in the Journal of Physiology [209], we have recently argued that the bimagrumab effects in patients with obesity are preferable to those of, e.g., semaglutide because the fat loss is not associated with muscle atrophy, as is the case with semaglutide treatment [210].”
From Effects of Skeletal Muscle Hypertrophy on Fat Mass and Glucose Homeostasis in Humans and Animals: A Narrative Review with Systematic Literature Search (2025) · cites this paper as [210]
The Change in Body Composition section (page not provided) reports that semaglutide reduced fat mass and that absolute lean body mass decreased in a 140-person DXA subpopulation. It does not establish muscle atrophy, and this trial does not compare semaglutide with bimagrumab. (LLM, conf=0.85)
Experimental — accuracy not yet measuredReal-world pancreatitis rates of approximately 4 to 8 per 1000 person-years with GLP-1RA are several fold higher than in the major weight loss RCTs of liraglutide.
“These real‐world pancreatitis rates of approximately 4 to 8 per 1000 person‐years with GLP‐1RA are several fold higher than in the major weight loss RCTs of liraglutide RCT. 17 , 18 , 19 , 26”
From Real‐world evidence on the utilization, clinical and comparative effectiveness, and adverse effects of newer <scp>GLP</scp> ‐ <scp>1RA</scp> ‐based weight‐loss therapies (2025) · cites this paper as [18]
Table 3 (section labeled “1000”; page not supplied) reports 0.2 acute-pancreatitis events per 100 person-years—about 2 per 1,000—in this weight-loss RCT. That supports a lower trial rate, but this was a semaglutide trial, not a liraglutide trial; the paper does not report the claimed real-world rates or make the stated comparison. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSemaglutide at a dose of 2.4 mg increases mean weight reduction to 15-20% in non-diabetic obese patients.
“the recently approved 2.4 mg dose of once-weekly GLP-1R agonist semaglutide (Wegovy) increases mean weight reduction in this population to 15–20% [[5], [6], [7], [8]]”
From Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice (2022) · cites this paper as [5]
The Abstract reports a mean weight reduction of 14.9% at week 68 with once-weekly 2.4 mg semaglutide plus lifestyle intervention in adults with overweight or obesity who did not have diabetes. That is approximately 15%, but the paper does not report a mean reduction as high as 20%; the Discussion says one third of treated participants lost at least 20%. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThere is observational data to infer an additive and possibly synergistic effect of exercise with GLP-1R agonism on weight loss.
“There is observational data to infer an additive and possibly synergistic effect of exercise with GLP-1R agonism on weight loss, suggesting non-anorectic mechanisms that are not well characterized [5,66].”
From Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice (2022) · cites this paper as [5]
The Procedures section (page not specified) says both trial groups received dietary counseling and were encouraged to increase physical activity. The Discussion reports greater weight loss with semaglutide plus lifestyle intervention than with placebo plus lifestyle intervention. The study was a randomized trial, not observational data, and did not isolate exercise or test whether its effect with semaglutide was additive or synergistic. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn three studies (n = 3375), semaglutide induced a greater improvement in health-related quality of life than placebo, evidenced by a higher SF-36 physical functioning score (MD 1.75 [95% CI 0.92, 2.58]; P < 0.0001).
“The findings from three studies (n = 3375) 16 -18 showed that semaglutide induced a more significant enhancement in health-related quality of life compared to placebo. This improvement was evidenced by the higher SF-36 physical functioning score (MD:1.75 [95% CI 0.92, 2.58]; P < 0.0001 [Figure S11]).”
From Efficacy and safety of semaglutide 2.4 mg for weight loss in overweight or obese adults without diabetes: An updated systematic review and meta‐analysis including the 2‐year <scp>STEP</scp> 5 trial (2024) · cites this paper as [16]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn four studies (n = 3087), semaglutide led to a greater percentage of trial discontinuations due to gastrointestinal adverse events relative to placebo (RR 5.36 [95% CI 2.49, 11.55]; P < 0.0001).
“Furthermore, four studies (n = 3087) 16,17,19,20 revealed that semaglutide led to a greater percentage of trial discontinuations due to GI AEs relative to placebo (RR 5.36, [95% CI 2.49, 11.55]; P < 0.0001 [Figure S16]).”
From Efficacy and safety of semaglutide 2.4 mg for weight loss in overweight or obese adults without diabetes: An updated systematic review and meta‐analysis including the 2‐year <scp>STEP</scp> 5 trial (2024) · cites this paper as [16]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn four studies (n = 3087), semaglutide caused a significant reduction in CRP compared with placebo (MD 38.92% [95% CI 43.69, 34.16]; P < 0.00001).
“Four studies (n = 3087) 16,17,19,20 reported a modification in levels of CRP, an indicator of inflammation. Evaluation of the combined analysis showed that semaglutide caused a significant reduction in CRP compared to placebo (MD: 38.92% [95% CI 43.69, 34.16]; P < 0.00001)”
From Efficacy and safety of semaglutide 2.4 mg for weight loss in overweight or obese adults without diabetes: An updated systematic review and meta‐analysis including the 2‐year <scp>STEP</scp> 5 trial (2024) · cites this paper as [16]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThe approval of semaglutide for weight management was based on the STEP clinical trial programme, which demonstrated significant weight reduction, improvement of cardiometabolic factors, and positive patient-reported outcomes.
“This approval was based on the Semaglutide Treatment Effect in People with Obesity (STEP) clinical trial programme, which demonstrated significant weight reduction, improvement of cardiometabolic factors, and positive patient-reported outcomes. 16 -20”
From Efficacy and safety of semaglutide 2.4 mg for weight loss in overweight or obese adults without diabetes: An updated systematic review and meta‐analysis including the 2‐year <scp>STEP</scp> 5 trial (2024) · cites this paper as [16]
The introduction (p. 990) identifies this study as part of the STEP programme, and the Discussion reports substantial weight loss, improved cardiometabolic risk factors, and improved participant-reported physical functioning. This paper reports one STEP trial; it does not establish that semaglutide’s weight-management approval was based on the programme. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSemaglutide groups demonstrated a significant reduction in weight at the end of the treatment period for various steps: 14.9% for STEP 1, 16% for STEP 3, 17.4% for STEP 4, 15.2% for STEP 5, and 15.8% for STEP 8.
“the semaglutide groups demonstrated a significant reduction in weight at the end of the treatment period for various steps, namely, 14.9% for STEP 1, 16% for STEP 3, 17.4% for STEP 4, 15.2% for STEP 5, and 15.8% for STEP 8.”
From Efficacy and safety of semaglutide 2.4 mg for weight loss in overweight or obese adults without diabetes: An updated systematic review and meta‐analysis including the 2‐year <scp>STEP</scp> 5 trial (2024) · cites this paper as [16]
The Abstract and Change in Body Weight section report a 14.9% mean weight reduction at week 68 for STEP 1, significantly greater than placebo. This paper reports the STEP 1 trial; our copy does not provide the claimed results for STEP 3, STEP 4, STEP 5, or STEP 8. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe safety profile of AMG 133 was similar to that of GLP-1RAs, including unimolecular GLP-1/GIPR agonist peptides.
“The safety profile of AMG 133 was similar to that of GLP-1RAs, including unimolecular GLP-1/GIPR agonist peptides6,7.”
From A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings (2024) · cites this paper as [6]
The Safety and Side-Effect Profile section reports adverse events for semaglutide, a GLP-1 receptor agonist, and the discussion (p. 1000) describes its safety findings as consistent with the GLP-1 receptor agonist class. The paper does not assess AMG 133 or unimolecular GLP-1/GIPR agonist peptides, so it cannot establish the claimed similarity for those treatments. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThis result is in contrast to observations with GLP-1 RAs, for which increased glucose tolerance and weight loss are observed in adults with obesity following treatment.
“This result is in contrast to observations with GLP-1 RAs, for which increased glucose tolerance and weight loss are observed in adults with obesity following treatment [15].”
From Results from three phase 1 trials of NNC9204-1177, a glucagon/GLP-1 receptor co-agonist: Effects on weight loss and safety in adults with overweight or obesity (2023) · cites this paper as [15]
The Change in Body Weight section reports substantially greater weight loss with semaglutide than with placebo. The Other Confirmatory and Supportive Secondary End Points and Exploratory End Points sections report improved glycated hemoglobin and fasting glucose, and more reversion from prediabetes to normoglycemia. These support improved glucose regulation, but the paper does not report a direct measure of glucose tolerance; it also studies semaglutide rather than GLP-1 receptor agonists as a class. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn the STEP 1 DXA subset, 95 participants treated with semaglutide lost 6.9 kg (~13%) lean soft tissue alongside 10.4 kg (~25%) fat mass, corresponding to ~40% of weight loss as lean soft tissue.
“In the STEP 1 trial, 95 participants treated with semaglutide in the DXA subset lost 6.9 kg (~13%) LST alongside 10.4 kg (~25%) FM, 2 corresponding to ~40% of weight loss as LST.”
From Preservation of lean soft tissue during weight loss induced by GLP-1 and GLP-1/GIP receptor agonists: A case series (2025) · cites this paper as [2]
The Change in Body Composition section reports that fat mass and lean body mass decreased with semaglutide in the DXA subpopulation, and the Discussion says the reduction in fat mass was greater. Our copy does not give the claimed 95-person treatment-group count, the 6.9 kg and 10.4 kg losses, their percentages, or the estimate that lean soft tissue made up about 40% of weight loss. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn recent trials, lean soft tissue loss comprised 26%-40% of weight loss during treatment with GLP-1 receptor agonists and dual GLP-1/GIP receptor agonists.
“though lean soft tissue loss comprised 26%–40% of weight loss in recent trials”
From Preservation of lean soft tissue during weight loss induced by GLP-1 and GLP-1/GIP receptor agonists: A case series (2025) · cites this paper as [2]
The Change in Body Composition section reports that lean body mass decreased in the semaglutide DXA subpopulation, supporting lean-mass loss during treatment. Our copy does not give the claimed 26%–40% share of weight loss or report a trial of a dual GLP-1/GIP receptor agonist. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSeveral RCTs have demonstrated a significantly higher prevalence of gallbladder disorders among patients treated with GLP-1 RAs compared to placebo.
“Several RCTs have demonstrated a significantly higher prevalence of gallbladder disorders among patients treated with GLP-1 RAs compared to placebo [29-32], as initially evidenced by the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, which reported acute gallstone disease rates of 3.1% in the liraglutide group versus 1.9% in the placebo”
From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [32]
The Safety and Side-Effect Profile reports gallbladder-related disorders in 2.6% of semaglutide participants versus 1.2% of placebo participants, and the Discussion says they were more common with semaglutide. This RCT therefore supports the higher prevalence, but our copy does not report a statistical-significance test for that difference. As one of several cited RCTs, it need not establish the claim about several trials by itself. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSemaglutide and tirzepatide are highly effective for weight reduction.
“clinical trials showed that semaglutide and tirzepatide were highly effective for weight reduction”
From Strategies for minimizing muscle loss during use of incretin‐mimetic drugs for treatment of obesity (2025) · cites this paper as [1]
The Discussion reports a mean weight loss of 14.9% with semaglutide, exceeding placebo plus lifestyle intervention by 12.4 percentage points. The paper does not report a trial or weight-loss finding for tirzepatide, so it supports only the semaglutide part of the claim. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIn phase 3 trials, women aged 65 years and older achieved sustained weight loss of 10-20%, with consistent cardiometabolic improvements.
“In phase 3 trials, women aged ≥ 65 years achieved sustained weight loss of 10–20%, with consistent cardiometabolic improvements.”
From A Narrative Review on GLP-1 Receptor Agonists for Obesity in Older Women: Maximizing Weight Loss While Preserving Lean Mass (2026) · cites this paper as [35]
The Change in Body Weight and Other Confirmatory and Supportive Secondary End Points sections report substantial weight loss through week 68 and improvements in cardiometabolic measures for the trial population overall. The Study Participants section says most participants were female but gives a mean age of 46; the cited results do not establish these outcomes specifically for women aged 65 or older. This paper also reports one trial, not multiple phase 3 trials. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn STEP trials, improvements in HbA1c, blood pressure, and lipid profiles in older women were significant despite attenuation of weight loss.
“Despite this attenuation, the improvements observed in metabolic parameters, such as HbA1c (glycated hemoglobin), blood pressure, and lipid profiles, were significant.”
From A Narrative Review on GLP-1 Receptor Agonists for Obesity in Older Women: Maximizing Weight Loss While Preserving Lean Mass (2026) · cites this paper as [35]
The Other Confirmatory and Supportive Secondary End Points section reports improvements in blood pressure, glycated hemoglobin, and fasting lipids with semaglutide; Table 2 reports a significant systolic blood-pressure difference and estimates favoring semaglutide for the other measures. These are results for the overall trial population, not specifically older women. The cited passages do not establish that the improvements persisted despite attenuated weight loss in that group. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn STEP 1 and STEP 5 subanalyses, women aged 65 years and older experienced significant reductions in body weight comparable to younger cohorts.
“In both trials, subanalyses specifically focusing on women aged 65 years and older showed that these individuals experienced significant reductions in body weight, comparable to those seen in younger cohorts.”
