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

IntroductionThe 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.MethodsIn 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.ResultsAfter 26 weeks, HbA1c reductions were superior with IDegLira versus unchanged GLP-1RA; estimated treatment difference −0.94% (−10.3 mmol/mol), p < 0.001. Mean HbA1c 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 HbA1c <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.ConclusionsIDegLira provided superior glycemic control versus unchanged GLP-1RA and represents an efficacious intensification approach in patients inadequately controlled on GLP-1RAs.Trial registrationClinicalTrials.gov #NCT01676116.FundingNovo Nordisk.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-016-0218-3) contains supplementary material, which is available to authorized users.

Use and effectiveness of a fixed‐ratio combination of insulin degludec/liraglutide (IDegLira) in a real‐world population with type 2 diabetes: Results from a European, multicentre, retrospective chart review study

“…In 26‐ (DUAL I) and 32‐week (DUAL VI) clinical trials involving patients uncontrolled on metformin ± pioglitazone, end‐of‐trial HbA1c ranged from 42 mmol/mol to 46 mmol/mol (6.0% to 6.4%) and was achieved at a mean dose of 38 to 41 U . Similar differences between real‐world data presented here and clinical trial data were observed for patients on basal insulin and GLP‐1RA . It is not clear why more stringent glycaemic targets were not pursued more aggressively, but reasons might relate to country‐specific guidelines, the expense/availability of further uptitration, patient‐led titration being guided by fear of hypoglycaemia, and other patient characteristics (e.g.…”

“…The efficacy and safety of IDegLira has been evaluated in patients with T2D and suboptimal glycaemic control on oral antidiabetic drugs (OADs), GLP‐1RA therapy and basal insulin therapy in the phase III DUAL clinical trial programme . DUAL I–VII demonstrated that IDegLira combined the clinical advantages of both mono‐components to reduce both fasting and prandial blood glucose levels and, furthermore, mitigated the major side effects associated with insulin (hypoglycaemia, weight gain) and GLP‐1RA therapy (nausea) …”

Methodological concerns with the meta-analysis comparing insulin degludec/liraglutide and insulin glargine/lixisenatide

“…The FPG at baseline was 7.3/ 7.4 mmol/L in one trial [6], whereas baseline FPG values ranged from 8.9 to 9.9 mmol/L in the other two IGlarLixi trials [3,4] and all the IDegLira trials [2,5,[7][8][9]. Furthermore, the target FPG was 4.4-5.6 mmol/L in all the IGlarLixi trials, whereas it was 4.0-5.0 mmol/L in all but one of the IDegLira trials.…”

“…First, the baseline medication differed between trials so that, depending upon the trial, some patients were previously on oral antidiabetic drugs (OADs) [2][3][4], some on basal insulin and OADs [5,6], and some on maximum tolerated dose of a GLP-1 RA [7]. These differences have not been accounted for in the analysis and can profoundly affect the possible impact of the FRC and therefore the conclusions of the analysis.…”

“…These differences have not been accounted for in the analysis and can profoundly affect the possible impact of the FRC and therefore the conclusions of the analysis. For example, for the comparison 'IDegLira vs. GLP-1 RA', the authors reported combined effects based on a trial in which patients were previously on OADs [2] and a trial in which patients were already on maximum-dose GLP-1 RA therapy (cited as an abstract, now fully published) [7]. Since the patients came from different pretrial regimens, it is not meaningful to provide estimated outcomes based on combining effect sizes from such different populations.…”