Tirzepatide: A New Anti-Obesity Medication

Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 2022;387:205-216. Obesity affects approximately 650 million adults worldwide and more than 40% of the adult population in the United States. Its complications, including cardiovascular disease and type 2 diabetes, impose a considerable economic burden and lead to increased morbidity and mortality. In many patients, lifestyle modifications and traditional obesity medications fail to achieve the desired weight loss of 10%-20% needed to reduce complications. Bariatric surgery, though effective, is an invasive approach with potential complications. Semaglutide was recently approved for chronic weight management, having demonstrated >10% placebo-subtracted weight loss, and qualifies as the first second-generation obesity medication. Tirzepatide, a dual gastric inhibitory polypeptide (GIP) and glucose-like peptide 1 (GLP-1) receptor agonist, induces more weight loss than semaglutide in patients with type 2 diabetes, paving the way to investigate its efficacy and safety in overweight or obese adults without diabetes. Jastreboff et al report findings from SURMOUNT-1, a 72-week multi-center, double-blind, randomized, placebo-controlled trial that enrolled 2539 adults without diabetes but who were overweight (body mass index [BMI] ≥27 kg/m2) with at least 1 weight-related complication, or obese (BMI ≥30 kg/m2). Participants were randomly assigned in a 1:1:1:1 ratio to receive once weekly subcutaneous injection of tirzepatide at 5 mg, 10 mg, or 15 mg or placebo along with lifestyle modification. The primary end point was percentage change in body weight from baseline to week 72. Secondary end points included weight reduction by 10%, 15%, or 20% or more by week 72. The mean age of participants was 45 years, with 69% female and 71% white. The mean body weight and BMI at baseline were 105 kg and 38 kg/m2, respectively. The mean changes in weight by week 72 were 15% (95% CI 14.2%-15.9%), 19.5% (18.5%-20.4%), 20.9% (19.9%-21.8%), and 3.1% (1.9%-4.3%) with 5 mg, 10 mg, 15 mg, and placebo, respectively. At week 72, 50% and 57% of participants in the 10 mg and 20 mg tirzepatide groups had ≥20% reduction in body weight, compared with 3% with placebo. The intervention group had significant improvements in cardiometabolic risk factors (waist circumference, systolic and diastolic blood pressure, fasting insulin, lipid and aspartate transaminase levels). Adverse events experienced by the intervention group were transient mild-to-moderate gastrointestinal symptoms (nausea, diarrhea, and constipation) encountered during dose escalation. Study limitations include the enrolled participants potentially representing a subpopulation with a greater commitment to weight-management efforts than the general population with obesity. The study was also relatively short in duration and mainly comprised a younger population cohort without particularly high baseline cardiometabolic risk factors. This raises the question whether tirzepatide confers cardioprotective effects similar to those seen after bariatric surgery. Furthermore, despite the compelling effects of tirzepatide on body weight reduction, there remain significant gaps in our understanding of its mechanism of action. Nonetheless, results from this trial are encouraging and are poised to expand the therapeutic armamentarium for obesity.