Curr Diab Rep (2014) 14:463 DOI 10.1007/s11892-013-0463-z
MACROVASCULAR COMPLICATIONS IN DIABETES (L PERREAULT, SECTION EDITOR)
Potential Anti-Atherosclerotic Effects of Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes Mellitus Sandeep Dhindsa & Ishwarlal Jialal
Published online: 5 January 2014 # Springer Science+Business Media New York 2014
Abstract Cardiovascular disease (CVD) is the leading cause of mortality in patients with diabetes. Pharmacotherapy that can reduce hyperglycemia and also exhibit pleiotropic effects that can result in a reduction in cardiovascular disease will be a major advance. Recently, the dipeptidyl-peptidase-4 inhibitors were introduced as ant-hyperglycemic therapy. Studies from numerous groups have reported effects that could potentially result in a reduction in CVD. Some of the drugs in this class, especially vildagliptin and sitagliptin, have been shown to reduce postprandial hyperlipidemia following a fat load, improve endothelial function as evidenced by increased forearm blood flow, and also display anti-inflammatory effects. Their effects on platelet function, blood pressure, and oxidative stress are very preliminary and need to be confirmed. Finally, they have been shown to reduce subclinical atherosclerosis by reducing carotid intimal-medial thickness. However, the final arbiter with respect to a reduction in CVD will be the ongoing clinical trials.
Keywords Inflammation . Endothelial function . Postprandial hyperlipidemia . Antioxidant . DPP-4 . This article is part of the Topical Collection on Macrovascular Complications in Diabetes S. Dhindsa Division of Endocrinology and Metabolism, Texas Tech University Health Sciences Center, Permian Basin Campus, Odessa, TX 79763, USA I. Jialal (*) Laboratory for Atherosclerosis and Metabolic Research, University of California Davis Medical Center, 4635 Second Ave, Res 1 Bldg, Rm 3000, Sacramento, CA 95817, USA e-mail: [email protected] I. Jialal VA Medical Center, Mather, CA 95655, USA
Atherosclerosis . Diabetes . CD26 . Lipids . CRP . Dipeptidyl peptidase 4 . T2DM
Introduction It is well known that type 2 diabetes (T2DM) doubles the risk of cardiovascular and total mortality [1]. However, it is not yet clear if the treatment of T2DM can reduce this risk. Recently the Look-AHEAD study (which was stopped early for futility after a mean follow-up 9.6 years) failed to show a benefit of therapeutic life style changes on cardiovascular events despite a significant weight reduction and a reduction in HbA1c [2]. Hence, the role of pharmacotherapy in the prevention of cardiovascular disease assumes a greater role. While there are data to suggest that metformin and pioglitazone can reduce cardiac events and mortality (secondary but not primary end points with pioglitazone) [3, 4], glycemic control has not yet been convincingly shown to reduce cardiac events [5]. It is therefore possible that drug specific mechanisms might underlie the cardiovascular effects of these drugs. Until 8 years ago, the drug treatment of T2DM was comprised of sulfonylureas, metformin, thiazolidinediones, and insulin. However, the use of drugs that work on the incretin system [glucagon like peptide (GLP)-1 receptor agonists and dipeptidyl-peptidase-4 (DPP-4) inhibitors] has increased tremendously over the past few years. Incretin hormones [GLP-1 and glucose-dependent insulinotropic polypeptide (GIP)] stimulate insulin secretion from the β cells and inhibit glucagon secretion from the α-cells of the pancreas in a hyperglycemic milieu. DPP-4 is an enzyme that is present in plasma and in many cells and tissues and rapidly inactivates GLP-1 and GIP-1. DPP-4 inhibitors (sitagliptin, saxagliptin, alogliptin, linagliptin, and vildagliptin), therefore, reduce the inactivation of GLP-1 and GIP-1, leading to increased plasma levels. This results in an inhibition glucagon secretion and an
463, Page 2 of 7
increase in insulin secretion in a glucose-dependent manner, resulting in a decrease in plasma glucose levels without causing hypoglycemia. Although these drugs were ushered in several years ago as part of the therapeutic armamentarium in reducing hyperglycemia in diabetic patients, data are emerging to support pleiotropic effects that could result in a reduction in cardiovascular events, the major cause of mortality in T2DM. DPP-4 is also expressed as CD26 on the membranes of lymphocytes and monocytes and functions as an inflammatory mediator. Indeed, DPP-4 inhibitors have recently been shown to have anti-inflammatory effects, attenuate postprandial hyperlipidemia, and improve endothelial dysfunction (discussed below). It is not yet known if this would translate into a reduction in cardiovascular outcomes. An interest in the potential anti-atherosclerotic effects of DPP-4 inhibitors was stimulated by reports that DPP-4 inhibitors may have cardioprotective effects. Meta-analyses of short-term clinical trials in patients with T2DM have shown a 30 % reduction in major cardiovascular events with use of DPP-4 inhibitors compared with other treatments for T2DM [6–9]. These trials were not designed to evaluate the effect of diabetes therapies on cardiovascular events, so these cardiovascular analyses are more exploratory and this reduction, therefore, needs to be considered an incidental and interesting finding. Since FDA now requires that all antihyperglycemic drugs approved for treatment of T2DM be studied to prove cardiovascular safety, multiple trials are being conducted on the effect of treatment with DPP-4 inhibitors on cardiovascular outcomes in T2DM (none have been completed so far). The major focus of this review is to describe the potential antiatherosclerotic effects of DPP-4 inhibitors with an emphasis on studies in patients with T2DM. Table 1 depicts the potential anti-atherosclerotic effects of DPP-4 inhibitors that will be discussed in this review.
Reduction in Glycemia and Mean Amplitude Glycemic Excursions (MAGE) As antihyperglycemic agents, DPP-4 inhibitors decrease HbA1c by ~0.6 % (ranging from 0.3 %–1.0 %) [10]. They do not cause weight gain or hypoglycemia. They have a mild effect on fasting hyperglycemia but significantly reduce postprandial hyperglycemia by increasing circulating levels of active GLP-1and GIP [10, 11]. Marfella et al. collected continuous glucose monitoring data in patients with T2DM treated with DPP-4 inhibitors for 3 months (sitagliptin and vildagliptin) and found that both the drugs lowered HbA1c, fasting glucose, postprandial glucose, and 24-hour mean glucose concentrations. Vildagliptin (but not sitagliptin) decreased mean amplitude glycemic excursions (MAGE; a measure of glycemic variability) [12, 13,
Curr Diab Rep (2014) 14:463 Table 1 Potential anti-atherosclerotic effects of DPP-4 inhibitors 1. Reducing glycemia including MAGE. 2. Improvement in endothelial function. 3. Anti-inflammatory effects. 4. Reduction of postprandial hyperlipidemia. DPP-4 dipeptidyl-peptidase-IV, MAGE mean amplitude glycemic excursion
14•]. MAGE is measured by calculating the mean of differences between consecutive peaks and nadirs of glucose. It is independent of mean glycemia and is a measure of glycemic instability. Studies have suggested that glycemic incursions are relevant to atherosclerosis in patients with diabetes [15, 16]. Barbieri et al. measured carotid intimal-medial thickness (IMT) in 90 patients randomized to vildagliptin 50 mg twice daily or sitagliptin 100 mg daily for 3 months [14•]. All measures of glycemia improved with both drugs but MAGE decreased only with vildagliptin. Change in MAGE also correlated with change in inflammation and oxidative stress. The authors postulated that DPP-4 inhibitors mediated reduction in MAGE decreases atherosclerosis via reduction of inflammation and oxidative stress, but they showed significant reductions in IMT with both drugs arguing against MAGE being the predominant mechanism.
