VPH-05881; No of Pages 7

Vascular Pharmacology xxx (2011) xxxxxx

Contents lists available at ScienceDirect

Vascular Pharmacology
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / v p h

Review

Cardiovascular effects of DPP-4 inhibition: Beyond GLP-1

Gian Paolo Fadini , Angelo Avogaro
Department of Clinical and Experimental Medicine, University of Padova, Faculty of Medicine, Padova, Italy Venetian Institute of Molecular Medicine, Padova, Italy

a r t i c l e

i n f o

a b s t r a c t
Dipeptydil-peptidase-4 (DPP-4) inhibitors are available as oral anti-hyperglycemic drugs for the treatment of type 2 diabetes. Their metabolic effect is mediated through sparing incretin hormones (such as glucagon-like peptide-1, GLP-1) from the rapid degradation by DPP-4. In turn, GLP-1 improves meal-stimulated insulin secretion by pancreatic -cells thus reducing hyperglycemia. It has been shown that GLP-1 signaling is also active in the cardiovascular system, where it may exert benecial effects. However, DPP-4 has several nonincretin substrates, and its immunomodulatory activity is known from decades. DPP-4 physiologically cleaves cytokines, chemokines and neuropeptides involved in inammation, immunity, and vascular function. Owing to these off-target mechanisms, DPP-4 inhibitors hold promise for cardiovascular protection, but may also face unexpected side effects. Herein, we review available data on the cardiovascular effects of DPP-4 inhibitors, with a special interest in GLP-1-independent mechanisms. The modulation of endothelial progenitor cells, inammatory pathway and ischemic response emerges as the major cardiovascular target of DPP-4 inhibitors. 2011 Elsevier Inc. All rights reserved.

Article history: Received 7 April 2011 Received in revised form 5 May 2011 Accepted 24 May 2011 Available online xxxx Keywords: Diabetes Cardiovascular DPP-IV Safety Gliptins

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Biology of dipeptidyl peptidase-4 . . . . . . . . . . . . . . . . . . 3. Possible cardiovascular effects of DPP-4i via GLP-1 modulation . . . . 4. Effects of DPP-4i on inammation . . . . . . . . . . . . . . . . . 5. Effects of DPP-4i on endothelial cells, nitric oxide and blood pressure 6. Effects of DPP-4i on vascular progenitor cells via SDF-1 . . . . . . 7. Myocardial effects of DPP-4i . . . . . . . . . . . . . . . . . . . . 8. Other off-target effects of DPP-4i and cautionary notes . . . . . . . 9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 0 0 0 0 0 0 0 0 0

1. Introduction Dipeptidyl peptidase-4 (DPP-4) inhibitors (from now on DPP-4i) are newly available drugs approved for the treatment of type 2 diabetes mellitus, either as monotherapy or in combination with oral agents (metformin, glitazones, and/or sulphonylureas) and insulin

See the original manuscript by Z. Shah et al., Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways, doi:10.1016/j.vph.2011.05.001 (this issue). Corresponding author at: Dept Clinical and Experimental Medicine, University of Padova, Via Giustiniani, 2, 35100 Padova, Italy. Tel.: + 39 049 8212172; fax: + 39 049 8212184. E-mail addresses: gianpaolo.fadini@unipd.it, gianpaolofadini@hotmail.com (G.P. Fadini). 1537-1891/$ see front matter 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.vph.2011.05.001

(Drucker and Nauck, 2006). Available DPP-4i include sitagliptin, vildagliptin and saxagliptin; other DPP-4i compounds are being developed and soon will reach the market, as many pharmaceutical companies have one in their pipeline. DPP-4i exert their antihyperglycemic effect mainly by improving meal-stimulated insulin secretion by pancreatic -cells. This is accomplished by sparing the hormone glucagon-like peptide-1 (GLP-1) from degradation by the enzyme DPP-4. GLP-1 is produced by ileal L-cells rapidly after ingestion of a meal and exerts its effects through: i) stimulation of insulin release; ii) inhibition of glucagon release; iii) slowing of gastric emptying. GLP-1, together with the glucose-dependent insulinotropic peptide (GIP)-1, belongs to the incretin hormone family and accounts for the so-called incretin effect, which refers to the higher insulin secretion induced by an oral glucose load compared to an equivalent intravenous glucose load. Physiologically, GLP-1 is degraded by DPP-4

