Skip to main content
Download PDF
Download ePub

The regulatory role of DPP4 in atherosclerotic disease

Cardiovascular Diabetology volume 16, Article number: 76 (2017) Cite this article

Abstract

The increasing prevalence of atherosclerosis has become a worldwide health concern. Although significant progress has been made in the understanding of atherosclerosis pathogenesis, the underlying mechanisms are not fully understood. Recent studies suggest dipeptidyl peptidase-4 (DPP4), a regulator of inflammation and metabolism, may be involved in the development of atherosclerotic diseases. There has been increasing clinical and pre-clinical evidence showing DPP4-incretin axis is involved in cardiovascular disease. Although the cardiovascular outcome of DPP4 inhibition or incretin analogues has been or being evaluated by several large scale clinical trials, the exact role of DPP4 in atherosclerotic diseases is not completely understood. In the current review, we will summarize the recent advances in direct and indirect regulatory role of DPP4 in atherosclerosis.

Background

Atherosclerosis, the primary cause of cardiovascular disease, is a chronic progressive condition with lipids and fibrous elements accumulated in the vessel wall of large arteries [1,2,3]. It accounts for 50% of all deaths in the Western countries [4]. The increasing prevalence of atherosclerosis has become a worldwide health concern [5]. Despite of rapid progress in atherosclerosis research in the recent years, the underlying mechanisms remain elusive. Dipeptidyl peptidase-4 (DPP4) inhibitors are a novel class of glucose-lowering drugs [6]. Various studies suggest DPP4 inhibitors may also possess cardioprotective effect [7,8,9,10,11,12], including atherosclerosis [13,14,15]. In the current review, we will summarize the recent advances in direct and indirect regulatory role of DPP4 in cardiovascular disease, especially in atherosclerosis.

Experimental evidence of the beneficial effects of DDP4 inhibition on cardiovascular disease

Dipeptidyl peptidase-4 is a membrane-bound enzyme that cleaves N-terminal dipeptide from its substrates. It belongs to the S9b dipeptidyl peptidases family [16]. There are over a dozen proteins identified as the substrates of DPP4. These include glucagon-like peptide (GLP) -1 and -2, glucose-dependent insulinotropic peptide (GIP) [17], stromal-cell-derived factor-1 (SDF-1) [18], GM-CSF [19], regulated on activation normal T-cell expressed and presumably secreted (RANTES) [20], eotaxin [21], neuropeptide Y (NPY) [22], etc. The molecular basis of catalytic activity of DPP4 has been reviewed elsewhere and we will only discuss the recent advances in DPP4 biology [23,24,25].

DPP4 inhibitors are being increasingly used in clinical for the treatment of type 2 diabetes as they are safe and weight neutral [26,27,28,29,30,31,32]. They preserve incretin hormones such as GLP-1 and GIP by inhibiting DPP4-mediated degradation, and thus could promote postprandial insulin secretion and reduce pancreatic β cell apoptosis [33,34,35,36]. Furthermore, antiapoptotic effects of DPP-4 inhibitor were observed in human umbilical vein endothelial cells (HUVECs) cultured under hypoxic condition. Besides, the CXCR4 antagonist or Stat3 inhibitor can abolish this effect. These results suggested that DPP-4 inhibitor has a potential for protecting vessels where CXCR4/Stat3 pathways might be involved [37]. In animal experiments, Salim HM et al. demonstrated that linagliptin ameliorated atherogenesis in non-diabetic ApoE −/− mice by inhibiting the oxidative stress [38], and it also showed that linagliptin prevents the development of aortic and endothelial stiffness in female mice resulting from western diet-induced vascular abnormalities [39]. We have previously also shown long-term enzymatic inhibition of DPP4 by sitagliptin or alogliptin reduced atherosclerotic plaque burden in Ldlr −/− and ApoE −/− mice, accompanied by reduced monocyte activation and migration [40]. In consistency with that, a recent study demonstrated 12-week anagliptin treatment suppressed atherosclerosis progression and macrophage infiltration in the plaque in cholesterol-fed rabbits [41], and 20-week teneligliptin administration inhibited the development of atherosclerosis in the aortic arch in ApoE −/− mice through restraining macrophage infiltration, downregulating lipid deposition and MCP-1 expression, and in vitro experiment GLP-1 analogue treatment suppressed the pro-inflammatory cytokines production [42]. Not only by reducing monocyte activation and migration, DPP4 inhibitor sitagliptin can attenuate atherosclerosis by promoting M2 macrophages polarization [43]. Acute in vitro DPP4 inhibition also relaxed pre-constricted aorta segments by activating Src-Akt-eNOS pathway in a GLP-1-independent manner [44]. In addition, combination therapy with DPP4 inhibitor and sodium-glucoase cotransporter 2 inhibitor showed the greatest suppression of plaque volume in the aortic root of diabetic ApoE −/− mice [45].

Interestingly, DPP4 inhibitor but not GLP-1 or GIP reduced incidence of angiotensin II-induced abdominal aortic aneurysm in ApoE −/− mice (40% in DPP4 inhibition group vs. 70% in control group) [46]. Using an experimental myocardial infarction model, Sauvé et al. examined the effects of DPP4 enzymatic inhibition or genetic deletion of DPP4 on cardiovascular function in normoglycemic and diabetic mice [47]. Dpp4 −/− mice displayed normal cardiac structure and function, with increased levels of phosphorylated AKT (pAKT), pGSK3β, and atrial natriuretic peptide (ANP) in the heart. After left anterior descending (LAD) coronary artery ligation, Dpp4 −/− mice showed a modestly improved survival and functional recovery from ischemia–reperfusion injury as measured by left ventricle developed pressure. Treatment of DPP4 enzymatic inhibitor sitagliptin also reduced mortality and enhanced functional recovery from ischemia–reperfusion injury in wild-type diabetic mice after myocardial infarction [47]. Consistently, treatment with DPP-4 inhibitor vildagliptin markedly improved the survival rate after myocardial infarction in type 2 diabetic rats, and the protective effect was linked with restoration of autophagic response resulting from increased both LC3-II protein level and autophagosomes after vildagliptin treatment [48]. Furthermore, Ma et al. also DPP4 inhibition exerted a potential strategy for treating cerebral vascular complications in T2DM through reducing oxidative stress and suppressing blood–brain barrier disruption [49]. Although a number of animal studies suggest DPP4 inhibition may have cardiovascular beneficial effects in addition to its glycemic lowering effect [8, 50, 51], while there was no study uncover the precise cells and tissues which is critical for incretin degradation. Recently, a study clearly showed that levels of soluble plasma DPP4 activity, incretin degradation, and glucose regulation rely heavily on endothelial cell-derived DPP4. Surprisingly, fasting GIP, but not GLP-1, was mainly degraded by bone marrow-derived DPP4 [52], and a study also demonstrated that active GIP levels were increased more than GLP-1 after DPP-4 inhibitor treatment [53]. Shigeta and colleagues also reported DPP4 expressed on the cardiac capillary endothelia is up-regulated by diabetes, resulting in a reduction in myocardial SDF-1 and increased interstitial fibrosis. Both genetic and pharmacological inhibition of DPP4 restored diabetes-induced SDF-1 and reversed pressure overload-induced diastolic left ventricular dysfunction by GLP-1-dependent mechanisms [54].

