Is type 2 diabetes really a coronary heart disease risk equivalent?

Vascular Pharmacology 59 (2013) 11–18

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Review

Is type 2 diabetes really a coronary heart disease risk equivalent? Christoph H. Saely a,b,c, Heinz Drexel a,b,c,d,⁎ a

Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria c Private University of the Principality of Liechtenstein, Triesen, Liechtenstein d Drexel University College of Medicine, Philadelphia, PA, USA b

a r t i c l e

i n f o

Article history: Received 25 April 2013 Received in revised form 8 May 2013 Accepted 11 May 2013 Keywords: Diabetes mellitus Coronary heart disease Coronary artery disease Cardiovascular disease Coronary heart disease risk equivalent

a b s t r a c t The concept of diabetes as a coronary heart risk (CHD) equivalent postulates that patients with diabetes who do not yet have CHD are at an equally high cardiovascular risk as non-diabetic patients with CHD. This implies important therapeutic, psychological, and economical consequences. However, whereas several reports support the concept of diabetes as a CHD risk equivalent, others refute it, and several investigations find that the cardiovascular risk conferred by diabetes is strongly modulated by sex (with diabetes conferring a greater risk increase in women), diabetes duration, concomitant risk factors, or the presence of subclinical atherosclerosis. A detailed review of the literature shows that the concept of diabetes as a CHD risk equivalent is overly simplistic, because not all patients with diabetes are at the same cardiovascular risk. An individualized approach to cardiovascular risk estimation and management appears mandatory in patients with diabetes. © 2013 Elsevier Inc. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Published observations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Studies supporting the concept of diabetes as a CHD risk equivalent . . . . . 2.2. Studies refuting the concept of diabetes as a CHD risk equivalent . . . . . . 2.3. Studies giving no simple yes-or-no answers . . . . . . . . . . . . . . . . 3. Meta-analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Attempts at explaining the discrepancies in the literature . . . . . . . . . . . . . 5. Clinical implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Screening for coronary artery disease in asymptomatic patients with diabetes 5.4. Psychological consequences . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Patients with diabetes mellitus are at a 2–3-fold increased risk of cardiovascular events (Franco et al., 2007; Nathan et al., 1997) and more than two thirds of patients with diabetes eventually die from

⁎ Corresponding author at: Vorarlberg Institute for Cardiovascular Investigation and Treatment (VIVIT), Feldkirch, Carinagasse 47, A-6807 Feldkirch, Austria. Tel.: +43 5522 303 2670; fax: +43 5522 303 7533. E-mail address: [email protected] (H. Drexel). 1537-1891/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.vph.2013.05.003

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cardiovascular disease (Centers for Disease Control and Prevention, 2007). Directing the attention of health care providers and researchers to diabetes as a high-risk condition has been of paramount importance, because efficient means to reduce cardiovascular risk are available. The influential National Cholesterol Education Programme Adult Treatment Panel III (NCEP-ATPIII) has strongly emphasized the importance of diabetes as a cardiovascular high-risk condition by considering it a coronary heart disease (CHD) risk equivalent, i.e. by stating that the cardiovascular event risk in patients with diabetes who do not have CHD is as high as the cardiovascular event risk in

