A 2025 Nature Medicine publication by McGowan et al. titled “A systematic review and meta-analysis of the efficacy and safety of pharmacological treatments for obesity in adults” represents one of the most comprehensive analyses to date of obesity management medications (OMMs). The review and network meta-analysis combined 56 randomized controlled trials (RCTs) including over 60,000 participants, examining six commonly used OMMs: orlistat, semaglutide, liraglutide, tirzepatide, naltrexone/bupropion, and phentermine/topiramate. The primary outcome was the percentage of total body weight loss (TBWL%) compared with placebo or active comparators.
According to McGowan et al. (2025), all medications produced statistically significant greater weight loss compared with placebo (P < 0.0001).
Among them, semaglutide and tirzepatide were the only agents to achieve a mean total body weight loss exceeding 10% at the study endpoints. Specifically, the analysis reported that “the estimated TBWL% was greater than 10% only for semaglutide and tirzepatide” (p. 3322).
A direct head-to-head comparison between semaglutide and liraglutide found a weighted mean difference of 9.4% (95% CI 6.8–12.0; P < 0.001) in favour of semaglutide. Similarly, tirzepatide demonstrated the highest overall TBWL% among all included treatments, though the authors noted that “no studies reported a mean baseline BMI < 30 kg m⁻²,” limiting applicability to overweight but non-obese populations.
Effects beyond weight reduction
The review assessed a range of secondary endpoints, including metabolic, cardiovascular, and quality-of-life outcomes. Reported effects varied by medication:
- Glycaemic control:
Tirzepatide produced “a significantly greater reduction in HbA1c compared to other OMMs,” while liraglutide and semaglutide were “associated with a greater reduction of fasting plasma glucose” (Table 1, McGowan et al. 2025). Both tirzepatide and semaglutide were also linked to higher rates of normoglycaemia restoration in patients with prediabetes. - Cardiovascular outcomes:
Semaglutide was “associated with a significantly lower risk for major adverse cardiovascular events (MACE)” and “a lower risk of all-cause mortality.” Tirzepatide showed a reduction in hospitalisation due to heart failure (HHF) in two RCTs, though its effect on MACE and cardiovascular mortality has not yet been fully established. - Other health domains:
Tirzepatide demonstrated efficacy in “remission of obstructive sleep apnoea syndrome and metabolic dysfunction-associated steatohepatitis (MASH),” while semaglutide “was effective in reducing pain in knee osteoarthritis.” Both agents were associated with reduced waist circumference and BMI compared with placebo.
Safety profile
Across all drugs, no medication except naltrexone/bupropion was associated with an increased rate of serious adverse events (SAEs) relative to placebo (Table 1). The authors report that “semaglutide was associated with a lower risk of all-cause mortality,” while “treatment discontinuation rates were similar to those observed in placebo arms.”
Regarding mental health, the review found no significant association between any OMM and suicide risk or major depression, noting that “these findings are reassuring given previous concerns regarding potential psychiatric adverse effects of weight-loss pharmacotherapies.”
Weight regain after discontinuation
The meta-analysis identified weight regain following treatment cessation as a recurring observation. Four trials (two with semaglutide, one with liraglutide, and one with tirzepatide) provided post-discontinuation data. Reported figures indicated regain of approximately 43–67% of lost weight within one year of stopping treatment. The authors emphasized that obesity is a chronic disease and that pharmacological therapy “should be used long term to manage the disease” (p. 3326).
Evidence quality and limitations
The authors rated the quality of evidence for the primary endpoint (TBWL%) as “high” for all OMMs using GRADE methodology. Nonetheless, several limitations were acknowledged:
- Most studies enrolled participants with BMI ≥ 30 kg m⁻², so findings cannot be generalized to those with lower BMI.
- The majority of data came from placebo-controlled trials rather than direct head-to-head comparisons.
- Long-term safety data beyond three years remain limited.
- Some endpoints, including mental health and quality of life, were insufficiently reported across trials to support strong conclusions.
Interpretation
In conclusion, the 2025 Nature Medicine meta-analysis provides robust evidence that semaglutide and tirzepatide produce the greatest average weight reduction among currently approved obesity treatments, with additional benefits for glycaemic control and certain obesity-related comorbidities. Both agents demonstrated acceptable safety profiles and were not associated with increased serious adverse events.
However, the study also underscores that pharmacological therapy is not curative, as weight regain commonly occurs when treatment stops. Continued research is needed to evaluate long-term outcomes, cost-effectiveness, and optimal strategies for maintaining weight and metabolic health after discontinuation.
Adaptog Recommendation
While pharmacological treatments such as semaglutide and tirzepatide have demonstrated strong clinical benefits, long-term success still depends on sustained lifestyle habits. As McGowan et al. (2025) note, “obesity is a chronic disease, and obesity management typically requires a combination of strategies to address the underlying biology of obesity,” including “lifestyle programs that incorporate dietary change and physical activity.”
Regular exercise, a nutrient-dense diet, and behavioural support remain critical for maintaining weight loss and metabolic improvements once achieved. The study also highlighted that stopping medication without lifestyle support often leads to “weight regain of up to 67% of lost weight within one year of discontinuation.”
At Adaptog, we recommend that individuals considering pharmacological treatment for obesity work with qualified clinicians to develop a comprehensive plan that includes balanced nutrition, consistent movement, and long-term health monitoring. Medication can be a powerful tool, but it is most effective when paired with ongoing lifestyle care and support.
