Physicians' Academy for Cardiovascular Education

Twincretin: Superior glycemic control and weight loss compared to GLP-1RA monotherapy in T2DM

Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial

Literature - Frias JP, Nauck MA, Van J et al. - The Lancet 2018; published online ahead of print

Introduction and methods

Glucagon-like peptide-1 receptor agonists (GLP-1RA) are associated with effective glycemic and body weight control in type 2 diabetes (T2DM), however, not all patients achieve their respective targets with GLP-1 RA therapy [1]. LY3298176 is a 39-amino acid synthetic peptide with agonist activity at both the glucose-dependent insulin-tropic polypeptide (GIP) and GLP-1 receptors, to be administered subcutaneously, once-weekly [2]. This randomized, double-blind, phase 2 study evaluated the dose-response relationship of LY3298176 (1, 5, 10, and 15 mg) in T2DM patients, and assessed the efficacy and safety in comparison with placebo and the GLP-1RA dulaglutide 1.5 mg.

For this purpose, 316 adult patients (aged 18-75) with T2DM for at least 6 months that was inadequately controlled with diet and exercise alone or with stable metformin therapy for at least 3 months before screening, and with a BMI of 23–50 kg/m² were randomly allocated (1:1:1:1:1:1) to one of the six parallel treatment groups for 26 weeks (placebo, LY3298176 1, 5, 10, and 15 mg, and dulaglutide 1.5 mg).

The primary efficacy outcome was change in HbA1c from baseline to 26 weeks in the modified intention-to-treat (mITT) population, defined as all participants who took at least one dose of study drug and had at least one post-baseline measurement of any outcome.

Main results

Twincretin: Superior glycemic control and weight loss compared to GLP-1RA monotherapy in T2DM


In this phase 2b study, LY3298176, a dual GIP and GLP-1 receptor agonist, led to a statistically significant and clinically meaningful dose-dependent improvement of glucose lowering and body weight reduction compared with dulaglutide and placebo

Editorial comment

In their editorial article, Stumvoll and Tschöp [4] note that it is too early for any far-reaching clinical conclusion or recommendation based on the results of the study of Frias et al.. Several issues need to be addressed, for example whether LY3298176 is also superior to semaglutide, the most effective GLP-1 receptor agonist, which patients will benefit most from the dual agonist, and what will be the optimal dosing. As the field moves toward a future of metabolic precision medicine, future decision-making processes might include identifying the best incretin-based therapy for any individual patient from a choice of single molecule combination therapeutics. Better understanding of respective mechanisms of action and reliable predictive markers will be of considerable value to appropriately personalize such therapeutic choices. The authors conclude: ‘The joint interpretation of encouraging results from pharmacologically optimized GLP-1 monoagonism and these new observations indicating superior benefits of a twincretin approach suggest that these treatment approaches could contribute to efforts to reduce the rising prevalence of obesity and type 2 diabetes.’


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