DPP-4 Inhibitors and Endothelial Function Endothelial dysfunction is believed to be the initial event in atherosclerosis following the negative impact of various noxious insults including dyslipidemia, the metabolic milieu of diabetes (hyperglycemia, increased free fatty acids, AGEs etc.), smoking, hypertension, etc. [17]. It was first shown by Nystrom et al. that infusion of GLP-1 compared with saline resulted in improvement in the endothelial function as evidence by the increase in flow mediated dilation in T2DM [18]. Recently, Irace et al. showed in T2DM that the GLP-1 receptor agonist, exenatide, improved flow mediated dilation over a 16-week period [19]. However, studies examining the effect of DPP-4 inhibitors on endothelial function are sparse. Van Poppel et al. reported the effect of the DPP-4 inhibitor, Vildagliptin, on endothelial-dependent vasodilation in patients with T2DM [20•]. They studied 16 patients with T2DM on oral glucose-lowering treatment. Participants received vildagliptin 100 mg/d or acarbose 300 mg/d for 4 consecutive weeks in a randomized, double-blind, cross-over design. At the end of each treatment period, forearm vasodilatory response to intra-arterial administered acetylcholine (endothelial-dependent vasodilation) was measured and also following sodium nitroprusside as a positive control for endothelial-independent vasodilation. In this study, they
Curr Diab Rep (2014) 14:463
showed that infusion of acetylcholine induced a dosedependent increase in forearm blood flow (FBF) in the experimental arm, which was increased significantly with vildagliptin therapy compared with acarbose (P=0.01 by 2way ANOVA). Importantly, vildagliptin did not significantly change the vascular response to sodium nitroprusside suggesting that the beneficial effect was mediated by a direct improvement in endothelial biology resulting in an increase in vasodilation and not a direct effect on smooth muscle cells. Since at baseline forearm blood flow in the vildagliptin group was higher than in the acarbose group, the authors expressed the data as absolute change in forearm blood flow (ΔFBF) above baseline. Vildagliptin therapy augmented the absolute increase in FBF in response to acetylcholine compared with acarbose. The authors failed to report on incretin levels to determine if the improvement correlated with GLP-1 or GIP or both. Kubota et al., in a single arm study without a comparator, showed that in 40 patients with T2DM treatment with sitagliptin 50 mg/d significantly improved endothelial flow mediated dilation. However, they did also not report on incretin levels [21]. Matsubara et al. studied 40 patients with T2DM who received either sitagliptin 50 mg/d or aggressive conventional treatment for 6 months. They assessed endothelial function by reactive hyperemic peripheral arterial tonometry index (RHI). Although HbA1c levels were similar at the end of the study, they showed a significant improvement in RHI and reduction in hsCRP in the sitagliptin group only. RHI increases correlated inversely with reductions in the prototypic marker of inflammation, C-reactive protein (CRP) [22]. CRP has been shown to induce endothelial dysfunction [23]. Once again incretin levels were not reported. The beneficial effect on endothelial biology with vildagliptin and sitagliptin could be due to the upregulation of GLP-1 and GLP-1 receptors in the endothelium resulting in an increase in the activity of endothelial nitric oxide synthase and other vasodilators, such as prostacyclin. However, nonGLP-1 related effects cannot be excluded. These mechanisms and the role of GIP need to be confirmed in future studies. Endothelial progenitor cells (EPC) have been shown to predict cardiovascular mortality [24], thus, it is also relevant to discuss the study by Fadini et al. who showed in a nonplacebo controlled study in 16 patients that 4 weeks of sitagliptin, a DPP-4 inhibitor, compared with no treatment resulted in an increase in EPC number defined by dual positivity for both kinase insert domain, receptor KDR, and CD34 and also an increase in the EPC mobilizing factor, stromalderived factor-1α (SDF-1α), a substrate for DPP-4, which can promote homing of EPC to sites of endothelial injury [25]. Although this is a very exciting preliminary report, it needs to be emphasized that this study lacked a placebo group and there was no measure of EPC functionality such as tubule formation, etc. [26]. However, since low EPC number has been shown to predict cardiovascular events, it is imperative
Page 3 of 7, 463
that this preliminary observation be confirmed in a trial of longer duration in patients with T2DM with a relevant comparator, as in the study of van Poppel et al. to confirm that indeed this is an additional beneficial effect of DPP-4 inhibitors on endothelial function.
DPP-4 Inhibitors and Inflammation Atherosclerosis is considered an inflammatory disease and diabetes is a pro-inflammatory state as manifest by both cellular and circulation biomarkers of inflammation [27]. The effect of a DPP-4 inhibitor, sitagliptin, on inflammatory mediators was recently published. In this study, 22 patients with T2DM received 100 mg of sitagliptin or placebo for 12 weeks [28•]. Sitagliptin resulted in 90 % suppression of DPP4 activity. GLP-1 concentrations increased by 60 %, consistent with the reduction in plasma DPP-4 activity, and HbA1c fell by 0.7 %. Blood pressure did not change. Triglycerides and free fatty acids decreased by 20 %. This was accompanied by a decrease in the mRNA expression of inflammatory mediators such as tumor necrosis factor alpha (TNF-α), toll like receptor 4 (receptor for endotoxin), chemokine receptor CCR2, and IKKβ (a kinase that leads to activation of the major inflammatory transcription factor NFκB) in mononuclear cells. Interestingly, the expression of these mediators, as well as NFκB binding activity, decreased within a few hours of ingestion of the sitagliptin tablet. Serum concentrations of CRP and IL-6 decreased by 24 % after 12 weeks of sitagliptin treatment. Sitagliptin treatment also induced a decrease in CD26 expression in mononuclear cells, consistent with the overall anti-inflammatory action of sitagliptin since CD26 mediates inflammatory signaling. It is possible that a portion of the anti-inflammatory effect of DPP-4 inhibitors may be mediated by the increase in endogenous GLP-1 concentrations or the decrease in free fatty acids and blood glucose concentrations. GLP-1 agonists are anti-inflammatory and this effect is independent of change in glycemia or weight loss [29]. However, the rapidity of antiinflammatory action (within 2 hours after ingestion of sitagliptin) and the small rise in GLP-1 concentrations (20 % at that time) make a direct action of DPP-4 inhibitors on the inflammatory mediators likely. The anti-inflammatory effect in the above mentioned study [28•] was seen in the fasting state while fasting blood glucose concentrations did not change. On the other hand, the effect of DPP-4 inhibitors on postprandial glycemia and lipemia (discussed later) are much starker. Barbieri et al. studied the effect of DPP-4 inhibitors (vildagliptin and sitagliptin) on postprandial inflammation and oxidative stress [14•]. Ninety subjects received either vildagliptin or sitagliptin for 12 weeks. Treatment with both DPP-4 inhibitors was associated with a decrease in the prandial TNF-α, IL-6, and IL-18 concentrations as well as plasma
463, Page 4 of 7
nitrotyrosine concentrations (discussed later). The reduction in these parameters was related to decrease in mean daily glucose fluctuations. However, while vildagliptin was associated with a significant decrease in MAGE, sitagliptin was not (as discussed above). Thus, a reduction in MAGE is only 1 of the possible mechanisms by which DPP-4 inhibitors can reduce inflammation since sitagliptin reduces inflammation but not MAGE. Interestingly, they failed to show an effect on CRP levels, the prototypic marker of inflammation, which has been shown to predict cardiovascular events in diabetes [30]. However, many other studies have shown a reduction in CRP with sitagliptin [28•, 31]. The reason for this inconsistency is not clear. Satoh-Asahara studied the effects of 50 mg of Sitagliptin in 24 Japanese patients with T2DM and compared those with untreated controls [31]. Sitagliptin decreased serum concentrations of inflammatory cytokines CRP and TNF-α while increasing the concentrations of anti-inflammatory cytokine IL-10. Expression of IL-10 in monocytes increased while that of TNF-α decreased. These changes in monocytes resulting in an increase in IL-10 and a decrease in TNF-α suggests that sitagliptin polarizes monocytes from a pro-inflammatory M1 phenotype to a reparative, anti-inflammatory M2 phenotype. Derosa et al. showed a reduction in CRP concentrations with both sitagliptin and vildagliptin [32, 33]. As discussed above in the section on endothelium function, a study in 20 patients with type 2 diabetes and coronary artery disease showed a remarkable decrease (>50 %) in CRP concentrations with sitagliptin therapy. This decrease correlated with the improvement in RHI. While there was no placebo group, 20 patients treated with routine care served as controls. HbA1c decreased by 0.65 % in control group (same as sitagliptin group) but there was no change in CRP concentrations. Interestingly, sitagliptin group also showed a decline in systolic blood pressures.
