Treatment intensification with stepwise addition of prandial insulin aspart boluses compared with full basal-bolus therapy (FullSTEP Study): a randomised, treat-to-target clinical trial.

We compared stepwise addition of bolus insulin with a full basal-bolus regimen in patients with type 2 diabetes inadequately controlled on basal insulin plus oral antidiabetic drugs. The FullSTEP study was a phase 4, 32-week, randomised, open-label, two-arm, parallel-group, multinational, treat-to-target, non-inferiority trial done at 150 sites across seven countries to assess the effectiveness of a stepwise dosing approach versus a basal-bolus regimen. In this trial, 401 patients (mean age 59·8 years [SD 9·3]; HbA1c 7·9% [63 mmol/mol]; mean diabetes duration 12·6 years [SD 8·0]) were block randomised (ratio 1:1) to receive either stepwise treatment or full basal-bolus treatment. Patients in the basal-bolus group received insulin aspart before every meal throughout the trial. Patients in the stepwise group received one bolus dose with the largest meal, with additional insulin aspart doses before the next largest meal added to their regimen at 11 weeks and 22 weeks if HbA1c remained at 7% or higher. The primary outcome was non-inferiority of stepwise addition of bolus insulin versus complete basal-bolus therapy, as assessed by change in HbA1c from baseline to 32 weeks (non-inferiority margin of 0·4%). This trial is registered with ClinicalTrials.gov, number NCT01165684. The study was started on Oct 27, 2010, and completed on April 25, 2012. After 32 weeks, HbA1c change from baseline was -0·98% (95% CI -1·09 to -0·87) for the stepwise group and -1·12% (-1·23 to -1·00) for the basal-bolus group; mean treatment difference 0·14 (95% CI -0·02 to 0·30), non-significant (p=0·0876). Fewer hypoglycaemic episodes occurred in the stepwise group than in the basal-bolus group (rate ratio 0·58 [95% CI 0·45 to 0·75]; p<0·0001). Treatment-emergent adverse events did not differ between the two treatment groups. The most frequently reported treatment-emergent adverse event were nasopharyngitis, influenza, diarrhoea, headache, peripheral oedema, and wrong drug given. Three participants died: two before randomisation and one in the basal-bolus group (due to severe acute myocardial infarction and respiratory tract inflammation). Stepwise prandial insulin intensification provides glycaemic control non-inferior to a full basal-bolus regimen after 32 weeks, with significantly lower hypoglycaemia risk and better patient satisfaction. Novo Nordisk.