Journal of Cardiovascular Nursing

Vol. 31, No. 3, pp 274Y283 x Copyright B 2016 Wolters Kluwer Health, Inc. All rights reserved.

Mechanisms of Cardiovascular Injury in Type 2 Diabetes and Potential Effects of Dipeptidyl Peptidase-4 Inhibition Betsy Dokken, NP, PhD, CDE Background: Cardiovascular (CV) disease is the major cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). The pathogenesis of CV disease in T2DM is complex and multifactorial and involves direct and indirect injury to the vasculature and heart. The impact of intensive glucose-lowering therapy with antihyperglycemic agents on CV outcomes is not clear, and questions remain as to which glucose-lowering agents may be beneficial to CV health in patients with T2DM. Purpose: This review discusses findings regarding the known mechanisms of CV injury in T2DM and current knowledge regarding the potential cardioprotective effects of dipeptidyl peptidase-4 (DPP-4) inhibitors. Conclusions: Dipeptidyl peptidase-4 inhibitors are relatively new antihyperglycemic agents. Their main mechanism of action is to inhibit the degradation of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic peptide by DPP-4. By increasing levels of glucagon-like peptide-1, glucose-dependent insulin secretion is enhanced, glucagon secretion is suppressed, and the rate of gastric emptying is decreased. Dipeptidyl peptidase-4 also degrades other substances that are important in the regulation of CV function and inflammation. Animal studies, small observational studies in humans, and analyses of clinical trial data suggest that DPP-4 inhibitors may have beneficial CV effects. Recent prospectively designed CV outcomes trials with saxagliptin and alogliptin in patients with T2DM and high CV risk presented evidence that these DPP-4 inhibitors neither increased nor decreased adverse CV outcomes in this select patient population. Clinical Implications: Dipeptidyl peptidase-4 inhibitors are promising therapies for the treatment of T2DM. Able to improve glycemic control without the risk of weight gain or hypoglycemia, they provide a safe alternative to sulfonylureas and are an effective adjunct to metformin. To date, this class of drugs seems to be at least neutral in terms of CV effects. Time will tell if these findings translate into a benefit for our patients. KEY WORDS:

cardiovascular disease, DPP-4 inhibitors, incretin, type 2 diabetes mellitus

C

ardiovascular (CV) disease is highly prevalent in patients with type 2 diabetes mellitus (T2DM) and is the primary cause of morbidity and mortality in these patients.1 Individuals with T2DM but without previous myocardial infarction have a risk of CV morbidity and mortality equivalent to that of individuals without Betsy Dokken, NP, PhD, CDE Assistant Professor of Medicine, Section of Endocrinology and Diabetes Research Program, University of Arizona, Tucson. Conflicts of interest and source of funding: Dr Dokken has been a member of advisory boards for Sanofi and Takeda Pharmaceuticals and is a speaker for Takeda Pharmaceuticals. She received no financial or monetary transfer of value for the writing of this manuscript. Dr Dokken prepared the initial draft of this manuscript and reviewed all revisions; subsequent editorial assistance was provided by Richard M. Edwards, PhD, and Janet E. Matsuura, PhD, of Complete Healthcare Communications, Inc. and was funded by Bristol-Myers Squibb and AstraZeneca.

Correspondence Betsy Dokken, NP, PhD, CDE, Department of Medicine, 1656 East Mabel St, University of Arizona, Tucson, AZ 85724-5218 ([email protected]). DOI: 10.1097/JCN.0000000000000245

diabetes but with previous myocardial infarction.2,3 For these reasons, diabetes is a variable in the assessment of CV risk.4 Current clinical practice recommendations highlight a variety of therapies to decrease CV risk in patients with T2DM, including aggressive management of blood pressure and lipids.1,5 However, the impact of intensive glucose-lowering therapy with antihyperglycemic agents on macrovascular outcomes is not entirely clear. In recent years, findings from several large randomized controlled trials have suggested no benefit,6,7 and possible harm,8 of intensive glycemic control on CV outcomes. Previous studies have suggested that some medications used to improve glycemic control in T2DM increase the risk for adverse CV effects. Sulfonylureas were historically tied to an increase in CV risk owing to the finding of higher CV mortality in patients treated with the sulfonylurea tolbutamide compared with placebo or insulin in the University Group Diabetes Program.9 This finding was not confirmed by the larger prospective United Kingdom Prospective Diabetes Study.10 Thiazolidinediones