Please cite this article as: Fadini, G.P., Avogaro, A., Cardiovascular effects of DPP-4 inhibition: Beyond GLP-1, Vascul. Pharmacol. (2011), doi:10.1016/j.vph.2011.05.001

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within minutes and is believed to act mainly in the splanchnic circulation (Drucker, 2006). Incretin-based therapies for type 2 diabetes include GLP-1 analogues and DPP-4i. GLP-1 analogues are engineered forms of GLP-1, which are made resistant to DPP-4 enzymatic digestion and have a half-life of hours to days. Unfortunately, owing to their biochemical nature, they are unsuitable for oral delivery and must be injected subcutaneously once (liraglutide) or twice (exenatide) daily. Though a once-weekly GLP-1 analogue is close to commercialization, the need for injections has somehow restricted the use of these agents. DPP-4i are chemicallyderived selective, competitive inhibitors of DPP-4 and can be administered orally. Typically, in randomized clinical trials, DPP-4i achieved a HbA1c reduction from 0.6% to 0.9% and, so far, have shown an optimal safety prole, as they are not associated with serious adverse effects. Importantly, the incidence of hypoglycemia in DPP-4i treated patients in clinical trials was similar to placebo and thus signicantly lower than with other insulin-secretagogues, such as sulphonylureas and meglitinides (Monami et al., 2010). For these reasons, DPP-4i are increasingly used in the treatment of type 2 diabetes. After the lesson learned with rosiglitazone that, despite preclinical evidence of vascular protection, has been withdrawn or has been limited in its use for cardiovascular safety concerns, regulatory agencies now require that all new drugs approved for the treatment of type 2 diabetes undergo a thorough cardiovascular safety scrutiny (Freemantle, 2010). Thus, besides glycemic efcacy and general safety, DPP-4i will need to show no harm to the patients in terms of major cardiovascular events in the ongoing randomized clinical trials. In the meanwhile, preclinical and preliminary clinical data suggest that DPP-4i hold interesting promise for cardiovascular protection. In this article, available evidence in support of a cardiovascular protective effect of DPP-4 inhibition will be reviewed, with a special focus on GLP-1independent mechanisms. 2. Biology of dipeptidyl peptidase-4 DPP-4, also known as adenosine deaminase complexing protein 2 or CD26 (EC 3.4.14.5), is expressed on the surface of several cell types, including lymphocytes and monocytes, and is associated with immunoregulatory functions (Augustyns et al., 1999; Iwata et al., 1999). It is a transmembrane glycoprotein, with serine exopeptidase activity that cleaves X-proline dipeptides from the N-terminus of polypeptides. Protein dimerization is required for catalytic activity, and glycosylation of the enzyme impacts on its physiological functions. DPP-4 substrates are proline- or alanine-containing peptides, which include growth factors, chemokines, neuropeptides, and vasoactive peptides (Drucker, 2007) (Table 1). Therefore, DPP-4 is not specic for GLP-1 and a wide range of DPP-4 substrates is known. However, it should be noted that DPP-4 does not play a physiologically relevant role in the regulation of all proteins which are theoretical substrates or have been shown to be cleaved by DPP-4. Some substrates may be cleaved by DPP-4 only at very high concentrations or in the presence of supraphysiological DPP-4 activity. In addition, dipeptide cleavage from the N-terminus of some substrates may not signicantly modify the biological activity of the protein for what concerns, for instance, receptor binding. Anyway, DPP-4 inhibition has the potential of profoundly affecting the global humoral milieu, with a range of possible pleiotropic effects, well beyond GLP-1 modulation. Mechanisms that regulate DPP-4 gene transcription and enzymatic activity are of particular interest, but are incompletely understood. It seems that the 5-anking region of the DPP-4 coding sequence contains DNA elements for gene expression (Gum et al., 2000). Regulation of DPP-4 expression and tissue restriction has been studied in several types of cancer, and it appears that surface DPP-4 is increased by hypoxia (Dang et al., 2008). Besides HIF-1, also the transcription factors HNFs have DPP-4 as a downstream target (Gu

