Vascular Protection in People with Diabetes

Abstract

Key Messages•Diabetes promotes both the development and adverse impact of cardiovascular disease (CVD) risk factors (e.g. hypertension, dyslipidemia, renal dysfunction) and, as a consequence, accelerates cardiovascular age. Persons with diabetes generally have a cardiovascular age 10 to 15 years in advance of their chronological age (1Booth G.L. Kapral M.K. Fung K. Tu J.V. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study.Lancet. 2006; 368: 29-36Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar).•Advanced cardiovascular age substantially increases both the proximate and lifetime risk for CVD events, resulting in a reduced life expectancy of approximately 12 years (2Manuel D.G. Schultz S.E. Health-related quality of life and health-adjusted life expectancy of people with diabetes in Ontario, Canada, 1996–1997.Diabetes Care. 2004; 27: 407-414Crossref PubMed Scopus (111) Google Scholar).•Although young patients with diabetes rarely will have a high proximate risk for CVD events, they have a relative proximate risk many fold greater than that of individuals without diabetes (1Booth G.L. Kapral M.K. Fung K. Tu J.V. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study.Lancet. 2006; 368: 29-36Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar).•All adults with diabetes require chronic disease care strategies that include health behaviour education and, for many individuals, pharmacological vascular protection, in order to promote CVD event risk reduction.•The requirement for pharmacological vascular protection therapies (statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and acetylsalicylic acid) should be determined by both an individual’s proximate and lifetime CVD event risk. •Diabetes promotes both the development and adverse impact of cardiovascular disease (CVD) risk factors (e.g. hypertension, dyslipidemia, renal dysfunction) and, as a consequence, accelerates cardiovascular age. Persons with diabetes generally have a cardiovascular age 10 to 15 years in advance of their chronological age (1Booth G.L. Kapral M.K. Fung K. Tu J.V. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study.Lancet. 2006; 368: 29-36Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar).•Advanced cardiovascular age substantially increases both the proximate and lifetime risk for CVD events, resulting in a reduced life expectancy of approximately 12 years (2Manuel D.G. Schultz S.E. Health-related quality of life and health-adjusted life expectancy of people with diabetes in Ontario, Canada, 1996–1997.Diabetes Care. 2004; 27: 407-414Crossref PubMed Scopus (111) Google Scholar).•Although young patients with diabetes rarely will have a high proximate risk for CVD events, they have a relative proximate risk many fold greater than that of individuals without diabetes (1Booth G.L. Kapral M.K. Fung K. Tu J.V. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study.Lancet. 2006; 368: 29-36Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar).•All adults with diabetes require chronic disease care strategies that include health behaviour education and, for many individuals, pharmacological vascular protection, in order to promote CVD event risk reduction.•The requirement for pharmacological vascular protection therapies (statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and acetylsalicylic acid) should be determined by both an individual’s proximate and lifetime CVD event risk. Persons with both type 1 and type 2 diabetes mellitus are at significantly increased risk of atherosclerotic cardiovascular disease (CVD) presenting as coronary heart disease, stroke and peripheral vascular disease (1Booth G.L. Kapral M.K. Fung K. Tu J.V. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study.Lancet. 2006; 368: 29-36Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar, 2Manuel D.G. Schultz S.E. Health-related quality of life and health-adjusted life expectancy of people with diabetes in Ontario, Canada, 1996–1997.Diabetes Care. 2004; 27: 407-414Crossref PubMed Scopus (111) Google Scholar, 3Haffner S.M. Lehto S. Rönnemaa T. et al.