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patients with CHD who do not have diabetes (Anon., 2001; Grundy et al., 2004). This allocation of patients with diabetes to the same risk category as patients with established CHD has important consequences for the affected individuals: i) Belonging to the highest risk category implies most aggressive risk factor control, in particular stringent lipid treatment goals, i.e. LDL cholesterol of at least b 100 mg/dl in the NCEP-ATP-III report (Anon., 2001; Grundy et al., 2004) and LDL cholesterol b70 mg/dl in the current guidelines for the management of dyslipidemia issued by the European Society of Cardiology/ European Atherosclerosis Society (Reiner et al., 2011). The latter guidelines allocate all patients with type 2 diabetes and those with type 1 diabetes who have target organ damage such as microalbuminuria to the category of very high cardiovascular risk, without explicitly stating that diabetes is a CHD risk equivalent. ii) Provided that patients with CHD receive maximum risk-reducing therapy, the concept of diabetes as a CHD risk equivalent renders further cardiovascular risk estimation within the population of patients with diabetes void of treatment consequences and thus unnecessary. iii) Being allocated to the same category of cardiovascular event risk as patients with CHD (in particular as those with a history of myocardial infarction) has important psychological consequences, which are not necessarily beneficial. Considering the already high and still increasing prevalence of diabetes as well as the limited health care resources even of affluent nations, the issue of diabetes as a CHD risk equivalent is of considerable importance also from an economical perspective. The question whether diabetes really is a CHD risk equivalent therefore appears to be not only one of scientific relevance, but also one of great practical importance, both at the patient and at the community level. 2. Published observations 2.1. Studies supporting the concept of diabetes as a CHD risk equivalent The whole concept of diabetes as CHD risk equivalent developed from a landmark study reported by Haffner et al. (1998), who, using data from Finnish registries, compared the seven-year incidence of fatal and non-fatal myocardial infarction among 1373 non-diabetic subjects with that among 1059 subjects with diabetes. Among 69 non-diabetic patients with prior myocardial infarction CHD mortality was not significantly different from that in 890 subjects with type 2 diabetes who did not have prior myocardial infarction. Also, the overall rate of fatal plus non-fatal myocardial infarction and of strokes was similar in these two groups. The authors concluded that diabetic patients without previous myocardial infarction have as high a risk of myocardial infarction as non-diabetic patients with previous myocardial infarction. Malmberg et al. (2000) addressed the impact of diabetes on longterm prognosis in patients with unstable angina and non-Q-wave myocardial infarction from the Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry. During two years of followup, very similar outcomes with regard to total mortality, cardiovascular death, new myocardial infarction, stroke, the combination of the above and new congestive heart failure were observed in 569 patients with diabetes who did not have previous cardiovascular disease (which here was defined as previous myocardial infarction, stroke, congestive heart failure, percutaneous coronary interventions, or coronary artery bypass grafting) and in 3503 patients without diabetes who had previous cardiovascular disease. Similar findings were published by Mukamal et al. (2001); these authors followed 1935 patients hospitalized with confirmed acute

