In adults with BMI ≥27 kg/m2 and type 2 diabetes, adding tirzepatide to a lifestyle intervention increased weight loss at 72 wk

The new drugs known as “twincretins” represent a major breakthrough for patients with overweight or obesity, prediabetes, or diabetes, but obstacles will include supply, lack of cost-effectiveness evidence, and insurance coverage, an ACP Journal club commentary said.

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).

The study was published by The Lancet on June 26. The following commentary by Mayer B. Davidson, MD, was published in the ACP Journal Club section of Annals of Internal Medicine on Nov. 7.

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.