ReviewClinical Implications of Cardiovascular Preventing Pleiotropic Effects of Dipeptidyl Peptidase-4 Inhibitors
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
References (28)
- et al.
Future perspectives on glucagon-like peptide-1 diabetes and cardiovascular risk
Nutr Metab Cardiovasc Dis
(2008) - et al.
Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes(DURATION-2): a randomized trial
Lancet
(2010) - et al.
Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism
Regul Pept
(2005) - et al.
Renal effects of glucagon-like peptide 1 in rats
Eur J Pharmacol
(2002) - et al.
Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel-group study
Clin Ther
(2008) - et al.
Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure
J Card Fail
(2006) - et al.
Safety and efficacy of SITAgliptin plus Granulocyte-colony-stimulating factor in patients suffering from Acute Myocardial Infarction (SITAGRAMI-Trial)—rationale, design and first analysis
Int J Cardiol
(2010) Dipeptidyl peptidase-4 inhibitors and the treatment of type 2 diabetes
Diabetes Care
(2007)- et al.
Glucose lowering and antidiabetogenic effects of incretin-based therapies: GLP-1 analogues and DPP-4 inhibitors
Expert Opin Investig Drugs
(2009) - et al.
Postprandial blood glucose is a strong predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the San Luigi Gonzaga diabetes study
J Clin Endocrinol Metab
(2006)