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: 229-234Crossref PubMed Scopus (5903) Google Scholar). For the vast majority of older persons with diabetes (age >40 years), both the proximate 10-year and lifetime CVD event risk becomes sufficiently high (>20%) to justify both health behaviour modification and pharmacological interventions. However, for many younger individuals with diabetes, their proximate 10-year CVD event risk may be low (4Stevens R.J. Kothari V. Adler A.I. et al.The UKPDS risk engine: a model for the risk of coronary heart disease in Type II diabetes (UKPDS 56).Clin Sci (Lond). 2001; 101: 671-679Crossref PubMed Scopus (1012) Google Scholar), yet both proximate and lifetime event rates are many times higher than for individuals of the same age without diabetes (1Booth G.L. Kapral M.K. Fung K. Tu J.V. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study.Lancet. 2006; 368: 29-36Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar, 5The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research GroupIntensive diabetes treatment and cardiovascular disease in patients with Type 1 diabetes.N Engl J Med. 2005; 353: 2643-2653Crossref PubMed Scopus (4137) Google Scholar). For these persons, their vascular age far exceeds their chronological age, significantly increasing their relative risk of CVD events. The term “vascular age” refers to models of CVD event risk that predict an individual’s CVD event risk and compare the event risk to age-adjusted CVD event risk (6Grover S.A. Lowensteyn I. Esrey K.L. et al.Do doctors accurately assess coronary risk in their patients? preliminary results of the coronary health assessment study.BMJ. 1995; 310: 975-978Crossref PubMed Scopus (161) Google Scholar). The greater the risk factor burden, the greater the vascular age and relative CVD event risk. Such a high relative risk indicates that early intervention before the arbitrary high-risk 10-year 20% event rate is reached may be beneficial (6Grover S.A. Lowensteyn I. Esrey K.L. et al.Do doctors accurately assess coronary risk in their patients? preliminary results of the coronary health assessment study.BMJ. 1995; 310: 975-978Crossref PubMed Scopus (161) Google Scholar, 7Ridker P.M. Danielson E. Fonseca F.A. et al.Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.N Engl J Med. 2008; 359: 2195-2207Crossref PubMed Scopus (5268) Google Scholar, 8Gaede P. Vedel P. Larsen N. et al.Multifactorial intervention and CAD in patients with type 2 diabetes.N Engl J Med. 2003; 348: 383-393Crossref PubMed Scopus (3813) Google Scholar, 9Gaede P. Lund-Andersen H. Parving H.H. Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes.N Engl J Med. 2008; 358: 580-591Crossref PubMed Scopus (2783) Google Scholar, 10Stock S. Drabik A. Büscher G. et al.German diabetes management programs improve quality of care and curb costs.Health Affairs. 2010; 29: 2197-2205Crossref PubMed Scopus (100) Google Scholar). Thus, the use of pharmacotherapy for CVD risk factor reduction in younger persons with diabetes, who are not at a high proximate risk and yet, as a consequence of diabetes, have a steep CVD event risk trajectory, can be justified by the potentially substantial long-term benefits of earlier interventions and lifelong therapy (8Gaede P. Vedel P. Larsen N. et al.Multifactorial intervention and CAD in patients with type 2 diabetes.N Engl J Med. 2003; 348: 383-393Crossref PubMed Scopus (3813) Google Scholar, 9Gaede P. Lund-Andersen H. Parving H.H. Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes.N Engl J Med. 2008; 358: 580-591Crossref PubMed Scopus (2783) Google Scholar, 10Stock S. Drabik A. Büscher G. et al.German diabetes management programs improve quality of care and curb costs.Health Affairs. 2010; 29: 2197-2205Crossref PubMed Scopus (100) Google Scholar, 11Bergner D.W. Goldberger J.J. Diabetes mellitus and sudden cardiac death: what are the data?.Cardiol J. 2010; 17: 117-129PubMed Google Scholar). Traditional CVD event risk models predict an individual’s proximate (5- to 10-year) CVD event risk based on risk factors, such as diabetes, dyslipidemia, hypertension and smoking. These models discriminate poorly between high- and low-risk individuals (12Guzder R.N. Gatling W. Mullee M.A. et al.Prognostic value of the Framingham cardiovascular risk equation and the UKPDS risk engine for coronary heart disease in newly diagnosed Type 2 diabetes: results from a United Kingdom study.Diabet Med. 2005; 22: 554-562Crossref PubMed Scopus (139) Google Scholar). Furthermore, they underestimate risk in younger individuals and have a low specificity; consequently, they cannot reliably exclude individuals with diabetes who are unlikely to benefit from long-term pharmacological vascular protection strategies before their proximate risk is high. Consequently, as most individuals with diabetes have a very high lifetime risk for a CVD event, a strategy that includes early vascular protection is justified (8Gaede P. Vedel P. Larsen N. et al.Multifactorial intervention and CAD in patients with type 2 diabetes.N Engl J Med. 2003; 348: 383-393Crossref PubMed Scopus (3813) Google Scholar, 9Gaede P. Lund-Andersen H. Parving H.H. Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes.N Engl J Med. 2008; 358: 580-591Crossref PubMed Scopus (2783) Google Scholar, 10Stock S. Drabik A. Büscher G. et al.German diabetes management programs improve quality of care and curb costs.Health Affairs. 2010; 29: 2197-2205Crossref PubMed Scopus (100) Google Scholar, 11Bergner D.W. Goldberger J.J. Diabetes mellitus and sudden cardiac death: what are the data?.Cardiol J. 2010; 17: 117-129PubMed Google Scholar, 12Guzder R.N. Gatling W. Mullee M.A. et al.Prognostic value of the Framingham cardiovascular risk equation and the UKPDS risk engine for coronary heart disease in newly diagnosed Type 2 diabetes: results from a United Kingdom study.Diabet Med. 2005; 22: 554-562Crossref PubMed Scopus (139) Google Scholar, 13Lloyd Jones D.M. Leip E.P. Larson M.G. et al.Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age.Circulation. 2006; 113: 791-798Crossref PubMed Scopus (927) Google Scholar, 14Stone J.A. Framing CVD event risk prediction.Can J Cardiol. 2011; 27: 171-173Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 15Fox C.S. Pencina M.J. Wilson P.W. et al.Lifetime risk of CAD among individuals with and without diabetes stratified by obesity status in the Framingham heart study.Diabetes Care. 2008; 31: 1582-1584Crossref PubMed Scopus (161) Google Scholar). Both type 1 and type 2 diabetes are associated with increased CVD risk. In young adults (aged 20 to 39 years), type 1 diabetes is an independent risk factor for premature CVD and mortality (16Laing S.P. Swerdlow A.J. Slater S.D. et al.The British Diabetic Association Cohort Study, II: cause-specific mortality in patients with insulin-treated diabetes mellitus.Diabet Med. 1999; 16: 466-471Crossref PubMed Scopus (296) Google Scholar). The presence of CVD in people with type 1 diabetes is related to age, duration of diabetes, presence of retinopathy, higher glycated hemoglobin (A1C) levels and higher albumin excretion rates, as well as traditional CVD risk factors, such as elevated total cholesterol and low-density lipoprotein-cholesterol (LDL-C), smoking and excess body weight (17Nathan D.M. Cleary P.A. Backlund J.Y. et al.Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research GroupIntensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.N Engl J Med. 2005; 353: 2643-2653Crossref PubMed Scopus (2078) Google Scholar). For all age groups, the majority of people with type 1 diabetes have at least 1 CV risk factor (18Schwab K.O. Doerfer J. Hecker W. et al.DPV Initiative of the German Working Group for Pediatric DiabetologySpectrum and prevalence of atherogenic risk factors in 27,358 children, adolescents, and young adults with type 1 diabetes. Cross-sectional data from the German diabetes documentation and quality management system (DPV).Diabetes Care. 2006; 29: 218-225Crossref PubMed Scopus (214) Google Scholar). Even if an individual with type 1 diabetes has a low proximate risk of a CV event (i.e. younger and shorter duration of diabetes), his or her long-term risk is very high. Vascular protective measures in patients with diabetes include health behaviour interventions (diet, weight modification, increased physical activity, smoking cessation) and pharmacological therapies (anti-platelet agents, statins, angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs], glycemic and blood pressure [BP] control). A systematic approach to all vascular protective measures has been proven to reduce the risk of CVD events. The STENO-2 trial showed the long-term benefits of an intensive multifactorial management strategy in patients with type 2 diabetes and microalbuminuria (8Gaede P. Vedel P. Larsen N. et al.Multifactorial intervention and CAD in patients with type 2 diabetes.N Engl J Med. 2003; 348: 383-393Crossref PubMed Scopus (3813) Google Scholar, 9Gaede P. Lund-Andersen H. Parving H.H. Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes.N Engl J Med. 2008; 358: 580-591Crossref PubMed Scopus (2783) Google Scholar). Patients were randomized to receive either usual care or intensive multifactorial therapy, where the goal was to optimize health behaviour and control BP, cholesterol and blood glucose to the treatment targets recommended by clinical practice guidelines. In the intensively managed group, behaviour interventions were more frequently achieved, and BP, lipid and glycemic levels were lower than in the subjects receiving usual care, although treatment targets were usually not achieved. After 8 years of follow-up, there was a 53% relative risk reduction in major CVD events (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.24–0.73) compared to usual care with a 20% absolute risk reduction. This meant that only 5 patients with type 2 diabetes and microalbuminuria needed to be treated with the intensive multifactorial approach for 8 years to prevent 1 cardiovascular event. Microvascular complications were also substantially reduced. After 13 years, the originally intensively managed group had a significantly lower mortality rate (30% vs. 50%, p=0.02). The number needed to treat (NNT) for mortality after 13 years was 5. The STENO-2 trial shows that a process-driven, multifactorial management strategy optimizing behaviour and pharmacological interventions had a major impact on a wide range of CVD outcomes, including a 46% lower mortality. Thus, all patients with diabetes should participate in a multifactorial strategy to reduce CVD risk. Smoking, in individuals with diabetes, is an independent risk factor for all-cause mortality. It increases the risk of myocardial infarction (MI) 3-fold, stroke by 30%, progression to end stage renal disease, and is associated with poorer glycemic control. Quitting smoking reduces CV risk, reduces the risk of renal disease and improves glycemic control (19Solberg L. Desai J.R. O’Connor P.J. et al.Diabetic patients who smoke: are they different?.Diabetes Care. 1999; 22: 1887-1898Crossref PubMed Scopus (255) Google Scholar, 20Haire-Joshu D. Glasgow R.E. Tibbs T.L. American Diabetes Association. Smoking and diabetes.Diabetes Care. 2004; 27: S74-S75PubMed Google Scholar). Regular exercise and physical activity are key components in the vascular protection paradigm as they have been shown to significantly reduce morbidity and mortality in persons with diabetes (21Warburton D.E. Nichol C.W. Bredin S.S.D. Health benefits of physical activity: the evidence.CMAJ. 2006; 174: 801-809Crossref PubMed Scopus (4670) Google Scholar). The benefits of regular physical activity are described in the Physical Activity and Diabetes chapter, p. S40. The benefits of a healthy diet are described in the Nutrition Therapy chapter, p. S45. Achievement and maintenance of a healthy body weight are discussed in the Weight Management in Diabetes chapter, p. S82. While optimal glycemic control is central to the prevention of microvascular complications of diabetes, the benefits of tight glycemic control to reduce the risk for macrovascular disease have been more difficult to show. The goals for glycemic control and the cardiovascular benefits are discussed in the Targets for Glycemic Control chapter, p. S31, and options for glycemic control are discussed in the Pharmacotherapy in Type 1 Diabetes chapter, p. S56, and the Pharmacologic Management of Type 2 Diabetes chapter, p. S61. BP control is necessary in a high proportion of patients with diabetes. The goals of treatment and options to achieve BP targets are discussed in the Treatment of Hypertension chapter, p. S117. Platelets play a pivotal role in the development of atherothrombosis. As patients with diabetes have increased in vitro platelet reactivity and aggregation, they might be expected to have enhanced benefit from platelet inhibition with agents such as acetylsalicylic acid (ASA). However, in vitro tests of platelet aggregation suggest that patients with diabetes have platelets that are more likely to be resistant to the inhibitory effect of ASA (22Angiolillo D.J. Suryadevara S. Aspirin and clopidogrel: efficacy and resistance in diabetes mellitus.Best Pract Res Clin Endocrinol Metab. 2009; 23: 375-388Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 23Angiolillo D.J. Fernandez-Ortiz A. Bernardo E. et al.Influence of aspirin resistance on platelet function profiles in patients on long-term aspirin and clopidogrel after percutaneous coronary intervention.Am J Cardiol. 