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Olowo‐Oribi BA, Salway RJ. Efficacy of tirzepatide, retatrutide, and semaglutide for weight loss in obese individuals without diabetes. Academic Emergency Medicine. Published online June 29, 2025:acem.70088.

Study Population: 15,491 obese individuals (mean body mass index: 30 to 41 kg/m²) without diabetes enrolled in 26 randomized controlled trials

Efficacy Endpoints

Weight loss

Harm Endpoints

Adverse events including nausea, vomiting, diarrhea, constipation, and biliary disease

Narrative

Obesity is a chronic disease contributing to significant global morbidity and mortality, with prevalence steadily rising. According to the World Obesity Federation, obesity currently affects 650 million adults, a number expected to reach one billion by 2030. By 2035, they project that 51% of the global population will be overweight.1 Obesity substantially increases the risk of chronic conditions such as type 2 diabetes, cardio-vascular disease, nonalcoholic fatty liver disease, and obstructive sleep apnea, while also diminishing overall quality of life.2 Although lifestyle modifications remain the safest first-line treatment, medical and surgical interventions may be necessary when these efforts prove insufficient. Given the invasiveness of surgery, pharmacotherapy has gained increasing attention as a viable option for effective and sustained weight management.3

Semaglutide, tirzepatide, and retatrutide are among the most extensively studied medications in their class, meaning there is more data available on their efficacy and safety compared to other agents. They also share similar mechanisms of action, which allow for comparisons across different subtypes. Additionally, semaglutide and tirzepatide are among the most popular and most widely used medications in this class.

Semaglutide (brand names: Ozempic, Wegovy, and Rybelsus) is a glucagon-like peptide-1 (GLP-1) receptor agonist administered at doses of up to 1 mg subcutaneously once weekly for the treatment of type 2 diabetes and the reduction of cardiovascular risk. In 2014, the U.S. Food and Drug Administration (FDA) approved semaglutide for weight loss.4 Its efficacy and safety at a dosage of 2.4 mg once weekly for individuals with overweight or obesity—regardless of weight-related complications such as hypertension or hyperlipidemia—have been well studied.5

Liraglutide (brand names: Victoza, Saxenda) is a glucagon-like peptide-1 (GLP-1) receptor agonist with a pharmacological pro-file comparable to that of semaglutide. It is initiated at a dose of 0.6 mg once daily for 1 week, with subsequent weekly increments of 0.6 mg until a target dose of 3 mg once daily is achieved. Initially approved for the management of type 2 diabetes mellitus, liraglutide received FDA approval in 2014 for chronic weight management. Its efficacy and adverse effect profile are similar to those observed with semaglutide, including gastrointestinal side effects.

Tirzepatide (brand names: Zepbound, Mounjaro), a novel glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 dual receptor agonist, is administered via weekly subcutaneous injections. It was approved by the FDA in November 2023 for the management of weight loss and obesity.6 While several weight loss medications exist, tirzepatide offers a synergistic mechanism targeting both GIP and GLP-1 pathways, leading to the possibility of enhanced metabolic benefits including weight loss.

Retatrutide, an investigational agent, not yet FDA-approved, acts as a triple agonist of the GIP, GLP-1, and glucagon (GCG) receptors. Several randomized controlled trials have evaluated its potential benefits, particularly its ability to enhance metabolic regulation through its unique multi-receptor activation.

The systematic review by Moiz et al.,7 analyzed 26 randomized controlled trials (RCTs) investigating the efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists, as well as dual and triple co-agonists, for weight loss in overweight or obese adults who did not have diabetes. The review included 15,491 participants (72% female) with a mean body mass index (BMI) of 30–40 kg/m² and a mean age of 34–57 years.

Twelve weight-loss agents were assessed, including three commercially available medications (tirzepatide, liraglutide, and semaglutide) and nine investigational agents, including retatrutide. Participants were required to have a BMI >30 kg /m² or a BMI >27 kg/m² with at least one weight-related comorbidity (e.g., hypertension or hyperlipidemia). Treatment duration ranged from 16 to 104 weeks, accounting for the dose titration period necessary to mitigate gastrointestinal side effects, as well as at least 4 weeks of treatment at a fixed dose.

Compared with placebo, tirzepatide (15 mg once weekly) led to a weight loss of up to 18% (95% CI, 16%–19%); semaglutide (2.4 mg) resulted in a weight loss of up to 14% (95% CI, 11%–17%); liraglutide (3.0 mg) resulted in a more moderate weight loss of 6% (95% CI, 4%–8%); and retatrutide (12 mg) achieved the highest weight reduction at 22% (95% CI, 19%–25%) from baseline.7

Due to significant heterogeneity among the included trials, the systematic review by Moiz et al.,7 did not conduct a meta-analysis. As a result, absolute risk differences, number-needed-to-treat, and number-needed-to-harm could not be calculated.7

A network meta-analysis by Pan et al.,8 included 31 randomized controlled trials (RCTs) with 35,458 participants to evaluate the efficacy of tirzepatide and semaglutide for weight loss, and a separate systematic review and meta-analysis by Tan et al.,9 reported similar findings, further reinforcing the superiority of tirzepatide over semaglutide for weight loss.