From A Narrative Review on GLP-1 Receptor Agonists for Obesity in Older Women: Maximizing Weight Loss While Preserving Lean Mass (2026) · cites this paper as [35]
The Change in Body Weight section reports significant weight loss for STEP 1 participants overall, and Study Participants says most were women. Neither section reports a subanalysis of women aged 65 or older or compares their results with younger cohorts. This paper describes one trial, not STEP 5; the copy provides no STEP 5 subanalysis. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe STEP program for semaglutide and the SURMOUNT trials for tirzepatide offer critical insights into the benefits of these therapies in older populations.
“Two major trial programs, the STEP program for semaglutide [35,36,37,38,39] and the SURMOUNT trials [40,41,42,43] for tirzepatide, offer critical insights into the benefits of these therapies in older populations.”
From A Narrative Review on GLP-1 Receptor Agonists for Obesity in Older Women: Maximizing Weight Loss While Preserving Lean Mass (2026) · cites this paper as [35]
The introduction (p. 990) identifies this trial as part of the STEP program, and the results report benefits of semaglutide in adults with overweight or obesity. But the Study Participants section reports a mean age of 46 years, and the cited trial does not establish benefits specifically in older populations. The separate SURMOUNT citations are not assessed here. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn women aged 65 years and older in the STEP trials, average weight loss ranged from 10-15%, with slight attenuation in participants aged over 70 years.
“On average, weight loss in this age group ranged from 10–15%, with a slight attenuation of this effect in participants aged over 70 years.”
From A Narrative Review on GLP-1 Receptor Agonists for Obesity in Older Women: Maximizing Weight Loss While Preserving Lean Mass (2026) · cites this paper as [35]
The Abstract reports mean weight loss of 14.9% with semaglutide, within the claimed range, but for the trial population overall. The Study Participants section (p. 993) reports sex and age separately; our copy does not report average weight loss for women aged 65 or older or attenuation above age 70. This paper reports STEP 1, not a pooled result across STEP trials. (LLM, conf=0.86)
Experimental — accuracy not yet measuredGLP-1 receptor agonists have demonstrated sustained, clinically significant body weight reductions in patients with T2DM and obesity.
“In particular, glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1ra) has demonstrated sustained, clinically significant body weight reductions in patients with T2DM and obesity (1–3).”
From Transforming body composition with semaglutide in adults with obesity and type 2 diabetes mellitus (2024) · cites this paper as [1]
The Change in Body Weight and Discussion sections report substantial, clinically meaningful weight loss with semaglutide at week 68 in adults with overweight or obesity. But the Participants section says diabetes was an exclusion criterion, so this trial does not establish sustained, clinically significant reductions in patients with T2DM. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIn STEP-1 (semaglutide), lean mass decreased by ~9.7% while fat mass fell by ~19.3%, with the proportion of lean mass increasing by ~3 percentage points.
“In STEP-1 (semaglutide), lean mass decreased by ~9.7% while fat mass fell by ~19.3%, with the proportion of lean mass increasing by ~3 percentage points (35).”
From GLP-1 agonists and exercise: the future of lifestyle prioritization (2025) · cites this paper as [35]
The Change in Body Composition section reports that fat mass and lean body mass decreased in the STEP-1 DXA subpopulation, while lean mass increased as a proportion of total body mass. Our copy does not give the claimed 9.7% and 19.3% decreases or the approximately 3-percentage-point increase, so those magnitudes are not verified. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe results obtained with retatrutide suggest potential superiority over semaglutide and tirzepatide regarding the magnitude of weight loss, possibly due to the additional activation of glucagon receptors and consequent increase in energy expenditure.
“Although both represent important therapeutic advances, the results obtained with retatrutide suggest potential superiority regarding the magnitude of weight loss, possibly as a result of the additional activation of the glucagon receptors and the consequent increase in energy expenditure”
From RETATRUTIDE USE IN THE TREATMENT OF METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE (MASLD) AND OBESITY: AN INTEGRATIVE REVIEW (2026) · cites this paper as WILDING et al., 2021
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredStudies with semaglutide showed relevant weight losses accompanied by consistent metabolic benefits, and in patients with steatohepatitis a significant increase in the rates of resolution of liver disease.
“Studies conducted with semaglutide showed relevant weight losses, accompanied by consistent metabolic benefits, while investigations in patients with steatohepatitis demonstrated a significant increase in the rates of resolution of liver disease”
From RETATRUTIDE USE IN THE TREATMENT OF METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE (MASLD) AND OBESITY: AN INTEGRATIVE REVIEW (2026) · cites this paper as WILDING et al., 2021
The Discussion reports substantial weight loss with semaglutide and greater improvements than placebo in cardiometabolic risk factors. The paper does not report a study in patients with steatohepatitis or an increased rate of liver-disease resolution, so it does not support that part of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGLP-1RAs were originally approved for diabetes treatment with the notable side effect of pronounced weight loss.
“Glucagon like peptide-1 receptor agonists (GLP-1RA) are a class of medications that were originally approved for diabetes treatment with the notable side effect of pronounced weight loss.23–25”
From The Effect of Semaglutide and GLP-1 RAs on Risk of Nonarteritic Anterior Ischemic Optic Neuropathy (2025) · cites this paper as [25]
The introduction (p. 990) says semaglutide was approved to treat type 2 diabetes and had induced weight loss in people with diabetes. It does not establish that GLP-1 receptor agonists as a class were originally approved for diabetes, or characterize weight loss as a side effect. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBody composition was assessed using DXA, which is the gold standard for this purpose.
“Body composition was assessed using DXA, which is the gold standard for this purpose.”
From Impact of Semaglutide on fat mass, lean mass and muscle function in patients with obesity: The <scp>SEMALEAN</scp> study (2026) · cites this paper as [6]
The Participants and End Points and Assessments sections (page not specified) state that a subpopulation underwent DXA to assess body composition. The paper does not describe DXA as the gold standard, so that part of the claim is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSemaglutide restores normoglycemia and reduces progression to type 2 diabetes in people with obesity and prediabetes.
“In STEP 1, semaglutide 2.4 mg OW led to 10–15% Weight loss and restoration of normoglycemia in 84.1% of prediabetic participants over 68 weeks [3].”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [3]
The Exploratory End Points section reports that 84.1% of semaglutide-treated participants with prediabetes reverted to normoglycemia at week 68, and the Discussion reports a mean weight loss of 14.9%. These findings support the cited sentence, but the supplied paraphrase adds reduced progression to type 2 diabetes, which the passages do not establish. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn STEP 1, ~13.6% of participants on semaglutide 2.4 mg did not meet the <5% total body weight loss threshold at 12-16 weeks despite adherence at week 68.
“In STEP 1, ~ 13.6% of participants on semaglutide 2.4 mg did not meet this threshold despite adherence at week 68 [3].”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [3]
The Change in Body Weight section (page not provided) reports that 86.4% of semaglutide participants with week-68 data lost at least 5%, so 13.6% did not. But this percentage includes participants regardless of treatment discontinuation; it does not establish that the 13.6% were adherent, nor does it describe their response at 12–16 weeks. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIn STEP 1, up to 74% of participants reported nausea with semaglutide 2.4 mg, yet discontinuation for GI reasons was relatively low (4.5%).
“In STEP 1, up to 74% of participants reported nausea with semaglutide 2.4 mg, yet discontinuation for GI reasons was relatively low (4.5%) [3].”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [3]
Table 3 (p. 1000) reports nausea in 44.2% of semaglutide participants, not 74%; the Safety and Side-Effect Profile identifies 74.2% as the rate for gastrointestinal disorders overall. Table 3 also confirms that 4.5% discontinued treatment because of gastrointestinal disorders. (LLM, conf=0.91)
Experimental — accuracy not yet measuredNew and emerging highly effective obesity management medications such as tirzepatide and semaglutide have contributed to major shifts in obesity care, with meaningful reductions in cardiovascular-related endpoints.
“New and emerging highly effective OMMs, such as tirzepatide and semaglutide, have contributed to major shifts in the practice of obesity care,7 with meaningful reductions in cardiovascular-related endpoints.8–11”
From Tirzepatide compared with semaglutide and 10-year cardiovascular disease risk reduction in obesity: <i>post-hoc</i> analysis of the SURMOUNT-5 trial (2025) · cites this paper as [8]
The Discussion reports substantial weight loss with semaglutide and improvements in cardiometabolic risk factors, including blood pressure and lipid levels. The Other Confirmatory and Supportive Secondary End Points section likewise reports reductions in blood pressure, but this trial did not establish reductions in clinical cardiovascular events; the Discussion says a cardiovascular outcomes trial was ongoing. The paper does not study tirzepatide. (LLM, conf=0.85)
Experimental — accuracy not yet measuredGLP-1s reduce body weight by 5% to 18% in trials, with modestly lower effects in real-world analyses.
“GLP‐1s reduce body weight by 5% to 18% in trials, with modestly lower effects in real‐world analyses, and multiple demonstrated clinical benefits.”
From Nutritional priorities to support <scp>GLP</scp> ‐1 therapy for obesity: A joint Advisory from the American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine Association, and The Obesity Society (2025) · cites this paper as [14]
The Results report 14.9% mean weight loss with semaglutide in a clinical trial, and the Discussion cites a 4.5% placebo-corrected reduction in a liraglutide trial. These passages support trial-based weight loss, but the paper does not establish a 5%–18% range for GLP-1s or compare trial results with real-world analyses. Page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredWeight reduction with GLP-1s is more rapid during the first 6 months and slows thereafter, with relative plateauing at 18 months.
“Generally, weight reduction is more rapid during the first 6 months and slows thereafter, with relative plateauing at 18 months [13, 14, 15].”
From Nutritional priorities to support <scp>GLP</scp> ‐1 therapy for obesity: A joint Advisory from the American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine Association, and The Obesity Society (2025) · cites this paper as [14]
The Change in Body Weight section reports that weight loss with semaglutide began by week 4 and reached its nadir at week 60, supporting a later leveling-off. It does not establish that loss was more rapid specifically during the first six months, and the trial’s weight outcomes end at week 68, before the claimed 18-month plateau. The finding also concerns semaglutide rather than GLP-1 drugs generally. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn the STEP 1 trial, of the average 13.6-kg weight reduction, 8.3 kg (62%) was fat mass and 5.3 kg (38%) was lean body mass.
“In the STEP 1 trial, of the average 13.6‐kg–weight reduction, 8.3 kg (62%) was fat mass and 5.3 kg (38%) was lean body mass (including muscle and other nonfat tissues) [14].”
From Nutritional priorities to support <scp>GLP</scp> ‐1 therapy for obesity: A joint Advisory from the American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine Association, and The Obesity Society (2025) · cites this paper as [14]
The Change in Body Composition section reports that fat mass and lean body mass decreased in the 140-participant DXA subgroup, supporting the claimed direction of change. Our copy does not give the claimed 13.6-kg total or the 8.3-kg/5.3-kg breakdown and percentages; the Change in Body Weight section instead reports a 15.3-kg mean reduction for the semaglutide group overall. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn the STEP 1 trial, semaglutide with general nutrition and physical activity instructions demonstrated a 14.9% weight reduction from baseline (vs. 2.4% with general nutrition and physical activity instructions alone).
“In comparison, the STEP 1 trial that included semaglutide with general nutrition and physical activity instructions demonstrated a 14.9% weight reduction from baseline (vs. 2.4% with general nutrition and physical activity instructions alone) [14].”
From Nutritional priorities to support <scp>GLP</scp> ‐1 therapy for obesity: A joint Advisory from the American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine Association, and The Obesity Society (2025) · cites this paper as [14]
The Abstract reports 14.9% mean weight loss with semaglutide versus 2.4% with placebo at week 68. However, the Procedures describe both groups receiving individual counseling every four weeks, a specified reduced-calorie diet, and encouragement to increase physical activity; the comparison was not with general instructions alone, and the control group also received placebo. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAlthough limited direct evidence has evaluated use of GLP-1s with or without RDN-provided MNT, the SCALE, STEP 1, SURMOUNT, and STEP 3 trials each demonstrated substantial weight reduction by combining GLP-1s with regular counseling sessions by RDNs or other qualified healthcare professionals.
“Although limited direct evidence has evaluated use of GLP‐1s with or without RDN‐provided MNT, the SCALE [13], STEP 1 [14], SURMOUNT [15], and STEP 3 [178] trials each demonstrated substantial weight reduction by combining GLP‐1s with regular counseling sessions by RDNs or other qualified healthcare professionals”
From Nutritional priorities to support <scp>GLP</scp> ‐1 therapy for obesity: A joint Advisory from the American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine Association, and The Obesity Society (2025) · cites this paper as [14]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredWeight loss of 15% or greater can lead to substantial clinical improvements, such as remission of T2D and significant reductions in cardiovascular risk factors.
“Weight loss of 15% or greater can lead to substantial clinical improvements, such as remission of T2D and significant reductions in cardiovascular risk factors [24]”
From Impact of Digital Engagement on Weight Loss Outcomes in Obesity Management Among Individuals Using GLP-1 and Dual GLP-1/GIP Receptor Agonist Therapy: Retrospective Cohort Service Evaluation Study (2025) · cites this paper as [24]
The Discussion reports that weight loss with semaglutide was accompanied by improvements in cardiometabolic risk factors, and that approximately half of treated participants lost at least 15% of their weight. But the Participants section says diabetes was an exclusion criterion, so the trial does not support the claim about type 2 diabetes remission. It also does not establish that the risk-factor improvements occurred specifically among those who lost at least 15%. (LLM, conf=0.89)
Experimental — accuracy not yet measuredLong-term adherence to obesity medications in a real-world setting is challenging because the medications are expensive and gastrointestinal adverse events are common.
