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Cited by 227Pharmacology and Obesity TreatmentDiabetes Treatment and ManagementBariatric Surgery and Outcomes

Semaglutide for the treatment of obesity

Open access
Chao, Ariana M., Tronieri, Jena S., Amaro, Anastassia, Wadden, Thomas A.·2023·Trends in Cardiovascular Medicine
DOI 10.1016/j.tcm.2021.12.008PMC PMC9209591
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Abstract

Semaglutide is a glucagon-like peptide-1 receptor agonist that was recently approved by the US Food and Drug Administration for chronic weight management. This paper reviews data on the mechanism of action, weight-loss and cardiometabolic efficacy, and safety of semaglutide 2.4 mg/week for obesity. Semaglutide has demonstrated the largest weight loss of any obesity medication to date with reductions of approximately 15% of initial weight at 68 weeks, accompanied by improvements in cardiovascular risks factors and physical functioning. The approval of this medication provides patients with greater options for weight management.

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Crossref · 10.1016/j.tcm.2021.12.008

Cites

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Claims the paper makes

0 of 88 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    In a 20-week trial, all liraglutide doses (1.2, 1.8, 2.4, 3.0 mg) produced significantly greater mean weight loss than placebo (4.8, 5.5, 6.3, 7.2 kg vs 2.8 kg).

    “The mean weight loss was significantly greater with all doses of liraglutide relative to placebo (4.8 kg, 5.5 kg, 6.3 kg, and 7.2 kg for liraglutide 1.2 mg, 1.8 mg, 2.4 mg, and 3.0 mg, respectively, versus 2.8 kg for placebo).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Astrup, 2009, Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study, Lancet source

      Not checked in the free run.

  • Premisecitation

    Liraglutide induces weight loss by reducing energy intake.

    “Liraglutide induces weight loss by reducing energy intake.(16)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Van Can, 2014, Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults, Int J Obes source

      Not checked in the free run.

  • Premisecitation

    Compared with placebo, liraglutide lowers ad libitum energy intake by 16% in a laboratory meal paradigm.

    “Compared to placebo, liraglutide lowers ad libitum energy intake by 16%, as shown with a laboratory meal paradigm.(16)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Van Can, 2014, Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults, Int J Obes source

      Not checked in the free run.

  • Premisecitation

    In that trial, liraglutide 2.4 and 3.0 mg produced significantly greater weight loss than orlistat 120 mg three times daily (4.1 kg).

    “Participants who received liraglutide 2.4 mg or 3.0 mg also lost significantly more weight than those assigned to orlistat (4.1 kg).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Astrup, 2009, Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study, Lancet source

      Not checked in the free run.

  • Premisecitation

    Compared with placebo, semaglutide 2.4 mg once weekly for 20 weeks reduced ad libitum energy intake by 35% in a laboratory meal paradigm.

    “Compared to placebo, semaglutide 2.4 mg (i.e., once-weekly for 20 weeks) reduced ad libitum energy intake by 35%, as shown with a laboratory meal paradigm.(30)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Friedrichsen, 2021, The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity, Diabetes Obes Metab source

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  • Classified as probably not a substantial claim. 9
  • May combine two claims. 37

  • Classified as probably not a substantial claim.

    Premisecitation

    GLP-1 has a half-life of 1 to 2 minutes due to N-terminal degradation by DPP-4.

    “The half-life of GLP-1 is 1 to 2 minutes due to N-terminal degradation by the enzyme dipeptidyl peptidase 4 (DPP-4).(8, 9)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Vilsbøll, 2003, Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [9] Holst, 2007, The physiology of glucagon-like peptide 1, Physiol Rev source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Semaglutide 2.4 mg/week produces about 15% weight loss at 68 weeks, the largest among obesity medications to date, and improves cardiovascular risk factors and physical functioning.

    “Semaglutide has demonstrated the largest weight loss of any obesity medication to date with reductions of approximately 15% of initial weight at 68 weeks, accompanied by improvements in cardiovascular risks factors and physical functioning.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Liraglutide relative to placebo reduced fasting blood glucose by 15.7 mg/dL, HbA1c by 0.5%, and systolic blood pressure by 2.8 mmHg.