Clinical trials on the cardiovascular effects of DPP4 inhibition

In contrast to the consistent beneficial cardiovascular effects of DPP4 inhibition on experimental animal models, the cardiovascular effects of DPP4 in human studies on seem more complicated and inconsistent (Table 1) [55,56,57,58,59,60,61,62,63].

Table 1 Dipeptidyl peptidase 4 inhibitors and atherosclerosis outcome trials
Full size table

Three months of vildagliptin (50 mg twice daily) or sitagliptin (100 mg once daily) also significantly reduced carotid intima-media thickness (IMT), a surrogate marker of atherosclerosis, in patients with type 2 diabetes [64]. Further analysis indicated this maybe relates to the reduction in daily acute glucose fluctuation and plasma LDL level [64]. A randomized controlled trial, the sitagliptin preventive study of IMT evaluation (SPIKE), demonstrated that sitagliptin 104-week treatment had a greater changes in the mean and left maximum IMT of the common carotid arteries, which measured by echography [65]. Besides, a study of preventive effects of alogliptin on diabetic atherosclerosis (SPEAD-A), which includes T2DM patients with alogliptin treatment (n = 172) or conventional treatment (n = 169), showed that 20 months of alogliptin treatment significantly changed the mean common and the right and left maximum IMT of the carotid arteries (P = 0.022, P = 0.025, P = 0.013, respectively) [66]. Similarly, in insulin-treated patients with type 2 diabetes mellitus (T2DM), a recently randomized trial was analyzed in according with SPIKE study, and the results showed that sitagliptin treatment could regress carotid IMT. The percentage of patients who showed a decrease of ≥0.10 mm in mean-IMT-CCA in the sitagliptin group was 28.9%, while the conventional group the percentage was 16.4% (P  =  0.022) [67]. Furthermore, aortic pulse wave velocity, a marker of early atherosclerosis [68], were significantly decreased in T2DM patients with 26 weeks of linagliptin administration in a small study with a limited number of participants (RELEASE) when compared with placebo (P  =  0.035) [69]. Kutoh et al. [70] recently reported that 12.5–25 mg/day alogliptin monotherapy for 3 months significantly improved insulin resistance and beta cell function and reduced atherogic lipids in type 2 diabetic patients with a better glycemic response to alogliptin. In another study, however, DPP4 inhibitor sitagliptin as an add-on in type 2 diabetic patients for 6 months did not improve atherogenic lipids including total cholesterol, LDL cholesterol, and malondialdehyde-modified LDL (an oxidized LDL increased in diabetes) [71]. In addition to previous study, a multicenter Randomized Controlled Trial (prospective, randomized, open label, blinded endpoint, PROLOGUE design) also revealed that sitagliptin treatment had no effect on the progression of carotid IMT in T2DM patients [72]. A further sub-analysis of the PROLOGUE study also showed that no significant effect of sitagliptin on the arterial stiffness and endothelial function in T2DM patients which are thought to contribute to the occurrence of atherosclerosis [73, 74]. However, PROLOGUE randomized controlled trial used carotid IMT as a marker of atherosclerosis, which can not entirely represent the status of atherosclerosis. Regarding the different conclusion reported by different clinical trials, Nozue et al. [75] design a prospective, non-randomized, multicenter trial performed in Japan, where T2DM patients who have intermediate coronary artery stenosis will be recruited. The diameter stenosis will be evaluated by coronary computed tomography angiography (CCTA) at the starting point and ending point (48 weeks alogliptin treatment). This clinical trial will provide a strong evidence for the effect of alogliptin in the anti-atherosclerosis.

It is reported that treatment with vildagliptin for 4 weeks in patients with type 2 diabetes improved forearm blood vasodilator responses to intra-arterially administered acetylcholine, but not to sodium nitroprusside [76]. Nakamura et al. [77] also reported that sitagliptin treatment for 12 weeks significantly improved flow-mediated dilatation in diabetic patients uncontrolled on sulfonylurea, metformin or pioglitazone treatment. In contrast, another study demonstrated that the flow-mediated dilation was suppressed by both sitagliptin and alogliptin [78].

Several large scale clinical trials were carried out to evaluate the cardiovascular effects of DPP4 inhibitors and GLP-1R agonists [79,80,81,82,83]. The cardiovascular safety of DPP4 inhibitors, especially in heart failure, has been questioned since 2013 when the first 2 large clinical trials assessing the cardiovascular safety of DPP4 inhibitors (EXAMINE and SAVOR-TIMI 53) were completed [84, 85]. Both of these trials demonstrated that DPP4 inhibitors do not increase overall cardiovascular risks. However, there was also no beneficial effect on primary cardiovascular outcomes in both trials. Interestingly, the SAVOR-TIMI 53 trial reported a 27% increase in hospitalization for heart failure in saxagliptin group, although no increased heart failure-related death was observed (3.5% vs. 2.8%; hazard ratio, 95% CI 1.27, 1.07–1.51; P = 0.007) [85]. In the EXAMINE trial, there were no heart failure-related outcomes reported in their first report although there were 28% of subjects having congestive heart failure at baseline [84]. After re-analysis, the heart failure hospitalization data of the EXAMINE trial was published in 2015, reporting a negative effect of alogliptin on the occurrences of heart failure hospitalization (3.1% in alogliptin vs. 2.9% in placebo group; HR 1.07, 0.79–1.46; P = 0.68) [86]. The 3rd large scale trial assessing the cardiovascular effect of DPP4 inhibitor, TECOS, finished in 2015. In consistency with the first two trials, sitagliptin neither increases nor reduces cardiovascular events (primary outcome incidence, 11.4% vs. 11.6%; HR 0.98, 95% CI 0.88–1.09) [87]. More importantly, the hospitalization rate for heart failure was identical in sitagliptin and placebo (3.1% vs. 3.1%; HR 1.00, 0.83–1.20; P = 0.98). Furthermore, a pre-specified patient-level pooled analysis of all available double-blind, randomized, controlled trials, ≥ 12 weeks’ duration (19 trials, 9459 subjects) also demonstrated that linagliptin was not associated with increased cardiovascular risk in T2DM patients [88]. Based on the three trials currently available, it seems the excessive heart failure effect may not be a class effect of DPP4 inhibitors. This will be further tested by the ongoing trials on linagliptin (CAROLINA and CARMELINA), both of which are expected to be completed in 2018.

