Randomized, 1-year comparison of three ways to initiate and advance insulin for type 2 diabetes: twice-daily premixed insulin versus basal insulin with either basal-plus one prandial insulin or basal-bolus up to three prandial injections

Aim Many patients with type 2 diabetes mellitus (T2DM) initiate insulin therapy when other treatments fail; how best to do this is poorly defined. Methods People with T2DM [n=588; glycated haemoglobin A1C (A1C)>7.0%, mean baseline 9.4%] were randomized to twice-daily premixed protamine-aspart/aspart insulin (PM - 2), once-daily insulin glargine plus zero to one prandial insulin glulisine injection (G+1), or insulin glargine plus zero to three prandial injections (G+3). Insulin was titrated for 60 weeks. Efficacy and safety outcomes were assessed. Results Discontinuation rates were 53 of the 194 (27%), 44 of the 194 (23%) and 38 of the 194 (20%), for PM-2, G+1 and G+3. Glycaemic control improved in all groups (A1C 7.2+/-1.37, 7.1+/-1.68 and 7.0+/-1.21% at 60?weeks; 7.5+/-1.29, 7.2+/-1.62 and 7.2+/-1.63% at endpoint). G+1 was statistically non-inferior to PM-2 in reducing A1C. G+3 was slightly superior to PM-2 in attaining <7.0% at 60?weeks, but only when the analysis included Good Clinical Practice non-adherent sites. Hypoglycaemia with plasma glucose <2.8 mmol/l was more frequent with PM-2 versus G+1 and G+3; [adjusted incidence: 46 (p=0.0087) vs. 33 (p=0.0045) and 31.5%; events per patient-year: 1.9 vs. 0.8 and 0.9, p=0.0001]. Insulin dosage and weight-gain were similar. Conclusion Basal insulin plus a single prandial injection is as effective in improving glycaemic control as premixed insulin. Full basal-prandial therapy is only slightly more effective than premixed insulin. Stepwise basal-prandial regimens improve glycaemic control with less hypoglycaemia than twice-daily premixed insulin.