“Despite the large weight losses with obesity medications, long-term adherence in a real-world setting is challenging since the medications are expensive and gastrointestinal adverse events are common.8,10,11”
From Healthy weight loss maintenance with exercise, GLP-1 receptor agonist, or both combined followed by one year without treatment: a post-treatment analysis of a randomised placebo-controlled trial (2024) · cites this paper as [8]
The introduction (p. 990) says cost limits use of available obesity medications, and the discussion (p. 1000) reports frequent gastrointestinal adverse events and some discontinuations after them. But this was a clinical trial with high adherence and a relatively short duration; it does not establish that cost and adverse events make long-term adherence difficult in real-world settings. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMost patients taking a GLP-1 receptor agonist achieve clinically meaningful weight loss.
“Although most patients taking a GLP-1 RA achieve clinically meaningful weight loss, heterogeneity in response exists.3,4,5,6,7,12”
From Discontinuation and Reinitiation of Dual-Labeled GLP-1 Receptor Agonists Among US Adults With Overweight or Obesity (2025) · cites this paper as [6]
The Discussion (p. 1000) reports that 86% of participants receiving semaglutide attained at least 5% weight loss. This supports the claim for once-weekly semaglutide plus lifestyle intervention in adults with overweight or obesity without diabetes, but the trial does not establish that most patients taking any GLP-1 receptor agonist achieve clinically meaningful weight loss. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMore than 70% of patients in clinical trials of GLP-1 receptor agonists reported adverse events, most often gastrointestinal, that were mild.
“More than 70% of patients in clinical trials of GLP-1 RAs reported adverse events, most often gastrointestinal (GI), that were mild.3,4,5,6,7”
From Discontinuation and Reinitiation of Dual-Labeled GLP-1 Receptor Agonists Among US Adults With Overweight or Obesity (2025) · cites this paper as [6]
The Safety and Side-Effect Profile reports adverse events in 89.7% of semaglutide recipients and identifies gastrointestinal events as the most frequent. It describes most gastrointestinal events as mild-to-moderate, not simply mild. These figures come from this semaglutide trial, rather than clinical trials of GLP-1 receptor agonists generally. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe health benefits seen with continued treatment with the maximum tolerated dose of tirzepatide during this study were achieved with a safety profile consistent with that previously reported in SURMOUNT and SURPASS trials and in studies of incretin-based therapies approved for the treatment of obesity and overweight.
“The health benefits seen with continued treatment with the maximum tolerated dose of tirzepatide during this study were achieved with a safety profile consistent with that previously reported in SURMOUNT and SURPASS trials and in studies of incretin-based therapies approved for the treatment of obesity and overweight.18,25,26,27,28,29,30,31,32”
From Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial (2024) · cites this paper as [30]
Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredMany randomized controlled trials included relatively few people from racial and ethnic minority groups and relatively small proportions of men.
“Third, many RCTs included relatively few people from racial and ethnic minority groups and relatively small proportions of men.81,99”
From Obesity Management in Adults (2023) · cites this paper as [81]
The Study Participants section reports that 74.1% of this trial’s participants were female and 75.1% were White. The discussion (p. 1000) explicitly identifies the preponderance of women and White participants as a limitation. This supports the claim for this RCT, but the paper does not establish that many RCTs had similar participant proportions. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPivotal randomized trials of GLP-1 RAs for obesity (STEP, SURMOUNT, SCALE) all incorporated intensive lifestyle interventions modeled on Diabetes Prevention Program-style curricula, and the magnitude of weight loss in the control arms confirms that structured lifestyle support produces clinically meaningful effects in this population even without GLP-1 RA therapy.
“pivotal randomized trials of GLP-1 RAs for obesity (STEP, SURMOUNT, SCALE) all incorporated intensive lifestyle interventions modeled on Diabetes Prevention Program-style curricula, and the magnitude of weight loss in the control arms of these trials confirms that structured lifestyle support produces clinically meaningful effects in this population even without GLP-1 RA therapy [9,13,76,77].”
From Adherence and Persistence with GLP-1-Based Therapies: International Real-World Evidence and the Role of Nutritional and Lifestyle Support—A Narrative Review (2026) · cites this paper as [9]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThe most successful weight-loss trials to date-including the STEP program for semaglutide and the SURMOUNT program for tirzepatide-have incorporated intensive lifestyle interventions as a core component of the trial protocol, modeled on the structured behavioral curricula pioneered by the Diabetes Prevention Program.
“The most successful weight-loss trials to date—including the STEP program for semaglutide [9] and the SURMOUNT program for tirzepatide [13]—have incorporated intensive lifestyle interventions as a core component of the trial protocol, modeled on the structured behavioral curricula pioneered by the Diabetes Prevention Program (DPP) [76,77].”
From Adherence and Persistence with GLP-1-Based Therapies: International Real-World Evidence and the Role of Nutritional and Lifestyle Support—A Narrative Review (2026) · cites this paper as [9]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredSemaglutide is superior to other GLP-1 receptor agonists for weight loss.
“noted superiority over other GLP-1RAs.”
From Semaglutide for the treatment of antipsychotic-associated weight gain in patients not responding to metformin – a case series (2023) · cites this paper as [31]
The Discussion reports greater placebo-corrected weight loss with semaglutide than was reported with liraglutide, another GLP-1 receptor agonist. It cautions that differences between the studies limit the comparison. It does not establish superiority over GLP-1 receptor agonists as a group. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSemaglutide has shown a placebo-subtracted weight loss of -12.7 kg versus -5.6 kg for liraglutide after 68 weeks.
“Regarding the subcutaneous treatments, the EMP for semaglutide was similar to liraglutide, whereas semaglutide has been shown to be more than twice as effective, with a PSWL of À12.7 kg versus À5.6 kg respectively, although this was after a longer treatment course of 68 weeks [10,24,25].”
From Estimated minimum prices and lowest available national prices for antiobesity medications: Improving affordability and access to treatment (2023) · cites this paper as [24]
The Change in Body Weight section reports a placebo-adjusted difference of −12.7 kg for semaglutide at week 68. The Discussion compares this trial with a 56-week liraglutide trial using percentage reductions, not the claimed −5.6 kg figure, and cautions that differences between the study populations limit the comparison. (LLM, conf=0.88)
Experimental — accuracy not yet measuredResults from the STEP 1 trial of semaglutide suggested that 40% of total weight loss was derived from lean mass.
“Results from the STEP 1 trial of semaglutide suggested that 40% of total weight loss was derived from lean mass.42”
From Effectiveness and safety of drugs for obesity (2024) · cites this paper as [42]
The Change in Body Composition section reports that lean body mass decreased in the STEP 1 DXA subpopulation, supporting the claim that some weight loss came from lean mass. Neither that section nor the Discussion gives a 40% share of total weight loss, so the cited paper does not support the claimed proportion. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPharmacologically assisted weight loss with GLP-1RAs and dual GLP-1R/GIPR agonists is approaching magnitudes close to that achieved with bariatric surgery.
“Recent studies have shown that pharmacologically assisted weight loss with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucagon-like peptide-1 receptor (GLP-1R)/ glucose-dependent insulinotropic polypeptide receptor agonists (GIP-RAs) is approaching magnitudes close to that achieved with bariatric surgery.1,39,92”
From Changes in lean body mass with <scp>glucagon‐like peptide</scp> ‐1‐based therapies and mitigation strategies (2024) · cites this paper as [1]
The Discussion (page not provided) says that one third of participants receiving semaglutide lost at least 20% of baseline weight, approaching the 20–30% reported after bariatric surgery. This supports the comparison for semaglutide, a GLP-1 receptor agonist, but the paper does not address dual GLP-1R/GIPR agonists. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIn STEP-1, lean mass was reduced by -6.92 kg or -13.2%, with weight reduction of -15.3 kg or -14.9%, yielding a fraction of weight lost from lean mass of 45.2%.
“In the STEP-1 trial of semaglutide, lean mass was reduced by À6.92 kg or À 13.2%, with a weight reduction of À15.3 kg or À14.9%, yielding a fraction of weight lost from lean mass of 45.2%. 1”
From Changes in lean body mass with <scp>glucagon‐like peptide</scp> ‐1‐based therapies and mitigation strategies (2024) · cites this paper as [1]
The Change in Body Weight section reports a −15.3 kg (−14.9%) change with semaglutide. The Change in Body Composition section says lean body mass decreased in the DXA subpopulation, but our copy does not give the claimed −6.92 kg, −13.2%, or 45.2% fraction. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMany patients treated with GLP-1RAs achieve clinically meaningful weight loss and improvements in cardiometabolic health.
“Many patients treated with GLP-1RAs achieve clinically meaningful weight loss while simultaneously demonstrating improvements in cardiometabolic health.45,46”
From Receipt of Glucagon-Like Peptide-1 Receptor Agonists Among Rural Patients with Obstructive Sleep Apnea and Excess Weight (2026) · cites this paper as [45]
Weekly semaglutide in a randomized controlled trial showed a 14.9% decrease in body weight after 68 weeks.
“an RCT involving the weekly semaglutide showed a 14.9% decrease in body weight after treatment for 68 weeks (42).”
From The Benefits of Exercise Training in Combination With Weight Loss Therapies (2025) · cites this paper as [42]
Two articles reported lean mass results for a subset rather than the full parent-trial sample.
“with two articles presenting LM outcomes in only a subset of participants from the parent trial (6, 7).”
The treatment effect on total body mass was nearly two times greater in trials using GLP1Ra-based therapies at doses indicated primarily for chronic weight management than in trials using doses indicated primarily for diabetes management: -10.2 kg versus -5.5 kg.
“However, the magnitude of the treatment effect on total body mass was nearly two times greater in trials using GLP1Ra-based therapies at dosages indicated primarily for chronic weight management (6, 7, 18, 21, 24) as compared to trials using dosages indicated primarily for diabetes management (17, 19, 20, 22): −10.2 kg (−16.3, −3.9) versus −5.5 kg (−8.7, −2.1), respectively.”
In a 68-week trial, semaglutide 2.4 mg reduced body weight by 14.9% (15.3 kg) versus 2.4% (2.6 kg) with placebo in middle-aged adults with overweight or obesity.
“A subsequent 68-week intervention in middle-aged adults with overweight or obesity using semaglutide (Sema) (2.4 mg) reduced body weight by 14.9% (À15.3 kg) versus 2.4% (À2.6 kg) in the placebo group (17).”
From Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition? (2024) · cites this paper as [17]
These safety findings are similar to those reported for therapies based on GLP-1 or GIP/GLP-1 agonism for the treatment of type 2 diabetes or obesity.
“These safety findings are similar to those reported for therapies based on GLP-1 or GIP/GLP-1 agonism for the treatment of type 2 diabetes or obesity41–45.”
From Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial (2024) · cites this paper as [43]
Although no head-to-head trial data exist, phase 2 data suggest that at higher doses retatrutide could lead to greater weight loss compared to the most efficacious approved treatments for obesity and type 2 diabetes such as tirzepatide 15 mg and semaglutide 2.4 mg.
“Although no data from head-to-head trials comparing retatrutide to other currently approved obesity treatments exist, data from the phase 2 studies with retatrutide suggest that at higher doses, retatrutide could lead to greater WL compared to the most efficacious approved treatments for obesity and T2D such as tirzepatide 15 mg and semaglutide 2.4 mg (Fig. 3) [8, 27, 45, 46, 49, 50].”
From Triple Agonism Based Therapies for Obesity (2025) · cites this paper as [8]
Nearly 50% of the retatrutide phase 2 obesity trial were men, which is higher than in phase 3 clinical trials with tirzepatide (32.5% in SURMOUNT-1) and semaglutide 2.4 mg (25.9% in STEP-1).
“Notably, nearly 50% of the retatrutide phase 2 obesity trial were men, which is higher than in phase 3 clinical trials with tirzepatide (32.5% in SURMOUNT-1 [27]) and semaglutide 2.4 mg (25.9% in STEP-1 [8]).”
From Triple Agonism Based Therapies for Obesity (2025) · cites this paper as [8]
In adults with overweight or obesity without diabetes, semaglutide produced 14.9% weight loss versus 2.4% with placebo in STEP 1.
“However, the weight loss was less pronounced than the 14.9% weight loss (vs. 2.4% with placebo) seen in the STEP 1 trial in adults with overweight or obesity without diabetes (129).”
The percentages of participants who experienced adverse events leading to treatment discontinuation and gastrointestinal adverse events with oral semaglutide 50 mg were similar to those observed with subcutaneous semaglutide 2.4 mg.
“The percentages of participants who experienced AE leading to treatment discontinuation as well as of those who experienced gastrointestinal AE with oral semaglutide 50 mg (Tables 2 and 3) were similar to those observed with subcutaneous semaglutide 2.4 mg (in STEP-1 and STEP-2 trials 6–7% discontinued treatment due to AE, 34–44% experienced nausea, 21–32% diarrhoea and 22–25% vomiting) [11, 29].”
From What is the pipeline for future medications for obesity? (2025) · cites this paper as [11]
In STEP 1, semaglutide produced mean weight reduction from baseline to week 68 of −14.9% versus −2.4% for placebo.
“Semaglutide, a glucagon-like peptide receptor agonist (GLP- 1 RA), was shown in STEP 1 to produce mean weight reduction from baseline to week 68 of − 14.9% for semaglutide versus − 2.4% for placebo, by treatment-policy or treatment-regimen estimand which is reported throughout this manuscript, except where noted [1].”
