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More Information on a Novel Insulin/GLP-1 Combo

Aug 22, 2013
Promising results from IDegLira and the DUAL I trial….

Novo Nordisk’s new drug IDegLira is a fixed-ratio combination of insulin degludec and the glucagonlike perptide-1 (GLP-1) agonist liraglutide. It combines the effects of insulin degludec and liraglutide in a once daily injection.

In the Dual Action of Liraglutide and Insulin Degludec in Type 2 Diabetes (DUAL I) study’s phase III trial, IDegLira significantly outperformed each medication alone in patients with type 2 diabetes. While presenting the results of the trial at the annual scientific sessions of the American Diabetes Association, Dr. John B. Buse stated that IDegLira demonstrated “substantial overall improvement in glycemic control with a low risk of hypoglycemia, weight gain and GI adverse events.”

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The formulation of IDegLira was not just some fluke or an attempt for Novo Nordisk to find a niche in the world of diabetes treatment. There is a therapeutic rationale behind this combination. The logic is that both insulin degludec and liraglutide have complementary characteristics to one another. This results in increased efficacy and a partial cross-cancellation of each medication’s side effects.

“Basal insulin is arguably the most powerful approach for controlling fasting blood glucose, and GLP-1 agonists have potent postprandial effects. The weight reduction associated with GLP-1 agonists could help mitigate the weight gain associated with basal insulin. The effects on alpha-cell function of GLP-agonists might reduce the hypoglycemia risk associated with basal insulin. And lastly, the process of individualized dosing that we use with basal insulin – getting the dose just right with regard to efficacy and safety – those concepts might reduce the GI side effects that are common with GLP-1 agonists,” explained Dr. Buse, professor of medicine, chief of the division of endocrinology and metabolism, and executive associate dean for clinical research at the University of North Carolina, Chapel Hill.

These stated benefits were shown in DUAL I. The 26-week, international, open-label, phase III trial had 1,663 type 2 diabetic subjects that were insulin-naïve and poorly controlled on Metformin with or without pioglitizone. Among the participants, 83% were on Metformin monotherapy and the remainder was on dual therapy.

Participants remained on their previous antidiabetic drug regimen in addition to IDegLira, insulin degludec, or liraglutide randomized in a 2:1:1 ratio, respectively. Participants in the insulin arms were started on 10 Units a day of insulin degludec and titrated twice weekly in 2-unit increments depending on their mean fasting plasma glucose. 10 units of IDegLira contained 10 units of insulin degludec and 1.8 mg of liraglutide.

The study’s primary endpoint was the reduction in participant hemoglobin A1c over the course of 26 weeks (results shown in chart above). IDegLira fared better than its individual components with an average drop to an HbA1c of 6.4% (insulin degludec averaged 6.9% and liraglutide averaged 7.0%). IDegLira also performed better in multiple secondary endpoints.

Dr. Buse noted that the fasting plasma glucose was reduced identically by 65 mg/dL with IDegLira and insulin degludec monotherapy from a baseline of 165 mg/dL. However, the final mean daily dose of the insulin degludec component of IDegLira was 38 units, 15 units a day less than insulin degludec monotherapy. Confirmed hypoglycemic events occurred at a lesser rate over the 26 weeks in the IDegLira arm compared to the insulin degludec arm despite the greater HA1c reduction with IDegLira.

During the trial, nausea was a complaint that patients had with liraglutide. The IDegLira group, on the other hand, had less than half the number of participants with reports of nausea when compared to liraglutide monotherapy. The final daily dose of liraglutide in the IDegLira group averaged 1.4 mg and 1.8 mg in the liraglutide monotherapy group.

“This is likely related more to the titration program and the lower starting dose in the IDegLira group than to the final total milligrams of liraglutide,” according to Dr. Buse.

Although not pleased by the study being open label as opposed to blinded, Session chair Julio Rosenstock of the Dallas Diabetes and Endocrine Center commented that the fixed-ratio combination is “a great concept” and hailed the phase III findings as “very, very impressive results.” Dr. Buse replied that a companion phase III trial, known as DUAL II, is blinded and results will be presented this fall at the annual meeting of the European Association for the Study of Diabetes in Barcelona.