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Potential Impact of Dipeptidyl Peptidase-4 Inhibitors on Cardiovascular Pathophysiology in Type 2 Diabetes Mellitus
DOI: 10.3810/pgm.2014.05.2756
Michael H. Davidson, MD University of Chicago, Pritzker School of Medicine, Chicago, IL
Abstract: Cardiovascular (CV) disease remains 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 includes abnormalities in endothelial cells, vascular smooth muscle cells, myocardium, platelets, and the coagulation cascade. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a newer class of agents that act by potentiating the action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. This review summarizes CV disease pathophysiology in T2DM and the potential effect of DPP-4 inhibitors on CV risk in patients with T2DM. Preclinical and small observational studies and post hoc analyses of clinical trial data suggest that DPP-4 inhibitors may have beneficial CV effects. Some effects of DPP-4 inhibitors are GLP-1 dependent, whereas others may be due to GLP-1–independent actions of DPP-4 inhibitors. Analyses of major adverse CV events occurring during clinical development of DPP-4 inhibitors found no increased risk of CV events or mortality and even a potential reduction in CV events. Two large CV outcome trials have been completed and report that saxagliptin and alogliptin did not increase or decrease adverse CV outcomes in patients with T2DM and CV disease or at high risk for adverse CV events. More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure, and there was a similar numerically increased risk of hospitalization for heart failure with alogliptin; however, the risk was not significantly greater compared with placebo. Dipeptidyl peptidase-4 inhibitors may affect some of the pathologic processes involved in the increased CV risk inherent in T2DM. Keywords: cardiovascular diseases; diabetes mellitus; dipeptidyl peptidase-4 inhibitor; endothelium
Introduction
Correspondence: Michael H. Davidson, MD, University of Chicago, Pritzker School of Medicine, Department of Medicine, 150 E. Huron Street, Suite 900, Chicago, IL, 60611. Tel: 773-834-4150 Fax: 908-741-6521 E-mail: [email protected]. edu
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Cardiovascular (CV) disease is the most common cause of mortality in patients with type 2 diabetes mellitus (T2DM) and accounts for approximately two thirds of deaths in these patients.1 Findings from epidemiologic studies have established an association between hyperglycemia and the risk for CV events and CV mortality.2 However, the CV benefits of intensive glycemic control with standard diabetes medications (metformin, sulfonylureas, thiazolidinediones, or insulin) remain in question.3 Indeed, there is some evidence that particular diabetes medications (rosiglitazone and possibly older sulfonylureas) may be associated with adverse CV events.4,5 Because of these uncertainties, regulatory agencies now require a more extensive assessment of CV risk for all new diabetes medications.6 New diabetes medications should have no deleterious effects on CV risk factors, have documented CV safety, and potentially provide CV benefits. Dipeptidyl peptidase-4
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Potential CV Impact of DPP-4 Inhibitors in T2DM
(DPP-4) inhibitors, a newer class of glucose-lowering agents, act by potentiating the action of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).7 This review summarizes CV disease pathophysiology in T2DM and the potential impact of DPP-4 inhibitors on CV risk in patients with T2DM.
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Methods
Relevant articles in English were identified by a PubMed search through 2013 using the terms dipeptidyl peptidase-4, dipeptidyl peptidase-4 inhibition, individual DPP-4 inhibitors, incretins, and cardiovascular. Bibliographies of retrieved papers were also searched for additional pertinent articles.
Cardiovascular Pathophysiology in T2DM
Type 2 diabetes mellitus contributes to CV disease via complex, multifactorial effects on endothelial and vascular smooth muscle cells, platelets, and myocardial function.
Endothelial and Vascular Smooth Muscle Cells
It is generally accepted that endothelial dysfunction, which is common in individuals who have T2DM or insulin resistance or who are at risk for developing T2DM,8 precedes the development of atherosclerosis.9 Endothelium-derived nitric oxide is a potent vasodilator that also inhibits platelet aggregation, suppresses the adhesion of leukocytes or monocytes to endothelial surfaces, inhibits inflammatory cytokine expression, and inhibits the proliferation and migration of vascular smooth muscle cells,10 all of which are important processes in the development of atherosclerosis. Hyperglycemia inhibits endothelial nitric oxide production11 and stimulates superoxide production in vitro.12 Hyperglycemia also activates the proinflammatory transcription nuclear factor κB in endothelial cells13 and vascular smooth muscle cells,14 which results in increases in the expression of adhesion molecules and promotes leukocyte adhesion to the endothelium. In support of these experimental findings, greater macrophage infiltration and greater smooth muscle cell apoptosis were found in plaques from individuals with diabetes, compared with individuals without diabetes,15,16 suggesting enhanced monocyte adherence to vessel walls and increased plaque instability in diabetes. Endothelial cell repair may also be compromised in diabetes. Bone marrow–derived endothelial progenitor cells (EPCs) are involved in the repair of damaged endothelium
and neovascularization.17 In patients with coronary artery disease (CAD), increased levels of circulating EPCs are related to a reduced risk of CV death and occurrence of a first major CV event.17 Numbers of EPCs are reduced in patients with T2DM and reduced further in patients with T2DM and peripheral vascular disease.18 Vascular smooth muscle function is also impaired in diabetes. Compared with control subjects, forearm blood flow was less responsive to exogenous nitric oxide donors in patients with T2DM.19
Heart
Diabetes appears to have direct effects on the heart, independent of CAD. For example, patients with T2DM and heart failure secondary to CAD had reduced myocardial glucose utilization, compared with that of patients with heart failure and CAD without T2DM.20 In the Strong Heart Study, T2DM was associated with increased left ventricular (LV) mass and wall thicknesses, reduced LV function, and increased arterial stiffness independent of arterial pressure and body mass index.21 In addition, T2DM was associated with abnormal early diastolic filling that was independent of age, arterial pressure, LV mass, and systolic function.22 Furthermore, among participants with T2DM, those with abnormal diastolic function had higher fasting plasma glucose, higher glycated hemoglobin (HbA1c), and a trend toward longer diabetes duration.
Platelets and Coagulation
Patients who develop T2DM frequently have coagulation abnormalities, including increased levels of fibrinogen, C-reactive protein, and plasminogen activator inhibitor-1.23 Moreover, platelets from individuals with diabetes have increased expression of adhesion molecules, increased aggregatory behavior,24 and reduced antiaggregatory responses to nitric oxide, insulin, and prostacyclin.23 Thus, in diabetes, increased platelet activation and aggregation and an increase in procoagulant factors, together with decreased fibrinolytic activity, lead to a prothrombotic state that favors thrombus formation.
Lipoprotein Metabolism
In patients with diabetes, there is overproduction of very low density lipoprotein (VLDL), mediated by an increased influx of free fatty acids into the liver.25 In the setting of hepatic insulin resistance, VLDL secreted by the liver has an increased triglyceride content and apolipoprotein (Apo) CIII synthesis is upregulated,25 leading to competition for ApoE
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receptor clearance of atherogenic remnant lipoproteins and decreased lipolysis. Increased hepatic secretion of enlarged VLDL with ApoCIII results in impaired conversion of VLDL to low-density lipoprotein (LDL).26 Triglyceride within VLDL is transferred into LDL and high-density lipoprotein (HDL) in exchange for cholesterol ester by cholesteryl ester transfer protein. After lipolysis by hepatic lipases, LDL and HDL sizes are significantly reduced. Therefore, the net result of hepatic insulin resistance is increased VLDL secretion, an abundance of small dense LDL, and very low HDL cholesterol—the hallmark features of the dyslipidemia associated with T2DM. In addition, due to impaired lipolysis of VLDL, competition develops for clearance of dietary fat, resulting in markedly enhanced postprandial lipemia. All of these factors result in increased CV risk in patients with T2DM.