From New drugs for the treatment of obesity: do we need approaches to preserve muscle mass? (2025) · cites this paper as [1]
Semaglutide at a dose of 2.4 mg has previously been shown to produce major weight loss in persons with overweight or obesity and to have favorable effects on cardiometabolic risk factors.
“has previously been shown to produce major weight loss in persons with overweight or obesity and to have favorable effects on cardiometabolic risk factors. 13,14”
From Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity (2023) · cites this paper as [13]
Semaglutide 2.4 mg has shown greater effectiveness compared to earlier anti-obesity medications.
“Semaglutide 2.4 mg, a recently approved selective GLP-1RA for long-term weight management in obese adults, has shown greater effectiveness compared to these earlier AOMs [27].”
The safety profile observed was consistent with findings from other incretin-based therapies, particularly similar to the safety profile of GLP-1 receptor agonists like liraglutide and semaglutide used for obesity treatment.
“The safety profile observed was consistent with findings from other incretin-based therapies, particularly similar to the safety profile of GLP-1RA like liraglutide and semaglutide used for obesity treatment [27, 42].”
GLP-1 receptor agonists such as semaglutide and tirzepatide demonstrated unprecedented efficacy in clinical trials.
“Recent advancements in obesity pharmacotherapy, particularly glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide, tirzepatide), revolutionized treatment paradigms, demonstrating unprecedented efficacy in clinical trials [6,7].”
From Obesity: Clinical Impact, Pathophysiology, Complications, and Modern Innovations in Therapeutic Strategies (2025) · cites this paper as [6]
The total weight reduction was approximately similar to the 15% weight loss observed after 68 weeks of treatment with semaglutide 2.4 mg once weekly as an adjunct to lifestyle change.
“The total weight reduction was approximately similar to the 15% weight loss that was observed after 68 weeks of treatment with the GLP-1 receptor agonist semaglutide, administered subcutaneously at a dose of 2.4 mg once weekly as an adjunct to lifestyle change (currently not approved by any governmental medical agencies at this dose and for this indication). 30”
From Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined (2021) · cites this paper as [30]
In the main phase of the STEP 1 trial, 68 weeks of treatment with semaglutide plus lifestyle intervention in adults with overweight/obesity produced clinically meaningful reductions in body weight, as well as improvements in cardiometabolic risk factors, and physical functioning.
“In the main phase of the STEP 1 trial, 68 weeks of treatment with semaglutide plus lifestyle intervention in adults with overweight/obesity produced clinically meaningful reductions in body weight, as well as improvements in cardiometabolic risk factors, and physical functioning. 16”
From Weight regain and cardiometabolic effects after withdrawal of semaglutide: The <scp>STEP</scp> 1 trial extension (2022) · cites this paper as [16]
GLP-1RAs have emerged as key agents for weight management, based on their marked efficacy as observed in randomized controlled trials.
“Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) have emerged as key agents for weight management, based on their marked efficacy as observed in randomized controlled trials.”
The three GLP-1RA-based agents currently approved for weight loss have all shown clear efficacy in promoting weight loss in randomized controlled trials.
“The three GLP‐1RA‐based agents currently approved for weight loss have all shown clear efficacy in promoting weight loss in randomized controlled trials (RCTs), 17 , 18 , 19 that is, in settings with good medication adherence among participants and a follow‐up of typically one to two years. 15”
In the STEP 1 trial, 2.4 mg/week semaglutide resulted in 15% mean weight loss over 68 weeks.
“In the STEP 1 trial, 2.4 mg·week−1 of the glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide resulted in 15% mean weight loss over 68 weeks. 2”
From Preservation of lean soft tissue during weight loss induced by GLP-1 and GLP-1/GIP receptor agonists: A case series (2025) · cites this paper as [2]
In the STEP 1 trial, participants completed individualized counseling sessions to promote a 500 kcal/day energy deficit and completion of at least 150 min/week physical activity.
“In the STEP 1 trial, participants completed individualized counseling sessions to promote a 500 kcal·day−1 energy deficit and completion of ⩾150 min·week−1 physical activity. 2”
From Preservation of lean soft tissue during weight loss induced by GLP-1 and GLP-1/GIP receptor agonists: A case series (2025) · cites this paper as [2]
Approximately 15% weight loss was observed in overweight and obese, non-diabetic adults across various treatment periods lasting up to 2 years with once-weekly subcutaneous semaglutide 2.4 mg (STEP-1 to STEP-6, STEP-8).
“Generally, approximately 15% weight loss was observed in overweight and obese, non-diabetic adults across various treatment periods, lasting up to 2 years (from STEP-1 to STEP-6, STEP-8) [72,73,74,75,76,77,78,79].”
From New Developments in Pharmacological Treatment of Obesity and Type 2 Diabetes—Beyond and within GLP-1 Receptor Agonists (2024) · cites this paper as [72]
Wilding et al. highlighted that combining Semaglutide treatment with lifestyle interventions effectively sustained clinically relevant weight loss in overweight or obese adults.
“Notably, Wilding et al. highlighted that combining Semaglutide treatment with lifestyle interventions effectively sustained clinically relevant weight loss in overweight or obese adults (1).”
From Transforming body composition with semaglutide in adults with obesity and type 2 diabetes mellitus (2024) · cites this paper as [1]
GLP-1-based weight loss is accompanied by some loss of lean mass, but fat loss predominates.
“Clinical studies using DEXA show that GLP-1–based weight loss is accompanied by some loss of lean mass, but fat loss predominates.”
From GLP-1 agonists and exercise: the future of lifestyle prioritization (2025) · cites this paper as [35]
Semaglutide promoted a mean reduction of approximately 14.9% of body weight.
“Semaglutide promoted a mean reduction of approximately 14.9% of body weight, while tirzepatide achieved losses close to 20.9%.”
From RETATRUTIDE USE IN THE TREATMENT OF METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE (MASLD) AND OBESITY: AN INTEGRATIVE REVIEW (2026) · cites this paper as WILDING et al., 2021
Few studies have used DXA, the gold standard for measuring body composition, and even fewer have assessed muscle function.
“Few studies have used DXA, 6 , 8 the gold standard for measuring body composition, and even fewer have assessed muscle function. 9 , 10”
From Impact of Semaglutide on fat mass, lean mass and muscle function in patients with obesity: The <scp>SEMALEAN</scp> study (2026) · cites this paper as [6]
Semaglutide 2.4 mg has demonstrated significant weight loss outcomes in clinical trials, with reductions in body weight exceeding 15% in many patients.
“Semaglutide, administered once weekly at a dose of 2.4 mg, has demonstrated significant weight loss outcomes in clinical trials, with reductions in body weight exceeding 15% in many patients. 5 , 6”
From Impact of Semaglutide on fat mass, lean mass and muscle function in patients with obesity: The <scp>SEMALEAN</scp> study (2026) · cites this paper as [6]
Semaglutide 2.4 mg in STEP 1 showed 14.9% weight loss over 68 weeks.
“STEP 1 showed 14.9% loss over 68 weeks [3].”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [3]
The STEP 1 and SURMOUNT-1 trials demonstrated clinically meaningful improvements in HRQoL measures (e.g., IWQOL-Lite, SF-36) even in people without diabetes or established cardiovascular disease.
“Both the STEP 1 and SURMOUNT-1 trials, evaluating semaglutide and tirzepatide, respectively, demonstrated clinically meaningful improvements in HRQoL measures as assessed by standardized tools (e.g., IWQOL-Lite, SF-36), even in people without diabetes or established cardiovascular disease [2, 3].”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [3]
Semaglutide resulted in 12% larger weight loss than placebo after 68 weeks.
“The GLP-1 receptor agonist, semaglutide, resulted in 12% larger weight loss than placebo after 68 weeks.8”
Heterogeneity in response to GLP-1 receptor agonist weight loss exists.
“Although most patients taking a GLP-1 RA achieve clinically meaningful weight loss, heterogeneity in response exists.3,4,5,6,7,12”
From Discontinuation and Reinitiation of Dual-Labeled GLP-1 Receptor Agonists Among US Adults With Overweight or Obesity (2025) · cites this paper as [6]
GLP-1 receptor agonists substantially lower weight, hemoglobin A1c levels, and cardiovascular risk.
“Although glucagon-like peptide-1 receptor agonists (GLP-1 RAs) substantially lower weight,3,4,5,6,7 hemoglobin A1c levels, and cardiovascular risk,8 trials suggest they must be continued for sustained effects.9,10”
From Discontinuation and Reinitiation of Dual-Labeled GLP-1 Receptor Agonists Among US Adults With Overweight or Obesity (2025) · cites this paper as [6]
In STEP 1, 68 weeks of treatment with once-weekly s.c. semaglutide 2.4 mg plus lifestyle intervention provided significant, clinically relevant reductions in body weight versus placebo among adults with overweight/obesity.
“In STEP 1, 68 weeks of treatment with once‐weekly s.c. semaglutide 2.4 mg plus lifestyle intervention provided significant, clinically relevant reductions in body weight versus placebo among adults with overweight/obesity.”
From Weight regain and cardiometabolic effects after withdrawal of semaglutide: The <scp>STEP</scp> 1 trial extension (2022) · cites this paper as [16]
The proportion with ≥5% weight loss at week 120 (48.2%) represented a substantial fall from that originally achieved at the end of 68 weeks of treatment (86.4%).
“although this proportion represented a substantial fall from that originally achieved at the end of 68 weeks of treatment (86.4%).”
From Weight regain and cardiometabolic effects after withdrawal of semaglutide: The <scp>STEP</scp> 1 trial extension (2022) · cites this paper as [16]
RCTs report retention rates often exceeding 85% over 68 weeks.
“While RCTs report retention rates often exceeding 85% over 68 weeks [9]”
Treatment of obesity with semaglutide 2.4 mg presents challenges including managing side effects, insurance coverage issues, and frequent national shortages.
“The treatment of obesity with semaglutide 2.4 mg presents challenges for both patients and providers, including managing side effects [8], insurance coverage issues [9], and frequent national shortages of the medication [10].”
From A Qualitative Analysis of Patient Experiences Using Semaglutide 2.4 mg for Weight Loss (2025) · cites this paper as [8]
Subcutaneous semaglutide 2.4 mg/wk produced a weight reduction of -14.9% compared with -2.4% for placebo after 68 weeks.
“Semaglutide (S/C) [2.4 mg/wk, price calculated for 10.25 mg per 30 days] Treatment À14.9% (À15.3 kg) vs. placebo À2.4% (À2.6 kg) [after 68 weeks] [10, 24]”
From Estimated minimum prices and lowest available national prices for antiobesity medications: Improving affordability and access to treatment (2023) · cites this paper as [24]
Semaglutide produces an average total weight loss of 14.9% at 68 weeks.
“Average total weight loss 14.9% at 68 weeks 42”
From Effectiveness and safety of drugs for obesity (2024) · cites this paper as [42]
Semaglutide 2.4 mg weekly led to a mean placebo-adjusted body weight reduction of 12.4% at 68 weeks in adults with obesity.
“In STEP-1, weekly semaglutide 2.4 mg led to a mean placebo-adjusted body weight reduction of 12.4% at 68 weeks in adults with obesity, with significant improvements in cardiometabolic risk factors.19”
From The Triple‐Agonist Revolution: Retatrutide and the Paradigm Shift in Multi‐Hormonal Pharmacotherapy for Obesity and Cardiometabolic Comorbidities (2026) · cites this paper as [19]
A cardiovascular outcome trial for naltrexone/bupropion-extended release was terminated early, and there was insufficient data to assess cardiovascular safety.
“A CVOT for naltrexone/bupropion-ER was terminated early, and there was insufficient data to assess CV safety.753”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [753]
The Trial Design and Oversight and End Points and Assessments sections describe a semaglutide-versus-placebo trial, including its cardiovascular-event safety assessments. Searches for naltrexone/bupropion-ER, early termination of a cardiovascular outcome trial, and insufficient cardiovascular-safety data found no passage addressing the claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe frequency of these side effects was 84% and 67% in subjects receiving JNJ-64565111 and 71% and 48% in subjects receiving liraglutide.
“The frequency of these side effects occurred in 84% and 67% of subjects receiving JNJ-64565111 and in 71% and 48% of subjects administered liraglutide101.”
From Transforming obesity: The advancement of multi-receptor drugs (2024) · cites this paper as [101]
The Safety and Side-Effect Profile and Table 3 (p. 1000) report adverse-event rates for semaglutide and placebo, not JNJ-64565111 and liraglutide. Searches for JNJ-64565111 and the four cited percentages found no passage reporting those rates for the named drugs. (LLM, conf=0.78)
Experimental — accuracy not yet measuredTreatment with JNJ-64565111 increased adverse effects, most notably nausea and vomiting, in both studies.
“In both studies, treatment with JNJ-64565111 resulted in an increased appearance of adverse effects, most notably nausea and vomiting101,102.”
From Transforming obesity: The advancement of multi-receptor drugs (2024) · cites this paper as [101]
Table 3 (p. 1000) and the Safety and Side-Effect Profile report more nausea and vomiting with semaglutide than with placebo in this trial. A search for JNJ-64565111 found no passage about that treatment, and the cited paper does not report the claimed result in both studies. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe magnitude of weight loss with retatrutide exceeded that seen with other pipeline multi-agonists such as CagriSema, mazdutide and survodutide.