274 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Cardiovascular Effects of DPP-4 Inhibitors 275

are associated with weight gain and fluid retention, which may contribute to an increased risk of heart failure in susceptible individuals.5,11 What makes these findings disturbing is that these drugs were all in widespread use before their CV effects had been fully elucidated. Moreover, in the case of thiazolidinediones, a CV benefit was suggested by the results of preclinical12,13 and early clinical14Y16 studies. Dipeptidyl peptidase-4 (DPP-4) inhibitors are relatively new antihyperglycemic agents. Their primary mechanism of action is to inhibit the degradation of the incretin hormones glucagon-like peptide-1 and glucosedependent insulinotropic peptide (Figure). By inhibiting the degradation of these endogenous hormones, the plasma concentrations are increased and subsequent effects of the hormones are enhanced. Increased glucagonlike peptide-1 action enhances glucose-dependent insulin secretion, suppresses glucagon secretion, and decreases the rate of gastric emptying,17 all of which can contribute to improved glycemic control in patients with T2DM.18 There are currently 5 different DPP-4 inhibitors approved in the United States or Europe for the treatment of diabetes: linagliptin, saxagliptin, sitagliptin, vildagliptin (Europe only), and alogliptin. These agents are weight neutral with a low risk of hypoglycemia when used as monotherapy or in combination with metformin.19 This article summarizes findings regarding the known mechanisms of CV injury in T2DM and current knowledge regarding the potential cardioprotective effects of DPP-4 inhibitors.

FIGURE. The incretin system. After a meal, neuroendocrine cells of the intestine secrete the incretin hormones glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Both hormones stimulate insulin secretion by pancreatic "-cells, in a glucose-dependent fashion. GLP-1 also decreases glucagon secretion from pancreatic !-cells, slows gastric emptying, and increases satiety. The enzyme dipeptidyl peptidase-4 (DPP-4) rapidly degrades both GLP-1 and GIP to inactive metabolites. DPP-4 inhibitors increase the half-life and bioavailability of GLP-1 and GIP, enhancing their physiological effect. Reproduced with permission from Jose T, Inzucchi SE. Cardiovascular effects of the DPP-4 inhibitors. Diab Vasc Dis Res 2012;9:109.

Methods A search of the PubMed database from 2009 to 2014 using the terms DPP-4 inhibitor, sitagliptin, saxagliptin, alogliptin, and linagliptin in combination with type 2 diabetes and cardiovascular disease was conducted for English-language articles. Bibliographies of retrieved papers were also searched for relevant publications. Articles were selected if they defined a mechanism of a potential CVeffect of DPP-4 inhibition. Meta-analyses of CVevents and CV outcomes trials with DPP-4 inhibitors were also included.

Mechanisms of Cardiovascular Injury in Type 2 Diabetes Diabetes is 1 of multiple risk factors, often occurring simultaneously in the same patient, that can initiate the pathologic continuum of CV disease.20 The continuum includes atherosclerosis, coronary artery disease, coronary microvascular dysfunction, coronary thrombosis, myocardial ischemia and infarction, arrhythmias, deleterious remodeling, ventricular enlargement, heart failure, and end-stage heart disease. This clinical continuum reflects a pathophysiologic progression from oxidative and mechanical stress and inflammation to early tissue dysfunction and injury, atherothrombosis, pathologic remodeling, heart failure, and death. The detrimental effects of T2DM on the CV system are multifactorial and involve direct and indirect injury to the vasculature and heart muscle.21,22 There are strong arguments to support the idea that the initial CV insult in diabetes is to the endothelium, the single-cell layer that lines all blood vessels, including those composing the capillary beds.23,24 The endothelium is the interface between the metabolic status of the patient and the vasculature; thus, any abnormalities in the blood, such as increased concentrations of lipids, glucose, or proinflammatory cytokines, can impair endothelial function.25 Hyperglycemia promotes altered vascular permeability,26 inflammation,22 endothelial apoptosis,23 and a procoagulant state27Vfactors that contribute to microvascular dysfunction and atherosclerosis. In addition to the adverse effects of hyperlipidemia and hyperglycemia on the vasculature, endothelial progenitor cells are reduced and dysfunctional in patients with T2DM.28 Endothelial progenitor cells circulate in the blood, have the ability to differentiate into endothelial cells, and are required for the repair of injured blood vessels and development of new vessels.28 Patients with T2DM also have a reduced incretin effect.29 The incretin effect is defined as the amplification of insulin secretion that is observed when glucose is taken orally as opposed to infused intravenously to provide similar plasma glucose concentrations.30 In fact, impaired insulin secretion in response to oral carbohydrate is found