Overview of the Incretin System and DPP-4 Inhibitors
Glucagon-like peptide-1 and GIP are secreted into the circulation by the intestine in response to nutrient intake and stimulate glucose-dependent insulin secretion (incretin effect; Figure 1). Glucagon-like peptide-1 also inhibits glucagon secretion, delays gastric emptying, increases feelings of satiety, and decreases food intake.7 In patients with T2DM, the secretion of GIP is near normal,27 whereas the secretion of GLP-1 is variable,27,28 and the insulinotropic response to GLP-1 is preserved, whereas responsiveness to GIP is reduced.29 Glucagon-like peptide-1 and GIP are rapidly degraded by DPP-4, a membrane-bound enzyme expressed in many tissues and also present as a soluble form in plasma.7 The DPP-4 inhibitors are oral agents that inhibit the degradation
Figure 1. Potential mechanisms whereby DPP-4 inhibitors can achieve cardiovascular protection. Arrows indicate stimulatory connections and ⊥ indicates inhibitory signals. Dashed lines indicate pathways without a defined molecular link to DPP-4 activity.
Reprinted from Vascular Pharmacology, 55, Fadini GP, Avogaro A, Cardiovascular effects of DPP-4 inhibition: beyond GLP-1, 10–16, Copyright 2011, with permission from Elsevier. Abbreviations: ACEi, angiotensin converting enzyme inhibitor; Akt, protein kinase B; BNPs, B-type natriuretic peptides; DPP-4, dipeptidyl peptidase-4; eNOS, endothelial nitric oxide synthase; EPC, endothelial progenitor cell; GLP-1, glucagon-like peptide-1; IL-6, interleukin-6; MCP-1, monocyte chemotactic protein-1; NPY, neuropeptide Y; PTH, parathyroid hormone; SDF-1α, stromal cell–derived factor-1α; SP, substance P; TNF-α, tumor necrosis factor-α.
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Potential CV Impact of DPP-4 Inhibitors in T2DM
of endogenous GLP-1 and GIP and, therefore, increase insulin secretion and decrease glucagon secretion.7 Currently approved DPP-4 inhibitors include sitagliptin, saxagliptin, linagliptin, and alogliptin, as well as vildagliptin (in Europe and South America only). Fixed‑dose combinations with metformin and of alogliptin with pioglitazone are also available. In clinical trials, DPP‑4 inhibitors reduce HbA1c levels by approximately 0.4% to 1.0%, compared with placebo, and are effective as monotherapy or as add-on to metformin, sulfonylureas, thiazolidinediones, or insulin.30,31 The DPP-4 inhibitors are generally well tolerated and are not associated with weight gain, hypoglycemia, or gastrointestinal symptoms.30 They are recommended as second- or thirdline agents in combination with metformin, sulfonylureas, thiazolidinediones, or insulin, and as monotherapy in patients who cannot receive metformin.32 Note that DPP-4 inhibitors target primarily postprandial glucose, which is more closely associated with carotid intimal thickness and a variety of atherosclerosis risk factors than is fasting plasma glucose or HbA1c level.33 Moreover, postprandial glucose may be a better predictor than fasting plasma glucose of CV events,34 CV mortality,2 and all-cause mortality.34
Cardiovascular Effects of DPP-4 Inhibitors
Findings from studies in experimental models and small observational studies in humans have provided evidence that DPP-4 inhibitors may have beneficial effects on the CV system by preventing the degradation of GLP-1 and other substrates.35 Results of studies in animals and human tissues have shown that GLP-1 receptors are present in the pancreas and many extrapancreatic tissues, including heart, blood vessels, lung, central nervous system, and kidney.35 Furthermore, DPP-4 has multiple substrates in addition to GLP-1 that are associated with cardioprotection in experimental models. For example, stromal cell–derived factor-1α (SDF-1α), which plays a key role in recruiting bone marrow–derived EPCs to sites of endothelial damage, is a substrate of DPP-4,36,37 as is B-type natriuretic peptide, involved in the regulation of body fluid homeostasis and vascular tone.38
Preclinical Studies: Selected Examples
Evidence for the potential benefits of GLP-1 and, by extension, DPP-4 inhibitors has come largely from animal studies. For example, GLP-1 administration increased nitric oxide and cardiac glucose uptake in models of cardiac ischemia39 and heart failure.40 In addition, GLP-1 reduced infarct size41
and improved LV function in models of ischemia/reperfusion injury.39 Long-term administration of GLP-1 also attenuated the development of hypertension and improved endothelial function and renal and cardiac damage in a model of saltsensitive hypertension.42 Many positive effects of DPP-4 inhibitors observed in animals may be independent of their effects on GLP-1 levels. For example, in diabetic mice, administration of SDF-1α, a DPP-4 substrate, reversed the defect in EPC homing to sites of vascular injury.37 Similarly, DPP-4 inhibition (in combination with granulocyte colony-stimulating factor) stabilized SDF-1α in the heart, enhanced myocardial progenitor cell homing and function, reduced cardiac remodeling, and improved heart function and survival after myocardial infarction (MI) in mice.43 Also, DPP-4 inhibition preserved glomerular filtration rate, increased stroke volume, decreased heart rate, and potentiated the positive inotropic effect of exogenous B-type natriuretic peptide in a heart failure model.44 Inhibition of DPP-4 increased the release of nitric oxide from aortic and glomerular cells harvested from Zucker obese45 or spontaneously hypertensive rats,46 and reduced blood pressure in spontaneously hypertensive rats.46 Finally, in models of diabetes, DPP-4 inhibition suppressed thrombogenic signaling47 and the formation of atherosclerotic lesions.48 Inflammation is associated with the development of diabetes and atherosclerosis.49 In diet-induced obese mice, sitagliptin significantly reduced adipose tissue and islet cell inflammation and macrophage infiltration into adipose tissue.50 Similarly, DPP-4 inhibition attenuated diet-induced adipose tissue inflammation and hepatic steatosis in a mouse model of diabetes.51 Treatment of obese Zucker rats with saxagliptin reduced soluble levels of CD40, an inflammatory biomarker, by over 10-fold.45
Clinical Studies
In humans, the potential beneficial CV effects of GLP-1 or DPP-4 inhibitors have been reported largely from small observational studies. For example, GLP-1 infusion improved endothelial function, measured as flow-mediated vasodilation, in patients with T2DM with52 or without53 CAD. Also, GLP-1 infusion improved LV function in patients (50% with diabetes) with acute MI and severe systolic dysfunction receiving standard post-MI therapy after successful primary angioplasty.54 In patients with T2DM, treatment with sitagliptin for 1 and 3 months inhibited platelet aggregation by 10% and 30%, respectively.55 Moreover, thrombin-induced aggregation and
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increases in intracellular calcium were inhibited in platelets pretreated with sitagliptin in vitro. Dipeptidyl peptidase-4 inhibition with sitagliptin (plus an oral glucose load) improved global and regional LV performance in response to dobutamine stress echocardiography and decreased postischemic stunning in patients with CAD.56 In patients with poorly controlled T2DM, 4 weeks of treatment with sitagliptin plus metformin with or without insulin secretagogues increased EPCs 2-fold and SDF‑1α by 50% and reduced levels of the inflammatory chemokine monocyte chemoattractant protein-1 by 25% compared with baseline measures. There were no changes in these parameters in patients not receiving sitagliptin.57 In a randomized, double-blind, crossover study in patients with T2DM receiving metformin ± sulfonylurea or thiazolidinedione, 4 weeks of treatment with vildagliptin improved endotheliumdependent vasodilation (forearm blood flow) compared with acarbose treatment.58 The Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) trial assessed the effects of vildagliptin (n = 128) versus placebo (n = 126) on LV function in patients with T2DM and heart failure with reduced LV ejection fraction. In a preliminary report, vildagliptin was noninferior to placebo after 52 weeks of treatment for the change from baseline in LV ejection fraction as assessed by echocardiography.59 There was a statistically significant increase in LV end diastolic volume (P = 0.007) and stroke volume (P = 0.002) in the vildagliptin group versus the control group. Although not statistically significant, a greater proportion of patients receiving vildagliptin versus placebo died from any cause (8.6% vs 3.2%) and from CV causes (5.5% vs 3.2%). Evidence for the benefits of lipid-lowering therapy in patients with T2DM has been demonstrated in multiple clinical trials, and it is well acknowledged that patients with T2DM have an increased prevalence of lipid abnormalities, contributing to their high risk of CV disease. Although DPP-4 inhibitors have little effect on fasting lipid profiles, these agents have significant beneficial effects on postprandial lipidemia. Sitagliptin was shown to reduce the area under the curve for triglycerides and ApoB48, as well as ApoB100,60 suggesting that DPP-4 inhibitors decrease postprandial plasma levels of triglyceride-rich lipoproteins of both intestinal and hepatic origin. Similar effects on postprandial lipemia have been demonstrated with vildagliptin.61
