The idea of combining glucagon-like peptide-1 (GLP-1) receptor agonist and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist for reducing glycated hemoglobin A1c (HbA1c) and body weight has already been circulated for quite some time.1 Recently, a double-blind, randomized, phase 2 study has tested the efficacy and safety profile of a novel dual-action agent that stimulates both GLP-1 and GIP receptors, and showed promising results such as HbA1c reduction and weight loss.2 Now dubbed as ‘twincretins’, the dual co-agonism concept appeared to be a promising way to enhance the management of type 2 diabetes.3
Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted in the distal ileum and colon, which has a function of stimulating insulin secretion and suppressing glucagon secretion.4 GLP-1 receptor agonist that mimics the action of GLP-1 has been widely recommended for type 2 diabetes management after being shown to provide benefit in cardiovascular outcomes by addressing key pathophysiological problems of type 2 diabetes.5,6
Unfortunately, some patients cannot receive the benefits offered by GLP-1 receptor agonists due to variation of characteristics in each patient,7 leading to the failure of glycemic and bodyweight control within the therapeutic targets.2 One solution to overcome this problem is to enhance the metabolic effects of GLP-1 receptor agonists by combining it with another enteropancreatic hormone with complementary or synergistic action, such as glucose-dependent insulinotropic polypeptide (GIP), which is a potent stimulator of glucose-dependent insulin secretion secreted from the enteroendocrine K cells.2
The concept of GLP-1 and GIP receptor co-agonist treatment as an additive effect on glucose and body weight regulation had already been proven in various preclinical studies with some positive results,1,8,9 and the concept is now ready to be tested in a clinical environment.
To assess the efficacy and safety of GLP-1 and GIP receptor agonists in patients with poorly controlled type 2 diabetes, a double-blind, randomized, phase 2 study was conducted with a novel dual GLP-1 and GIP receptor agonist, LY3298176.2 The study recruited 318 participants aged 18-75 years and with a body-mass index of 23-50kg/m2 who had type 2 diabetes for at least 6 months (HbA1c level of 7.0%-10.5%, inclusive) that was inadequately controlled with diet and exercise alone or with stable metformin therapy for at least 3 months.2
The eligible participants were randomly allocated (1:1:1:1:1:1) to one of the six parallel treatment groups, which included the placebo group, LY3298176 1mg group, LY3298176 5mg group, LY3298176 10mg group, LY3298176 15mg group, and dulaglutide 1.5mg group, all given as a subcutaneous injection once-weekly.2 All six treatment groups had 1-week screening, 2-week lead-in period, then treated with the corresponding intervention for 26 weeks, and monitored for an extra 4-week for safety outcomes.2 All statistical analyses were performed as an intention-to-treat analysis.2
The results showed that across all dosage levels of LY3298176, HbA1c level reductions from baseline ranged between 0.4% to 11.3%, while the placebo group increased HbA1c from baseline by 0.1%, and dulaglutide group reduced HbA1c from baseline by 1.1%.2 When compared with placebo, all dosage levels of LY3298176 led to a significantly greater HbA1c reduction (p=0.0004, p=0.0001, p<0.0001, and p<0.0001, from the lowest to the highest dose, respectively), whereas in comparison with dulaglutide, only LY3298176 5mg, 10mg, and 15mg produced statistically significant reduction in HbA1c (p=0.0152, p=0.0001, p<0.0001, respectively).2
Reductions in body weight as compared to baseline were also significant in the LY3298176 5mg, 10mg, and 15mg groups when compared with the placebo group (-4.8kg, -8.7kg, and -11.3kg vs.
-0.4kg with placebo; p<0.0001 for all 3 pairs of comparisons).2 As compared with dulaglutide, the differences in weight change from baseline were significant in the 10mg and 15mg group (-8.7kg and -11.3kg vs. -2.7kg with dulaglutide; p<0.0001 for both comparisons).2
The safety and tolerability profile of the novel agent appeared to be acceptable, with gastrointestinal events and decreased appetites being the most common treatment-emergent adverse events.2 Moreover, the safety profiles of LY3298176 were similar to that of dulaglutide except in the 15mg group, which was associated with more gastrointestinal events.2
Based on the study results, the novel dual-action agent appeared to lower HbA1c better than dulaglutide, which re-emphasized that “the strategy of dual and triple co-agonism [based on combinatorial integration of multiple gut hormones into one molecule] is promising,” said Dr. Michael Stumvoll from the University of Leipzig, Germany, and Dr. Matthias Tschöp, from Helmholtz Institute for Metabolism, Munich, Germany, who have dubbed the dual co-agonists ‘twincretins’.3
Although the results were fascinating for the field, Dr. Stumvoll and Dr. Tschöp warned for overenthusiasm before more evidence are made available. “Despite the small but significant competitive edge of this twincretin over a classic GLP-1 mono-agonist, it is too early for any far-reaching clinical conclusion or recommendation,” they concluded.3
1. Finan B, Ma T, Ottaway N, et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med. 2013;5(209):209ra151-209ra151.
2. Frias JP, Nauck MA, Van J, et al. 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. Lancet. 2018. [epub ahead of print]
3. Twincretin, a Dual GIP/GLP-1 Agonist, Excites in Type 2 Diabetes. Medscape. 2018 (Accessed October 30, 2018, at https://www.medscape.com/viewarticle/902962#vp_1)
4. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696-1705.
5. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.
6. Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol. 2018. [epub ahead of print]
7. Monami M, Dicembrini I, Nreu B, et al. Predictors of response to glucagon-like peptide-1 receptor agonists: a meta-analysis and systematic review of randomized controlled trials. Acta diabetologica. 2017;54(12):1101-1114.
8. Bokvist K, Brown R, Coskun T, et al. LY3298176, a novel long-acting GIP/GLP-1 coagonist, shows enhanced activity on weight loss and energy utilisation whilst maintaining its efficacy for glycaemic control. 53rd EASD Annual Meeting. September 11-15, 2017. Lisbon, Portugal. Abstract 862.
9. Finan B, Yang B, Ottaway N, et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med. 2015;21(1):27.