Liraglutide Boosts Weight Loss but Safety Concerns Cloud Long-Term Use

Obesity affects hundreds of millions globally and is strongly linked to cardiovascular disease, type 2 diabetes, and other chronic conditions. Lifestyle interventions alone often fail to produce durable weight loss, driving interest in pharmacological options like GLP-1 receptor agonists. Liraglutide, originally developed for type 2 diabetes, has received regulatory approval for obesity management in many countries at a 3 mg daily subcutaneous dose. This Cochrane review aimed to rigorously evaluate its benefits and harms across a range of clinically relevant outcomes.

Researchers searched CENTRAL, MEDLINE, Embase, LILACS, and two trials registries through December 2024. They included 24 RCTs with 9,937 participants aged 31–64 years, drawn primarily from middle- and high-income countries. Most trials compared liraglutide to placebo; two compared it to structured lifestyle programs, and a small number included active comparators like semaglutide or orlistat. Seventeen studies focused on specific subpopulations including people with type 2 diabetes, non-alcoholic fatty liver disease, polycystic ovary syndrome, and obstructive sleep apnea. All studies had medium-term follow-up (26–68 weeks), and three provided long-term data (104–162 weeks).

At medium-term follow-up, liraglutide likely doubled the proportion of participants achieving ≥5% weight loss compared to placebo (RR 2.10, 95% CI 1.80–2.45; moderate-certainty evidence). However, evidence for overall percentage weight change was very uncertain (MD −4.72%, 95% CI −5.32 to −4.12; very low certainty), driven by high heterogeneity. At long-term follow-up, liraglutide likely sustained the advantage in ≥5% weight loss (RR 1.78; moderate certainty), though percentage weight change showed low-certainty evidence of little meaningful difference. On quality of life measured by the IWQOL-Lite-CT physical function scale, liraglutide showed little to no clinically meaningful benefit at either timepoint (moderate certainty). Effects on MACE were likely small (RR 0.86 at medium term; moderate certainty), and mortality data were very uncertain across both timeframes.

On the safety side, liraglutide may increase any adverse events (RR 1.07; low certainty) and likely increases serious adverse events (RR 1.20; low certainty) at medium term. Adverse events leading to treatment withdrawal were nearly doubled (RR 1.98; very low certainty). Long-term safety data echoed these concerns, with low-certainty evidence suggesting increased serious adverse events and a clear signal of higher withdrawal rates (RR 2.16; low certainty).

A major caveat is that 22 of 24 included studies were funded by the drug manufacturer (Novo Nordisk), with significant manufacturer involvement in study design, conduct, and analysis in 13 of those. This raises serious concerns about publication bias and selective outcome reporting. The review also noted limited geographic diversity and a near-complete absence of truly long-term data beyond three years. The authors conclude that while liraglutide likely helps more people achieve clinically meaningful short-term weight loss, its broader impact on hard endpoints—mortality, cardiovascular outcomes, and quality of life—remains uncertain, and its adverse event profile may limit real-world tolerability and adherence.