Understanding the type 2 diabetes mellitus and cardiovascular disease risk paradox.

All rights reserved: reproduction in whole or part not permitted. All permission requests to reproduce or adapt published material must be directed to the journal office in Conshohocken, PA, no othe rpersons of offices are authorized to act on our behalf.

Reprints: [email protected] -- [email protected]

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

Understanding the Type 2 Diabetes Mellitus and Cardiovascular Disease Risk Paradox

Postgraduate Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 04/11/15 For personal use only.

DOI: 10.3810/pgm.2014.05.2767

Jennifer B. Green, MD Associate Professor of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Duke Clinical Research Institute, Durham, NC

Abstract: Patients with diabetes have approximately a 2-fold increase in the risk for coronary heart disease, stroke, and death from vascular causes compared with patients who do not have diabetes. Interventions targeted at modifiable risk factors, such as smoking cessation and management of hypertension and dyslipidemia, reduce the risk of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM). Paradoxically, large randomized studies have failed to conclusively show that intensively lowering glucose reduces CVD event rates in patients with T2DM, despite pathophysiologic and epidemiologic evidence suggesting that hyperglycemia contributes to CVD. Although initiation of intensive glycemic control early in the disease course may be associated with a reduction in the long-term risk of cardiovascular (CV) events, this approach in those with long-standing or complicated T2DM is not of clear benefit and may even be harmful in some. Failure to mitigate risk with antihyperglycemic therapy and the potential for some treatments to increase CVD risk underlies a treatment paradox. New glucose-lowering therapies are now subject to close scrutiny for CV safety before and after drug approval. Results from the first trials designed to meet the recent CV regulatory requirements have shown no increased risk of major adverse CV events but also no CV benefit from dipeptidyl peptidase-4 inhibitor therapy, as well as a potentially increased risk of hospitalization for heart failure. Conclusive evidence of CV risk reduction with glucose-lowering therapy is still lacking and scrutiny of additional agents is necessary. Type 2 diabetes mellitus is a heterogeneous disease, for which patient-centered, individualized care, and goal-setting is appropriate. Interventions that focus on the management of CV risk factors and glucose lowering with medications that are not cardiotoxic represent an optimal and attainable treatment approach. Keywords: type 2 diabetes mellitus; cardiovascular; glucose-lowering therapy; hypertension; lipids

Introduction

Correspondence: Jennifer B. Green, MD, DUMC Box 3850, 2400 Pratt St, Room 7039, North Pavilion, Durham, NC 27705. Tel: 919-668-8401 Fax: 919-668-7058 E-mail: [email protected]

190

Patients with type 2 diabetes mellitus (T2DM) are at high risk of cardiovascular (CV) events and excess mortality from CV disease (CVD).1 Both CVD and T2DM share similar risk factors, etiology, and pathophysiology.2–5 These 2 disorders may represent a continuous spectrum of a common disease process characterized by persistent lowgrade inflammation leading to insulin resistance and atherogenic plaque formation. Notably, an increased risk of CVD often precedes a formal diagnosis of T2DM.6,7 The prospective epidemiologic Nurses’ Health Study showed a significantly elevated relative risk of myocardial infarction (MI) and stroke in women that began to increase as much as 15 years before diagnosis of T2DM.7 Data from longitudinal studies show that men and women with new-onset T2DM have an increased risk of all-cause and CVD-associated mortality compared with patients without T2DM.8,9

© Postgraduate Medicine, Volume 126, Issue 3, May 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.


Understanding the T2DM and CVD Risk Paradox

Landmark data showing that the risk of coronary heart disease (CHD) in patients with T2DM and no previous MI is similar to the risk in those without T2DM and a previous MI10 led to the designation of T2DM as a CHD risk equivalent.11 Recent evaluation of patient-level data from 102 studies continue to support an approximate 2-fold increase in the risk of CHD, stroke, and death from vascular causes in patients with diabetes compared with those without diabetes (Figure 1).12 The increased risk of CVD in patients with diabetes remains even after adjustment for traditional risk factors.12–14 Findings from the Copenhagen City Heart Study of 13 105 participants included an increased risk of first MI in patients with T2DM independent of smoking status, cholesterol levels, and other risk factors.13 Specifically, the relative risk was increased 1.5- to 4.5- fold in women and 1.5- to 2-fold in men. Post-MI mortality at acute care hospitals15 and Veterans Administration centers16 in the United States has decreased over the past decades in those with and without diabetes due to advances in the management of CVD and its underlying risk factors. Although the gap has narrowed, all-cause and CVD-associated mortality remain higher in US adults with diabetes compared with adults without diabetes.1,16 This disparity is not unique to the United States. Epidemiologic data from Sweden and Canada show that despite improvements in long-term survival after stroke17 or MI,18 a post-event mortality gap between those with and without diabetes was still present in the early part of this decade. Results from a United Kingdom cohort study evaluating current CVD mortality from T2DM among middle-aged adults (40–65 years) showed that those with T2DM experienced a 2-fold increased risk of all-cause mortality and a 3-fold increased risk of CV mortality compared with individuals without T2DM.19 Interventions aimed at modifiable risk factors, such as smoking cessation, blood pressure (BP) management, and statin use, reduce CVD risk in individuals with T2DM. Whether the management of hyperglycemia mitigates the excess CVD and associated mortality risk in T2DM is a topic of ongoing debate. Thus, this review discusses the evolution of the understanding of the paradoxical relationship between CVD and T2DM, which includes the impact of intensive glycemic management on CV outcomes; the sometimes unexpected CV effects of individual glucose-lowering therapies; regulatory requirements to assess the CV impact of new glucose-lowering therapies; and nonglycemic strategies to reduce CVD risk in patients with T2DM. This review focuses primarily on the known CV effects of the major classes of drugs recommended in the joint guidelines issued by the American Diabetes Association and the European

Association for the Study of Diabetes (ADA/EASD),20 and the recently approved selective sodium glucose cotransporter-2 (SGLT2) inhibitors.

Methods

For this narrative review, relevant articles were obtained from PubMed searches using the terms diabetes[Title/Abstract] and cardiovascular[Title/Abstract] or heart[Title/Abstract] or hypertension[Title/Abstract], with limits for English language, clinical trial, or meta-analysis. Priority was given to recent papers that discussed CV rather than glycemic outcomes. A separate PubMed search using the terms cardiovascular disease and diabetes and cholesterol, and then either secondary prevention or primary prevention was also conducted; results were limited to English language clinical trials or meta-analyses in the last 5 years. Additional papers were obtained based on the reference lists of the selected articles and the author’s historical knowledge of the subject area. Studies for inclusion in this review were also identified from ADA/EASD guidelines. Additionally, information on CV outcomes trials for T2DM treatments was obtained from ClinicalTrials.gov.

Intensive Glycemic Control and CVD Risk

Pathophysiologic and epidemiologic evidence suggest that hyperglycemia contributes to CVD. Hyperglycemia promotes endothelial dysfunction and atherogenic lesion formation.21 Moreover, epidemiologic studies show a relationship between glycated hemoglobin (HbA1c) concentrations and increased risk of CVD.21–23 Paradoxically, large randomized studies have failed to conclusively show that intensively lowering glucose reduces CVD event rates in patients with T2DM.24–28 Two large long-term trials, the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) and the Veterans Affairs Diabetes Trial (VADT), showed no significant reduction in CV events with intensive glucose-lowering therapy directed at a target HbA1c level # 6.5 or , 6.0, respectively.27,28 Moreover, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was halted early (after 3.5 years) because of an increased risk of death in patients assigned to intensive glycemic control.26 Alternately, the United Kingdom Prospective Diabetes Study (UKPDS) of patients with newlydiagnosed T2DM showed more favorable effects of intensive glycemic therapy. During the initial study period, patients with tighter glycemic control experienced a nonsignificant

© Postgraduate Medicine, Volume 126, Issue 3, May 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 191 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Jennifer B. Green


Figure 1. HRs for vascular outcomes in patients with versus patients without diabetes at baseline (N = 530 083). All HRs were adjusted for age, smoking status, BMI, and SBP, and, where appropriate, stratified by sex and trial arm.

