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Insulin Glargine Up-Titration vs Insulin Degludec/Liraglutide

JAMA; 2016 Mar 1; Lingvay, Manghi, et al

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Treatment with degludec/liraglutide compared with up-titration of glargine among patients with uncontrolled type 2 diabetes taking glargine and metformin resulted in noninferior HbA1c levels, with secondary analysis indicating greater HbA1c level reduction after 26 weeks of treatment in the degludec/liraglutide group. This according to a phase 3, multicenter, 26-week, randomized, open-label trial among 557 patients with uncontrolled diabetes treated with glargine (20 to 50 U) and metformin (≥1500 mg/d) with glycated hemoglobin (HbA1c) levels of 7% to 10% and a BMI of 40 or lower. Researchers found:

• Baseline HbA1c level was 8.4% with degludec/liraglutide vs 8.2% for the glargine group.

• HbA1c level reduction was greater with degludec/liraglutide vs glargine (-1.81% vs -1.13%), meeting criteria for noninferiority, and also meeting criteria for statistical superiority.

• Treatment with degludec/liraglutide was also associated with weight loss compared with weight gain with glargine (-1.4 kg vs 1.8 kg), and fewer confirmed hypoglycemic episodes.

Citation: Lingvay I, Manghi, F, Garcia-Hernández P, et al. Effect of insulin glargine up-titration vs insulin degludec/liraglutide on glycated hemoglobin levels in patients with uncontrolled type 2 diabetes. JAMA 2016; 315;(9):898-907. doi:10.1001/jama.2016.1252.

Commentary: GLP-1 inhibitors and insulin work through complementary mechanisms to achieve control of blood glucose levels. GLP-1 inhibitors have been shown to provide equivalent A1c reduction when compared to basal insulin, without the associated weight gain and hypoglycemia that occurs with basal insulin.1 When added to basal insulin, GLP-1 receptor agonists can provide equivalent control of blood glucose levels as the addition of prandial insulin, again without weight gain and with a lower incidence of hypoglycemia.2 This study shows that the combination of insulin degludec, a new insulin with an extended duration of action of approximately 42 hours, and the GLP-1 receptor agonist liraglutide, give significantly better A1c control than insulin glargine alone, with a lower incidence of hypoglycemia and weight loss instead of weight gain. Currently, there are two combination GLP-1/insulin combination medications awaiting FDA review: Novo Nordisk’s liraglutide/insulin degludec and Sanofi’s lixisenatide/insulin glargine.3,4 —Neil Skolnik, MD

1.) Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149. doi:10.2337/dc14-2441.

2.) Rosenstock J. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: A comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care 2014;37:1–9. doi:10.2337/dc14-0001.

3.) Novo Nordisk files NDA at FDA for Xultophy, combination of Tresiba (insulin degludec) and Victoza (liraglutide) to treat type 2 diabetes. epgonline.org. http://www.epgonline.org/news/novo-nordisk-files-nda-at-fda-for-xultophy-combination.cfm. Published September 29, 2015. Accessed March 14, 2016.

4.) FDA accepts Sanofi new drug application for once-daily fixed-ratio combination of insulin glargine and lixisenatide. Finance.yahoo.com/news/fda-accepts-sanofi-drug-application130000058.html;_ylt=A0LEV1B8UeJWZYYAerpXNyoA;_ylu=X3oDMTEyZDg5bjJwBGNvbG8DYmYxBHBvcwM0BHZ0aWQDQjExNTlfMQRzZWMDc3I-. Published February 22, 2016. Accessed March 14, 2016.

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