1236 DIABETES CARE, VOLUME 23, NUMBER 9, S EPTEMBER 2000 R esponse to diet and oral sulfonylurea agents in the treatment of type 2 dia- betes is variable and often short-lived, with 5–10% of patients becoming nonre- sponsive each year (1). Multiple treatment options are available at the time of sec- ondary sulfonylurea failure. Most com- monly, the emphasis of these therapies is to focus on fasting and preprandial glucose values, and little attention is paid to post- prandial glucose control (2,3). The importance of postprandial glu- cose control is evident in the literature. Postprandial hyperglycemia has been asso- ciated with increased risk of microvascular (4–6) and macrovascular (7–10) compli- cations. The risk of cardiovascular disease and all-cause mortality increases with increasing postprandial blood glucose val- ues (7). The Honolulu Heart Study demon- strated an increased risk of fatal coronary heart disease events alone and in combi- nation with nonfatal myocardial infarc- tion that was independently related to increased postchallenge glucose levels (8). Furthermore, the Diabetes Intervention Study demonstrated that postprandial blood glucose was an independent risk factor for mortality in patients with newly diagnosed type 2 diabetes, but fasting blood glucose (FBG) was not (9). There- fore, intervention aimed at lowering the 2-h postprandial blood glucose may be important in reducing diabetic complica- tions and mortality and may be an impor- tant focus for therapy. The present study was designed to compare the efficacy and safety profile of 3 treatment strategies in patients with type 2 diabetes uncontrolled on sulfonylurea agents alone. These combination treatment regimens with glyburide (G) focused on either fasting glucose (bedtime NPH insulin plus glyburide [NPH+G]), postprandial blood glucose (preprandial insulin lispro plus glyburide [L +G]), or premeal glucose (metformin plus glyburide [M+G]) and allowed for the comparison of the impact of each on overall metabolic control. From Eli Lilly and Company (E.J.B., R.G.B., C.J.G., A.Z., K.E.R.), Indianapolis, Indiana; the University of Texas Medical Branch (C.A.S.), Galveston, Texas; and the Diabetes and Glandular Disease Clinic (S.S.), San Antonio, Texas. Address correspondence and reprint requests to Edward J. Bastyr III, MD, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285. E-mail: ejbIII@ lilly.com. Received for publication 30 November 1999 and accepted in revised form 8 May 2000. E.J.B., R.G.B., C.J.G., A.J.Z. and K.E.R. are employed by Eli Lilly and Company. E.J.B., R.G.B., C.J.G., and K.E.R. hold stock in Eli Lilly and Company. E.J.B., R.G.B., and S.S. have received grant support from Eli Lilly and Company. S.S. is a member of the Lilly Device Consultants Advisory Board and has received honoraria from Eli Lilly and Company. Abbreviations: ANOVA, analysis of variance; DCCT, Diabetes Control and Complications Trial; DTSQ, Diabetes Treatment Satisfaction Questionnaire; FBG, fasting blood glucose; L+G, preprandial insulin lispro plus glyburide; M+G, metformin plus glyburide; NPH+G, bedtime NPH insulin plus glyburide; UKPDS, U.K. Prospective Diabetes Study. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Therapy Focused on Lowering Postprandial Glucose, Not Fasting Glucose, May Be Superior for Lowering HbA 1c O R I G I N A L A R T I C L E O BJECTI V E — To compare the overall efficacy of combination therapies focused on fasting or postprandial blood glucose in patients with type 2 diabetes not adequately controlled with oral sulfonylurea agents alone. RESEARCH DESIGN AND M ETHODS — A total of 135 patients were randomly assigned for 3 months to 1 of 3 combination regimens with glyburide (G) that addressed post- prandial blood glucose with insulin lispro (L+G), premeal blood glucose with metformin (M+G), or fasting blood glucose (FBG) with bedtime NPH insulin (NPH+G). RESULTS — At end point, HbA 1c was significantly lower with all therapies ( P = 0.001) and was significantly lower for L+G (7.68 ± 0.88%) compared with either NPH+G (8.51 ± 1.38%, P = 0.003) or M+G (8.31 ± 1.31%, P = 0.025). FBG at end point was significantly lower for NPH+G (8.49 ± 2.36 mmol/l) compared with either L+G (10.57 ± 1.97 mmol/l, P = 0.001) or M+G (9.69 ± 2.89 mmol/l, P = 0.029). The mean 2-h postprandial glucose after a test meal was significantly lower for L+G (10.87 ± 2.88 mmol/l) versus NPH+G (12.21 ± 3.12 mmol/l, P = 0.052) or versus M+G (12.72 ± 3.26 mmol/l, P = 0.009). The overall rate of hypoglycemia (episodes per 30 days) was low and not statistically significant between groups ( P = 0.156). CO N CLUSI O N S — Adding a second antihyperglycemic agent, regardless of its timing of action, lowers HbA 1c and glucose values. However, when insulin lispro was used to focus on postprandial blood glucose, there was a greater impact on overall metabolic control. These data support the importance of lowering postprandial blood glucose to optimize overall glycemic control and thus improve long-term outcomes. Diabetes Care 23:1236–1241, 2000 EDWARD J. BASTYR III, MD CHARLES A. STUART , MD ROBERT G. BRODOWS, MD SHERWYN SCHWARTZ, MD CASEY J. GRAF , PHARMD ANTHONY ZAGAR, MS KENNETH E. ROBERTSON, PHARMD FOR THE IOEZ STUDY GROUP Clinical Care/Education/Nutrition Downloaded from http://diabetesjournals.org/care/article-pdf/23/9/1236/451957/10977012.pdf by guest on 10 December 2023