et al., 2008). Moreover, the DPP4 gene promoter contains a putative Stat binding site, which can be activated by interferons and retinoic acid, among others (Bauvois et al., 2000). Importantly, metformin has also been demonstrated as a previously unrecognized DPP-4i (Lenhard et al., 2004), although the mechanisms are not entirely understood and the issue is rather controversial (Cho and Kieffer, 2011). Finally, it is possible that glucose control modulates DPP-4 activity per se (Ryskjaer et al., 2006). 3. Possible cardiovascular effects of DPP-4i via GLP-1 modulation A series of experimental and preliminary clinical data suggest that GLP-1 itself has favorable cardiovascular effects (reviewed in (Anagnostis et al., 2011) and (Okerson and Chilton, 2010)). For instance, in vitro, the GLP-1 agonist exendin-4 was shown to stimulate proliferation of human coronary artery endothelial cells through endothelial nitric oxide synthase (eNOS)-, protein kinase A (PKA)- and phosphoinositolo-3 kinase (PI3K/Akt)-dependent pathways (Erdogdu et al., 2010). Others have conrmed that endothelial effects of GLP-1 are mediated by an increase nitric oxide bioavailability (Hattori et al., 2010) through GLP-1 receptor-dependent and -independent pathways (Ban et al., 2008). Quite interestingly, it has been recently shown that in vitro treatment with GLP-1 was also able to increase proliferation of the vasculoprotective endothelial progenitor cells (EPCs, see below), through an action on VEGF (Xiao-Yun et al., 2011). Using an in vivo model of vascular injury (mechanical endothelial damage to the femoral artery in mice), Goto et al. found that continuous infusion of exendin-4 (a GLP-1 agonist) reduced neointimal formation at 4 weeks after injury without altering body weight or various metabolic parameters (Goto et al., 2011). From in vitro studies, the authors suggest that this effect was mediated by the ability of GLP-1 to suppress PDGF-induced proliferation of vascular smooth muscle cells. A similar ability of exenatide to attenuate intimal hyperplasia following balloon catheter induced vascular injury was shown in Zucker rats, a model of type 2 diabetes (Murthy et al., 2010). Data obtained using ischemia-reperfusion (I/R) injury of isolated mouse hearts show that cardioprotection by exendin-4 involves ERK1/2, in addition to PI3-K signaling (Ban et al., 2010). In a rat model of chronic heart failure, GLP-1 analogues were able to improve cardiac function and morphology, with a concomitant amelioration of hyperglycemia and hyperinsulinemia (Liu et al., 2010). In a canine model of dilated cardiomyopathy induced by pacing, recombinant GLP-1 improved left ventricular performance, at least in part through an increase in myocardial glucose uptake (Nikolaidis et al., 2004a). In humans, preliminary data conrm the ability of GLP-1 to protect from high glucose-induced endothelial dysfunction in the post-meal phase (Ceriello et al., 2011). In patients with heart failure, pilot studies suggest protection by infusion of GLP-1 (Nikolaidis et al., 2004b; Sokos et al., 2006). As a clinical readout, in a large retrospective analysis, patients prescribed with the GLP-1 analogue exenatide had a signicant 20% reduction of CVD events compared with patients on other glucose-lowering agents (Best et al., 2011). Thus, it is arguable that DPP-4 inhibition in vivo provides vascular protection through an increase in GLP-1 bioavailability and signaling. Studies showing vascular benets of GLP-1 were carried out using either native GLP-1 or recombinant GLP-1 analogues at high concentrations or in a way that induced supraphysiological GLP-1 signaling. Thus, even if DPP-4 inhibition may lead to similar effects, the effects of GLP-1 analogues and DPP-4i may be different, as DPP-4 inhibition restores GLP-1 signaling within the physiological range. In a small pilot clinical trial on patients with coronary artery disease awaiting revascularization, the acute administration of the DPP-4i sitagliptin improved myocardial response to dobutamine stress and reduced features of myocardial stunning (Read et al., 2010). Although sitagliptin increased glucose load-induced GLP-1 concentrations, the link between GLP-1 and restoration of myocardial function remains

