Patient-directed titration to achieve glycaemic goals in type 2 diabetes using once-daily basal insulin: results of the TITRATE randomized controlled trial Blonde L, Merilainen M, Karwe V, Raskin P on behalf of the TITRATE Investigators ( Diabetes Obes Metab. 2009;116: ) TITRATE Sridhar Nadamuni

Background Type 2 diabetes patients: Poor glycaemic control Treatment: Insulin initiation + lifestyle changes + oral antidiabetes drugs (OADs) Current Rx guidelines: Early insulin treatment Long-acting basal insulin analogues (insulin detemer): Low intrapatient variability and low rate of nocturnal hypoglycaemia, however, – Inadequate/suboptimal dose titration leads to treatment failure Solution: Patient self-management and patient-directed insulin titration

TITRATE Trial Design and Primary Outcome 4.4–6.1 mmol/l (80–110 mg/dl) Insulin detemir 0.1–0.2 U/kg or 10 U once daily Randomized Levemir ® (insulin detemir) Adults with Type2 Diabetes (on metformin, s ulphonylurea, glinidines,TZDs) 2-week screening Inclusion Insulin naïve; BMI: 45 kg/m 2; HbA1c: >7.0 < 9.0% Exclusion Pregnancy, breast feeding,poor contraception; Allergies, Prior participation in trial within the past 3 months; Substance abuse 3.9–5.0 mmol/l (70–90 mg/dl) Self-titration of insulin every 3 days Primary Endpoint % of Subjects: HbA1c <7% at 20 Weeks ( ITT Population ) 64.3% 54.5%

Study Flow 244 randomized 122 randomized to 3.9–5.0 mmol/l 122 randomized to 4.4–6.1 mmol/l 15 withdrawn: 2 AE, 8 non-compliant, 5 other 18 withdrawn: 3 AE, 4 non-compliant, 5 Other Safety (N = 121) Efficacy (ITT) (N = 121) Completers (N = 107) Safety (N = 122) Efficacy (ITT) (N = 122) Completers (N = 104) 20 weeks Baseline

Efficacy Results (a)% of subjects reaching HbA1c levels <7 and 6.5% at 20 weeks (ITT-LOCF population) (b) Mean HbA1c reduction by week – ITT population. FPG, fasting plasma glucose

Conclusions TITRATE study suggests that patient-directed, titration algorithms using once-daily insulin detemir are safe and efficacious. Patient- and Physician-directed titration can safely lower FPG targets in Type 2 Diabetes to recommended HbA1c levels. The 3.9–5.0 mmol/l FPG target showed superior efficacy compared with the 4.4–6.1 mmol/l target. Majority of subjects in both treatment groups achieved the combined overall average HbA1c below the ADA- recommended level of <7%. Patients achieved their treatment goals with minimal effect on weight, a low risk of hypoglycaemia and 24-h efficacy.