There were two large trials examining the cardiovascular safety of GLP-1R agonists recently completed, one on lixisenatide (ELIXA) and one on liraglutide (LEADER). The ELIXA trial indicates lixisenatide is neither inferior nor superior to placebo in terms of cardiovascular safety. In addition, there were similar hospitalization rates for heart failure compared with placebo (HR 0.96; 95% CI 0.75–1.23) [89]. Surprisingly, the LEADER trial indicates a beneficial effect of liraglutide on cardiovascular outcomes. Liraglutide significantly reduced the risk of major adverse cardiovascular events [90]. These data suggest the heart failure effect of saxagliptin is independent of preservation of incretins.

Mechanisms by which DDP4 participates in cardiovascular disease

Chronic inflammation is key process in the pathogenesis of atherosclerosis. DPP4 inhibition may reduce monocyte migration to atherosclerotic plaque in response to TNFα and soluble DPP4 [40], it also up-regulates the adiponectin expression which exerts anti-inflammation [91]. Recent study also showed that T2DM patients with GLP-1 analogues or DPP4 inhibitors treatment had a significant smaller portion of plaque area occupied by macrophages and T-cells compared with the patients who never used GLP-1 analogues or DPP4 inhibitors, and the difference was closely associated with adiponectin and adaptor protein PH domain and leucine zipper containing 1 (APPL1) which can be induced by GLP-1 in ex vivo cell culture system [92]. Inhibition of DPP4 also results in elevation of SDF-1, a chemoattractant for many types of hematopoietic stem cells and progenitor cells such as cardiac stem cells, endothelial progenitor cells, and mesenchymal stem cells [18, 93,94,95,96]. Enhancement of SDF-1-mediated hematopoietic stem cell and progenitor cell chemotaxisand repopulation may then promote neovascularization and recovery of tissue injury [18]. Nevertheless, the enhancement of angiogenesis through SDF-1-mediated epithelial progenitor cell migration and repopulation may contribute to plaque instability [97].

Many groups have shown that DPP4 inhibition is able to lower lipid levels [98,99,100,101,102,103]. DPP4 inhibitors treatment following a high-fat liquid formula significantly reduced triglyceride-rich lipoproteins apoB48 in healthy individuals [103,104,105]. Three-month alogliptin monotherapy has been shown to reduce atherogic lipids in type 2 diabetic patients who had a better glycemic response to alogliptin [70]. In consistency, diabetic patients treated with vildagliptin (50 mg bid for 4 weeks) [106] or sitagliptin (100 mg/day for >6 weeks) [107] or alogliptin (25 mg/day for 7 days) [108] also displayed decreased postprandial plasma triglyceride, chylomicron apoB48 after mixed meal challenge.

In a follow-up study of SAVOR-TIMI 53, the authors suggest the increased heart failure hospitalization rate in saxagliptin group might be related to previous history of heart failure, low glomerular filtrate rate (eGFR < 60 ml/m), highbrain natriuretic peptide (BNP) and high albumin/creatinine ratio. In addition, Zhou et al. [109] presented results that DPP4 inhibitor can evoke significant diuretic and natriuretic responses and increased GFR by potentially affecting on renal sodium and water handling, which might be benefit to heart failure. BNP is able to promote vasodilation and natriuresis and it can be degraded by DPP4 to a less potent metabolite BNP(3–32) [110]. BNP also promotes norepinephrine release, which may counteract the beneficial effects of BNP-mediated vasodilation and natriuresis on heart failure [111]. Treatment of sitagliptin 200 mg/day increased forearm blood flow and decreased forearm vascular resistance in healthy humans, while BNP infusion also caused vasodilation in a dose-dependent manner [112, 113]. However, the authors did not observe an effect of sitagliptin on BNP-mediated vasodilation [112]. In addition, DPP4 inhibition has also been shown to induce vasodilation by promoting endothelial nitric oxide synthase (eNOS)-mediated NO release independent of GLP-1R signaling [44, 114]. DPP4 inhibition-mediated GLP-1R signaling may also activate Epac2 and induce atrial natriuretic peptide (ANP) release from the atrium, and thus dilate vessels [115]. DPP4 inhibition has been shown to increase sympathetic activation by preserving substance P [113] and thus may increase systolic blood pressure [112]. GLP-1R agonist may also activate sympathetic nervous system and increase heart rate [116]. A recent study reported that genetic deficiency of DPP4 improve cardiac function, whereas chemical inhibition of DPP4 by MK-0626 induced cardiac hypertrophy and impaired cardiac function, indicating drug related unspecific effects might negatively impact cardiac function [117].

Conclusions

The cardiovascular side effect is a big concern of oral anti-diabetic drugs. The cardiovascular safety of DPP4 inhibitors, as a new class of oral anti-diabetic drugs, has drawn much attention. The three large trials recently completed indicate DPP4 inhibitors as a class are safe from cardiovascular perspective. Many preclinical and clinical studies have shown DPP4 inhibitors may modulate atherosclerotic disease by reducing plasma lipids, suppressing inflammation, and promoting vascular relaxation (Fig. 1). However, inhibition of DPP4 may also exacerbate cardiovascular disease by enhancing sympathetic activation and angiogenesis. Ongoing trials assessing the cardiovascular effects of DPP4 inhibitors and GLP-1R agonists will provide further insights into the cardiovascular actions of DPP4 inhibitors.

Fig. 1
figure 1

Mechanisms underlying the cardiovascular action of DPP4 inhibition: ATH, atherosclerosis; ANP, atrial natriuretic peptide; CM, chylomicron; EC, endothelial cell; HR, heart rate; NO, nitric oxide; SDF-1, stromal-cell-derived factor-1

Full size image

Abbreviations

DPP4:

dipeptidyl peptidase-4

GLP-1:

glucagon-like peptide-1

GIP:

glucose-dependent insulinotropic peptide

SDF-1:

stromal-cell-derived factor-1

RANTES:

regulated on activation normal T cell expressed and presumably secreted

NPY:

neuropeptide

References

  1. Raskob GE, Angchaisuksiri P, Blanco AN, Buller H, Gallus A, Hunt BJ, Hylek EM, Kakkar A, Konstantinides SV, McCumber M, et al. Thrombosis: a major contributor to global disease burden. Arterioscler Thromb Vasc Biol. 2014;34(11):2363–71.

    CAS  PubMed  Article  Google Scholar 

  2. Falk E, Nakano M, Bentzon JF, Finn AV, Virmani R. Update on acute coronary syndromes: the pathologists’ view. Eur Heart J. 2013;34(10):719–28.

    CAS  PubMed  Article  Google Scholar 

  3. Palombo C, Kozakova M. Arterial stiffness, atherosclerosis and cardiovascular risk: pathophysiologic mechanisms and emerging clinical indications. Vasc Pharmacol. 2016;77:1–7.

    CAS  Article  Google Scholar 

  4. Lusis AJ. Atherosclerosis. Nature. 2000;407(6801):233–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Herrington W, Lacey B, Sherliker P, Armitage J, Lewington S. Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease. Circ Res. 2016;118(4):535–46.