The Effect of DPP-4 Inhibitors on Lipids and Lipoproteins The totality of published data would support a neutral effect of DPP-4 inhibitors on the fasting lipid profile. However, it is well accepted that diabetes is a state with an exaggerated postprandial hyperlipidemia, which also is considered as a predictor of cardiovascular events [34–36]. Also it has been argued that postprandial dyslipidemia in diabetes induces oxidative stress, inflammation, and endothelial dysfunction [35]. Valid biomarkers of postprandial hyperlipidemia following an oral fat load include measurement of plasma triglycerides, remnant particles, and apolipoprotein B-48 (apoB-48) levels. Studies have reported a beneficial effect of DPP-4 inhibitor therapy on these and other postprandial measures.
Curr Diab Rep (2014) 14:463
Matikainen et al. conducted a randomized double blind study in drug-naïve patients with T2DM [37]. The patients received vildagliptin (100 mg/d, n=15), or placebo (n=16) for 4 weeks. Relative to placebo, 4 weeks of treatment with vildagliptin decreased the area under the curve (AUC)0-8h as defined as the incremental AUC (IAUC) for total plasma triglycerides, and for chylomicron triglycerides following a fat meal. There was a decrease in chylomicron apoB-48 and total cholesterol levels. Also it is important to point out that relative to placebo, vildagliptin did not significantly affect very low density lipoprotein (VLDL)/intermediate-density lipoprotein (IDL) triglyceride and cholesterol concentrations. Concurrent with the reduction in these measures of postprandial lipemia, vildagliptin increased intact GLP-1 levels. In accord with the published data, they also reported no significant effect on the fasting lipid profile, including apoB-48 and apoB-100. They argued for a predominant effect on chylomicron metabolism in the intestine. Tremblay et al. also investigated the effect of the DPP-4 inhibitor, sitagliptin, therapy on postprandial lipoprotein levels in patients with T2DM [38•]. They studied 36 subjects with T2DM in a double-blind, cross-over study using sitagliptin (100 mg/d) or placebo for 6 weeks with a 4 week washout period between the 2 phases. At the end of each phase of treatment, patients underwent an oral lipid tolerance test and blood samples were taken over an 8 hour period. Compared with placebo, sitagliptin therapy (100 mg/day) resulted in a significant decrease in the area under the curve (AUC) for plasma triglyceride, plasma apoB-48, plasma apoB, VLDL-cholesterol and for free fatty acids. Also they showed a significant increase in AUC for postprandial plasma intact GLP-1 and GIP. Most recently, Eliasson et al. also conducting a study of a different DPP-4 inhibitor, alogliptin (Alo), compared with pioglitazone on postprandial lipemia [39]. They assessed the effect of Alo monotherapy, 25 mg/d and Alo co-administered with pioglitazone (Pio) 30 mg/d vs placebo on triacylglycerol (TG)rich lipoproteins in T2DM before and after a high-fat meal. Seventy-one patients were studied on usual anti-diabetic therapies in a 16-week duration study, which was placebo controlled. Patients received a high-fat mixed meal before and 4 and 16 weeks after randomization to Alo, Alo/Pio, and placebo, (n=25, 22, and 24, respectively). Blood samples were collected up to 8 hours after meal injection. At 16 weeks Alo and Alo/Pio vs placebo produced similar significant reductions in total postprandial TG responses as well as in chylomicron TG, and VLDL1 TG. Postprandial chylomicron apoB-48 AUC showed a significant decrease following Alo. Interestingly they did not show a significant change in postprandial FFA levels amongst groups, but they showed a significant increase in GLP-1. To summarize, compared with placebo, 16-weeks therapy of Alo resulted in a significant decrease in the incremental AUC0-8h for TGs, for chylomicron TGs, for chylomicron apoB-48, for chylomicron apoB-100, VLDL1 TG, VLDL1 apoB-48, and VLDL1 apoB.
Curr Diab Rep (2014) 14:463
Page 5 of 7, 463
Thus, although it appears that DPP-4 inhibitors have a neutral effect on the fasting lipid profile, studies from at least 3 groups have now confirmed that 3 different DPP-4 inhibitors significantly attenuate the postprandial hyperlipemia of both intestinal and hepatic origin in T2DM and this class effect was paralleled by an increase in plasma incretin levels. Since similar effects have been reported for GLP-1 receptor agonists, increased GLP-1 activity resulting from DPP-4 inhibition could be advanced as the major mechanism. This could be a very critical and important mechanism for potential reduction in atherosclerosis and cardiovascular events.
Other Possible Mechanisms Underlying Beneficial Effect of DPP-4 Inhibitors on Cardiovascular Risk A potential mechanism of vascular protection by DPP-4 inhibitors may be by limiting oxidative stress. Increased oxidative stress is a hallmark of T2DM [44]. Both circulating and cellular biomarkers have clearly defined diabetes as a condition with increased oxidative stress. Data with regards to the effect of DPP-4 inhibitors on oxidative stress are scant. Recently, Rizzo et al. showed in a study of duration of 12-weeks that compared with baseline, 2 DPP-4 inhibitors, sitagliptin (100 mg per day) and vildagliptin (100 mg per day), n=45 in both groups, resulted in a significant reduction in plasma of an accepted biomarker of oxidative stress, nitrotyrosine. It is important to emphasize that both sitagliptin and vildagliptin treatment for 3 months induced reductions in prandial as well as interprandial nitrotyrosine levels [14•]. Although nitrotyrosine levels were significantly decreased with both sitagliptin therapy and vildagliptin therapy the authors suggested that vildagliptin was superior to sitagliptin in reducing oxidative stress based on their findings [13]. Koren et al. compared sitagliptin 100 mg/ d to glibenclamide 5 mg/d for a duration of 3 months on various plasma biomarkers in 34 patients with T2DM. Interestingly in this study, they did not show a significant reduction in hsCRP or 8-Isoprostane, another accepted biomarker of oxidative stress [45]. Further studies examining the effect of DPP4 inhibitors on both circulating and cellular biomarkers of oxidative stress is
urgently needed to confirm if indeed these DPP-4 inhibitors are antioxidants in T2DM. There are other potential mechanisms that may contribute to the possible anti-atherosclerotic benefits of DPP-4 inhibitors. However, these mechanisms have not been shown consistently or the observations are preliminary. For example, (1) some studies have reported that DPP-4 inhibitors can lower blood pressure by 2–3 mm Hg [40]. However, this effect has not been seen consistently; (2) one study reported that sitagliptin can inhibit platelet aggregability in healthy subjects and patients with T2DM [41]. This observation needs confirmation; and (3) increased CD26 expression in mononuclear cells appears to be associated with decreased recovery of left ventricular function following myocardial infarction [42]. Treatment with sitagliptin decreased CD26 expression in mononuclear cells and improved the capacity in vitro of mononuclear cells to “home in” to infarct area and help in repair and recovery. This concept will be further tested in an ongoing trial of sitagliptin and granulocyte colony stimulating factor in patients with acute myocardial infarction [43].