“Moreover, the magnitude of WL with retatrutide also exceeded that seen with other pipeline multi-agonists such as CagriSema (cagrilintide, an amylin agonist, in combination with semaglutide), mazdutide and survodutide (Fig. 4) [8, 27, 35, 36, 45, 46, 49–53].”
From Triple Agonism Based Therapies for Obesity (2025) · cites this paper as [8]
The Discussion reports 14.9% mean weight loss with semaglutide versus placebo, but it does not compare retatrutide with CagriSema, mazdutide, or survodutide. Searches for those drugs and for multi-agonist comparisons found no passage addressing the claimed ranking. (LLM, conf=0.78)
Experimental — accuracy not yet measuredSemaglutide users can regain two-thirds of their loss within one year off treatment.
“Semaglutide users can regain two-thirds of their loss within one year off treatment [6].”
From Obesity: Clinical Impact, Pathophysiology, Complications, and Modern Innovations in Therapeutic Strategies (2025) · cites this paper as [6]
The Procedures section (page not supplied) describes only seven weeks without treatment after the 68-week treatment period. The Change in Body Weight section reports weight loss during the trial, but our copy does not report how much weight participants regained one year after stopping; searches for two-thirds regain and post-treatment weight regain found no such result. (LLM, conf=0.76)
Experimental — accuracy not yet measuredDual GIP/GLP-1 agonists such as tirzepatide have demonstrated unprecedented mean weight losses of >20% in the SURMOUNT-1 trial, validating co-agonism as a superior strategy.
“Dual GIP/GLP-1 agonists such as tirzepatide have already demonstrated unprecedented mean weight losses of >20% in the SURMOUNT-1 trial, validating co-agonism as a superior strategy [6].”
From Obesity: Clinical Impact, Pathophysiology, Complications, and Modern Innovations in Therapeutic Strategies (2025) · cites this paper as [6]
The Discussion reports a 14.9% mean weight loss with semaglutide, and the Change in Body Weight section reports that some semaglutide participants lost at least 20%. Searches for tirzepatide, SURMOUNT-1, dual GIP/GLP-1 agonism, and a mean loss above 20% found no passage addressing those claims or establishing co-agonism as superior. (LLM, conf=0.78)
Experimental — accuracy not yet measuredSGLT2 inhibitors improve HFpEF outcomes, but have variable and modest effects on health status and exercise function, with resultant significant residual risk.
“Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve HFpEF outcomes, 13,14 but have variable and modest effects on health status and exercise function, with resultant significant residual risk. 15-17”
From Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials (2024) · cites this paper as [14]
The Exploratory End Points section reports physical-functioning improvements with semaglutide in adults with overweight or obesity. A search of our copy for SGLT2 inhibitors, HFpEF, and residual risk found no passage addressing the attributed claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe weaker weight loss in type 2 diabetes than in obese people without diabetes was also observed in trials.
“Semaglutide and tirzepatide initiators appeared to achieve the greatest weight loss in real life, and weight loss effects were weaker for patients with T2D than for obese people without diabetes, 52 , 58 , 65 , 67 which was also observed in trials. 18 , 75”
From Real‐world evidence on the utilization, clinical and comparative effectiveness, and adverse effects of newer <scp>GLP</scp> ‐ <scp>1RA</scp> ‐based weight‐loss therapies (2025) · cites this paper as [18]
The Participants section says diabetes was an exclusion criterion, and the conclusion (p. 1000) reports 14.9% mean weight loss with semaglutide in adults without diabetes. Our copy does not compare their weight loss with that of patients with type 2 diabetes; searches for a weaker effect in that group found no such comparison. (LLM, conf=0.76)
Experimental — accuracy not yet measuredClinical evidence demonstrated that the combination of the GLP-1 and GIP pathways promotes benefits superior to those observed with isolated GLP-1 agonists.
“Clinical evidence demonstrated that the combination of these two pathways promotes benefits superior to those observed with isolated GLP-1 agonists, a fact initially evidenced by the results obtained with tirzepatide in the treatment of obesity”
From RETATRUTIDE USE IN THE TREATMENT OF METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE (MASLD) AND OBESITY: AN INTEGRATIVE REVIEW (2026) · cites this paper as WILDING et al., 2021
The Discussion compares weight loss with semaglutide and liraglutide, both GLP-1 receptor agonists. Our copy does not address combined GLP-1 and GIP activity or tirzepatide, so it cannot verify the claimed superiority of the combined pathways (searched: tirzepatide, GIP, and dual GLP-1/GIP agonism). (LLM, conf=0.76)
Experimental — accuracy not yet measuredAcross major trials, women, especially premenopausal, tend to experience greater relative weight loss with GLP-1 RAs and dual incretin therapies such as tirzepatide.
“Across major trials, women, especially premenopausal, tend to experience greater relative weight loss with GLP-1 RAs and dual incretin therapies such as tirzepatide [2, 3].”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [3]
The Study Participants section reports that 74.1% of participants were female, and Change in Body Weight reports overall weight loss with semaglutide. Neither compares weight loss by sex or menopausal status. Searches for sex differences, premenopausal participants, and tirzepatide found no passage supporting the attributed trend across therapies or trials. (LLM, conf=0.76)
Experimental — accuracy not yet measuredReal-world effectiveness of GLP-1 RAs lags trial efficacy, largely owing to high discontinuation rates.
“However, real-world effectiveness lags trial efficacy, largely owing to high discontinuation rates.”
From Adherence and Persistence with GLP-1-Based Therapies: International Real-World Evidence and the Role of Nutritional and Lifestyle Support—A Narrative Review (2026) · cites this paper as [9]
The Trial Design and Statistical Analysis sections describe a randomized trial, not a comparison with real-world GLP-1 RA use. The Discussion reports high trial adherence, and Table 3 reports discontinuation due to adverse events, but neither establishes that real-world effectiveness lags trial efficacy or that discontinuation largely explains such a gap. Searches for real-world effectiveness, adherence, and discontinuation found no passage addressing that claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredFor type 2 diabetes, complementary disease-modifying therapies may reduce or eliminate the need for insulin administration.
“For type 2 diabetes, complementary disease-modifying therapies that may reduce or eliminate the need for insulin administration have also represented a rapidly expanding field of interest130–132.”
From 100 years of insulin: celebrating the past, present and future of diabetes therapy (2021) · cites this paper as [132]
The Discussion describes a trial in adults without diabetes, and the introduction (p. 990) notes that semaglutide is approved to treat type 2 diabetes. Neither passage says that it reduces or eliminates the need for insulin administration. Searches for insulin requirements and treatment discontinuation found no passage addressing that claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredSemaglutide achieved up to 15% mean weight loss that was maintained for at least two years.
“semaglutide demonstrated up to 15% mean weight loss (8), sustained over at least two years (9)”
From Regional trends and disparities in newer <scp>GLP1</scp> receptor agonist initiation among real‐world adult patients eligible for obesity treatment (2025) · cites this paper as [8]
Newer GLP-1 receptor agonists including liraglutide, semaglutide, and tirzepatide have demonstrated better effectiveness, health benefits, and safety.
“have shown greater effectiveness, health benefits, and safety profiles (7; 8).”
From Regional trends and disparities in newer <scp>GLP1</scp> receptor agonist initiation among real‐world adult patients eligible for obesity treatment (2025) · cites this paper as [8]
STEP 1 and 3 randomly assigned participants 2:1 to semaglutide (up to 2.4 mg weekly) or placebo for 68 weeks, alongside lifestyle intervention or intensive behavioral therapy.
“In STEP 1 and 3, participants were randomized 2:1 to escalating doses of semaglutide up to 2.4 mg/week or placebo for 68 weeks as an adjunct to either lifestyle intervention”
In STEP 1-4, semaglutide 2.4 mg versus placebo, added to lifestyle management or intensive behavioral therapy, produced mean weight reductions of 6-15% in people with and without type 2 diabetes.
“The STEP 1, 2, 3, and 4 trials demonstrated that semaglutide 2.4 mg compared with placebo, as adjunct to lifestyle management or intensive behavioral therapy, led to mean weight losses of 6–15% in participants with and without type 2 diabetes (14,18–20).”
All three trials followed Good Clinical Practice and the Declaration of Helsinki, and every participant gave written informed consent.
“All three trials were conducted according to the International Conference on Harmonisation Good Clinical Practice Guideline and the Declaration of Helsinki; all participants provided written informed consent (14,18,19).”
Semaglutide has been shown to lower body weight by up to 16% when used in conjunction with lifestyle recommendations.
“Semaglutide has been shown to lower body weight by up to 16% when used in conjunction with lifestyle recommendations [10, 11, 12, 13].”
From Semaglutide for cardiovascular event reduction in people with overweight or obesity: <scp>SELECT</scp> study baseline characteristics (2023) · cites this paper as [10]
Semaglutide 2.4 mg subcutaneous once-weekly treatment has been demonstrated to provide significant and sustained mean weight loss of up to 16%, significant CV risk factor improvements, and proven CV benefit in patients with diabetes and prior CV events.
“The study uses standard‐of‐care preventive measures along with semaglutide 2.4 mg subcutaneous once‐weekly treatment, which has been demonstrated to provide significant and sustained mean weight loss of up to 16% [10, 11, 12, 13, 24, 25], significant CV risk factor improvements, and proven CV benefit in patients with diabetes and prior CV events [16, 26].”
From Semaglutide for cardiovascular event reduction in people with overweight or obesity: <scp>SELECT</scp> study baseline characteristics (2023) · cites this paper as [10]
In the phase III Semaglutide Treatment Effect in People with obesity (STEP) 1-4 studies, weekly semaglutide 2.4 mg demonstrated substantial, clinically meaningful weight losses and improvements in cardiometabolic parameters and patient-reported outcomes.
“In the phase III Semaglutide Treatment Effect in People with obesity (STEP) 1‐4 studies, weekly semaglutide 2.4 mg demonstrated substantial, clinically meaningful weight losses and improvements in cardiometabolic parameters and patient‐reported outcomes.”
Semaglutide is contraindicated in patients with personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 or known hypersensitivity to semaglutide.
“Contraindicated in patients with personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 or known hypersensitivity to semaglutide.”
From Anti-Obesity Medications and Investigational Agents: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2022 (2022) · cites this paper as [43]
Semaglutide at 2.4 mg subcutaneously per week is approved for treatment of obesity.
“Semaglutide at 2.4 mg subcutaneously per week is approved for treatment of obesity.”
From Anti-Obesity Medications and Investigational Agents: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2022 (2022) · cites this paper as [43]
Average weight reduction with semaglutide is about 15%.
“Average weight reduction is about 15%.”
From Anti-Obesity Medications and Investigational Agents: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2022 (2022) · cites this paper as [43]
Semaglutide at lower injectable doses 0.25-2.0 mg per week, and at oral doses of 7-14 mg per day, is indicated to lower blood sugar in patients with type 2 diabetes mellitus.
“Glucagon-like peptide-1 receptor agonist that at lower injectable doses 0.25–2.0 mg per week, and at oral doses of 7–14 mg per day, is indicated to lower blood sugar in patients with type 2 diabetes mellitus.”
From Anti-Obesity Medications and Investigational Agents: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2022 (2022) · cites this paper as [43]
Semaglutide 2.4 mg subcutaneously once weekly produced an overall mean weight reduction of 15% in the cited study.
“Semaglutide 2.4 mg subcutaneously once weekly | Overall mean = 15%≥5% = 86%≥10% = 69%≥15% = 51%≥20% = 32%”
From Anti-Obesity Medications and Investigational Agents: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2022 (2022) · cites this paper as [43]
SMG often causes adverse reactions, mainly gastrointestinal side effects including nausea, diarrhea, and vomiting, generally mild to moderate and gradually alleviated in most patients.
“Like other GLP-1R agonists, SMG often causes adverse reactions. The main adverse reactions were gastrointestinal side effects, including nausea, diarrhea, and vomiting. These adverse reactions are generally mild to moderate and gradually alleviated in most patients (100, 104).”
From GLP−1 receptor agonists for the treatment of obesity: Role as a promising approach (2023) · cites this paper as [100]
In STEP1, 1961 non-diabetic adults with BMI 30 or ≥27 with >1 weight-related coexisting disease treated with SMG 2.4 mg weekly for 68 weeks had average weight loss 15.3 kg; more patients achieved ≥5% (86.4% vs 31.5%), ≥10% (69.1% vs 12.0%), and ≥15% (50.5% vs 4.9%) weight loss compared with placebo.
“In the STEP1 trial (100), Wilding et al. recruited 1961 non-diabetic adults with a BMI of 30 kg/m2 (or ≥27 kg/m2 with more than 1 body weight-related coexisting disease). The SMG group (once 2.4 mg, once a week) was treated for 68 weeks, and the average weight loss in the SMG group was 15.3 kg. More patients in the SMG group achieved a weight loss of ≥ 5% (86.4% vs. 31.5%), ≥ 10% (69.1% vs. 12.0%”
From GLP−1 receptor agonists for the treatment of obesity: Role as a promising approach (2023) · cites this paper as [100]
Semaglutide at 2.4 mg per week induces an average weight loss between 9.6% and 17.4%.
“In particular, at a dosage of 2.4 mg per week, it has been shown to induce an average weight loss between 9.6% and 17.4%, as well as a reduction in waist circumference and arterial hypertension and an improvement of lipid profile [34,35,36,37,39].”
From GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives (2023) · cites this paper as [34]
The STEP trial programme assessed the effect of a high dose of the GLP-1 receptor agonist semaglutide (2.4 mg once weekly by subcutaneous injection) and typically noted about a 15% reduction in body weight during treatment periods up to 2 years in overweight and obese adults who did not have type 2 diabetes.
“The STEP trial programme assessed the effect of a high dose of the GLP-1RA semaglutide (2.4 mg once weekly by subcutaneous injection: Weygovy ) and typically noted about a 15% reduction in body weight during treatment periods up to 2 years in overweight and obese adults who did not have T2DM (STEP-1, 3, 4, 5, 8) [16-23].”
From Recent advances in peptide-based therapies for obesity and type 2 diabetes (2024) · cites this paper as [16]
In people without diabetes, 86.4% to 88.7% of those treated with semaglutide lose at least 5% of baseline body weight.
“The proportion of subjects who lost ≥ 5% of baseline body weight was 86.4–88.7% [15–17, 19].”
From Efficacy of GLP-1 RA Approved for Weight Management in Patients With or Without Diabetes: A Narrative Review (2022) · cites this paper as [15]
In people without diabetes, semaglutide 2.4 mg produces a mean weight loss 10.3% to 17.4% greater than placebo.
“Semaglutide resulted in 10.3–17.4% difference in mean weight compared to placebo [15–17, 19].”
From Efficacy of GLP-1 RA Approved for Weight Management in Patients With or Without Diabetes: A Narrative Review (2022) · cites this paper as [15]
The FDA efficacy benchmark criteria for weight-management products were met in the STEP 1, STEP 3, STEP 4, and STEP 8 trials of semaglutide.
“Both efficacy benchmark criteria for weight management products were met in STEP 1, 3, 4 and 8 trials [15–17, 19].”
From Efficacy of GLP-1 RA Approved for Weight Management in Patients With or Without Diabetes: A Narrative Review (2022) · cites this paper as [15]
STEP 2 had a greater proportion of men (49.1%) than STEP 1, STEP 3, and STEP 4 (19.0% to 25.9%).
“While the STEP 2 trail included 51% female participants [22], the STEP 1, STEP 3 and STEP 4 trials included 73%, 81% and 79% female participants, respectively [15–17]. Thus, STEP 2 has a greater proportion of men (49.1%) than the other trials (19.0–25.9%).”
From Efficacy of GLP-1 RA Approved for Weight Management in Patients With or Without Diabetes: A Narrative Review (2022) · cites this paper as [15]
The percentage of Caucasian participants was 76%, 62%, 76%, and 84% in STEP 1 through STEP 4, respectively.
“The percentage of Caucasian participants in each study was 76%, 62%, 76% and 84% for the STEP 1–4 trials, respectively [15–17, 22].”
From Efficacy of GLP-1 RA Approved for Weight Management in Patients With or Without Diabetes: A Narrative Review (2022) · cites this paper as [15]
Semaglutide 2.4 mg plus lifestyle intervention was associated with a mean body weight change of −14.9% after 68 weeks in adults with a body mass index above 27 kg/m2.
“in the STEP 1 clinical trial, which included 1961 adults with a body mass index above 27 kg/m2, semaglutide 2.4 mg in addition to a lifestyle intervention was associated with a mean change in body weight of −14.9% after 68 weeks [4]”
From What Is Food Noise? A Conceptual Model of Food Cue Reactivity (2023) · cites this paper as [4]
Main published trials (STEP 1 through STEP 5, STEP 8, and STEP TEENS) did not include participants who reported symptoms of major depressive disorder within 2 years before screening, limiting their ability to assess psychiatric adverse events in people with a recent history of depression.
“the main trials for which data have been published (STEP 1 through STEP 5, STEP 8, and STEP TEENS) did not include participants who reported having symptoms of major depressive disorder within 2 years before screening, which limits their ability to assess psychiatric adverse events in people with a recent history of depression [3,4,93,94,95,96,97].”
From What Is Food Noise? A Conceptual Model of Food Cue Reactivity (2023) · cites this paper as [4]
Clinical trials conducted so far lack statistically significant evidence for an association between semaglutide and depressive symptoms or suicidal ideation.
“Despite the lack of statistically significant evidence for such association in clinical trials conducted so far [4,92]”
From What Is Food Noise? A Conceptual Model of Food Cue Reactivity (2023) · cites this paper as [4]
In the STEP 1 trial, up to 40% of total body weight loss was attributable to lean body mass reduction, exceeding the approximate 25% commonly seen with standard caloric restriction.
“The trial, which led to the approval of semaglutide for obesity treatment, revealed that up to 40% of total body weight loss could be attributed to lean body mass reduction, exceeding the approximate 25% commonly seen with standard caloric restriction [2].”
From Muscle Loss in Obesity Therapy as a Therapeutic Target: Trial Design and Endpoints for Regulatory Discussions (2025) · cites this paper as [1]
MRI and CT scans can attribute approximately 50% of adipose tissue volume to what is technically referred to as 'lean body mass'.
“According to Johansson, the fundamental contrast lies between dual‐energy X‐ray absorptiometry (DXA) and magnetic resonance imaging (MRI), where recent studies frequently highlight that MRI and CT scans can attribute approximately 50% of adipose tissue volume to what is technically referred to as ‘lean body mass’ [1].”
From Muscle Loss in Obesity Therapy as a Therapeutic Target: Trial Design and Endpoints for Regulatory Discussions (2025) · cites this paper as [1]
Trials like STEP 1 and SURMOUNT 1 report changes in lean body mass but often lack details on measurement specificity.
“Trials like STEP 1 and SURMOUNT 1 report changes in lean body mass [1, 9], but often lack details on measurement specificity.”
From Muscle Loss in Obesity Therapy as a Therapeutic Target: Trial Design and Endpoints for Regulatory Discussions (2025) · cites this paper as [1]
Compared to semaglutide and tirzepatide, bimagrumab demonstrates a more favourable ratio of fat-to-lean mass loss.
“Compared to agents like semaglutide and tirzepatide (as shown in STEP 1 and SURMOUNT‐1) [1, 9], bimagrumab demonstrates a more favourable ratio of fat‐to‐lean mass loss.”
From Muscle Loss in Obesity Therapy as a Therapeutic Target: Trial Design and Endpoints for Regulatory Discussions (2025) · cites this paper as [1]
Compared with other selective GLP-1 analogues, semaglutide is more potent and has higher affinity for GLP-1R, resulting in greater weight loss and glucose-lowering properties.
“Compared with other selective GLP-1 analogues, semaglutide is more potent and has higher affinity for GLP-1R, resulting in greater weight loss and glucose-lowering properties (45–47).”
From The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission (2023) · cites this paper as [47]
In the STEP-1 trial, semaglutide 2.4 mg achieved 14.9% weight loss at week 68, with only a modest additional 0.3% (−15.2%) reduction observed at week 104 in STEP-5, despite nearly doubling treatment duration.
“In the STEP‐1 trial, semaglutide 2.4 mg achieved 14.9% weight loss at week 68, with only a modest additional 0.3% (−15.2%) reduction observed at week 104 in STEP‐5, despite nearly doubling treatment duration [29, 33].”
From Efficacy and Safety of Orforglipron in Obese Adults With or Without Diabetes: A Systematic Review and Meta‐Analysis (2025) · cites this paper as [29]
Non-diabetic patients demonstrated greater weight loss (−8.5%) compared to diabetic patients (−4.87%).
“Notably, non‐diabetic patients demonstrated greater weight loss (−8.5%) compared to diabetic patients (−4.87%), a finding consistent with previous GLP‐1 agonist studies [29, 30, 31, 32].”
From Efficacy and Safety of Orforglipron in Obese Adults With or Without Diabetes: A Systematic Review and Meta‐Analysis (2025) · cites this paper as [29]
The reductions in body weight, BMI, and waist circumference with orforglipron are lower than those seen with injectable GLP-1 receptor agonists such as semaglutide (15%-17% weight loss) and tirzepatide (15%-22% weight loss) but clinically meaningful and comparable to those observed with other oral anti-obesity agents.
“These reductions are lower than the effects seen with injectable GLP‐1 receptor agonists such as semaglutide (15%–17% weight loss) and tirzepatide (15%–22% weight loss) but clinically meaningful and comparable to those observed with other oral anti‐obesity agents [14, 29].”
From Efficacy and Safety of Orforglipron in Obese Adults With or Without Diabetes: A Systematic Review and Meta‐Analysis (2025) · cites this paper as [29]
Orlistat three times daily in long-term trials has potential benefits for weight (mean total loss about 7%) and cardiovascular risk factors, but placebo-subtracted weight loss is about 3% and side effects limit its use.
“Orlistat three-times daily [56][57][58][59] was found in long-term trials to have potential benefits for both weight (mean total loss ≈7%) and cardiovascular risk factors, but placebo-subtracted weight losses are ≈3% and side-effects such oily stools limit its use.60”
From Approach to Obesity Treatment in Primary Care: A Review (2024) · cites this paper as [56]
In the STEP 1 trial, nausea occurred in 44.2% with semaglutide versus 17.4% with placebo.
“Nausea occurred in 44.2% vs. 17.4%, diarrhea 31.5% vs. 15.9%, vomiting 24.8% vs. 6.6%, and constipation 23.4% vs. 9.5%.”
From Gastrointestinal Adverse Effects of Anti-Obesity Medications in Non-Diabetic Adults: A Systematic Review (2025) · cites this paper as [13]
In the STEP 1 trial, semaglutide recipients experienced GI disorders in 74.2% versus 47.9% with placebo.
“In the STEP 1 trial, semaglutide recipients experienced GI disorders in 74.2% versus 47.9% with placebo.”
From Gastrointestinal Adverse Effects of Anti-Obesity Medications in Non-Diabetic Adults: A Systematic Review (2025) · cites this paper as [13]
In the STEP 1 trial, diarrhea occurred in 31.5% with semaglutide versus 15.9% with placebo.
“Nausea occurred in 44.2% vs. 17.4%, diarrhea 31.5% vs. 15.9%, vomiting 24.8% vs. 6.6%, and constipation 23.4% vs. 9.5%.”
From Gastrointestinal Adverse Effects of Anti-Obesity Medications in Non-Diabetic Adults: A Systematic Review (2025) · cites this paper as [13]
In the STEP 1 trial, discontinuation due to GI events occurred in 4.5% on semaglutide versus 0.8% on placebo.
“Discontinuation due to GI events occurred in 4.5% on semaglutide vs. 0.8% on placebo [13].”
From Gastrointestinal Adverse Effects of Anti-Obesity Medications in Non-Diabetic Adults: A Systematic Review (2025) · cites this paper as [13]
In the STEP 1 trial, constipation occurred in 23.4% with semaglutide versus 9.5% with placebo.
“Nausea occurred in 44.2% vs. 17.4%, diarrhea 31.5% vs. 15.9%, vomiting 24.8% vs. 6.6%, and constipation 23.4% vs. 9.5%.”
From Gastrointestinal Adverse Effects of Anti-Obesity Medications in Non-Diabetic Adults: A Systematic Review (2025) · cites this paper as [13]
In the STEP 1 trial, vomiting occurred in 24.8% with semaglutide versus 6.6% with placebo.
“Nausea occurred in 44.2% vs. 17.4%, diarrhea 31.5% vs. 15.9%, vomiting 24.8% vs. 6.6%, and constipation 23.4% vs. 9.5%.”
From Gastrointestinal Adverse Effects of Anti-Obesity Medications in Non-Diabetic Adults: A Systematic Review (2025) · cites this paper as [13]
Multiple trials reported that the most commonly observed AEs included nausea, diarrhea, constipation, and abdominal discomfort.
“Multiple trials reported the most commonly observed AEs included nausea, diarrhea, constipation, and abdominal discomfort [3,6,9,12,13].”
From Gastrointestinal Adverse Effects of Anti-Obesity Medications in Non-Diabetic Adults: A Systematic Review (2025) · cites this paper as [13]
In the STEP 1 trial, semaglutide produced substantial weight loss, of which approximately 30% was attributed to lean tissue, while fat loss predominated.
“In the STEP 1 trial, semaglutide produced substantial weight loss, of which approximately 30% was attributed to lean tissue, while fat loss predominated [21, 22].”
From Muscle loss and GLP-1R agonists use (2025) · cites this paper as [21]
Across all drug classes, the timing of GI adverse events strongly implicates the dose-escalation phase as the key driver of intolerance.
“Across all drug classes, the timing of GI AEs strongly implicates the dose-escalation phase as the key driver of intolerance [6,7,13].”
From Gastrointestinal Adverse Effects of Anti-Obesity Medications in Non-Diabetic Adults: A Systematic Review (2025) · cites this paper as [13]
GLP-1RA therapy results in significant reductions in fat mass, accompanied by smaller but measurable decreases in lean mass.
“Clinical trial evidence consistently shows that GLP-1RA therapy results in significant reductions in fat mass, accompanied by smaller but measurable decreases in lean mass.”
From Muscle loss and GLP-1R agonists use (2025) · cites this paper as [21]
GLP-1 receptor agonists (semaglutide, liraglutide, exenatide, orforglipron) consistently produced the highest frequency of GI events among approved pharmacotherapies.
“GLP-1 receptor agonists (semaglutide, liraglutide, exenatide, orforglipron) consistently produced the highest frequency of GI events among approved pharmacotherapies [6,7,9,10,13].”