    CAS  PubMed  Article  Google Scholar 

  6. Inzucchi SE, McGuire DK. New drugs for the treatment of diabetes: part II: incretin-based therapy and beyond. Circulation. 2008;117(4):574–84.

    PubMed  Article  Google Scholar 

  7. Gilbert RE, Krum H. Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy. Lancet. 2015;385(9982):2107–17.

    CAS  PubMed  Article  Google Scholar 

  8. Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J. 2015;36(34):2288–96.

    PubMed  Article  Google Scholar 

  9. Zhong J, Gong Q, Goud A, Srinivasamaharaj S, Rajagopalan S. Recent advances in dipeptidyl-peptidase-4 Inhibition therapy: lessons from the bench and clinical trials. J Diabetes Res. 2015;2015:606031.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  10. Hausenloy DJ, Whittington HJ, Wynne AM, Begum SS, Theodorou L, Riksen N, Mocanu MM, Yellon DM. Dipeptidyl peptidase-4 inhibitors and GLP-1 reduce myocardial infarct size in a glucose-dependent manner. Cardiovasc Diabetol. 2013;12:154.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. Chinda K, Palee S, Surinkaew S, Phornphutkul M, Chattipakorn S, Chattipakorn N. Cardioprotective effect of dipeptidyl peptidase-4 inhibitor during ischemia-reperfusion injury. Int J Cardiol. 2013;167(2):451–7.

    PubMed  Article  Google Scholar 

  12. Kubota A, Takano H, Wang H, Hasegawa H, Tadokoro H, Hirose M, Kobara Y, Yamada-Inagawa T, Komuro I, Kobayashi Y. DPP-4 inhibition has beneficial effects on the heart after myocardial infarction. J Mol Cell Cardiol. 2016;91:72–80.

    CAS  PubMed  Article  Google Scholar 

  13. Silva Junior WS, Godoy-Matos AF, Kraemer-Aguiar LG. Dipeptidyl peptidase 4: a new link between diabetes mellitus and atherosclerosis? Biomed Res Int. 2015;2015:816164.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. Remm F, Franz WM, Brenner C. Gliptins and their target dipeptidyl peptidase 4: implications for the treatment of vascular disease. Eur Heart J Cardiovasc Pharmacother. 2016;2(3):185–93.

    PubMed  Article  Google Scholar 

  15. Singh TP, Vangaveti VN, Malabu UH. Dipeptidyl peptidase-4 inhibitors and their potential role in the management of atherosclerosis—a review. Diabetes Metab Syndr. 2015;9(4):223–9.

    PubMed  Article  Google Scholar 

  16. Gong Q, Rajagopalan S, Zhong J. Dpp4 inhibition as a therapeutic strategy in cardiometabolic disease: incretin-dependent and -independent function. Int J Cardiol. 2015;197:170–9.

    PubMed  Article  Google Scholar 

  17. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696–705.

    CAS  PubMed  Article  Google Scholar 

  18. Zhong J, Rajagopalan S. Dipeptidyl peptidase-4 regulation of SDF-1/CXCR4 Axis: implications for cardiovascular disease. Front Immunol. 2015;6:477.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. Broxmeyer HE, Hoggatt J, O’Leary HA, Mantel C, Chitteti BR, Cooper S, Messina-Graham S, Hangoc G, Farag S, Rohrabaugh SL, et al. Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis. Nat Med. 2012;18(12):1786–96.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Van Damme J, Struyf S, Wuyts A, Van Coillie E, Menten P, Schols D, Sozzani S, De Meester I, Proost P. The role of CD26/DPP IV in chemokine processing. Chem Immunol. 1999;72:42–56.

    PubMed  Article  Google Scholar 

  21. Lambeir AM, Proost P, Durinx C, Bal G, Senten K, Augustyns K, Scharpe S, Van Damme J, De Meester I. Kinetic investigation of chemokine truncation by CD26/dipeptidyl peptidase IV reveals a striking selectivity within the chemokine family. J Biol Chem. 2001;276(32):29839–45.

    CAS  PubMed  Article  Google Scholar 

  22. Kos K, Baker AR, Jernas M, Harte AL, Clapham JC, O’Hare JP, Carlsson L, Kumar S, McTernan PG. DPP-IV inhibition enhances the antilipolytic action of NPY in human adipose tissue. Diabetes Obes Metab. 2009;11(4):285–92.

    CAS  PubMed  Article  Google Scholar 

  23. Zhong J, Maiseyeu A, Davis SN, Rajagopalan S. DPP4 in cardiometabolic disease: recent insights from the laboratory and clinical trials of DPP4 inhibition. Circ Res. 2015;116(8):1491–504.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev. 2014;35(6):992–1019.

    CAS  PubMed  Article  Google Scholar 

  25. Ussher JR, Drucker DJ. Cardiovascular actions of incretin-based therapies. Circ Res. 2014;114(11):1788–803.

    CAS  PubMed  Article  Google Scholar 

  26. Lehrke M, Marx N, Patel S, Seck T, Crowe S, Cheng K, von Eynatten M, Johansen OE. Safety and tolerability of linagliptin in patients with type 2 diabetes: a comprehensive pooled analysis of 22 placebo-controlled Studies. Clin Ther. 2014;36(8):1130–46.

    CAS  PubMed  Article  Google Scholar 

  27. Lau DC, Teoh H. Impact of current and emerging glucose-lowering drugs on body weight in type 2 diabetes. Can J Diabetes. 2015;39(Suppl 5):S148–54.

    PubMed  Article  Google Scholar 

  28. Hansen HH, Hansen G, Paulsen S, Vrang N, Mark M, Jelsing J, Klein T. The DPP-IV inhibitor linagliptin and GLP-1 induce synergistic effects on body weight loss and appetite suppression in the diet-induced obese rat. Eur J Pharmacol. 2014;741:254–63.

    CAS  PubMed  Article  Google Scholar 

  29. Lind M. Incretin therapy and its effect on body weight in patients with diabetes. Prim Care Diabetes. 2012;6(3):187–91.

    PubMed  Article  Google Scholar 

  30. Meneghini LF, Orozco-Beltran D, Khunti K, Caputo S, Damci T, Liebl A, Ross SA. Weight beneficial treatments for type 2 diabetes. J Clin Endocrinol Metab. 2011;96(11):3337–53.

    CAS  PubMed  Article  Google Scholar 

  31. Foley JE, Jordan J. Weight neutrality with the DPP-4 inhibitor, vildagliptin: mechanistic basis and clinical experience. Vasc Health Risk Manag. 2010;6:541–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Kalra S, Kalra B, Unnikrishnan A, Agrawal N, Kumar S. Optimizing weight control in diabetes: antidiabetic drug selection. Diabetes, Metab Syndr Obes. 2010;3:297–9.

    CAS  Article  Google Scholar 

  33. Karaca M, Magnan C, Kargar C. Functional pancreatic beta-cell mass: involvement in type 2 diabetes and therapeutic intervention. Diabetes Metab. 2009;35(2):77–84.

