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Patients with diabetes mellitus have a 2-4 fold increase in macrovascular complications, such as heart disease and stroke, compared to the general population.1 Among patients with type 2 diabetes mellitus (T2DM), the impact of glycemic control on macrovascular complications remains inconclusive.2 In 1998, the United Kingdom Prospective Diabetes Study (UKPDS 33) demonstrated a 25% relative risk reduction in microvascular complications among patients with newly diagnosed T2DM treated with sulfonylureas or insulin compared to lifestyle modifications; however no significant effect was witnessed on macrovascular complications.3 In the UKPDS 34, metformin showed a positive benefit among newly diagnosed obese T2DM patients in reducing microvascular and macrovascular events, as well as all-cause mortality compared to sulfonylureas, insulin and lifestyle modifications.4 The UKPDS 34 also found that T2DM patients initially treated with a sulfonylurea, then with metformin added, had a significant increase in diabetic deaths versus sulfonylurea monotherapy. This specific finding in UKPDS 34 raised questions and concerns regarding the potential adverse effect of these two agents used in combination for the management of T2DM, and epidemiologic studies have found conflicting results of the combination on diabetes-related outcomes.4 Because cardiovascular disease is a major cause of mortality in T2DM, therapies to manage T2DM ideally should not have a negative effect on macrovascular complications.

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The Study on the Prognosis and Effect of Antidiabetic Drugs on Type 2 Diabetes Mellitus with Coronary Artery Disease (SPREAD-DIMCAD) was a randomized, double-blind, placebo-controlled, prospective trial that compared the effects of two of the most commonly used antidiabetic agents, sulfonylureas (glipizide) and metformin, on cardiovascular (CV) outcomes and mortality among high-risk Chinese patients. Adult patients were eligible for inclusion if they had a prior diagnosis of T2DM and coronary artery disease (CAD). Patients were excluded for any of the following: severe organ dysfunction, psychiatric disease, infection, neutropenia, congenital heart disease, rheumatic heart disease, hypertrophic cardiomyopathy, and the inability to switch from insulin therapy to an oral agent. The primary endpoint was the composite of recurrent CV events, defined as death from a CV cause, death from any cause, nonfatal myocardial infarction, nonfatal stroke or arterial revascularization. The secondary endpoints included new or worsening angina, new or worsening heart failure, new critical cardiac arrhythmia, and new peripheral vascular events. Hypoglycemia and microvascular complications were also measured.5

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Of the 565 patients screened for inclusion, 304 were enrolled and underwent randomization; 148 patients received glipizide and 156 received metformin. The target for both groups was a hemoglobin A1c (HbA1c) of <7%, fasting blood glucose (FBG) <7 mmol/L [126 mg/dL], and postprandial blood glucose (PPBG) <10 mmol/L [180 mg/dL]. Patients received an initial dose of glipizide 15 mg or metformin 750 mg daily. The doses were titrated to 30 mg and 1500 mg respectively, within 3 months, if goals were not reached. If the specified goals were not demonstrated after 3 months, NPH insulin was added to the maximum dose oral therapy. The patient population was mainly males (~78%) with a mean age of 63.3 years and mean HbA1c of 7.6%. The baseline characteristics between the two groups were similar with the exception of the PPBG, wherein the metformin group was significantly higher (p=0.014).5

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After a median follow up of 5 years, metformin resulted in a significantly lower rate of the primary end point or CV outcomes in comparison with glipizide yielding a number needed to treat of 10 (HR 0.54; 95% CI 0.3-0.9; p=0.026). In the glipizide group, 52 patients (35.1%) experienced a total of 60 primary events, while 39 patients in the metformin group (25%) had a total of 43 events. There were no statistically significant ...

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