*Includes fatal and nonfatal events. Reprinted from The Lancet, 375, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, et al, Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Copyright © 2010, with permission from Elsevier.12 Abbreviations: BMI, body mass index; CI, confidence interval; HRs, hazard ratios; SBP, systolic blood pressure;

reduction in the relative risk of MI,25 which persisted and was found to be statistically significant at the 10-year posttrial follow up.29 Patients randomized to more intensive glycemic control in the UKPDS were also found to have a significant 13% relative risk reduction in all-cause mortality at the 10-year posttrial follow up.29 Several hypotheses have been generated to explain why these landmark studies had inconsistent outcomes related to the intensity of glycemic management. Three meta-analyses that included data from these trials calculated risk reductions of 14% to 17% for MI, and no significant increase or decrease in risk of CV mortality conveyed by intensive glycemic management.30–32 Individually, some of these studies may have been underpowered or of inadequate duration to show the impact of intensive glycemic control on CV events. In addition, aggressive management of CV risk factors in these trials may have minimized the likelihood of detecting differences in CV outcomes attributable to the degree of glycemic control.33 Although postulated as a potential risk factor for the increased mortality observed in the ACCORD trial, a definitive link between hypoglycemia and mortality was not established.33 However, a recent meta-analysis has suggested that severe hypoglycemia is associated with an increased risk of CVD, and that avoidance of severe hypoglycemia may be important in reducing the risk of CV events.34 In addition, the timing of intensive glycemic intervention, in trials other than the UKPDS, may have been too late to affect macrovascular outcomes. Diabetes is associated with accelerated atherosclerosis, and participants in these trials already had 192

well-established T2DM (≈ 10 years). Subanalyses of these data suggest that more intensive glycemic management may reduce CV events in patients with a shorter duration of disease and lower baseline levels of HbA1c.33 In contrast, patients with higher HbA1c values at baseline, lack of significant HbA1c improvement despite intensification of therapy, or a previous CV event did not benefit from an intensive glycemic control strategy. Patients without established complications appear more likely to benefit from intensive therapy. Similarly, the UKPDS, which did find a CV benefit attributable to intensive glycemic control, included only patients with recently diagnosed T2DM.29 More recent analyses have still not defined the optimal strategy to reduce CV events through glycemic control. The Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial assessed if early intervention with insulin glargine could reduce CV events or mortality in participants with prediabetes or early T2DM; the results showed no effect of early glycemic intervention in reducing overall CV events or mortality.35 A recent meta-analysis of 13 randomized controlled trials of intensive glycemic control estimated that this glucose-lowering strategy conveyed a relative risk reduction of 15% for nonfatal MI,36 which is similar to that found in other meta-analyses.30−32 However, no significant reduction in all-cause or CV mortality was noted; thus the authors commented that, “a reduction in myocardial infarctions without a reduction in mortality must be considered cautiously.”36 Additionally, intensive therapy was associated with an increased risk of severe hypoglycemia, highlighting



the need for glucose-lowering strategies which minimize this risk.36


CV Implications of T2DM Therapies: History and Recent Developments

The lack of conclusive evidence of macrovascular risk reduction with glucose-lowering therapy coincided with emerging concerns about the CV safety of glucose-lowering agents already being used. The failure to mitigate risk or the potential to increase the risk of CV events with T2DM treatments directed at improving CV outcomes underlies a treatment paradox. For example, the peroxisome proliferator–activated receptor (PPAR) receptor ligands held promise as T2DM agents that might positively affect CV outcomes.37 These agonists provide glycemic control through the γ receptor and some also improve lipid profiles via the α receptor.38 These agents include the thiazolidinedione PPAR-γ agonists rosiglitazone and pioglitazone, and the dual PPAR-α/γ agonists muraglitazar and aleglitazar; paradoxically, some of these agents have been associated with an increased CV risk.39–41 Development programs for the dual PPAR agents were halted because of increased CV mortality in trials of muraglitazar,40 and safety concerns (eg, heart failure) and a lack of CV benefit from aleglitazar therapy.41 Rosiglitazone initially showed promise based on surrogate CV end points, but results from a controversial meta-analysis suggested an increased risk of CV events in rosiglitazone-treated patients.39,42 The US Food and Drug Administration (FDA) severely restricted use of rosiglitazone in the United States, and the European Medicines Agency withdrew the drug from the European market; however, the FDA has since relaxed its restrictions after reanalysis of RECORD (Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes) trial data.43,44 Of note, results from the PROactive (PROspective PioglitAzone Clinical Trial In macroVascular Events) trial suggest that pioglitazone does not increase the risk of CV events, including nonfatal MI and nonfatal stroke.45 However, all thiazolidinedione drugs increase the risk of fluid retention and congestive heart failure46 and are contraindicated in patients with class III or IV heart failure.47 The CV issues noted with available and emerging T2DM therapies have prompted the FDA and the European Medicines Agency to require evidence showing that new T2DM agents do not significantly increase the risk of CV events.48,49 Most new antihyperglycemic agents will eventually require a large CV outcomes trial post approval to definitively

assess CV risk. Despite their widespread use, the long-term CV effects of many antihyperglycemic agents currently available may remain unknown as their approval was traditionally based on glucose-lowering efficacy and overall (rather than CV) tolerability and safety.20 Metformin is the first choice of therapy for most T2DM patients with no conditions to preclude its use, such as significant renal dysfunction or unstable heart failure.20,46,50 Preclinical data suggest that metformin may provide cardioprotection to ischemia-reperfusion injury through a glucoseindependent mechanism,51 and some clinical trials data suggest that metformin improves macrovascular outcomes.52 However, metformin monotherapy is usually inadequate to control glycemia during the long term.53 Thus, combinations of glucose-lowering medications are ultimately required by the majority of patients with T2DM.53,54 Sulfonylureas are a widely used class of glucoselowering therapies, commonly prescribed in combination with metformin. However, controversy surrounds their CV safety profile.55 Results from observational studies56–59 and meta-analyses60–62 are inconsistent regarding the CV impact of sulfonylurea therapy. The sulfonylurea class exerts its insulin secretory actions via inhibition of the adenosine triphosphate–sensitive potassium (KATP) channel on the pancreatic β cell.63 The KATP channel is also present on cardiac myocytes. Inhibition of cardiac KATP channels may prevent ischemic preconditioning, which is the mechanism suggested for the adverse CV consequences associated with this drug class in cohort studies. The binding affinity for pancreatic over cardiac KATP channel subunits varies among the available agents,64 which may account for clinical differences. However, preferential use of gliclazide in the CV outcomes trial ADVANCE was not associated with an increase in risk27 and sulfonylurea use in the intensive arm of the UKPDS did not increase CV risk either.25 Thus, different degrees of risk (if present) may be associated with individual agents, and the effects may differ based on patient characteristics. A greater level of CV risk may be associated with the use of early generation sulfonylureas, and those sulfonylureas are most likely to cause hypoglycemia. Because many of the sulfonylureas have been on the market for a long time, definitive CV outcomes trials of these agents seem unlikely. However, other types of studies may provide additional CV safety information (eg, the Comparative Effectiveness Study of Major Glycemia-lowering Medications for Treatment of Type 2 Diabetes [GRADE]).65 Glucagon-like peptide-1 (GLP-1) receptor agonists, such as exenatide and liraglutide, are subcutaneously administered



