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

doi:10.1016/j.vph.2011.05.001

Vascular Pharmacology

Volume 55, Issues 1–3, July–September 2011, Pages 10-16

https://doi.org/10.1016/j.vph.2011.05.001 Get rights and content

Abstract

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 β-cells thus reducing hyperglycemia. It has been shown that GLP-1 signaling is also active in the cardiovascular system, where it may exert beneficial effects. However, DPP-4 has several non-incretin substrates, and its immunomodulatory activity is known from decades. DPP-4 physiologically cleaves cytokines, chemokines and neuropeptides involved in inflammation, 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, inflammatory pathway and ischemic response emerges as the major cardiovascular target of DPP-4 inhibitors.

Graphical abstract

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 (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 anti-hyperglycemic effect mainly by improving meal-stimulated insulin secretion by pancreatic β-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 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 chemically-derived 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 profile, 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 significantly 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 efficacy 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-1-independent mechanisms.

Section snippets

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

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

Effects of DPP-4i on inflammation

Chronic low grade inflammation plays a pivotal role in all manifestations of cardiovascular disease. As reviewed by Hansson(2009), inflammatory processes and immunoregulatory mechanisms contribute to the risk for myocardial infarction and stroke by modulating atherosclerotic plaque growth and complications. Inflammation is also a key feature in the setting of heart failure, through excess TNF-α levels as well as bacterial infection during exacerbations (Murray and Freeman, 2003, Niebauer et

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

Effects of DPP-4i on vascular progenitor cells via SDF-1α

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 so-called 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

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). Sauvè 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 high-fat diet and streptozotocin. Dpp4−/− mice showed an increased survival after MI compared with dpp4+/+ mice and an activation of proteins associated with cardiomyocyte

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 identified off-target 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

Conclusions

We have summarized the current evidence indicating the possible cardiovascular benefits 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

References (75)

J.B. Byrd et al.
Dipeptidyl peptidase IV deficiency increases susceptibility to angiotensin-converting enzyme inhibitor-induced peritracheal edema
J. Allergy Clin. Immunol.
(2007)
K.W. Christopherson et al.
Cell surface peptidase CD26/DPPIV mediates G-CSF mobilization of mouse progenitor cells
Blood
(2003)
M. De La Luz Sierra et al.
Differential processing of stromal-derived factor-1alpha and stromal-derived factor-1beta explains functional diversity
Blood
(2004)
D.J. Drucker
The biology of incretin hormones
Cell Metab.
(2006)
D.J. Drucker et al.
The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes
Lancet
(2006)
O. Erdogdu et al.
Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptor
Mol. Cell. Endocrinol.
(2010)
G.P. Fadini et al.
Endothelial progenitor cells in the natural history of atherosclerosis
Atherosclerosis
(2007)
G.P. Fadini et al.
Endothelial progenitor cells as resident accessory cells for post-ischemic angiogenesis
Atherosclerosis
(2009)
G.P. Fadini et al.
Low CD34+ cell count and metabolic syndrome synergistically increase the risk of adverse outcomes
Atherosclerosis
(2009)
H. Goto et al.
Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury
Biochem. Biophys. Res. Commun.
(2011)

J.R.J. Gum et al.

Analysis of dipeptidyl peptidase IV gene regulation in transgenic mice: DNA elements sufficient for promoter activity in the kidney, but not the intestine, reside on the proximal portion of the gene 5′-flanking region

FEBS Lett.

(2000)

G.K. Hansson

Atherosclerosis—an immune disease: the Anitschkov Lecture 2007

Atherosclerosis

(2009)

B. Heissig et al.

Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand

Cell

(2002)

J.M. Lenhard et al.

Reduced serum dipeptidyl peptidase-IV after metformin and pioglitazone treatments

Biochem. Biophys. Res. Commun.

(2004)

M. Monami et al.

Dipeptydil peptidase-4 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials

Nutr. Metab. Cardiovasc. Dis.

(2010)

J. Niebauer et al.

Endotoxin and immune activation in chronic heart failure: a prospective cohort study

Lancet

(1999)

G.G. Sokos 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)

N.N. Ta et al.

DPP-4 (CD26) inhibitor alogliptin inhibits TLR4-mediated ERK activation and ERK-dependent MMP-1 expression by U937 histiocytes

Atherosclerosis

(2010)

W. Takasawa et al.

Inhibition of dipeptidyl peptidase 4 regulates microvascular endothelial growth induced by inflammatory cytokines

Biochem. Biophys. Res. Commun.