    CAS  PubMed  Article  Google Scholar 

  34. Maida A, Hansotia T, Longuet C, Seino Y, Drucker DJ. Differential importance of glucose-dependent insulinotropic polypeptide vs glucagon-like peptide 1 receptor signaling for beta cell survival in mice. Gastroenterology. 2009;137(6):2146–57.

    CAS  PubMed  Article  Google Scholar 

  35. Takeda Y, Fujita Y, Honjo J, Yanagimachi T, Sakagami H, Takiyama Y, Makino Y, Abiko A, Kieffer TJ, Haneda M. Reduction of both beta cell death and alpha cell proliferation by dipeptidyl peptidase-4 inhibition in a streptozotocin-induced model of diabetes in mice. Diabetologia. 2012;55(2):404–12.

    CAS  PubMed  Article  Google Scholar 

  36. Shirakawa J, Amo K, Ohminami H, Orime K, Togashi Y, Ito Y, Tajima K, Koganei M, Sasaki H, Takeda E, et al. Protective effects of dipeptidyl peptidase-4 (DPP-4) inhibitor against increased beta cell apoptosis induced by dietary sucrose and linoleic acid in mice with diabetes. J Biol Chem. 2011;286(29):25467–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Nagamine A, Hasegawa H, Hashimoto N, Yamada-Inagawa T, Hirose M, Kobara Y, Tadokoro H, Kobayashi Y, Takano H. The effects of DPP-4 inhibitor on hypoxia-induced apoptosis in human umbilical vein endothelial cells. J Pharm Sci. 2017;133(1):42–8.

    CAS  Article  Google Scholar 

  38. Salim HM, Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Yagi S, Soeki T, Shimabukuro M, Sata M. Dipeptidyl peptidase-4 inhibitor, linagliptin, ameliorates endothelial dysfunction and atherogenesis in normoglycemic apolipoprotein-E deficient mice. Vasc Pharmacol. 2016;79:16–23.

    CAS  Article  Google Scholar 

  39. Manrique C, Habibi J, Aroor AR, Sowers JR, Jia G, Hayden MR, Garro M, Martinez-Lemus LA, Ramirez-Perez FI, Klein T, et al. Dipeptidyl peptidase-4 inhibition with linagliptin prevents western diet-induced vascular abnormalities in female mice. Cardiovasc Diabetol. 2016;15:94.

    PubMed  PubMed Central  Article  Google Scholar 

  40. Shah Z, Kampfrath T, Deiuliis JA, Zhong J, Pineda C, Ying Z, Xu X, Lu B, Moffatt-Bruce S, Durairaj R, et al. Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation. 2011;124(21):2338–49.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Hirano T, Yamashita S, Takahashi M, Hashimoto H, Mori Y, Goto M. Anagliptin, a dipeptidyl peptidase-4 inhibitor, decreases macrophage infiltration and suppresses atherosclerosis in aortic and coronary arteries in cholesterol-fed rabbits. Metabolism. 2016;65(6):893–903.

    CAS  PubMed  Article  Google Scholar 

  42. Salim HM, Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Yagi S, Soeki T, Shimabukuro M, Sata M. Teneligliptin, a dipeptidyl peptidase-4 inhibitor, attenuated pro-inflammatory phenotype of perivascular adipose tissue and inhibited atherogenesis in normoglycemic apolipoprotein-E-deficient mice. Vasc Pharmacol. 2017.

  43. Brenner C, Franz WM, Kuhlenthal S, Kuschnerus K, Remm F, Gross L, Theiss HD, Landmesser U, Krankel N. DPP-4 inhibition ameliorates atherosclerosis by priming monocytes into M2 macrophages. Int J Cardiol. 2015;199:163–9.

    CAS  PubMed  Article  Google Scholar 

  44. Shah Z, Pineda C, Kampfrath T, Maiseyeu A, Ying Z, Racoma I, Deiuliis J, Xu X, Sun Q, Moffatt-Bruce S, et al. Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways. Vasc Pharmacol. 2011;55(1–3):2–9.

    CAS  Article  Google Scholar 

  45. Terasaki M, Hiromura M, Mori Y, Kohashi K, Kushima H, Ohara M, Watanabe T, Andersson O, Hirano T. Combination therapy with a sodium-glucose cotransporter 2 inhibitor and a dipeptidyl peptidase-4 Inhibitor additively suppresses macrophage foam cell formation and atherosclerosis in diabetic mice. Int J Endocrinol. 2017;2017:1365209.

    PubMed  PubMed Central  Article  Google Scholar 

  46. Kohashi K, Hiromura M, Mori Y, Terasaki M, Watanabe T, Kushima H, Shinmura K, Tomoyasu M, Nagashima M, Hirano T. A dipeptidyl peptidase-4 inhibitor but not incretins suppresses abdominal aortic aneurysms in angiotensin II-infused apolipoprotein E-null mice. J Atheroscler Thromb. 2016;23(4):441–54.

    CAS  PubMed  Article  Google Scholar 

  47. Sauve M, Ban K, Momen MA, Zhou YQ, Henkelman RM, Husain M, Drucker DJ. Genetic deletion or pharmacological inhibition of dipeptidyl peptidase-4 improves cardiovascular outcomes after myocardial infarction in mice. Diabetes. 2010;59(4):1063–73.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Murase H, Kuno A, Miki T, Tanno M, Yano T, Kouzu H, Ishikawa S, Tobisawa T, Ogasawara M, Nishizawa K, et al. Inhibition of DPP-4 reduces acute mortality after myocardial infarction with restoration of autophagic response in type 2 diabetic rats. Cardiovasc Diabetol. 2015;14:103.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. Ma M, Hasegawa Y, Koibuchi N, Toyama K, Uekawa K, Nakagawa T, Lin B, Kim-Mitsuyama S. DPP-4 inhibition with linagliptin ameliorates cognitive impairment and brain atrophy induced by transient cerebral ischemia in type 2 diabetic mice. Cardiovasc Diabetol. 2015;14:54.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  50. Avogaro A, Fadini GP. The effects of dipeptidyl peptidase-4 inhibition on microvascular diabetes complications. Diabetes Care. 2014;37(10):2884–94.

    CAS  PubMed  Article  Google Scholar 

  51. Pala L, Rotella CM. The role of DPP4 activity in cardiovascular districts: in vivo and in vitro evidence. J Diabetes Res. 2013;2013:590456.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Mulvihill EE, Varin EM, Gladanac B, Campbell JE, Ussher JR, Baggio LL, Yusta B, Ayala J, Burmeister MA, Matthews D, et al. Cellular sites and mechanisms linking reduction of dipeptidyl peptidase-4 activity to control of incretin hormone action and glucose homeostasis. Cell Metab. 2017;25(1):152–65.

    CAS  PubMed  Article  Google Scholar 

  53. Yanagimachi T, Fujita Y, Takeda Y, Honjo J, Sakagami H, Kitsunai H, Takiyama Y, Abiko A, Makino Y, Kieffer TJ, et al. Dipeptidyl peptidase-4 inhibitor treatment induces a greater increase in plasma levels of bioactive GIP than GLP-1 in non-diabetic subjects. Mol Metab. 2017;6(2):226–31.