Jennifer B. Green

antihyperglycemic agents that enhance insulin secretion and suppress glucagon secretion in a glucose-dependent manner, delay gastric emptying, and increase satiety.66 Preclinical and proof-of-concept studies suggest the potential for CV benefits with GLP-1 receptor agonist therapy mediated through GLP-1 receptors present on myocardial tissues and receptor-independent mechanisms.67 Administration of native GLP-1 or exenatide has been associated with reduced infarct size after ischemia-reperfusion injury in animal models.68–70 Preliminary clinical trials of GLP-1 infusions show enhanced left ventricular function in patients undergoing angioplasty after MI,66 with congestive heart failure,71 or with coronary artery disease undergoing dobutamine stress testing. 72 Additionally, a double-blind placebo-controlled trial of 172 patients with ST-segment elevation MI found that intravenous infusion of exenatide administered at the time of reperfusion improved the myocardial salvage index.73 Findings from several clinical trials of GLP-1 receptor agonists in patients with T2DM show beneficial effects on some CV risk factors, including reductions in body weight, decreases in BP, and improved lipid profiles.74–76 Separate retrospective pooled analyses of CV safety data obtained from adverse event reporting from 12 studies of exenatide (twice daily) and 15 studies of liraglutide showed risk ratios for the primary major adverse CV event (MACE) end point of 0.70 (95% CI, 0.38–1.31)77 and 0.73 (95% CI, 0.38–1.41),78 respectively. These results suggest that GLP-1 agonists do not increase CV risk. A combined meta-analysis of 20 trials of liraglutide or exenatide with $ 1 reported major CV event yielded a Mantel-Haenszel odds ratio (MH-OR) for MACE of 0.74 (95% CI, 0.50–1.08).79 Double-blind, prospective, randomized, placebo-controlled trials are ongoing to evaluate the effects of dulaglutide (REWIND [Researching Cardiovascular Events With a Weekly Incretin in Diabetes]),80 exenatide (EXSCEL [Exenatide Study of Cardiovascular Event Lowering Trial]),81 liraglutide (LEADER [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results]),82 and lixisenatide (ELIXA [Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010]),83 on MACE in patients with T2DM and at high risk for CV events. The dipeptidyl peptidase-4 (DPP-4) inhibitors are oral agents that prevent the cleavage of several physiologically important peptides, including the incretin hormones GLP-1, and glucose-dependent insulinotropic polypeptide.84 Improvements in glycemia result primarily from the prolonged action of GLP-1. In addition to possible CV effects mediated 194

through GLP-1, the presence of targets for DPP-4 outside the gut suggests that DPP-4 may play a direct role in the CV system.37,85 Inhibitors of DPP-4 increase the availability of intact B-type natriuretic peptide (1–32),84 which may play a role in heart failure, and of stromal cell-derived factor-1α, which may facilitate homing of endothelial progenitor cells to sites of CV damage.86,87 Preclinical studies37,85 of DPP-4 inhibition have shown decreased infarct size and improved cardiac function in models of ischemia or ischemia-reperfusion injury,88 and clinical investigations of DPP-4 inhibition have shown improved left ventricular function in response to dobutamine stress testing.89 With respect to CV risk factors, meta-analyses demonstrate that DPP-4 inhibitors have neutral effects on weight,90–92 lipid levels,91,92 and BP.91,92 Trials of sitagliptin have shown small improvements in BP for hypertensive patients93 and enhancement of the effects of submaximal angiotensin-converting enzyme inhibitor (ACEI) therapy.94 However, DPP-4 inhibition appears to attenuate the effect of higher dose ACEI therapy, possibly induced by activation of the sympathetic nervous system through substance P.94 The diminished degradation of substance P has also been proposed as a mechanism underlying the small absolute increase in the risk of angioedema observed with concomitant vildagliptin and ACEI use.95 More research is needed to fully elucidate the clinical relevance and frequency of BP effects and angioedema with chronic DPP-4 inhibitor and ACEI administration. Pooled CV safety data from controlled clinical trials for the 5 currently marketed DPP-4 inhibitors (including vildagliptin [available outside of the US]), suggest that DPP-4 inhibitors do not increase the risk of MACE in T2DM patients.91,92,96–99 Additionally, a meta-analysis of safety data from 63 published studies of DPP-4 inhibitors found a reduced risk of MACE (MH OR, 95% CI, 0.71 [0.59–0.86]).100 These data provide reassurance that a CV safety signal is not present. However, the included trials were based on DPP-4 clinical development programs that were designed to demonstrate glycemic efficacy and tolerability, and not CV safety; were trials of short duration; and generally underrepresented patients with increased CV risk. The first 2 large, prospective, placebo-controlled, longterm trials designed to meet the FDA’s regulatory requirements for the safety and efficacy of DPP-4 inhibitors with regard to CV outcomes in patients with T2DM at high risk for CV events have shown no increase or decrease in the risk of major CV events with saxagliptin or alogliptin therapy (Table 1).101,102 The larger and longer of the 2 trials, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients




with Diabetes Mellitus (SAVOR-TIMI 53), included 16 492 patients with T2DM who had a history of, or were at risk for, CV events and followed patients for # 2.9 years (median, 2.1 years).101 The EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE (EXAMINE) trial included 5380 patients with T2DM who experienced an acute MI or unstable angina requiring hospitalization within the previous 15–90 days and followed patients for # 40 months (median, 18 months).102 In both trials, the upper limit of the 95% CI for the hazard ratio (HR) for MACE was , 1.3 (the FDA’s prespecified safety boundary), but not , 1.0.101,102 Therefore, saxagliptin and alogliptin met the noninferiority criterion (ie, no increased CV risk), although they did not demonstrate CV superiority compared with placebo when added to the standard of care.101,102 The SAVOR-TIMI 53 trial showed a statistically significant and unexpected increase in the risk of hospitalization for heart failure (HR, 1.27; 95% CI, 1.07–1.51; P = 0.007), which was speculated as a potentially false-positive result because of the multiplicity of statistical testing.101 The study investigators cautioned against presuming that this finding was a class effect and indicated that further study was warranted.101 Results of additional analyses showed that the risk of the primary composite CV end point was similar among patients with or without a history of heart failure who received saxagliptin (HR, 1.13 [95% CI, 0.89–1.43] vs 0.97 [0.85–1.10]; P = 0.28 for interaction).103 The HRs for the secondary composite end point (primary end point plus hospitalization for heart failure) were also similar in the saxagliptin groups with and without a history of heart failure (HR, 1.06 [95% CI, 0.89–1.27] vs 1.01 [0.91–1.11]; P = 0.63 for interaction).The published manuscript describing the primary analysis of the EXAMINE trial did not include information

about hospitalization for heart failure.102 Subsequent post hoc analyses, which have not been published at the time of this review, have reportedly shown no statistically significant increase in the composite CV outcome inclusive of hospitalization for heart failure with alogliptin compared with placebo. Furthermore, the authors report that alogliptin therapy did not result in a worsening of heart failure outcomes in those with a previous history of heart failure.103 Further study regarding the association between DPP-4 inhibition and heart failure risk is necessary given these findings. A physiologic link may be plausible as the DPP-4 enzyme is involved in the metabolism of a large number of potentially cardioactive substrates. The effects of other DPP-4 inhibitors on CV outcomes are being evaluated in additional prospective long-term studies. The Trial to Evaluate Cardiovascular Outcomes after treatment with Sitagliptin (TECOS)104 is a trial assessing the effect of sitagliptin compared with placebo on a primary composite MACE end point of CV death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization, which has enrolled . 14 000 patients with study completion expected at the end of 2014. The Cardiovascular Outcome study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes (CAROLINA)105 is the only prospective CV outcomes trial of a DPP-4 inhibitor to include an active comparator (glimepiride)55; the primary MACE end point55 is the same as that in the TECOS study.104 The CAROLINA trial currently has enrolled 6000 patients and is expected to complete in 2018.105 The Cardiovascular And Renal Microvascular Outcome Study With Linagliptin In Patients With Type 2 Diabetes Mellitus at High Vascular Risk (CARMELINA)106 trial will also assess the long-term effect of linagliptin on CV outcomes compared with placebo. As post hoc analysis of

Table 1. Results From Prospective CV Outcomes Trials of DPP-4 Inhibitors Trial

Study Drug

Inclusion Criteria

Primary Composite Patients, n (%) Endpoint Placebo DPP-4 Inhibitor

HR (95% CI)

P value

EXAMINE101 (n = 5380)

Alogliptin (n = 2701)

CV death, nonfatal MI, or nonfatal stroke

316 (11.8)

305 (11.3)

0.96 (# 1.16)

0.32

SAVOR-TIMI 53102 (n = 16 492)

Saxagliptin (n = 8280)

Men and women, $ 18 years, with T2DM Acute coronary syndrome (15–90 days before randomization) Men and women, $ 40 years, with T2DM Preexisting history of CVD or multiple risk factors for vascular disease

CV death, nonfatal MI, or nonfatal ischemic stroke

609 (7.2)

613 (7.3)

1.00 (0.89–1.12)

0.99

Abbreviations: CV, cardiovascular; CVD, cardiovascular disease; DPP-4, dipeptidyl peptidase-4; EXAMINE, EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE; HbA1c, glycated hemoglobin; HR, hazard ratio; MI, myocardial infarction; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus; T2DM, type 2 diabetes. © Postgraduate Medicine, Volume 126, Issue 3, May 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 195 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.


