The Efficacy of IDegLira (Insulin Degludec/Liraglutide Combination) in Adults with Type 2 Diabetes Inadequately Controlled with a GLP-1 Receptor Agonist and Oral Therapy: DUAL III Randomized Clinical Trial

Abstract

Introduction: The progressive nature of type 2 diabetes necessitates treatment intensification. This often involves intensification with oral antidiabetic drugs (OADs) initially, followed by other agents, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), with the majority of patients eventually requiring insulin therapy. Therefore, this trial aimed to investigate the efficacy of IDegLira (combination of insulin degludec and liraglutide) in controlling glycemia in adults with type 2 diabetes who were inadequately controlled on a GLP-1RA and OADs.

Methods: In this 26-week open-label phase 3b trial, patients on maximum-dose GLP-1RA therapy (liraglutide once daily or exenatide twice daily) with metformin alone or with pioglitazone and/or sulfonylurea were randomized 2:1 to IDegLira once daily (n = 292) or to unchanged GLP-1RA therapy (n = 146), continuing OADs at the pre-trial dose.

Results: After 26 weeks, HbA_1c reductions were superior with IDegLira versus unchanged GLP-1RA; estimated treatment difference -0.94% (-10.3 mmol/mol), p < 0.001. Mean HbA_1c reduced from 7.8% to 6.4% (61.5 to 46.9 mmol/mol) with IDegLira and from 7.7 to 7.4% (60.8 to 57.1 mmol/mol) with unchanged GLP-1RA. With IDegLira, 75% and 63% of patients achieved HbA_1c <7% and ≤6.5%, compared with 36% and 23% on unchanged GLP-1RA, respectively. Fasting plasma glucose and 9-point self-monitored blood glucose profiles improved significantly more with IDegLira versus unchanged GLP-1RA. The mean change in weight was +2.0 kg with IDegLira, versus -0.8 kg with unchanged GLP-1RA. Rates of confirmed hypoglycemia were low, but higher with IDegLira versus unchanged GLP-1RA. The safety profile of IDegLira was consistent with previous findings; both treatments were well tolerated and the rate of nausea was low in both groups. IDegLira improved patient-reported outcomes versus unchanged GLP-1RA.

Conclusions: IDegLira provided superior glycemic control versus unchanged GLP-1RA and represents an efficacious intensification approach in patients inadequately controlled on GLP-1RAs.

Trial registration: ClinicalTrials.gov #NCT01676116.

Funding: Novo Nordisk.

Keywords: Clinical trial; GLP-1 receptor agonist; IDegLira; Insulin therapy; Type 2 diabetes.

Fig. 1

a Glycemic efficacy HbA_1c over time. Mean observed values with error bars (standard error of the mean) based on FAS and LOCF imputed data. ETD is from ANCOVA analysis, and change in HbA_1c (Δ) values are observed; both are based on FAS and LOCF imputed data. Dotted lines represent ADA/EASD and AACE HbA_1c targets of <7.0% and ≤6.5%, respectively. b Patients achieving the HbA_1c target. Treatment comparisons are from a logistic regression model based on FAS and LOCF imputed data. c FPG over time. Mean observed values with error bars (standard error of the mean) based on FAS and LOCF imputed data. ETD is from ANCOVA analysis, and change in FPG (Δ) values are observed; both are based on FAS and LOCF imputed data. d Mean nine-point SMBG profile at weeks 0 and 26. *p < 0.001 (post hoc analysis). Mean values are based on FAS, with missing profiles imputed using LOCF; SMBG was assessed with a glucose meter as plasma-equivalent values of capillary whole blood glucose. ANCOVA analysis of covariance, EOR estimated odds ratio, EOT end of trial, FAS full analysis set, FPG fasting plasma glucose, GLP-1RA glucagon-like peptide-1 receptor agonist, IDegLira insulin degludec/liraglutide combination, LOCF last observation carried forward, SMBG self-monitored blood glucose

Fig. 2

Glycemic control during the first 4 weeks of the trial. Values are the median with interquartile range, based on FAS and with missing values imputed using LOCF. FAS full analysis set, GLP-1RA glucagon-like peptide-1 receptor agonist, IDegLira insulin degludec/liraglutide combination, LOCF last observation carried forward, SMBG self-monitored blood glucose

Fig. 3

Body weight over time. Values are the mean with error bars (standard error of the mean), based on FAS and with missing values imputed using LOCF. Estimated treatment differences are from an ANCOVA analysis. ANCOVA analysis of covariance, FAS, full analysis set, GLP-1RA glucagon-like peptide-1 receptor agonist, IDegLira insulin degludec/liraglutide combination, LOCF last observation carried forward