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276 Journal of Cardiovascular Nursing x May/June 2016 in patients with T2DM very early in the course of the disease.30 In a study conducted in a group of healthy, glucose-tolerant first-degree relatives of patients with T2DM, Jensen et al31 induced insulin resistance and analyzed blood glucose responses after both intravenous and oral glucose. They found a reduction in the incretin effect in those who developed insulin resistance versus those who did not, even when normal glucose tolerance remained. Those who developed glucose intolerance in addition to insulin resistance demonstrated a further decline in the incretin effect. These changes were not caused by altered secretion of incretins but by a loss of the insulinotropic properties of the incretin hormones. In patients with overt T2DM, efficient disposal of orally ingested carbohydrate may be completely lost,30 as commonly observed in clinical practice. It appears that postprandial glucagon-like peptide-1 secretion is defective in patients with a long duration of T2DM as well as those with very poor glycemic control.30 However, in contrast to the study by Jensen et al,31 Vilsboll et al32 found that infusion of pharmacologic doses of glucagon-like peptide-1 elicited a robust first-phase insulin secretion from "-cells. To date, there is no evidence to suggest that the loss of glucagon-like peptide-1 secretion or action is associated with the high burden of CV disease in patients with T2DM. However, there is ample evidence that excessive postprandial glycemic excursions are associated with endothelial dysfunction and increased CV risk.33 Therefore, we can speculate that because incretin-based therapies target postprandial hyperglycemia, they also may improve vascular function and reduce the risk of CV disease in patients with T2DM.34

Preclinical and Human Observational Studies Effects of Glucagon-Like Peptide-1 and Glucagon-Like Peptide-1 Receptor Agonists on the Cardiovascular System In recent years, a number of investigators have found beneficial effects of glucagon-like peptide-1 and glucagonlike peptide-1 receptor agonists in the heart and vasculature. Because of the hormone’s ability to mitigate postprandial hyperglycemia35,36 and hypertriglyceridemia37,38 via multiple mechanisms, it also mitigates the metabolically mediated postprandial endothelial dysfunction observed in patients with T2DM.39 However, glucagon-like peptide-1 is also cardioprotective and vasculoprotective, independent of its metabolic effects. In vitro, glucagon-like peptide-1 or glucagon-like peptide-1 receptor agonist prevented endothelial cell injury after exposure to advanced glycation end products40 and oxidative stress.41 The mechanisms for this protection are not yet clear. However, early in vitro findings suggest that glucagon-like peptide-1 modulates intracellular calcium signaling in human coronary endothelial cells,42

