Contribution of Liraglutide in the Fixed-Ratio Combination of Insulin Degludec and Liraglutide (IDegLira)

Abstract

OBJECTIVEInsulin degludec/liraglutide (IDegLira) is a novel combination of insulin degludec (IDeg) and liraglutide. This trial investigated the contribution of the liraglutide component of IDegLira versus IDeg alone on efficacy and safety in patients with type 2 diabetes. RESEARCH DESIGN AND METHODSIn a 26-week, double-blind trial, patients with type 2 diabetes (A1C 7.5-10.0% [58-86 mmol/mol]) on basal insulin (20-40 units) and metformin with or without sulfonylurea/glinides were randomized (1:1) to once-daily IDegLira + metformin or IDeg + metformin with titration aiming for fasting plasma glucose between 4 and 5 mmol/L. Maximum allowed doses were 50 dose steps (equal to 50 units IDeg plus 1.8 mg liraglutide) and 50 units for IDeg. The primary end point was change in A1C from baseline. RESULTSA total of 413 patients were randomized (mean A1C 8.8% [73 mmol/mol]; BMI 33.7 kg/m 2 ). IDeg dose, alone or as part of IDegLira, was equivalent (45 units). A1C decreased by 1.9% (21 mmol/mol) with IDegLira and by 0.9% (10 mmol/mol) with IDeg (estimated treatment difference 21.1% [95% CI 21.3, 20.8], 212 mmol/mol [95% CI 214, 29; P < 0.0001). Mean weight reduction with IDegLira was 2.7 kg vs. no weight change with IDeg, P < 0.0001. Hypoglycemia incidence was comparable (24% for IDegLira vs. 25% for IDeg). Overall adverse events were similar, and incidence of nausea was low in both groups (IDegLira 6.5% vs. IDeg 3.5%). CONCLUSIONSIDegLira achieved glycemic control superior to that of IDeg at equivalent insulin doses without higher risk of hypoglycemia and with the benefit of weight loss. These findings establish the efficacy and safety of IDegLira and the distinct contribution of the liraglutide component.Basal insulin therapy, often in combination with oral agents, including metformin, is well established for the treatment of patients with type 2 diabetes. Once initiated, basal insulin is usually continued even when control is not achieved (1,2). Indeed, more than half of patients with type 2 diabetes treated with basal insulin do not achieve glycemic control (A1C #7.0% [53 mmol/mol]) (1,3,4) and are therefore at increased risk of developing diabetes complications. Delayed or suboptimal

Preserved pharmacokinetic exposure and distinct glycemic effects of insulin degludec and liraglutide in IDegLira, a fixed‐ratio combination therapy

“…Moreover, the dose/exposureresponse analyses showed that both monocomponents of IDegLira distinctly contribute to overall glycemic control, supporting efficacy data from the clinical trial program for IDegLira. 3,4 As such, it can be concluded that by combining 2 complementary modes of action, IDegLira is a valuable addition to the treatment options available in T2D, offering a convenient, well-tolerated, and multitargeted once-daily therapeutic option with the potential for improved glycemic control.…”

“…IDegLira may be initiated and titrated, as performed with basal insulin, and administered in dose steps, in which 1 dose step is defined as 1 unit IDeg/0.036 mg liraglutide and can be titrated up to a maximum of 50 dose steps (50 units/1.8 mg). 3,4 IDeg is a new-generation basal insulin with an ultralong duration of action, providing a flat and stable glucose-lowering effect. [5][6][7][8] IDeg has been shown to be efficacious in lowering glycated hemoglobin (HbA 1c ) and fasting plasma glucose (FPG) levels in subjects with T2D, [9][10][11] with fewer hypoglycemic episodes, particularly nocturnal episodes, versus insulin glargine.…”

“…Clinical benefits of IDegLira have been confirmed in 2 phase 3 clinical trials. 3,4 IDegLira is designed to be titrated according to individual glycemic control and not intended for direct substitution of its monocomponents. Nevertheless, to leverage the clinical experience with IDeg and liraglutide and in accordance with the European Medicines Agency guidelines for fixed-combination medicinal products, 24 the 2 studies discussed in this article provide a comparison of the pharmacokinetics (PK) of IDegLira versus the monocomponents.…”

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

“…no maximum dose specified, as was the case with the basal insulin in two of three IDegLira comparisons with insulin) with those between an FRC and a capped insulin comparator (as was the case with glargine in two of three IGlarLixi comparisons with insulin). As seen in the DUAL II (capped) [5] and DUAL V (uncapped) [8] trials, end-of-trial differences in HbA 1c and fasting plasma glucose (FPG) favoring the FRC were larger, and the weight benefit was smaller, when the insulin dose was capped in the comparator arm. As a consequence, comparing results across trials, not taking these differences into account, will not reflect the true similarity or difference between regimens.…”

“…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.…”