Jennifer B. Green

pooled clinical trial data suggests that linagliptin may reduce albuminuria,107 this trial is also designed and powered to assess the impact of linagliptin therapy on renal outcomes, including end-stage renal disease, loss of . 50% of estimated glomerular filtration rate from baseline, and renal death.106 Long-term CV trials are also ongoing for emerging classes of glucose-lowering therapy, including the SGLT2inhibitors, which block the reabsorption of glucose through the renal proximal tubule resulting in increased urinary excretion of glucose.108 The SGLT-2 inhibitors have shown efficacy in lowering HbA1c, fasting plasma glucose, and body weight; small decreases in BP may also occur.109–111 Long-term CV trials for the agents in this class include the CANagliflozin cardioVascular Assessment Study (CANVAS),112 the Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58),113 and the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME).114 Early, and therefore nondefinitive, data collected from the ongoing CANVAS trial and submitted to the FDA suggest no increased risk in overall MACE; however, a numeric increase in the risk of stroke was observed, particularly in the first 30 days of use.115,116 This imbalance in early CV events was not evident in the non-CANVAS trials, although the small number of events prevented any definitive conclusions. Excluding the CANVAS study, a meta-analysis of data from 8 phase 2 and 3 trials revealed an HR of 0.65 (95% CI, 0.35–1.21) for canagliflozin versus comparators in the composite MACE-plus end point of CV death, MI, stroke, and hospitalization for unstable angina.116 Similarly, an HR of 0.67 (95% CI, 0.42–1.08) for this end point was reported for dapagliflozin versus comparators in its FDA regulatory submission.117 Although pooled data suggest that the SGLT-2 class does not increase overall CV risk, longterm studies will provide much needed evidence regarding CV risks and benefits. New insulin products appear likely to need the same risk assessment required of other new T2DM drugs evaluated by the FDA. Although the CV safety of insulin therapy has long been debated,118 preferential use of insulin to achieve intensive glycemic control in the UKPDS did not increase CV risk.25,32 Furthermore, the Bypass Angioplasty Revascularization Investigation 2 Diabetes119 (BARI 2D) trial of patients with T2DM and ischemic heart disease, which compared CV outcomes with an insulin-providing strategy (insulin and/or secretagogue therapy) compared with an insulin-sensitization strategy, found that major CV event rates and mortality were comparable with either approach to glycemic management. 196

As discussed earlier, the ORIGIN trial was a randomized, double-blind study in 12 537 adults who were aged $ 50 years with prediabetes or early T2DM and CVD or CV risk factors.35 Participants received insulin (targeted to a fasting plasma glucose , 95 mg/dL) or standard care in combination with omega-3 fatty acids. The results showed that therapy with insulin glargine resulted in no significant increase or decrease in the primary composite CV end point (HR, 1.02; 95% CI, 0.94–1.11; P = 0.63).35 However, the FDA did not grant approval of the more recently developed insulin degludec because an increased risk of CV events could not be conclusively be ruled out. In the FDA’s review of updated data from 17 trials, 95 events were observed in the pooled insulin degludec and insulin degludec/aspart groups (incidence rate of 18.4 per 1000 person-years) compared with 37 events in comparator groups (primarily insulin glargine) at 7 days after treatment discontinuation. These rates yielded an HR of 1.30 (95% CI, 0.88–1.93) for the composite MACEplus end point of CV death, nonfatal stroke, nonfatal MI, and unstable angina.120 In summary, despite an increasing number of welldesigned, long-term, prospective, adjudicated CV outcomes studies with newer T2DM agents, convincing evidence to support the use of any individual antihyperglycemic agent to reduce CV risk is lacking. By design, newer trials have included patients at increased CVD risk, therefore enrolling patients with a longer duration of T2DM. Similar to the trials of intensive glucose-lowering strategies, these studies suggest that a CV benefit via glucose lowering may be harder to achieve in patients with late- compared with early-stage disease. However, enrollment of these patients in trials of T2DM drug safety is critical to the assessment of therapeutic risk.

Comprehensive Approach to Managing Cardiometabolic Risk in T2DM

Managing CV risk in patients with T2DM requires a comprehensive approach to treating underlying risk factors and overlapping comorbidities.46,50,121 Particular attention should be paid to the treatment of BP and lipids, and smoking cessation and weight management. The American Association of Clinical Endocrinologists (AACE) 2013 diabetes algorithm provides specific treatment schemas for overweight and obese patients with cardiometabolic or biomechanical complications and for CVD risk factor modification (lipids and hypertension).46 Although the ADA standards of care do not provide specific treatment algorithms, they do provide




recommendations for management of BP and lipids.50 Both sets of guidelines provide glycemic, lipid, and BP treatment goals. Patient-centered individualization of goals is a fundamental principle in both the AACE algorithm and the joint position statement issued by the ADA and EASD.20,46 Moreover, the AACE and ADA/EASD guidelines advocate lifestyle modification as the cornerstone of therapy for T2DM and modification of CV risk.20,46,50 Smoking is a modifiable CVD risk factor that has been shown to be a predictor of CVD14,122 and CVD-associated mortality.123 In the prospective, community-based Framingham Offspring cohort study, smoking cessation, even with subsequent weight gain, was associated with a significant decrease in CVD risk in patients without T2DM. The decrease in risk was similar in those with diabetes, but did not reach statistical significance perhaps because of limited power.124 In the Nurses’ Health Study, the risk of CHD increased as cigarette intake increased; however, the risk in those who had ceased smoking for . 10 years was similar to the risk in women with diabetes who never smoked.122 Despite the well-recognized association between smoking and increased CVD risk, the prevalence of smoking among those with T2DM has remained relatively unchanged in the past decade.125 All patients with diabetes who smoke should be counseled to stop and should be assisted with cessation efforts. Hypertension and dyslipidemia often occur concurrently with T2DM. Findings from several studies show that improvement in BP control in patients with T2DM can reduce the risk of macrovascular events.126–130 For example, the UKPDS BP substudy showed a 32% reduction in T2DMrelated mortality and a 44% reduction in stroke with intensive BP control (goal , 150/85 mm Hg; mean 144/82 mm Hg) compared with less intensive control (goal , 180/105 mm Hg; mean 154/87 mm Hg).131 A much lower target, however, may not be associated with any additional long-term benefit. The ACCORD BP trial examined intensive lowering of systolic BP to a target , 120 mm Hg compared with standard treatment targeting a systolic BP , 140 mm Hg in patients with T2DM at high risk for CVD.132 The mean BPs achieved with intensive compared with standard therapy were 119/64 and 134/71 mm Hg, respectively, but no difference between groups was observed in the primary composite end point (nonfatal MI, nonfatal stroke, and CVD death). Based largely on CV outcomes data from the ACCORD trial, the ADA currently recommends a BP goal , 140/80 mm Hg for most patients with diabetes, which is less stringent than previously recommended. The ACEI and angiotensin II