(2010)

C.H. Wang et al.

Enalapril increases ischemia-induced endothelial progenitor cell mobilization through manipulation of the CD26 system

J. Mol. Cell. Cardiol.

(2006)

M.M. Zaruba et al.

Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction

Cell Stem Cell

(2009)

W. Zhai et al.

Ischemia/reperfusion injury: The role of CD26/dipeptidyl-peptidase-IV-inhibition in lung transplantation

Transplant. Proc.

(2006)

P. Anagnostis et al.

Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control

Diabetes Obes. Metab.

(2011)

K. Augustyns et al.

The unique properties of dipeptidyl-peptidase IV (DPP IV / CD26) and the therapeutic potential of DPP IV inhibitors

Curr. Med. Chem.

(1999)

K. Ban et al.

Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways

Circulation

(2008)

K. Ban et al.

Glucagon-like peptide (GLP)-1(9–36)amide-mediated cytoprotection is blocked by exendin(9–39) yet does not require the known GLP-1 receptor

Endocrinology

(2010)

B. Bauvois et al.

Regulation of CD26/DPPIV gene expression by interferons and retinoic acid in tumor B cells

Oncogene

(2000)

J.H. Best et al.

Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the LifeLink database

Diabetes Care

(2011)

N.J. Brown et al.

Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema

Hypertension

(2009)

P. Busek et al.

Modulation of substance P signaling by dipeptidyl peptidase-IV enzymatic activity in human glioma cell lines

Physiol. Res.

(2008)

A. Ceriello et al.

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

(2011)

Y.M. Cho et al.

New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser

Diabetologia

(2011)

D.T. Dang et al.

Hypoxia-inducible factor-1 target genes as indicators of tumor vessel response to vascular endothelial growth factor inhibition

Cancer Res.

(2008)

A.D. Dobrian et al.

Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice

Am. J. Physiol. Endocrinol. Metab.

(2011)

D.J. Drucker

Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes. Preclinical biology and mechanisms of action

Diabetes Care

(2007)

G.P. Fadini et al.

Potential manipulation of endothelial progenitor cells in diabetes and its complications

Diabetes Obes. Metab.

(2010)

G.P. Fadini et al.

The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes mellitus. Possible role of stromal derived factor-1{alpha}

Diabetes Care

(2010)

Cited by (193)