DPP-4 Inhibitors and CV Outcomes
Two large randomized CV outcomes clinical trials with DPP‑4 inhibitors have recently been completed, and several 60
others are in progress (Table 1). In the Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus trial (SAVOR),62 adult patients (N = 16 492) with T2DM and a history of established CV disease or multiple CV risk factors received saxagliptin or placebo and were followed for # 2.9 years (median follow-up was 2.1 years). Patients also received standard of care for T2DM and CV risk factors. The primary composite end point of CV death, nonfatal MI, or nonfatal stroke occurred in 7.3% of patients receiving saxagliptin compared with 7.2% of those receiving placebo (hazard ratio [HR], 1.00; 95% CI, 0.89–1.12; noninferiority P , 0.001; superiority P = 0.99). The major secondary composite end point (CV death, nonfatal MI, nonfatal stroke, hospitalization for heart failure, hospitalization for unstable angina, or hospitalization for coronary revascularization) occurred in 12.8% of patients in the saxagliptin group versus 12.4% of patients in the placebo group (HR, 1.02; 95% CI, 0.94–1.11; P = 0.66). A component of the secondary composite end point, hospitalization for heart failure, occurred more frequently with saxagliptin (3.5%) than with placebo (2.8%; HR, 1.27; 95% CI, 1.07–1.51; P = 0.007). A secondary end point of all-cause mortality occurred in 4.9% of patients in the saxagliptin group compared with 4.2% in the placebo group (HR, 1.11; 95% CI, 0.96–1.27; P = 0.15). The number of patients with acute or chronic pancreatitis was low and similar in both groups (saxagliptin, 0.3%; placebo, 0.3%). Five cases of pancreatic cancer were reported in the saxagliptin group versus 12 in the placebo group. The EXamination of cAardiovascular outcoMes with alogliptIN versus standard of carE in patients with T2DM and acute coronary syndrome (EXAMINE) trial63 assessed the effects of alogliptin versus placebo in patients (N = 5380) with T2DM and an acute coronary syndrome within 15 to 90 days prior to randomization. Patients continued to receive standard care for T2DM and CV risk factors and were followed for up to 40 months (median 18 months). The primary composite end point of CV death, nonfatal MI, or nonfatal stroke occurred in 11.3% of patients randomized to alogliptin versus 11.8% of those randomized to placebo (HR, 0.96; upper bound of CI, # 1.16; P , 0.001 for noninferiority; P = 0.32 for superiority). There was no difference between alogliptin and placebo in the major secondary composite end point of CV death, nonfatal MI, nonfatal stroke, or urgent revascularization due to unstable angina (HR, 0.95; upper bound of CI, # 1.14; P = 0.26 for superiority). Death from any cause occurred in 5.7% of patients receiving alogliptin versus 6.5% of those receiving placebo (HR, 0.88; 95% CI, 0.71–1.09; P = 0.23 for superiority). A post-hoc analysis of
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Potential CV Impact of DPP-4 Inhibitors in T2DM
Table 1. Cardiovascular Outcome Trials With DPP-4 Inhibitors Trial
Drug
N
Patients
Saxagliptin vs 16 492 Men and women aged $ 40 years SAVOR NCT01107886 placebo with T2DM and established CV disease and/or multiple risk factors EXAMINE64 Alogliptin vs 5380 Men and women aged $ 18 NCT00968708 placebo years with T2DM and acute MI or unstable angina requiring hospitalization Sitagliptin vs 14 000 Men and women aged $ 50 years TECOS71 NCT00790205 placebo with T2DM and preexisting CV disease CAROLINA72 Linagliptin vs 6000 Men and women aged 40–85 years NCT01243424 glimepiride with T2DM and preexisting CV disease or specified diabetes end-organ damage; or aged $ 70 years; or $ 2 specified CV risk factors CARMELINA73 Linagliptin vs 8300 Men and women aged $ 18 NCT01897532 placebo years with T2DM and micro- or macroalbuminuria and previous macrovascular disease and/or impaired renal function
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62
Primary Outcome
Start Date
Completion Date
Composite of CV death, nonfatal MI, or nonfatal ischemic stroke
May 2010
May 2013
Composite of CV death, nonfatal MI, or nonfatal stroke
September 2009 June 2013
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 2008 December 2014 (estimated) October 2010
Composite of CV death, nonfatal July 2013 MI, nonfatal stroke, or hospitalization for unstable angina pectoris; secondary outcome of renal death, end-stage renal disease, and a sustained decrease of $ 50% in eGFR
September 2018 (estimated)
January 2018 (estimated)
Abbreviations: CARMELINA, CArdiovascular and Renal Microvascular outcomE study with LINAgliptin; CAROLINA, CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 diabetes; CV, cardiovascular; eGFR, estimated glomerular filtration rate; EXAMINE, EXamination of cAardiovascular outcoMes with alogliptIN versus 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.
the composite end point of CV mortality and hospitalization for heart failure found a numerically higher proportion of patients hospitalized for heart failure for alogliptin (3.9%) versus placebo (3.3%). However, the increased risk was not statistically significant (HR, 1.19; 95% CI, 0.90–1.58).64 Acute pancreatitis occurred in 12 (0.4%) patients receiving alogliptin and in 8 (0.3%) receiving placebo (P = 0.50). Chronic pancreatitis was reported in 5 (0.2%) and 4 (0.1%) patients in the alogliptin and placebo groups, respectively (P = 1.0). There were no reports of pancreatic cancer. Pooled analyses of major adverse cardiovascular events (MACE) occurring during the clinical development of sitagliptin, saxagliptin, linagliptin, alogliptin, and vildagliptin are available; all found no increase in MACE,63,65–69 and some studies reported a possible CV benefit65,66 (Table 2). In a pooled analysis of 19 double-blind trials of sitagliptin (12 weeks to 2 years) that included data from 10 246 patients with T2DM who received either sitagliptin 100 mg/d (n = 5429) or a comparator (placebo or an active comparator, n = 4817), the incidence rates for nonadjudicated MACE (ischemic events or CV death) were 0.6 and 0.9 per 100 patient-years in the sitagliptin group and comparator groups, respectively.68 The risk ratio for sitagliptin‑exposed versus nonexposed patients
was 0.68 (95% CI, 0.41–1.12), suggesting no increased risk of CV events with sitagliptin. The risk for CV events (adjudicated) was analyzed across 8 randomized phase 2 and 3 trials with saxagliptin 2.5 to 100 mg/d (saxagliptin, n = 3356; comparator, n = 1251; duration, 16–116 weeks).65 Confirmed CV events occurred in 22 (0.7%) patients receiving saxagliptin and 18 (1.4%) patients treated with comparator. The relative risk with saxagliptin versus various comparators for a composite end point of CV death, MI, or stroke was 0.43 (95% CI, 0.23–0.80) using blinded retrospective event adjudication by an independent group. The data suggest no increased risk of CV events and possibly a reduction in CV events with saxagliptin. In an expanded pool of 20 randomized phase 2 and 3 clinical trials (n = 9156), the incidence rates for adjudicated MACE (CV death, MI, or stroke) were 0.9 and 1.1 per 100 patient-years for saxagliptin and control, respectively. The Cox proportional HR was 0.75 (95% CI, 0.46–1.21), suggesting no increased risk of MACE. Incidence rates per 100 patient-years for nonadjudicated heart failure were 0.34 for saxagliptin and 0.62 for control. The HR was 0.55 (95% CI, 0.27–1.12), suggesting no increased risk of heart failure with saxagliptin.