    “Liraglutide, relative to placebo, resulted in declines of 15.7 mg/dL in fasting blood glucose, 0.5% in hemoglobin A1c, and 2.8 mmHg in systolic blood pressure.(24)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Khera, 2018, Effects of weight-loss medications on cardiometabolic risk profiles: a systematic review and network meta-analysis, Gastroenterology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GLP-1 stimulates insulin release, inhibits glucagon release, slows gastric emptying, and reduces food intake.

    “It stimulates insulin release and secretion in hyperglycemic states, inhibits glucagon release in hyperglycemic or euglycemic states, slows gastric emptying, and reduces food intake.(6, 7)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Lee, 2014, Anti-diabetic actions of glucagon-like peptide-1 on pancreatic beta-cells, Metabolism source

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    • cites [7] Donnelly, 2012, The structure and function of the glucagon-like peptide-1 receptor and its ligands, Br J Pharmacol source

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  • May combine two claims.

    Premisecitation

    A meta-analysis found liraglutide produced mean 5.2 kg placebo-subtracted weight loss at 1 year, with 63% achieving at least 5% and 34% at least 10% weight loss.

    “A meta-analysis showed that liraglutide produced a mean 5.2 kg placebo-subtracted weight loss at 1 year, with 63% of participants achieving a ≥5% weight loss, inclusive of 34% of participants who lost ≥10% of initial weight.(23)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Khera, 2016, Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Weight losses of 5% or more of initial weight ameliorate obesity complications, with larger losses producing greater health benefits.

    “Weight losses of 5% or more of initial weight help to ameliorate these complications, with larger losses producing greater health benefits.(3)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] 2013, Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes, NEJM source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    GLP-1 is released from L-cells in the distal small intestine and colon after oral nutrient intake.

    “Glucagon-like peptide 1 (GLP-1) is a hormone released from the proglucagon gene in L-cells of the distal small intestine and colon in response to oral nutrient intake.(5)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Koliaki, 2011, Incretin-based therapy: a powerful and promising weapon in the treatment of type 2 diabetes mellitus, Diabetes Ther source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Liraglutide has little known effect on energy expenditure.

    “It has little known effect on energy expenditure.(16)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Van Can, 2014, Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults, Int J Obes source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    GLP-1 binds to receptors in pancreatic beta cells, gastric mucosa, kidney, heart, and hypothalamus.

    “The hormone binds to GLP-1 receptors expressed in tissues such as the pancreatic beta cells, gastric mucosa, kidney, heart, and hypothalamus.(6, 7)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Lee, 2014, Anti-diabetic actions of glucagon-like peptide-1 on pancreatic beta-cells, Metabolism source

      Not checked in the free run.

    • cites [7] Donnelly, 2012, The structure and function of the glucagon-like peptide-1 receptor and its ligands, Br J Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    In STEP 4, continued semaglutide versus placebo was associated with better outcomes for waist circumference, systolic blood pressure, HbA1c, fasting plasma glucose, fasting serum insulin, lipid profile, and physical functioning.

    “Continued semaglutide, relative to the switch to placebo, was associated with better outcomes for waist circumference, systolic blood pressure, hemoglobin A1c, fasting plasma glucose, fasting serum insulin, lipid profile, and physical functioning on the SF-36 (Table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Rubino, 2021, Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    In STEP 1, semaglutide relative to placebo produced larger reductions in waist circumference, systolic and diastolic blood pressure, HbA1c, fasting glucose, total cholesterol, LDL cholesterol, triglycerides, and CRP, and greater improvements in HDL cholesterol and physical functioning.

    “Semaglutide-treated participants, relative to placebo, achieved larger reductions in waist circumference, systolic and diastolic blood pressure, hemoglobin A1c, fasting blood glucose, total cholesterol, LDL cholesterol, triglycerides, and c-reactive protein.”
    • Also stated in: § Weight-Loss and Cardiometabolic Efficacy · plain
      “They also experienced greater improvements in HDL cholesterol, and in physical functioning as assessed by the 36-item Short Form Health Survey (SF-36) and by the Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL-Lite-CT) questionnaires (Table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Wilding, 2021

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Semaglutide has a half-life of 155 to 184 hours, allowing once-weekly subcutaneous dosing without compromising weight loss efficacy.