The entero-insular axis and metabolic syndrome
2023, Metabolic Syndrome: From Mechanisms to Interventions
This chapter introduces the concept of entero-insular axis defined by gut-derived factors that control endocrine pancreas incorporating both historical as well as modern perspectives. It is focused mostly on the clinically relevant mediators namely incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1), and their negative regulator dipeptidyl peptidase-4 (DPP4). Detailed discussions on the impact of these mediators on various pathophysiological facets of metabolic syndrome are elaborated. A note on the future prospects in research and clinical practice has been incorporated at the end.
Sitagliptin, a dipeptidyl peptidase-4 inhibitor, attenuates apoptosis of vascular smooth muscle cells and reduces atherosclerosis in diabetic apolipoprotein E–deficient mice
2021, Vascular Pharmacology
Sitagliptin, a dipeptidyl peptidase-4(DPP-4) Inhibitor, has been found to have an anti-atherosclerotic effect. Since apoptosis of vascular smooth muscle cells (VSMCs) contributes to the occurrence of diabetic atherosclerosis. This study aimed to examine whether sitagliptin suppresses the atherosclerosis progression to hyperglycemia in a low-dose streptozotocin (STZ)-induced diabetic mouse model, and then investigated the effect of sitagliptin on VSMCs apoptosis and its underlying mechanism.
In vivo studies, eight-week-old low-dose STZ-induced diabetic apolipoprotein E (apoE)–deficient (apoE−/−) mice fed a high-fat diet were administered a DPP-4 inhibitor, sitagliptin, 200 mg/kg/day, or Lantus insulin by daily subcutaneous injection of 1 unit/mouse over a period of 12 weeks. Aortic atherosclerosis and apoptosis in the plaque were determined using dUTP-biotin nick end labeling (TUNEL) staining and immunohistochemistry. In vitro studies utilized the VSMCs for determination of glucagon-like peptide 1 receptor (GLP-1R) and DPP-4 expression and flow cytometry and Western blotting were used to determine apoptosis and protein expression, respectively. Sitagliptin significantly reduced atherosclerotic lesion area (7.00 ± 0.13 vs. 12.80 ± 2.7%, p = 0.003) and suppressed vascular smooth muscle cell apoptosis (2.30 ± 1.34 vs. 4.8 ± 1.93%, p = 0.003) compared with vehicle treatment. In addition, sitagliptin significantly increased the expression of β-catenin in the aortic tissue(0.56 ± 0.13 vs.0.17 ± 0.02, p = 0.008)compared with vehicle treatment. In cultured mouse VSMCs, sitagliptin enhanced GLP-1 activity significantly retarded oxidative stress (H₂O₂)–induced apoptosis compared with GLP-1 or sitagliptin alone. Sitagliptin increased GLP-1-induced cytosolic levels of β-catenin compared with GLP-1 alone, resulted in increasing the expression of survivin, and suppressed proinflammatory cytokines, i.e., interleukin-6(IL-6) and tumor necrosis factor-alpha(TNF-α), production in response to H₂O₂. In conclusion, these results indicated that the anti-atherosclerotic effect of sitagliptin is mediated, at least in part, by its inhibition of VSMCs apoptosis.
Antidiabetic drugs and oxidized low-density lipoprotein: A review of anti-atherosclerotic mechanisms
2021, Pharmacological Research
Cardiovascular disease is one of the leading causes of mortality globally. Atherosclerosis is an important step towards different types of cardiovascular disease. The role of oxidized low-density lipoprotein (oxLDL) in the initiation and progression of atherosclerosis has been thoroughly investigated in recent years. Moreover, clinical trials have established that diabetic patients are at a greater risk of developing atherosclerotic plaques. Hence, we aimed to review the clinical and experimental impacts of various classes of antidiabetic drugs on the circulating levels of oxLDL. Metformin, pioglitazone, and dipeptidyl peptidase-4 inhibitors were clinically associated with a suppressive effect on oxLDL in patients with impaired glucose tolerance. However, there is an insufficient number of studies that have clinically evaluated the relationship between oxLDL and newer agents such as agonists of glucagon-like peptide 1 receptor or inhibitors of sodium-glucose transport protein 2. Next, we attempted to explore the multitude of mechanisms that antidiabetic agents exert to counter the undesirable effects of oxLDL in macrophages, endothelial cells, and vascular smooth muscle cells. In general, antidiabetic drugs decrease the uptake of oxLDL by vascular cells and reduce subsequent inflammatory signaling, which prevents macrophage adhesion and infiltration. Moreover, these agents suppress the oxLDL-induced transformation of macrophages into foam cells by either inhibiting oxLDL entrance, or by facilitating its efflux. Thus, the anti-inflammatory, anti-oxidant, and anti-apoptotic properties of antidiabetic agents abrogate changes induced by oxLDL, which can be extremely beneficial in controlling atherosclerosis in diabetic patients.
Diabetes and kidney disease: emphasis on treatment with SGLT-2 inhibitors and GLP-1 receptor agonists
2021, Metabolism: Clinical and Experimental
Kidney disease is a frequent microvascular complication of both type 1 and type 2 diabetes. Historic trials have demonstrated that a tight glycaemic control is the most powerful approach to decrease the chances of developing diabetic nephropathy. However, having an HbA1c < 7% does not completely suppress the risk of kidney disease. The observed residual risk is likely ascribable to two phenomena: 1- the presence of risk factors and alterations additive to and independent of glycaemia, and 2- the activation of long-lasting imbalances by periods of exposure to uncontrolled glycemia, a phenomenon referred to as metabolic memory or legacy effect. Long-lasting oxidative stress, epigenetic alterations, cellular senescence, and the resulting chronic low-grade inflammation are all candidate mechanisms explaining the development of nephropathy despite proper control of risk factors. Recently, two classes of drugs, i.e. glucagon-like peptide (GLP) 1 receptor agonists (RA) and sodium-glucose transporter 2 inhibitors (SGLT-i) have changed this scenario. Indeed, cardiovascular outcome and other trials have clearly shown a renoprotective effect for these drugs, well-beyond their glucose-lowering properties. In this review, we summarize: 1- selected key trials and mechanisms underlying the development of diabetic kidney disease and 2- the results relative to renal endpoints in clinical trials of GLP-1 RA and SGLT-2i. Then, we briefly discuss some of the hypotheses posited to explain the marked renoprotective properties of these two classes, evidencing the still existing gaps in knowledge and proposing future directions to further implement the use of these powerful, disease-modifying drugs.
Beneficial and deleterious effects of sitagliptin on a methionine/choline-deficient diet-induced steatohepatitis in rats
2021, Biochimie
Non-alcoholic fat liver disease (NAFLD) is the most common chronic liver disease in the world. NAFLD is a spectrum of diseases ranging from simple steatosis to hepatic carcinoma. The complexity of pathomechanisms makes treatment difficult. The oral antidiabetic agents, dipeptidyl peptidase four inhibitors (DPP-4i) have been proposed as possible therapeutic agents. This study was performed using a well-established NAFLD model in rats to elucidate whether sitagliptin could prevent steatohepatitis. Rats were fed a methionine/choline-deficient (MCD) diet with or without sitagliptin treatment for six weeks. Liver tissue was examined to estimate sitagliptin’s effect on the development of NASH. The MCD diet decreased the SAM/SAH ratio, and increased plasma levels of homocysteine, free fatty acids, and long-chain acylcarnitines in the MCD rats. MMP2 and Col1A2 expression also increased under the MCD diet. Sitagliptin treatment did not reverse these effects and increased steatosis and long-chain acylcarnitines. In conclusion, sitagliptin was ineffective to prevent from NAFLD in the MCD rat model. This result challenges previous data reporting beneficial effects and is consistent with the clinical trials’ negative results.
Diabetes pharmacotherapy and circulating stem/progenitor cells. State of the art and evidence gaps
2020, Current Opinion in Pharmacology
Diabetes is burdened with the development of several end-organ complications leading to excess mortality. Though the causes of such organ damage are far from being clarified, diabetes has been redefined as a disease of impaired damage control, wherein ongoing damage is not adequately compensated by activation of repair processes. Bone marrow-derived hematopoietic stem/progenitor cells (HSPCs) and their descendants endothelial progenitor cells (EPCs) have been extensively studied as major players in tissue homeostasis as well as biomarkers of diabetic complication risk. Thus, strategies to raise the levels of circulating HSPCs/EPCs have attracted interest for their potential to modify the future risk of complications. We herein discuss state-of-the-art of the effects exerted by diabetes pharmacotherapy on such cell populations. Further, we highlight which outstanding questions remain to be addressed for a more comprehensive understanding of this topic.

