Tirzepatide: The Most Effective Drug Therapy for Prevention of Type 2 Diabetes

Abstract

Obesity is a main trigger for development of type 2 diabetes. Tirzepatide is a dual receptor agonist of glucagon-like 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and is a potent agent for controlling glycemic control and reducing body weight. Accordingly, tirzepatide was evaluated in addition to lifestyle changes to decrease incidence of type 2 diabetes in obese subjects with obesity and prediabetes in an extension study of the SURMOUNT-1 trial. The latter was a randomized, double-blind trial of 72 weeks to evaluate the effects of tirzepatide on weight reduction in 2,539 participants with obesity; 40% (n=1,032) of those subjects had prediabetes. The authors of SURMOUNT-1 study examined the frequency of new-onset type 2 diabetes in the 1,032 subjects with pre-diabetes from baseline to week 176 and week 193 after a 17-week off tirzepatide or placebo. After 176 weeks, type 2 diabetes was diagnosed in 1.5% (n=4), 2.0% (n=5), 0.4% (n=1), and 13.3% (n=36) in subjects randomized to tirzepatide 5 mg, 10 mg, and 15 mg, and placebo, respectively. At 176 weeks, compared with placebo, risk of type 2 diabetes in the pooled tirzepatide groups, was decreased by 93%; hazard ratio (HR) 0.07, 95% CI, 0.0 to 0.1; P<0.001. This 93% reduction in incidence of type 2 diabetes was superior to that achieved by the maximum doses of the GLP-1 receptor agonists liraglutide (79% reduction) and semaglutide (73% reduction), and by the anti-obesity agent phentermine/topiramate (76% reduction). However, subjects’ characteristics in studies evaluating these 4 drugs were different. At 176 weeks, achievement of at least 5% of weight loss resulted in remission of prediabetes to normoglycemia in 96% and 83% of subjects with tirzepatide and placebo, respectively. Weight loss seems to be a main factor leading to prevention of type 2 diabetes in all previous drugs. Other mechanisms such as amelioration of beta-cell function and a decrease in insulin resistance may be involved in case of tirzepatide. Overall, tolerance to tirzepatide was satisfactory. Yet, 12.3% of individuals discontinued tirzepatide 15 mg due to adverse effects versus 5.9% in the placebo group. Gastrointestinal (GI) adverse effects were the main safety issue related to tirzepatide. In summary, tirzepatide is currently the most effective agent for diabetes prevention and reversion to normoglycemia in subjects with obesity and prediabetes. Further studies are needed to examine the long-term efficacy, safety, and cost-effectiveness of tirzepatide for prevention of type 2 diabetes.