Recently, the results of a Phase IIb clinical trial conducted by Eli Lilly and Company on its dual GIP and GLP-1 receptor agonist (GIP/GLP-1 RA, LY3298176) demonstrated robust and clinically significant effects in lowering blood glucose and reducing body weight in patients with type 2 diabetes. The six-month trial data revealed that patients’ HbA1c levels decreased by 2.4% from baseline, and their mean body weight decreased by 11.3 kg (12.7%). These findings were presented at the 54th Annual Meeting of the European Association for the Study of Diabetes in Berlin on October 4, 2018, and simultaneously published in The Lancet.
Once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists integrate the actions of two incretin hormones into a novel molecule, offering superior clinical glycemic benefits compared to GLP-1 receptor agonists alone.
Dr. Juan P. Frias, President and Chief Investigator of the National Institutes of Health, stated: “The results of this Phase IIb study on the dual GIP/GLP-1 receptor agonist are unprecedented, with impressive effects on glycemic control and weight loss, holding promise to become a new mainstream treatment regimen for patients with type 2 diabetes. The new wave of innovations in incretin-based research for the treatment of type 2 diabetes is breathtaking. The clinical benefits of GLP-1 receptor agonists have been extensively demonstrated, and we look forward to seeing more new molecules that integrate the dual agonistic action on GIP and GLP-1 receptors bring clinical benefits to patients with type 2 diabetes in the future.”
Two statistical methods were employed to evaluate and compare the efficacy of four doses (1 mg, 5 mg, 10 mg, and 15 mg) of GIP/GLP-1 receptor agonists versus placebo and dulaglutide 1.5 mg in patients with type 2 diabetes. The first method utilized a dose-response model to assess treatment effects in populations including those who discontinued treatment and those who received rescue medication. The second method assessed treatment effects in the population that remained on treatment without rescue medication¹.
At Week 26, the primary study analysis demonstrated that all doses of the GIP/GLP-1 RA exhibited a robust dose-response compared with placebo.1
Compared with dulaglutide and placebo, GIP/GLP-1 RA significantly improved all clinical observation endpoints in all treated patients:
· Decrease in HbA1c：All dose groups of the GIP/GLP-1 RA [GIP/GLP-1 RA: -1.6% (5 mg), -2.0% (10 mg), -2.4% (15 mg)] and the dulaglutide treatment group [-1.1% (1.5 mg)] showed significant changes in blood glucose levels compared to the placebo group (0.1%) from baseline (mean absolute reduction).
· HbA1c Target Achievement:The high-dose GIP/GLP-1 RA group achieved the most significant reduction in HbA1c. The 10 mg and 15 mg treatment groups attained the target of HbA1c levels ≤ 5.7%, corresponding to the normal glycemic range without diabetes [18% (10 mg) and 30% (15 mg)]. Furthermore, nearly 90% of treated patients achieved the HbA1c target of ≤ 7% [GIP/GLP-1 RA: 69.1% (5 mg), 90.0% (10 mg), and 77.4% (15 mg); dulaglutide: 51.9% (1.5 mg)].
· Weight Loss:The GIP/GLP-1 RA group achieved significant weight loss [−4.8 kg (5 mg), −8.7 kg (10 mg), and −11.3 kg (15 mg)], as did the dulaglutide group [−2.7 kg (1.5 mg)], whereas the placebo group showed a weight loss of −0.4 kg. More than one-third of patients treated with GIP/GLP-1 RA [10 mg (39.2%), 15 mg (37.7%)] achieved at least 10% weight reduction, and one-quarter of patients treated with GIP/GLP-1 RA 15 mg achieved at least 15% weight reduction.
The safety profile of GIP/GLP-1 RA is similar to that of GLP-1 RA. The most common adverse reactions are dose-dependent gastrointestinal events. These adverse events primarily include nausea [20% (5 mg), 22% (10 mg), 40% (15 mg)], diarrhea [24% (5 mg and 10 mg), 32% (15 mg)], and vomiting [8% (5 mg), 16% (10 mg), 26% (15 mg)]. Most were mild to moderate in severity, transient in nature, and typically occurred during the dose titration phase. The adverse event profile of dulaglutide 1.5 mg was consistent with previous studies. No patients in any treatment group reported serious hypoglycemic adverse events in this study. Further studies on dose optimization to manage the gastrointestinal adverse reactions associated with these medications are currently underway and will be published next year.
Dr. Jeff Emmick, Vice President of Diabetes Product Development at Eli Lilly, remarked, “Despite significant progress in diabetes management, patients with type 2 diabetes often require additional therapeutic options as the disease progresses. This is why our researchers remain committed to continuous innovation—to help patients live better lives. We set high standards for this Phase II study, and the results have exceeded our expectations. We are thrilled to continue the development of GIP/GLP-1 receptor agonists, with the hope of adding another powerful agent to our comprehensive portfolio for diabetes care.”
Eli Lilly plans to launch the large-scale Phase III SURPASS clinical trial program to more comprehensively evaluate the safety and efficacy of its GIP/GLP-1 RA. These Phase III trials are scheduled to commence in early 2019 and conclude in 2021. Eli Lilly is also evaluating strategies for developing GIP/GLP-1 RA for weight loss and other indications.
Regarding this Phase IIb Study 1
This Phase IIb study employed a randomized, placebo-controlled design over 26 weeks (6 months) to compare the efficacy differences among four different doses (1 mg, 5 mg, 10 mg, and 15 mg) of Eli Lilly’s long-acting dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, dulaglutide (1.5 mg), and placebo in patients with type 2 diabetes. The primary endpoint was to evaluate whether once-weekly GIP/GLP-1 RA treatment demonstrated superiority over placebo in reducing HbA1c from baseline at Week 26.
Secondary endpoints included changes from baseline in body weight, fasting plasma glucose (FPG), and waist circumference at Week 26; the proportion of patients achieving body weight reductions of ≤5% and ≥10% from baseline; the proportion of patients achieving target HbA1c control; and changes from baseline in lipid laboratory parameters.
References:
1. 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; published online October 4. DOI: 10.1016/S0140-6736(18)32260-8. Available at: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32260-8/fulltext.