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Michael H. Davidson
Table 2. Analysis of Major Adverse Cardiovascular Events From Phase 2 and 3 Clinical Trials of DPP-4 Inhibitors
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Patients, n
CV Events
DPP-4 inhibitor
Trials, n
Composite end point
Drug
Comparator
Drug, n (%)
Comparator, n (%)
Risk (95% CI)
Sitagliptin68
19
5429
4817
0.6/100a
0.9/100a
0.68 (0.41–1.12)b
Saxagliptin65 Saxagliptin69 Linagliptin66
8 20 8
3356 5701 3319
1251 3455 1920
22 (0.7) 0.9/100a 11 (0.3)
18 (1.4) 1.1/100a 23 (1.2)
0.43 (0.23–0.80)c 0.75 (0.46–1.21)c 0.34 (0.16–0.70)d
Alogliptin63
11
4168
1860
13 (0.3)
10 (0.5)
0.64 (0–1.4)
Vildagliptin67
25
Ischemic events or CV death MI, stroke, or CV death CV death, MI, or stroke CV death, stroke, MI, or hospitalization for unstable angina CV death, nonfatal MI, or nonfatal stroke ACS, TIA, stroke, or CV death
1393 (50 mg once daily) 6116 (50 mg twice daily)
6061
10 (0.7) (50 mg once daily) 81 (1.3) (50 mg twice daily)
91 (1.5)
0.88 (0.37–2.11)e 0.84 (0.62–1.14)e
Incidence rates per 100 patient-years. Risk ratio. c Cox relative risk. d Hazard ratio. e Mantel-Haenszel risk ratio. Abbreviations: ACS, acute coronary syndrome; CV, cardiovascular; DPP-4, dipeptidyl peptidase-4; MI, myocardial infarction; TIA, transient ischemic attack. a
b
In a meta-analysis of CV events from 8 phase 3 trials of linagliptin 5 or 10 mg/d (linagliptin, n = 3319, median duration 175 days [range, 1–617]; placebo or comparator, n = 1920, median duration 179 days [range, 1–619]), the primary CV end point (composite of CV death, stroke, MI, or hospitalization for unstable angina) occurred in 11 (0.3%) patients receiving linagliptin and 23 (1.2%) receiving comparators.66 The HR of 0.34 for the primary end point showed significantly lower risk with linagliptin than comparators (95% CI, 0.16–0.70). The results indicated that linagliptin does not increase CV risk and support a potential reduction of CV events versus comparators. Analysis of MACE in 11 phase 2 and 3 trials for alogliptin (n = 4168) versus placebo or comparator (n = 1860) found no significant treatment difference for the adjudicated composite end point of CV death, nonfatal MI, and nonfatal stroke (HR, 0.64; 95% CI, 0.0–1.4).63 The individual events were also distributed similarly across treatment groups. No significant treatment difference between alogliptin and placebo or comparator was evident for other serious CV events of angina, arrhythmias, and heart failure. The relative risk for a composite adjudicated CV event (acute coronary syndrome, transient ischemic attack, stroke, or cerebrovascular death) was assessed in patients treated with vildagliptin (n = 7509), compared with those treated with placebo or comparator (n = 6061), for 12 weeks to $ 2 years in 25 phase 3 trials.67 The relative risk for the composite CV event end point for vildagliptin 50 mg once daily was 62
0.88 (95% CI, 0.37–2.11) and twice daily was 0.84 (95% CI, 0.62–1.14), suggesting that vildagliptin was not associated with an increased risk of CV events. A meta-analysis of 70 clinical trials also found that DPP-4 inhibitors reduced the risk of CV events, especially MI, and all-cause mortality.70 Although preclinical studies and observational studies in humans suggest that DPP-4 inhibition may have CV benefits, meta-analyses of clinical trials have not demonstrated superiority of DPP-4 inhibitors versus placebo or other antihyperglycemic medications in reducing adverse CV events in patients with T2DM. Moreover, the results of CV outcomes trials such as SAVOR62 and EXAMINE64 found that rates of MACE with saxagliptin and alogliptin were similar to rates with placebo. It should be noted, however, that SAVOR and EXAMINE enrolled patients with a history of CV disease or with multiple CV risk factors and T2DM duration of 7 to 10 years. Because these patients were also receiving standard-ofcare treatment for T2DM and CV disease (β-blockers, statins, and renin-angiotensin-system blockers), it is possible that any additional CV benefit of DPP-4 inhibition would be difficult to detect on such a background of CV medications. Whether or not DPP-4 inhibitors prevent or delay CV complications in patients with less advanced T2DM and CV disease is unknown.
Conclusion
It is well established that patients with T2DM experience significant morbidity and mortality from CV disease. Treatment
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Potential CV Impact of DPP-4 Inhibitors in T2DM
recommendations emphasize achieving glycemic control and targeting common comorbidities, including hypertension and dyslipidemia. Whereas the findings of epidemiologic studies have established an association between hyperglycemia and the risk for CV events and mortality, evidence for CV benefits of glycemic control with standard diabetes medications is lacking. There is considerable interest in developing therapies that might offer CV advantages in addition to controlling hyperglycemia. Based mainly on results from preclinical studies and small mechanistic studies, DPP-4 inhibitors, via actions on GLP-1 as well as by those independent of GLP-1, may affect some of the pathologic processes involved in the increased CV risk inherent in T2DM. Whether DPP-4 inhibition is associated with significant attenuation of CV risk awaits the full results of several large prospectively designed CV outcome clinical trials. Results reported from 2 of these trials, the SAVOR and EXAMINE trials, show that saxagliptin and alogliptin do not increase adverse CV events, nor do they reduce adverse CV events compared with placebo when added to current standard of care with or without other T2DM therapies in patients with a history of CV disease or with multiple CV risk factors.
Acknowledgments
Editorial support was provided by Richard M. Edwards, PhD, and Janet E. Matsuura, PhD, from Complete Healthcare Communications, Inc. (Chadds Ford, PA), and was funded by Bristol-Myers Squibb and AstraZeneca LP.
Conflict of Interest Statement
Michael H. Davidson, MD, serves on advisory boards or as a consultant for AbbVie, Amgen, Aegerion, Esperion, Lipidemx, Merck, Sanofi, and Vindico. Dr Davidson is a member of the speakers bureau for Merck; he also owns shares of stock in Omthera Pharmaceuticals, Inc. (chief medical officer). Omthera Pharmaceuticals, Inc. is a wholly owned subsidiary of Zeneca, Inc., and is a member of the AstraZeneca group of companies.
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44. Gomez N, Touihri K, Matheeussen V, et al. Dipeptidyl peptidase IV inhibition improves cardiorenal function in overpacing-induced heart failure. Eur J Heart Fail. 2012;14(1):14–21. 45. Mason RP, Jacob RF, Kubant R, et al. Effect of enhanced glycemic control with saxagliptin on endothelial nitric oxide release and CD40 levels in obese rats. J Atheroscler Thromb. 2011;18(9):774–783. 46. Mason RP, Jacob RF, Kubant R, Ciszewski A, Corbalan JJ, Malinski T. Dipeptidyl peptidase-4 inhibition with saxagliptin enhanced nitric oxide release and reduced blood pressure and sICAM-1 levels in hypertensive rats. J Cardiovasc Pharmacol. 2012;60:467–473. 47. Matsui T, Nishino Y, Takeuchi M, Yamagishi S. Vildagliptin blocks vascular injury in thoracic aorta of diabetic rats by suppressing advanced glycation end product-receptor axis. Pharmacol Res. 2011;63(5):383–388. 48. Ta NN, Schuyler CA, Li Y, Lopes-Virella MF, Huang Y. DPP-4 (CD26) inhibitor alogliptin inhibits atherosclerosis in diabetic apolipoprotein E-deficient mice. J Cardiovasc Pharmacol. 2011;58(2):157–166. 49. Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917): 868–874. 50. Dobrian AD, Ma Q, Lindsay JW, et al. Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice. Am J Physiol Endocrinol Metab. 2011;300(2):E410–E421. 51. Shirakawa J, Fujii H, Ohnuma K, et al. Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice. Diabetes. 2011;60(4):1246–1257. 52. Nystrom T, Gutniak MK, Zhang Q, et al. Effects of glucagonlike peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004;287(6):E1209–E1215. 53. Koska J, Schwartz EA, Mullin MP, Schwenke DC, Reaven PD. Improvement of postprandial endothelial function after a single dose of exenatide in individuals with impaired glucose tolerance and recent-onset type 2 diabetes. Diabetes Care. 2010;33(5):1028–1030. 54. Nikolaidis LA, Mankad S, Sokos GG, et al. Effects of glucagonlike peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109(8):962–965. 55. Gupta AK, Verma AK, Kailashiya J, Singh SK, Kumar N. Sitagliptin: anti-platelet effect in diabetes and healthy volunteers. Platelets. 2012;23(8):565–570. 56. Read PA, Khan FZ, Heck PM, Hoole SP, Dutka DP. DPP-4 inhibition by sitagliptin improves the myocardial response to dobutamine stress and mitigates stunning in a pilot study of patients with coronary artery disease. Circ Cardiovasc Imaging. 2010;3(2):195–201. 57. Fadini GP, Boscaro E, Albiero M, et al. The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromal-derived factor-1alpha. Diabetes Care. 2010;33(7):1607–1609. 58. van Poppel PC, Netea MG, Smits P, Tack CJ. Vildagliptin improves endothelium-dependent vasodilatation in type 2 diabetes. Diabetes Care. 2011;34(9):2072–2077. 59. McMurray JJ. The Vildagliptin in Ventricular Dysfunction Diabetes Trial (VIVIDD). Presented at: Heart Failure Congress 2013 of the European Society of Cardiology, May 25–28, 2013, Lisbon, Portugal. 60. Tremblay AJ, Lamarche B, Deacon CF, Weisnagel SJ, Couture P. Effect of sitagliptin therapy on postprandial lipoprotein levels in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13(4):366–373. 61. Matikainen N, Manttari S, Schweizer A, et al. Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes. Diabetologia. 2006;49(9):2049–2057. 62. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–1326. 63. White WB, Pratley R, Fleck P, et al. Cardiovascular safety of the dipeptidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus. Diabetes Obes Metab. 2013;15(7):668–673.
