Introduction
Obesity is a globally prevalent chronic health condition associated with increased morbidity and mortality, contributing to cardiovascular disease, type 2 diabetes, and reduced quality of life. Pharmacological advances targeting weight loss pathways, especially glucagon-like peptide-1 receptor agonists (GLP-1RAs) and related incretin-based therapies, have offered promising adjuncts to lifestyle modification for obesity management. This article critically compares three recently updated Cochrane systematic reviews assessing tirzepatide, semaglutide, and liraglutide, focusing on efficacy, safety, and patient-important outcomes to inform clinical decision-making.
Background
Obesity’s pathophysiology involves complex neuroendocrine and metabolic dysregulation. Pharmacotherapies acting through GLP-1 pathways enhance satiety and reduce energy intake. Tirzepatide uniquely combines dual agonism of GIP and GLP-1 receptors, semaglutide is a selective GLP-1RA, and liraglutide is an older GLP-1RA formulation. These agents have undergone multiple randomized controlled trials (RCTs) to evaluate their role in adults living with obesity across diverse populations.
Study Designs and Populations
All three Cochrane reviews synthesized randomized controlled trials involving adult participants with obesity, typically with BMI thresholds meeting obesity criteria, and frequently included individuals with obesity-related comorbidities such as type 2 diabetes, heart failure, or sleep apnea. Follow-up durations ranged from six months to over three years. Intervention doses varied within recommended clinical ranges: tirzepatide (5 to 15 mg weekly), semaglutide (various doses, mostly 2.4 mg weekly), and liraglutide (daily doses). The trials primarily originated from middle- and high-income countries, with a notable influence from pharmaceutical sponsors in study design, conduct, and reporting.
Key Efficacy Findings
Weight Loss
The mean percentage reduction in body weight and proportion of participants achieving ≥5% weight loss constitute primary efficacy outcomes across reviews:
| Parameter | Tirzepatide | Semaglutide | Liraglutide |
|---|---|---|---|
| Mean % Weight Reduction (Medium-term) | -16.03% (95% CI: -18.91 to -13.14) | -10.73% (95% CI: -12.24 to -9.21) | -4.72% (95% CI: -5.32 to -4.12) |
| Proportion Achieving ≥5% Weight Loss (Risk Ratio) | 3.60 (95% CI: 2.44 to 5.30) | 2.68 (95% CI: 2.30 to 3.12) | 2.10 (95% CI: 1.80 to 2.45) |
| Long-term Weight Reduction (MD) | -15.66% (3.5 years) | -11.11% (26 months) | -4.34% (104–162 weeks) |
| Long-term ≥5% Weight Loss (RR) | 2.81 | 2.74 | 1.78 |
These data indicate tirzepatide achieves the greatest weight loss efficacy, followed by semaglutide, then liraglutide. Both tirzepatide and semaglutide demonstrate sustained effects long term, whereas liraglutide’s weight-related effects are more modest.
Safety and Adverse Events
Non-Serious and Serious Adverse Events (AEs)
All agents show a potential increase in non-serious adverse events relative to placebo, predominantly gastrointestinal symptoms such as nausea, vomiting, and diarrhea. The risk ratios are:
– Tirzepatide: Non-serious AEs RR ~1.33 (low certainty);
– Semaglutide: Non-serious AEs RR ~1.11 (low certainty);
– Liraglutide: Any AEs RR ~1.07 (low certainty).
Serious adverse events data remain very uncertain across all agents, with wide confidence intervals and very low-certainty evidence. Rates of adverse events leading to treatment withdrawal show:
– Tirzepatide: Possible increase (RR 2.06 medium-term, low certainty).
– Semaglutide: Likely increase (RR 1.84 medium-term, moderate certainty).
– Liraglutide: Very uncertain increase (RR 1.98 medium-term).
Cardiovascular and Mortality Outcomes
Major adverse cardiovascular events (MACE) and mortality are critically important for clinical impact:
– Tirzepatide shows likely little to no difference in MACE or mortality compared with placebo.
– Semaglutide may reduce MACE (RR 0.63 medium-term; 0.81 long-term) and mortality (RR ~0.69 medium-term; 0.82 long-term), although certainty is low to moderate.