DPP-4 Inhibitors, Atherosclerosis, and CVD Barbieri et al. reports on the effect of 2 DPP-4 inhibitors, Sitagliptin (100 mg/day) and Vildagliptin (50 mg twice a day) on carotid intimal-medial thickness (IMT) an accepted surrogate of clinical atherosclerosis [46], over a 12 week period in an open label prospective study [14•]. There were 45 patients with T2DM in each group inadequately controlled on metformin therapy. At baseline, IMT correlated with LDL, total cholesterol, inflammatory mediators, and oxidative stress and measures of glycemia (HbA1c, fasting glucose, postprandial glucose concentrations, and MAGE). Blood pressure and fasting lipids did not change after 3 months. In both groups there was a significant reduction in carotid IMT after 12 weeks and the data suggest that there was a significantly greater reduction in IMT with Vildagliptin. A major weakness of this study was the lack of an arm without a DPP-4 inhibitor. They also showed that the benefit on IMT correlated with change in
Table 2 Summary of potential anti-atherosclerotic effects of different DPP-4 inhibitors
↓ Postprandial hyperlipidemia ↑ Endothelial function Anti-inflammatory effects ↓ Carotid IMT
Vildagliptin
Sitagliptin
Saxagliptin
Alogliptin
Linagliptin
+ + + +
+ + + +
-
+ -
-
DPP-4 dipeptidyl-peptidase-IV, IMT intimal-medial thickness + denotes published studies support this effect − denotes no published studies to date
463, Page 6 of 7
MAGE, supporting the hypothesis in which the study was predicated. In multivariate analyses, change in MAGE and baseline LDL cholesterol were predictors of change in IMT, explaining 26 % of the variability. However, they also showed a significant reduction in inflammatory score comprising IL-6, IL-18, and TNF-α and a biomarker of oxidative stress, Nitrotyrosine. Authors postulated that DPP-4 inhibitors mediated reduction in MAGE decreases atherosclerosis via reduction of inflammation and oxidative stress however, their findings of a reduction in IMT with sitagliptin without a change in MAGE contradicts their premise of the pivotal role of MAGE accounting for the benefit. Hence, in what can be viewed at best as an exciting preliminary report, it appears that DPP-4 inhibitors have the potential of reducing atherosclerosis burden and hopefully CVE in the ongoing large trials [26]. Although reducing MAGE can be advanced as a plausible mechanism based on the published literature this class of drugs improve endothelial function, and reduce inflammation and postprandial hyperlipidemia. The authors did not comment on treatment effects on postprandial triglycerides or FFA and this could be an additional mechanism explaining their observations. In a study of 14 patients with CAD (1 with diabetes) and preserved LV function, using dobutamine stress echocardiography to assess LV dysfunction, a single dose of Sitagliptin 100 mg/d vs placebo by increasing GLP-1 improved global and regional LV performance in response to stress and mitigated postischemic stunning [47]. Although both these preliminary studies are very promising we must await the results of the randomized prospective trials with cardiovascular endpoints, which are ongoing since they will answer this provocative and promising question, which appears to be backed by the retrospective studies [6, 48, 49].
Conclusions DPP-4 inhibitors offer a convenient and attractive therapy for patients with T2DM because they do not cause weight gain or hypoglycemia. However, the DPP-4 enzyme is widely expressed in many tissues of the human body such as endothelium and epithelial cells, intestines, kidneys, brain, and myocardium. DPP-4/CD26 is expressed on circulating Tlymphocytes. Interesting preliminary data highlighting the effects of this class of medications on cardiovascular risk factors and surrogate markers of atherosclerosis have emerged. Therefore, the pleiotropic effects of DPP-4 inhibitors in the realm of cardiovascular disease have been garnering attention of investigators around the world. DPP-4 inhibitors are clearly anti-inflammatory, improve endothelial dependent vasodilation, and reduce postprandial lipemia. Table 2 summarizes the potential anti-atherosclerotic effects of the different DPP-4 inhibitors. It would appear that both sitagliptin and
Curr Diab Rep (2014) 14:463
vildagliptin hold the greatest promise with respect to reduction in CVE based on the published studies. Preliminary data suggest that they may reduce oxidative stress and increase endothelial progenitor cell number. Vildagliptin in particularly appears to effectively reduce glycemic excursions. It remains to be seen whether DPP-4 inhibitors can hold up to their promise in long-term randomized controlled trials that have cardiovascular events as the primary endpoint.
Acknowledgments We would like to thank Gerred Smith for help with manuscript preparation. Compliance with Ethics Guidelines Conflict of Interest Sandeep Dhindsa has received honoraria from Abbvie and Janssen. Ishwarlal Jialal serves on the Speakers’ Bureau and received honoraria from Merck. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References Papers of particular interest, published recently, have been highlighted as: • Of importance
1.
Seshasai SR, Kaptoge S, Thompson A, et al. Emerging risk factors collaboration: diabetes mellitus, fasting glucose, and risk of causespecific death. N Engl J Med. 2011;364:829–41. 2. Wing RR, Bolin P, Brancati FL, et al. Look AHEAD Research Group: cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369:145–54. 3. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854–65. 4. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the proactive study (prospective pioglitazone clinical trial in macrovascular events): a randomized controlled trial. Lancet. 2005;366:1279–89. 5. Hemmingsen B, Lund SS, Gluud C, et al. Intensive glycemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomized clinical trials. BMJ. 2011; (PMID: 22115901). 6. Jose T, Inzucchi SE. Cardiovascular effects of the DPP-4 inhibitors. Diabetes Vasc Dis Res. 2012;9:109–16. 7. Monami M, Ahren B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metabol. 2013;15:112–20. 8. Monami M, Dicembrini I, Martelli D, Mannucci E. Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized clinical trials. Curr Med Res Opin. 2011;27 Suppl 3:57–64. 9. Scheen AJ. Cardiovascular effects of gliptins. Nat Rev Cardiol. 2013;10:73–84.
Curr Diab Rep (2014) 14:463 10.
11.
12.
13.
14.•
15.
16.
17. 18.
19.
20.•
21.
22.
23.
24. 25.
26. 27. 28.•
29.
Nauck MA. Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. Am J Med. 2011;124(1 Suppl):S3–S18. Muscelli E, Casolaro A, Gastaldelli A, et al. Mechanisms for the antihyperglycemic effect of sitagliptin in patients with type 2 diabetes. J Clin Endocrinol Metab. 2012;97:2818–26. Marfella R, Barbieri M, Grella R, et al. Effects of vildagliptin twice daily vs sitagliptin once daily on 24-hour acute glucose fluctuations. J Diabetes Complicat. 2010;24:79–83. Rizzo MR, Barbieri M, Marfella R, Paolisso G. Reduction of oxidative stress and inflammation by blunting daily acute glucose fluctuations in patients with type 2 diabetes: role of dipeptidyl peptidase-IV inhibition. Diabetes Care. 2012;35:2076–82. Barbieri M, Rizzo MR, Marfella R, et al. Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors. Atherosclerosis. 2013;227:349–54. Interesting preliminary study showing benefit of Vildagliptin and Sitagliptin on sub-clinical atherosclerosis as evidenced by a decrease in carotid IMT. Di Flaviani A, Picconi F, Di Stefano P, et al. Impact of glycemic and blood pressure variability on surrogate measures of cardiovascular outcomes in type 2 diabetic patients. Diabetes Care. 2011;34:1605–9. Monnier L, Mas E, Ginet C, et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006;295:1681–7. Orasanu G, Plutzky J. The pathologic continuum of diabetic vascular disease. J Am Coll Cardiol. 2009;53:S35–42. Nystrom T, Gutniak MK, Zhang Q, et al. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004;287:E1209–15. Irace C, DeLuca S, Shehaj E, et al. Exenatide improves endothelial function assessed by flow mediated dilation technique in subjects with type 2 diabetes: results from an observational research. Diabetes Vasc Dis Res. 2012;10:72–7. van Poppel PCM, Netea MG, Smits P, Tack CJ. Vildagliptin improves endothelium-dependent vasodilatation in type 2 diabetes. Diabetes Care. 2011;34:2072–7. First report showing a significant improvement in flow mediated dilation with Vildagliptin therapy compared with acarbose. Kubota Y, Miyamoto M, Takagi G, et al. The Dipeptidyl Peptidase4 Inhibitor Sitagliptin improves vascular endothelial function in Type 2 Diabetes. J Korean Med Sci. 2012;27:1364–70. Matsubara J, Sugiyama S, Akiyama E, et al. Dipeptidyl Peptidase-4 Inhibitor, Sitagliptin, improves endothelial dysfunction in association with its anti-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes. Circ J. 2013;77:1337–44. Hein TW, Singh I, Vasquez-Vivar J, et al. Human C-reactive protein induces endothelial dysfunction and uncoupling of eNOS in vivo. Atherosclerosis. 2009;206:61–8. Devaraj S, Jialal I. Dysfunctional endothelial progenitor cells in metabolic syndrome. Exp Diabetes Res. 2012; (PMID: 21941528). Fadini GP, Boscaro E, Albiero M, et al. The oral dipeptidyl peptidase4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes. Diabetes Care. 2010;33:1607–9. Jialal I, Bajaj M. Commentary: DPP-4 inhibitors and atherosclerosis: the promise. Atherosclerosis. 2013;227:224–5. Devaraj S, Dasu MR, Jialal I. Diabetes is a proinflammatory state: a translational perspective. Expert Rev Endocrinol Metab. 2010;5:19–28. Makdissi A, Ghanim H, Vora M, et al. Sitagliptin exerts an antiinflammatory action. J Clin Endocrinol Metab. 2012;97:3333–41. First comprehensive report on the anti-inflammatory effects of Sitagliptin. Acute (
MACROVASCULAR COMPLICATIONS IN DIABETES (L PERREAULT, SECTION EDITOR)
Potential Anti-Atherosclerotic Effects of Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes Mellitus Sandeep Dhindsa & Ishwarlal Jialal
Published online: 5 January 2014 # Springer Science+Business Media New York 2014
Abstract Cardiovascular disease (CVD) is the leading cause of mortality in patients with diabetes. Pharmacotherapy that can reduce hyperglycemia and also exhibit pleiotropic effects that can result in a reduction in cardiovascular disease will be a major advance. Recently, the dipeptidyl-peptidase-4 inhibitors were introduced as ant-hyperglycemic therapy. Studies from numerous groups have reported effects that could potentially result in a reduction in CVD. Some of the drugs in this class, especially vildagliptin and sitagliptin, have been shown to reduce postprandial hyperlipidemia following a fat load, improve endothelial function as evidenced by increased forearm blood flow, and also display anti-inflammatory effects. Their effects on platelet function, blood pressure, and oxidative stress are very preliminary and need to be confirmed. Finally, they have been shown to reduce subclinical atherosclerosis by reducing carotid intimal-medial thickness. However, the final arbiter with respect to a reduction in CVD will be the ongoing clinical trials.