receptor blockers are first-line choices for the management of hypertension in diabetes; however, many patients will require additional agents to meet BP goals.46,50 The ADA also recommends administration of $ 1 medication of an antihypertensive regimen at bedtime.50 Lipid abnormalities in patients with T2DM are typically characterized by decreased levels of high-density lipoprotein cholesterol; increased levels of triglycerides and very lowdensity lipoprotein cholesterol; and an increased proportion of small, dense, atherogenic low-density lipoprotein cholesterol (LDL-C).133 A UKPDS substudy showed that an increased concentration of LDL-C was a strong predictor of coronary artery disease and fatal or nonfatal MI.123 Furthermore, LDL-C reduction with statin therapy in T2DM is effective in primary and secondary CV risk reduction.134–136 A meta-analysis of 4 randomized placebo-controlled clinical trials of patients aged . 40 years with T2DM and no prior vascular disease showed a significant reduction (25%) in the risk of a first major CV or cerebrovascular event (relative risk, 0.75; 95% CI, 0.67–0.85) with statin therapy.137 Although different statins were used in the trials, the doses were equivalent based on their LDL-C–lowering effect. In patients with established T2DM and CVD, studies confirm that the lowering of LDL-C with statin therapy decreases the risk of subsequent CV events.134–136 In general, the ADA and AACE guidelines recommend statin therapy for all patients with T2DM and established CVD, and for many patients aged , 40 years with known CV risk factors.46,50 New guidelines for the treatment of blood cholesterol, released by the American College of Cardiology and American Heart Association, further expand the indications for statin therapy in those with T2DM.138 The percentage of US adults with diabetes who met BP, glycemic, and cholesterol level goals has increased since 1988.139 Despite these improvements, only 18.8% of these adults met all 3 goals between 2007 and 2010. Approximately half of patients with diabetes met any 1 goal, with 52.5%, 51.1%, and 56.2% achieving an HbA1c , 7.0%, BP , 130/80 mm Hg, or LDL-C , 100 mg/dL, respectively.139 These results were similar to those from another analysis of US survey data showing that 33.4% to 48.7% of patients with diabetes still did not meet goals for glycemic control, BP, or LDL-C level, and only 14.3% met all 3 targets plus nonsmoking status between 2007 and 2010.125 In addition, data from patients with diabetes in 3 large randomized controlled trials, Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE), BARI 2D, and Comparison of Two Treatments for Multivessel


Jennifer B. Green


Figure 2. Kaplan–Meier estimates of the risk of death from any cause and from CV causes and the number of CV events according to treatment group in the Steno-2 Study. A) Cumulative incidence of the risk of death from any cause (the study’s primary end point) during the 13.3-year study period.a B) Cumulative incidence of a secondary composite end point of CV events, including death from CV causes, nonfatal stroke, nonfatal MI, CABG, PCI, revascularization for peripheral atherosclerotic artery disease, and amputation.a C) Number of events for each component of the composite end point.

198




a I bars represent standard errors. From The New England Journal of Medicine, Gaede P, Lund-Andersen H, Parving HH, Pedersen O, Effect of a multifactorial intervention on mortality in type 2 diabetes, 358, 580–591. Copyright © 2008 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.141 Abbreviations: CABG, coronary-artery bypass grafting; CV, cardiovascular; MI, myocardial infarction; PCI, percutaneous coronary intervention.

Coronary Artery Disease in Individuals With Diabetes (FREEDOM) – showed that only 18.0, 23.0%, and 8.0% of patients, respectively, met all 4 prespecified treatment targets at 1 year. 140 Evidence suggests that targeting multiple outcomes reduces CV risk in patients with T2DM.141,142 Although difficult to achieve, these goals are clearly meaningful. For example, the Steno-2 Study investigators reported that an intensive multifactorial intervention including glycemic control and use of renin-angiotensin system blockers, aspirin, and lipid-lowering agents (primarily statins), significantly reduced the risk of nonfatal CVD, CVD-related mortality, and all-cause mortality in patients with T2DM and microalbuminuria (Figure 2).141 All patients in the Steno-2 Study received low-dose aspirin as primary prevention.141 Patients with diabetes have an altered coagulation system characterized by increased levels of prothrombotic coagulation factors, hyperactive platelets, and decreased fibrinolysis, thus providing a rationale for use of antiplatelet therapy.143 Trial data support the use of aspirin as secondary prevention in patients with diabetes and a history of CVD. However, the net benefit of aspirin as primary prevention among patients with diabetes but without a previous CVD event is not as clear.50,144–147 Therefore, the most recent ADA standards of care recommend that aspirin treatment (75–162 mg/d) be

reserved for patients with diabetes with a prior history of CVD or at high CVD risk (ie, most men aged . 50 years and women aged . 60 years who have $ 1 additional major risk factor).50

Summary: Resolving the Paradox

Patients with T2DM are at an increased risk of CVD-associated morbidity and mortality despite an increasing array of therapeutic treatment options. Unanswered questions remain regarding whether CVD mortality rates will accelerate as the prevalence of obesity and T2DM increase.148,149 Glycemic control is clearly important in reducing the risk of microvascular complications, but may not reduce CV risk in all individuals affected by T2DM. Although initiation of intensive glycemic control early in the disease course may be associated with a reduction in the long-term risk of CV events, such an approach in patients with long-standing or complicated T2DM is not of clear benefit and may, in some cases, be harmful. Trials of intensive glycemic control have shown that T2DM is a heterogeneous disease, providing an impetus for patient-centered, individualized care. This approach considers the patient’s established complications, support system, preferences, and needs, and represents a fundamental principle of recent guideline updates.



Jennifer B. Green

Assessment of diabetes drug safety has moved away from surrogate end points, such as effects on glycemia, inflammatory markers, and even lipids, and is focused on the effects of glucose-lowering therapies on major adverse CV outcomes, such as MI, stroke, and CV death. Outcomes trials on the effects of glucose-lowering therapies will be expensive and time consuming; however, the results will provide a greater assurance of diabetes drug safety than in previous decades. Results from the first trials have demonstrated the overall CV safety of DPP-4 inhibitors, but underscore the need for treatment plans that are less glucocentric and more comprehensive. Interventions that focus on appropriate management of lipids, BP, and smoking cessation are of proven effectiveness in reducing CVD risk for T2DM.

Acknowledgments

The author meets criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE), was fully responsible for all content and editorial decisions, and was involved at all stages of manuscript development. The author received no compensation related to the development of the manuscript. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Marissa Buttaro, MPH, RPh, of Envision Scientific Solutions, Inc. Boehringer Ingelheim was given the opportunity to check the data used in the review for factual accuracy only.

Conflict of Interest Statement

Jennifer B. Green, MD, has received institutional grant support from Amylin Pharmaceuticals, Inc. (now Bristol-Myers Squibb) and Merck and Co., Inc. and consultancy fees from Merck and Co., Inc. She has also been compensated for serving on a committee and developing educational materials for The Endocrine Society, and for providing editorial services for a journal published by Bioscientifica.

References 1. Gregg EW, Cheng YJ, Saydah S, et al. Trends in death rates among U.S. adults with and without diabetes between 1997 and 2006: findings from the National Health Interview Survey. Diabetes Care. 2012;35(6):1252–1257. 2. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002;287(19):2570–2581. 3. Festa A, D’Agostino R Jr, Tracy RP, Haffner SM; Insulin Resistance Atherosclerosis Study. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes. 2002;51(4):1131–1137. 4. Stern MP. Diabetes and CV disease. The “common soil” hypothesis. Diabetes. 1995;44(4):369–374.

