Response to intensive therapy steps and to glipizide dose in combination with insulin in type 2 diabetes: VA feasibility study on glycemic control and complications (VA CSDM)

OBJECTIVE - The feasibility study for the VA Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes (VA CSDM) prospectively studied 153 insulin-requiring type 2 diabetes patients, randomized between an intensively treated arm and a standard treatment arm during a mean follow-up of 27 months. The glycemic response to each of the progressive, sequential phases of insulin treatment was assessed, along with the incidence of hypoglycemic reactions and the relative efficacy of different doses of glipizide in combination with fixed doses of insulin. RESEARCH DESIGN AND METHODS - Five medical centers participated; half of the patients were assigned to the intensive treatment arm aiming for normal HM1c levels. Age of patients was 60 +/- 6 years, duration of diabetes 8 +/- 3 years, and BMI 30.7 +/- 4 kg/m(2). A four-step management technique was used, with patients moving to the next step if the operational goals were not met: Phase I, evening intermediate or long-acting insulin; phase II, added daytime glipizide; phase III, two injections of insulin alone; and phase IV, multiple daily insulin injections. Home glucose monitoring measurements were done twice daily and at 3:00 A.M. once a week. Hypoglycemic reactions and home glucose monitoring results were recorded and counted in each of the treatment phases. RESULTS - Baseline HbA(1c) was 9.3 +/- 1.8%, and fasting plus serum glucose was 11.4 +/- 3.3 mmol/l. Fasting serum glucose fell to near normal in phase I, and remained so in the other treatment phases. An HbA(1c) separation of 2.1% between the arms was maintained during the course of the study, while the intensive arm kept HbA,, levels below 7.3% (P = 0.001). Most of the decrease in HbA(1c) occurred with one injection of insulin alone (phase I, -1.4%) or adding daytime glipizide (phase II, -1.9% compared with baseline). HbA(1c) did not decrease further after substituting two injections of insulin alone, with twice the insulin dose. Multiple daily injections resulted in an additional HbA(1c) fall (-2.4% compared with baseline). However, two-thirds of the patients were still on one or mio injections a day at the end of the study. Changes in home glucose monitoring levels paralleled those of the HbA(1c), as did the increments in number of reported hypoglycemic reactions, virtually all either "mild" or "moderate" in character. For the combination of glipizide and insulin (phase II), the only significant effect was obtained with daily doses up to 10 mg a day; there were no significant additional benefits with up to fourfold higher daily doses, and HbA(1c) levels had an upward trend with doses >20 mg/day. CONCLUSIONS - A simple regime of a single injection of insulin, alone or with glipizide, seemed sufficient to obtain clinically acceptable levels of HbA(1c) for most obese, insulin-requiring type 2 diabetes patients. Further decrease of HbA(1c) demanded multiple daily injections at the expense of doubling the insulin dose and the rate of hypoglycemic events. In combination therapy, doses of glipizide >20 mg/day offered no additional benefit.