Keywords Inflammation . Endothelial function . Postprandial hyperlipidemia . Antioxidant . DPP-4 . This article is part of the Topical Collection on Macrovascular Complications in Diabetes S. Dhindsa Division of Endocrinology and Metabolism, Texas Tech University Health Sciences Center, Permian Basin Campus, Odessa, TX 79763, USA I. Jialal (*) Laboratory for Atherosclerosis and Metabolic Research, University of California Davis Medical Center, 4635 Second Ave, Res 1 Bldg, Rm 3000, Sacramento, CA 95817, USA e-mail: [email protected] I. Jialal VA Medical Center, Mather, CA 95655, USA
Atherosclerosis . Diabetes . CD26 . Lipids . CRP . Dipeptidyl peptidase 4 . T2DM
Introduction It is well known that type 2 diabetes (T2DM) doubles the risk of cardiovascular and total mortality [1]. However, it is not yet clear if the treatment of T2DM can reduce this risk. Recently the Look-AHEAD study (which was stopped early for futility after a mean follow-up 9.6 years) failed to show a benefit of therapeutic life style changes on cardiovascular events despite a significant weight reduction and a reduction in HbA1c [2]. Hence, the role of pharmacotherapy in the prevention of cardiovascular disease assumes a greater role. While there are data to suggest that metformin and pioglitazone can reduce cardiac events and mortality (secondary but not primary end points with pioglitazone) [3, 4], glycemic control has not yet been convincingly shown to reduce cardiac events [5]. It is therefore possible that drug specific mechanisms might underlie the cardiovascular effects of these drugs. Until 8 years ago, the drug treatment of T2DM was comprised of sulfonylureas, metformin, thiazolidinediones, and insulin. However, the use of drugs that work on the incretin system [glucagon like peptide (GLP)-1 receptor agonists and dipeptidyl-peptidase-4 (DPP-4) inhibitors] has increased tremendously over the past few years. Incretin hormones [GLP-1 and glucose-dependent insulinotropic polypeptide (GIP)] stimulate insulin secretion from the β cells and inhibit glucagon secretion from the α-cells of the pancreas in a hyperglycemic milieu. DPP-4 is an enzyme that is present in plasma and in many cells and tissues and rapidly inactivates GLP-1 and GIP-1. DPP-4 inhibitors (sitagliptin, saxagliptin, alogliptin, linagliptin, and vildagliptin), therefore, reduce the inactivation of GLP-1 and GIP-1, leading to increased plasma levels. This results in an inhibition glucagon secretion and an
463, Page 2 of 7
increase in insulin secretion in a glucose-dependent manner, resulting in a decrease in plasma glucose levels without causing hypoglycemia. Although these drugs were ushered in several years ago as part of the therapeutic armamentarium in reducing hyperglycemia in diabetic patients, data are emerging to support pleiotropic effects that could result in a reduction in cardiovascular events, the major cause of mortality in T2DM. DPP-4 is also expressed as CD26 on the membranes of lymphocytes and monocytes and functions as an inflammatory mediator. Indeed, DPP-4 inhibitors have recently been shown to have anti-inflammatory effects, attenuate postprandial hyperlipidemia, and improve endothelial dysfunction (discussed below). It is not yet known if this would translate into a reduction in cardiovascular outcomes. An interest in the potential anti-atherosclerotic effects of DPP-4 inhibitors was stimulated by reports that DPP-4 inhibitors may have cardioprotective effects. Meta-analyses of short-term clinical trials in patients with T2DM have shown a 30 % reduction in major cardiovascular events with use of DPP-4 inhibitors compared with other treatments for T2DM [6–9]. These trials were not designed to evaluate the effect of diabetes therapies on cardiovascular events, so these cardiovascular analyses are more exploratory and this reduction, therefore, needs to be considered an incidental and interesting finding. Since FDA now requires that all antihyperglycemic drugs approved for treatment of T2DM be studied to prove cardiovascular safety, multiple trials are being conducted on the effect of treatment with DPP-4 inhibitors on cardiovascular outcomes in T2DM (none have been completed so far). The major focus of this review is to describe the potential antiatherosclerotic effects of DPP-4 inhibitors with an emphasis on studies in patients with T2DM. Table 1 depicts the potential anti-atherosclerotic effects of DPP-4 inhibitors that will be discussed in this review.
Reduction in Glycemia and Mean Amplitude Glycemic Excursions (MAGE) As antihyperglycemic agents, DPP-4 inhibitors decrease HbA1c by ~0.6 % (ranging from 0.3 %–1.0 %) [10]. They do not cause weight gain or hypoglycemia. They have a mild effect on fasting hyperglycemia but significantly reduce postprandial hyperglycemia by increasing circulating levels of active GLP-1and GIP [10, 11]. Marfella et al. collected continuous glucose monitoring data in patients with T2DM treated with DPP-4 inhibitors for 3 months (sitagliptin and vildagliptin) and found that both the drugs lowered HbA1c, fasting glucose, postprandial glucose, and 24-hour mean glucose concentrations. Vildagliptin (but not sitagliptin) decreased mean amplitude glycemic excursions (MAGE; a measure of glycemic variability) [12, 13,
Curr Diab Rep (2014) 14:463 Table 1 Potential anti-atherosclerotic effects of DPP-4 inhibitors 1. Reducing glycemia including MAGE. 2. Improvement in endothelial function. 3. Anti-inflammatory effects. 4. Reduction of postprandial hyperlipidemia. DPP-4 dipeptidyl-peptidase-IV, MAGE mean amplitude glycemic excursion
14•]. MAGE is measured by calculating the mean of differences between consecutive peaks and nadirs of glucose. It is independent of mean glycemia and is a measure of glycemic instability. Studies have suggested that glycemic incursions are relevant to atherosclerosis in patients with diabetes [15, 16]. Barbieri et al. measured carotid intimal-medial thickness (IMT) in 90 patients randomized to vildagliptin 50 mg twice daily or sitagliptin 100 mg daily for 3 months [14•]. All measures of glycemia improved with both drugs but MAGE decreased only with vildagliptin. Change in MAGE also correlated with change in inflammation and oxidative stress. The authors postulated that DPP-4 inhibitors mediated reduction in MAGE decreases atherosclerosis via reduction of inflammation and oxidative stress, but they showed significant reductions in IMT with both drugs arguing against MAGE being the predominant mechanism.
