Tirzepatide triumphs in significant weight reduction for people with type 2 diabetes

In a recent article published in The Lancet, researchers performed a double-blinded, placebo-controlled phase III randomized clinical trial (RCT) SURMOUNT-2 in seven countries between March 29, 2021, and April 10, 2023.

The study included adults aged ≥18 years with a body-mass index (BMI)≥ 27 kg/m2, with glycated hemoglobin (HbA1c) of 7–10, and type 2 diabetes (T2D). The study aimed to assess the effectiveness and safety of tirzepatide vs. placebo as a weight management treatment.

Specifically, they evaluated the safety profile and efficacy of 10 or 15mg subcutaneous tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) receptor agonist, or placebo for 72 weeks, when given once weekly.

Study: Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Image Credit: cozyta/Shutterstock.com

Background

Obesity raises the risk of nearly 200 weight-related issues, of which type two diabetes (T2D), cardiovascular diseases (CVDs), and chronic kidney disease are fatal. The American and European Diabetes Associations agree that 5 to 15% weight reduction is key to T2D management and translates to health benefits beyond glycaemic control.

In fact, greater bodyweight reduction (≥10%) improves cardiometabolic risk factors, which can even lead to remission of diabetes.

In a previous clinical trial, tirzepatide treatment reduced body weight by up to 20.9% after 72 weeks in obese people who did not suffer from T2D, besides improving other health-related outcomes in a dose-dependent manner.

Its GIP and GLP-1 receptor agonist activity synergized glucose and lipid homeostasis that governs food consumption and appetite.

Thus, the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved tirzepatide to treat T2D in adults.

The molecule is also under development for chronic weight management. However, studies in obese people with T2D often have less weight reduction in response to anti-obesity medication treatment than those without diabetes.

About the study

In the present phase III SURMOUNT trial of tirzepatide, researchers investigated its efficacy and safety as a chronic weight reduction and maintenance treatment.

Accordingly, they designed this 72-week trial and conducted it in 77 sites (multicenter) across India, Argentina, Japan, Brazil, Russia, the USA, and Taiwan. All study participants received diet, exercise, or oral antihyperglycaemic medication for T2D management three months before study screening which lasted three weeks.

The team randomly assigned (1:1:1) all participants to receive tirzepatide 10 mg, 15 mg, or placebo, which they administered subcutaneously using a single-dose pen for 72 weeks. There was a four-week safety follow-up period following the treatment period.

First, the team-initiated treatment with 2·5 mg once weekly tirzepatide (or matching placebo) and increased the dose by 2·5 mg every four weeks until they reached the target dose, i.e., 10 or 15 mg, sometime between 12 and 20 weeks. 

This trial had two coprimary endpoints; first, the researchers determined the percent change in body weight from baseline to week 72, and second, they assessed weight reduction from baseline of at least 5% at week 72. 

The team controlled for type one error rate in secondary endpoints, specifically for bodyweight reductions of 10%, 15%, and 20% at week 72. Likewise, they assessed the change from baseline in HbA1c, fasting glucose, waist size, systolic blood pressure, and fasting lipid concentrations at week 72.

In a post hoc analysis, the team evaluated the change in the number of antihyperglycaemic medications participants took by week 72. The safety endpoints of the study included treatment-emergent adverse and serious adverse events, level two or three hypoglycemia accompanied by severe cognitive impairment.

Results

The researchers screened 1,514 participants for eligibility during the study period, enrolling 938 participants. Next, they randomly assigned 312, 311, and 315 enrolees to receive tirzepatide 10 mg, tirzepatide 15 mg, and a matching placebo, which comprised the study's intent to treat the population.

In study participants with a BMI≥ 27 kg/m2 and T2D, tirzepatide 10 mg and 15 mg once weekly doses reduced body weight by 12·8% and 14·7%, respectively, vs. 3·2% with placebo. 

Encouragingly, up to 83% of participants treated with tirzepatide attained clinically significant ≥5% weight reduction, with up to 50% and one-third of the participants reaching 15% or higher and 20% or higher weight reduction. 

Also, 49% of the tirzepatide-treated participants reached normoglycaemia, i.e., HbA1c <5·7%, whereas only 3% attained this benchmark in the placebo group. More importantly, there were no cases of severe hypoglycemia among those reaching this HbA1c target post-tirzepatide treatment.

In addition, drug treatment triggered only mild to moderate gastrointestinal events in some participants, e.g., diarrhea and nausea.

Furthermore, tirzepatide treatment markedly improved the cardiometabolic risk factors of study participants. Examples include systolic BP, fasting triglycerides, and high- and non-high-density lipoprotein cholesterol. 

Conclusions

According to the authors, SURMOUNT-2 is one of the first RCTs of tirzepatide conducted in obese adults with T2D that assessed body weight reduction and not HbA1c reduction as the primary outcome.

Both 10 and 15 mg tirzepatide doses conferred clinically significant bodyweight reductions accompanied by improved HbA1c and other cardiometabolic risk factors. It attained a body weight reduction that exceeded levels of weight reduction of approved anti-obesity medications.

This trial brought forth a promising treatment for obese people with type 2 diabetes.

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.