and thus may attenuate deleterious calcium overload in the heart. Moreover, glucagon-like peptide-1 attenuates the secretion of endothelium-derived contracting factors in coronary endothelial cells,42 which may explain, in part, its ability to improve coronary blood flow in experimental models.43 Activation of glucagon-like peptide-1 receptor attenuated endothelial dysfunction in a mouse model prone to atherosclerosis, reduced the expression of vascular adhesion molecules in cultured endothelial cells,44 and improved endothelial function in hypertensive rats.45 In humans, glucagon-like peptide-1 improved endothelial function in patients with coronary artery disease, but findings of improvement or no effect have been reported for healthy subjects.46,47 In addition, glucagon-like peptide-1 and glucagon-like peptide-1 receptor agonist protect myocardium from ischemia-reperfusion injury in animal models.48Y53 In fact, early evidence suggests that glucagon-like peptide-1 receptor expression is upregulated in the heart in response to ischemia.54 The cardioprotective and vasculoprotective effects of glucagon-like peptide-1 appear to be partially independent of the known glucagon-like peptide-1 receptor because neither pharmacologic blockade of the glucagonlike peptide-1 receptor signaling pathway55 nor knockout of the glucagon-like peptide-1 receptor in mice55 completely abolishes all of the observed effects. Effects of Dipeptidyl Peptidase-4 Inhibition on the Cardiovascular System Dipeptidyl peptidase-4 is a widely expressed enzyme that degrades multiple bioactive substrates. Dipeptidyl peptidase-4 exists as both a membrane-bound form and a circulating form.56 In the CV system, DPP-4 has been localized to both vascular smooth muscle and endothelial cells.56 Dipeptidyl peptidase-4 activity in the systemic circulation can influence the concentration of glucagon-like peptide-1 and other substrates reaching the coronary vasculature and the myocardium and thus may promote CV effects. Some of the substrates that are degraded by DPP-4 include brain natriuretic peptide, stromal cellYderived factor-1!, neuropeptide Y,56 and the protein RANTES57 (regulated upon activation, normal T cell expressed and secreted58), as well as the incretins glucagon-like peptide-1, glucagon-like peptide-2, and insulinotropic peptide. Several of these DPP-4 substrates are associated with protective CV effects in experimental models, and prolonging the action of these cardioprotective DPP-4 substrates may provide a mechanism by which DPP-4 inhibitors may reduce CV risk via multiple signaling pathways. Endogenous brain natriuretic peptide plays a key role in regulating body fluid homeostasis and vascular tone. Brain natriuretic peptide is upregulated in patients with heart failure59 and is commonly used clinically as a

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Cardiovascular Effects of DPP-4 Inhibitors 277

biomarker for cardiac remodeling.60 However, patients with heart failure seem to have an attenuated response to brain natriuretic peptide. Because brain natriuretic peptide is cleaved by DPP-4, yielding a truncated version that has reduced activity, Gomez et al59 investigated the effects of DPP-4 inhibition in a porcine model of pacing-induced heart failure. In this model, addition of sitagliptin preserved glomerular filtration rate, reduced heart rate, increased stroke volume, and potentiated the positive inotropic effects of infused brain natriuretic peptide. Compared with the pigs receiving placebo, myocardial gene expression of brain natriuretic peptide was not upregulated in those receiving sitagliptin. In contrast, Yin et al61 found that both myocardial protein expression and plasma concentration of brain natriuretic peptide were increased in a rat model of postmyocardial infarction heart failure, and this was unchanged by pretreatment with vildagliptin. The potential influence of chronic DPP-4 inhibition on endogenous levels of brain natriuretic peptide, which might possibly interfere with the clinical interpretation of brain natriuretic peptide levels in patients with heart failure and the possible CV benefits of DPP-4 inhibition, requires further study. Stromal cellYderived factor-1! is a DPP-4 substrate that mobilizes endothelial progenitor cells to areas that require repair, such as the myocardium after an ischemic event.62 Interestingly, endothelial progenitor cells are present in decreased numbers in diabetes (types 1 and 2), and their proliferation, adhesion, and ability to repair damaged vasculature are impaired in patients with diabetes.63,64 Theoretically, DPP-4 inhibition may improve EPC function in diabetes and improve endothelial function and tissue repair. In fact, stromal cellYderived factor-1! is upregulated in the heart after myocardial infarction in mice65 and protects the heart after myocardial infarction by promoting the formation of new blood vessels.66 Moreover, treatment with the DPP-4 inhibitor sitagliptin was associated with an increase in endothelial progenitor cells in patients with T2DM, although EPC function was not investigated in this study.67 Neuropeptide Y is best known as a neuroendocrine peptide; however, it is the most abundant neuropeptide in the heart, particularly in coronary arteries. Neuropeptide Y mediates vasoconstriction68 and arterial smooth muscle proliferation69; therefore, DPP-4 inhibition could possibly lead to increased levels of circulating neuropeptide Y that may promote deleterious effects on blood pressure and atherosclerosis. In 1 study, the DPP-4 inhibitor sitagliptin was shown to augment the renovascular effects of the potent vasoconstrictor angiotensin II in isolated perfused kidneys from hypertensive rats.70 However, in a clinical trial, sitagliptin had a very modest blood pressureYlowering effect in patients with mild to moderate hypertension who did not have diabetes.71 Moreover, treatment of diabetic apolipoprotein E knock-