200

5. McPhillips JB, Barrett-Connor E, Wingard DL. Cardiovascular disease risk factors prior to the diagnosis of impaired glucose tolerance and non-insulin-dependent diabetes mellitus in a community of older adults. Am J Epidemiol. 1990;131(3):443–453. 6. Preis SR, Pencina MJ, Mann DM, D’Agostino RB Sr, Savage PJ, Fox CS. Early-adulthood cardiovascular disease risk factor profiles among individuals with and without diabetes in the Framingham Heart Study. Diabetes Care. 2013;36(6):1590–1596. 7. Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care. 2002;25(7):1129–1134. 8. Aguilar D, Solomon SD, Køber L, et al. Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial. Circulation. 2004;110(12):1572–1578. 9. Smith NL, Barzilay JI, Kronmal R, Lumley T, Enquobahrie D, Psaty BM. New-onset diabetes and risk of all-cause and cardiovascular mortality: the Cardiovascular Health Study. Diabetes Care. 2006;29(9):2012–2017. 10. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4):229–234. 11. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143–3421. 12. Emerging Risk Factors Collaboration, Sarwar N, Gao P, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies [Erratum in Lancet. 2010;376(9745):958]. Lancet. 2010;375(9733):2215–2222. 13. Almdal T, Scharling H, Jensen JS, Vestergaard H. The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. Arch Intern Med. 2004;164(13):1422–1426. 14. Spencer EA, Pirie KL, Stevens RJ, et al; Million Women Study Collaborators. Diabetes and modifiable risk factors for cardiovascular disease: the prospective Million Women Study. Eur J Epidemiol. 2008;23(12):793–799. 15. Gore MO, Patel MJ, Kosiborod M, et al; National Registry of Myocardial Infarction Investigators. Diabetes mellitus and trends in hospital survival after myocardial infarction, 1994 to 2006: data from the National Registry of Myocardial Infarction. Circ Cardiovasc Qual Outcomes. 2012;5(6):791–797. 16. Kamalesh M, Subramanian U, Ariana A, Sawada S, Tierney W. Similar decline in post-myocardial infarction mortality among subjects with and without diabetes. Am J Med Sci. 2005;329(5):228–233. 17. Eriksson M, Carlberg B, Eliasson M. The disparity in long-term survival after a first stroke in patients with and without diabetes persists: the Northern Sweden MONICA study. Cerebrovasc Dis. 2012;34(2):153–160. 18. Booth GL, Kapral MK, Fung K, Tu JV. Recent trends in cardiovascular complications among men and women with and without diabetes. Diabetes Care. 2006;29(1):32–37. 19. Taylor KS, Heneghan CJ, Farmer AJ. All-cause and cardiovascular mortality in middle-aged people with type 2 diabetes compared with people without diabetes in a large U.K. primary care database. Diabetes Care. 2013;36(8):2366–2371. 20. Inzucchi SE, Bergenstal RM, Buse JB, et al; American Diabetes Association; European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) [Erratum in Diabetes Care. 2013;36(2):490]. Diabetes Care. 2012;35(6):1364–1379.



Understanding the T2DM and CVD Risk Paradox 21. Reusch JE, Wang CC. Cardiovascular disease in diabetes: where does glucose fit in? J Clin Endocrinol Metab. 2011;96(8):2367–2376. 22. Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med. 2004;141(6):421–431. 23. Gao L, Matthews FE, Sargeant LA, Brayne C; MRC CFAS. An investigation of the population impact of variation in HbA1c levels in older people in England and Wales: from a population based multi-centre longitudinal study. BMC Public Health. 2008;8:54. 24. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group [Erratum in Lancet. 1998;352(9139):1558]. Lancet. 1998;352(9131):854–865. 25. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group [Erratum in Lancet. 1999;354(9178):602]. Lancet. 1998;352(9131):837–853. 26. Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545–2559. 27. ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. New Engl J Med. 2008;358(24):2560–2572. 28. Duckworth W, Abraira C, Moritz T, et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes [Erratum in N Engl J Med. 2009;361(10):1024–1025, and N Engl J Med. 2009;361(10):1028]. New Engl J Med. 2009;360(2): 129–139. 29. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577–1589. 30. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet. 2009;373(9677):1765–1772. 31. Mannucci E, Monami M, Lamanna C, Gori F, Marchionni N. Prevention of cardiovascular disease through glycemic control in type 2 diabetes: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2009;19(9):604–612. 32. Control Group; Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes [Erratum in Diabetologia. 2009;52(1):2470]. Diabetologia. 2009;52(11):2288–2298. 33. Skyler JS, Bergenstal R, Bonow RO, et al; American Diabetes Association; American College of Cardiology Foundation; American Heart Association. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association [Erratum in Diabetes Care. 2009;32(4):754]. Diabetes Care. 2009;32(1): 187–192. 34. Goto A, Arah OA, Goto M, Terauchi Y, Noda M. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ. 2013;347:f4533. 35. ORIGIN Trial Investigators; Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319–328. 36. Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, et al. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ. 2011;343:d4169. 37. Ussher JR, Sutendra G, Jaswal JS. The impact of current and novel anti-diabetic therapies on cardiovascular risk. Future Cardiol. 2012;8(6):895–912.

38. Henry RR, Lincoff AM, Mudaliar S, Rabbia M, Chognot C, Herz M. Effect of the dual peroxisome proliferator-activated receptor-alpha/ gamma agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, doseranging study. Lancet. 2009;374(9684):126–135. 39. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes [Erratum in N Engl J Med. 2007;357(1):100]. N Engl J Med. 2007;356(24): 2457–2471. 40. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005;294(20):2581–2586. 41. Roche halts investigation of aleglitazar following regular safety review of phase III trial [media release]. Basel, Switzerland: Roche; July 10, 2013. http://www.roche.com/media/media_releases/medcor-2013–07–10.htm. Accessed May 1, 2014. 42. Nissen SE, Wolski K. Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Arch Intern Med. 2010;170(14):1191–1201. 43. FDA Drug Safety Communication: FDA requires removal of some prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines. Silver Spring, MD: US Food And Drug Administration; November 25, 2013. http://www.fda.gov/Drugs/DrugSafety/ ucm376389.htm. Accessed May 1, 2014. 44. Mahaffey KW, Hafley G, Dickerson S, et al. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am Heart J. 2013;166(2):240–249.e1. 45. Dormandy JA, Charbonnel B, Eckland DJ, et al; PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279–1289. 46. Garber AJ, Abrahamson MJ, Barzilay JI, et al; American Association of Clinical Endocrinologists. AACE comprehensive diabetes management algorithm 2013. Endocr Pract. 2013;19(2):327–336. 47. Pioglitazone (Actos) [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2013. http://www.takeda.us/products/. Accessed May 1, 2014. 48. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry: diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. http://www. fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm071627.pdf. Published December 2008. Accessed May 1, 2014. 49. European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. http://www.ema.europa.eu/docs/en_GB/document_library/ Scientific_guideline/2012/06/WC500129256.pdf. Published May 14, 2012. Accessed May 1, 2014. 50. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014;379(Suppl 1):S14–S80. 51. Whittington HJ, Hall AR, McLaughlin CP, Hausenloy DJ, Yellon DM, Mocanu MM. Chronic metformin associated cardioprotection against infarction: not just a glucose lowering phenomenon. Cardiovasc Drugs Ther. 2013;27(1):5–16. 52. Rojas LB, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5(1):6. 53. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;281(21):2005–2012. 54. U.K. prospective diabetes study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group [Erratum in Diabetes. 1996;45(11):1655]. Diabetes. 1995;44(11):1249–1258.



Jennifer B. Green 55. Rosenstock J, Marx N, Kahn SE, et al. Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: rationale for the active-comparator CAROLINA trial. Diab Vasc Dis Res. 2013;10(4):289–301. 56. Schramm TK, Gislason GH, Vaag A, et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study [Erratum in Eur Heart J. 2012;33(10):1183]. Eur Heart J. 2011;32(15):1900–1908. 57. Tzoulaki I, Molokhia M, Curcin V, et al. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ. 2009;339:b4731. 58. Johnson JA, Majumdar SR, Simpson SH, Toth EL. Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care. 2002;25(12):2244–2248. 59. Evans JM, Ogston SA, Emslie-Smith A, Morris AD. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia. 2006;49(5):930–936. 60. Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013;15(10):938–953. 61. Phung OJ, Schwartzman E, Allen RW, Engel SS, Rajpathak SN. Sulphonylureas and risk of cardiovascular disease: systematic review and meta-analysis. Diabet Med. 2013;30(10):1160–1171. 62. Rao AD, Kuhadiya N, Reynolds K, Fonseca VA. Is the combination of sulfonylureas and metformin associated with an increased risk of cardiovascular disease or all-cause mortality?: a meta-analysis of observational studies. Diabetes Care. 2008;31(8):1672–1678. 63. Brady PA, Terzic A. The sulfonylurea controversy: more questions from the heart. J Am Coll Cardiol. 1998;31(5):950–956. 64. Proks P, Reimann F, Green N, Gribble F, Ashcroft F. Sulfonylurea stimulation of insulin secretion. Diabetes. 2002;51(Suppl 3):S368–S376. 65. Nathan DM, Buse JB, Kahn SE, et al; GRADE Study Research Group. Rationale and design of the glycemia reduction approaches in diabetes: a comparative effectiveness study (GRADE). Diabetes Care. 2013;36(8):2254–2261. 66. Drucker DJ. Biologic actions and therapeutic potential of the proglucagon-derived peptides. Nat Clin Pract Endocrinol Metab. 2005;1(1):22–31. 67. Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptordependent and -independent pathways [Erratum in Circulation. 2008;118(4):e81]. Circulation. 2008;117(18):2340–2350. 68. Chinda K, Chattipakorn S, Chattipakorn N. Cardioprotective effects of incretin during ischaemia-reperfusion. Diab Vasc Dis Res. 2012;9(4):256–269. 69. Fields AV, Patterson B, Karnik AA, Shannon RP. Glucagon-like peptide-1 and myocardial protection: more than glycemic control. Clin Cardiol. 2009;32(5):236–243. 70. Bose AK, Mocanu MM, Carr RD, Yellon DM. Glucagon like peptide-1 is protective against myocardial ischemia/reperfusion injury when given either as a preconditioning mimetic or at reperfusion in an isolated rat heart model. Cardiovasc Drugs Ther. 2005;19(1):9–11. 71. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagonlike peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006;12(9):694–699. 72. Read PA, Khan FZ, Dutka DP. Cardioprotection against ischaemia induced by dobutamine stress using glucagon-like peptide-1 in patients with coronary artery disease. Heart. 2012;98(5):408–413. 73. Lønborg J, Vejlstrup N, Kelbæk H, et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J. 2012;33(12):1491–1499.