myocardial infarction over a mean follow-up period of 3.7 years. Total mortality was 17%. For 243 patients with diabetes who did not have a previous myocardial infarction and for 393 non-diabetic patients with previous myocardial infarction, the respective hazard ratios for total mortality compared with non-diabetic subjects without prior myocardial infarction were 2.3 and 2.2; the respective hazard ratios for cardiovascular mortality were 1.8 and 1.5, with overlapping 95% confidence intervals. Ho et al. (2003) investigated whether diabetes confers a stroke risk equivalent to that imparted by a history of pre-existing stroke, analyzing pooled data from nine prospective epidemiological studies in the United States. From a grand total of 27,269 patients, 567 had previous myocardial infarction but no diabetes nor previous stroke, 432 previous stroke but no diabetes nor previous myocardial infarction, and 2091 had diabetes but no previous myocardial infarction nor stroke. In these patient groups, 10-year stroke mortality was 0.9% in the previous myocardial infarction group, 7.2% in the previous stroke group, and 2.0% in the diabetes group. Because after multivariate adjustment for nine variables the difference between the previous stroke group and the diabetes group was no longer significant, the authors concluded that diabetes confers a risk of mortality from stroke as high as does a previous stroke. The higher stroke risk with diabetes than with previous myocardial infarction remained significant also after adjustment. Natarajan et al. (2005) evaluated the relationship between diabetes duration and CHD mortality in 10,871 adults over 20 years of follow-up, using the 1971–1992 National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. Myocardial infarction at baseline was defined on the basis of participant self-report of a physician-diagnosed heart attack. Among men, 113 had recent diabetes diagnosed b10 years before but no previous myocardial infarction, 64 long-standing diabetes diagnosed at least 10 years before, and 360 had no diabetes but had a previous myocardial infarction. Among women the respective numbers of patients in these three groups were 200, 85, and 225. Cardiovascular mortality rates among men were 31.9, 34.3, and 40.0% in those with recent diabetes, longstanding diabetes, or previous myocardial infarction, respectively; in both groups with diabetes, cardiovascular mortality was not significantly different from that of men without diabetes who had a previous myocardial infarction. Among women, the respective cardiovascular mortality rates in these three groups were 20.0, 34.1, and 28.0%; the risk of cardiovascular death in women with recent diabetes was not significantly different from that in women with prior myocardial infarction; it was significantly higher in women with long-standing diabetes who did not have prior myocardial infarction than in women with previous myocardial infarction who did not have diabetes. Whiteley et al. (2005) performed a prospective cohort study on 7052 men and 8354 women from Scotland over a follow-up period of 25 years. Subjects were considered to have pre-existing CHD when they had a history of angina or ECG tracings suggestive of underlying coronary artery disease. Among men, 74 had diabetes but no prior CHD, whereas 1402 had CHD but not diabetes; among women, the respective numbers of subjects in these patient categories were 77 and 1613. Among men, event rates per 1000 person years in patients with diabetes only versus patients with CHD only were 23.4 vs 21.3% for CHD mortality, 34.2 vs 32.2% for vascular mortality, and 54.0 vs 50.5% for total mortality; among women, the corresponding death rates were 16.9 vs 9.8%, 29.8 vs 16.6%, and 46.7 vs 29.2%, respectively. Regarding both total and CHD death, the risk was not significantly different between patients with diabetes only and patients with myocardial infarction only among men, whereas it was even higher in the diabetes-only group among women (Table 1). Juutilainen et al. (2005) recorded cardiovascular disease and CHD deaths in a Finnish population-based study of 1373 non-diabetic and 1059 diabetic subjects who were followed-up over 18 years. From the included subjects, 432 had diabetes but no evidence of prior CHD

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Table 1 Overview of published observations. Favors diabetes as a CHD risk equivalent

Patients in DM+/ CAD - group (n)

Patients in DM–/ CAD + group (n)

Event rate in DM+/ CAD - group (%)

Event rate in DM–/ CAD + group (%)

Haffner et al. (1998) Malmberg et al. (2000) Mukamal et al. (2001) Natarajan et al. (2005) Whiteley et al. (2005) Juutilainen et al. (2005) Gowdak et al. (2007) Rashidi et al. (2008) Hadaegh et al. (2010) Simons and Simons (1998) Lotufo et al. (2001) Evans et al. (2002) (cross-sectional study) Evans et al. (2002)(cohort study) Eberly et al. (2003) Lee et al. (2004) Vaccaro et al. (2004) Saely et al. (2012) Natarajan et al. (2003) Becker et al. (2003) Hu et al. (2005) Hu et al. (2001) Cho et al. (2002) Wannamethee et al. (2004)

+ + + + + + + + + − − −

890 569 243 69 men, 58 women 74 men, 77 women 69 63 443 221 men, 348 women 130 2317 1155

69 3503 393 63 men, 144 women 1402 men, 1613 women 432 61 789 228 men, 285 women 478 5906 1347

20.2 13.0 28 ~40% in men, ~20% in women ~75% in men, ~75% in women ~40% 66.7% 48.1% 16.7% in men, 12.6% in women 31.5% 3.8% 24.6%

18.8 12.8 24 ~40% in men, ~20% in women ~75% in men, ~50% in women ~40% 68.7% 49.0% 20.8% in men, 11.2% in women 52.7% 7.5% 32.5%

−

3403

5350

4.2%

12.3%

− − − − o o o o o o

1122 1460 4809 50 103 men, 75 women 27 men, 28 women 496 men, 466 women 3705 1285 202

21.8% 9.7% 31.2% 22.0% 18.4% in men, 21.3% in women ~40% in both men and women 17.1% in men, 15.9% in women 37.0% 11.6% 17.8%