DPP-4 Inhibitors and Endothelial Function Endothelial dysfunction is believed to be the initial event in atherosclerosis following the negative impact of various noxious insults including dyslipidemia, the metabolic milieu of diabetes (hyperglycemia, increased free fatty acids, AGEs etc.), smoking, hypertension, etc. [17]. It was first shown by Nystrom et al. that infusion of GLP-1 compared with saline resulted in improvement in the endothelial function as evidence by the increase in flow mediated dilation in T2DM [18]. Recently, Irace et al. showed in T2DM that the GLP-1 receptor agonist, exenatide, improved flow mediated dilation over a 16-week period [19]. However, studies examining the effect of DPP-4 inhibitors on endothelial function are sparse. Van Poppel et al. reported the effect of the DPP-4 inhibitor, Vildagliptin, on endothelial-dependent vasodilation in patients with T2DM [20•]. They studied 16 patients with T2DM on oral glucose-lowering treatment. Participants received vildagliptin 100 mg/d or acarbose 300 mg/d for 4 consecutive weeks in a randomized, double-blind, cross-over design. At the end of each treatment period, forearm vasodilatory response to intra-arterial administered acetylcholine (endothelial-dependent vasodilation) was measured and also following sodium nitroprusside as a positive control for endothelial-independent vasodilation. In this study, they
Curr Diab Rep (2014) 14:463
showed that infusion of acetylcholine induced a dosedependent increase in forearm blood flow (FBF) in the experimental arm, which was increased significantly with vildagliptin therapy compared with acarbose (P=0.01 by 2way ANOVA). Importantly, vildagliptin did not significantly change the vascular response to sodium nitroprusside suggesting that the beneficial effect was mediated by a direct improvement in endothelial biology resulting in an increase in vasodilation and not a direct effect on smooth muscle cells. Since at baseline forearm blood flow in the vildagliptin group was higher than in the acarbose group, the authors expressed the data as absolute change in forearm blood flow (ΔFBF) above baseline. Vildagliptin therapy augmented the absolute increase in FBF in response to acetylcholine compared with acarbose. The authors failed to report on incretin levels to determine if the improvement correlated with GLP-1 or GIP or both. Kubota et al., in a single arm study without a comparator, showed that in 40 patients with T2DM treatment with sitagliptin 50 mg/d significantly improved endothelial flow mediated dilation. However, they did also not report on incretin levels [21]. Matsubara et al. studied 40 patients with T2DM who received either sitagliptin 50 mg/d or aggressive conventional treatment for 6 months. They assessed endothelial function by reactive hyperemic peripheral arterial tonometry index (RHI). Although HbA1c levels were similar at the end of the study, they showed a significant improvement in RHI and reduction in hsCRP in the sitagliptin group only. RHI increases correlated inversely with reductions in the prototypic marker of inflammation, C-reactive protein (CRP) [22]. CRP has been shown to induce endothelial dysfunction [23]. Once again incretin levels were not reported. The beneficial effect on endothelial biology with vildagliptin and sitagliptin could be due to the upregulation of GLP-1 and GLP-1 receptors in the endothelium resulting in an increase in the activity of endothelial nitric oxide synthase and other vasodilators, such as prostacyclin. However, nonGLP-1 related effects cannot be excluded. These mechanisms and the role of GIP need to be confirmed in future studies. Endothelial progenitor cells (EPC) have been shown to predict cardiovascular mortality [24], thus, it is also relevant to discuss the study by Fadini et al. who showed in a nonplacebo controlled study in 16 patients that 4 weeks of sitagliptin, a DPP-4 inhibitor, compared with no treatment resulted in an increase in EPC number defined by dual positivity for both kinase insert domain, receptor KDR, and CD34 and also an increase in the EPC mobilizing factor, stromalderived factor-1α (SDF-1α), a substrate for DPP-4, which can promote homing of EPC to sites of endothelial injury [25]. Although this is a very exciting preliminary report, it needs to be emphasized that this study lacked a placebo group and there was no measure of EPC functionality such as tubule formation, etc. [26]. However, since low EPC number has been shown to predict cardiovascular events, it is imperative
Page 3 of 7, 463
that this preliminary observation be confirmed in a trial of longer duration in patients with T2DM with a relevant comparator, as in the study of van Poppel et al. to confirm that indeed this is an additional beneficial effect of DPP-4 inhibitors on endothelial function.
DPP-4 Inhibitors and Inflammation Atherosclerosis is considered an inflammatory disease and diabetes is a pro-inflammatory state as manifest by both cellular and circulation biomarkers of inflammation [27]. The effect of a DPP-4 inhibitor, sitagliptin, on inflammatory mediators was recently published. In this study, 22 patients with T2DM received 100 mg of sitagliptin or placebo for 12 weeks [28•]. Sitagliptin resulted in 90 % suppression of DPP4 activity. GLP-1 concentrations increased by 60 %, consistent with the reduction in plasma DPP-4 activity, and HbA1c fell by 0.7 %. Blood pressure did not change. Triglycerides and free fatty acids decreased by 20 %. This was accompanied by a decrease in the mRNA expression of inflammatory mediators such as tumor necrosis factor alpha (TNF-α), toll like receptor 4 (receptor for endotoxin), chemokine receptor CCR2, and IKKβ (a kinase that leads to activation of the major inflammatory transcription factor NFκB) in mononuclear cells. Interestingly, the expression of these mediators, as well as NFκB binding activity, decreased within a few hours of ingestion of the sitagliptin tablet. Serum concentrations of CRP and IL-6 decreased by 24 % after 12 weeks of sitagliptin treatment. Sitagliptin treatment also induced a decrease in CD26 expression in mononuclear cells, consistent with the overall anti-inflammatory action of sitagliptin since CD26 mediates inflammatory signaling. It is possible that a portion of the anti-inflammatory effect of DPP-4 inhibitors may be mediated by the increase in endogenous GLP-1 concentrations or the decrease in free fatty acids and blood glucose concentrations. GLP-1 agonists are anti-inflammatory and this effect is independent of change in glycemia or weight loss [29]. However, the rapidity of antiinflammatory action (within 2 hours after ingestion of sitagliptin) and the small rise in GLP-1 concentrations (20 % at that time) make a direct action of DPP-4 inhibitors on the inflammatory mediators likely. The anti-inflammatory effect in the above mentioned study [28•] was seen in the fasting state while fasting blood glucose concentrations did not change. On the other hand, the effect of DPP-4 inhibitors on postprandial glycemia and lipemia (discussed later) are much starker. Barbieri et al. studied the effect of DPP-4 inhibitors (vildagliptin and sitagliptin) on postprandial inflammation and oxidative stress [14•]. Ninety subjects received either vildagliptin or sitagliptin for 12 weeks. Treatment with both DPP-4 inhibitors was associated with a decrease in the prandial TNF-α, IL-6, and IL-18 concentrations as well as plasma
463, Page 4 of 7
nitrotyrosine concentrations (discussed later). The reduction in these parameters was related to decrease in mean daily glucose fluctuations. However, while vildagliptin was associated with a significant decrease in MAGE, sitagliptin was not (as discussed above). Thus, a reduction in MAGE is only 1 of the possible mechanisms by which DPP-4 inhibitors can reduce inflammation since sitagliptin reduces inflammation but not MAGE. Interestingly, they failed to show an effect on CRP levels, the prototypic marker of inflammation, which has been shown to predict cardiovascular events in diabetes [30]. However, many other studies have shown a reduction in CRP with sitagliptin [28•, 31]. The reason for this inconsistency is not clear. Satoh-Asahara studied the effects of 50 mg of Sitagliptin in 24 Japanese patients with T2DM and compared those with untreated controls [31]. Sitagliptin decreased serum concentrations of inflammatory cytokines CRP and TNF-α while increasing the concentrations of anti-inflammatory cytokine IL-10. Expression of IL-10 in monocytes increased while that of TNF-α decreased. These changes in monocytes resulting in an increase in IL-10 and a decrease in TNF-α suggests that sitagliptin polarizes monocytes from a pro-inflammatory M1 phenotype to a reparative, anti-inflammatory M2 phenotype. Derosa et al. showed a reduction in CRP concentrations with both sitagliptin and vildagliptin [32, 33]. As discussed above in the section on endothelium function, a study in 20 patients with type 2 diabetes and coronary artery disease showed a remarkable decrease (>50 %) in CRP concentrations with sitagliptin therapy. This decrease correlated with the improvement in RHI. While there was no placebo group, 20 patients treated with routine care served as controls. HbA1c decreased by 0.65 % in control group (same as sitagliptin group) but there was no change in CRP concentrations. Interestingly, sitagliptin group also showed a decline in systolic blood pressures.
