Superior efficacy of insulin degludec/liraglutide versus insulin glargine U100 as add-on to sodium-glucose co-transporter-2 inhibitor therapy: A randomized clinical trial in people with uncontrolled type 2 diabetes

Abstract

Aim: To investigate the efficacy and safety of insulin degludec/liraglutide (IDegLira) versus insulin glargine 100 units/mL (IGlar U100) as add-on to sodium-glucose co-transporter-2 (SGLT2) inhibitor therapy.

Materials and methods: In this 26-week, phase IIIb, open-label, parallel-group, treat-to-target trial, conducted at 74 sites in 11 countries, insulin-naïve people aged ≥18 years with glycated haemoglobin (HbA1c) 53-97 mmol/mol (7.0-11.0%), body mass index 20-40 kg/m² and inadequately controlled type 2 diabetes (T2D) on SGLT2 inhibitor ± oral antidiabetic drugs were randomized 1:1 to once-daily IDegLira or IGlar U100, both as add-on to existing therapy. The primary endpoint was change in HbA1c from baseline to week 26.

Results: A total of 210 participants were randomized to each treatment arm. Mean HbA1c reductions were 21 mmol/mol (1.9%-points) with IDegLira and 18 mmol/mol (1.7%-points) with IGlar U100; confirming non-inferiority (P < 0.0001) and superiority of IDegLira (difference in HbA1c change -3.90 mmol/mol; 95% confidence interval [CI] -5.45; -2.35 (-0.36%-points; 95% CI -0.50, -0.21)). Superiority for IDegLira over IGlar U100 was also confirmed for: body weight (difference -1.92 kg; 95% CI -2.64, -1.19); severe or blood-glucose-confirmed symptomatic hypoglycaemia (rate ratio 0.42; 95% CI 0.23, 0.75); total daily insulin dose (difference -15.37 U; 95% CI -19.60, -11.13). The overall treatment-emergent adverse event rate was higher with IDegLira as a result of higher increased lipase and nausea rates.

Conclusions: The favourable safety and efficacy profile of IDegLira in people with uncontrolled T2D on SGLT2 inhibitors, and lower weight gain and hypoglycaemia risk versus IGlar U100, suggest that clinicians should consider IDegLira initiation in this population.

Keywords: GLP-1 analogue; SGLT2 inhibitor; insulin therapy; liraglutide; randomized trial; type 2 diabetes.

Figure 1

Results for (A), change in glycated haemoglobin (HbA1c) over time, (B), change in body weight, (C), severe or blood glucose‐confirmed hypoglycaemia, (D), daily total insulin dose, (E), FPG over time and (F), nine‐point self‐measured blood glucose (SMBG) profile. (A) Mean observed values with error bars (SEM) based on full analysis set, including data obtained after premature discontinuation. P value is from the superiority test. (B) Mean observed values with error bars (SEM) based on full analysis set, including data obtained after premature treatment discontinuation. (C) Mean cumulative frequency based on safety analysis set. Severe or blood glucose‐confirmed symptomatic: an episode that is severe according to the American Diabetes Association classification or blood glucose‐confirmed by a plasma glucose value <3.1 mmol/L (<56 mg/dL) with symptoms consistent with hypoglycaemia. (D–E) Mean observed values with error bars (SEM) based on full analysis set, including data obtained after premature treatment discontinuation. (F) Nine‐point SMBG profile at baseline and week 26. *Statistically significant difference between end of trial means in favour of IDegLira versus IGlar U100. Mean observed values with error bars (standard error of the mean) based on full analysis set. 26†: estimated mean values and the corresponding error bars at week 26 with missing data derived using unconditional reference based multiple imputation. The response and change from baseline in response after 26 weeks for glycated haemoglobin (HbA1c) and body weight are assessed using an analysis of covariance (ANCOVA) model with treatment, pre‐trial oral antidiabetic drug (OAD) and region as factors and corresponding baseline value as covariate. Data obtained after premature treatment discontinuation are included in the analysis. Number of treatment‐emergent severe or blood glucose‐confirmed symptomatic hypoglycaemic episodes are analysed using a negative binomial regression model with a log link and the logarithm of the exposure time as offset. The model includes treatment and pre‐trial OAD as fixed factors. Missing data are imputed using multiple imputation (conditioning on expected event rate before premature treatment discontinuation or withdrawal from trial as if treated with IGlar U100). The actual daily total insulin dose after 26 weeks is analysed using an ANCOVA model with treatment, pre‐trial OAD and region as factors and baseline HbA1c as covariate. Data obtained after premature treatment discontinuation are included in the analysis. Missing data are imputed using unconditional reference based on multiple imputation. CI, confidence interval; ETD, estimated treatment difference; FPG, fasting plasma glucose; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine 100 units/mL; N, number of patients

Figure 2

Patients achieving composite outcomes with (A), glycated haemoglobin (HbA1c) <53 mmol/mol (<7%) and (B), HbA1c ≤48 mmol/mol (≤6.5%) at week 26. ^†Treatment‐emergent severe or blood glucose‐confirmed symptomatic hypoglycaemia episodes in the last 12 weeks of treatment. The response after 26 weeks was analysed using a logistic regression model with treatment, pre‐trial oral antidiabetic drug (OAD) and region as factors and HbA1c baseline value as covariate. Data obtained after premature treatment discontinuation were included in the analysis. Missing data were imputed using unconditional reference based multiple imputation. P value: two‐sided P value for test of no difference. No correction for multiplicity testing. IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine 100 units/mL