202

74. Blonde L, Klein EJ, Han J, et al. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab. 2006;8(4):436–447. 75. Chiquette E, Toth PP, Ramirez G, Cobble M, Chilton R. Treatment with exenatide once weekly or twice daily for 30 weeks is associated with changes in several cardiovascular risk markers. Vasc Health Risk Manag. 2012;8:621–629. 76. Nauck M, Frid A, Hermansen K, et al; LEAD-2 Study Group. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32(1):84–90. 77. Ratner R, Han J, Nicewarner D, Yushmanova I, Hoogwerf BJ, Shen L. Cardiovascular safety of exenatide BID: an integrated analysis from controlled clinical trials in participants with type 2 diabetes. Cardiovasc Diabetol. 2011;10:22. 78. Marso SP, Lindsey JB, Stolker JM, et al. Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2: 3 liraglutide clinical development studies. Diab Vasc Dis Res. 2011;8(3):237–240. 79. Monami M, Cremasco F, Lamanna C, et al. Glucagon-like peptide-1 receptor agonists and cardiovascular events: a meta-analysis of randomized clinical trials. Exp Diabetes Res. 2011;2011:215764. 80. National Institutes of Health. Researching Cardiovascular Events With a Weekly Incretin In Diabetes (REWIND). http://clinicaltrials. gov/show/NCT01394952. Updated September 3, 2013. Accesed May 1, 2014. 81. National Institutes of Health. Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL): A Trial To Evaluate Cardiovascular Outcomes After Treatment With Exenatide Once Weekly In Patients With Type 2 Diabetes Mellitus. http://www.clinicaltrials.gov/ct2/show/ NCT01144338. Updated April 2, 2014. Accesed May 1, 2014. 82. National Institutes of Health. Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results - A Long Term Evaluation (LEADER). http://www.clinicaltrials.gov/ct2/show/ NCT01179048. Updated March 10, 2014. Accesed May 1, 2014. 83. National Institutes of Health. Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010 (Lixisenatide) (ELIXA). http:// clinicaltrials.gov/ct2/show/NCT01147250. Updated October 17, 2013. Accesed May 1, 2014. 84. Vanderheyden M, Bartunek J, Goethals M, et al. Dipeptidyl-peptidase IV and B-type natriuretic peptide. From bench to bedside. Clin Chem Lab Med. 2009;47(3):248–252. 85. Green JB. The dipeptidyl peptidase-4 inhibitors in type 2 diabetes mellitus: cardiovascular safety. Postgrad Med. 2012;124(4):54–61. 86. Fadini GP, Avogaro A. Cardiovascular effects of DPP-4 inhibition: beyond GLP-1. Vascul Pharmacol. 2011;55(1–3):10–16. 87. 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 stromalderived factor-1alpha. Diabetes Care. 2010;33(7):1607–1609. 88. Hocher B, Sharkovska Y, Mark M, Klein T, Pfab T. The novel DPP-4 inhibitors linagliptin and BI 14361 reduce infarct size after myocardial ischemia/reperfusion in rats. Int J Cardiol. 2013;167(1):87–93. 89. 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. 90. Monami M, Iacomelli I, Marchionni N, Mannucci E. Dipeptydil peptidase-4 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2010;20(4):224–235. 91. Johansen OE, Neubacher D, von Eynatten M, Patel S, Woerle HJ. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol. 2012;11:3.



Understanding the T2DM and CVD Risk Paradox 92. Cobble ME, Frederich R. Saxagliptin for the treatment of type 2 diabetes mellitus: assessing cardiovascular data. Cardiovasc Diabetol. 2012;11:6. 93. Mistry GC, Maes AL, Lasseter KC, et al. Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J Clin Pharmacol. 2008;48(5):592–598. 94. Marney A, Kunchakarra S, Byrne L, Brown NJ. Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans. Hypertension. 2010;56(4):728–733. 95. Brown NJ, Byiers S, Carr D, Maldonado M, Warner BA. Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema. Hypertension. 2009;54(3):516–523. 96. Frederich R, Alexander JH, Fiedorek FT, et al. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med. 2010;122(3):16–27. 97. Schweizer A, Dejager S, Foley JE, Couturier A, Ligueros-Saylan M, Kothny W. Assessing the cardio-cerebrovascular safety of vildagliptin: meta-analysis of adjudicated events from a large phase III type 2 diabetes population [Erratum in Diabetes Obes Metab. 2010;12(9):832]. Diabetes Obes Metab. 2010;12(6):485–494. 98. White WB, Pratley R, Fleck P, Munsaka M, Hisada M, Wilson C, Menon V. Cardiovascular safety of the dipetidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus. Diabetes Obes Metab. 2013;15(7):668–673. 99. Williams-Herman D, Engel SS, Round E, et al. Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC Endocr Disord. 2010;10:7. 100. Monami M, Ahrén 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. 101. Scirica BM, Bhatt DL, Braunwald E, et al; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and Cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–1326. 102. White WB, Cannon CP, Heller SR, et al; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327–1335. 103. Scirica BM, Braunwald E, Bhatt DL. Saxagliptin, alogliptin, and cardiovascular outcomes. N Engl J Med. 2014;370(5):483–484. 104. National Institutes of Health. Sitagliptin Cardiovascular Outcome Study (0431–082 AM1) (TECOS). http://clinicaltrials.gov/show/ NCT00790205. Accessed May 1, 2014. 105. National Institutes of Health. CAROLINA: Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients with Type 2 Diabetes. http://clinicaltrials.gov/ct2/show/NCT01243424?term = linagl iptin&rank = 12. Updated April 2, 2014. Accessed May 1, 2014. 106. National Institutes of Health. CARMELINA: Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus at High Vascular Risk. http://clinicaltrials.gov/ct2/ show/NCT01897532?term = CARMELINA&rank = 1. Updated April 20, 2014. Accessed May 1, 2014. 107. Groop PH, Cooper ME, Perkovic V, Emser A, Woerle HJ, von Eynatten M. Linagliptin lowers albuminuria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction. Diabetes Care. 2013;36(11):3460–3468. 108. Mather A, Pollock C. Glucose handling by the kidney. Kidney Int Suppl. 2011;(120):S1–S6. 109. Bailey CJ, Gross JL, Hennicken D, Iqbal N, Mansfield TA, List JF. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebocontrolled 102-week trial. BMC Med. 2013;11:43. 110. Rosenstock J, Aggarwal N, Polidori D, et al; Canagliflozin DIA 2001 Study Group. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care. 2012;35(6):1232–1238.