    “This formulation results in slower degradation and a half-life 155 to 184 hours, allowing for once-weekly subcutaneous dosing without compromising weight loss efficacy.(11, 26)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Knudsen, 2019, The discovery and development of liraglutide and semaglutide, Front Endocrinol (Lausanne) source

      Not checked in the free run.

    • cites [26] Lau, 2015, Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide, J Med Chem source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    In STEP 3, semaglutide-treated participants were more likely than placebo to lose at least 5%, 10%, 15%, and 20% of initial weight, with 35.7% versus 3.7% meeting the 20% criterion.

    “Semaglutide-treated participants were more likely than placebo to lose ≥5%, ≥10%, ≥15%, and ≥20% of initial weight, with 35.7% and 3.7% of participants, respectively, meeting the last criterion (Figure 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Wadden, 2021, Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Semaglutide's structural modifications allow reversible albumin binding, reducing renal clearance and DPP-4 degradation while maintaining high GLP-1 receptor affinity.

    “It has structural modifications to allow for reversible albumin binding, reducing renal clearance and decreasing degradation by DPP-4, while also allowing for sufficiently high GLP-1R affinity.(11, 26)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Knudsen, 2019, The discovery and development of liraglutide and semaglutide, Front Endocrinol (Lausanne) source

      Not checked in the free run.

    • cites [26] Lau, 2015, Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide, J Med Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most gastrointestinal events with semaglutide were mild-to-moderate, transient, and occurred during the first 20 weeks during dose escalation.

    “Most gastrointestinal events were mild-to-moderate in severity, transient, and occurred during the first 20 weeks of treatment during dose escalation.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [34] Wilding, 2021

      Not checked in the free run.

    • cites [35] Davies, 2021, Semaglutide 2• 4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial, Lancet source

      Not checked in the free run.

    • cites [36] Wadden, 2021, Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Semaglutide promotes insulin secretion from pancreatic beta cells and decreases glucagon secretion in a glucose-dependent manner.

    “Semaglutide promotes insulin secretion from beta cells in the pancreas and decreases glucagon secretion in a glucose-dependent manner.(27, 28)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Ahmann, 2018, Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial, Diabetes Care source

      Not checked in the free run.

    • cites [28] Ahrén, 2017, Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial, Lancet Diabetes Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In STEP 1-3, nausea occurred in 33.7-58.2% of semaglutide versus 9.2-22.1% placebo; diarrhea in 21.3-36.1% versus 11.9-22.1%; vomiting in 21.8-27.3% versus 2.7-10.8%; and constipation in 17.4-36.9% versus 5.5-24.5%.

    “In STEP trials 1–3, the percent of participants in the semaglutide 2.4 mg vs placebo groups who experienced nausea was 33.7–58.2% versus 9.2–22.1%; diarrhea was 21.3–36.1% vs 11.9–22.1%; vomiting was 21.8–27.3% vs 2.7–10.8%; and constipation was 17.4–36.9% vs 5.5–24.5%.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [34] Wilding, 2021

      Not checked in the free run.

    • cites [35] Davies, 2021, Semaglutide 2• 4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial, Lancet source

      Not checked in the free run.

    • cites [36] Wadden, 2021, Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In STEP 4, from weeks 20 to 68, the continued semaglutide group lost 7.9 percentage points of randomization weight while the placebo-switched group gained 6.9 percentage points, with an estimated treatment difference of -14.8 (95% CI -16.0 to -13.5, p<0.001).

    “Those who remained on semaglutide lost 7.9 percentage points of their randomization weight from weeks 20 to 68, whereas those switched to placebo gained 6.9 percentage points (estimated treatment differences = −14.8; 95% CI=−16.0 to −13.5 percentage points; p<0.001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Rubino, 2021, Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    In STEP 1, significantly more semaglutide than placebo participants achieved at least 5%, 10%, and 15% weight reductions.

    “Significantly more participants in the semaglutide than in the placebo group achieved reductions of ≥5%, ≥10%, and ≥15% (Figure 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Wilding, 2021

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    In STEP 3, semaglutide versus placebo had greater reductions in waist circumference, systolic and diastolic blood pressure, CRP, HbA1c, and lipids except HDL.