out mice (prone to atherosclerosis) with the DPP-4 inhibitor alogliptin reduced the size of atherosclerotic plaques.72 Similar antiatherogenic effects were found in low-density lipoprotein receptor knockout mice, also prone to atherosclerosis.73 High glucose concentrations inhibit endothelial nitric oxide synthase in vitro,74 and T2DM is associated with decreased nitric oxide synthesis.75,76 The reduced bioavailability of nitric oxide may account, in part, for impaired endothelium-dependent vasodilation77 and other aspects of vascular disease in T2DM.78 In hypertensive animal models, DPP-4 inhibitors increase the bioavailability of nitric oxide, improve endothelial function, and reduce blood pressure and inflammation.79,80 In Zucker obese rats fed a high-fat diet (T2DM model), saxagliptin improved nitric oxide release from endothelial cells and reduced inflammatory biomarkers.81 Moreover, glucagon-like peptide-1 increased nitric oxide and myocardial glucose uptake in models of cardiac ischemia82 and heart failure.83 The protein RANTES is a chemokine involved in the inflammatory response. To date, no studies have directly investigated the relationship between DPP-4 inhibition and changes in the circulation of endogenous RANTES. In addition, insulinotropic peptide is released from intestinal endocrine cells after food intake. Like glucagon-like peptide-1, it acts as an insulin secretagogue.84 At this time, the role of insulinotropic peptide in the CV system has not been as well characterized as that of glucagon-like peptide-1. As discussed above, glucagon-like peptide-1 has multiple beneficial effects on the heart and vasculature.56 Glucagon-like peptide-2, which is cosecreted along with glucagon-like peptide-1 from intestinal endocrine cells, binds to and activates a specific receptor (the glucagon-like peptide-2 receptor), expressed predominantly in the gastrointestinal tract and the central nervous system.85,86 Although it has vasoactive properties, its effects are localized to the gut, and to date, there is no evidence linking glucagon-like peptide-2 to the heart or systemic circulation.86

Cardiovascular Effects of Dipeptidyl Peptidase-4 Inhibition: Clinical Evidence Until recently, information on CV risk and potential benefits of DPP-4 inhibitors has been limited to small studies and meta-analyses performed on data from clinical studies. For example, in a pilot study of patients with coronary artery disease, a single dose of the DPP-4 inhibitor sitagliptin improved left ventricular function during dobutamine stress testing.87 A meta-analysis of data from 70 randomized controlled clinical trials found that DPP-4 inhibitors reduced the risk of CV events, especially MI, and all-cause mortality compared with placebo or comparator.88 However, the small number

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278 Journal of Cardiovascular Nursing x May/June 2016 of trials for some DPP-4 inhibitors and differences in reporting major adverse cardiac events precluded differentiation among the drugs. Recent meta-analyses of clinical trials of sitagliptin,89 saxagliptin,90 linagliptin,91 vildagliptin,92 and alogliptin93 found that these DPP-4 inhibitors were not associated with an increased risk of CV events, and some analyses suggested a potential reduction of CV events.90,91 However, these meta-analyses are based on data from phase 2 and 3 clinical trials that typically exclude patients at high CV risk.

All DPP-4 inhibitors have been or are currently being assessed in large, multicenter trials for adverse CV outcomes (Table 1). These outcome trials are primarily intended to meet regulatory requirements to show that the drugs do not increase CV disease risk in patients with T2DM. In addition, some studies are designed to test the hypothesis that DPP-4 inhibitors have CV benefits in patients with T2DM. In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus trial,94

TABLE 1 Ongoing and Recently Completed Cardiovascular Outcome Trials With Dipeptidyl Peptidase-4 Inhibitors Trial

