New combination drug has better efficacy in glucose control and weight loss than when taken separately.
Glucagon-like peptide-1 (GLP-1) receptor agonists help increase insulin secretion from beta cells and suppress glucagon secretion from alpha-cells. An added benefit of these antidiabetic medications is that they slow gastric emptying and promote satiety. Glucose-dependent insulinotropic polypeptides (GIP) stimulate insulin secretion. A new drug, called LY3298176, is a dual mix of GIP and GLP-1 receptor agonists. It should theoretically stimulate insulin release and suppress glucagon thus having a major impact on blood glucose levels. The efficacy and safety of LY3298176 is still under investigation, but the following study showed promising results.
A double-blind, randomized, phase 2 study focused on patients with type 2 diabetes who were given either 1mg, 5mg, 10mg, 15mg of LY3298176, placebo, or dulaglutide 1.5mg for 26 weeks. All were administered as once-weekly injections. Baseline characteristics were similar among groups, with all having uncontrolled type 2 diabetes for over 6 months. BMI, metformin use, and HbA1c were stratified among groups. The primary endpoints was a change in HbA1c at 26 weeks. Secondary endpoints included change in HbA1c at 12 weeks, change in mean body weight, fasting glucose levels, waist circumference, total cholesterol, LDL and HDL cholesterol, triglycerides, and amount of patients reaching HbA1c target, and amount of patients with 5% and 110% body weight reduction at 26 weeks.
Results showed that out of 318 patients, the effect of LY3298176 on HbA1c was significant and dose dependent. In the 1mg group, the mean change from baseline in HbA1c was -1.06%, -1.73% for the 5 mg group, -1.89% for the 10 mg group, and -1.94% for 15 mg group, as compared to -0.06% in the placebo group. There was a total mean difference of -1.00% (-1.22% to -0.79%) for 1 mg, -1.67% (-1.88% to -1.46%) for 5 mg, -1.83% (-2.04% to -1.61%) for 10 mg, and -1.89% (-2.11% to -1.67%) for 15 mg.
As for secondary outcomes, data was just as impressive. Looking at achieving target HbA1c levels, only 12% of patients on placebo reached a goal of <7%, whereas 33-90% of the LY3298176 group reached target, and 52% of the dulaglutide group achieved HbA1c levels less than 7% at 26 weeks. Weight loss of at least 5% occurred in 14-71% of the LY3298176 group, 22% in the dulaglutide group and 0% of patients in the placebo group reached 5% weight reduction. The 12-week outcomes were similar to results at two weeks for all secondary outcomes.
Major adverse events in LY3298176 were gastrointestinal related, like nausea, vomiting, and diarrhea. These events were dose-related with 23.1% for 1 mg of LY3298176, 32.7% for 5 mg LY3298176, 51% for 10 mg LY3298176, and 66% for 15 mg LY3298176, 42.6% for dulaglutide, 9.8% for placebo. Most adverse events were mild to moderate. Decreased appetite was the second most common adverse event (3.8% for 1 mg LY3298176, 20% for 5 mg LY3298176, 25.5% for 10 mg LY3298176, 18.9% for 15 mg LY3298176, 5.6% for dulaglutide, 2% for placebo). There were no reports of severe hypoglycemia.
This study therefore indicates that LY3298176 is effective and safe for use in people who have type 2 diabetes. The dual action of GIP and GLP-1 receptor agonist shows better efficacy than dulaglutide and its effects are dose dependent. The main benefits were seen in glucose control and weight loss. This drug may have a new place in treatment regimens for the management of type 2 diabetes.
- Dual GIP/GLP-1 receptor agonists lower HbA1c and have higher rates of weight loss than GLP-1 agonist alone.
- Main safety concerns are gastrointestinal effects and were mild to moderate.
- LY3298176 is still only in phase 2 trials but did show efficacy and safety in people who have type 2 diabetes.
Juan Pablo Frias, Prof Michael A Nauck, Joanna Van, Mark E Kutner, Xuewei Cui, Charles Benson, MD 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. The Lancet. (October 04, 2018) DOI:https://doi.org/10.1016/S0140-6736(18)32260-8
Angela Reyes, Pharm.D. Candidate, LECOM College of Pharmacy