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Erschienen in: Cardiovascular Diabetology 1/2017

Open Access 01.12.2017 | Review

The regulatory role of DPP4 in atherosclerotic disease

verfasst von: Lihua Duan, Xiaoquan Rao, Chang Xia, Sanjay Rajagopalan, Jixin Zhong

Erschienen in: Cardiovascular Diabetology | Ausgabe 1/2017

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.
Abkürzungen
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

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 [13]. 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 [712], including atherosclerosis [1315]. 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 [2325].
DPP4 inhibitors are being increasingly used in clinical for the treatment of type 2 diabetes as they are safe and weight neutral [2632]. 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 [3336]. 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) [5563].
Table 1
Dipeptidyl peptidase 4 inhibitors and atherosclerosis outcome trials
Study
Study design
Drug
Duration
Result
SPIKE
Randomized/blinded-endpoint
Sitagliptin
104-week
The mean IMT and left maximum IMT of common carotid arteries were reduced
SPEAD-A
Randomized/blinded-end point
Alogliptin
24-month
The progression of carotid IMT was attenuated
RELEASE
Randomized/double-blind
Linagliptin
26 weeks
Aortic PWV was decreased
PROLOGUE
Randomized/blinded-end point
Sitagliptin
24-month
No additional effect on the progression of carotid IMT
TRACT
Non-randomized
Alogliptin
48-week
Not end. Intermediate coronary artery stenosis of T2DM patients will be evaluated by CCTA
CCTA, coronary computed tomography angiography; IMT, intima-media thickness; PWV, pulse wave velocity; T2DM, type 2 diabetes mellitus
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 [7983]. 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, 9396]. 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 [98103]. DPP4 inhibitors treatment following a high-fat liquid formula significantly reduced triglyceride-rich lipoproteins apoB48 in healthy individuals [103105]. 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.

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).