Carnethon et al. (2010) Howard et al. (2006)

o o

659 2026

658 283 4625 342 191 men, 109 women 178 men, 156 women 982 men, 326 women 1302 2038 379 with angina pectoris, 547 with prior myocardial infarction 868 47

34.7% 20.8% 40.0% 39.5% 40.8% in men, 12.8% in women ~40% in men, ~60% in women 32.6% in men, 16.3% in women 54.2% 19.2% 17.9% in those with angina, 25.6% in those with prior myocardial infarction 24.5% 62%

20.0% 11–47% (depending on the presence of concomitant risk factors)

+ — Supports the concept of diabetes as a coronary heart disease risk equivalent, − — refutes the concept of diabetes as a coronary heart disease risk equivalent, o — does not give a simple yes or no answer to the question whether diabetes is a coronary heart disease risk equivalent.

(including any of myocardial infarction, ischemic ECG changes, or angina pectoris), and 430 did not have diabetes but had evidence of CHD. The hazard ratios for CHD death, cardiovascular death, non-cardiovascular death, and all-cause death did not significantly differ between patients with diabetes who did not have prior evidence of CHD and those with evidence of prior CHD who did not have diabetes. However, patients with diabetes who did not have evidence of prior CHD were at a significantly higher risk of CHD death, cardiovascular death, non-cardiovascular death, and all-cause death than those without diabetes but with evidence of CHD at baseline. These results regarding the respective risks conferred by diabetes and pre-existing CHD were qualitatively the same for men and women; however quantitatively the impact of diabetes was even stronger among women than among men. Gowdak et al. (2007) in a set of 288 high-risk renal transplant candidates investigated whether diabetes confers a cardiovascular risk equivalent to that of coronary artery disease in this population. From the included patients, 61 did not have diabetes but had coronary stenoses with at least 70% lumen narrowing at angiography, whereas 51 had diabetes but did not have such coronary lumen narrowing. Comparing these two groups, the incidence rates during 5 years of follow-up were 45.9 and 29.4% (p b 0.05) for fatal or non-fatal major coronary events, 39.3 vs 33.3% (p = n.s.) for overall mortality, and 66.7 vs 68.7% (p = n.s.) for cardiovascular death. Somewhat surprisingly, Kaplan–Meier curves did not show a significant difference between these groups with regard to the incidence of major coronary events. The authors concluded that no difference could be observed comparing the prognosis of patients with diabetes without coronary artery disease and patients without diabetes who had coronary artery disease. Rashidi et al. (2008) used the Cardiovascular Health Study to identify 789 patients with a baseline history of myocardial infarction but without diabetes or chronic kidney disease (estimated glomerular filtration rate b60 mL/min), 443 patients with diabetes but not previous

myocardial infarction nor chronic kidney disease, and 667 patients with chronic kidney disease but not previous myocardial infarction or diabetes. During a follow-up of 8.6 years, 15.7% died of cardiovascular causes in the myocardial infarction group, and 15.8 and 13% in the diabetes and the chronic kidney disease groups, respectively. Hazard ratios did not differ significantly between these groups. Hadaegh et al. (2010) analyzed data from a population-based cohort study of 2267 men and 2931 women over a mean follow-up period of 7.6 years; prior CHD was defined as self-reported or ECG-diagnosed CHD at baseline. Among men, 228 had CHD at baseline but not diabetes; 69 had known diabetes but not CHD; and 152 had newly diagnosed diabetes but not CHD. The respective numbers of patients in these groups among women were 285, 138 and 210. Incident CHD was defined as definite or probable myocardial infarction, unstable angina, angiographically proven CHD or CHD death. CHD event rates in patients of the three groups described above were 20.2, 15.9, and 17.1% among men and 13.7, 13.8, and 9.0% among women, respectively. Compared with those with baseline CHD but without diabetes, the risk of CHD events did not differ significantly in patients without baseline CHD but with known diabetes in both genders; the coronary event risk in the group without baseline CHD but with newly diagnosed diabetes was similar in men but marginally – albeit non-significantly – lower in women. 2.2. Studies refuting the concept of diabetes as a CHD risk equivalent Simons and Simons (1998), in response to the study by Haffner et al. (1998), wrote a letter to the Editor of the New England Journal of Medicine where they published their 98-month follow-up data from the Dubbo study, which investigated a cohort of elderly Australian subjects. Here, the incidence of CHD was significantly lower in 130 diabetic subjects without prior CHD than in 478 non-diabetic subjects with prior CHD (31.5% vs 52.7%; p b 0.04); prior CHD in the Dubbo

