Tirzepatide Bests Semaglutide For A1c, Weight Loss in Indirect Comparison of Clinical Trial Data


A network meta-analysis suggests tirzepatide may be more effective than semaglutide in reducing HbA1c and body weight in type 2 diabetes but may increase gastrointestinal adverse events, especially at higher doses.

Thomas Karagiannis, MD, PhD, MSc | Credit: Aristotle University of Thessaloniki

Thomas Karagiannis, MD, PhD, MSc
Credit: Aristotle University of Thessaloniki

A network meta-analysis of nearly 2 dozen trials examining semaglutide and tirzepatide suggests tirzepatide could provide more efficacious reductions in HbA1c and superior reductions in body weight relative to semaglutide.

Leveraging data from 22 trials among people with type 2 diabetes, results of the study, which will be presented at the European Association for the Study of Diabetes 2023 annual meeting, indicate tirzepatide 5, 10, and 15 mg were more efficacious in reducing HbA1c compared to semaglutide 0.5, 1.0, and 2.0 mg, respectively, but this improvement in HbA1c could come with increased risk of gastrointestinal events, particularly with elevated doses of tirzepatide.1

“In people with type 2 diabetes, tirzepatide 5, 10, and 15 mg were more efficacious in reducing HbA1c compared to semaglutide 0.5, 1.0, and 2.0 mg, respectively. Tirzepatide also was also more effective for weight loss than semaglutide, with a larger weight-loss effect at higher doses. High-dose tirzepatide (15 mg) was associated with increased risk for vomiting versus low- and medium-dose semaglutide," explained investigators.2

Few pharmacologic agents have captured the attention of the general public in the same manner as semaglutide and tirzepatide in recent years. Driven by success in randomized clinical trials in patient populations with type 2 diabetes and obesity, the incretin-based therapies have emerged and been recognized as paradigm-shifting agents with the potential to have a significant impact on population-level health.

A beneficiary of the established safety and efficacy profile of the GLP-1 receptor agonist class, the dual GIP/GLP-1 receptor agonist tirzepatide began its ascent into the spotlight of cardiometabolic medicine at the American Diabetes Association 2021 annual meeting with the release of data from the SURPASS program. The trials within this phase 3 clinical program would serve as the foundation of tirzepatide’s May 2022 approval as an adjunct for improving glycemic control in adults with type 2 diabetes. The subsequent release of data from the SURMOUNT program detailing safety and efficacy in people with obesity or overweight has the agent expecting a decision on an application for a chronic weight management indication by the end of 2023.3

The story for semaglutide followed a different path. Initially approved in 2017 in 0.5 mg and 1.0 mg dosages as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes, Novo Nordisk went on to develop an oral version of semaglutide and a 2.0 mg formulation, which received approval as adjuncts in type 2 diabetes in 2019 and 2021, respectively.4,5,6 In the same year semaglutide 2.0 received approval in type 2 diabetes, it was catapulted into the spotlight when a 2.4 mg formulation became the first agent to receive approval from the FDA as a treatment for chronic weight management since 2014.7

In the current study, a team led by Thomas Karagiannis, MD, PhD, MSc, of the Aristotle University of Thessaloniki, sought to compare the safety and efficacy profiles of the agents in type 2 diabetes through a meta-analysis of randomized controlled trials. To do so, investigators perfumed a search of the Medline and Cochrane Library databases for trials assessing subcutaneous doses of tirzepatide in 5, 10, or 15 mg doses or subcutaneous disease of semaglutide in 0.5, 1.0, and 2.0 mg doses for at least 12 weeks.1

From their search, investigators identified 22 randomized controlled trials with a total population of 18,742 patients with type 2 diabetes. The primary outcome of interest for the meta-analysis was differences in effects on HbA1c, body weight, and risk of adverse events.1

Upon analysis, results indicated the most efficacious effects for reducing HbA1c relative to placebo from the selected trials were observed with tirzepatide 15 mg (Mean Difference [MD], -2.00%; 95% Confidence Interval [CI], -2.16 to -1.84), tirzepatide 10 mg (MD, -1.86%; 95% CI, -2.02 to -1.84), and semaglutide 2.0 mg (MD, -1.62%; 95% CI, -1.96 to -1.28). In their analyses, investigators found each of the 3 tirzepatide doses included in the study reduced HbA1c to a greater extent than the low-, medium-, and high-dose of semaglutide.1

For body weight outcomes, results suggested tirzepatide was more efficacious than semaglutide in reducing body weight when compared against placebo therapy. When performing between-drug comparisons, investigators found both tirzepatide 10 and 15 mg were more efficacious in lowering body weight versus either semaglutide 1.0 or 2.0 mg. Additionally, tirzepatide 5 mg was more efficacious relative to semaglutide 0.5 and 1.0 mg.1

When assessing safety profiles, results indicated all doses of tirzepatide and semaglutide increased risk for gastrointestinal adverse events, with tirzepatide 15 mg associated with the greatest relative increase in risk for nausea (Risk Ratio [RR], 3.57; 95% CI, 2.56 to 4.76), vomiting (RR, 4.35; 95% CI, 3.03 to 6.25), and diarrhea (RR, 2.04; 95% CI, 1.56 to 2.63) compared with placebo therapy. Investigators highlighted between-drug comparisons yielded non-significant results, except for tirzepatide 15 mg compared with semaglutide 1.0 mg (RR, 1.39; 95% CI, 1.03 to 1.85) and 0.5 mg (RR, 1.85; 95% CI, 1.35 to 2.56) in vomiting, and compared semaglutide 0.5 mg (RR, 1.45; 95% CI, 1.09 to 1.92) in nausea.1

“In summary the 3 tirzepatide doses were more effective than the 3 respective semaglutide doses, with the difference between the two drugs being larger with the higher doses," investigators concluded.2


  1. Karagiannis T, Avgerinos I, Malandris K, et al. Tirzepatide compared to subcutaneous semaglutide for type 2 diabetes: a network meta-analysis. European Association for the Study of Diabetes (EASD) 2023 Annual Meeting. Published online September 22, 2023.
  2. Tirzepatide more effective in blood sugar control and body weight loss than semaglutide, shows meta-analysis of 22 studies. EurekAlert! Accessed September 25, 2023. https://www.eurekalert.org/news-releases/1002351.
  3. Office of the Commissioner. FDA approves novel, dual-targeted treatment for type 2 diabetes. U.S. Food and Drug Administration. May 13, 2022. Accessed September 25, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-dual-targeted-treatment-type-2-diabetes.
  4. Ozempic® (semaglutide) approved in the US. Novo Nordisk. December 5, 2017. Accessed September 25, 2023. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=712.
  5. Office of the Commissioner. FDA approves first oral GLP-1 treatment for type 2 diabetes. U.S. Food and Drug Administration. September 20, 2019. Accessed September 25, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-glp-1-treatment-type-2-diabetes.
  6. Novo Nordisk receives FDA approval of higher-dose Ozempic® 2 mg providing increased glycemic control for adults with type 2 diabetes. Novo Nordisk. March 28, 2022. Accessed September 25, 2023. https://www.novonordisk-us.com/media/news-archive/news-details.html?id=108097.
  7. Office of the Commissioner. FDA approves new drug treatment for Chronic Weight Management, first since 2014. U.S. Food and Drug Administration. June 4, 2021. Accessed September 25, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014.
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