111. Ferrannini E, Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ. A phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15(8):721–728. 112. Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)--a randomized placebo-controlled trial. Am Heart J. 2013;166(2):217–223.e211. 113. National Institutes of Health. Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58). http://clinicaltrials.gov/show/NCT01730534. Updated February 4, 2014. Accessed May 1, 2014. 114. National Institutes of Health. BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients. http://clinicaltrials.gov/ct2/show/NCT01131676. Updated Apri 30, 2014. Accessed May 1, 2014. 115. Mary H. Parks; Center for Drug Evaluation and Research. Summary review: Invocana (canagliflozin). http://www.accessdata.fda.gov/ drugsatfda_docs/nda/2013/204042Orig1 s000SumR.pdf. Published March 29, 2013. Accessed May 1, 2014. 116. US Food and Drug Administration. FDA briefing document: NDA 204042, Invokana (canagliflozin) tablets. http://www.fda.gov/ downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM334550. pdf. Published January 10, 2013. Accessed May 1 , 2014. 117. US Food and Drug Administration. FDA briefing document: NDA 202293, Dapagliflozin tablets, 5 and 10 mg. http://www.fda.gov/ downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ drugsEndocrinologicandMetabolicDrugs/AdvisoryCommittee/ ucm262994.pdf. Published July 19, 2011. Accessed May 1, 2014. 118. Currie CJ, Johnson JA. The safety profile of exogenous insulin in people with type 2 diabetes: justification for concern. Diabetes Obes Metab. 2012;14(1):1–4. 119. BARI 2D Study Group; Frye RL, August P, Brooks MM, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009;360(24):2503–2515. 120. US Food and Drug Administration. FDA briefing document: NDA 203313 and NDA 203314, insulin Degludec and insulin Degludec/ Aspart. http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM327015.pdf. Published November 8, 2012. Accessed May 1, 2014. 121. Rajpathak SN, Aggarwal V, Hu FB. Multifactorial intervention to reduce cardiovascular events in type 2 diabetes. Curr Diab Rep. 2010;10(1):16–23. 122. Al-Delaimy WK, Manson JE, Solomon CG, et al. Smoking and risk of coronary heart disease among women with type 2 diabetes mellitus. Arch Intern Med. 2002;162(3):273–279. 123. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ. 1998;316(7134):823–828. 124. Clair C, Rigotti NA, Porneala B, et al. Association of smoking cessation and weight change with cardiovascular disease among adults with and without diabetes. JAMA. 2013;309(10):1014–1021. 125. Ali MK, Bullard KM, Saaddine JB, Cowie CC, Imperatore G, Gregg EW. Achievement of goals in U.S. diabetes care, 1999–2010 [Erratum in N Engl J Med. 2013;369(6):587]. N Engl J Med. 2013;368(17):1613–1624. 126. Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group [Erratum in JAMA. 1997;277(17):1356]. JAMA. 1996;276(23):1886–1892. 127. Patel A; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370(9590):829–840.



Jennifer B. Green 128. Turnbull F, Neal B, Algert C, et al; Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med. 2005;165(12):1410–1419. 129. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351(9118):1755–1762. 130. Tuomilehto J, Rastenyte D, Birkenhäger WH, et al. Effects of calciumchannel blockade in older patients with diabetes and systolic hypertension. Systolic Hypertension in Europe Trial Investigators. N Engl J Med. 1999;340(9):677–684. 131. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group [Erratum in BMJ. 1999;318(7175):29]. BMJ. 1998;317(7160):703–713. 132. ACCORD Study Group; Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575–1585. 133. Krentz AJ. Lipoprotein abnormalities and their consequences for patients with type 2 diabetes. Diabetes Obes Metab. 2003;5(Suppl 1): S19–S27. 134. Arca M. Atorvastatin efficacy in the prevention of cardiovascular events in patients with diabetes mellitus and/or metabolic syndrome. Drugs. 2007;67(Suppl 1):43–54. 135. Colhoun HM, Betteridge DJ, Durrington PN, et al; CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435):685–696. 136. Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterollowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361(9374):2005–2016. 137. de Vries FM, Denig P, Pouwels KB, Postma MJ, Hak E. Primary prevention of major cardiovascular and cerebrovascular events with statins in diabetic patients: a meta-analysis. Drugs. 2012;72(18):2365–2373. 138. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [published online ahead of print November 7, 2013]. J Am Coll Cardiol. doi:10.1016/j.jacc.2013.11.002.

204

139. Stark Casagrande S, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1988–2010. Diabetes Care. 2013;36(8):2271–2279. 140. Farkouh ME, Boden WE, Bittner V, et al. Risk factor control for coronary artery disease secondary prevention in large randomized trials. J Am Coll Cardiol. 2013;61(15):1607–1615. 141. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6):580–591. 142. Griffin SJ, Borch-Johnsen K, Davies MJ, et al. Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial [Erratum in Lancet. 2012;379(9818):804]. Lancet. 2011;378(9786):156–167. 143. Alzahrani SH, Ajjan RA. Coagulation and fibrinolysis in diabetes. Diab Vasc Dis Res. 2010;7(4):260–273. 144. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. ETDRS Investigators. JAMA. 1992;268(10):1292–1300. 145. Belch J, MacCuish A, Campbell I, et al; Prevention of Progression of Arterial Disease and Diabetes Study Group; Diabetes Registry Group; Royal College of Physicians Edinburgh. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ. 2008;337:a1840. 146. Antithrombotic Trialists’ (ATT) Collaboration; Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849–1860. 147. Ogawa H, Nakayama M, Morimoto T, et al; Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial [Erratum in JAMA. 2009;301(18):1882, and JAMA. 2012;308(18):1861]. JAMA. 2008;300(18):2134–2141. 148. Franco M, Bilal U, Orduñez P, et al. Population-wide weight loss and regain in relation to diabetes burden and cardiovascular mortality in Cuba 1980–2010: repeated cross sectional surveys and ecological comparison of secular trends. BMJ. 2013;346:f1515. 149. Barengo NC, Katoh S, Moltchanov V, Tajima N, Tuomilehto J. The diabetes-cardiovascular risk paradox: results from a Finnish populationbased prospective study. Eur Heart J. 2008;29(15):1889–1895.


Cardiovascular risk in type 1 diabetes mellitus.

Importance of cardiovascular disease risk management in patients with type 2 diabetes mellitus.

Type 2 diabetes mellitus and fracture risk.

Disparities in Cardiovascular Disease and Type 2 Diabetes Risk Factors in Blacks and Whites: Dissecting Racial Paradox of Metabolic Syndrome.

Metabolic control and cardiovascular risk factors in type 2 diabetes mellitus patients according to diabetes duration.

Type 2 diabetes mellitus and periodontal disease.

Adiponectin, type 2 diabetes and cardiovascular risk.

Novel Biomarkers to Improve the Prediction of Cardiovascular Event Risk in Type 2 Diabetes Mellitus.

Cardiovascular disease in diabetes mellitus: risk factors and medical therapy.

[Type 2 diabetes mellitus and cardiovascular risk factors: is comprehensive treatment required?].

Clinical Update: Cardiovascular Disease in Diabetes Mellitus: Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes Mellitus - Mechanisms, Management, and Clinical Considerations.

Empagliflozin and Cerebrovascular Events in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk.

Cardiovascular control during exercise in type 2 diabetes mellitus.

Cardiovascular disease risk in type 1 diabetes.

Paraoxonase-1 gene Q192R and L55M polymorphisms and risk of cardiovascular disease in Egyptian patients with type 2 diabetes mellitus.

[Primary cardiovascular prevention with statins in type 2 diabetes mellitus].

Relationship of Dickkopf1 (DKK1) with cardiovascular disease and bone metabolism in Caucasian type 2 diabetes mellitus.

[The importance of vascular risk in type 2 diabetes mellitus].

Summaries for Patients. The Obesity Paradox in Type 2 Diabetes Mellitus.

Peroxiredoxin isoforms are associated with cardiovascular risk factors in type 2 diabetes mellitus.

Thoracic periaortic adipose tissue in relation to cardiovascular risk in type 2 diabetes mellitus.

Effects of canagliflozin on cardiovascular risk factors in patients with type 2 diabetes mellitus.

Dietary fish intake and the risk for type 2 diabetes and cardiovascular disease: new insights.

Predicting cardiovascular risk in type 2 diabetes: the heterogeneity challenges.