THERAPEUTIC COMPARISON OF METFORMIN AND SULFONYLUREA, ALONE AND IN VARIOUS COMBINATIONS - A DOUBLE-BLIND CONTROLLED-STUDY

OBJECTIVE- To assess and compare the therapeutic efficacy and safety o f metformin (M) and sulfonylurea (glyburide, G), alone and in various combinations, in patients with noninsulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS- Of 165 patients (fasting blood g lucose [FBG] greater than or equal to 6.7 mmol/l) initially treated wi th diet alone, 144 (FBG still greater than or equal to 6.7 mmol/l) wer e randomized to double-blind, double-dummy controlled treatment with M , G, or primary combination therapy (MG). The dose was titrated, with FBG <6.7 mmol/l as target, using, at most, six dose levels. The first three dose levels comprised increasing single-drug therapy (M or G) or primary combination at increasing but low dosage (MGL), and the secon d three levels were composed of various high-dose combinations, i.e., add-on therapy (M/G or G/M) and primary combination escalated to high dosage (MGH). Medication was maintained for 6 months after completed d ose titration. RESULTS- The FBG target was achieved in 9% of patients after diet alone. Single-drug therapy was insufficient in 36% and MGL in 25% (NS) of the randomized patients. There was further improvement in glucose control by the high-dose combinations. Mean FBG +/- SE was reduced (P = 0.001) from 9.1 +/- 0.4 to 7.0 +/- 0.2 mmol/l in those ma intained on single-drug treatment or low-dose primary combination. Tho se treated with different high-dose combinations had a large mean FBG reduction, from 13.3 +/- 0.8 to 7.8 +/- 0.6 mmol/l. HbA(1c) levels sho wed corresponding reductions, and glycemic levels rose after drug disc ontinuation. Fasting C-peptide rose during treatment with G and MGL bu t not with M, while fasting insulin was not significantly changed. Mea l-stimulated C-peptide and insulin levels were unchanged by M but incr eased by G and, to a lesser extent, by MGL. There were no significant insulin or C-peptide differences between the different high-dose combi nations (M/G, G/M, and MGH). Body weight did not change following trea tment with M or combination but increased by 2.8 +/- 0.7 kg following G alone. Blood pressure was unchanged. Overall effects on plasma lipid s were small; with no significant differences between groups. Drug saf ety was satisfactory, even if the reporting of (usually modest) advers e events was high; the profile, but not the frequency, differed betwee n groups. CONCLUSIONS - Dose-effect titrated treatment with either met formin or glyburide promotes equal degrees of glycemic control. The fo rmer, but not the latter, is able to achieve this control without incr easing body weight or hyperinsulinemia. Near-normal glycemia can be ob tained by a combination of metformin and sulfonylurea, even in advance d NIDDM.