CHENGDU — Sheyu Li and colleagues at West China Hospital and Sichuan University in Chengdu, China, conducted a systematic review and network meta-analysis of 262 randomized trials involving 99,791 patients to assess GLP-1 receptor agonists and other obesity therapies. Their findings indicate that tirzepatide and cagrilintide-semaglutide produced the greatest weight loss among these agents at one year, while subcutaneous semaglutide and tirzepatide were also associated with reduced cardiovascular risks.

Moderate- to high-certainty evidence from the analysis showed that tirzepatide resulted in a mean weight difference of -14.9% at one year compared to lifestyle modification alone. Cagrilintide-semaglutide achieved a mean weight difference of -14.8%. Other agents also showed reductions: oral semaglutide resulted in -10.9%, orforglipron in -9.9%, and subcutaneous semaglutide in -9.8%. Phentermine-topiramate was associated with a mean weight difference of -8.1%.

Subcutaneous semaglutide was associated with a reduced risk of heart failure, with a risk ratio of 0.43, and tirzepatide also showed a reduced risk with a risk ratio of 0.49. Subcutaneous semaglutide was linked to a reduced risk of all-cause mortality, with a risk ratio of 0.81, and a reduced risk of myocardial infarction, with a risk ratio of 0.72. However, the evidence for GLP-1 drugs in reducing kidney failure or improving quality of life beyond a subjective threshold was less certain.

Li noted that while obesity drugs result in variable weight loss, "Obesity drugs produce variable weight loss at 1 year, with larger benefits generally accompanied by greater harms and discontinuation." She also stated that "Most agents do not improve quality of life meaningfully and few show cardiovascular benefits." Li added that "Decisions in clinical practice should consider trade-offs between benefits and harms within the context of shared decision making."

The meta-analysis identified gastrointestinal events as common harms associated with naltrexone-bupropion, oral semaglutide, orforglipron, and tirzepatide, with risk ratios for these events ranging from 3.1 to 4.2. An increased risk of fatigue was detected with naltrexone-bupropion (risk ratio of 8.9), with 331 more cases per 1,000 people over one year. Orforglipron showed a fatigue risk ratio of 3.4 (100 more cases per 1,000 people), and CagriSema a risk ratio of 3.2 (92 more cases per 1,000 people). The absolute risk increase for discontinuation due to any adverse event ranged from 19 per 1,000 people for orlistat to 94 per 1,000 people for orforglipron over one year. Tirzepatide was associated with a 25.7% reduction in fat mass and an 8.3% reduction in lean mass.

Marie Spreckley, PhD, from the University of Cambridge, said that the findings "The findings do not show that obesity medications have no wider health benefits." She added, "Rather, they highlight that while the evidence for weight loss is strong, evidence for some longer-term outcomes is still developing and differs considerably between individual medications." Hamid Merchant, PhD, MPharm, of the University of East London, said that "A more accurate interpretation would be that while obesity medicines vary in their benefits and harms, several produce substantial weight loss, some demonstrate important cardiovascular benefits, and the quality-of-life findings depend heavily on how clinically meaningful improvement is defined."

Why It Matters

This systematic review provides a comprehensive analysis of the efficacy and safety of various GLP-1 receptor agonists and other obesity treatments. The findings offer guidance for healthcare professionals in navigating the expanding options for obesity management. The study highlights both the weight loss and cardiovascular benefits associated with certain drugs, such as tirzepatide and subcutaneous semaglutide, as well as potential adverse effects and limitations in evidence for long-term outcomes like kidney protection and quality of life.

The review's emphasis on considering trade-offs between benefits and harms underscores the complexity of treatment decisions in clinical practice. The differing perspectives from experts like Sheyu Li, Marie Spreckley, and Hamid Merchant on the interpretation of the quality-of-life data indicate ongoing discussions in the medical community about comprehensive patient care beyond just weight reduction.