Semaglutide for the treatment of obesity

In the paper

“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).”

What the sources say

• Supported

  The Confirmatory and Supportive Secondary End Points section reports better waist circumference, systolic blood pressure, HbA1c, fasting plasma glucose, lipid profile, and SF-36 physical functioning outcomes with continued semaglutide versus placebo. Table 2 also reports a greater reduction in fasting serum insulin with continued semaglutide (-18% versus 0%; P < .001). (LLM, conf=0.95)

  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

In the paper

“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.”

What the sources say

• Not checked yetcites [34] Wilding, 2021
• Not checked yetcites [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
• Partly supported

  The Adverse Events section reports that gallbladder-related disorders, mainly cholelithiasis, occurred in 4.9% of semaglutide participants versus 1.5% of placebo participants in STEP 3. The paper’s passages do not provide the stated gallbladder-disorder percentages for STEP 1 or STEP 2, so this source supports only the STEP 3 portion of the sentence. Page numbers were not available in our copy. (LLM, conf=0.90)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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)”

What the sources say

• Not checked yetcites [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 yetcites [9] Holst, 2007, The physiology of glucagon-like peptide 1, Physiol Rev source

In the paper

“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.”

In the paper

“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)”

What the sources say

• Not checked yetcites [24] Khera, 2018, Effects of weight-loss medications on cardiometabolic risk profiles: a systematic review and network meta-analysis, Gastroenterology source

In the paper

“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)”

What the sources say

• Not checked yetcites [6] Lee, 2014, Anti-diabetic actions of glucagon-like peptide-1 on pancreatic beta-cells, Metabolism source
• Not checked yetcites [7] Donnelly, 2012, The structure and function of the glucagon-like peptide-1 receptor and its ligands, Br J Pharmacol source

In the paper

“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)”

What the sources say

• Not checked yetcites [23] Khera, 2016, Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis, JAMA source

In the paper

“Weight losses of 5% or more of initial weight help to ameliorate these complications, with larger losses producing greater health benefits.(3)”

What the sources say

• Not checked yetcites [3] 2013, Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes, NEJM source

In the paper

“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)”

What the sources say

• Not checked yetcites [5] Koliaki, 2011, Incretin-based therapy: a powerful and promising weapon in the treatment of type 2 diabetes mellitus, Diabetes Ther source

In the paper

“It has little known effect on energy expenditure.(16)”

What the sources say

• Not checked yetcites [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

In the paper

“The hormone binds to GLP-1 receptors expressed in tissues such as the pancreatic beta cells, gastric mucosa, kidney, heart, and hypothalamus.(6, 7)”

What the sources say

• Not checked yetcites [6] Lee, 2014, Anti-diabetic actions of glucagon-like peptide-1 on pancreatic beta-cells, Metabolism source
• Not checked yetcites [7] Donnelly, 2012, The structure and function of the glucagon-like peptide-1 receptor and its ligands, Br J Pharmacol source

In the paper

“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).”

What the sources say

• Not checked yetcites [34] Wilding, 2021

In the paper

“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)”

What the sources say

• Not checked yetcites [11] Knudsen, 2019, The discovery and development of liraglutide and semaglutide, Front Endocrinol (Lausanne) source
• Not checked yetcites [26] Lau, 2015, Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide, J Med Chem source

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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)”

What the sources say

• Not checked yetcites [11] Knudsen, 2019, The discovery and development of liraglutide and semaglutide, Front Endocrinol (Lausanne) source
• Not checked yetcites [26] Lau, 2015, Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide, J Med Chem source

In the paper

“Most gastrointestinal events were mild-to-moderate in severity, transient, and occurred during the first 20 weeks of treatment during dose escalation.”

What the sources say

• Not checked yetcites [34] Wilding, 2021
• Not checked yetcites [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 yetcites [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

In the paper

“Semaglutide promotes insulin secretion from beta cells in the pancreas and decreases glucagon secretion in a glucose-dependent manner.(27, 28)”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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%.”

What the sources say

• Not checked yetcites [34] Wilding, 2021
• Not checked yetcites [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 yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“Significantly more participants in the semaglutide than in the placebo group achieved reductions of ≥5%, ≥10%, and ≥15% (Figure 3).”

What the sources say

• Not checked yetcites [34] Wilding, 2021

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“Semaglutide is a long-acting GLP-1 receptor agonist with 94 percent homology with native human GLP-1.”

What the sources say

• Not checked yetcites [11] Knudsen, 2019, The discovery and development of liraglutide and semaglutide, Front Endocrinol (Lausanne) source
• Not checked yetcites [26] Lau, 2015, Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide, J Med Chem source

In the paper

“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).”

What the sources say

• Not checked yetcites [34] Wilding, 2021

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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)”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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)”

What the sources say

• Not checked yetcites [49] Carlson, 1993, Intensive insulin therapy and weight gain in IDDM, Diabetes source
• Not checked yetcites [50] Brown, 2017, Insulin-associated weight gain in obese type 2 diabetes mellitus patients: What can be done?, Diabetes Obes and Metab source

In the paper

“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.”

In the paper

“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)”

What the sources say

• Not checked yetcites [51] Baraboi, 2011, Brain activation following peripheral administration of the GLP-1 receptor agonist exendin-4, Am J Physiol Regul Integr Comp Physiol source

In the paper

“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.”

What the sources say

• Not checked yetcites [34] Wilding, 2021

In the paper

“The oral formulation may improve convenience, acceptance, and adherence.”

In the paper

“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)”

What the sources say

• Not checked yetcites [53] Erlinger, 2000, Gallstones in obesity and weight loss, Eur J Gastroenterol Hepatol source

In the paper

“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).”

What the sources say

• Not checked yetcites [39] Marso, 2016, Semaglutide and cardiovascular outcomes in patients with type 2 diabetes, NEJM source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [3] 2013, Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes, NEJM source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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)”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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)”

What the sources say

• Not checked yetcites [43] Wadden, 2005, Randomized trial of lifestyle modification and pharmacotherapy for obesity, NEJM source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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)”

What the sources say

• Not checked yetcites [60] Lee, 2020, The cost-effectiveness of pharmacotherapy and lifestyle intervention in the treatment of obesity, Obes Sci Pract source