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70. Monami M, Ahren B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013;15(2):112–120. 71. TECOS: a randomized, placebo controlled clinical trial to evaluate cardiovascular outcomes after treatment with sitagliptin in patients with type 2 diabetes mellitus and inadequate glycemic control. ClinicalTrials. gov. http://clinicaltrials.gov/ct2/show/NCT00790205?term = NCT007 90205&rank = 1. Accessed January 20, 2014. 72. CAROLINA: cardiovascular outcome study of linagliptin versus glimepiride in patients with type 2 diabetes. ClinicalTrials.gov. http:// clinicaltrials.gov/ct2/show/NCT01243424?term = nct01243424& rank=1. Accessed January 20, 2014. 73. Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus at high vascular risk. ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT01897532?term = N CT01897532&rank=1. Accessed January 20, 2014.
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C L I N I C A L F O C U S : D I A B E T E S A N D C O N C O M I TA N T D I S O R D E R S
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Potential Impact of Dipeptidyl Peptidase-4 Inhibitors on Cardiovascular Pathophysiology in Type 2 Diabetes Mellitus
DOI: 10.3810/pgm.2014.05.2756
Michael H. Davidson, MD University of Chicago, Pritzker School of Medicine, Chicago, IL
Abstract: Cardiovascular (CV) disease remains 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 includes abnormalities in endothelial cells, vascular smooth muscle cells, myocardium, platelets, and the coagulation cascade. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a newer class of agents that act by potentiating the action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. This review summarizes CV disease pathophysiology in T2DM and the potential effect of DPP-4 inhibitors on CV risk in patients with T2DM. Preclinical and small observational studies and post hoc analyses of clinical trial data suggest that DPP-4 inhibitors may have beneficial CV effects. Some effects of DPP-4 inhibitors are GLP-1 dependent, whereas others may be due to GLP-1–independent actions of DPP-4 inhibitors. Analyses of major adverse CV events occurring during clinical development of DPP-4 inhibitors found no increased risk of CV events or mortality and even a potential reduction in CV events. Two large CV outcome trials have been completed and report that saxagliptin and alogliptin did not increase or decrease adverse CV outcomes in patients with T2DM and CV disease or at high risk for adverse CV events. More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure, and there was a similar numerically increased risk of hospitalization for heart failure with alogliptin; however, the risk was not significantly greater compared with placebo. Dipeptidyl peptidase-4 inhibitors may affect some of the pathologic processes involved in the increased CV risk inherent in T2DM. Keywords: cardiovascular diseases; diabetes mellitus; dipeptidyl peptidase-4 inhibitor; endothelium
Introduction
Correspondence: Michael H. Davidson, MD, University of Chicago, Pritzker School of Medicine, Department of Medicine, 150 E. Huron Street, Suite 900, Chicago, IL, 60611. Tel: 773-834-4150 Fax: 908-741-6521 E-mail: [email protected]. edu
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Cardiovascular (CV) disease is the most common cause of mortality in patients with type 2 diabetes mellitus (T2DM) and accounts for approximately two thirds of deaths in these patients.1 Findings from epidemiologic studies have established an association between hyperglycemia and the risk for CV events and CV mortality.2 However, the CV benefits of intensive glycemic control with standard diabetes medications (metformin, sulfonylureas, thiazolidinediones, or insulin) remain in question.3 Indeed, there is some evidence that particular diabetes medications (rosiglitazone and possibly older sulfonylureas) may be associated with adverse CV events.4,5 Because of these uncertainties, regulatory agencies now require a more extensive assessment of CV risk for all new diabetes medications.6 New diabetes medications should have no deleterious effects on CV risk factors, have documented CV safety, and potentially provide CV benefits. Dipeptidyl peptidase-4
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Potential CV Impact of DPP-4 Inhibitors in T2DM
(DPP-4) inhibitors, a newer class of glucose-lowering agents, act by potentiating the action of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).7 This review summarizes CV disease pathophysiology in T2DM and the potential impact of DPP-4 inhibitors on CV risk in patients with T2DM.
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Methods
Relevant articles in English were identified by a PubMed search through 2013 using the terms dipeptidyl peptidase-4, dipeptidyl peptidase-4 inhibition, individual DPP-4 inhibitors, incretins, and cardiovascular. Bibliographies of retrieved papers were also searched for additional pertinent articles.
Cardiovascular Pathophysiology in T2DM
Type 2 diabetes mellitus contributes to CV disease via complex, multifactorial effects on endothelial and vascular smooth muscle cells, platelets, and myocardial function.
Endothelial and Vascular Smooth Muscle Cells
It is generally accepted that endothelial dysfunction, which is common in individuals who have T2DM or insulin resistance or who are at risk for developing T2DM,8 precedes the development of atherosclerosis.9 Endothelium-derived nitric oxide is a potent vasodilator that also inhibits platelet aggregation, suppresses the adhesion of leukocytes or monocytes to endothelial surfaces, inhibits inflammatory cytokine expression, and inhibits the proliferation and migration of vascular smooth muscle cells,10 all of which are important processes in the development of atherosclerosis. Hyperglycemia inhibits endothelial nitric oxide production11 and stimulates superoxide production in vitro.12 Hyperglycemia also activates the proinflammatory transcription nuclear factor κB in endothelial cells13 and vascular smooth muscle cells,14 which results in increases in the expression of adhesion molecules and promotes leukocyte adhesion to the endothelium. In support of these experimental findings, greater macrophage infiltration and greater smooth muscle cell apoptosis were found in plaques from individuals with diabetes, compared with individuals without diabetes,15,16 suggesting enhanced monocyte adherence to vessel walls and increased plaque instability in diabetes. Endothelial cell repair may also be compromised in diabetes. Bone marrow–derived endothelial progenitor cells (EPCs) are involved in the repair of damaged endothelium
and neovascularization.17 In patients with coronary artery disease (CAD), increased levels of circulating EPCs are related to a reduced risk of CV death and occurrence of a first major CV event.17 Numbers of EPCs are reduced in patients with T2DM and reduced further in patients with T2DM and peripheral vascular disease.18 Vascular smooth muscle function is also impaired in diabetes. Compared with control subjects, forearm blood flow was less responsive to exogenous nitric oxide donors in patients with T2DM.19
Heart
Diabetes appears to have direct effects on the heart, independent of CAD. For example, patients with T2DM and heart failure secondary to CAD had reduced myocardial glucose utilization, compared with that of patients with heart failure and CAD without T2DM.20 In the Strong Heart Study, T2DM was associated with increased left ventricular (LV) mass and wall thicknesses, reduced LV function, and increased arterial stiffness independent of arterial pressure and body mass index.21 In addition, T2DM was associated with abnormal early diastolic filling that was independent of age, arterial pressure, LV mass, and systolic function.22 Furthermore, among participants with T2DM, those with abnormal diastolic function had higher fasting plasma glucose, higher glycated hemoglobin (HbA1c), and a trend toward longer diabetes duration.