Treatment

N

Patients

SAVOR NCT01107886

Saxagliptin vs placebo

16 492

EXAMINE NCT00968708

Alogliptin vs placebo

TECOS NCT00790205

Sitagliptin vs placebo

14 000

Men and women aged Q40 y with T2DM and established CV disease and/or multiple risk factors Men and women aged Q18 y with T2DM and acute MI or unstable angina requiring hospitalization Men and women aged Q50 y with T2DM and preexisting CV disease

CAROLINA NCT01243424

Linagliptin vs glimepiride

6000

CARMELINA

Linagliptin vs placebo

8300

5380

Men and women aged 40Y85 y with preexisting CV disease or specified diabetes end-organ damage, or aged Q70 y, or Q2 specified CV risk factors Men and women Q18 y with T2DM and albuminuria and previous macrovascular disease and/or impaired renal function

Primary Outcome

Status/Estimated Completion

Reference

Composite of CV death, nonfatal MI, or nonfatal ischemic stroke

Completed

Scirica et al94

Composite of CV death, nonfatal MI, or nonfatal stroke

Completed

White et al95

Composite of CV death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization Composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina

December 2014

Green et al97

September 2018

Rosenstock et al98

January 2018

ClinicalTrials.gov99

Composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina pectoris. Secondary outcome of renal death, end-stage renal disease and a sustained decrease of Q50% in estimated glomerular filtration rate

Abbreviations: CARMELINA, Cardiovascular and Renal Microvascular Outcome Study With Linagliptin; CAROLINA, Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Patients With Type 2 Diabetes; CV, cardiovascular; EXAMINE, Examination of Cardiovascular Outcomes With Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome; MI, myocardial infarction; SAVOR, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus; T2DM, type 2 diabetes mellitus; TECOS, Trial Evaluating Cardiovascular Outcomes With Sitagliptin.

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Cardiovascular Effects of DPP-4 Inhibitors 279 TABLE 2 Results From the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial End-point

Saxagliptin (n = 8280), n (%)

Placebo (n = 8212), n (%)

Hazard Ratio (95% CI)

P

613 (7.3) 1059 (12.8)

609 (7.2) 1034 (12.4)

1.00 (0.89Y1.12) 1.02 (0.94Y1.11)

.99 .66

1.11 1.03 0.95 1.11 1.19 1.27 0.91 1.08

.15 .72 .52 .38 .24 .007 .18 .46

Primary composite end-point of CV death, MI, or stroke Secondary composite end-point of CV death, MI, stroke, hospitalization for unstable angina, heart failure, or coronary revascularization Individual component end-points Death from any cause Death from CV causes MI Ischemic stroke Hospitalization for unstable angina Hospitalization for heart failure Hospitalization for coronary revascularization Doubling of creatinine level, initiation of dialysis, renal transplantation, or creatinine >6.0 mg/dL Hospitalization for hypoglycemia

420 269 265 157 97 289 423 194

(4.9) (3.2) (3.2) (1.9) (1.2) (3.5) (5.2) (2.2)

53 (0.6)

378 260 278 141 81 228 459 178

(4.2) (2.9) (3.4) (1.7) (1.0) (2.8) (5.6) (2.0)

43 (0.5)

(0.96Y1.27) (0.87Y1.22) (0.80Y1.12) (0.88Y1.39) (0.89Y1.60) (1.07Y1.51) (0.80Y1.04) (0.88Y1.32)

1.22 (0.82Y1.83)

.33

94

Data are from Scirica et al. Abbreviations: CI, confidence interval; CV, cardiovascular; MI, myocardial infarction.

adult patients (N = 16 492) with T2DM and a history of established CV disease or multiple CV risk factors received saxagliptin or placebo for a median of 2.1 years. The primary end-point was a composite of CV death, nonfatal myocardial infarction, or nonfatal ischemic stroke. Throughout the trial, patients continued to receive standard-of-care antihyperglycemic (except for other DPP-4 inhibitors or glucagon-like peptide-1 receptor agonist) and CV disease therapy. Saxagliptin did not increase, nor did it decrease, the rate of adverse CV events compared with placebo (Table 2). More patients in the saxagliptin group (3.5%) than in the placebo group (2.8%) were hospitalized for heart failure (P = .007). However, these patients did not experience an increase in CV death, nonfatal myocardial infarction, or nonfatal stroke. This finding needs to be further investigated. Rates of adjudicated acute and chronic pancreatitis

