restricted access 17. Antidiabetic Drugs and Cardiovascular Risk: Where Do We Stand?
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INTRODUCTION Type 2 diabetes (T2D) is a major global health prob­ lem, imposing a huge economic burden on society. It is a progressive chronic condition associated with insulin re­ sis­ tance or the inability to produce enough insulin ­ because of impaired beta cell function. T2D patients have a very high prevalence and incidence of coronary heart disease (1). A number of clinical ­ trials have found that heart and blood vessel diseases are major­ causes of morbidity and mortality in T2D patients (2). According to reports of vari­ ous major clinical ­ trials that the dif­ fer­ ent classes of glucose-­ lowering drugs associated with ­ either decrease or increase the risk of cardiovascular (CV) events in patients with diabetes (3). Therefore, to reduce the incidence of CV morbidity and mortality in T2D patients, it is very impor­ tant to select an appropriate glucose-­ lowering agent according to the patient’s disease state and associated comorbidities. ANTIDIABETIC DRUGS Biguanides: Metformin Metformin is an insulin-­ sensitizing agent recommended as a best initial choice for T2D patients ­ unless ­ there are any contraindications or risk of lactic acidosis (4). According to the 2012 joint statement of the American Diabetes Association (ADA) and the Eu­ ro­ pean Foundation for the Study of Diabetes (EFSD), metformin is a cornerstone treatment for T2D patients along with lifestyle modifications such as proper diet and exercise (5). The main finding of the United Kingdom Prospective Diabetes Study (UKPDS) was that glucose-­ lowering drugs (metformin, sulfonylureas, insulin)­ were associated with reduced risk of heart and blood vessel diseases in diabetic patients (see ­ Table 17-1) (6). That finding is supported by other clinical ­ trials such as the Hyperinsulinemia: the Outcome of its Metabolic Effects (HOME) trial (7) and the Prevention of Restenosis with Tranilast and its Outcomes (PRESTO) trial (8), which concluded that metformin reduced the risk of CV complications and heart failure in T2D patients (9). Additional clinical ­ trials such as the Veterans Affairs Diabetes Trial (VADT) (10), the Action in Diabetes and Vascular Disease (ADVANCE) trial (11), and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study group (12) also reported on the impact of glucose-­ lowering drugs including metformin on CV CHAPTER 17 Antidiabetic Drugs and Cardiovascular Risk Where Do We Stand? Rajesh Kumar Antidiabetic Drugs / 195 any effect on CV outcome in T2D patients (see­ Table 17-1).A few other studies made similar findings about repaglinide, that it did not increase or decrease CV risk in T2D patients (24).The glinides increase insulin secretion for a very short duration, resulting in a lower incidence of hypoglycemia and weight gain; they can also be used in diabetic patients with renal insufficiency (25). Thiazolidinediones Thiazolidinediones (TZDs), also known as glitazones , are potent insulin sensitivity agents that specifically target insulin re­ sis­ tance and improve glycemic control in T2D patients (26). It has been reported that rosiglitazone increased the risk of macrovascular complications (27), but the REC­ ORD study found that rosiglitazone did not increase any adverse CV events (16). The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) reported a 10% risk reduction in macrovascular complications (e.g., acute coronary syndrome) and a 16% reduction in stroke and myo­ car­ dial infarction for patients on pioglitazone therapy (see ­ Table 17-1) (28). The Insulin Re­ sis­ tance Intervention ­ After Stroke (IRIS) trial also reported beneficial effects of pioglitazone on cardiovascular outcome and a significant decrease in the incidence of stroke and myo­ car­ dial infarction in patients on pioglitazone (29). The Carotid Intima-­ Media Thickness in Atherosclerosis Using Pioglitazone (CHICAGO) trial showed a significant reduction in carotid intima-­ media thickness (CIMT) in T2D patients on pioglitazone compared with glimepiride (30). The Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation (PERISCOPE) trial showed regression in coronary atherosclerosis in T2D patients on pioglitazone (31). The ACT NOW Study similarly found that pioglitazone reduced CIMT (32).­ These dif­ fer­ ent CV outcomes of pioglitazone and rosiglitazone could be due to their distinct effects on lipid metabolism (33). Dif­ fer­ ent ­ Randomized Controlled Trails reported that pioglitazone had more beneficial effects on lipid metabolism, reducing triglycerides by 10% and increasing HDL cholesterol by 15%, but with no effect on LDL cholesterol (3,33). Rosiglitazone showed no effect on triglycerides and increases of 10% in HDL and LDL cholesterol (see ­ Table 17-1) (3). ­ These differences might be linked with the morbidity and mortality in T2D patients (13,14). However, ­ these ­ trials reported controversial results. Therefore, the se­ lection of...


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