    CAS  PubMed  Article  Google Scholar 

  54. Shigeta T, Aoyama M, Bando YK, Monji A, Mitsui T, Takatsu M, Cheng XW, Okumura T, Hirashiki A, Nagata K, et al. Dipeptidyl peptidase-4 modulates left ventricular dysfunction in chronic heart failure via angiogenesis-dependent and -independent actions. Circulation. 2012;126(15):1838–51.

    CAS  PubMed  Article  Google Scholar 

  55. Trujillo JM, Wettergreen SA, Nuffer WA, Ellis SL, McDermott MT. Cardiovascular outcomes of new medications for type 2 diabetes. Diabetes Technol Ther. 2016;18(12):749–58.

    PubMed  Article  Google Scholar 

  56. Mudaliar U, Zabetian A, Goodman M, Echouffo-Tcheugui JB, Albright AL, Gregg EW, Ali MK. Cardiometabolic risk factor changes observed in diabetes prevention programs in US Settings: a systematic review and meta-analysis. PLoS medicine. 2016;13(7):e1002095.

    PubMed  PubMed Central  Article  Google Scholar 

  57. Bae EJ. DPP-4 inhibitors in diabetic complications: role of DPP-4 beyond glucose control. Arch Pharmacal Res. 2016;39(8):1114–28.

    CAS  Article  Google Scholar 

  58. Kawase H, Bando YK, Nishimura K, Aoyama M, Monji A, Murohara T. A dipeptidyl peptidase-4 inhibitor ameliorates hypertensive cardiac remodeling via angiotensin-II/sodium-proton pump exchanger-1 axis. J Mol Cell Cardiol. 2016;98:37–47.

    CAS  PubMed  Article  Google Scholar 

  59. Ou HT, Chang KC, Li CY, Wu JS. Risks of cardiovascular diseases associated with dipeptidyl peptidase-4 inhibitors and other antidiabetic drugs in patients with type 2 diabetes: a nation-wide longitudinal study. Cardiovasc Diabetol. 2016;15:41.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  60. Kankanala SR, Syed R, Gong Q, Ren B, Rao X, Zhong J. Cardiovascular safety of dipeptidyl peptidase-4 inhibitors: recent evidence on heart failure. Am J Transl Res. 2016;8(5):2450–8.

    PubMed  PubMed Central  Google Scholar 

  61. Son JW, Kim S. Dipeptidyl peptidase 4 inhibitors and the risk of cardiovascular disease in patients with type 2 diabetes: a tale of three studies. Diabetes Metab J. 2015;39(5):373–83.

    PubMed  PubMed Central  Article  Google Scholar 

  62. Secrest MH, Udell JA, Filion KB. The cardiovascular safety trials of DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors. Trends Cardiovasc Med. 2017;27(3):194–202.

    CAS  PubMed  Article  Google Scholar 

  63. Fisman EZ, Tenenbaum A. Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes. Cardiovasc Diabetol. 2015;14:129.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. Barbieri M, Rizzo MR, Marfella R, Boccardi V, Esposito A, Pansini A, Paolisso G. Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors. Atherosclerosis. 2013;227(2):349–54.

    CAS  PubMed  Article  Google Scholar 

  65. Mita T, Katakami N, Shiraiwa T, Yoshii H, Onuma T, Kuribayashi N, Osonoi T, Kaneto H, Kosugi K, Umayahara Y, et al. Sitagliptin attenuates the progression of carotid intima-media thickening in insulin-treated patients with type 2 diabetes: the sitagliptin preventive study of intima-media thickness evaluation (SPIKE): a randomized controlled trial. Diabetes Care. 2016;39(3):455–64.

    CAS  PubMed  Article  Google Scholar 

  66. Mita T, Katakami N, Yoshii H, Onuma T, Kaneto H, Osonoi T, Shiraiwa T, Kosugi K, Umayahara Y, Yamamoto T, et al. Alogliptin, a dipeptidyl peptidase 4 inhibitor, prevents the progression of carotid atherosclerosis in patients with type 2 diabetes: the study of preventive effects of alogliptin on diabetic atherosclerosis (SPEAD-A). Diabetes Care. 2016;39(1):139–48.

    CAS  PubMed  Article  Google Scholar 

  67. Mita T, Katakami N, Shiraiwa T, Yoshii H, Gosho M, Shimomura I, Watada H. The effect of sitagliptin on the regression of carotid intima-media thickening in patients with type 2 diabetes mellitus: a post hoc analysis of the sitagliptin preventive study of intima-media thickness evaluation. Int J Endocrinol. 2017;2017:1925305.

    PubMed  PubMed Central  Article  Google Scholar 

  68. Cruickshank K, Riste L, Anderson SG, Wright JS, Dunn G, Gosling RG. Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function? Circulation. 2002;106(16):2085–90.

    PubMed  Article  Google Scholar 

  69. de Boer SA, Heerspink HJ, Juarez Orozco LE, van Roon AM, Kamphuisen PW, Smit AJ, Slart RH, Lefrandt JD, Mulder DJ. Effect of linagliptin on pulse wave velocity in early type 2 diabetes: a randomized, double-blind, controlled 26-week trial (RELEASE). Diabetes, Obes Metab. 2017.

  70. Kutoh E, Kaneoka N, Hirate M. Alogliptin: a new dipeptidyl peptidase-4 inhibitor with potential anti-atherogenic properties. Endocr Res. 2015;40(2):88–96.

    CAS  PubMed  Article  Google Scholar 

  71. Ohira M, Yamaguchi T, Saiki A, Ban N, Kawana H, Nagayama D, Nagumo A, Murano T, Shirai K, Tatsuno I. Metformin reduces circulating malondialdehyde-modified low-density lipoprotein in type 2 diabetes mellitus. Clin Invest Med. 2014;37(4):E243–51.

    CAS  PubMed  Article  Google Scholar 

  72. Oyama J, Murohara T, Kitakaze M, Ishizu T, Sato Y, Kitagawa K, Kamiya H, Ajioka M, Ishihara M, Dai K, et al. The effect of sitagliptin on carotid artery atherosclerosis in type 2 diabetes: the PROLOGUE randomized controlled trial. PLoS Med. 2016;13(6):e1002051.

    PubMed  PubMed Central  Article  Google Scholar 

  73. Tomiyama H, Miwa T, Kan K, Matsuhisa M, Kamiya H, Nanasato M, Kitano T, Sano H, Ohno J, Iida M, et al. Impact of glycemic control with sitagliptin on the 2-year progression of arterial stiffness: a sub-analysis of the PROLOGUE study. Cardiovasc Diabetol. 2016;15(1):150.