    “Participants in the semaglutide group, relative to placebo, had greater reductions in waist circumference, systolic and diastolic blood pressure, c-reactive protein, hemoglobin A1c, and lipids (with the exception of HDL; Table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Wadden, 2021, Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In STEP 2, the estimated treatment difference for semaglutide 2.4 mg versus placebo was -6.2 percentage points (95% CI -7.3 to -5.2, p<0.001), and versus semaglutide 1.0 mg was 2.7 percentage points (95% CI -3.7 to -1.6, p<0.0001).

    “The estimated treatment difference for semaglutide 2.4 mg vs placebo was −6.2 percentage points (95% CI −7.3 to −5.2, p<0.001), and for semaglutide 2.4 mg vs semaglutide 1.0 mg was 2.7 percentage points (95% CI −3.7 to −1.6, p<0.0001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Davies, 2021, Semaglutide 2• 4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Semaglutide is a long-acting GLP-1 receptor agonist with 94% homology to native human GLP-1.

    “Semaglutide is a long-acting GLP-1 receptor agonist with 94 percent homology with native human GLP-1.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Knudsen, 2019, The discovery and development of liraglutide and semaglutide, Front Endocrinol (Lausanne) source

      Not checked in the free run.

    • cites [26] Lau, 2015, Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide, J Med Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In STEP 1, semaglutide-treated participants lost 14.9% of baseline weight versus 2.4% for placebo, with an estimated treatment difference of -12.4 percentage points (95% CI -13.4 to -11.5).

    “Semaglutide-treated patients lost 14.9% of baseline weight compared with 2.4% for placebo (estimated treatment difference = −12.4 percentage points, 95% CI −13.4 to −11.5; Table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Wilding, 2021

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    In STEP 2, semaglutide 2.4 mg versus placebo had greater reductions in waist circumference, A1c, fasting glucose, systolic blood pressure, triglycerides, CRP, and physical functioning scores.

    “The semaglutide 2.4 mg group, compared with placebo, had significantly greater reductions in waist circumference, A1c, fasting glucose, systolic blood pressure, triglycerides, c-reactive protein, and physical functioning scores on the SF-36 and IWQOL-Lite-CT (Table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Davies, 2021, Semaglutide 2• 4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gallbladder-related disorders were reported in 2.6% versus 1.2% in STEP 1, 0.2% versus 0.7% in STEP 2, and 4.9% versus 1.5% in STEP 3 for semaglutide versus placebo.

    “Gallbladder-related disorders (primarily cholelithiasis) were reported in 2.6% vs 1.2% of participants on semaglutide vs placebo in STEP 1, 0.2% vs 0.7% of participants in STEP 2, and 4.9% vs 1.5% in STEP 3.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [34] Wilding, 2021

      Not checked in the free run.

    • cites [35] Davies, 2021, Semaglutide 2• 4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial, Lancet source

      Not checked in the free run.

    • cites [36] Wadden, 2021, Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial, JAMA source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Gallstone formation might also stem from direct GLP-1 and agonist effects on bile secretion or from drug-induced changes in gallbladder motility.

    “Cholelithiasis formation may also be a result of the direct action of GLP-1 and its agonist on biliary secretion and/or drug-induced modification of gallbladder motility.(56)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Nexøe-Larsen, 2018, Effects of liraglutide on gallbladder emptying: A randomized, placebo-controlled trial in adults with overweight or obesity, Diabetes Obes Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In STEP 4, substantial weight is lost during the 16-week dose-escalation phase, but maximum weight loss is not reached until the full dose has been taken for a year.

    “STEP 4 revealed two very important findings, the first which is that patients will lose substantial amounts of weight during the 16-week upward titration period but will not achieve their maximum weight loss until taking the full dose for 1 year.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Rubino, 2021, Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial, JAMA source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    A once-weekly injection schedule might deter some people who dislike injecting medication.

    “While participants only need to inject themselves once a week, this may limit use for some individuals who are reluctant to inject a medication.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Possible reasons for smaller weight reductions in diabetes include lower resting metabolic rate after better glycemic control, poorer dietary adherence and defensive snacking from hypoglycemia fear, and less glycosuria.

    “Mechanisms responsible for smaller weight losses in patients with diabetes may include reductions in resting metabolic rate, which occur with improved glycemic control (accompanying weight loss), decreased dietary adherence and “defensive snacking” related to fears of hypoglycemia, as well as reduced glycosuria.(49, 50)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [49] Carlson, 1993, Intensive insulin therapy and weight gain in IDDM, Diabetes source

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    • cites [50] Brown, 2017, Insulin-associated weight gain in obese type 2 diabetes mellitus patients: What can be done?, Diabetes Obes and Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    More than half of STEP 1 participants lost at least 15% of baseline weight, and 30% lost at least 20%, a loss approaching that produced by sleeve gastrectomy.

