First study to examine the mechanism(s) by which the addition of rosiglitazone or bedtime glargine insulin improves glucose homeostasis in poorly controlled Type 2 patients on metformin plus a sulfonylurea. The study sought to examine the mechanisms by which the addition of glargine insulin or rosiglitazone improves glycemic control in type 2 diabetic subjects poorly controlled on maximally effective doses of metformin plus sulfonylurea.
Subjects (aged 47 ± 11 years, BMI 31 ± 5 kg/m2, HbA1c [A1C] 9.4 ± 1.3%) received bedtime glargine insulin (titrated based on the fasting plasma glucose [FPG], n = 10) or rosiglitazone (4 mg twice daily, n = 10). At baseline and after 4 months, A1C was measured and an oral glucose tolerance test and a 3-h euglycemic insulin clamp with glucose were performed.
Results showed that A1C and FPG decreased similarly in the glargine insulin and rosiglitazone. After 4 months, endogenous glucose production (EGP) declined similarly with glargine insulin and rosiglitazone. The hepatic insulin resistance index declined in the rosiglitazone group and did not change in the glargine group. At 4 months, glargine insulin and rosiglitazone increased, but the increment was greater in the rosiglitazone group. Diastolic blood pressure was reduced only by rosiglitazone.
Other than fasting plasma triglyceride concentration, which was higher in the rosiglitazone group, there were no significant differences in baseline characteristics between the groups. Baseline weight, FPI concentration, and hepatic insulin resistance index (IRI) were slightly, although not significantly, higher in the rosiglitazone group. All subjects in the rosiglitazone group took 4 mg rosiglitazone twice daily throughout the study. The average bedtime dose of glargine insulin was 17 ± 2 units/day at the conclusion of the trial.
When comparing therapeutic options, it is important to consider the effect of the intervention on other metabolic/cardiovascular parameters and the mechanism(s) by which improved glycemic control is achieved. Rosiglitazone significantly reduced diastolic blood pressure and raised plasma HDL cholesterol (beneficial cardiovascular effects) but raised plasma total and LDL cholesterol levels. In contrast, glargine insulin had no effect on blood pressure, HDL cholesterol, or triglyceride levels but significantly reduced total and LDL cholesterol. At present, it is not possible to assign a weighting value to the beneficial effects of glargine versus rosiglitazone on plasma lipid levels and blood pressure.
In summary, addition of glargine insulin or rosiglitazone in poorly controlled type 2 diabetic patients on metformin/sulfonylurea similarly reduced A1C, FPG, and mean plasma glucose concentration during an OGTT. Rosiglitazone produced these changes by enhancing hepatic and peripheral tissue (muscle) sensitivity to insulin, while the glucose-lowering action of glargine insulin was related to suppression of hepatic glucose production by nocturnal hyperinsulinemia. Peripheral, but not hepatic, tissue sensitivity to insulin was modestly improved by glargine insulin, most likely secondary to amelioration of glucotoxicity. Both therapeutic interventions have beneficial effects and, mechanistically, the addition of either glargine insulin or a thiazolidinedione are reasonable therapeutic options in poorly controlled type 2 diabetic patients who are on maximally effective doses of metformin plus sulfonylurea.
Diabetes Care. 2006;29(11):2371-2377