Please cite this article as: Fadini, G.P., Avogaro, A., Cardiovascular effects of DPP-4 inhibition: Beyond GLP-1, Vascul. Pharmacol. (2011), doi:10.1016/j.vph.2011.05.001

G.P. Fadini, A. Avogaro / Vascular Pharmacology xxx (2011) xxxxxx Table 1 Substrates of DPP-4 and potential effects. CLIP, corticotropin-like intermediate lobe peptide; GCP-1, GCP-2, granulocyte chemotactic protein-2; GRP, gastrin-releasing peptide; PHM, peptide histidine methionine. List of substrates is not intended to be exhaustive and has been modied from (Drucker, 2007).

Substrate Inflammation Endothelium Angiogenesis Metabolism Angioedema

EFFECTS

Other

CNS

Description Inhibits trypsin and related proteolytic enzymes Causes vasodilates and increases vascular permeability Opioid-like effects on the CNS Modulates the neuroendocrine function ACTH-derived endogenous modulator of pancreatic exocrine function, sleep and CNS Endogenous opioid-peptides Selectively reduces fat intake (or CCL11) Chemotactive for eosinophils, implicated in asthma (or CXCL6) Recruits neutrophils Stimulates GH production and release by binding to the Elicits gastrin release and regulates gastric acid secretion and motor function Allows childhood growth and anabolism in adults. Insulin counter-regulatory Allows lactation, regulate fertility and is counter-regulatory Major role in specific immunity Major regulator of inflammation, cell proliferation, differentiation, apoptosis (or CXCL10) Attracts leukocytes to the endothelium. Involved in bone marrow colony formation and angiogenesis (or CCL2) Recruits leukocytes to sites of tissue injury, infection, and inflammation (or CCL5) Recruits leukocytes into inflammatory sites Stimulates chemotaxis, stem/progenitor cell mobilization and homing Regulation of energy balance, memory and learning (see text) Neurotransmitter and neuromodulator, role in neurogenic inflammation (see text) Reduces appetite, inhibits gastric motility and increases water and electrolyte absorption in the colon Causes vasodilates and possibly act as a neurotransmitter Promotes insulin secretion, slowing gastric emptying, reducing appetite (see text) Intestinal growth and function, reduction in bone resorption, neuroprotection Inhibits GI motility and acid secretion. Stimulates insulin secretion and promotes fatty acid metabolism

Aprotinin Bradykinin -Casomorphin-2 Chromogranin CLIP Endomorphin-2 Enterostatin Eotaxin GCP-2 GHRH GRP IGF-1 Prolactin IL-2 IL-1 IP-10 MCP-1, -2, -3 RANTES SDF-1, -1 NPY Substance P PYY PHM GLP-1 GLP-2 GIP

speculative. A specic interest should be devoted to the study of DPP4i effects beyond those carried out by GLP-1. Herein, we would like to suggest that studies looking at the cardiovascular effects of DPP-4i should be carefully aware of the confounding role of restored GLP-1 levels and should establish whether observed results are mediated or not by GLP-1, especially in vivo. 4. Effects of DPP-4i on inammation Chronic low grade inammation plays a pivotal role in all manifestations of cardiovascular disease. As reviewed by Hansson (2009), inammatory processes and immunoregulatory mechanisms

contribute to the risk for myocardial infarction and stroke by modulating atherosclerotic plaque growth and complications. Inammation is also a key feature in the setting of heart failure, through excess TNF- levels as well as bacterial infection during exacerbations (Murray and Freeman, 2003; Niebauer et al., 1999). In the small controlled trial mentioned above, we found that 4 week sitagliptin therapy, besides increasing EPCs and SDF-1, was also associated with a signicant reduction of the pro-inammatory chemockine MCP-1 (Fadini et al., 2010a). MCP-1 plays an important role in regulating homing of activated monocytes into atherosclerotic plaques as well as into the inamed visceral fat, thereby acting at two key pathologic processes frequently seen in diabetic patients.