    “More than half of participants in STEP 1 lost 15% or more of baseline weight, and 30% of participants lost 20% of initial weight, a loss that approaches that produced by sleeve gastrectomy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Semaglutide's gastrointestinal side effects might arise from altered gastric emptying, intestinal motility, secretion of other gut peptide hormones, or direct or indirect central nervous system actions.

    “They could be the result of the effect of the medication on gastrointestinal functions such as gastric emptying, intestinal motility, secondary changes in the secretion of other gastrointestinal peptide hormones, and/or direct or indirect effects on the central nervous system.(51)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Baraboi, 2011, Brain activation following peripheral administration of the GLP-1 receptor agonist exendin-4, Am J Physiol Regul Integr Comp Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    STEP 1 found semaglutide increased placebo-subtracted weight loss to 12.5 kg, with a mean 14.9% reduction in baseline weight at 68 weeks, compared with 7-8% for most other anti-obesity medications.

    “STEP 1 found that semaglutide increased this value to 12.5 kg, with a mean 14.9% reduction in baseline weight at 68 weeks, compared with to 7%−8% for most other AOM.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Wilding, 2021

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    An oral form of semaglutide might make treatment more convenient, acceptable, and easier to stick with.

    “The oral formulation may improve convenience, acceptance, and adherence.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    How GLP1 receptor agonists cause gallstones is not known, but it might involve the large, rapid weight loss some patients experience.

    “The exact mechanism of development of cholelithiasis in GLP1-RAs is unknown but may be attributable to large, rapid weight losses experienced by some patients.(53)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Erlinger, 2000, Gallstones in obesity and weight loss, Eur J Gastroenterol Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In SUSTAIN-6, the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke occurred in 6.6% of semaglutide-treated participants versus 8.9% of placebo (HR 0.74, 95% CI 0.58-0.95; p<0.001 for noninferiority; p=0.02 for superiority).

    “The primary composite outcome -- death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke -- occurred in significantly fewer participants treated by semaglutide (6.6%) than by placebo (8.9%) (HR, 0.74; 95% CI, 0.58 to 0.95; p<0.001 for noninferiority; p=0.02 for superiority).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] Marso, 2016, Semaglutide and cardiovascular outcomes in patients with type 2 diabetes, NEJM source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    In STEP 2, the 68-week weight reduction was 9.6%, roughly one-third smaller than that seen in people without diabetes across three other STEP trials.

    “However, the week-68 loss of 9.6% was approximately one-third less than that observed in participants without diabetes in the three other STEP trials reviewed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Davies, 2021, Semaglutide 2• 4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Greater weight loss reliably produces greater improvements in cardiometabolic risk factors and quality of life, as observed in the STEP trials.

    “Greater weight loss reliably produces greater improvements in several cardiometabolic risk factors,(3) as well as quality of life,(41) as was observed in the STEP trials.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] 2013, Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes, NEJM source

      Not checked in the free run.

    • cites [41] Pearl, 2018, Short-and long-term changes in health-related quality of life with weight loss: results from a randomized controlled trial, Obesity source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Among people taking semaglutide 2.4 mg, gastrointestinal side effects were frequent, usually mild to moderate, and most people recovered without stopping treatment.

    “As with all GLP-1 medications, gastrointestinal side effects were common in participants who took semaglutide 2.4 mg, though most were mild-to-moderate, and the majority of participants recovered without treatment discontinuation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Wharton, 2021, Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss, Diabetes Obes and Metab

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In type 2 diabetes, several studies have found absolute cost savings and cost-effectiveness for semaglutide 1.0 mg relative to other diabetes drugs.

    “Several studies in patients with type 2 diabetes (in different countries) have shown absolute cost savings with semaglutide 1.0 mg, as well as the cost effectiveness of semaglutide 1.0 mg compared to other diabetes pharmacotherapies.(58, 59)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [58] Viljoen, 2019, Evaluation of the long-term cost-effectiveness of once-weekly semaglutide versus dulaglutide for treatment of type 2 diabetes mellitus in the UK, Diabetes Obes Metab source

      Not checked in the free run.

