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The results of the cardiovascular outcome trials comparing the SGLT2 inhibitor empagliflozin and the glucagon-like peptide-1 receptor agonist liraglutide to placebo have been recently published. Interestingly, empagliflozin and liraglutide treatments significantly reduce cardiovascular events in subjects with type 2 diabetes. The mechanisms underlying the observed cardioprotective effects of empagliflozin and liraglutide are speculative and future studies are needed to better understand these results. However, since reduction in the primary outcome was evident 3 months after starting empagliflozin and 24 months after starting liraglutide, it is tempting to hypothesize that the cardiovascular benefits observed in diabetic patients treated with empagliflozin are due to its hemodynamic effects and to metabolic substrate shift induced by the mild and persistent hyperketonemia, while the positive effects of liraglutide treatment may be attributable to biologic changes of atherosclerotic lesions.

Clinical trials of glucose-lowering strategies in patients with type 2 diabetes mellitus (T2DM) have shown a favorable effect of intensive glycemic control on microvascular complications but failed to show a clear benefit on cardiovascular events. In 2008, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have required stringent criteria to approve new glucose-lowering drugs, demanding proof of cardiovascular safety. As a result of these regulatory requirements, a number of cardiovascular outcome trials in T2DM have been conducted examining the cardiovascular safety of novel glucose-lowering drugs. Dipeptidyl peptidase 4 (DPP4) inhibitors, analogs of glucagon-like peptide 1 (GLP-1), and inhibitors of the renal sodium-glucose linked transporter-2 (SGLT2) are new classes of glucose-lowering drugs for subjects with T2DM. The results of the cardiovascular outcome trials comparing the DPP4 inhibitors saxagliptin, alogliptin, and sitagliptin or the GLP-1 analog lixisenatide to placebo have demonstrated that these drugs are safe. The results of a cardiovascular outcome trial comparing the SGLT2 inhibitor empagliflozin to placebo have been published. Notably, empagliflozin treatment has been associated with a significant reduction in the primary composite cardiovascular outcome. Although the question regarding the positive effect of glycemic control on cardiovascular risk is still unanswered, current evidence suggests that a multifactorial approach aimed at treating not only hyperglycemia but also classical cardiovascular risk factors is necessary in order to reduce the risk of cardiovascular events in patients with T2DM.

Tight glycemic control represents one of the major goals of the therapeutic management of diabetes mellitus. However, several clinical studies have reported that an intensive glucose-lowering treatment, especially when insulin or sulfonylureas are used, is associated with an increased risk of hypoglycemia and may exert negative effects on the cardiovascular risk. Hypoglycemia is the major side effect of antidiabetic therapy and it has also been associated with adverse cardiovascular events. The surge of sympathetic activity during hypoglycemic episodes may induce cardiac and cerebral ischemia and promote potentially fatal arrhythmias. In addition, hypoglycemic episodes have a negative effect on patient compliance to the antidiabetic treatment and consequently may worsen glycemic control, thus increasing the risk of micro- and macroangiopathic complications of diabetes. Therefore, in order to counteract the cardiovascular risk it is necessary achieving a good glycemic control through therapeutic strategies associated with a lower risk of hypoglycemia. Unlike treatment with sulfonylureas, glucagon-like peptide-1 analogs and dipeptidyl peptidase-4 inhibitors have been demonstrated to improve metabolic control without inducing hypoglycemia and, therefore, represent a new therapeutic option for type 2 diabetes, which offer the advantage of combining glucose-lowering activity with a low risk of hypoglycemia, thus providing a greater cardiovascular protection.

Obesity and dyslipidemia often coexist in patients with type 2 diabetes and contribute to increase the risk of cardiovascular events. Pharmacological treatments of diabetes often result in weight gain, an undesirable event associated with a worse cardiovascular risk profile and decreased adherence to therapy. Dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs have been shown to improve glycemic control without promoting weight gain and to exert beneficial effects on lipid profile by reducing total and LDL cholesterol, triglycerides, and free fatty acid levels. DPP-4 inhibitors have demonstrated to be weight neutral whereas treatment with GLP-1 analogs is associated with a significant weight loss. DPP-4 and GLP-1 analogs represent a new therapeutic option for type 2 diabetes, which offers the advantage of combining glycemic control with beneficial effects on body weight and lipid profile, thus providing greater cardiovascular protection.