Please cite this article as: Fadini, G.P., Avogaro, A., Cardiovascular effects of DPP-4 inhibition: Beyond GLP-1, Vascul. Pharmacol. (2011), doi:10.1016/j.vph.2011.05.001

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DPP-4 has long been considered as having a role in immunomodulation. As atherosclerosis is an immuno-inammatory disease, it is possible that DPP-4i modulates responses occurring within early or late atherosclerotic lesions. Ta et al. have recently demonstrated that the specic DPP-4i alogliptin inhibited LPS-induced ERK phosphorylation in U937 histiocytes, a model of cells involved in the progression of atherosclerosis, such as foam cells (Ta et al., 2010). Downstream of ERK, DPP-4i was able to prevent activation of MMPs via the Toll-like receptor pathway, which contributes to the destabilization of atherosclerotic plaques leading to acute vascular events. In diabetes, inammation plays an important role not only in the vascular bed, but also in the adipose tissue and within pancreatic islets. In mice on a high fat diet, the DPP-4i sitagliptin reduced the number of inammatory cells and CD11b +F4/80 + macrophages within the stromal vascular fraction of visceral adipose tissue depots. Sitagliptin also reduced mRNA expression of a range of inammatory genes, such as IL-6, TNF-alpha, and IL-12 in the adipose tissue, and MCP-1, IL-6, IL-12, and IP-10 in the endocrine islets (Dobrian et al., 2011). These data suggest that, in a high-fat-diet model of obesity and insulin resistance, sitagliptin reduces pancreatic islet and adipose tissue inammation, concurrent with improved glucose metabolism, indicating that DPP-4i has anti-inammatory effects that enhance positive effects for metabolic and vascular function. These data have been conrmed in a diabetic mouse model with glucokinase haploinsufciency, as DPP-4i prevented inltration by T-cells and pro-inammatory macrophages and decreased the expression of PAI-1. Interestingly, in both wild-type and diabetic mice, DPP-4i prevented fat accumulation within the liver (Shirakawa et al., 2011), which is another feature of the metabolic syndrome and type 2 diabetes dependent on systemic inammation. Visceral fat accumulation and inammation, as well as non-alcoholic fatty liver disease are independently associated with vascular disease, through release of cytokines, induction of hypercoagulation and hyperbrinolysis and atherogenic dyslipidemia (Targher et al., 2011). Therefore, it is arguable that improvement in these inammatory conditions associated with type 2 diabetes contributes to vascular protection by DPP-4i. As visceral fat inltration and fatty liver contribute to compromise insulin sensitivity and glucose metabolism, the effects of these inammatory end-points may also contribute to couple vascular benets with the improved glucose control in patients on DPP-4i. 5. Effects of DPP-4i on endothelial cells, nitric oxide and blood pressure DPP-4 is expressed on endothelial cells, especially in the microvascular circulation (Matheeussen et al., 2011). Importantly, DPP-4 activity and expression is increased in vitro by high glucose only in microvascular endothelial cells (Pala et al., 2010), providing a rationale for the use of DPP-4i to protect endothelial cells from the detrimental effects of hyperglycemia. It has been shown that pharmacologic or genetic (siRNA) DPP-4 inhibition increases endothelial cell growth in vitro. As a functional readout of this stimulation of endothelial cells, reduced DPP-4 activity was associated with improved endothelial cell migration, aortic sprouting and angiogenesis in an in vivo Matrigel plug assay (Takasawa et al., 2010). Very recently, Shah et al. sought to determine the effects of acute DPP-4 inhibition on vascular tone, through an action on endothelial cells. They showed that pre-contracted aortic segments were dosedependently relaxed by the DPP-4 inhibitor alogliptin. The effect of alogliptin is at least in part mediated by the endothelium because it was reduced in aortic rings deprived of the intimal layer or treated with the endothelial nitric oxide synthase (eNOS) inhibitor L-NMMA. In cultured endothelial cells, alogliptin increased activation of the Akt-eNOS pathway and induced NO release. Therefore, these data suggest that DPP-4i regulates vascular tone through an action on the nitric oxide system. Given that GLP-1 itself stimulates eNOS via its