    • cites [59] Wilkinson, 2018, Cost of achieving HbA1c treatment targets and weight loss responses with once-weekly semaglutide versus dulaglutide in the United States, Diabetes Ther source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The STEP 3 study did not suggest fully additive weight loss when intensive behavioral therapy was combined with semaglutide, unlike when intensive behavioral therapy was combined with anti-obesity medications producing 5-6% weight reduction.

    “Thus, the study did not suggest the occurrence of fully additive weight loss, which had been observed when IBT was combined with AOM that produced a mean reduction of only 5%−6% of initial weight.(43)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Wadden, 2005, Randomized trial of lifestyle modification and pharmacotherapy for obesity, NEJM source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In STEP 2, HbA1c fell by 1.5-1.6% in both dose groups, with no significant difference between them.

    “HbA1c improved markedly in both groups – by 1.5–1.6% - but did not differ significantly, affirming the different doses prescribed for the management of obesity vs type 2 diabetes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Davies, 2021, Semaglutide 2• 4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There are few cost analyses of anti-obesity drugs used specifically for weight management, and one study found semaglutide might not be cost-effective due to its high price.

    “However, few cost evaluations have been conducted for AOM specifically for weight management; one study suggested that semaglutide may not be cost-effective because of its high price.(60)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Lee, 2020, The cost-effectiveness of pharmacotherapy and lifestyle intervention in the treatment of obesity, Obes Sci Pract source

      Not checked in the free run.

42 of 42

  • The paper relies on this without support.

    Comprehensive lifestyle intervention remains the cornerstone of obesity treatment, but suboptimal weight losses and weight regain are common with this approach.

    “Comprehensive lifestyle intervention remains the cornerstone of obesity treatment, but suboptimal weight losses and weight regain are common with this approach.”

  • The paper relies on this without support.

    The efficacy and safety results from the STEP trials apply to the broader population of adults with obesity or overweight.

    “Taken together, the first four STEP trials have revealed several critical findings concerning the induction and maintenance of weight loss.”

  • The paper relies on this without support.

    The cardiovascular outcome results from SUSTAIN-6 with semaglutide 0.5 or 1.0 mg in patients with type 2 diabetes apply to semaglutide 2.4 mg in patients with obesity without diabetes.

    “The small mean increase in pulse rate does not appear to adversely affect cardiovascular outcomes, as revealed by results of the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6).(39)”

  • The paper relies on this without support.

    For most people, obesity is a chronic condition that can be managed but not cured.

    “with the recognition that obesity, for most individuals, is a chronic condition that can be managed by not cured.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • US medication count does not match the list

    Minor

    The text says five medications are approved in the US but names six.

  • STEP 2 treatment difference has the opposite sign from its confidence interval

    Minor

    The reported difference is positive 2.7 percentage points, while both limits of its confidence interval are negative.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Davies, 2015, Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial, JAMA, 314, 687, 10.1001/jama.2015.9676 · DOI · Paper page

Cited by

Sorted by citations

Authors
Chao, A. M., Tronieri, J. S., Amaro, A., & Wadden, T. A.
Affiliations
University of Pennsylvania (US)
Corresponding author
Chao, Ariana M.
ORCID
Venue
Trends in Cardiovascular Medicine
Publisher
Elsevier BV
Published
2023-04
Volume
33
Issue
3
Pages
159-166
ISSN
1050-1738 (ISSN-L)
DOI
10.1016/j.tcm.2021.12.008
PMC
PMC9209591
OpenAlex
W4200213833
Cited by
227
References
50
Citations by year
2026: 71 · 2025: 83 · 2024: 48 · 2023: 19 · 2022: 6
FWCI
2.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Trends in Cardiovascular Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Nursing Research
  • National Institutes of Health (K23NR017209)
Topics
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Surgery › Bariatric Surgery and Outcomes
Keywords
semaglutide, obesity, GLP-1 receptor agonists, weight loss, cardiometabolic risk, cardiovascular risk factors, drug safety, mechanism of action, weight management
MeSH terms
Semaglutide, Diabetes Mellitus, Type 2, Glucagon-Like Peptides, Humans, Hypoglycemic Agents, Obesity, Weight Loss

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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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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