    PubMed  PubMed Central  Article  Google Scholar 

  74. Maruhashi T, Higashi Y, Kihara Y, Yamada H, Sata M, Ueda S, Odawara M, Terauchi Y, Dai K, Ohno J, et al. Long-term effect of sitagliptin on endothelial function in type 2 diabetes: a sub-analysis of the PROLOGUE study. Cardiovasc Diabetol. 2016;15(1):134.

    PubMed  PubMed Central  Article  Google Scholar 

  75. Nozue T, Fukui K, Takamura T, Sozu T, Hibi K, Kishi S, Michishita I. Effects of alogliptin on fractional flow reserve evaluated by coronary computed tomography angiography in patients with type 2 diabetes: rationale and design of the TRACT study. J Cardiol. 2017;69(3):518–22.

    PubMed  Article  Google Scholar 

  76. van Poppel PC, Netea MG, Smits P, Tack CJ. Vildagliptin improves endothelium-dependent vasodilatation in type 2 diabetes. Diabetes Care. 2011;34(9):2072–7.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. Nakamura K, Oe H, Kihara H, Shimada K, Fukuda S, Watanabe K, Takagi T, Yunoki K, Miyoshi T, Hirata K, et al. DPP-4 inhibitor and alpha-glucosidase inhibitor equally improve endothelial function in patients with type 2 diabetes: EDGE study. Cardiovasc Diabetol. 2014;13:110.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. Ayaori M, Iwakami N, Uto-Kondo H, Sato H, Sasaki M, Komatsu T, Iizuka M, Takiguchi S, Yakushiji E, Nakaya K, et al. Dipeptidyl peptidase-4 inhibitors attenuate endothelial function as evaluated by flow-mediated vasodilatation in type 2 diabetic patients. J Am Heart Assoc. 2013;2(1):e003277.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  79. Kurose T, Hamamoto Y, Seino Y. Evaluation of large-scale clinical trials on cardiovascular disease risk in patients with type 2 diabetes mellitus treated with DPP-4 inhibitors and new class of drugs. J Diabetes Investig. 2017.

  80. Rehman MB, Tudrej BV, Soustre J, Buisson M, Archambault P, Pouchain D, Vaillant-Roussel H, Gueyffier F, Faillie JL, Perault-Pochat MC, et al. Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: meta-analysis of placebo-controlled randomized clinical trials. Diabetes Metab. 2017;43(1):48–58.

    CAS  PubMed  Article  Google Scholar 

  81. Fitchett DH, Udell JA, Inzucchi SE. Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes. Eur J Heart Fail. 2017;19(1):43–53.

    CAS  PubMed  Article  Google Scholar 

  82. Mannucci E, Monami M. Cardiovascular safety of incretin-based therapies in type 2 diabetes: systematic review of integrated analyses and randomized controlled trials. Adv Ther. 2017;34(1):1–40.

    CAS  PubMed  Article  Google Scholar 

  83. Gupta P, White WB. Cardiovascular safety of therapies for type 2 diabetes. Expert Opin Drug Saf. 2017;16(1):13–25.

    CAS  PubMed  Article  Google Scholar 

  84. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327–35.

    CAS  PubMed  Article  Google Scholar 

  85. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26.

    CAS  PubMed  Article  Google Scholar 

  86. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385(9982):2067–76.

    CAS  PubMed  Article  Google Scholar 

  87. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232–42.

    CAS  PubMed  Article  Google Scholar 

  88. Rosenstock J, Marx N, Neubacher D, Seck T, Patel S, Woerle HJ, Johansen OE. Cardiovascular safety of linagliptin in type 2 diabetes: a comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events. Cardiovasc Diabetol. 2015;14:57.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  89. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Kober LV, Lawson FC, Ping L, Wei X, Lewis EF, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247–57.

    CAS  PubMed  Article  Google Scholar 

  90. Buse JB. The LSC: liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(18):1798–9.

    PubMed  Google Scholar 

  91. Ida S, Murata K, Betou K, Kobayashi C, Ishihara Y, Imataka K, Uchida A, Monguchi K, Kaneko R, Fujiwara R, et al. Effect of trelagliptin on vascular endothelial functions and serum adiponectin level in patients with type 2 diabetes: a preliminary single-arm prospective pilot study. Cardiovasc Diabetol. 2016;15(1):153.

    PubMed  PubMed Central  Article  Google Scholar 

  92. Barbieri M, Marfella R, Esposito A, Rizzo MR, Angellotti E, Mauro C, Siniscalchi M, Chirico F, Caiazzo P, Furbatto F, et al. Incretin treatment and atherosclerotic plaque stability: role of adiponectin/APPL1 signaling pathway. J Diabetes Complicat. 2017;31(2):295–303.

    PubMed  Article  Google Scholar 

  93. Broxmeyer HE, Capitano M, Campbell TB, Hangoc G, Cooper S. Modulation of hematopoietic chemokine effects in vitro and in vivo by DPP-4/CD26. Stem Cells Dev. 2016;25(8):575–85.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Connelly KA, Advani A, Zhang Y, Advani SL, Kabir G, Abadeh A, Desjardins JF, Mitchell M, Thai K, Gilbert RE. Dipeptidyl peptidase-4 inhibition improves cardiac function in experimental myocardial infarction: role of stromal cell-derived factor-1alpha. J Diabetes. 2016;8(1):63–75.

    CAS  PubMed  Article  Google Scholar 

  95. Theiss HD, Vallaster M, Rischpler C, Krieg L, Zaruba MM, Brunner S, Vanchev Y, Fischer R, Grobner M, Huber B, et al. Dual stem cell therapy after myocardial infarction acts specifically by enhanced homing via the SDF-1/CXCR4 axis. Stem Cell Res. 2011;7(3):244–55.

    CAS  PubMed  Article  Google Scholar 

  96. Kanki S, Segers VF, Wu W, Kakkar R, Gannon J, Sys SU, Sandrasagra A, Lee RT. Stromal cell-derived factor-1 retention and cardioprotection for ischemic myocardium. Circu Heart Fail. 2011;4(4):509–18.

    CAS  Article  Google Scholar 

  97. Khurana R, Simons M, Martin JF, Zachary IC. Role of angiogenesis in cardiovascular disease: a critical appraisal. Circulation. 2005;112(12):1813–24.

    PubMed  Article  Google Scholar 

  98. Zhong J, Maiseyeu A, Rajagopalan S. Lipoprotein effects of incretin analogs and dipeptidyl peptidase 4 inhibitors. Clin Lipidol. 2015;10(1):103–12.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Akita K, Isoda K, Shimada K, Daida H. Dipeptidyl-peptidase-4 inhibitor, alogliptin, attenuates arterial inflammation and neointimal formation after injury in low-density lipoprotein (LDL) receptor-deficient mice. J Am Heart Assoc. 2015;4(3):e001469.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  100. Lutz TA, Osto E. Glucagon-like peptide-1, glucagon-like peptide-2, and lipid metabolism. Curr Opin Lipidol. 2016;27(3):257–63.