The Effect of DPP-4 Inhibitors on Lipids and Lipoproteins The totality of published data would support a neutral effect of DPP-4 inhibitors on the fasting lipid profile. However, it is well accepted that diabetes is a state with an exaggerated postprandial hyperlipidemia, which also is considered as a predictor of cardiovascular events [34–36]. Also it has been argued that postprandial dyslipidemia in diabetes induces oxidative stress, inflammation, and endothelial dysfunction [35]. Valid biomarkers of postprandial hyperlipidemia following an oral fat load include measurement of plasma triglycerides, remnant particles, and apolipoprotein B-48 (apoB-48) levels. Studies have reported a beneficial effect of DPP-4 inhibitor therapy on these and other postprandial measures.
Curr Diab Rep (2014) 14:463
Matikainen et al. conducted a randomized double blind study in drug-naïve patients with T2DM [37]. The patients received vildagliptin (100 mg/d, n=15), or placebo (n=16) for 4 weeks. Relative to placebo, 4 weeks of treatment with vildagliptin decreased the area under the curve (AUC)0-8h as defined as the incremental AUC (IAUC) for total plasma triglycerides, and for chylomicron triglycerides following a fat meal. There was a decrease in chylomicron apoB-48 and total cholesterol levels. Also it is important to point out that relative to placebo, vildagliptin did not significantly affect very low density lipoprotein (VLDL)/intermediate-density lipoprotein (IDL) triglyceride and cholesterol concentrations. Concurrent with the reduction in these measures of postprandial lipemia, vildagliptin increased intact GLP-1 levels. In accord with the published data, they also reported no significant effect on the fasting lipid profile, including apoB-48 and apoB-100. They argued for a predominant effect on chylomicron metabolism in the intestine. Tremblay et al. also investigated the effect of the DPP-4 inhibitor, sitagliptin, therapy on postprandial lipoprotein levels in patients with T2DM [38•]. They studied 36 subjects with T2DM in a double-blind, cross-over study using sitagliptin (100 mg/d) or placebo for 6 weeks with a 4 week washout period between the 2 phases. At the end of each phase of treatment, patients underwent an oral lipid tolerance test and blood samples were taken over an 8 hour period. Compared with placebo, sitagliptin therapy (100 mg/day) resulted in a significant decrease in the area under the curve (AUC) for plasma triglyceride, plasma apoB-48, plasma apoB, VLDL-cholesterol and for free fatty acids. Also they showed a significant increase in AUC for postprandial plasma intact GLP-1 and GIP. Most recently, Eliasson et al. also conducting a study of a different DPP-4 inhibitor, alogliptin (Alo), compared with pioglitazone on postprandial lipemia [39]. They assessed the effect of Alo monotherapy, 25 mg/d and Alo co-administered with pioglitazone (Pio) 30 mg/d vs placebo on triacylglycerol (TG)rich lipoproteins in T2DM before and after a high-fat meal. Seventy-one patients were studied on usual anti-diabetic therapies in a 16-week duration study, which was placebo controlled. Patients received a high-fat mixed meal before and 4 and 16 weeks after randomization to Alo, Alo/Pio, and placebo, (n=25, 22, and 24, respectively). Blood samples were collected up to 8 hours after meal injection. At 16 weeks Alo and Alo/Pio vs placebo produced similar significant reductions in total postprandial TG responses as well as in chylomicron TG, and VLDL1 TG. Postprandial chylomicron apoB-48 AUC showed a significant decrease following Alo. Interestingly they did not show a significant change in postprandial FFA levels amongst groups, but they showed a significant increase in GLP-1. To summarize, compared with placebo, 16-weeks therapy of Alo resulted in a significant decrease in the incremental AUC0-8h for TGs, for chylomicron TGs, for chylomicron apoB-48, for chylomicron apoB-100, VLDL1 TG, VLDL1 apoB-48, and VLDL1 apoB.
Curr Diab Rep (2014) 14:463
Page 5 of 7, 463
Thus, although it appears that DPP-4 inhibitors have a neutral effect on the fasting lipid profile, studies from at least 3 groups have now confirmed that 3 different DPP-4 inhibitors significantly attenuate the postprandial hyperlipemia of both intestinal and hepatic origin in T2DM and this class effect was paralleled by an increase in plasma incretin levels. Since similar effects have been reported for GLP-1 receptor agonists, increased GLP-1 activity resulting from DPP-4 inhibition could be advanced as the major mechanism. This could be a very critical and important mechanism for potential reduction in atherosclerosis and cardiovascular events.
Other Possible Mechanisms Underlying Beneficial Effect of DPP-4 Inhibitors on Cardiovascular Risk A potential mechanism of vascular protection by DPP-4 inhibitors may be by limiting oxidative stress. Increased oxidative stress is a hallmark of T2DM [44]. Both circulating and cellular biomarkers have clearly defined diabetes as a condition with increased oxidative stress. Data with regards to the effect of DPP-4 inhibitors on oxidative stress are scant. Recently, Rizzo et al. showed in a study of duration of 12-weeks that compared with baseline, 2 DPP-4 inhibitors, sitagliptin (100 mg per day) and vildagliptin (100 mg per day), n=45 in both groups, resulted in a significant reduction in plasma of an accepted biomarker of oxidative stress, nitrotyrosine. It is important to emphasize that both sitagliptin and vildagliptin treatment for 3 months induced reductions in prandial as well as interprandial nitrotyrosine levels [14•]. Although nitrotyrosine levels were significantly decreased with both sitagliptin therapy and vildagliptin therapy the authors suggested that vildagliptin was superior to sitagliptin in reducing oxidative stress based on their findings [13]. Koren et al. compared sitagliptin 100 mg/ d to glibenclamide 5 mg/d for a duration of 3 months on various plasma biomarkers in 34 patients with T2DM. Interestingly in this study, they did not show a significant reduction in hsCRP or 8-Isoprostane, another accepted biomarker of oxidative stress [45]. Further studies examining the effect of DPP4 inhibitors on both circulating and cellular biomarkers of oxidative stress is
urgently needed to confirm if indeed these DPP-4 inhibitors are antioxidants in T2DM. There are other potential mechanisms that may contribute to the possible anti-atherosclerotic benefits of DPP-4 inhibitors. However, these mechanisms have not been shown consistently or the observations are preliminary. For example, (1) some studies have reported that DPP-4 inhibitors can lower blood pressure by 2–3 mm Hg [40]. However, this effect has not been seen consistently; (2) one study reported that sitagliptin can inhibit platelet aggregability in healthy subjects and patients with T2DM [41]. This observation needs confirmation; and (3) increased CD26 expression in mononuclear cells appears to be associated with decreased recovery of left ventricular function following myocardial infarction [42]. Treatment with sitagliptin decreased CD26 expression in mononuclear cells and improved the capacity in vitro of mononuclear cells to “home in” to infarct area and help in repair and recovery. This concept will be further tested in an ongoing trial of sitagliptin and granulocyte colony stimulating factor in patients with acute myocardial infarction [43].