Adverse Events

Gastrointestinal-related adverse events were common among these medications. Moiz et al.,7 reported overall adverse event rates (any adverse event) of 87% in treatment groups, compared to 79% in placebo groups. The gastrointestinal adverse events occurred in approximately 86% of participants treated with GLP-1 agonists versus 31% of the placebo group. Approximately 14% of the patients treated with GLP-1 agonists enrolled in studies included in the systematic review by Moiz et al. discontinued their treatment due to adverse events. This rate was only approximately 2% in the placebo group.7

Adverse events leading to treatment discontinuation were most frequently observed during dose escalation. More serious complications included severe gastrointestinal events, biliary disorders (such as cholecystitis and cholelithiasis), pancreatitis, and psychiatric disorders. The risk of pancreatitis seems to be minimal. A study analyzing data from four large-scale cardiovascular outcome trials involving 33,457 patients with type 2 diabetes reported 123 cases of acute pancreatitis over a median follow-up of 2.1 to 3.8 years. The analysis found no increased risk of acute pancreatitis associated with GLP-1 treatment compared to placebo.10^, 11

The association between GLP-1 receptor agonists (GLP-1 RAs) and psychiatric conditions such as depression, anxiety, and suicidal behavior remains unclear. While a large cohort study of over 160,000 patients with obesity found significantly higher risks among GLP-1 RA users—including a 195% increase in major depression, 108% in anxiety, and 106% in suicidal behavior12—meta-analyses of randomized controlled trials (RCTs) have not confirmed these findings. One meta-analysis of over 84,000 patients found no significant difference in psychiatric adverse events between GLP-1 RAs and placebo, and another involving 27 RCTs and more than 32,000 participants reported a very low incidence of suicide-related events without statistical significance.13^, 14

Caveats

The systematic review summarized here provides valuable insights into the role of GLP-1 receptor agonists in weight management.7 However, several limitations should be acknowledged.

One major limitation is the absence of head-to-head RCTs directly comparing different GLP-1 receptor agonists. This gap limits the ability to evaluate relative efficacy and safety profiles across agents. Additionally, significant variability in study designs, populations, dosages, and outcome measures introduced heterogeneity, preventing the authors from conducting a meta-analysis. As a result, the findings could not be quantitatively synthesized.

Many of the included studies had relatively short follow-up periods, restricting the assessment of long-term efficacy and safety in adults without diabetes. While gastrointestinal issues were the most frequently reported adverse events, the limited study durations and sample sizes may have constrained the detection of rarer or long-term adverse effects. Some systematic reviews may not comprehensively capture severe adverse effects due to underreporting or limited study durations, leading to an incomplete safety profile. Furthermore, publication bias remains a concern, as studies with positive results are more likely to be published, potentially skewing conclusions regarding the efficacy and safety of GLP-1 receptor agonists.

These limitations highlight the need for more comprehensive, long-term studies, including direct comparisons between different GLP-1 receptor agonists.

Management of Adverse Events

To effectively manage and mitigate the side effects of GLP-1 receptor agonists, particularly during the dose escalation phase, a combination of gradual dose increases, dietary modifications, and close monitoring is essential. Gastrointestinal discomfort is a common adverse effect, and slowing the dosage escalation can help minimize these symptoms. If symptoms persist after a dose increase, returning to a previously tolerated dose or extending the titration period may be necessary. Dietary adjustments can also significantly reduce gastrointestinal discomfort. Avoiding heavy or spicy foods, consuming small, frequent meals, and using simple cooking methods such as steaming and baking are recommended. Staying hydrated, avoiding liquid meals during dinner, and choosing digestion-friendly snacks such as fruit can further alleviate symptoms. In cases of severe nausea or vomiting, short-term use of antiemetics may be considered. If side effects remain unmanageable, switching to an alternative GLP-1 receptor agonist or discontinuing the medication may be appropriate, depending on the patient's response.15^, 16 Despite these interventions, approximately 10% of patients discontinue these medications because of adverse events.17 Tailoring treatment to the individual's nutritional needs and lifestyle preferences may improve long-term adherence and overall treatment success.

Ongoing research is expected to provide further insight into the comparative safety and efficacy of these treatments for weight management, including mitigating the side effects.

In summary, both semaglutide and tirzepatide demonstrated significant efficacy in weight reduction, with tirzepatide outperforming semaglutide—likely due to its dual mechanism targeting both GLP-1 and GIP receptors. Additionally, retatrutide, a triple agonist, exhibited the highest weight loss efficacy in healthy individuals. Although not yet approved for commercial use, retatrutide may significantly influence future weight management strategies.

Gastrointestinal adverse effects were commonly observed across all agents but were generally transient, occurring primarily during initiation and dose escalation.

Overall, dual and triple agonists have demonstrated superior weight loss outcomes compared to single agonists. Among these, tirzepatide and retatrutide—acting on GLP-1 and GIP receptors—appear to be the most effective. Although these medications offer substantial weight loss benefits and have a generally manageable safety profile, the limited and heterogeneous evidence—such as the lack of head-to-head RCTs, short follow-up periods, incomplete data on long-term harms, and absence of clinical outcome endpoints beyond weight loss—underscores the need for more robust, long-term studies to confirm their safety and efficacy. Therefore, we have assigned an NNT color recommendation of Yellow (Unclear if benefits/More data needed) to GLP-1 receptor agonists. Specifically noted in the study by Wiling et al.18 When patients stop taking these medications, it appears their cardiovascular risk profiles are worse than prior to treatment. Therefore, large-scale RCTs with extended follow-up periods are still needed to fully understand their long-term cardiovascular benefits and potential risks.

The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.

Author

Bastu Adebayo Olowo-Oribi, MD; Salway Richard James, MD
Supervising Editors: Kabir Yadav, MD

Published/Updated

August 12, 2025