An industry-funded trial of tirzepatide, which is a glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide receptor agonist, found that the drug caused significantly more weight loss than placebo when added to a lifestyle intervention. The study (SURMOUNT-2) randomized 938 patients to tirzepatide, 10 mg; tirzepatide, 15 mg; or placebo and found that significantly more participants treated with tirzepatide lost at least 5% of their body weight (79% to 83% vs. 32% on placebo).
Two nutrient-stimulated gastrointestinal hormones—GLP-1 and glucose-dependent insulinotropic polypeptide (GIP)—are released after eating. Semaglutide, a GLP-1 receptor agonist that remains active for up to a week after subcutaneous injection, resulted in a mean 15% weight loss in people without diabetes who had overweight or obesity. Tirzepatide, a GLP-1 receptor agonist combined with GIP, produced an even greater mean weight loss of 20% in the same population, which is probably related to the GIP effect on energy balance.
SURMOUNT-2 confirmed the extra difficulty in losing weight for persons with diabetes, showing a mean weight loss of 15% with tirzepatide, which was about 5% less than in SURMOUNT-1. In addition to weight loss, HbA1c levels fell by 2.0% from a baseline of 8.0% in these patients, who were not receiving insulin. Other positive clinical outcomes with tirzepatide included a 6.3–mm Hg reduction from baseline in systolic blood pressure and 27% reduction from baseline in fasting triglyceride levels.
Weight loss ≥5% is necessary for clinical benefits, although this is difficult for most people to achieve and certainly to maintain. Given their effectiveness for weight loss, high doses of GLP-1 receptor agonists, alone or combined with GIP (the new term is “twincretins”), are a major breakthrough that will be favored for persons without diabetes who have overweight or obesity, with prediabetes, or with diabetes. Intensive lifestyle interventions were a part of all treatment groups in clinical trials—real-world studies should answer the question of whether such interventions are needed for the drugs' effectiveness.
Trials evaluating new twincretins, and even a combination of a twincretin plus a glucagon receptor agonist, are in progress or have recently reported results. The biggest challenges to the use of these new weight-loss drugs are supply, lack of cost-effectiveness evidence, and insurance coverage.