were low (e0.3%) and similar across treatment groups. There were 12 cases of pancreatic cancer in the placebo group versus 5 cases in the saxagliptin group (P = .095). The Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care in Patients With T2DM and Acute Coronary Syndrome trial95 assessed the effects of alogliptin versus placebo on the primary composite end-point of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke in patients (N = 5380) with T2DM who had experienced either an acute myocardial infarction or unstable angina requiring hospitalization within 15 to 90 days of randomization. As in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus trial, patients continued to receive standard treatment for T2DM and CV risk factors. After a median follow-up of 18 months, alogliptin did not increase or decrease

TABLE 3 Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care in Patients With T2DM and Acute Coronary Syndrome Trial Alogliptin (n = 2701), n (%)

End-point Primary composite end-point of CV death, nonfatal MI, or nonfatal stroke Secondary composite end-point of CV death, nonfatal MI, nonfatal stroke, or urgent revascularization due to unstable angina within 24 h after hospital admission Individual component end points CV death Nonfatal MI Nonfatal stroke Death from any cause CV deathb

Placebo (n = 2679), n (%)

Hazard Ratio (95% CI)

P

a

.32

305 (11.3)

316 (11.8)

0.96 (e1.16)

344 (12.7)

359 (13.4)

0.95 (e1.14)a

.26

89 187 29 153 112

111 173 32 173 130

0.79 1.08 0.91 0.88 0.85

.10 .47 .71 .23 .21

(3.3) (6.9) (1.1) (5.7) (4.1)

(4.1) (6.5) (1.2) (6.5) (4.9)

Data are from White et al.95 Abbreviations: CI, confidence interval; CV, cardiovascular; MI, myocardial infarction; T2DM, type 2 diabetes mellitus. a Value in parenthesis is the upper boundary of the 1-sided repeated CI at ! = .01. b Deaths that occurred as primary end-point events and deaths that occurred after a nonfatal primary end-point event.

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(0.60Y1.04) (0.88Y1.33) (0.55Y1.50) (0.71Y1.09) (0.66Y1.10)

280 Journal of Cardiovascular Nursing x May/June 2016

What’s New and Important h Dipeptidyl peptidase-4 inhibitors improve glycemic control without the risk of weight gain or hypoglycemia, provide a safe alternative to sulfonylureas, and are an effective adjunct to metformin. h Preclinical studies using glucagon-like peptide-1 or DPP-4 inhibition suggest that DPP-4 inhibitors may be beneficial to CV health. h To date, this class of drugs appears to be at least neutral in terms of CV effects. Time will tell if these findings translate into a benefit for our patients.

5.

6.

7.

8.

the occurrence of the primary composite end-point (Table 3). A post hoc analysis found that similar proportions of patients receiving alogliptin (3.9%) and placebo (3.3%) were hospitalized for heart failure.96 Incidences of acute and chronic pancreatitis were low (e0.4%) and similar between alogliptin and placebo groups. There were no cases of pancreatic cancer.

9.

10.

Summary and Implications In conclusion, DPP-4 is an enzyme with multiple known substrates, affecting a variety of physiologic pathways. A growing body of preclinical data and observational studies in humans suggests that DPP-4 inhibition may provide beneficial CV effects. These effects can be explained by multiple mechanisms, acting via a number of endogenous peptides that are preserved at higher plasma concentrations owing to attenuated degradation by the enzyme DPP-4. Although some of these mechanisms are metabolic (decreased hyperglycemia and hyperlipidemia), many involve pathways that are independent of improved glycemic control. However, recent prospectively designed CV outcomes trials with saxagliptin and alogliptin in patients with T2DM and high CV risk presented evidence that these DPP-4 inhibitors neither increased nor decreased adverse CV outcomes in this select patient population. The results of CV outcomes trials with other DPP-4 inhibitors are forthcoming. Time will tell if these findings translate into a benefit for our patients. REFERENCES

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Mechanisms of Cardiovascular Injury in Type 2 Diabetes and Potential Effects of Dipeptidyl Peptidase-4 Inhibition.

Cardiovascular (CV) disease is the major cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). The pathogenesis of CV dis...
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