Weight loss efficiency and safety of tirzepatide: A Systematic review

**Background:** Obesity affects approximately 30% of the global population and is a major risk factor for cardiovascular disease and diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as liraglutide and semaglutide have been approved for weight loss, but tirzepatide—a first-in-class dual GIP and GLP-1 receptor agonist approved by the FDA in May 2022—may offer superior efficacy. This systematic review and meta-analysis aimed to evaluate the weight loss efficacy and safety of tirzepatide in patients with T2DM and obesity.

**Methods:** The authors systematically searched PubMed, EMBASE, Cochrane Library, Web of Science, and Clinical Trials databases from inception to October 5, 2022. Search terms included 'Tirzepatide', 'LY3298176', and 'Mounjaro'. Only RCTs involving adults with obesity (with or without T2DM) comparing tirzepatide to placebo or active comparators were included. Two researchers independently screened studies and extracted data; disagreements were resolved by a third researcher. The Cochrane Collaboration bias assessment tool was used for quality assessment. Statistical analysis was performed using Review Manager 5.3. Mean difference (MD) was used for continuous outcomes and odds ratio (OR) for dichotomous variables, both with 95% confidence intervals. Fixed-effects models were used when I² ≤ 50% and P > 0.1; random-effects models were applied otherwise.

**Key Results:** Ten studies (12 reports) involving 9,873 patients were included. Study durations ranged from 12 to 72 weeks. Tirzepatide significantly reduced body weight versus placebo by -9.81 kg (95% CI: -12.09 to -7.52), versus GLP-1 RAs by -1.05 kg (95% CI: -1.48 to -0.63), and versus insulin by -1.93 kg (95% CI: -2.81 to -1.05). Dose-response analysis showed: 5 mg: MD -7.52 kg (95% CI: -10.86 to -4.18), 10 mg: MD -10.48 kg (95% CI: -15.34 to -5.62), 15 mg: MD -10.91 kg (95% CI: -14.81 to -7.01) versus placebo. For ≥5% weight loss, tirzepatide 15 mg versus placebo showed OR 21.41 (95% CI: 16.37–28.00); versus basal insulin OR 75.38 (95% CI: 50.05–113.54). For ≥15% weight loss, tirzepatide 15 mg versus placebo showed OR 27.14 (95% CI: 19.66–37.47); versus basal insulin OR 174.26 (95% CI: 69.74–435.43). HbA1c was also significantly reduced: tirzepatide 15 mg versus placebo MD -1.87% (95% CI: -2.03 to -1.70), versus GLP-1 RAs MD -0.89% (95% CI: -1.00 to -0.77), versus insulin MD -1.10% (95% CI: -1.18 to -1.01). For safety, any adverse events were higher with tirzepatide versus placebo (OR 1.59, 95% CI: 1.29–1.95) and basal insulin (OR 1.55, 95% CI: 1.25–1.91), but similar to GLP-1 RAs (OR 1.15, 95% CI: 1.00–1.32). Serious adverse events did not differ significantly between tirzepatide and placebo or basal insulin, but were higher versus GLP-1 RAs (e.g., tirzepatide 5 mg OR 2.08, 95% CI: 1.32–3.28). Hypoglycemia risk was lower with tirzepatide versus basal insulin (e.g., 15 mg OR 0.25, 95% CI: 0.14–0.46) and similar to placebo and GLP-1 RAs. Gastrointestinal adverse events were more frequent with tirzepatide versus placebo (nausea 15 mg OR 4.19, 95% CI: 2.37–7.39; vomiting OR 5.76, 95% CI: 3.51–9.45; diarrhea OR 2.65, 95% CI: 1.58–4.44; decreased appetite OR 4.27, 95% CI: 2.84–6.43) and basal insulin, but similar to GLP-1 RAs. Sensitivity analysis excluding SURMOUNT-1 (obesity without T2DM) reduced heterogeneity substantially.

**Clinical Implications:** Tirzepatide demonstrates clinically meaningful weight loss in patients with T2DM and obesity, superior to placebo, GLP-1 RAs, and insulin across all three doses. The magnitude of weight loss—particularly the high odds of achieving ≥15% body weight reduction—positions tirzepatide as a potentially transformative pharmacotherapy for obesity. However, gastrointestinal side effects are common and may affect tolerability, particularly at higher doses. Clinicians should counsel patients about these effects, which are typically mild-to-moderate and transient. The lower hypoglycemia risk versus insulin is advantageous, especially in T2DM patients. Limitations include industry sponsorship of all included RCTs, only one trial (SURMOUNT-1) focused on obesity without T2DM, and high statistical heterogeneity for some outcomes, partly explained by population differences. Ongoing trials may further clarify long-term efficacy and safety.