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study was diagnosed based on positive responses to a myocardial infarction questionnaire, or the Rose angina questionnaire, or on diagnostic ECG changes. Also Lotufo et al. (2001) investigated the impact of diabetes and of prior CHD, defined as previous myocardial infarction or angina, on CHD mortality in 91,285 US male physicians aged 40–84 years who participated in the Physicians' Health Study. Over 5 years of follow-up, the 2317 men with a history of diabetes but not CHD compared with the 5906 men with a history of CHD but not of diabetes showed similar all-cause mortality, but significantly lower mortality from CHD. Evans et al. (2002) compared the risks of cardiovascular outcomes between patients with type 2 diabetes and patients with established CHD both in a cross-sectional study and in a cohort-study, using datasets from Scotland. For the overall cross-sectional evaluation, a cross-section of the original population aged 45–64 in 1988 was selected; from these subjects, 1155 patients with diabetes of a mean duration of 6 years but without previous myocardial infarction and 1347 patients with previous myocardial infarction but without a history of diabetes were identified. During eight years of follow-up, the adjusted risk ratio for death in the myocardial infarction group compared with the diabetes group was 1.33 [1.14 to 1.55], while that for hospital admission for myocardial infarction was 2.27 [1.82 to 2.83]. These ratios were almost identical in men and women. For the cohort study, all patients from the dataset with type 2 diabetes first diagnosed between January 1988 and December 1995 and all patients who had a first hospital admission with a primary or secondary diagnosis of myocardial infarction between January 1988 and December 1995 were enrolled, as the starting dates of the follow-up period the dates of the diagnosis of diabetes and of the admission for myocardial infarction were defined, respectively. Overall, 3403 patients with diabetes and 5350 patients with myocardial infarction were followed until December 1995. In the diabetes cohort 35.1% died, of whom 6.5% suffered cardiovascular deaths, and 4.2% were hospitalized for myocardial infarction. In the myocardial infarction cohort 48.8% died, of whom 20.1% suffered cardiovascular deaths and 12.2% were hospitalized for myocardial infarction. Statistical testing confirmed that total as well as of cardiovascular mortality and the risk of hospitalization for myocardial infarction were significantly higher for patients with previous myocardial infarction than for those with diabetes. Again, there were no differences between men and women. Eberly et al. (2003) investigated 11,645 men participating in the Multiple Risk Factor Intervention Trial who survived to the end of the 6 in-trial years and were grouped according to during-trial incident diabetes and non-fatal cardiovascular disease, which was defined as coronary bypass surgery, non-fatal stroke, or non-fatal myocardial infarction. During 18 post-trial years, 1122 participants who had developed diabetes but not non-fatal cardiovascular disease during the trial, when compared with the 658 patients who had developed non-fatal cardiovascular disease but not diabetes, showed a significantly lower all-cause mortality, cardiovascular mortality and CHD mortality. Lee et al. (2004) followed a total of 13,790 African American and white men and women ages 45–64 years who participated in the Atherosclerosis Risk in Communities study. Comparing 1460 patients with diabetes who had no prior myocardial infarction and 283 non-diabetic patients who had a prior myocardial infarction, the authors, over an average follow-up period of 9 years, found a significantly lower risk of fatal CHD, of non-fatal myocardial infarction and of cardiovascular mortality in the diabetes versus the prior myocardial infarction group, but no significant difference in the risk of fatal or nonfatal stroke. Vaccaro et al. (2004) compared the 25-years mortality of 4809 men with diabetes but without self-reported previous myocardial infarction and of 4625 men with myocardial infarction but without diabetes, who were screened for the Multiple Risk Factor Intervention Trial. Over a median follow-up time of 25 years, cardiovascular mortality was lower in patients with diabetes only than in those with myocardial infarction only, owing to an excess of CHD deaths. In contrast, non-cardiovascular mortality was higher in the diabetes-only