Platelets and Coagulation
Patients who develop T2DM frequently have coagulation abnormalities, including increased levels of fibrinogen, C-reactive protein, and plasminogen activator inhibitor-1.23 Moreover, platelets from individuals with diabetes have increased expression of adhesion molecules, increased aggregatory behavior,24 and reduced antiaggregatory responses to nitric oxide, insulin, and prostacyclin.23 Thus, in diabetes, increased platelet activation and aggregation and an increase in procoagulant factors, together with decreased fibrinolytic activity, lead to a prothrombotic state that favors thrombus formation.
Lipoprotein Metabolism
In patients with diabetes, there is overproduction of very low density lipoprotein (VLDL), mediated by an increased influx of free fatty acids into the liver.25 In the setting of hepatic insulin resistance, VLDL secreted by the liver has an increased triglyceride content and apolipoprotein (Apo) CIII synthesis is upregulated,25 leading to competition for ApoE
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Michael H. Davidson
receptor clearance of atherogenic remnant lipoproteins and decreased lipolysis. Increased hepatic secretion of enlarged VLDL with ApoCIII results in impaired conversion of VLDL to low-density lipoprotein (LDL).26 Triglyceride within VLDL is transferred into LDL and high-density lipoprotein (HDL) in exchange for cholesterol ester by cholesteryl ester transfer protein. After lipolysis by hepatic lipases, LDL and HDL sizes are significantly reduced. Therefore, the net result of hepatic insulin resistance is increased VLDL secretion, an abundance of small dense LDL, and very low HDL cholesterol—the hallmark features of the dyslipidemia associated with T2DM. In addition, due to impaired lipolysis of VLDL, competition develops for clearance of dietary fat, resulting in markedly enhanced postprandial lipemia. All of these factors result in increased CV risk in patients with T2DM.
Overview of the Incretin System and DPP-4 Inhibitors
Glucagon-like peptide-1 and GIP are secreted into the circulation by the intestine in response to nutrient intake and stimulate glucose-dependent insulin secretion (incretin effect; Figure 1). Glucagon-like peptide-1 also inhibits glucagon secretion, delays gastric emptying, increases feelings of satiety, and decreases food intake.7 In patients with T2DM, the secretion of GIP is near normal,27 whereas the secretion of GLP-1 is variable,27,28 and the insulinotropic response to GLP-1 is preserved, whereas responsiveness to GIP is reduced.29 Glucagon-like peptide-1 and GIP are rapidly degraded by DPP-4, a membrane-bound enzyme expressed in many tissues and also present as a soluble form in plasma.7 The DPP-4 inhibitors are oral agents that inhibit the degradation
Figure 1. Potential mechanisms whereby DPP-4 inhibitors can achieve cardiovascular protection. Arrows indicate stimulatory connections and ⊥ indicates inhibitory signals. Dashed lines indicate pathways without a defined molecular link to DPP-4 activity.
Reprinted from Vascular Pharmacology, 55, Fadini GP, Avogaro A, Cardiovascular effects of DPP-4 inhibition: beyond GLP-1, 10–16, Copyright 2011, with permission from Elsevier. Abbreviations: ACEi, angiotensin converting enzyme inhibitor; Akt, protein kinase B; BNPs, B-type natriuretic peptides; DPP-4, dipeptidyl peptidase-4; eNOS, endothelial nitric oxide synthase; EPC, endothelial progenitor cell; GLP-1, glucagon-like peptide-1; IL-6, interleukin-6; MCP-1, monocyte chemotactic protein-1; NPY, neuropeptide Y; PTH, parathyroid hormone; SDF-1α, stromal cell–derived factor-1α; SP, substance P; TNF-α, tumor necrosis factor-α.
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Potential CV Impact of DPP-4 Inhibitors in T2DM
of endogenous GLP-1 and GIP and, therefore, increase insulin secretion and decrease glucagon secretion.7 Currently approved DPP-4 inhibitors include sitagliptin, saxagliptin, linagliptin, and alogliptin, as well as vildagliptin (in Europe and South America only). Fixed‑dose combinations with metformin and of alogliptin with pioglitazone are also available. In clinical trials, DPP‑4 inhibitors reduce HbA1c levels by approximately 0.4% to 1.0%, compared with placebo, and are effective as monotherapy or as add-on to metformin, sulfonylureas, thiazolidinediones, or insulin.30,31 The DPP-4 inhibitors are generally well tolerated and are not associated with weight gain, hypoglycemia, or gastrointestinal symptoms.30 They are recommended as second- or thirdline agents in combination with metformin, sulfonylureas, thiazolidinediones, or insulin, and as monotherapy in patients who cannot receive metformin.32 Note that DPP-4 inhibitors target primarily postprandial glucose, which is more closely associated with carotid intimal thickness and a variety of atherosclerosis risk factors than is fasting plasma glucose or HbA1c level.33 Moreover, postprandial glucose may be a better predictor than fasting plasma glucose of CV events,34 CV mortality,2 and all-cause mortality.34
Cardiovascular Effects of DPP-4 Inhibitors
Findings from studies in experimental models and small observational studies in humans have provided evidence that DPP-4 inhibitors may have beneficial effects on the CV system by preventing the degradation of GLP-1 and other substrates.35 Results of studies in animals and human tissues have shown that GLP-1 receptors are present in the pancreas and many extrapancreatic tissues, including heart, blood vessels, lung, central nervous system, and kidney.35 Furthermore, DPP-4 has multiple substrates in addition to GLP-1 that are associated with cardioprotection in experimental models. For example, stromal cell–derived factor-1α (SDF-1α), which plays a key role in recruiting bone marrow–derived EPCs to sites of endothelial damage, is a substrate of DPP-4,36,37 as is B-type natriuretic peptide, involved in the regulation of body fluid homeostasis and vascular tone.38
Preclinical Studies: Selected Examples
Evidence for the potential benefits of GLP-1 and, by extension, DPP-4 inhibitors has come largely from animal studies. For example, GLP-1 administration increased nitric oxide and cardiac glucose uptake in models of cardiac ischemia39 and heart failure.40 In addition, GLP-1 reduced infarct size41
and improved LV function in models of ischemia/reperfusion injury.39 Long-term administration of GLP-1 also attenuated the development of hypertension and improved endothelial function and renal and cardiac damage in a model of saltsensitive hypertension.42 Many positive effects of DPP-4 inhibitors observed in animals may be independent of their effects on GLP-1 levels. For example, in diabetic mice, administration of SDF-1α, a DPP-4 substrate, reversed the defect in EPC homing to sites of vascular injury.37 Similarly, DPP-4 inhibition (in combination with granulocyte colony-stimulating factor) stabilized SDF-1α in the heart, enhanced myocardial progenitor cell homing and function, reduced cardiac remodeling, and improved heart function and survival after myocardial infarction (MI) in mice.43 Also, DPP-4 inhibition preserved glomerular filtration rate, increased stroke volume, decreased heart rate, and potentiated the positive inotropic effect of exogenous B-type natriuretic peptide in a heart failure model.44 Inhibition of DPP-4 increased the release of nitric oxide from aortic and glomerular cells harvested from Zucker obese45 or spontaneously hypertensive rats,46 and reduced blood pressure in spontaneously hypertensive rats.46 Finally, in models of diabetes, DPP-4 inhibition suppressed thrombogenic signaling47 and the formation of atherosclerotic lesions.48 Inflammation is associated with the development of diabetes and atherosclerosis.49 In diet-induced obese mice, sitagliptin significantly reduced adipose tissue and islet cell inflammation and macrophage infiltration into adipose tissue.50 Similarly, DPP-4 inhibition attenuated diet-induced adipose tissue inflammation and hepatic steatosis in a mouse model of diabetes.51 Treatment of obese Zucker rats with saxagliptin reduced soluble levels of CD40, an inflammatory biomarker, by over 10-fold.45