View all citing articles on Scopus

^☆: 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).

View full text

ReviewCardiovascular effects of DPP-4 inhibition: Beyond GLP-1☆

Abstract

Graphical abstract

Introduction

Section snippets

Biology of dipeptidyl peptidase-4

Possible cardiovascular effects of DPP-4i via GLP-1 modulation

Effects of DPP-4i on inflammation

Effects of DPP-4i on endothelial cells, nitric oxide and blood pressure

Effects of DPP-4i on vascular progenitor cells via SDF-1α

Myocardial effects of DPP-4i

Other off-target effects of DPP-4i and cautionary notes

Conclusions

J. Allergy Clin. Immunol.

Blood

Blood

Cell Metab.

Lancet

Mol. Cell. Endocrinol.

Atherosclerosis

Atherosclerosis

Atherosclerosis

Biochem. Biophys. Res. Commun.

FEBS Lett.

Atherosclerosis

Cell

Biochem. Biophys. Res. Commun.

Nutr. Metab. Cardiovasc. Dis.

Lancet

J. Card. Fail.

Atherosclerosis

Biochem. Biophys. Res. Commun.

J. Mol. Cell. Cardiol.

Cell Stem Cell

Transplant. Proc.

Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control

Diabetes Obes. Metab.

The unique properties of dipeptidyl-peptidase IV (DPP IV / CD26) and the therapeutic potential of DPP IV inhibitors

Curr. Med. Chem.

Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways

Circulation

Glucagon-like peptide (GLP)-1(9–36)amide-mediated cytoprotection is blocked by exendin(9–39) yet does not require the known GLP-1 receptor

Endocrinology

Regulation of CD26/DPPIV gene expression by interferons and retinoic acid in tumor B cells

Oncogene

Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the LifeLink database

Diabetes Care

Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema

Hypertension

Modulation of substance P signaling by dipeptidyl peptidase-IV enzymatic activity in human glioma cell lines

Physiol. Res.

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

New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser

Diabetologia

Hypoxia-inducible factor-1 target genes as indicators of tumor vessel response to vascular endothelial growth factor inhibition

Cancer Res.

Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice

Am. J. Physiol. Endocrinol. Metab.

Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes. Preclinical biology and mechanisms of action

Diabetes Care

Potential manipulation of endothelial progenitor cells in diabetes and its complications

Diabetes Obes. Metab.

The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes mellitus. Possible role of stromal derived factor-1{alpha}

Diabetes Care

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