2006; 97: 38-43Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). Despite the proven advantages of ASA therapy in patients with established CVD, the evidence for benefits of ASA therapy for the primary prevention of coronary artery disease (CAD) events in persons with diabetes is less robust. In the general population, ASA reduces nonfatal MI in men without a history of CVD (24Berger J.S. Roncaglioni M.C. Avanzini F. et al.Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials.JAMA. 2006; 295: 306-313Crossref PubMed Scopus (705) Google Scholar). In women without a history of CVD, the Women's Health Study (WHS) indicated that ASA reduces the risk for stroke but not for MI (25Ridker P.M. Cook N.R. Lee I.M. et al.A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.N Engl J Med. 2005; 352: 1293-1304Crossref PubMed Scopus (1710) Google Scholar). Yet, the benefits in patients with diabetes are less apparent. The Antithrombotic Trialists meta-analysis included 95 randomized trials of antiplatelet therapy published up to 1997. Of these, only 9 trials with 5000 people had diabetes. Compared to a 22% reduction in the risk of major CV events among all 140 000 high-risk subjects on antiplatelet therapy, subjects with diabetes showed no significant benefit (7% ± 8% risk reduction) (26Collaborative overview of randomised trials of antiplatelet therapy—I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration.BMJ. 1994; 308: 81-106Crossref PubMed Scopus (709) Google Scholar). Primary CVD prevention trials conducted specifically in people with diabetes also have shown very little benefit. The Early Treatment of Diabetic Retinopathy Study (ETDRS) and the Japanese Prevention of Atherosclerosis with ASA in Diabetes (JPAD) trial included patients with diabetes without known atherosclerotic disease (27Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. ETDRS Investigators.JAMA. 1992; 268: 1292-1300Crossref PubMed Scopus (515) Google Scholar, 28Ogawa H. Nakayama M. Morimoto T. et al.Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.JAMA. 2008; 300: 2134-2141Crossref PubMed Scopus (691) Google Scholar). The ETDRS trial with ASA 650 mg demonstrated a borderline significant reduction of fatal and nonfatal MI (relative risk [RR] 0.85, 95% CI 0.73–1.00) yet no reduction of stroke (RR 1.18, 95% CI 0.88–1.58) (27Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. ETDRS Investigators.JAMA. 1992; 268: 1292-1300Crossref PubMed Scopus (515) Google Scholar). The JPAD trial used ASA 81 to 100 mg and showed no significant benefit for either MI or stroke (28Ogawa H. Nakayama M. Morimoto T. et al.Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.JAMA. 2008; 300: 2134-2141Crossref PubMed Scopus (691) Google Scholar). The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial in patients with diabetes and peripheral vascular disease showed that ASA 100 mg did not reduce CAD, death, nonfatal MI or stroke (29Belch J. MacCuish A. Campbell I. et al.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: a1840Crossref PubMed Scopus (580) Google Scholar). However, poor adherence to treatment, with only 50% of patients taking assigned therapy after 5 years, may have played a role in the apparently absent treatment effect in these patients with vascular disease. Meta-analysis of the diabetes cohorts from large clinical trials, such as WHS, British Male Doctors (BMD), Hypertension Optimal Treatment (HOT), Primary Prevention Project (PPP), and Thrombosis Prevention Trial (TPT), also have suggested that ASA has little or no benefit for the primary prevention of CAD events (25Ridker P.M. Cook N.R. Lee I.M. et al.A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.N Engl J Med. 2005; 352: 1293-1304Crossref PubMed Scopus (1710) Google Scholar, 30Peto R. Gray R. Collins R. et al.Randomised trial of prophylactic daily aspirin in British male doctors.Br Med J (Clin Res Ed). 1988; 296: 313-316Crossref PubMed Scopus (1047) Google Scholar, 31Hansson L. Zanchetti A. Carruthers S.G. 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: 1755-1762Abstract Full Text Full Text PDF PubMed Scopus (5425) Google Scholar, 32Sacco M. Pellegrini F. Roncaglioni M.C. et al.Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial.Diabetes Care. 2003; 26: 3264-3272Crossref PubMed Scopus (379) Google Scholar, 33Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council's General Practice Research Framework.Lancet. 