Clinical Studies
In humans, the potential beneficial CV effects of GLP-1 or DPP-4 inhibitors have been reported largely from small observational studies. For example, GLP-1 infusion improved endothelial function, measured as flow-mediated vasodilation, in patients with T2DM with52 or without53 CAD. Also, GLP-1 infusion improved LV function in patients (50% with diabetes) with acute MI and severe systolic dysfunction receiving standard post-MI therapy after successful primary angioplasty.54 In patients with T2DM, treatment with sitagliptin for 1 and 3 months inhibited platelet aggregation by 10% and 30%, respectively.55 Moreover, thrombin-induced aggregation and
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Michael H. Davidson
increases in intracellular calcium were inhibited in platelets pretreated with sitagliptin in vitro. Dipeptidyl peptidase-4 inhibition with sitagliptin (plus an oral glucose load) improved global and regional LV performance in response to dobutamine stress echocardiography and decreased postischemic stunning in patients with CAD.56 In patients with poorly controlled T2DM, 4 weeks of treatment with sitagliptin plus metformin with or without insulin secretagogues increased EPCs 2-fold and SDF‑1α by 50% and reduced levels of the inflammatory chemokine monocyte chemoattractant protein-1 by 25% compared with baseline measures. There were no changes in these parameters in patients not receiving sitagliptin.57 In a randomized, double-blind, crossover study in patients with T2DM receiving metformin ± sulfonylurea or thiazolidinedione, 4 weeks of treatment with vildagliptin improved endotheliumdependent vasodilation (forearm blood flow) compared with acarbose treatment.58 The Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) trial assessed the effects of vildagliptin (n = 128) versus placebo (n = 126) on LV function in patients with T2DM and heart failure with reduced LV ejection fraction. In a preliminary report, vildagliptin was noninferior to placebo after 52 weeks of treatment for the change from baseline in LV ejection fraction as assessed by echocardiography.59 There was a statistically significant increase in LV end diastolic volume (P = 0.007) and stroke volume (P = 0.002) in the vildagliptin group versus the control group. Although not statistically significant, a greater proportion of patients receiving vildagliptin versus placebo died from any cause (8.6% vs 3.2%) and from CV causes (5.5% vs 3.2%). Evidence for the benefits of lipid-lowering therapy in patients with T2DM has been demonstrated in multiple clinical trials, and it is well acknowledged that patients with T2DM have an increased prevalence of lipid abnormalities, contributing to their high risk of CV disease. Although DPP-4 inhibitors have little effect on fasting lipid profiles, these agents have significant beneficial effects on postprandial lipidemia. Sitagliptin was shown to reduce the area under the curve for triglycerides and ApoB48, as well as ApoB100,60 suggesting that DPP-4 inhibitors decrease postprandial plasma levels of triglyceride-rich lipoproteins of both intestinal and hepatic origin. Similar effects on postprandial lipemia have been demonstrated with vildagliptin.61
DPP-4 Inhibitors and CV Outcomes
Two large randomized CV outcomes clinical trials with DPP‑4 inhibitors have recently been completed, and several 60
others are in progress (Table 1). In the Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus trial (SAVOR),62 adult patients (N = 16 492) with T2DM and a history of established CV disease or multiple CV risk factors received saxagliptin or placebo and were followed for # 2.9 years (median follow-up was 2.1 years). Patients also received standard of care for T2DM and CV risk factors. The primary composite end point of CV death, nonfatal MI, or nonfatal stroke occurred in 7.3% of patients receiving saxagliptin compared with 7.2% of those receiving placebo (hazard ratio [HR], 1.00; 95% CI, 0.89–1.12; noninferiority P , 0.001; superiority P = 0.99). The major secondary composite end point (CV death, nonfatal MI, nonfatal stroke, hospitalization for heart failure, hospitalization for unstable angina, or hospitalization for coronary revascularization) occurred in 12.8% of patients in the saxagliptin group versus 12.4% of patients in the placebo group (HR, 1.02; 95% CI, 0.94–1.11; P = 0.66). A component of the secondary composite end point, hospitalization for heart failure, occurred more frequently with saxagliptin (3.5%) than with placebo (2.8%; HR, 1.27; 95% CI, 1.07–1.51; P = 0.007). A secondary end point of all-cause mortality occurred in 4.9% of patients in the saxagliptin group compared with 4.2% in the placebo group (HR, 1.11; 95% CI, 0.96–1.27; P = 0.15). The number of patients with acute or chronic pancreatitis was low and similar in both groups (saxagliptin, 0.3%; placebo, 0.3%). Five cases of pancreatic cancer were reported in the saxagliptin group versus 12 in the placebo group. The EXamination of cAardiovascular outcoMes with alogliptIN versus standard of carE in patients with T2DM and acute coronary syndrome (EXAMINE) trial63 assessed the effects of alogliptin versus placebo in patients (N = 5380) with T2DM and an acute coronary syndrome within 15 to 90 days prior to randomization. Patients continued to receive standard care for T2DM and CV risk factors and were followed for up to 40 months (median 18 months). The primary composite end point of CV death, nonfatal MI, or nonfatal stroke occurred in 11.3% of patients randomized to alogliptin versus 11.8% of those randomized to placebo (HR, 0.96; upper bound of CI, # 1.16; P , 0.001 for noninferiority; P = 0.32 for superiority). There was no difference between alogliptin and placebo in the major secondary composite end point of CV death, nonfatal MI, nonfatal stroke, or urgent revascularization due to unstable angina (HR, 0.95; upper bound of CI, # 1.14; P = 0.26 for superiority). Death from any cause occurred in 5.7% of patients receiving alogliptin versus 6.5% of those receiving placebo (HR, 0.88; 95% CI, 0.71–1.09; P = 0.23 for superiority). A post-hoc analysis of
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Potential CV Impact of DPP-4 Inhibitors in T2DM
Table 1. Cardiovascular Outcome Trials With DPP-4 Inhibitors Trial
Drug
N
Patients
Saxagliptin vs 16 492 Men and women aged $ 40 years SAVOR NCT01107886 placebo with T2DM and established CV disease and/or multiple risk factors EXAMINE64 Alogliptin vs 5380 Men and women aged $ 18 NCT00968708 placebo years with T2DM and acute MI or unstable angina requiring hospitalization Sitagliptin vs 14 000 Men and women aged $ 50 years TECOS71 NCT00790205 placebo with T2DM and preexisting CV disease CAROLINA72 Linagliptin vs 6000 Men and women aged 40–85 years NCT01243424 glimepiride with T2DM and preexisting CV disease or specified diabetes end-organ damage; or aged $ 70 years; or $ 2 specified CV risk factors CARMELINA73 Linagliptin vs 8300 Men and women aged $ 18 NCT01897532 placebo years with T2DM and micro- or macroalbuminuria and previous macrovascular disease and/or impaired renal function
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62
Primary Outcome
Start Date
Completion Date
Composite of CV death, nonfatal MI, or nonfatal ischemic stroke
May 2010
May 2013
Composite of CV death, nonfatal MI, or nonfatal stroke
September 2009 June 2013
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 2008 December 2014 (estimated) October 2010
Composite of CV death, nonfatal July 2013 MI, nonfatal stroke, or hospitalization for unstable angina pectoris; secondary outcome of renal death, end-stage renal disease, and a sustained decrease of $ 50% in eGFR
September 2018 (estimated)
January 2018 (estimated)
Abbreviations: CARMELINA, CArdiovascular and Renal Microvascular outcomE study with LINAgliptin; CAROLINA, CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 diabetes; CV, cardiovascular; eGFR, estimated glomerular filtration rate; EXAMINE, EXamination of cAardiovascular outcoMes with alogliptIN versus 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.