group than in the myocardial infarction-only group; all-cause mortality was similar. Booth et al. (2006) did a population-based retrospective cohort study using Canadian health claims, and identified 379,003 adults with and 9,018,082 adults without diabetes mellitus living in Ontario. In this investigation, age-specific rates of acute myocardial infarction were significantly lower for all age groups of patients with diabetes without recent acute myocardial infarction than for those with a recent acute myocardial infarction but without diabetes. Importantly, however, the transition to a high-risk category with a 10-year incidence of severe cardiovascular events (cardiovascular mortality, myocardial infarction, or stroke) of at least 20% occurred at a younger age for men and women with diabetes than for those without diabetes, with a mean difference of almost 15 years. The authors concluded that diabetes confers a risk equivalent to aging by 15 years, and that age should be taken into account in the targeting of risk-reducing interventions among people with diabetes. Buyken et al. (2007) investigated the respective impact of diabetes and of coronary artery disease on the 10-year incidence of coronary events (fatal or non-fatal myocardial infarction, sudden coronary death) in 5389 men participating in the Prospective Cardiovascular Münster Study who did not have prior evidence of CHD. Of 406 men with diabetes mellitus 13.3% suffered a coronary event within 10 years, which was well below the 20% 10-year event risk considered to characterize patients with a risk equivalent to that of established CHD. Using the PROCAM calculator, less than one third of men with diabetes were found to be at a cardiovascular event risk of 20% or higher. Our group (Saely et al., 2012), in a cohort of 750 angiographically characterized patients, prospectively evaluated to what extent pre-existing coronary artery disease accounts for the increased vascular event risk of patients with type 2 diabetes. The baseline prevalence of significant coronary artery disease, i.e. of coronary stenosis with lumen narrowing of at least 50% was higher in patients with diabetes than in non-diabetic subjects; prospectively, type 2 diabetic patients without significant coronary artery disease at angiography (n = 50) had a significantly lower event rate than the 342 non-diabetic patients with significant coronary artery disease (22.0 vs 39.5%; p = 0.007). These data confirmed and extended earlier observations reported by us (Saely et al., 2010, 2004). 2.3. Studies giving no simple yes-or-no answers Natarajan et al. (2003) performed an analysis of pooled data from the Framingham Heart and Framingham Offspring Studies, including 2494 men and 2740 women. Among men, 103 had diabetes but not CHD defined as myocardial infarction, coronary insufficiency, or angina pectoris, while 191 had CHD but not diabetes; among women, 75 and 109 patients were in these respective categories. Over 20 years of follow-up, male patients with diabetes but without CHD were at a lower risk of CHD mortality than patients with CHD but without diabetes, whereas the opposite was found among women. Becker et al. (2003), in Caucasian individuals participating in the Dutch Hoorn study, investigated the 10-year risk of fatal and nonfatal cardiovascular events (including CHD, defined by the presence of prolonged typical chest pain, ECG changes, enzymes, and percutaneous transluminal angioplasty or coronary artery bypass grafting, congestive heart failure, transient ischaemic attack or stroke, or peripheral atherosclerotic disease). The 63 men with diabetes who did not have baseline cardiovascular disease (which was defined as a history of myocardial infarction, coronary surgery or angioplasty, angina pectoris, transient ischemic attack or stroke, intermittent claudication, and/or use of nitrates), when compared with the 178 men who had prior cardiovascular disease but not diabetes had a significantly lower risk of cardiovascular events during the follow-up, whereas the 90 women with diabetes but without cardiovascular disease, compared with the 156 women with cardiovascular disease but without diabetes, showed a similar cardiovascular event rate.