1998; 351: 233-241Abstract Full Text Full Text PDF PubMed Scopus (862) Google Scholar, 34Baigent 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: 1849-1860Abstract Full Text Full Text PDF PubMed Scopus (2800) Google Scholar, 35Calvin A.D. Aggarwal N.R. Murad M.H. et al.Aspirin for the primary prevention of cardiovascular events: a systematic review and meta-analysis comparing patients with and without diabetes.Diabetes Care. 2009; 32: 2300-2306Crossref PubMed Scopus (87) Google Scholar, 36de Berardis G. Sacco M. Strippoli G.F. et al.Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials.BMJ. 2009; 339: b4531Crossref PubMed Scopus (332) Google Scholar, 37Zhang C. Sun A. Zhang P. et al.Aspirin for primary prevention of cardiovascular events in patients with diabetes: a meta-analysis.Diabetes Res Clin Pract. 2010; 87: 211-218Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 38Pignone M. Alberts M.J. Colwell J.A. et al.Aspirin for primary prevention of cardiovascular events in people with diabetes: a position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation.Diabetes Care. 2010; 33: 1395-1402Crossref PubMed Scopus (167) Google Scholar). The Baigent meta-analysis included BMD, PHS, WHS, TPT, and HOT and showed a modest 12% reduction of CVD events (RR 0.88, 95% CI 0.82–0.94) (34Baigent 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: 1849-1860Abstract Full Text Full Text PDF PubMed Scopus (2800) Google Scholar). However, the other 4 meta-analyses that also included ETDRS, JPAD, and POPADAD showed no significant reduction in either CAD events or stroke for patients with diabetes (35Calvin A.D. Aggarwal N.R. Murad M.H. et al.Aspirin for the primary prevention of cardiovascular events: a systematic review and meta-analysis comparing patients with and without diabetes.Diabetes Care. 2009; 32: 2300-2306Crossref PubMed Scopus (87) Google Scholar, 36de Berardis G. Sacco M. Strippoli G.F. et al.Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials.BMJ. 2009; 339: b4531Crossref PubMed Scopus (332) Google Scholar, 37Zhang C. Sun A. Zhang P. et al.Aspirin for primary prevention of cardiovascular events in patients with diabetes: a meta-analysis.Diabetes Res Clin Pract. 2010; 87: 211-218Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 38Pignone M. Alberts M.J. Colwell J.A. et al.Aspirin for primary prevention of cardiovascular events in people with diabetes: a position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation.Diabetes Care. 2010; 33: 1395-1402Crossref PubMed Scopus (167) Google Scholar). ASA increases gastrointestinal bleeding 50% to 70% (39Derry S. Loke Y.K. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis.BMJ. 2000; 321: 1183-1187Crossref PubMed Scopus (645) Google Scholar), but the absolute rates of bleeding are low, with a risk of approximately 3 per 10 000 in the overall population. It is likely the risk is higher in patients with diabetes, with an estimate of 1 to 2 per 1000 in middle-aged individuals and as high as >5 per 1000 in people >70 years old (39Derry S. Loke Y.K. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis.BMJ. 2000; 321: 1183-1187Crossref PubMed Scopus (645) Google Scholar). In summary, pooled estimates suggest that for primary prevention of CVD events in people with diabetes, ASA results in no reduction of CAD events and stroke but an important increase in gastrointestinal hemorrhage. Thus, despite a plethora of data, there remains sufficient uncertainty about the use of ASA in the primary prevention of CAD events in persons with diabetes, and its routine use in primary CVD event prevention is not recommended. ASA has been shown to reduce CVD events in patients with established CVD disease (40Bhatt D.L. Marso S.P. Hirsch A.T. et al.Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus.Am J Cardiol. 2002; 90: 625-628Abstract Full Text Full Text PDF PubMed Scopus (369) Google Scholar). The clinical trial evidence, as reflected in the 2011 Canadian Cardiovascular Society Guidelines on the Use of Antiplatelet Therapy in the Outpatient Setting, supports the use of ASA 75 to 162 mg daily for the secondary prevention of CAD events in those with diabetes (41Bell A.D. Roussin A. Cartier R. et al.The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society guidelines.Can J Cardiol. 2011; 27: S1-S59Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). The benefit of ACE inhibition for vascular protection with ramipril 10 mg daily was demonstrated by the Heart