the composite end point of CV mortality and hospitalization for heart failure found a numerically higher proportion of patients hospitalized for heart failure for alogliptin (3.9%) versus placebo (3.3%). However, the increased risk was not statistically significant (HR, 1.19; 95% CI, 0.90–1.58).64 Acute pancreatitis occurred in 12 (0.4%) patients receiving alogliptin and in 8 (0.3%) receiving placebo (P = 0.50). Chronic pancreatitis was reported in 5 (0.2%) and 4 (0.1%) patients in the alogliptin and placebo groups, respectively (P = 1.0). There were no reports of pancreatic cancer. Pooled analyses of major adverse cardiovascular events (MACE) occurring during the clinical development of sitagliptin, saxagliptin, linagliptin, alogliptin, and vildagliptin are available; all found no increase in MACE,63,65–69 and some studies reported a possible CV benefit65,66 (Table 2). In a pooled analysis of 19 double-blind trials of sitagliptin (12 weeks to 2 years) that included data from 10 246 patients with T2DM who received either sitagliptin 100 mg/d (n = 5429) or a comparator (placebo or an active comparator, n = 4817), the incidence rates for nonadjudicated MACE (ischemic events or CV death) were 0.6 and 0.9 per 100 patient-years in the sitagliptin group and comparator groups, respectively.68 The risk ratio for sitagliptin‑exposed versus nonexposed patients
was 0.68 (95% CI, 0.41–1.12), suggesting no increased risk of CV events with sitagliptin. The risk for CV events (adjudicated) was analyzed across 8 randomized phase 2 and 3 trials with saxagliptin 2.5 to 100 mg/d (saxagliptin, n = 3356; comparator, n = 1251; duration, 16–116 weeks).65 Confirmed CV events occurred in 22 (0.7%) patients receiving saxagliptin and 18 (1.4%) patients treated with comparator. The relative risk with saxagliptin versus various comparators for a composite end point of CV death, MI, or stroke was 0.43 (95% CI, 0.23–0.80) using blinded retrospective event adjudication by an independent group. The data suggest no increased risk of CV events and possibly a reduction in CV events with saxagliptin. In an expanded pool of 20 randomized phase 2 and 3 clinical trials (n = 9156), the incidence rates for adjudicated MACE (CV death, MI, or stroke) were 0.9 and 1.1 per 100 patient-years for saxagliptin and control, respectively. The Cox proportional HR was 0.75 (95% CI, 0.46–1.21), suggesting no increased risk of MACE. Incidence rates per 100 patient-years for nonadjudicated heart failure were 0.34 for saxagliptin and 0.62 for control. The HR was 0.55 (95% CI, 0.27–1.12), suggesting no increased risk of heart failure with saxagliptin.
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Table 2. Analysis of Major Adverse Cardiovascular Events From Phase 2 and 3 Clinical Trials of DPP-4 Inhibitors
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Patients, n
CV Events
DPP-4 inhibitor
Trials, n
Composite end point
Drug
Comparator
Drug, n (%)
Comparator, n (%)
Risk (95% CI)
Sitagliptin68
19
5429
4817
0.6/100a
0.9/100a
0.68 (0.41–1.12)b
Saxagliptin65 Saxagliptin69 Linagliptin66
8 20 8
3356 5701 3319
1251 3455 1920
22 (0.7) 0.9/100a 11 (0.3)
18 (1.4) 1.1/100a 23 (1.2)
0.43 (0.23–0.80)c 0.75 (0.46–1.21)c 0.34 (0.16–0.70)d
Alogliptin63
11
4168
1860
13 (0.3)
10 (0.5)
0.64 (0–1.4)
Vildagliptin67
25
Ischemic events or CV death MI, stroke, or CV death CV death, MI, or stroke CV death, stroke, MI, or hospitalization for unstable angina CV death, nonfatal MI, or nonfatal stroke ACS, TIA, stroke, or CV death
1393 (50 mg once daily) 6116 (50 mg twice daily)
6061
10 (0.7) (50 mg once daily) 81 (1.3) (50 mg twice daily)
91 (1.5)
0.88 (0.37–2.11)e 0.84 (0.62–1.14)e
Incidence rates per 100 patient-years. Risk ratio. c Cox relative risk. d Hazard ratio. e Mantel-Haenszel risk ratio. Abbreviations: ACS, acute coronary syndrome; CV, cardiovascular; DPP-4, dipeptidyl peptidase-4; MI, myocardial infarction; TIA, transient ischemic attack. a
b
In a meta-analysis of CV events from 8 phase 3 trials of linagliptin 5 or 10 mg/d (linagliptin, n = 3319, median duration 175 days [range, 1–617]; placebo or comparator, n = 1920, median duration 179 days [range, 1–619]), the primary CV end point (composite of CV death, stroke, MI, or hospitalization for unstable angina) occurred in 11 (0.3%) patients receiving linagliptin and 23 (1.2%) receiving comparators.66 The HR of 0.34 for the primary end point showed significantly lower risk with linagliptin than comparators (95% CI, 0.16–0.70). The results indicated that linagliptin does not increase CV risk and support a potential reduction of CV events versus comparators. Analysis of MACE in 11 phase 2 and 3 trials for alogliptin (n = 4168) versus placebo or comparator (n = 1860) found no significant treatment difference for the adjudicated composite end point of CV death, nonfatal MI, and nonfatal stroke (HR, 0.64; 95% CI, 0.0–1.4).63 The individual events were also distributed similarly across treatment groups. No significant treatment difference between alogliptin and placebo or comparator was evident for other serious CV events of angina, arrhythmias, and heart failure. The relative risk for a composite adjudicated CV event (acute coronary syndrome, transient ischemic attack, stroke, or cerebrovascular death) was assessed in patients treated with vildagliptin (n = 7509), compared with those treated with placebo or comparator (n = 6061), for 12 weeks to $ 2 years in 25 phase 3 trials.67 The relative risk for the composite CV event end point for vildagliptin 50 mg once daily was 62
0.88 (95% CI, 0.37–2.11) and twice daily was 0.84 (95% CI, 0.62–1.14), suggesting that vildagliptin was not associated with an increased risk of CV events. A meta-analysis of 70 clinical trials also found that DPP-4 inhibitors reduced the risk of CV events, especially MI, and all-cause mortality.70 Although preclinical studies and observational studies in humans suggest that DPP-4 inhibition may have CV benefits, meta-analyses of clinical trials have not demonstrated superiority of DPP-4 inhibitors versus placebo or other antihyperglycemic medications in reducing adverse CV events in patients with T2DM. Moreover, the results of CV outcomes trials such as SAVOR62 and EXAMINE64 found that rates of MACE with saxagliptin and alogliptin were similar to rates with placebo. It should be noted, however, that SAVOR and EXAMINE enrolled patients with a history of CV disease or with multiple CV risk factors and T2DM duration of 7 to 10 years. Because these patients were also receiving standard-ofcare treatment for T2DM and CV disease (β-blockers, statins, and renin-angiotensin-system blockers), it is possible that any additional CV benefit of DPP-4 inhibition would be difficult to detect on such a background of CV medications. Whether or not DPP-4 inhibitors prevent or delay CV complications in patients with less advanced T2DM and CV disease is unknown.
Conclusion
It is well established that patients with T2DM experience significant morbidity and mortality from CV disease. Treatment
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Potential CV Impact of DPP-4 Inhibitors in T2DM
recommendations emphasize achieving glycemic control and targeting common comorbidities, including hypertension and dyslipidemia. Whereas the findings of epidemiologic studies have established an association between hyperglycemia and the risk for CV events and mortality, evidence for CV benefits of glycemic control with standard diabetes medications is lacking. There is considerable interest in developing therapies that might offer CV advantages in addition to controlling hyperglycemia. Based mainly on results from preclinical studies and small mechanistic studies, DPP-4 inhibitors, via actions on GLP-1 as well as by those independent of GLP-1, may affect some of the pathologic processes involved in the increased CV risk inherent in T2DM. Whether DPP-4 inhibition is associated with significant attenuation of CV risk awaits the full results of several large prospectively designed CV outcome clinical trials. Results reported from 2 of these trials, the SAVOR and EXAMINE trials, show that saxagliptin and alogliptin do not increase adverse CV events, nor do they reduce adverse CV events compared with placebo when added to current standard of care with or without other T2DM therapies in patients with a history of CV disease or with multiple CV risk factors.
Acknowledgments
Editorial support was provided by Richard M. Edwards, PhD, and Janet E. Matsuura, PhD, from Complete Healthcare Communications, Inc. (Chadds Ford, PA), and was funded by Bristol-Myers Squibb and AstraZeneca LP.
Conflict of Interest Statement
Michael H. Davidson, MD, serves on advisory boards or as a consultant for AbbVie, Amgen, Aegerion, Esperion, Lipidemx, Merck, Sanofi, and Vindico. Dr Davidson is a member of the speakers bureau for Merck; he also owns shares of stock in Omthera Pharmaceuticals, Inc. (chief medical officer). Omthera Pharmaceuticals, Inc. is a wholly owned subsidiary of Zeneca, Inc., and is a member of the AstraZeneca group of companies.
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