Twincretin, a Dual GIP/GLP-1 Agonist, Excites in Type 2 Diabetes

BERLIN — A novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor dual agonist combined into a single drug (LY3298176, Lilly), dubbed a "twincretin," shows average reductions in HbA_1c of up to 2.4% and weight loss of up to 11.3 kg (24.9 lb), according to 6-month data in patients with type 2 diabetes.

Principal investigator Juan Pablo Frias, MD, from the National Research Institute, Los Angeles, California, presented the results of the phase 2b study here at the European Association for the Study of Diabetes (EASD) 2018 Annual Meeting.

"These phase 2b clinical trial results for GIP/GLP-1 receptor agonist are unprecedented, and the impressive blood glucose and weight reductions seen may lead to a new treatment option for people with type 2 diabetes," he remarked.

The study was simultaneously published in The Lancet.

The clinically meaningful effects on glucose lowering and weight loss of the dual GIP/GLP-1 receptor stimulation, compared with selective agonism of the GLP-1 receptor with dulaglutide, one of the comparators in the trial, suggests "its potential for greater metabolic effects versus selective GLP-1 receptor stimulation, especially for weight reduction," Frias and colleagues highlight in their article.

"In my experience as an investigator and clinician, I have never seen this magnitude of HbA_1c reduction, in this percentage of patients, who are normalizing their glucose, and with this level of weight loss too, which is certainly more than with dulaglutide," he added, asserting that "this combination has the potential to be a very promising treatment for type 2 diabetes in the future."

Writing in an accompanying commentary, Michael Stumvoll, MD, University of Leipzig, and Matthias Tschöp, MD, Helmholtz Institute for Metabolism, Munich, Germany, say: "These findings re-emphasize that the strategy of dual and triple co-agonism is promising, with potential to reverse the obesity and type 2 diabetes pandemic."

Tschöp also commented following the EASD presentation. In a nutshell, "Yes, I am impressed by these data," he said.

And commenting from the audience, Steven Kahn, MD, University of Washington School of Medicine in Seattle, said: "This is unbelievable, and from a patient perspective it is a new hope. How much of this effect is due to body weight and unloading the basal demand by reducing weight?"

Dual Effect of GIP/GLP-1 Receptor Agonist, Four Doses Studied

Single molecules that simultaneously target the GIP and GLP-1 receptors first emerged in 2013. Frias commented on the combined activity, highlighting the treatment effect contributed by the GIP component.

"The 5-mg and 10-mg doses of the dual agonist showed superior efficacy compared to dulaglutide with respect to HbA_1c lowering and weight reduction, but with similar event rates, suggesting the addition of GIP activity complements the pharmacology of the selective GLP-1 agonist, so we see something from both components, the GLP-1 and the GIP."

In the study, LY3298176 was given subcutaneously (SC) once weekly at one of four doses (1, 5, 10, or 15 mg) and compared with placebo and SC dulaglutide 1.5 mg/week. Treatment continued over a 26-week period, with a 4-week safety follow-up.

The randomized, double-blind study was conducted at 47 sites across Europe and the United States. Participants were aged 18–75 years, had a baseline body mass index (BMI) of 23–50 kg/m² and HbA_1c of 7.0–10.5%, and had type 2 diabetes for at least 6 months inadequately controlled with diet and exercise alone or with stable metformin therapy for at least 3 months. In total, 283 patients completed the study.

The primary objective was measuring the dose-response effect on HbA_1c of LY3298176 relative to placebo at 26 weeks.

Robust HbA_1c Reductions With LY3298176

According to the presentation by Frias here at the meeting, which were the "on-treatment" results (and do not include data on efficacy after discontinuation of study therapy and after initiation of rescue therapy), the change in HbA_1c was -1.6% with the 5-mg dose of LY3298176, rising to -2.4% with 15 mg. By comparison, the change in HbA_1c with dulaglutide was -1.1% (1.5-mg dose) and 0.1% with placebo.

"These are very robust HbA_1c reductions," Frias remarked.

The higher doses of LY3298176 provided the most substantial HbA_1c reductions, with up to 18% of patients on 10 mg and 30% on 15 mg achieving HbA_1c levels of less than 5.7% (normoglycemia). 