receptor pathway, the authors correctly demonstrated that blocking of the GLP-1 receptor did not abolish the effects of alogliptin in isolated aortic rings (Shah et al., 2011). This vascular relaxation effect of DPP-4i per se may have important clinical implications on blood pressure. Indeed, preliminary data in a small Japanese cohort suggest that the DPP-4i sitagliptin may lower blood pressure (Ogawa et al., 2010). These results are in line with a pre-clinical experience in the spontaneously hypertensive rat model, in which the blood pressure rise over time was partially prevented by treatment with the DPP-4i sitagliptin (Pacheco et al., 2011). 6. Effects of DPP-4i on vascular progenitor cells via SDF-1 One of the most exciting advancements of cardiovascular research in the last years is the discovery that a subset of circulating cells contributes to endothelial homeostasis and vascular repair. These socalled endothelial progenitor cells (EPCs) are derived from the bone marrow and can be mobilized into the bloodstream in response to many stimuli (Fadini and Avogaro, 2010). Vascular damage or ischemia, through the release of growth factors and cytokines, inform the bone marrow of the need for EPCs, which then specically home to damaged tissues. Locally, EPCs are able to form a patch at sites of endothelial denudation and reconstitute the anatomical integrity of the intimal layer (Fadini et al., 2007). Subsequently, EPCs differentiate into mature endothelial cells and complete functional reconstitution of the normal vasculature. In the presence of ischemia, gradients of chemokines generated by hypoxia stimulate EPCs to migrate in the subendothelial space and to contribute to the formation of new blood vessels, either by secreting growth factors or by physically integrating into the nascent vasculature (Fadini et al., 2009a). Importantly, a low EPCs level predicts incident cardiovascular events in different cohorts of patients (Fadini et al., 2010b), including those with diabetes and the metabolic syndrome (Fadini et al., 2009b). One of the most important soluble regulator of EPCs is the stromal derived factor (SDF)-1, which acts by binding to its receptor CXCR4. SDF-1 stimulates EPC mobilization from the bone marrow through induction of MMP-9, cleavage of membrane bound kit ligand and attenuation of progenitor cells/stromal cells interactions (Heissig et al., 2002). In the periphery, hypoxia-induced SDF-1 gradients guide EPC homing to ischemic tissues. Interestingly SDF-1 is a physiological substrate of DPP-4 (De La Luz Sierra et al., 2004). Therefore, DPP-4 inhibition is expected to increase SDF-1 bioavailability and activity, with the eventual stimulation of EPCs. While the potential role of DPP-4 in hematopoietic stem cell mobilization has been hypothesized years ago (Christopherson et al., 2003), the cardiovascular implications of the stimulation of vascular progenitors has emerged only in recent years. Zaruba et al. have demonstrated in mice that genetic deletion or pharmacologic inhibition of DPP-4 is able to increase the homing of CXCR4 + EPCs at sites of myocardial damage, resulting in a reduced cardiac remodeling and improved heart function and survival (Zaruba et al., 2009). This study in animals provided a rationale to use DPP-4i for vascular repair through stimulation of EPCs. In a small controlled trial in patients with type 2 diabetes, we have shown that a 4 week course of therapy with the DPP-4i sitagliptin was followed by increases in SDF-1 plasma concentrations and circulating EPC levels. These effects were unrelated to changes in nitrite/nitrate levels or to reduction in plasma glucose, suggesting that they are GLP-1independent (Fadini et al., 2010a). In two studies using different pharmacological approaches, Wang et al. found that inhibition of DPP4 may be the underlying mechanism by which certain drugs (such as enalapril and cyclosporine) modulate EPC level and function and improve recovery of ischemic tissues, possibly through an increase in SDF-1 activity (Wang et al., 2006, 2008). The role of DPP-4 in regulating the homing of EPCs to sites of cardiovascular damage is conrmed also in the presence of endoglin mutations causing type 1 hereditary haemorrhagic telangiectasia: cells of these patients display

Please cite this article as: Fadini, G.P., Avogaro, A., Cardiovascular effects of DPP-4 inhibition: Beyond GLP-1, Vascul. Pharmacol. (2011), doi:10.1016/j.vph.2011.05.001