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Literatur
1.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
2.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
3.
Zurück zum Zitat Palombo C, Kozakova M. Arterial stiffness, atherosclerosis and cardiovascular risk: pathophysiologic mechanisms and emerging clinical indications. Vasc Pharmacol. 2016;77:1–7.CrossRef Palombo C, Kozakova M. Arterial stiffness, atherosclerosis and cardiovascular risk: pathophysiologic mechanisms and emerging clinical indications. Vasc Pharmacol. 2016;77:1–7.CrossRef
5.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
6.
Zurück zum Zitat Inzucchi SE, McGuire DK. New drugs for the treatment of diabetes: part II: incretin-based therapy and beyond. Circulation. 2008;117(4):574–84.PubMedCrossRef Inzucchi SE, McGuire DK. New drugs for the treatment of diabetes: part II: incretin-based therapy and beyond. Circulation. 2008;117(4):574–84.PubMedCrossRef
7.
Zurück zum Zitat Gilbert RE, Krum H. Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy. Lancet. 2015;385(9982):2107–17.PubMedCrossRef Gilbert RE, Krum H. Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy. Lancet. 2015;385(9982):2107–17.PubMedCrossRef
8.
Zurück zum Zitat Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J. 2015;36(34):2288–96.PubMedCrossRef Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J. 2015;36(34):2288–96.PubMedCrossRef
9.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
10.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
11.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
12.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
13.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
14.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
15.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
16.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
17.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
18.
Zurück zum Zitat Zhong J, Rajagopalan S. Dipeptidyl peptidase-4 regulation of SDF-1/CXCR4 Axis: implications for cardiovascular disease. Front Immunol. 2015;6:477.PubMedPubMedCentralCrossRef Zhong J, Rajagopalan S. Dipeptidyl peptidase-4 regulation of SDF-1/CXCR4 Axis: implications for cardiovascular disease. Front Immunol. 2015;6:477.PubMedPubMedCentralCrossRef
19.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
20.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
21.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
22.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
23.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
24.
Zurück zum Zitat Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev. 2014;35(6):992–1019.PubMedCrossRef Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev. 2014;35(6):992–1019.PubMedCrossRef
25.
Zurück zum Zitat Ussher JR, Drucker DJ. Cardiovascular actions of incretin-based therapies. Circ Res. 2014;114(11):1788–803.PubMedCrossRef Ussher JR, Drucker DJ. Cardiovascular actions of incretin-based therapies. Circ Res. 2014;114(11):1788–803.PubMedCrossRef
26.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
27.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
28.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
29.
Zurück zum Zitat Lind M. Incretin therapy and its effect on body weight in patients with diabetes. Prim Care Diabetes. 2012;6(3):187–91.PubMedCrossRef Lind M. Incretin therapy and its effect on body weight in patients with diabetes. Prim Care Diabetes. 2012;6(3):187–91.PubMedCrossRef
30.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
31.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
32.
Zurück zum Zitat 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.CrossRef 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.CrossRef
33.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
34.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
35.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
36.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
37.
Zurück zum Zitat 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.CrossRef 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.CrossRef
38.
Zurück zum Zitat 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.CrossRef 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.CrossRef
39.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
40.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
41.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
42.
Zurück zum Zitat 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. 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.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
44.
Zurück zum Zitat 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.CrossRef 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.CrossRef
45.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
46.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
47.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
48.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
49.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
50.
Zurück zum Zitat Avogaro A, Fadini GP. The effects of dipeptidyl peptidase-4 inhibition on microvascular diabetes complications. Diabetes Care. 2014;37(10):2884–94.PubMedCrossRef Avogaro A, Fadini GP. The effects of dipeptidyl peptidase-4 inhibition on microvascular diabetes complications. Diabetes Care. 2014;37(10):2884–94.PubMedCrossRef
51.
52.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
53.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
54.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
55.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
56.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
57.
Zurück zum Zitat Bae EJ. DPP-4 inhibitors in diabetic complications: role of DPP-4 beyond glucose control. Arch Pharmacal Res. 2016;39(8):1114–28.CrossRef Bae EJ. DPP-4 inhibitors in diabetic complications: role of DPP-4 beyond glucose control. Arch Pharmacal Res. 2016;39(8):1114–28.CrossRef
58.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
59.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
60.
Zurück zum Zitat 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.PubMedPubMedCentral 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.PubMedPubMedCentral
61.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
62.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
63.
64.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
65.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
66.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
67.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
68.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
69.
Zurück zum Zitat 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. 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.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
71.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
72.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
73.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
74.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
75.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
76.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
77.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
78.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
79.
Zurück zum Zitat 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. 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.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
81.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
82.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
83.
Zurück zum Zitat Gupta P, White WB. Cardiovascular safety of therapies for type 2 diabetes. Expert Opin Drug Saf. 2017;16(1):13–25.PubMedCrossRef Gupta P, White WB. Cardiovascular safety of therapies for type 2 diabetes. Expert Opin Drug Saf. 2017;16(1):13–25.PubMedCrossRef
84.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
85.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
86.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
87.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
88.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
89.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
90.
Zurück zum Zitat Buse JB. The LSC: liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(18):1798–9.PubMed Buse JB. The LSC: liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(18):1798–9.PubMed
91.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
92.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
93.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
94.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
95.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
96.
Zurück zum Zitat 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.CrossRef 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.CrossRef
97.
Zurück zum Zitat Khurana R, Simons M, Martin JF, Zachary IC. Role of angiogenesis in cardiovascular disease: a critical appraisal. Circulation. 2005;112(12):1813–24.PubMedCrossRef Khurana R, Simons M, Martin JF, Zachary IC. Role of angiogenesis in cardiovascular disease: a critical appraisal. Circulation. 2005;112(12):1813–24.PubMedCrossRef
98.
Zurück zum Zitat Zhong J, Maiseyeu A, Rajagopalan S. Lipoprotein effects of incretin analogs and dipeptidyl peptidase 4 inhibitors. Clin Lipidol. 2015;10(1):103–12.PubMedPubMedCentralCrossRef Zhong J, Maiseyeu A, Rajagopalan S. Lipoprotein effects of incretin analogs and dipeptidyl peptidase 4 inhibitors. Clin Lipidol. 2015;10(1):103–12.PubMedPubMedCentralCrossRef
99.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
100.
Zurück zum Zitat Lutz TA, Osto E. Glucagon-like peptide-1, glucagon-like peptide-2, and lipid metabolism. Curr Opin Lipidol. 2016;27(3):257–63.PubMedCrossRef Lutz TA, Osto E. Glucagon-like peptide-1, glucagon-like peptide-2, and lipid metabolism. Curr Opin Lipidol. 2016;27(3):257–63.PubMedCrossRef
101.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
102.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
103.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
104.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
105.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
106.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
107.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
108.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
109.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
110.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
111.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
112.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
113.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
114.
Zurück zum Zitat 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
115.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
116.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
117.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
Metadaten
Titel
The regulatory role of DPP4 in atherosclerotic disease
verfasst von
Lihua Duan
Xiaoquan Rao
Chang Xia
Sanjay Rajagopalan
Jixin Zhong
Publikationsdatum
01.12.2017
Verlag
BioMed Central
Erschienen in
Cardiovascular Diabetology / Ausgabe 1/2017
Elektronische ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-017-0558-y

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