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Hu et al. (2005) aimed at investigating the associations of type 2 diabetes and of a history of myocardial infarction with CHD, stroke, cardiovascular and total mortality, and whether these effects are different in men and women. The authors followed a cohort of 51,735 men and women from Finland over a mean period of 17.2 years. At study entry, among men, 469 had diabetes but no prior myocardial infarction and 982 did not have diabetes but had a history of myocardial infarction. The corresponding numbers of women in these two patient categories were 466 and 326, respectively. When patients with diabetes but without prior myocardial infarction were compared with patients with prior myocardial infarction but without diabetes, incidence rates were 17.1 and 32.6% (p b 0.05) for CHD mortality, 6.0 and 2.7% (p = n.s.) for stroke mortality, 25.6 and 37.7% (p b 0.05) for cardiovascular mortality, and 41.7 and 51.9% (p b 0.05) for total mortality; among women, the respective incidence rates were 15.9 and 16.3% (p b 0.05) for CHD mortality, 6.4 and 8.0% (p = n.s.) for stroke mortality, 25.8 and 26.3% (p b 0.05) for cardiovascular mortality, and 41.2 and 35.9% (p b 0.005) for total mortality. Interaction analyses showed significant sex differences with regard to the respective impact of diabetes and of prior myocardial infarction on CHD, cardiovascular mortality, and total mortality. Pajunen et al. (2005) compared the risk of acute coronary events in diabetic and non-diabetic persons with or without prior myocardial infarction, stratified by age and sex, using a population-based myocardial infarction register from Finland, and relating its data to prevalence estimates of myocardial infarction and diabetes from a Finnish population survey. The rate of recurrent myocardial infarction among non-diabetic men with prior myocardial infarction was higher than the incidence of first myocardial infarction among diabetic men aged 45 to 54 years; the rate ratio was 2.14 [1.40–3.27] among men aged 50. Among elderly men, diabetes however conferred a higher risk than prior myocardial infarction. Diabetic women had a similar risk of suffering a first myocardial infarction as non-diabetic women with a prior myocardial infarction had for suffering a recurrent myocardial infarction, without a prominent age effect. Hu et al. (2001) over a long follow-up period of 20 years investigated the impact of type 2 diabetes and of a history of prior CHD on mortality from all causes and from CHD among women aged 30– 55 years who participated in the Nurses' Health Study. A total of 3705 women had diabetes but did not report a history of myocardial infarction, and 1302 reported a history of myocardial infarction but not of diabetes. Overall, all-cause mortality as well as CHD mortality were lower in the first than in the latter group. Importantly however, the risk of fatal CHD strongly increased with increasing diabetes duration; cardiovascular mortality was higher in women without prior myocardial infarction who had a reported diabetes duration of more than 15 years than in those who had a history of prior myocardial infarction but not of diabetes. Cho et al. (2002) examined type 2 diabetes and prior myocardial infarction in relation to 10-year mortality among 51,316 men aged 40–75 years who participated in the Health Professional Follow-up Study. From the total cohort, 1285 men had a history of diabetes but not of myocardial infarction, whereas 2038 had a history of myocardial infarction but not of diabetes. Total mortality did not differ significantly between these groups, whereas cardiovascular mortality as well as CHD mortality were significantly lower in the diabetes than in the myocardial infarction group. However, in this study the patients with the longest diabetes duration (26 or more years) had an approximately similar event risk as post myocardial infarction patients without diabetes. Wannamethee et al. (2004) followed up 5934 men aged 52– 74 years for up to 10 years. From these men, 202 had diabetes but no prior CHD, 379 doctor diagnosed angina but no diabetes nor prior myocardial infarction, and 547 doctor diagnosed myocardial infarction but no diabetes. In these three groups, the respective event rates were 17.8, 17.9, and 25.6% for major CHD events, 12.9, 12.4, and 18.5% for all CHD

