Review
Clinical Implications of Cardiovascular Preventing Pleiotropic Effects of Dipeptidyl Peptidase-4 Inhibitors

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Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel drugs for the treatment of type 2 diabetes mellitus. They exert their action through inhibition of the catabolism of locally secreted incretins such as glucagon-like peptide-4 (GLP-4) and glucose-dependent insulinotropic polypeptide (GIP) by inhibiting enzyme DPP-4. GLP-1 and GIP are secreted from the gastrointestinal tract in response to food intake. GLP-1 is secreted from L cells present in the mucosa of the small intestine and colon, whereas GIP is secreted from K cells of the jejunum. These 2 incretins lower blood glucose levels and postprandial hyperglycemia by stimulating insulin release from b cells of the pancreas, thus increasing insulin sensitivity, delaying gastrointestinal emptying, decreasing food intake through early satiety, and causing weight loss in the long term. However, their action is short-lived (2 to 3 minutes) because of catabolism by the DPP-4 enzyme. The importance of DPP-4 inhibitors lies in their blockade of the DPP-4 enzyme leading to the prevention of their catabolism and thus increasing their blood levels, extending the duration of their action, and improving their blood glucose-lowering effect. In addition to their antidiabetic action, recent experimental and clinical studies have demonstrated a pleiotropic cardiovascular protective effect of these agents independent of their antidiabetic action. They prevent atherosclerosis, improve endothelial dysfunction, lower blood pressure, and prevent myocardial injury. All these actions are discussed in this concise review. In conclusion, DPP-4 inhibitors are novel antidiabetic agents with pleiotropic cardiovascular protective effects in addition to their antidiabetic action.

Section snippets

DPP-4 Inhibitors and Their Mechanism of Action

There are several DPP-4 inhibitors for the treatment of type 2 diabetes mellitus, some approved by the Food and Drug Administration and others still in development (Table 1). Although they have different chemical structures, all successfully inhibit the DPP-4 enzyme and prevent the catabolism of GLP-1 and GIP. Of the 2 incretins, most of the action (80%) is mediated though GLP-1.2 The action of GLP-1 can be increased by the prevention of its catabolism by GLP-1 receptor stimulators such as

Cardiovascular Protective Actions of DPP-4 Inhibitors

The cardiovascular protective effects of DPP-4 inhibitors are basically mediated through their control of diabetes because diabetes is a major risk factor for cardiovascular complications. However, recent experimental and clinical evidence has suggested that these agents exert additional cardioprotective effects by mechanisms independent of diabetic control.8, 11 All actions of DPP-4 inhibitors are mediated through the incretins GLP-1 and GIP and especially GLP-1 as depicted in Figure 2 and

Atherogenesis

An experimental study in knockout mice for the low-density lipoprotein receptor treated with the DPP-4 inhibitor alogliptin showed a decrease in serum lipids compared to controls.12 These 6-week-old mice were fed a high-fat diet or normal chow for 4 weeks and then randomized to a vehicle or alogliptin (40 mg/kg/day) for 12 weeks. Alogliptin decreased adipose tissue macrophages, inflammatory biomarkers CD11b and CD11c, aortic plaque, and aortic plaque macrophages in mice fed the high-fat and

Endothelium

Emerging evidence has suggested beneficial endothelial effects of GLP-1, possibly mediated through GLP-1 receptors present in endothelial and smooth muscle cells in blood vessels.11 Previous animal studies have demonstrated that GLP-1 induces an endothelium-dependent vasorelaxation that is dependent on nitric oxide (NO) generation.8 NO is a well-known endothelium-dependent vasodilator and has been shown to improve survival of human aortic endothelial cells after ischemia–reperfusion.8 Also,

Hypertension

Clinical and experimental studies have shown a moderate BP-lowering effect induced by GLP-1.3, 8 The main mechanism for this effect of GLP-1 has been attributed to increased diuresis and natriuresis owing to an inhibition of sodium reabsorption from the proximal renal tubule.17 In anesthetized rats, administration of recombinant GLP-1 resulted in a 13-fold increase in urine flow and sodium excretion from the innervated kidney and a 39% increase in glomerular filtration fraction.17 Urine flow,

Myocardium

Accumulating evidence from experimental and clinical studies has suggested a direct effect of GLP-1 on the myocardium in addition to its indirect effects through control of diabetes. Also, GLP-1 receptors have been identified in rodent and human hearts.8

Experimental Studies

Cardiac function and structure have been assessed by hemodynamic monitoring and echocardiography in DPP-4 knockout (DPP-4−/−) mice versus wild-type (DPP-4+/+) controls after an acute myocardial infarction produced by ligation of the left anterior descending coronary artery.21 In addition, similar studies have been performed in streptozotocin-induced diabetic mice fed a high-fat diet after an acute myocardial infarction under sustained DPP-4 inhibition with sitagliptin. Sitagliptin improved

Clinical Studies

In human studies, infusion of GLP-1 has been shown to have cardioprotective effects. In 1 study, GLP-1 (2.5 pmol/kg/min) given by infusion was added to a background therapy in 12 patients with New York Heart Association class III to IV heart failure. Results of this treatment were compared to those of 9 patients with a similar class of heart failure treated with a standard background therapy alone.24 GLP-1 infusion significantly improved left ventricular ejection fraction from 21 ± 3% to 27 ±

Discussion

DPP-4 inhibitors are a novel class of antidiabetic drugs with important pleiotropic cardiovascular protective effects. Their mechanism of action is mediated through the incretins GLP-1 and GIP by blocking enzyme DPP-4 and thus preventing their catabolism. This action increases blood levels of these incretins and prolongs the duration of their life because it is very short (2 to 3 minutes). The incretins and especially GLP-1, which accounts for 80% of the action, decrease blood glucose levels by

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