Efficacy and safety of liraglutide compared to sulphonylurea during Ramadan in patients with type 2 diabetes (LIRA-Ramadan): a randomized trial

Abstract

Aims: Compare effects of liraglutide 1.8 mg and sulphonylurea, both combined with metformin, on glycaemic control in patients with type 2 diabetes (T2D) fasting during Ramadan.

Materials and methods: In this up to 33-week, open-label, active-controlled, parallel-group trial, adults [glycated haemoglobin (HbA1c) 7%-10% (53-86 mmol/mol); body mass index ≥20 kg/m(2) ; intent to fast] were randomized (1:1) ≥10 weeks before Ramadan to either switch to once-daily liraglutide (final dose 1.8 mg) or continue pre-trial sulphonylurea at maximum tolerated dose, both with metformin.

Primary endpoint: change in fructosamine, a validated marker of short-term glycaemic control, during Ramadan.

Results: Similar reductions in fructosamine levels were observed for both groups during Ramadan [liraglutide (-12.8 µmol/L); sulphonylurea (-16.4 µmol/L); estimated treatment difference (ETD) 3.51 µmol/L (95% CI: -5.26; 12.28); p = 0.43], despite lower fructosamine levels in the liraglutide group at start of Ramadan. Fewer documented symptomatic hypoglycaemic episodes were reported in liraglutide-treated (2%, three subjects) versus sulphonylurea-treated patients (11%, 18 subjects). No severe hypoglycaemic episodes were reported by either group. Body weight decreased more during Ramadan with liraglutide (ETD: -0.54 kg; 95% CI: -0.94;-0.14; p = 0.0091). The proportion of patients reporting adverse events was similar between groups. Liraglutide led to greater HbA1c reduction [ETD: -0.59% (-6.40 mmol/mol), 95% CI: -0.79; -0.38%; -8.63; -4.17 mmol/mol; p < 0.0001].

Conclusions: Despite lower fructosamine levels and body weight at the beginning of Ramadan, use of liraglutide showed similar glycaemic improvements, fewer hypoglycaemic episodes and greater body weight reduction compared with sulphonylurea. LIRA-Ramadan provides evidence for liraglutide being safe and efficacious for management of T2D during Ramadan fasting.

Trial registration: ClinicalTrials.gov NCT01917656.

Keywords: GLP-1; Ramadan; body weight; fasting; fructosamine; hypoglycaemia; liraglutide; metformin; sulphonylurea; type 2 diabetes.

Figure 1

Efficacy. (A) Change in fructosamine (µmol/L) from baseline to end of Ramadan. (B) Change in FPG (mmol/L) from baseline to EoT. (C) Change in body weight from baseline to EoT. (D) Change in HbA1c from baseline to EoT. The time between visits 6 and 8 could be up to 18 weeks. EoT, end of treatment; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; SU, sulphonylurea.

Figure 2

Hypoglycaemic episodes during Ramadan. (A) Proportion of subjects with confirmed and ADA‐classified hypoglycaemia. (B) Mean cumulative function of ADA‐classified documented symptomatic hypoglycaemic episodes; number of episodes per subject. Confirmed [patient unable to self treat and/or with PG <3.1 mmol/L (56 mg/dL)] and ADA‐classified hypoglycaemia [ADA: total ADA‐classified episodes; severe: patient unable to self treat; documented symptomatic: PG <3.9 mmol/L (70 mg/dL); asymptomatic: PG <3.9 mmol/L (70 mg/dL); relative: symptomatic and PG >3.9 mmol/L (70 mg/dL); probable symptomatic: episode during which symptoms of hypoglycaemia are not accompanied by plasma glucose determination (presumably caused by plasma glucose concentration ≤3.9 mmol/L {70 mg/dL}); relative: symptomatic and PG >3.9 mmol/L (70 mg/dL); unclassifiable: where hypoglycaemic episode could not be allocated to any of the above groups]. ADA, American Diabetes Association; CI, confidence interval; HbA1c, glycated haemoglobin; OR, odds ratio; PG, plasma glucose.

Figure 3

Responders for composite endpoints. (A) Proportion of subjects reaching targets at end of Ramadan (visit 12). (B) Proportion of subjects reaching targets at EoT (visit 14). Estimated proportion of subjects meeting targets (%) based on logistic regression model with treatment, country and stratification groups as fixed factors and the HbA1c value at baseline as a covariate, and baseline weight as covariate in the composite endpoints, including no weight gain. These analyses are based on subjects entering Ramadan. OR: liraglutide/SU. ADA, American Diabetes Association; EoT, end of treatment; HbA1c, glycated haemoglobin; OR, odds ratio; SU, sulphonylurea.