Dual benefits of twincretin in T2D: HbA1c reduction & weight loss
Treatment with twincretin, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP)-1 receptor agonist combined into a single drug (LY3298176), not only reduced blood glucose in patients with type 2 diabetes (T2D) – it came with an added benefit of weight loss, with no increase in hypoglycaemia in a phase IIb trial.
Dual GIP/GLP-1 receptor stimulation led to a clinically meaningful and superior HbA1c control, with greater weight loss and an acceptable tolerability profile compared with selective agonism of the GLP-1 receptor with dulaglutide. “In my experience as an investigator and clinician, I have never seen this magnitude of HbA1c 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,” said principal investigator Dr Juan Pablo Frias of the National Research Institute in Los Angeles, California, US, who presented 26 weeks data on LY3298176 at the EASD 2018. “Results for GIP/GLP-1 receptor agonist were unprecedented … and may lead to a new treatment option for T2D.”
Frias and his team compared various doses of LY3298176 with subcutaneous dulaglutide 1.5 mg/week or placebo in 316 patients aged 18–75 years, with a baseline BMI of 23–50 kg/m2 and T2D for at least 6 months (average HbA1c, 8.1 percent) that was inadequately controlled with diet and exercise alone or stable metformin therapy for 3 months before screening. The treatment period was for 26 weeks, with a 4-week safety follow-up. The primary outcome was the dose-response effect of LY3298176 on HbA1c relative to placebo at 26 weeks. In total, 283 patients completed the study which was conducted at 47 sites across Europe and the US. [Lancet 2018;doi:10.1016/S0140-6736(18)32260-8]
Mean changes from baseline in HbA1c with LY3298176 were -1.73 percent for 5 mg, -1.89 percent for 10 mg, and -1.94 percent for 15 mg. By contrast, the change in HbA1c was -1.21 with dulaglutide and -0.06 with placebo. The higher doses of LY3298176 provided the most substantial HBA1c reductions with up to 18 percent of patients on 10 mg and 30 percent on 15 mg achieving normoglycaemia (HbA1c <5.7 percent). On top of that, up to 90 percent of patients on LY3298176 reached standard near-normoglycaemia (HBA1c <7 percent).
In terms of weight loss, which is one of the secondary endpoints, “up to 70 percent [of patients on twincretin] lost over 5 percent of bodyweight, 40 percent lost over 10 percent, and 25 percent lost over 15 percent on the 10 –15 mg doses,” Frias said. At week 26, there was an average of 11.3 kg weight reduction with LY329817 15 mg vs 2.7 with dulaglutide, for a difference of 8.6 kg in favour of LY3298176.
Gastrointestinal events (nausea, diarrhoea, and vomiting) were the most common treatment-emergent adverse events. The incidence of GI side effects was similar between LY3298176 and dulaglutide, except for an increased frequency with the 15 mg dose. There were no differences in the incidence of hypoglycaemia between patients on 10–15 mg doses of LY3298176 and dulaglutide. Importantly, there was no incidence of severe hypoglycaemia.
In an accompanying commentary, Dr Michael Stumvoll of the Universitätsklinikum Leipzig, and Dr Matthias Tschöp of the Helmholtz Zentrum München, both in Germany, said the findings “re-emphasize that the strategy of dual and triple co-agonism is promising, with a potential to reverse the obesity and T2D pandemic.”
“With all due caution … this trial is the next logical step towards replacing GLP-1 mono-agonists with dual or, perhaps eventually, triple agonists. 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 added. [Lancet 2018;doi:10.1016/S0140-6736(18)32466-8]