Endocrinology · Medical Literature
Effectiveness & safety of semaglutide in weight reduction in obese nondiabetic patients: A systematic review and meta-analysis.
Abstract
Obesity is a chronic multifactorial disease characterized by excess adiposity and persistent low-grade systemic inflammation, contributing substantially to cardiometabolic morbidity and mortality. Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist approved for chronic weight management, promotes weight loss by reducing appetite, delaying gastric emptying, and decreasing energy intake while also demonstrating potential anti-inflammatory effects. Although semaglutide has shown promising efficacy for weight reduction, an updated evaluation of its efficacy and safety in nondiabetic individuals with overweight or obesity is warranted. A systematic review and meta-analysis was conducted according to PRISMA 2020 guidelines. PubMed/MEDLINE, Embase, Scopus, and CINAHL were searched from inception to March 2025 for randomized controlled trials evaluating subcutaneous semaglutide in adults with overweight or obesity without type 2 diabetes mellitus. The primary outcome was the percentage change in body weight from baseline. Secondary outcomes included overall gastrointestinal adverse events, nausea, vomiting, diarrhea, constipation, treatment discontinuation due to adverse events, and serious adverse events. Pooled estimates were calculated using a random-effects model. Four randomized controlled trials involving 3613 participants met the eligibility criteria. Semaglutide produced significantly greater weight loss than placebo (mean difference: -11.85%; 95% confidence interval [CI]: -12.81 to - 10.90; P < .00001). Overall gastrointestinal adverse events were significantly more frequent with semaglutide, with nausea, vomiting, diarrhea, and constipation representing the most commonly reported events. Treatment discontinuation due to adverse events was also significantly higher in the semaglutide group (RR 2.62, 95% CI: 1.70-4.03; P = .001). Serious adverse events, including acute pancreatitis and cholelithiasis, were uncommon. Subcutaneous semaglutide is an effective treatment for weight reduction in adults with overweight or obesity without type 2 diabetes mellitus but is associated with an increased risk of gastrointestinal adverse events, particularly nausea, vomiting, diarrhea, and constipation, as well as higher treatment discontinuation. Serious adverse events were rare. Further long-term randomized trials are needed to evaluate the durability of weight loss and the long-term safety profile of semaglutide.
Clinical relevance
Obesity affects hundreds of millions of adults globally and is a primary driver of cardiometabolic morbidity and mortality; yet evidence-based pharmacotherapy options remain limited. This systematic review and meta-analysis provides an updated, high-level synthesis of semaglutide's efficacy and safety specifically in nondiabetic adults with overweight or obesity — a population increasingly encountered in endocrinology and primary care practice. The findings are timely given semaglutide's expanding regulatory approvals for chronic weight management and rising real-world prescribing volumes.
Key findings
1. Semaglutide produced a statistically and clinically significant reduction in body weight compared to placebo, with a pooled mean difference of -11.85% (95% CI: -12.81 to -10.90; P < .00001), based on 4 RCTs including 3,613 nondiabetic participants with overweight or obesity. 2. Overall gastrointestinal (GI) adverse events were significantly more frequent in the semaglutide group compared to placebo, with nausea, vomiting, diarrhea, and constipation identified as the most commonly reported individual GI events. 3. Treatment discontinuation due to adverse events was significantly higher in the semaglutide group versus placebo (RR 2.62; 95% CI: 1.70–4.03; P = .001), indicating a more than 2.5-fold increased relative risk of drug discontinuation attributable to adverse events. 4. Serious adverse events, including acute pancreatitis and cholelithiasis, were reported but characterized as uncommon across the pooled trial population. 5. The meta-analysis was conducted per PRISMA 2020 guidelines using a random-effects model, incorporating data from RCTs identified across PubMed/MEDLINE, Embase, Scopus, and CINAHL from inception through March 2025, strengthening the rigor and contemporaneity of the evidence synthesis. 6. No specific subgroup analyses by semaglutide dose or duration of therapy were extractable from the reported abstract data; long-term durability of weight loss and extended safety profiles remain unestablished from the current evidence base.
Practice implications
Subcutaneous semaglutide should be considered a first-line pharmacotherapeutic option for adults with overweight or obesity without type 2 diabetes mellitus, given its robust and clinically meaningful ~11.85% mean body weight reduction versus placebo; patient selection should prioritize those who have failed lifestyle interventions and who do not have contraindications such as a personal or family history of medullary thyroid carcinoma or MEN2. Clinicians should counsel patients proactively about the high likelihood of GI adverse events — particularly nausea, vomiting, diarrhea, and constipation — and employ gradual dose-escalation strategies to improve tolerability and minimize the significantly elevated risk of treatment discontinuation (RR 2.62). Given the rarity but clinical significance of serious adverse events such as acute pancreatitis and cholelithiasis, baseline risk stratification and prompt evaluation of abdominal symptoms during therapy are warranted, and enrollment of patients in long-term registries or trials is encouraged to better characterize the durability of weight loss and the extended safety profile of semaglutide.