RESPONSE TO INTENSIVE THERAPY STEPS AND TO GLIPIZIDE DOSE IN COMBINATION WITH INSULIN IN TYPE-2 DIABETES - VA FEASIBILITY STUDY ON GLYCEMICCONTROL AND COMPLICATIONS (VA CSDM)

OBJECTIVE - The feasibility study for the VA Cooperative Study on Glyc emic Control and Complications in Type 2 Diabetes (VA CSDM) prospectiv ely studied 153 insulin-requiring type 2 diabetes patients, randomized between an intensively treated arm and a standard treatment arm durin g a mean follow-up of 27 months. The glycemic response to each of the progressive, sequential phases of insulin treatment was assessed, alon g with the incidence of hypoglycemic reactions and the relative effica cy of different doses of glipizide in combination with fixed doses of insulin. RESEARCH DESIGN AND METHODS - Five medical centers participat ed; half of the patients were assigned to the intensive treatment arm aiming for normal HM1c levels. Age of patients was 60 +/- 6 years, dur ation of diabetes 8 +/- 3 years, and BMI 30.7 +/- 4 kg/m(2). A four-st ep management technique was used, with patients moving to the next ste p 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 dail y and at 3:00 A.M. once a week. Hypoglycemic reactions and home glucos e monitoring results were recorded and counted in each of the treatmen t phases. RESULTS - Baseline HbA(1c) was 9.3 +/- 1.8%, and fasting plu s 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 be low 7.3% (P = 0.001). Most of the decrease in HbA(1c) occurred with on e injection of insulin alone (phase I, -1.4%) or adding daytime glipiz ide (phase II, -1.9% compared with baseline). HbA(1c) did not decrease further after substituting two injections of insulin alone, with twic e the insulin dose. Multiple daily injections resulted in an additiona l 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 t he study. Changes in home glucose monitoring levels paralleled those o f the HbA(1c), as did the increments in number of reported hypoglycemi c reactions, virtually all either ''mild'' or ''moderate'' in characte r. For the combination of glipizide and insulin (phase II), the only s ignificant effect was obtained with daily doses up to 10 mg a day; the re 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, a lone or with glipizide, seemed sufficient to obtain clinically accepta ble levels of HbA(1c) for most obese, insulin-requiring type 2 diabete s patients. Further decrease of HbA(1c) demanded multiple daily inject ions at the expense of doubling the insulin dose and the rate of hypog lycemic events. In combination therapy, doses of glipizide >20 mg/day offered no additional benefit.