DPP-4 Inhibitors, Atherosclerosis, and CVD Barbieri et al. reports on the effect of 2 DPP-4 inhibitors, Sitagliptin (100 mg/day) and Vildagliptin (50 mg twice a day) on carotid intimal-medial thickness (IMT) an accepted surrogate of clinical atherosclerosis [46], over a 12 week period in an open label prospective study [14•]. There were 45 patients with T2DM in each group inadequately controlled on metformin therapy. At baseline, IMT correlated with LDL, total cholesterol, inflammatory mediators, and oxidative stress and measures of glycemia (HbA1c, fasting glucose, postprandial glucose concentrations, and MAGE). Blood pressure and fasting lipids did not change after 3 months. In both groups there was a significant reduction in carotid IMT after 12 weeks and the data suggest that there was a significantly greater reduction in IMT with Vildagliptin. A major weakness of this study was the lack of an arm without a DPP-4 inhibitor. They also showed that the benefit on IMT correlated with change in
Table 2 Summary of potential anti-atherosclerotic effects of different DPP-4 inhibitors
↓ Postprandial hyperlipidemia ↑ Endothelial function Anti-inflammatory effects ↓ Carotid IMT
Vildagliptin
Sitagliptin
Saxagliptin
Alogliptin
Linagliptin
+ + + +
+ + + +
-
+ -
-
DPP-4 dipeptidyl-peptidase-IV, IMT intimal-medial thickness + denotes published studies support this effect − denotes no published studies to date
463, Page 6 of 7
MAGE, supporting the hypothesis in which the study was predicated. In multivariate analyses, change in MAGE and baseline LDL cholesterol were predictors of change in IMT, explaining 26 % of the variability. However, they also showed a significant reduction in inflammatory score comprising IL-6, IL-18, and TNF-α and a biomarker of oxidative stress, Nitrotyrosine. Authors postulated that DPP-4 inhibitors mediated reduction in MAGE decreases atherosclerosis via reduction of inflammation and oxidative stress however, their findings of a reduction in IMT with sitagliptin without a change in MAGE contradicts their premise of the pivotal role of MAGE accounting for the benefit. Hence, in what can be viewed at best as an exciting preliminary report, it appears that DPP-4 inhibitors have the potential of reducing atherosclerosis burden and hopefully CVE in the ongoing large trials [26]. Although reducing MAGE can be advanced as a plausible mechanism based on the published literature this class of drugs improve endothelial function, and reduce inflammation and postprandial hyperlipidemia. The authors did not comment on treatment effects on postprandial triglycerides or FFA and this could be an additional mechanism explaining their observations. In a study of 14 patients with CAD (1 with diabetes) and preserved LV function, using dobutamine stress echocardiography to assess LV dysfunction, a single dose of Sitagliptin 100 mg/d vs placebo by increasing GLP-1 improved global and regional LV performance in response to stress and mitigated postischemic stunning [47]. Although both these preliminary studies are very promising we must await the results of the randomized prospective trials with cardiovascular endpoints, which are ongoing since they will answer this provocative and promising question, which appears to be backed by the retrospective studies [6, 48, 49].
Conclusions DPP-4 inhibitors offer a convenient and attractive therapy for patients with T2DM because they do not cause weight gain or hypoglycemia. However, the DPP-4 enzyme is widely expressed in many tissues of the human body such as endothelium and epithelial cells, intestines, kidneys, brain, and myocardium. DPP-4/CD26 is expressed on circulating Tlymphocytes. Interesting preliminary data highlighting the effects of this class of medications on cardiovascular risk factors and surrogate markers of atherosclerosis have emerged. Therefore, the pleiotropic effects of DPP-4 inhibitors in the realm of cardiovascular disease have been garnering attention of investigators around the world. DPP-4 inhibitors are clearly anti-inflammatory, improve endothelial dependent vasodilation, and reduce postprandial lipemia. Table 2 summarizes the potential anti-atherosclerotic effects of the different DPP-4 inhibitors. It would appear that both sitagliptin and
Curr Diab Rep (2014) 14:463
vildagliptin hold the greatest promise with respect to reduction in CVE based on the published studies. Preliminary data suggest that they may reduce oxidative stress and increase endothelial progenitor cell number. Vildagliptin in particularly appears to effectively reduce glycemic excursions. It remains to be seen whether DPP-4 inhibitors can hold up to their promise in long-term randomized controlled trials that have cardiovascular events as the primary endpoint.
Acknowledgments We would like to thank Gerred Smith for help with manuscript preparation. Compliance with Ethics Guidelines Conflict of Interest Sandeep Dhindsa has received honoraria from Abbvie and Janssen. Ishwarlal Jialal serves on the Speakers’ Bureau and received honoraria from Merck. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References Papers of particular interest, published recently, have been highlighted as: • Of importance
1.
Seshasai SR, Kaptoge S, Thompson A, et al. Emerging risk factors collaboration: diabetes mellitus, fasting glucose, and risk of causespecific death. N Engl J Med. 2011;364:829–41. 2. Wing RR, Bolin P, Brancati FL, et al. Look AHEAD Research Group: cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369:145–54. 3. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854–65. 4. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the proactive study (prospective pioglitazone clinical trial in macrovascular events): a randomized controlled trial. Lancet. 2005;366:1279–89. 5. Hemmingsen B, Lund SS, Gluud C, et al. Intensive glycemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomized clinical trials. BMJ. 2011; (PMID: 22115901). 6. Jose T, Inzucchi SE. Cardiovascular effects of the DPP-4 inhibitors. Diabetes Vasc Dis Res. 2012;9:109–16. 7. Monami M, Ahren B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metabol. 2013;15:112–20. 8. Monami M, Dicembrini I, Martelli D, Mannucci E. Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized clinical trials. Curr Med Res Opin. 2011;27 Suppl 3:57–64. 9. Scheen AJ. Cardiovascular effects of gliptins. Nat Rev Cardiol. 2013;10:73–84.
Curr Diab Rep (2014) 14:463 10.
11.
12.
13.
14.•
15.
16.
17. 18.
19.
20.•
21.
22.
23.
24. 25.
26. 27. 28.•
29.
Nauck MA. Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. Am J Med. 2011;124(1 Suppl):S3–S18. Muscelli E, Casolaro A, Gastaldelli A, et al. Mechanisms for the antihyperglycemic effect of sitagliptin in patients with type 2 diabetes. J Clin Endocrinol Metab. 2012;97:2818–26. Marfella R, Barbieri M, Grella R, et al. Effects of vildagliptin twice daily vs sitagliptin once daily on 24-hour acute glucose fluctuations. J Diabetes Complicat. 2010;24:79–83. Rizzo MR, Barbieri M, Marfella R, Paolisso G. Reduction of oxidative stress and inflammation by blunting daily acute glucose fluctuations in patients with type 2 diabetes: role of dipeptidyl peptidase-IV inhibition. Diabetes Care. 2012;35:2076–82. Barbieri M, Rizzo MR, Marfella R, et al. Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors. Atherosclerosis. 2013;227:349–54. Interesting preliminary study showing benefit of Vildagliptin and Sitagliptin on sub-clinical atherosclerosis as evidenced by a decrease in carotid IMT. Di Flaviani A, Picconi F, Di Stefano P, et al. Impact of glycemic and blood pressure variability on surrogate measures of cardiovascular outcomes in type 2 diabetic patients. Diabetes Care. 2011;34:1605–9. Monnier L, Mas E, Ginet C, et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006;295:1681–7. Orasanu G, Plutzky J. The pathologic continuum of diabetic vascular disease. J Am Coll Cardiol. 2009;53:S35–42. Nystrom T, Gutniak MK, Zhang Q, et al. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004;287:E1209–15. Irace C, DeLuca S, Shehaj E, et al. Exenatide improves endothelial function assessed by flow mediated dilation technique in subjects with type 2 diabetes: results from an observational research. Diabetes Vasc Dis Res. 2012;10:72–7. van Poppel PCM, Netea MG, Smits P, Tack CJ. Vildagliptin improves endothelium-dependent vasodilatation in type 2 diabetes. Diabetes Care. 2011;34:2072–7. First report showing a significant improvement in flow mediated dilation with Vildagliptin therapy compared with acarbose. Kubota Y, Miyamoto M, Takagi G, et al. The Dipeptidyl Peptidase4 Inhibitor Sitagliptin improves vascular endothelial function in Type 2 Diabetes. J Korean Med Sci. 2012;27:1364–70. Matsubara J, Sugiyama S, Akiyama E, et al. Dipeptidyl Peptidase-4 Inhibitor, Sitagliptin, improves endothelial dysfunction in association with its anti-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes. Circ J. 2013;77:1337–44. Hein TW, Singh I, Vasquez-Vivar J, et al. Human C-reactive protein induces endothelial dysfunction and uncoupling of eNOS in vivo. Atherosclerosis. 2009;206:61–8. Devaraj S, Jialal I. Dysfunctional endothelial progenitor cells in metabolic syndrome. Exp Diabetes Res. 2012; (PMID: 21941528). Fadini GP, Boscaro E, Albiero M, et al. The oral dipeptidyl peptidase4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes. Diabetes Care. 2010;33:1607–9. Jialal I, Bajaj M. Commentary: DPP-4 inhibitors and atherosclerosis: the promise. Atherosclerosis. 2013;227:224–5. Devaraj S, Dasu MR, Jialal I. Diabetes is a proinflammatory state: a translational perspective. Expert Rev Endocrinol Metab. 2010;5:19–28. Makdissi A, Ghanim H, Vora M, et al. Sitagliptin exerts an antiinflammatory action. J Clin Endocrinol Metab. 2012;97:3333–41. First comprehensive report on the anti-inflammatory effects of Sitagliptin. Acute (
