Diabetes mellitus is a metabolic disease with a growing prevalence worldwide, affecting 171 million people in 2000 and an expected 366 million people in 2030 [1].. Currently available therapies for type 2 diabetes have various limitations and are associated with increased risk of hypoglycemia, weight gain, gastrointestinal side effects or edema and heart failure.~A new and promising class of drugs are the gliptins. Gliptins act by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4), which is responsible for the rapid inactivation of glucagon-like peptide-1 (GLP-1) - an incretin hormone of the gut [2-4], thereby enhancing and prolonging the effects of GLP-1. GLP-1 - member of the incretin hormones - is released into the blood after meal ingestion and stimulates the insulin secretion in a glucose dependent manner. This accounts for the marked prandial insulin response, which prevents prandial hyperglycemia. Several efficacy studies demonstrated a significant improvement of HbA1c with gliptins. In addition, gliptins improved fasting as well as prandial glucose levels and did not induce weight gain. Due to these positive metabolic effects in combination with a very small spectrum of side effects gliptins might very well be part of the standard therapy for type 2 diabetes in the future.~Apart form surrogate parameters like reduction of fasting and postprandial blood glucose levels or improvement of HbA1c, the effect of gliptins on micro- and macrovascular function and cardiovascular outcome has not been the primary focus of current studies. However, infusion of GLP-1, the incretin hormone affected by gliptins has been reported to ameliorate endothelial dysfunction in patients suffering from coronary artery disease [5] and it was recently shown that infusion of GLP-1 into healthy human subjects increases both normal and ACh-induced vasodilatation [6]. In studies on rats with diabetes, GLP-1 infusion nearly re-established their normal vascular tone [7] and there are further data from experimental animals that indicate a beneficial effect of GLP-1 on endothelial function [8].~Diabetes mellitus is strongly associated with microangiopathy and macroangiopathy and is a strong independent risk factor for cardiovascular disease and cardiovascular mortality [9]. Endothelial dysfunction which plays a crucial role in the atherosclerotic process is commonly observed in patients with diabetes mellitus and already prediabetes and has - amongst other factors - been linked to fasting and postprandial hyperglycemia. Taken into account that gliptins reduce hyperglycemia and hyperglycemic peaks by preventing inactivation of GLP-1, which exerted beneficial effects on the endothelium in previous studies it is of major interest whether therapy with gliptins improves endothelial function of the micro- and macrovasculature and thereby might prove to affect cardiovascular morbidity and mortality in diabetic patients in the long term. The retina offers the unique opportunity to directly visualize and investigate the microvasculature in vivo [10-14].~References~Wild S, Roglic G, Green A, Sicree R, King H: Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047-1053.~Deacon CF, Ahren B, Holst JJ: Inhibitors of dipeptidyl peptidase iv: A novel approach for the prevention and treatment of type 2 diabetes? Expert Opin Investig Drugs 2004;13:1091-1102.~Deacon CF: Therapeutic strategies based on glucagon-like peptide 1. Diabetes 2004;53:2181-2189.~Holst JJ, Deacon CF: Glucagon-like peptide-1 mediates the therapeutic actions of dpp-iv inhibitors. Diabetologia 2005;48:612-615.~Nystrom T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahren B, Sjoholm A: Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab 2004;287:E1209-1215.~Basu A, Charkoudian N, Schrage W, Rizza RA, Basu R, Joyner MJ: Beneficial effects of glp-1 on endothelial function in humans: Dampening by glyburide but not by glimepiride. Am J Physiol Endocrinol Metab 2007;293:E1289-1295.~Ozyazgan S, Kutluata N, Afsar S, Ozdas SB, Akkan AG: Effect of glucagon-like peptide-1(7-36) and exendin-4 on the vascular reactivity in streptozotocin/nicotinamide-induced diabetic rats. Pharmacology 2005;74:119-126.~Yu M, Moreno C, Hoagland KM, Dahly A, Ditter K, Mistry M, Roman RJ: Antihypertensive effect of glucagon-like peptide 1 in dahl salt-sensitive rats. J Hypertens 2003;21:1125-1135.~Laakso M: Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes 1999;48:937-942.~Delles C, Michelson G, Harazny J, Oehmer S, Hilgers KF, Schmieder RE: Impaired endothelial function of the retinal vasculature in hypertensive patients. Stroke 2004;35:1289-1293.~Harazny JM, Ritt M, Baleanu D, Ott C, Heckmann J, Schlaich MP, Michelson G, Schmieder RE: Increased wall:Lumen ratio of retinal arterioles in male patients with a history of a cerebrovascular event. Hypertension 2007;50:623-629.~Ritt M, Schmieder RE: Wall-to-lumen ratio of retinal arterioles as a tool to assess vascular changes. Hypertension 2009;54:384-387.~Oehmer S, Harazny J, Delles C, Schwarz T, Handrock R, Michelson G, Schmieder RE: Valsartan and retinal endothelial function in elderly hypertensive patients. Blood Press 2006;15:185-191.~Ott C, Schlaich MP, Harazny J, Schmidt BM, Michelson G, Schmieder RE: Effects of angiotensin ii type 1-receptor blockade on retinal endothelial function. J Hypertens 2008;26:516-522.
Diabetes mellitus is a metabolic disease with a growing prevalence worldwide. Currently available therapies for type 2 diabetes have various limitations and are associated with increased risk of hypoglycemia, weight gain, gastrointestinal side effects or edema and heart failure.~A new and promising class of drugs are the gliptins. Several efficacy studies demonstrated a significant improvement of HbA1c with gliptins. In addition, gliptins improved fasting as well as prandial glucose levels and did not induce weight gain. Due to these positive metabolic effects in combination with a very small spectrum of side effects gliptins might very well be part of the standard therapy for type 2 diabetes in the future.~Apart form surrogate parameters like reduction of fasting and postprandial blood glucose levels or improvement of HbA1c, the effect of gliptins on micro- and macrovascular function and cardiovascular outcome has not been the primary focus of current studies. Diabetes mellitus is strongly associated with microangiopathy and macroangiopathy and is a strong independent risk factor for cardiovascular disease and cardiovascular mortality. Endothelial dysfunction which plays a crucial role in the atherosclerotic process is commonly observed in patients with diabetes mellitus and already prediabetes and has - amongst other factors - been linked to fasting and postprandial hyperglycemia. Taken into account that gliptins reduce hyperglycemia and hyperglycemic peaks by preventing inactivation of GLP-1, which exerted beneficial effects on the endothelium in previous studies it is of major interest whether therapy with gliptins improves endothelial function.