Treatment Intensification with Insulin Degludec/Insulin Aspart Twice Daily: Randomized Study to Compare Simple and Step-Wise Titration Algorithms

Objective: This 26-week, multicenter, randomized, open-label, parallel-group, treat-to-target trial in adults with type 2 diabetes compared the efficacy and safety of treatment intensification algorithms with twice-daily (BID) insulin degludec/insulin aspart (IDegAsp).Methods: Patients randomized 1:1 to IDegAsp BID used either a ‘Simple’ algorithm (twice-weekly dose adjustments based on a single prebreakfast and pre-evening meal self-monitored plasma glucose [SMPG] measurement; IDegAsp[BID_Simple], n = 136) or a ‘Stepwise’ algorithm (once-weekly dose adjustments based on the lowest of 3 pre-breakfast and 3 pre-evening meal SMPG values; IDegAsp[BID_Step-wise], n = 136).Results: After 26 weeks, mean change from baseline in glycated hemoglobin (HbA1c) with IDegAsp[BID_Simple] was noninferior to IDegAsp[BID_Step-wise] (-15 mmol/mol versus -14 mmol/mol; 95% confidence interval [CI] upper limit, <4 mmol/mol) (baseline HbA1c: 66.3 mmol/mol IDegAsp[BID_Simple] and 66.6 mmol/mol IDegAsp[BID_Step-wise]). The proportion of patients who achieved HbA1c <7.0% (<53 mmol/mol) at the end of the trial was 66.9% with IDegAsp[BID_Simple] and 62.5% with IDegAsp[BID_Step-wise]. Fasting plasma glucose levels were reduced with each titration algorithm (-1.51 mmol/L IDegAsp[BID_Simple] versus -1.95 mmol/L IDegAsp[BID_Step-wise]). Weight gain was 3.8 kg IDegAsp[BID_Simple] versus 2.6 kg IDegAsp[BID_Step-wise], and rates of overall confirmed hypoglycemia (5.16 episodes per patient-year of exposure [PYE] versus 8.93 PYE) and nocturnal confirmed hypoglycemia (0.78 PYE versus 1.33 PYE) were significantly lower with IDegAsp[BID_Step-wise] versus IDegAsp[BID_Simple]. There were no significant differences in insulin dose increments between groups.Conclusion: Treatment intensification with IDegAsp[BID_Simple] was noninferior to IDegAsp[BID_Step-wise]. Both titration algorithms were well tolerated; however, the more conservative step-wise algorithm led to less weight gain and fewer hypoglycemic episodes. Clinicaltrials.gov: NCT01680341Abbreviations:AEs = adverse eventsANOVA = analysis of varianceBID = twice-dailyBID_Simple = ‘Simple’ algorithm twice-weekly dose adjustments based on a single pre-breakfast and pre–evening meal self-monitored plasma glucose measurementBID_Step-wise = ‘Step-wise’ algorithm once-weekly dose adjustments based on the lowest of 3 prebreakfast and 3 pre–evening meal self-monitored plasma glucose valuesCI = confidence intervalETD = estimated mean treatment differenceFPG = fasting plasma glucoseHbA1c = glycated hemoglobinIAsp = insulin aspartIDeg = insulin degludecIDegAsp = insulin degludec/insulin aspartIGlar = insulin glargineOAD = oral antidiabetic drugPYE = patient-year of exposureSMPG = self-monitored plasma glucoseSU = sulfonylureaT2D = type 2 diabetes