From Gastrointestinal Adverse Effects of Anti-Obesity Medications in Non-Diabetic Adults: A Systematic Review (2025) · cites this paper as [13]
Gallbladder-related events and rare pancreatitis cases were more frequently observed with GLP-1 based drugs.
“Gallbladder-related events and rare pancreatitis cases were more frequently observed with GLP-1 based drugs, consistent with their known effects on biliary motility and lipid metabolism rather than direct pancreatic toxicity [4,6,13].”
From Gastrointestinal Adverse Effects of Anti-Obesity Medications in Non-Diabetic Adults: A Systematic Review (2025) · cites this paper as [13]
For incretin-based agents, nausea and diarrhea are primarily mediated by delayed gastric emptying, activation of central satiety centers in the hypothalamus, and enhanced vagal signaling that collectively slow motility.
“For incretin-based agents, nausea and diarrhea are primarily mediated by delayed gastric emptying, activation of central satiety centers in the hypothalamus, and enhanced vagal signaling that collectively slow motility [4,6,8,11,13].”
From Gastrointestinal Adverse Effects of Anti-Obesity Medications in Non-Diabetic Adults: A Systematic Review (2025) · cites this paper as [13]
Individualized titration schedules, reassurance about symptom transience, and short-term symptomatic therapy can maintain adherence and limit discontinuation to below 5-7% once maintenance dosing is achieved.
“Individualized titration schedules, reassurance about symptom transience, and short-term symptomatic therapy can maintain adherence and limit discontinuation to below 5–7% once maintenance dosing is achieved [6,11,12,13].”
From Gastrointestinal Adverse Effects of Anti-Obesity Medications in Non-Diabetic Adults: A Systematic Review (2025) · cites this paper as [13]
The higher frequency of gallbladder-related events and rare pancreatitis with GLP-1 based drugs is consistent with known effects on biliary motility and lipid metabolism rather than direct pancreatic toxicity.
“Gallbladder-related events and rare pancreatitis cases were more frequently observed with GLP-1 based drugs, consistent with their known effects on biliary motility and lipid metabolism rather than direct pancreatic toxicity [4,6,13].”
From Gastrointestinal Adverse Effects of Anti-Obesity Medications in Non-Diabetic Adults: A Systematic Review (2025) · cites this paper as [13]
Weight reduction with GLP-1s is generally more rapid during the first 6 months and slows thereafter, with relative plateauing at 18 months.
“Generally, weight reduction is more rapid during the first 6 months and slows thereafter, with relative plateauing at 18 months [13,15,16].”
In the STEP 1 trial, of the average 13.6 kg weight reduction, 8.3 kg (62%) was fat mass and 5.3 kg (38%) was lean body mass (including muscle and other non-fat tissues).
“In the STEP 1 trial, of the average 13.6 kg weight reduction, 8.3 kg (62 %) was fat mass and 5.3 kg (38 %) was lean body mass (including muscle and other non-fat tissues) [14].”
During dose escalation in clinical trials, subjects were allowed to remain at a GLP-1 dose for up to 8 weeks, as needed, to allow GI side effects to dissipate.
“During dose escalation in the clinical trials, subjects were allowed to remain at a GLP-1 dose for up to 8 weeks, as needed, to allow GI side effects to dissipate [15,16].”
In the STEP 1 trial, semaglutide with general nutrition and physical activity instructions demonstrated a 14.9 % weight reduction from baseline versus 2.4 % with instructions alone.
“In comparison, the STEP 1 trial that included semaglutide with general nutrition and physical activity instructions demonstrated a 14.9 % weight reduction from baseline (versus 2.4 % with general nutrition and physical activity instructions alone) [14].”
The SCALE, STEP 1, SURMOUNT, and STEP 3 trials each demonstrated substantial weight reduction by combining GLP-1s with regular counseling sessions by RDNs or other qualified healthcare professionals.
“the SCALE [13], STEP 1 [14], SURMOUNT [15], and STEP 3 [169] trials each demonstrated substantial weight reduction by combining GLP-1s with regular counseling sessions by RDNs or other qualified healthcare professionals”
In STEP 1 and STEP 3, patients on semaglutide lost 14.8-16.0% body weight compared to 2.4-5.7% in the placebo group at 68 weeks.
“In STEP 1 and STEP 3, patients on semaglutide lost 14.8–16.0% BW compared to 2.4–5.7% in the placebo group at 68 weeks26,27.”
From Incretin-based therapies for the treatment of obesity-related diseases (2024) · cites this paper as [27]
In the STEP-1 clinical trial for semaglutide, a significant proportion of weight loss was due to lean mass (∼40%).
“Notably, the STEP-1 clinical trial for semaglutide noted that a significant proportion of weight loss was due to lean mass (∼40 %) [5].”
From Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism (2024) · cites this paper as [5]
Using this mouse model, the authors recapitulate lean mass loss as observed in overweight and obese humans treated with GLP-1 receptor agonists.
“Nevertheless, using this model we recapitulate lean mass loss as observed in overweight and obese humans treated with GLP-1 receptor agonists.”
From Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism (2024) · cites this paper as [5]
The lean mass loss attributable to weight loss in this mouse model is less than what is reported in humans.
“The weight loss attributable to lean mass reported here is less than what is reported in humans”
From Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism (2024) · cites this paper as [5]
In a clinical trial of semaglutide, weight loss is attributable to losses of both fat and lean mass, with approximately 40% of weight loss reported to be fat-free mass.
“The weight loss observed in a clinical trial of semaglutide is attributable to losses of both fat and lean mass, with ∼40 % of weight loss reported to be fat-free mass [5].”
From Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism (2024) · cites this paper as [5]
The amount of weight lost with GLP1-RA in this real-world group matches the results of the SCALE, SUSTAIN, and STEP trials.
“The magnitude of weight loss observed with GLP1-RA in this real-life patient population is consistent with findings from the SCALE, SUSTAIN, and STEP clinical trials, which are based on patients without bariatric surgery.”
The present study includes patients with type 2 diabetes, who have been shown to lose less weight with GLP1-RA therapy.
“The current study includes patients with T2D that have been shown to lose less weight with GLP1-RA therapy [29, 30, 32, 33]”
The STEP 1 and 2 studies reported weight loss of 12.4% and 6.2%, respectively, with semaglutide 2.4 mg weekly versus placebo over 68 weeks.
“The STEP 1 and 2 studies, investigating the weight effect of semaglutide 2.4 mg weekly versus placebo over 68 weeks, reported a weight loss of 12.4% and 6.2%, respectively [32, 33].”
Previous studies have shown that GLP1-RAs tend to induce less weight loss in patients with type 2 diabetes than in those without.
“previous studies have shown that GLP1-RAs tend to induce less weight loss in patients with than without T2D [29, 30, 32, 33]”
In non-surgical patients with obesity, semaglutide induces clinically important weight loss and improvement in cardiometabolic risk factors.
“In non-surgical patients with obesity, semaglutide induces clinically important weight loss and improvement in cardiometabolic risk factors [16].”
Across the phase 3 STEP program, semaglutide 2.4 mg subcutaneously weekly plus lifestyle modification in people with obesity without type 2 diabetes produced body weight reduction from baseline ranging from 12.1% to 18.2%.
“Across the phase 3 STEP program for semaglutide 2.4 mg s.c.weekly plus lifestyle modification in individuals living with obesity without T2D, the body weight reduction from baseline ranged from 12.1% to 18.2%.107-113”
From Management of type 2 diabetes, obesity, or nonalcoholic steatohepatitis with high‐dose GLP‐1 receptor agonists and GLP‐1 receptor‐based co‐agonists (2024) · cites this paper as [112]
A proportion of people are not able to tolerate higher doses of GLP-1 RAs due to dose-dependent adverse events.
“Additionally, a proportion of people are not able to tolerate the higher doses of GLP-1 RAs due to dose-dependent adverse events making even more difficult for them to achieve the individualized metabolic and WL targets [17,20].”
Semaglutide 2.4 mg once weekly and liraglutide 3 mg once daily have received approval for chronic weight management.
“The efficacy of the injectable GLP-1 RAs semaglutide and liraglutide in inducing WL and weight maintenance through appetite reduction has led to clinical trials assessing higher doses of these molecules as treatments for obesity and both semaglutide 2.4 mg once weekly and liraglutide 3 mg once daily have now received approval for chronic weight management [17,18].”
The efficacy of injectable GLP-1 RAs semaglutide and liraglutide in inducing WL and weight maintenance through appetite reduction has led to clinical trials assessing higher doses for obesity.
“The efficacy of the injectable GLP-1 RAs semaglutide and liraglutide in inducing WL and weight maintenance through appetite reduction has led to clinical trials assessing higher doses of these molecules as treatments for obesity and both semaglutide 2.4 mg once weekly and liraglutide 3 mg once daily have now received approval for chronic weight management [17,18].”
Early data for some oral GLP-1 RAs suggest similar efficacy in glycemia and WL to injectable GLP-1 RAs.
“In addition, a number of oral GLP-1 RAs are under development to offer an alternative option to people reluctant to injectable treatments, with early data for some of them suggesting similar efficacy in glycemia and WL to injectable GLP-1 RAs [17,23].”
A number of oral GLP-1 RAs are under development to offer an alternative option to people reluctant to injectable treatments.
“In addition, a number of oral GLP-1 RAs are under development to offer an alternative option to people reluctant to injectable treatments, with early data for some of them suggesting similar efficacy in glycemia and WL to injectable GLP-1 RAs [17,23].”
In randomized trials, GLP-1s produce placebo-adjusted weight reduction of 5% to 18% among individuals with obesity or overweight and weight-related complications.
“In the original phase 3 randomized trials for obesity, average weight reduction compared to placebo has ranged from 5.3% to 17.8% after 56 to 72 wk (Table 1), with improvements in several obesity-related risks and complications [[13], [14], [15]].”
In the STEP 1 trial, of the average 13.6-kg weight reduction, 8.3 kg (62%) was fat mass and 5.3 kg (38%) was lean body mass.
“In the STEP 1 trial, of the average 13.6-kg–weight reduction, 8.3 kg (62%) was fat mass and 5.3 kg (38%) was lean body mass (including muscle and other nonfat tissues) [14].”
In the STEP 1 trial, semaglutide with general nutrition and physical activity instructions demonstrated a 14.9% weight reduction from baseline versus 2.4% with general nutrition and physical activity instructions alone.
“In comparison, the STEP 1 trial that included semaglutide with general nutrition and physical activity instructions demonstrated a 14.9% weight reduction from baseline (versus 2.4% with general nutrition and physical activity instructions alone) [14].”
Although limited direct evidence has evaluated use of GLP-1s with or without RDN-provided MNT, the SCALE, STEP 1, SURMOUNT, and STEP 3 trials each demonstrated substantial weight reduction by combining GLP-1s with regular counseling sessions by RDNs or other qualified healthcare professionals.
“Although limited direct evidence has evaluated use of GLP-1s with or without RDN-provided MNT, the SCALE [13], STEP 1 [14], SURMOUNT [15], and STEP 3 [178] trials each demonstrated substantial weight reduction by combining GLP-1s with regular counseling sessions by RDNs or other qualified healthcare professionals (such lifestyle support was also provided to the placebo group in each trial).”
In STEP 1, individuals randomized to semaglutide 2.4 mg achieved an average weight reduction of 14.9% compared to 2.4% for placebo, a treatment difference of 12.4%.
“In STEP 1, individuals randomized to semaglutide achieved an average weight reduction of 14.9% compared to 2.4% for placebo (treatment difference of 12.4%).”
From New Frontiers in Obesity Treatment: GLP-1 and Nascent Nutrient-Stimulated Hormone-Based Therapeutics (2023) · cites this paper as [33]
In STEP 1, one-third of the semaglutide group lost ≥20% body weight versus only 1.7% in the placebo group.
“Furthermore, one-third of the semaglutide group lost ≥20% body weight versus only 1.7% achieving this target in the placebo group (33).”
From New Frontiers in Obesity Treatment: GLP-1 and Nascent Nutrient-Stimulated Hormone-Based Therapeutics (2023) · cites this paper as [33]
In randomized controlled trials, semaglutide and tirzepatide have demonstrated greater weight reduction in patients with obesity without type 2 diabetes compared to other FDA-approved obesity medications.
“In randomized controlled trials, the long‐acting glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) semaglutide and glucose‐dependent insulinotropic polypeptide (GIP) and GLP‐1 dual receptor agonist tirzepatide have demonstrated greater weight reduction in patients with obesity without T2D compared to other obesity medications (OMs) previously approved by the Food and Drug Administration (FDA) [3,”
From Changes in weight and glycemic control following obesity treatment with semaglutide or tirzepatide by discontinuation status (2025) · cites this paper as [3]
The average weight reduction in this cohort was lower than that observed in the main phase 3 trials of semaglutide 2.4 mg (STEP 1) and tirzepatide 5 to 15 mg (SURMOUNT-1).
“The average weight reduction in this cohort was lower than that observed in the main phase 3 trials of semaglutide 2.4 mg (STEP 1) and tirzepatide 5 to 15 mg (SURMOUNT‐1), in which 14.9% and 15.0% and 20.9% weight reduction, respectively, was demonstrated in patients with overweight or obesity (without T2D) plus a lifestyle intervention [3, 4].”
