Type 2 diabetes mellitus (T2DM) continues to rise globally, with an estimated 643 million individuals projected to be affected by 2030. The chronic nature of the disease imposes a significant burden on both healthcare systems and patients, particularly due to its strong association with cardiovascular complications. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as promising therapeutic options by enhancing insulin secretion and suppressing appetite. However, the wide variety of available agents, differing in dosing frequency, efficacy, and side-effect profiles, makes selecting the optimal therapy a challenge.
A recent large-scale analysis published in Scientific Reports aimed to clarify this therapeutic landscape. The Bayesian network meta-analysis evaluated the efficacy and safety of eight GLP-1 RAs in adults with T2DM, focusing on glucose control, weight loss, and adverse effects. The findings provide critical evidence to guide clinicians, patients, and policymakers in optimizing diabetes treatment.
The meta-analysis included 64 randomized controlled trials involving 25,572 adults with T2DM. It compared eight GLP-1 RAs—exenatide twice daily (EBID), exenatide once weekly (EQW), oral and injectable semaglutide, albiglutide, lixisenatide, dulaglutide, liraglutide, and tirzepatide—against one another, as well as against placebo and conventional therapies such as insulin, metformin, SGLT2 inhibitors, DPP-4 inhibitors, and sulfonylureas. Primary outcomes included changes in HbA1c, fasting plasma glucose (FPG), body weight, BMI, blood pressure, cholesterol levels, and incidence of adverse events.
Tirzepatide demonstrated the most substantial HbA1c reduction (−2.3 percentage points), followed by semaglutide (−1.5) and liraglutide (−1.2). Lixisenatide was the only drug associated with an increase in HbA1c compared to conventional treatments. Similarly, for FPG reduction, tirzepatide led with a −3.1 mmol/L decrease, followed by semaglutide (−2.0) and liraglutide (−1.6). In terms of weight loss, tirzepatide again ranked highest, achieving a reduction of −9.1 kg versus placebo and −10 kg versus standard therapies. Semaglutide (−2.8 kg), EBID (−1.8 kg), and liraglutide (−1.2 kg) produced more modest weight loss, while albiglutide and other short-acting agents showed minimal effect. These results align with the findings from the SURPASS-2 trial by Frías et al., where tirzepatide (15 mg) outperformed semaglutide (1 mg) in reducing both HbA1c (−2.46% vs −1.86%) and body weight (−11.2 kg vs −5.7 kg), reinforcing tirzepatide’s superior efficacy.
Gastrointestinal side effects, particularly nausea and vomiting, were most commonly reported with semaglutide, dulaglutide, liraglutide, lixisenatide, and tirzepatide, with a threefold increase in risk compared to placebo. EBID and semaglutide were associated with a higher incidence of hypoglycemia, whereas liraglutide and lixisenatide showed a protective effect against hypoglycemia compared to conventional treatments.
Another analysis by Wen et al. reported that tirzepatide led to a significantly greater average weight loss (−11.4%) compared to semaglutide (−7.3%), with a pooled mean difference of −4.84 kg (95% CI: −6.21 to −3.47) in favor of tirzepatide. Both drugs shared similar rates of mostly mild to moderate gastrointestinal side effects, further supporting tirzepatide’s weight-lowering advantage among GLP-1 RAs.
No significant differences were observed in blood pressure or cholesterol levels across GLP-1 RAs and comparators. Other adverse events were evenly distributed, and the statistical analyses confirmed the robustness of the findings.
This comprehensive review identifies tirzepatide as the most effective GLP-1 RA for both glycemic and weight control in T2DM, likely due to its dual agonist activity on both GLP-1 and GIP receptors. Semaglutide consistently ranked second in efficacy, while liraglutide offered a more favorable safety profile for patients prone to hypoglycemia. The limited efficacy of short-acting agents and albiglutide highlights a growing clinical preference for long-acting and dual-action therapies. These insights can aid in the individualization of diabetes care, especially in aligning treatment with weight management goals and tolerability.
References
- Ren X, Hua H, Wu Y, Zhang W, Long X, Bai Y, et al. Efficacy and safety of GLP-1 agonists in the treatment of T2DM: A systematic review and network meta-analysis. Sci Rep. 2025 Jul 6;15(1):24103.
- Frías JP, Davies MJ, Rosenstock J, Manghi FCP, Landó LF, Bergman BK, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. New England Journal of Medicine. 2021 Aug 4;385(6):503–15.
- Wen J, Syed B, Nadora D, How-Volkman C, Bernstein E, Truong A, et al. Tirzepatide Versus Semaglutide on Weight Loss in Type 2 Diabetes Patients: A Systematic Review and Meta-Analysis of Direct Comparative Studies. Endocrinol Diabetes Metab. 2025 May;8(3):e70045.