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higher DPP-4 expression and its inhibition was able to restore the defective EPCs homing (Post et al., 2010). Recent data suggest that parathyroid hormone (PTH) inhibits DPP-4, leading to an increased concentration of plasma SDF-1 and favoring the homing of bone marrow-derived CXCR4+ EPCs to sites of experimental myocardial infarction in mice (Huber et al., 2011). Therefore, the action on SDF1 emerges as a hitherto unrecognized off-target effect of DPP-4i, with important implications for cardiovascular protection. Finally, it should be taken into account that the relationship between DPP-4 activity and angiogenesis may be mediated by modulation of the Neuropeptide Y (NPY) signaling (Li et al., 2003; Pons et al., 2004). After being processed by DPP-4, NPY136 is converted to its shorter form (NPY336), thus shifting its activity from Y1-mediated vasoconstriction and vascular smooth muscle cell growth to Y2/Y5-mediated angiogenesis (Lee et al., 2003). However, in the setting of NPY signaling modulation, the effect of DPP-4 may be even detrimental, regarding vascular smooth muscle proliferation, and intimal hyperplasia (Kitlinska et al., 2003). 7. Myocardial effects of DPP-4i High quality data in mice indicate that DPP-4i per se may be an interesting target to improve cardiovascular outcome after myocardial infarction (MI). Sauv et al. induced MI in wild type mice and in mice treated with the DPP-4i inhibitor sitagliptin or with genetic deletion of DPP-4 (dpp4/) after induction of diabetes with highfat diet and streptozotocin. Dpp4/ mice showed an increased survival after MI compared with dpp4+/+ mice and an activation of proteins associated with cardiomyocyte survival (Sauve et al., 2010). As mentioned above, a pilot study indicated that DPP-4i with sitagliptin acutely improved myocardial response to dobutamine stress and reduced features of myocardial stunning (Read et al., 2010). This study is backed by experimental data using ex vivo hearts from obese, pre-diabetic (DIO) rats: Huisamen et al. found that, after ischemia/reperfusion injury, treatment with a DPP4 inhibitor reduced the infarct size and was associated with activation of the cardiopro-

tective PI-3K/Akt pathway (Huisamen et al., 2010). In vitro, the authors found no evidence of increased glucose uptake by cardiomyocytes, an effect that is consistent with a GLP-1-independent mechanism (Nikolaidis et al., 2004a, 2005). Importantly, the benecial effects of DPP-4i on left ventricular function after MI may be mediated by the improved SDF-1 signaling. For instance, Zhang et al. implanted mesenchymal stem cell sheets with the DPP-4i diprotin over the surface of infarcted left ventricles and found an improvement in post-ischemic angiogenesis and myocardial performance, with concomitant SDF-1 upregulation (Zhang et al., 2010). These data are in line with the possible favorable effects of DPP-4i on ischemia/ reperfusion injury in the setting of organ transplantation (Zhai et al., 2006). A recent review article (Zaruba and Franz, 2010), summarizes the rationale of preserving functional SDF-1 by DPP-4i after ischemia through enhancement of endogenous stem cell recruitment and exogenous stem cell therapies. Finally, in the setting of diabetic cardiomyopathy and heart failure, it will be of interest to understand whether the supposed actions of DPP-4 on B-type natriuretic peptides (Vanderheyden et al., 2009) have clinically relevant effects. Therefore, studies exploring whether DPP-4i increase the bioavailability of intact BNP(132) and delay the progression of heart failure are welcome. 8. Other off-target effects of DPP-4i and cautionary notes DPP-4i are designed as glucose-lowering agents for the treatment of type 2 diabetes thanks to their effects on the incretin system. Therefore, any other biological consequence of DPP-4 inhibition should be considered off-target. Several of these so far identied offtarget effects still lack a molecular mechanistic explanation. For instance, it is not clear how DPP-4 inhibition may affect intracellular signaling pathways; a possible signaling activity of CD26/DPP-4 per se should be distinguished from a possible paracrine/autocrine humoral signaling. Among the many possible pathways modiable through DPP-4 inhibition, it is worth mentioning the interaction with angiotensin-

Metformin

DPP-4 inhibitors
DPP-4 activity

Glucose control

Transcriptional regulation

Other substances (e.g. PTH)

GLP-1
Pancreas eNOS

Akt

SDF-1
Inflammation
MCP-1, IL-6, TNF-

Neuropeptides

NPY
Bone marrow

SP

Endothelium
Stomach

ACEi EPC

Metabolic effects

Smooth muscle

Vascular protection

Blood pressure

Angioedema
BNPs

Glucose uptake Inotropism

Myocardial protection

Inotropism

Fig. 1. Potential mechanisms whereby DPP-4 inhibitors can achieve cardiovascular protection. Arrows indicate stimulatory connections, while indicates inhibitory signals. Dashed lines indicate pathways without a dened molecular link to DPP-4 activity.