"To me, most impressive is the percentage of patients who achieved normoglycemia, with one in five at the 10-mg dose and nearly a third on the 15-mg dose," said Frias. In addition, up to 90% of people reached the recommended HbA_1c target of 7% or less.

Key secondary objectives were weight loss and tolerability and safety of LY3298176, among others.

With respect to weight loss with LY3298176 at 26 weeks, "at 15 mg, weight reduction was an average of over 10 kg (12% of body weight). So a nice dose-response was seen here," he reported.

Dulaglutide produced a 2.7-kg weight reduction at week 26, while with 15 mg of LY3298176, there was an 11.3-kg average weight loss, which was 8.6-kg more than with dulaglutide, Frias explained.

"On the 10-15 mg doses, up to 70% lost over 5% of body weight, 40% lost over 10%, and 25% lost over 15%," he said.

Regarding adverse events, most were seen with the higher doses of LY3298176, said Frias. "There were no side effects that were unexpected or not seen with GLP-1 agonists. The most common were nausea, vomiting, and diarrhea, and most were mild to moderate in intensity and transient in nature, often dissipating with time," he reported.

Gastrointestinal side events were dose-related (seen among 23.1% of those taking 1 mg of LY3298176 and 66.0% of those taking 15 mg, compared with 42.6% for dulaglutide and 9.8% for placebo).

Treatment discontinuations were higher in the 15 mg group of LY3298176 than in the other dosage groups, most occurring during titration. "Slow titration mitigates much of this issue," said Frias.

The proportion of patients with at least one episode of hypoglycemia was similar across patients on 10-mg and 15-mg doses of LY3298176, and dulaglutide. "Importantly from a clinical perspective there was no severe hypoglycemia," he said, adding that "heart rate and blood pressure effects were similar to those seen with dulaglutide, and antidrug antibodies were low titer in general."

Results that include all numbers except efficacy data collected after initiation of rescue therapy are available in The Lancet publication.

"Twincretins" Look Good but Too Early for Any Far Reaching Conclusion

Regarding the adverse event profile of LY3298176, Stumvoll and Tschöp point out in their editorial that "pulse rate did not differ in those treated with LY3298176, which gives this GIP and GLP-1 co-agonist an important edge over a GLP-1 and glucagon co-agonist (MEDI0382), with which increases of 6 to 8 bpm in heart rate were reported."

MEDI0382 is being developed by MedImmune. Results from a phase 2a study reported earlier this year showed the drug improved glycemic control, with a significantly greater drop in HbA_1c from baseline than placebo (-0.9% vs -0.6%; P = .0004) (Lancet. 2018;391:2607-2618).

The new findings with LY3298176 re-emphasize that "the strategy of dual and triple co-agonism (based on combinatorial integration of multiple gut hormones into one molecule) is promising," say Stumvoll and Tschöp, who have dubbed such dual co-agonists "twincretins."

"With all due caution that is appropriate when analyzing a study of only 26 weeks' duration, this trial is the next logical step towards replacing GLP-1 mono-agonists with dual or, perhaps eventually, triple agonists," they add.

"However, 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 conclude.

Lilly said it plans to further study three doses of LY3298176 (5, 10, and 15 mg) but is not yet sure which dose it will carry forward to the phase 3 SURPASS program.

Frias has reported receiving grants from Eli Lilly during the study; grants and personal fees from AstraZeneca, Johnson and Johnson, Merck, Novo Nordisk, and Sanofi; and grants from Boehringer Ingelheim, Bristol-Myers Squibb, Elcelyx Therapeutics, Janssen, Lexicon Pharmaceuticals, Ligand Pharmaceuticals, Novartis, Pfizer, and Theracos outside the submitted work. Tschöp is a scientific advisory board member of ERX Pharmaceuticals. Stumvoll served on the advisory board for AstraZeneca in 2017.

European Association for the Study of Diabetes (EASD) 2018 Annual Meeting; October 3, 2018; Berlin, Germany.

Lancet. Published online October 4, 2018. Full text, Editorial

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