Intensive therapy in newly diagnosed type 2 diabetes: results of a 6-year randomized trial

Abstract

Background: This study aimed to assess the efficacy of early intensive diabetes therapy with either insulin plus metformin (INS) or triple oral therapy (TOT) with metformin, glyburide, and pioglitazone on glycemic control and A-cell function.

Methods: Fifty-eight treatment-naive newly diagnosed patients with type 2 diabetes underwent a 3-month lead-in treatment period with insulin and metformin, then were randomized to INS or TOT for 6 years. β-Cell function was measured using mixed-meal challenge test. β-Cell function remained stable throughout the 6-year study in both groups, as measured by the C-peptide area under the curve (AUC; P = 0.13), the AUC C-peptide/AUC glucose (P = 0.9), and by the disposition index (P = 0.8). Excellent glycemic control was maintained in both groups (end-of-study hemoglobinA1c, 7.3% [SD, 1.7%] INS vs 6.4% [1.4%] TOT; P = 0.4). There were 8 treatment failures (confirmed hemoglobinA1c, 98%) in INS and 6 in TOT (P = 0.93). The predictors of treatment failure included higher fasting glucose (P = 0.008), fasting C-peptide (P = 0.008), systolic blood pressure (P = 0.004), and lower insulin sensitivity (P = 0.04) at randomization.

Conclusions: Early intensive treatment at the time of type 2 diabetes diagnosis-initial short-term insulin treatment followed by either insulin-based or intensive oral hypoglycemic-based therapy-stabilizes β-cell function for at least 6 years. Treatment failure was independent of intervention and was associated with worse disease pathology at baseline.

Figure 1

Participant Flowchart. INS- insulin group (treated with insulin+metformin); TOT – triple oral therapy group (treated with metformin+glyburide+pioglitazone); w/o – without.

Figure 2

Major study outcomes, by treatment group, as measured over the 6-year study follow-up. A: HbA1c. B: BMI. C: Treatment compliance. D: AUC_C/AUC_G from mixed meal challenge test. E: Matsuda Index (measure of insulin sensitivity) derived from mixed meal challenge test. F: Disposition Index (DI) from mixed meal challenge test.

Figure 3

Assessment of treatment failure over the 6-year study period in the insulin (INS) and triple oral therapy (TOT) groups. A: Kaplan-Meier curve depicting time of treatment regimen failure by group. The numbers represent the number of patients at risk at each timepoint by treatment group. B: Hazard ratios from Cox proportional hazards models for prediction of treatment failure. Hazard ratios represent per 1 unit change in the predictor variable except for age, fasting glucose, and systolic blood pressure (per 10 unit change), HbA1c and DI (per 0.1 unit change), and AUCC/AUCG ratio (per 0.01 unit change).

Figure 4

Comparison of the changes in HbA1c, AUCc/AUCG, Matsuda index, Disposition Index (DI), and weight over time in the INS group (panels A, C, E, G, I) and TOT group (panels B, D, F, H, J) by failure status,

Figure 5

Results of modified Diabetes Quality of Life Questionnaire in the insulin treated (INS) and triple oral therapy (TOT) groups. All patients were given the questionnaire to complete at randomization and at 6, 18, 42, and 72 months after randomization. Patients randomly assigned to TOT did not complete the two questions regarding insulin. The results are reported as means ± SD of the Likert scale score of 1–5. Both groups had similar responses at month 72 except for current health perception which was better at month 72 in the INS group compared to the TOT group (Group×Month 72 interaction, p=0.002).