Safety and efficacy of insulin degludec/liraglutide (IDegLira) added to sulphonylurea alone or to sulphonylurea and metformin in insulin-naïve people with Type 2 diabetes: the DUAL IV trial

Abstract

Aim: To investigate the safety and efficacy of insulin degludec/liraglutide (IDegLira), a novel combination product, as add-on therapy for people with Type 2 diabetes uncontrolled on sulphonylurea therapy.

Methods: In this 26-week, double-blind trial, adults with Type 2 diabetes [HbA_1c 53-75 mmol/mol (7.0-9.0%)] were randomized to IDegLira (n = 289) or placebo (n = 146) as add-on to pre-trial sulphonylurea ± metformin, titrating to a fasting glycaemic target of 4.0-6.0 mmol/l. Treatment initiation was at 10 dose steps, and maximum dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide).

Results: The mean HbA_1c decreased from 63 mmol/mol (7.9%) to 46 mmol/mol (6.4%) with IDegLira and to 57 mmol/mol (7.4%) with placebo [estimated treatment difference -11 mmol/mol (95% CI -13; -10) or -1.02% (95% CI -1.18; -0.87); P < 0.001]. The HbA_1c target of 53 mmol/mol (<7%) was achieved by 79.2% of participants in the IDegLira group vs 28.8% in the placebo group [estimated odds ratio 11.95 (95% CI 7.22; 19.77); P < 0.001]. Mean weight change was +0.5 kg with IDegLira vs -1.0 kg with placebo [estimated treatment difference 1.48 kg (95% CI 0.90; 2.06); P < 0.001]. Confirmed hypoglycaemia occurred in 41.7 and 17.1% of IDegLira- and placebo-treated participants, respectively, with rates of 3.5 vs 1.4 events/patient-years of exposure [estimated rate ratio 3.74 (95% CI 2.28; 6.13); P < 0.001]. IDegLira was generally well tolerated. The rates of serious adverse events were 20.3 and 8.0 per 100 patient-years of exposure with IDegLira and placebo, respectively, without obvious patterns in the type of events.

Conclusions: IDegLira can be used in people uncontrolled with sulphonylurea ± metformin to improve efficacy with a safety profile in line with previous DUAL trials.

Figure 1

Participant disposition. AE, adverse event; FAS, full analysis set; SAS, safety analysis set.

Figure 2

(a) Glycaemic efficacy (HbA_1c) over time. Mean observed values with error bars (sem) based on full analysis set (FAS) and last observation carried forward (LOCF) imputed data. Treatment difference estimated using an ancova model. ‐‐‐ American Diabetes Association/European Association for the Study of Diabetes HbA_1c target <7.0%; American Association of Clinical Endocrinologists HbA_1c target ≤6.5%. Estimated treatment difference (ETD [95% CI]); *P < 0.001. (b) Fasting plasma glucose (FPG) over time. Mean observed values with error bars (sem) based on FAS and LOCF imputed data. Treatment difference estimated using an ancova model. ETD [95% CI], *P < 0.001. (c) Nine‐point self‐monitored blood glucose profile. Mean observed values based on FAS and LOCF imputed data. *P < 0.05 based on linear mixed model with an unstructured residual covariance matrix. (d) Change in body weight. Mean observed values with error bars (sem) based on FAS and LOCF imputed data. Treatment difference estimated using an ancova model. ETD [95% CI], *P < 0.001. EOT, end of trial.