    CAS  PubMed  Article  Google Scholar 

  101. Duvnjak L, Blaslov K. Dipeptidyl peptidase-4 inhibitors improve arterial stiffness, blood pressure, lipid profile and inflammation parameters in patients with type 2 diabetes mellitus. Diabetol Metab Syndr. 2016;8:26.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. Furuhashi M, Hiramitsu S, Mita T, Fuseya T, Ishimura S, Omori A, Matsumoto M, Watanabe Y, Hoshina K, Tanaka M, et al. Reduction of serum FABP4 level by sitagliptin, a DPP-4 inhibitor, in patients with type 2 diabetes mellitus. J Lipid Res. 2015;56(12):2372–80.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. Xiao C, Dash S, Morgantini C, Patterson BW, Lewis GF. Sitagliptin, a DPP-4 inhibitor, acutely inhibits intestinal lipoprotein particle secretion in healthy humans. Diabetes. 2014;63(7):2394–401.

    PubMed  PubMed Central  Article  Google Scholar 

  104. Ahn CH, Kim EK, Min SH, Oh TJ, Cho YM. Effects of gemigliptin, a dipeptidyl peptidase-4 inhibitor, on lipid metabolism and endotoxemia after a high-fat meal in patients with type 2 diabetes. Diabetes Obes Metab. 2017;19(3):457–62.

    CAS  PubMed  Article  Google Scholar 

  105. Eliasson B, Moller-Goede D, Eeg-Olofsson K, Wilson C, Cederholm J, Fleck P, Diamant M, Taskinen MR, Smith U. Lowering of postprandial lipids in individuals with type 2 diabetes treated with alogliptin and/or pioglitazone: a randomised double-blind placebo-controlled study. Diabetologia. 2012;55(4):915–25.

    CAS  PubMed  Article  Google Scholar 

  106. Matikainen N, Manttari S, Schweizer A, Ulvestad A, Mills D, Dunning BE, Foley JE, Taskinen MR. Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes. Diabetologia. 2006;49(9):2049–57.

    CAS  PubMed  Article  Google Scholar 

  107. Tremblay AJ, Lamarche B, Deacon CF, Weisnagel SJ, Couture P. Effect of sitagliptin therapy on postprandial lipoprotein levels in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13(4):366–73.

    CAS  PubMed  Article  Google Scholar 

  108. Noda Y, Miyoshi T, Oe H, Ohno Y, Nakamura K, Toh N, Kohno K, Morita H, Kusano K, Ito H. Alogliptin ameliorates postprandial lipemia and postprandial endothelial dysfunction in non-diabetic subjects: a preliminary report. Cardiovasc Diabetol. 2013;12:8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. Zhou X, Huang CH, Lao J, Pocai A, Forrest G, Price O, Roy S, Kelley DE, Sullivan KA, Forrest MJ. Acute hemodynamic and renal effects of glucagon-like peptide 1 analog and dipeptidyl peptidase-4 inhibitor in rats. Cardiovasc Diabetol. 2015;14:29.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  110. Muskiet MH, Smits MM, Morsink LM, Diamant M. The gut-renal axis: do incretin-based agents confer renoprotection in diabetes? Nat Rev Nephrol. 2014;10(2):88–103.

    CAS  PubMed  Article  Google Scholar 

  111. Chan NY, Seyedi N, Takano K, Levi R. An unsuspected property of natriuretic peptides: promotion of calcium-dependent catecholamine release via protein kinase G-mediated phosphodiesterase type 3 inhibition. Circulation. 2012;125(2):298–307.

    CAS  PubMed  Article  Google Scholar 

  112. Devin JK, Pretorius M, Nian H, Yu C, Billings FTt, Brown NJ. Dipeptidyl-peptidase 4 inhibition and the vascular effects of glucagon-like peptide-1 and brain natriuretic peptide in the human forearm. J Am Heart Assoc. 2014;3(4):e001075.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. Devin JK, Pretorius M, Nian H, Yu C, Billings FTt, Brown NJ. Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition. Hypertension. 2014;63(5):951–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. Ishii M, Shibata R, Kondo K, Kambara T, Shimizu Y, Tanigawa T, Bando YK, Nishimura M, Ouchi N, Murohara T. Vildagliptin stimulates endothelial cell network formation and ischemia-induced revascularization via an endothelial nitric-oxide synthase-dependent mechanism. J Biol Chem. 2014;289(39):27235–45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. Kim M, Platt MJ, Shibasaki T, Quaggin SE, Backx PH, Seino S, Simpson JA, Drucker DJ. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med. 2013;19(5):567–75.

    CAS  PubMed  Article  Google Scholar 

  116. Gardiner SM, March JE, Kemp PA, Bennett T. Mesenteric vasoconstriction and hindquarters vasodilatation accompany the pressor actions of exendin-4 in conscious rats. J Pharmacol Exp Ther. 2006;316(2):852–9.

    CAS  PubMed  Article  Google Scholar 

  117. Mulvihill EE, Varin EM, Ussher JR, Campbell JE, Bang KW, Abdullah T, Baggio LL, Drucker DJ. Inhibition of dipeptidyl peptidase-4 impairs ventricular function and promotes cardiac fibrosis in high fat-fed diabetic mice. Diabetes. 2016;65(3):742–54.

    CAS  PubMed  Article  Google Scholar 

Download references

Authors’ contributions

LD, XR, CX reviewed the literature and wrote the first draft. SR, JZ reviewed the literature and finalized the manuscript. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

Competing interests

JZ is currently receiving a Grant (IIS2015-10485) from BoehringerIngelheim. The remaining authors declare that they have no competing interests.

Funding

This work was supported by Grants from NIH (K01 DK105108), AHA (17GRNT33670485, 15SDG25700381 and 13POST17210033), Mid-Atlantic Nutrition Obesity Research Center (NORC) under NIH Award Number P30DK072488, BoehringerIngelheim (IIS2015-10485), and National Natural Science Foundation of China (81671544).

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author information

Authors and Affiliations

  1. Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, Xiamen, 361003, Fujian, China

    Lihua Duan

  2. Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, 2103 Cornell Rd., Wolstein Research Building 4525, Cleveland, OH, 44106, USA

    Lihua Duan, Xiaoquan Rao, Chang Xia, Sanjay Rajagopalan & Jixin Zhong

  3. Department of Microbiology and Immunology, Wuhan Polytechnic University, Wuhan, 430023, Hubei, China

    Chang Xia

Authors
  1. Lihua Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoquan Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chang Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sanjay Rajagopalan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jixin Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jixin Zhong.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Duan, L., Rao, X., Xia, C. et al. The regulatory role of DPP4 in atherosclerotic disease. Cardiovasc Diabetol 16, 76 (2017). https://doi.org/10.1186/s12933-017-0558-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12933-017-0558-y

Keywords

  • Dipeptidyl peptidase
  • Gliptins
  • Atherosclerosis
  • Incretin
  • DPP4 inhibitor

Cardiovascular Diabetology

ISSN: 1475-2840