Tirzepatide Wins on Weight Loss, But at a Gastrointestinal Cost

A meta-analysis presented by Dr Thomas Karagiannis from the Aristotle University of Thessaloniki, Greece, at the 2024 Annual Meeting of the European Association for the Study of Diabetes shed light on the effectiveness and tolerability of three popular weight loss drugs: semaglutide, liraglutide, and tirzepatide.
Liraglutide, semaglutide, and tirzepatide are approved in varying doses for adults for the treatment of overweight (BMI ≥ 27 kg/m² plus a weight-related comorbidity) or obesity. “Despite their widespread use, there are few randomised controlled trials (RCTs) that directly compare tirzepatide, subcutaneous semaglutide, and liraglutide,” Karagiannis noted.
To address this, his team conducted a network meta-analysis to assess the effectiveness and tolerability of these drugs. “All three drugs resulted in significant weight reduction compared to placebo, with tirzepatide 15 mg being the most effective dose. Both tirzepatide doses were more effective than semaglutide and liraglutide,” Karagiannis reported.
36 RCTs With Over 35,000 Patients Analysed
In January 2024, the researchers searched PubMed and the Cochrane Central Register of Controlled Trials for RCTs examining tirzepatide (10 mg or 15 mg once weekly), semaglutide (2.4 mg subcutaneously once weekly), or liraglutide (3.0 mg once daily) compared to placebo. The trials involved adults with a BMI of ≥ 27 kg/m² to < 30 kg/m² and at least one weight-related comorbidity, or those with obesity (BMI ≥ 30 kg/m²).
The analysis included 36 RCTs with a total of 35,378 participants. The average age of participants was 47.3 years, with an average BMI of 36.8 kg/m² and an average weight of 102.9 kg. Half of the participants were female.
Karagiannis and his colleagues calculated the mean percentage change in body weight from baseline, the risk ratios (RRs) for achieving at least a 5% weight reduction, and the likelihood of experiencing gastrointestinal side effects (nausea, vomiting, and diarrhoea). “All RCTs compared these drugs with placebo, with only one study directly comparing semaglutide with liraglutide,” Karagiannis noted.
Tirzepatide Leads in Weight Loss
The meta-analysis showed that tirzepatide 15 mg was the most effective for weight loss, followed by tirzepatide 10 mg, semaglutide 2.4 mg, and liraglutide 3.0 mg.
When compared with placebo, the relative risk (RR) of achieving at least a 5% weight reduction was:
2.65 (95% CI, 2.06-3.42) for tirzepatide 15 mg, 
2.61 (95% CI, 1.92-3.55) for tirzepatide 10 mg, 
2.48 (95% CI, 2.02-3.03) for semaglutide 2.4 mg, 
2.07 (95% CI, 1.77-2.42) for liraglutide 3.0 mg. 
All three medications increased the risk of gastrointestinal side effects compared with placebo. Tirzepatide 10 mg had the highest RR for nausea at 3.32 (95% CI, 2.74-4.04), while tirzepatide 15 mg had the highest RR for vomiting at 5.98 (95% CI, 4.14-8.65) and diarrhoea at 2.95 (95% CI, 2.39-3.65). Notable differences were observed between tirzepatide 15 mg and liraglutide for vomiting, and between both tirzepatide doses compared to semaglutide and liraglutide for diarrhoea.
Higher Risk for Gastrointestinal Problems
While tirzepatide outperformed both semaglutide and liraglutide in terms of weight reduction, this benefit came with an increased risk of gastrointestinal side effects. “Tirzepatide showed the highest efficacy in reducing body weight, especially at the 15 mg dose, but it also led to more frequent gastrointestinal issues, particularly diarrhoea,” explained Karagiannis.
Other Side Effects
Constipation is another common side effect of incretin-based therapies and can sometimes occur alongside diarrhoea. However, this was not addressed in the meta-analysis. When selecting a therapy, particularly for patients who may be sensitive to gastrointestinal issues or for whom weight loss is a priority over tolerability.
When asked about whether one medication is better tolerated than another, Karagiannis remarked, “I’m not aware of any study that directly compared tolerability.” Still, he noted that since all three medications are effective for weight loss, patients who struggle with side effects on one drug could consider switching to another option.
This story was translated from Medscape’s German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. 
 
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