BERLIN – Patients with type 2 diabetes mellitus (T2DM) achieved “impressive” drops in glycated hemoglobin, or HbA1c, of up to 2.4% and in body weight of up to 11.3 kg with the investigational drug LY3298176 in a phase 2b trial.
The primary endpoint was the change in HbA1c at 26 weeks, which showed significant reductions from baseline of 1.6%, 2%, and 2.4% for the 5-mg, 10-mg, and 15-mg doses, respectively, of the drug tested. By comparison, a drop of just 1.1% was seen for dulaglutide, and 0.1% for placebo.
The higher doses of LY3298176, which is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and the glucagonlike peptide–1 (GLP-1) receptor, used in the trial helped up to 90% of patients achieve an HbA1c of 7% or less, 82% of patients to achieve an HbA1c of 6.5% or less, and up to 30% of patients to achieve an HbA1c of less than 5.7%, a range which is considered normal for people without diabetes.
As for weight loss, the 5-mg, 10-mg, and 15-mg doses of LY3298176 helped patients achieve significant –4.8-kg, –8.7-kg, and –11.3-kg changes from baseline, respectively. These were greater than those seen with dulaglutide (–2.7 kg) and placebo (–0.4 kg).
More than one third of patients treated with the novel drug achieved at least a 10% or more change in their starting body weight, with a quarter of patients on the 15-mg dose achieving a 15% or more change in bodyweight.
“These are very, very impressive data both from an A1c-lowering perspective and also from a weight reduction perspective,” said the study’s principal investigator Juan Frias, MD, at a press briefing held at the annual meeting of the European Association for the Study of Diabetes (EASD).
GLP-1 receptor agonist therapy is a recommended treatment for T2DM because it addresses many of the important pathophysiologic problems, from blood glucose control and weight loss to reducing cardiovascular risk, Dr. Frias observed.
He added that the first GLP-1 receptor agonists became available in the United States in 2005. Their use in T2DM has recently been further endorsed in a consensus report (Diabetes Care. 2018 Sep.; Diabetologia. 2018. ) issued jointly by the American Diabetes Association and the EASD.
“Despite the potency of these agents, many of our patients are not achieving adequate glycemic or weight control, so we could always use new agents that are more potent as long as they’re safe for the patient,” said Dr. Frias, who is a clinical endocrinologist and the chief executive officer at the National Research Institute in Los Angeles
LY3298176 is a novel unimolecular, multifunctional peptide that is being developed by Eli Lilly as a dual GIP/GLP-1 receptor agonist for the treatment of T2DM. It consists of 39 amino acids linked to a C20 fatty–diacid moiety and has a mean half-life of around 5 days, which means it can be dosed weekly, Dr. Frias observed.
The effect of targeting both GIP and the GLP-1 receptor simultaneously is possibly both additive and complementary, Dr. Frias suggested. Additive effects may include a decrease in food intake and an increase in insulin secretion, with opposing effects on glucagon secretion, with the additional effects of increased glucose uptake with GIP and delayed gastric emptying with GLP-1 receptor agonism.
“When you think back on what the history, biology, and discovery of these compounds was, it isn’t at all obvious you’d pair these two [to make] a so-called ‘twincreatin’ – there is so much overlap,” said Matthias Tschöp, MD, who was invited to discuss the findings after the presentation at the EASD meeting.
, who is the head of the division of neuroendocrinology at the Institute for Diabetes and Obesity at Helmholtz Zentrum München in Neuherberg , Germany, noted that it’s an interesting combination, but it’s not the only approach being tested – there are other twincretin combinations. GIP on its own doesn’t seem to do much, but it must be the combination that is important, it was suggested during discussion.
A total of 318 patients with T2DM and a starting HbA1c of 7%-10.5% were studied and randomized equally to one of six weekly treatment groups: LY3298176 at doses of either 1 mg, 5 mg, 10 mg, or 15 mg, given subcutaneously; 1.5 mg of dulaglutide; or a placebo injection.
The two highest doses of LY3298176 were titrated rather quickly, Dr. Frias said, and this is important when it comes to the side effect profile. In a subsequent study, the dose titration schedule was amended to prolong the titration period to try to avoid some of the side effects seen, according to Dr. Frias.
Adverse events predominantly affected the gastrointestinal system, with any grade nausea, vomiting, and diarrhea seen in a respective 20%-40%, 7%-26%, and 24%-32% of patients taking the 5-mg, 10-mg, and 15-mg doses. Corresponding rates in dulaglutide-treated patients were, approximately, 30%, 9%, and 17%.
“The safety profile of the dual agonist is really similar to that which you see with selective GLP-1 receptor agonists,” Dr. Frias observed. “The most common adverse events were seen at the higher doses and pertained to GI tolerability, but the majority of these events were mild to moderate and dissipated with time and [could] be reduced significantly by appropriate titration.”
Dr. Frias said: “This novel dual GIP/GLP-1 receptor agonist certainly has the potential to be become a very promising treatment option for patients with type 2 diabetes.”
He added: “In my experience as an investigator, as a clinician, I’ve never really seen this magnitude of A1c reduction in this percentage of patients and also with this level of weight loss as well, certainly greater than with a selective GLP-1 receptor agonist.”
Further long-term studies are needed, and the phase 3 program in T2DM will be called SURPASS, according to a press statement issued by Eli Lilly. The phase 3 studies are expected to begin “no later than early 2019,” the statement said, and be completed in late 2021. The drug company also noted that it is “evaluating next steps in the study of GIP/GLP-1 RA for obesity and other conditions.”
SOURCE: Frias JP et al. EASD 2018, ; Frias JP et al. Lancet. 2018 Oct 4. .