From Changes in weight and glycemic control following obesity treatment with semaglutide or tirzepatide by discontinuation status (2025) · cites this paper as [3]
Discontinuation rates in this study were considerably higher than the rates of discontinuation at approximately 1 year in the main phase 3 trials (17.1% for semaglutide 2.4 mg injection in STEP 1 and 14.3-16.4% for tirzepatide 5-15 mg in SURMOUNT-1).
“In this study, 20.4% of patients discontinued their obesity pharmacotherapy early, and 32.0% discontinued late, which is considerably higher than the rates of discontinuation at ~1 year in the main phase 3 trials (including 17.1% for semaglutide 2.4 mg injection [STEP 1] and 14.3%–16.4% for tirzepatide 5–15 mg [SURMOUNT‐1] [3, 4]).”
From Changes in weight and glycemic control following obesity treatment with semaglutide or tirzepatide by discontinuation status (2025) · cites this paper as [3]
Existing data suggest that marked adipose tissue loss with semaglutide and tirzepatide occurs with concomitant muscle loss.
“Existing data suggest that marked adipose tissue loss with semaglutide and tirzepatide occurs with concomitant muscle loss202,204,205.”
From Sarcopenic obesity in older adults: a clinical overview (2024) · cites this paper as [204]
Nineteen publications reported gallstones or gallbladder-related disorders in 0-3.1% of patients treated with liraglutide, 0.2-7% with semaglutide, and 0-2.9% with tirzepatide.
“Nineteen publications reported gallstones or gallbladder-related disorders [11-14,30,36,40,52,62,65,74,77,78,84,85,93,94,103] in 0-3.1%, 0.2-7%, 0-2.9% of patients treated with liraglutide, semaglutide, and tirzepatide, respectively.”
From Symptomatic Adverse Events and Quality of Life Related to Incretin-Based Medicines for Obesity: A Systematic Review Involving >400,000 Subjects (2025) · cites this paper as [13]
Changes to lean body mass and bone mineral density were reported in 8 of the 81 identified publications.
“Changes to lean body mass (LBM) defined as total body weight minus fat mass, and bone mineral density were reported in 8 of the 81 identified publications [12,13,37,45,50,73,75,87].”
From Symptomatic Adverse Events and Quality of Life Related to Incretin-Based Medicines for Obesity: A Systematic Review Involving >400,000 Subjects (2025) · cites this paper as [13]
In the STEP 1-4 trials (semaglutide), the proportion of participants experiencing nausea increased from 0 to ~20% from Week 0 to Week 20 (dose escalation or run-in period), then decreased to ~4% by Week 68 (maintenance phase).
“In the STEP 1-4 trials (semaglutide), the proportion of participants experiencing nausea increased from 0 to ~20% from Week 0 to Week 20 (dose escalation or run-in period), then decreased to ~4% by Week 68 (maintenance phase) [13,65,84,93,98].”
From Symptomatic Adverse Events and Quality of Life Related to Incretin-Based Medicines for Obesity: A Systematic Review Involving >400,000 Subjects (2025) · cites this paper as [13]
Semaglutide 2.4 mg is associated with mean weight loss exceeding 15% of initial body weight over 68 weeks.
“Semaglutide 2.4 mg, for example, has been associated with mean weight loss exceeding 15% of initial body weight over 68 weeks [13]”
From Unintended Consequences of Obesity Pharmacotherapy: A Nutritional Approach to Ensuring Better Patient Outcomes (2025) · cites this paper as [13]
In the STEP 1 trial, semaglutide treatment resulted in an average lean mass reduction of 6.9 kg (−13.2%) out of a total 15.3 kg (−14.9%) weight loss, representing approximately 45% of the total weight lost as lean mass.
“In the STEP 1 trial, semaglutide treatment resulted in an average lean mass reduction of 6.9 kg (−13.2%) out of a total 15.3 kg (−14.9%) weight loss, representing approximately 45% of the total weight lost as lean mass [13].”
From Unintended Consequences of Obesity Pharmacotherapy: A Nutritional Approach to Ensuring Better Patient Outcomes (2025) · cites this paper as [13]
Several clinical trials of GLP-1 receptor agonists and related pharmacotherapies have reported that a proportion of total weight loss occurs as lean mass, though the magnitude varies by drug, population, and methodology.
“Several clinical trials of GLP-1 receptor agonists and related pharmacotherapies have reported that a proportion of total weight loss occurs as lean mass, though the magnitude varies by drug, population, and methodology.”
From Unintended Consequences of Obesity Pharmacotherapy: A Nutritional Approach to Ensuring Better Patient Outcomes (2025) · cites this paper as [13]
The FDA approved semaglutide in June 2021 for long-term weight management in overweight or people with obesity.
“the FDA approved semaglutide in June 2021 for long-term weight management in overweight or people with obesity (31–33).”
From Gastrointestinal adverse events associated with semaglutide: A pharmacovigilance study based on FDA adverse event reporting system (2022) · cites this paper as [31]
The first multicenter real-world cohort study reported an average 13.4% loss, comparable to the STEP 1 clinical trial data, implying a variable response to semaglutide in different trial and real-world settings.
“Conversely, the first multicenter real-world cohort study reported an average 13.4% loss (97), comparable to the STEP 1 clinical trial data (79), implying a variable response to semaglutide in different trial and real-world settings.”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [79]
Gastrointestinal side effects are typically classed as mild or moderate, and reported to subside in most patients following titration up to maintenance doses, although they still lead to permanent discontinuation of treatment in 4% to 10% of participants.
“Gastrointestinal side effects are typically classed as mild or moderate, and reported to subside in most patients following titration up to maintenance doses (77, 79, 104), although they still lead to permanent discontinuation of treatment in 4% to 10% of participants (77, 79, 95).”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [79]
Semaglutide achieved previously unseen anti-obesity-medication-mediated weight-loss effects of up to 15%.
“Semaglutide represented a step-change in the efficacy of AOMs, achieving previously unseen AOM-mediated weight-loss effects of up to 15% (77‐79), thus approaching the gold standard of bariatric surgery.”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [79]
Substantial response variability exists within patient populations, with the STEP and SURMOUNT trials reporting that 10% to 15% of individuals lose <5% on semaglutide or tirzepatide, respectively, and are thus classed as nonresponders.
“Looking beyond headline weight loss results, substantial response variability exists within patient populations, with the STEP and SURMOUNT trials reporting that 10% to 15% of individuals lose <5% on semaglutide or tirzepatide, respectively, and are thus classed as “nonresponders” (77, 79, 80, 94, 100).”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [79]
The 4-year SELECT clinical trial reported 8.7% placebo-subtracted weight loss, markedly lower than 12.5% in STEP 1 at 68 weeks.
“Furthermore, the 4-year SELECT clinical trial—the longest AOM study of semaglutide to date—reported 8.7% placebo-subtracted weight loss, markedly lower than 12.5% in STEP 1 at 68 weeks (79, 95).”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [79]
GLP-1RA efficacy is lessened in participants with a lower starting weight/BMI or with prior exposure to GLP-1RAs, and it is reduced by a third in type 2 diabetics and in male individuals.
“Notably, GLP-1RA efficacy is lessened in participants with a lower starting weight/BMI or with prior exposure to GLP-1RAs (95, 102), and it is reduced by a third in type 2 diabetics and in male individuals (79, 93, 95‐97, 99).”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [79]
Loss of lean body mass is a common side effect of GLP-1RAs, with studies reporting that lean mass loss accounts for ∼45% and ∼25% of total loss for semaglutide and tirzepatide, respectively.
“The loss of lean body mass is another common side effect of GLP-1RAs, with studies reporting that lean mass loss accounts for ∼45% and ∼25% of total loss for semaglutide (79, 105) and tirzepatide (98), respectively.”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [79]
The STEP3 trial included an 8-week low-calorie diet prior to semaglutide initiation, which did not result in notably greater weight loss than the STEP1 trial which did not include such a lead-in.
“However, the STEP3 trial did include an 8-week low-calorie diet prior to semaglutide initiation (94), which did not result in notably greater weight loss than the STEP1 trial which did not include such a lead-in (79)”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [79]
GLP1R agonist obesity drugs produce aversive effects such as nausea and vomiting, and these effects may contribute to their therapeutic efficacy.
“The most successful obesity therapeutics – glucagon-like peptide-1 receptor (GLP1R) agonists – cause aversive responses such as nausea and vomiting1,2, effects which may contribute to their efficacy.”
From Dissociable hindbrain GLP1R circuits for satiety and aversion (2024) · cites this paper as [2]
Long-acting GLP-1RAs exert substantial and sustained body weight losses.
“Long-acting GLP-1RAs exert substantial and sustained body weight losses,18”
From The cardioprotective effects of semaglutide exceed those of dietary weight loss in mice with HFpEF (2023) · cites this paper as [18]
Long-acting GLP-1 receptor agonists have demonstrated improvements in CVD risk factors including waist circumference, SBP, triglycerides, HDL cholesterol, and LDL in individuals with obesity.
“Long-acting glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated promising weight reduction in recent studies, 14,15 together with improvements in CVD risk factors including waist circumference, systolic blood pressure (SBP), triglycerides, high-density lipoprotein (HDL) cholesterol, and lowdensity lipoprotein (LDL) in individuals with obesity.16,17”
In a phase 3 study investigating semaglutide for weight loss in patients with obesity or overweight, participants who received semaglutide demonstrated improvements in cardiometabolic risk factors.
“In a phase 3 study investigating the effect of semaglutide, a GLP-1 receptor agonist, on weight loss in patients with obesity or overweight, participants who received semaglutide demonstrated improvements in cardiometabolic risk factors.15”
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Jensen, S. B. K., Blond, M. B., Sandsdal, R. M., Olsen, L. M., Juhl, C. R., Lundgren, J. R., Janus, C., Stallknecht, B. M., Holst, J. J., Madsbad, S., et al. (2024) · eClinicalMedicine · doi:10.1016/j.eclinm.2024.102475 · Cited by 207 · see citing works
Semaglutide, delayed gastric emptying, and intraoperative pulmonary aspiration: a case report
Klein, S. R., & Hobai, I. A. (2023) · Canadian Journal of Anesthesia/Journal canadien d'anesthésie · doi:10.1007/s12630-023-02440-3 · Cited by 207 · see citing works
A review of current guidelines for the treatment of obesity
(2022) · The American Journal of Managed Care · doi:10.37765/ajmc.2022.89292 · Cited by 207 · see citing works
Urva, S., Coskun, T., Loh, M. T., Du, Y., Thomas, M. K., Gurbuz, S., Haupt, A., Benson, C. T., Hernandez-Illas, M., D’Alessio, D. A., et al. (2022) · The Lancet · doi:10.1016/s0140-6736(22)02033-5 · Cited by 202 · see citing works
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“4 mg demonstrated substantial, clinically meaningful weight losses and improvements in cardiometabolic parameters and patient-reported outcomes.(8-11) Gastrointestinal (GI) adverse events (AEs), most commonly mild-tomoderate nausea, are a dose-dependent class effect of GLP-1RAs.”
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- Authors
- Wilding, J. P. H., Batterham, R. L., Calanna, S., Davies, M., Van Gaal, L. F., Lingvay, I., McGowan, B. M., Rosenstock, J., Tran, M. T. D., Wadden, T. A., Wharton, S., Yokote, K., Zeuthen, N., & Kushner, R. F.
- Affiliations
- University College London Hospitals NHS Foundation Trust (GB)
- University College Hospital (GB)
- From the Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool (J.P.H.W.), University College London Centre for Obesity Research, Division of Medicine, University College London (R.L.B.), the National Institute of Health Research, UCLH Biomedical Research Centre (R.L.B.), the Centre for Weight Management and Metabolic Surgery, University College London Hospital (R.L.B.), and the Department of Diabetes and Endocrinology, Guy’s and St. Thomas’ NHS Foundation Trust (B.M.M.), London, and the Diabetes Research Centre, University of Leicester (M.D.) and the NIHR Leicester Biomedical Research Centre (M.D.), Leicester — all in the United Kingdom; Novo Nordisk, Søborg, Denmark (S.C., M.T.D.T., N.Z.); the Department of Endocrinology, Diabetology, and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium (L.F.V.G.); the Departments of Internal Medicine/Endocrinology and Population and Data Sciences, University ...
- Northwestern University (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2021-03-18
- Volume
- 384
- Issue
- 11
- Pages
- 989-1002
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W3127371223
- Semantic Scholar
- 00089c657bd5b957b51f67c6c9b80c7d17ce9c5a
- Cited by
- 5,205
- References
- 40
- Citations by year
- 2026: 1566 · 2025: 1350 · 2024: 965 · 2023: 657 · 2022: 386 · 2021: 270 · 2020: 4
- FWCI
- 332.33
- Type
- journal article
- Language
- en
- Open access
- green
- discovery.ucl.ac.uk
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- HAL (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Novo Nordisk
- Topics
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- obesity, overweight, weight loss, GLP-1 receptor agonists, lifestyle intervention, cardiometabolic risk factors, physical function, nausea and diarrhea, adverse events, weight-related comorbidities, sleep duration, medication adherence, treatment discontinuation, rescue interventions, body mass index
- MeSH terms
- Healthy Lifestyle, Semaglutide, Adult, Body Composition, Cholelithiasis, Diarrhea, Double-Blind Method, Glucagon-Like Peptides, Female, Humans, Injections, Subcutaneous, Lipids, Male, Middle Aged, Nausea, Obesity, Prediabetic State, Weight Loss, Body Mass Index, Anti-Obesity Agents, Glucagon-Like Peptide 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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