– Liraglutide likely results in little to no difference in MACE and very uncertain mortality effects.
Quality of Life (QoL)
All three agents show little to no clinically meaningful difference in quality of life scales (IWQOL-Lite-CT, SF-36, EQ-5D-5L), with moderate to low-certainty evidence.
Comparative Summary
The following table summarizes the comparative strengths and limitations:
| Outcome | Tirzepatide | Semaglutide | Liraglutide |
|---|---|---|---|
| Weight Loss Efficacy | Highest efficacy, sustained up to 3.5 years | High efficacy, sustained to 26 months | Modest efficacy, less sustained long term |
| Non-serious AEs | Increased risk, gastrointestinal predominant | Increased risk, gastrointestinal predominant | Increased risk, gastrointestinal predominant |
| Serious AEs | Uncertain evidence | Uncertain evidence | Uncertain evidence, possible increase noted |
| Adverse Events Leading to Withdrawal | Likely increased (low certainty) | Likely increased (moderate certainty) | Uncertain but likely increased |
| MACE | Likely no significant difference | May reduce events (low to moderate certainty) | Likely no significant difference |
| Mortality | Likely no significant difference (moderate certainty) | May reduce (low to moderate certainty) | Very uncertain |
| Quality of Life | Little to no difference | Little to no difference | Little to no difference |
| Evidence Certainty | Moderate for weight, low to very low for safety | High for weight (medium-term), moderate for key other outcomes | Very low to moderate, evidence downgraded for risk of bias |
| Funding Bias Concerns | All studies funded by manufacturer | Mostly manufacturer funded | Majority manufacturer funded |
Expert Commentary
The data illustrate that tirzepatide, as a dual GIP/GLP-1 receptor agonist, shows superior weight loss efficacy compared with semaglutide and liraglutide, likely reflecting synergistic mechanisms. Semaglutide remains a potent GLP-1RA with robust high-certainty evidence for weight loss. Liraglutide, although previously a standard GLP-1RA for obesity, demonstrates comparatively modest effects. Safety profiles are consistently dominated by gastrointestinal adverse events; however, the certainty of serious event data is low, necessitating cautious interpretation.
The cardiovascular benefits apparent with semaglutide, albeit with low-certainty evidence, align with prior cardiovascular outcome trials, meriting further investigation. Tirzepatide’s effects on cardiovascular outcomes remain uncertain due to limited long-term data. The consistency of the QoL data suggests pharmacotherapy improves weight but may not translate to measurable quality of life improvements, perhaps reflecting multidimensional QoL determinants beyond weight alone.
A key limitation of all evidence is the predominant industry funding, raising concerns regarding reporting bias and influencing study design or publication. Furthermore, the underrepresentation of diverse populations limits generalizability.
Conclusions
Among pharmacotherapies for obesity assessed via Cochrane systematic reviews, tirzepatide demonstrates the greatest weight reduction efficacy sustained over extended duration, surpassing semaglutide and liraglutide. Semaglutide also shows significant and sustained weight loss with compelling evidence quality, while liraglutide’s effects are more modest. Safety profiles are acceptable but warrant vigilance given increased minor adverse events and uncertainty around serious events. Cardiovascular and mortality benefits are more evident with semaglutide, though evidence remains inconclusive.
Clinicians should consider individual patient factors, treatment goals, and tolerability when selecting agents. Further independent, long-term comparative studies in broader populations are essential to elucidate comprehensive benefit-risk profiles and inform guidelines. Transparency regarding conflicts of interest and standardized outcome reporting will enhance evidence reliability.
Funding and Registration
All three Cochrane reviews were funded by the World Health Organization (WHO) and registered prospectively on PROSPERO (CRD420250654193). Studies included in the reviews predominantly received funding or involvement from their respective drug manufacturers.
References
1. Franco JV, et al. Tirzepatide for adults living with obesity. Cochrane Database Syst Rev. 2025;10(10):CD016018.
2. Bracchiglione J, et al. Semaglutide for adults living with obesity. Cochrane Database Syst Rev. 2025;10(10):CD015092.pub2.
3. Meza N, et al. Liraglutide for adults living with obesity. Cochrane Database Syst Rev. 2025;10(10):CD016017.