Please cite this article as: Fadini, G.P., Avogaro, A., Cardiovascular effects of DPP-4 inhibition: Beyond GLP-1, Vascul. Pharmacol. (2011), doi:10.1016/j.vph.2011.05.001

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G.P. Fadini, A. Avogaro / Vascular Pharmacology xxx (2011) xxxxxx Busek, P., Stremenov, J., Krepela, E., Sedo, A., 2008. Modulation of substance P signaling by dipeptidyl peptidase-IV enzymatic activity in human glioma cell lines. Physiol. Res. 57, 443449. Byrd, J.B., Shreevatsa, A., Putlur, P., Foretia, D., McAlexander, L., Sinha, T., Does, M.D., Brown, N.J., 2007. Dipeptidyl peptidase IV deciency increases susceptibility to angiotensin-converting enzyme inhibitor-induced peritracheal edema. J. Allergy Clin. Immunol. 120, 403408. Ceriello, A., Esposito, K., Testa, R., Bongli, A.R., Marra, M., Giugliano, D., 2011. The possible protective role of Glucagon-LikePeptide1onEndothelium during the meal and evidence for an endothelial resistance to Glucagon-Like Peptide 1 in diabetes. Diabetes Care 34, 697702. Cho, Y.M., Kieffer, T.J., 2011. New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser. Diabetologia 54, 219222. 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converting enzyme (ACE) inhibitors in their anti-hypertensive effect and in the development of angioedema. The interaction between neuropeptides and DPP-4i suggest that this class of drugs may increase blood pressure (Jackson et al., 2008). However, clinical experience indicates that blood pressure tend to fall during DPP-4i therapy, an effect that may be mediated by eNOS stimulation, or by improved glycemic control (Ogawa et al., 2010). Marney et al. found that, while sitagliptin may lower blood pressure per se, when used concomitantly with enalapril, the anti-hypertensive effect of ACE inhibition is reduced, likely due to an overactivation of the sympathetic nervous system (Marney et al., 2010). A plausible explanation of this effect is the increased concentration of substance P (SP), which is a DPP-4 substrate and stimulates the sympathetic tone (Busek et al., 2008), and of NPY. Indeed, experimental data indicate that DPP-4i may enhance the renovascular angiotensin-II effects, at least in the spontaneous hypertensive rat model (Tofovic et al., 2010). Finally, the interaction between DPP-4i and ACEi has been also shown to be responsible of an increased risk of ACEi-related angioedema (Brown et al., 2009), through the decreased catabolism of members of the kinin system (Byrd et al., 2007). Taken together, these data suggest that non-incretin targets of DPP-4 may have benecial or detrimental important effects beyond glycemic control and vascular protection. Given the high risk of renal disease and the frequent use of ACEi in diabetic patients, the relevance of these potential effects of DPP-4i will need to be tested in the clinical setting. 9. Conclusions We have summarized the current evidence indicating the possible cardiovascular benets of DPP-4i. While DPP-4i have been developed as drugs for type 2 diabetes based on their ability to increase GLP-1 bioavailability, many other effects of DPP-4 are known since decades, and may have potentially important clinical implications. While waiting for the results of randomized trials for cardiovascular event prevention with DPP-4i, very preliminary clinical data suggest cardiovascular safety by the DPP-4i (Monami et al., 2010) and possible protection of the DPP-4i saxagliptin (Wolf et al., 2009). Available data suggest that DPP-4i holds promise for vascular protection beyond GLP-1 (Fig. 1), through endothelial repair, antiinammatory effects and blunting of ischemic injury. On the other side, off-target effects on neuropeptides and renal hemodynamic modulation must be carefully balanced in the setting of cardiovascular safety. References
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