Nature Reviews Endocrinology | 2021
The dawning of dual-acting incretin drugs
Abstract
0123456789();: Nature reviews | Endocrinology Patients with type 2 diabetes mellitus (T2DM) can be treated effectively with glucagon-like peptide 1 (GLP1) receptor agonists, such as semaglutide. Now, two phase III clinical trials report efficacy and safety findings of a novel dual-acting glucose-dependent insulinotropic polypeptide (GIP) and GLP1 receptor agonist — tirzepatide — in patients with T2DM. Incretin hormones (such as GLP1 and GIP) stimulate insulin secretion after nutrient intake, under hyperglycaemic conditions. GLP1 receptor agonists are effective glucose-lowering therapies that also have beneficial effects on appetite reduction and reducing body weight. GIP has similar effects to GLP1, and also induces glucagon secretion under euglycaemic or hypoglycaemic conditions. A single compound that targets both factors might have a greater effect on blood levels of glucose and body weight than selective GLP1 receptor agonists. The first trial, published in the New England Journal of Medicine, assessed three different dosages of once-weekly tirzepatide (5 mg, 10 mg and 15 mg) against once-weekly semaglutide (1 mg) in 1,879 patients with T2DM. “This was a randomized, open-label, active-control, multinational, parallel, four-arm study,” explains corresponding author Juan P. Frías. “Semaglutide was chosen as the comparator, as it had previously been shown to be superior in head-to-head trials versus other weekly GLP1 receptor agonists.” After 40 weeks, the tirzepatide treatment groups showed estimated mean changes from baseline in HbA1c of −2.01% (5 mg), −2.24% (10 mg) and −2.30% (15 mg), compared with −1.86% after semaglutide treatment. “I think a particularly clinically relevant secondary endpoint was the composite endpoint of the proportion of patients achieving an HbA1c ≤6.5% and weight loss ≥10% and no clinically significant hypoglycaemia (<54 mg/dl (3.0 mmol)),” says Frías. “This composite endpoint was achieved by approximately 32%, 51% and 60% of patients treated with tirzepatide 5 mg, 10 mg and 15 mg, respectively, and by 22% of semaglutide-treated patients.” The researchers concluded that tirzepatide at all doses was noninferior and superior to semaglutide with respect to the mean change in HbA1c from baseline over 40 weeks. The second trial, published in The Lancet, compared tirzepatide with placebo in 478 patients with T2DM that was inadequately controlled by diet and exercise alone. The study design was a four-arm, 40-week, multicentre, randomized, double-blind, placebo-controlled, parallel group trial. Patients were randomized to receive once-weekly tirzepatide (5 mg, 10 mg or 15 mg) or volume-matched placebo. “The conventional therapeutic approach for patients who do not respond to diet and exercise interventions has been to start metformin followed by sequential combination therapy according to HbA1c levels,” explains corresponding author Julio Rosenstock. “However, tirzepatide, which induced impressive reductions of around 2% from a baseline HbA1c of 7.9% together with a weight loss of 7–10 kg, might change such a treatment paradigm, positioning tirzepatide as an initial therapy and potentially enabling remission of T2DM in more than 50% of patients.” Of note, no severe or clinically important occurrences of hypoglycaemia were recorded. Both trials reported that the most frequent adverse effects in patients treated with tirzepatide are mild to moderate gastrointestinal symptoms. However, the authors of both studies state that the gastrointestinal-related adverse effect profile is similar to that reported with GLP1 receptor agonists. Long-term cardiovascular trials are currently ongoing to establish the cardiovascular safety of tirzepatide. In conclusion, these phase III clinical trials provide encouraging findings for the use of a novel GIP and GLP1 receptor agonist in patients with T2DM. However, further investigations are required to establish long-term safety. Whether other dual-acting or triple-acting incretin mimetics will prove successful in clinical trials as potential novel therapies for T2DM remains to be seen.