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deaths, 69.4, 63.2, and 69.3% for case fatality, 9.9, 5.8, and 8.6% for major stroke events, 18.3, 16.8 and 26.7% for cardiovascular mortality, and 31.2, 31.1, and 40.6% for total mortality. Statistical testing in adjusted models failed to show significant differences between outcomes among patients with diabetes and those with prior myocardial infarction; however the authors, based on absolute numbers, concluded that men with diabetes only have a cardiovascular disease risk intermediate between men with angina and men with previous myocardial infarction. Importantly, the risk among patients with diabetes increased with increasing diabetes duration and approached the risk among men with myocardial infarction when diabetes duration was 12 years or more. Carnethon et al. (2010) in 3997 adults aged 65 years or older who participated in the Cardiovascular Health Study tested whether cardiovascular and all-cause mortality among participants with established CHD (defined as a history of myocardial infarction, angina, or coronary revascularization) were similar to those in participants with diabetes. From the total study population, 659 patients had diabetes but not CHD at baseline; 868 had CHD but not diabetes. In these two groups, during a mean follow-up period of 11.3 years, CHD mortality was 20.0 vs 24.5%, cardiovascular disease mortality was 32.0 vs 35.0%, and total mortality was 71.0 vs 71.4%; after multivariate adjustment, these differences were not statistically significant, with the exception of total mortality, which was higher among patients with diabetes than among those with pre-existing CHD. When the analyses with regard to CHD were restricted to the 49% of participants who had had myocardial infarctions, similar patterns of association in relation to cardiovascular disease mortality and total mortality were observed; however, myocardial infarction alone as compared with diabetes alone conferred a modest but statistically significantly elevated risk for CHD death. Howard et al. (2006) studied the influence of single and multiple risk factors on the 10-year cumulative incidence of fatal and nonfatal CHD and cardiovascular disease in diabetic and non-diabetic subjects, with or without baseline CHD or cardiovascular disease, in a cohort of 4549 American Indians participating in the Strong Heart Study. The data set included 47 non-diabetic patients with CHD defined as prior myocardial infarction, prior coronary revascularization, previous angiographic documentation of coronary stenoses or pathologic Q waves on the electrocardiogram, and 2008 patients with diabetes who did not have previous cardiovascular disease. Diabetic men and women without previous cardiovascular disease overall had 10-year cumulative CHD incidence rates of 25.9 and 19.1%, respectively, compared with 57.4 and 58.4% for non-diabetic men and women with previous CHD. Importantly, diabetic individuals with one or two risk factors had a 10-year cumulative incidence of CHD that was only 1.4 times higher than that of non-diabetic individuals (14%), whereas in diabetic subjects with multiple risk factors the 10-year incidence of CHD was > 40%; indeed the incidence of fatal CHD was higher in these subjects than in non-diabetic subjects with previous CHD.

3. Meta-analyses Bulugahapitiya et al. (2009) performed a systematic review including cohort or observational studies with hard clinical endpoints, including total major CHD events (fatal or non-fatal myocardial infarction), stratified for patients with diabetes but no previous myocardial infarction and patients without diabetes but with previous myocardial infarction. Studies with less than 100 subjects, follow-up of less than 4 years or without information for calculating CHD event rates were excluded from this analysis; thirteen studies were included, involving 45,108 patients. The duration of follow-up was 5–25 years (mean 13.4 years) and the age range was 25–84 years. Patients with diabetes without prior myocardial infarction had a 43% lower risk of developing fatal or non-fatal myocardial infarction compared with patients without diabetes with previous myocardial infarction, with a summary odds ratio of 0.56 and 95% confidence intervals of 0.53–0.60.

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Lee et al. (2012) conducted a meta-analysis focusing on whether the CHD risk equivalence of diabetes differs between men and women. Individuals with diabetes but without cardiovascular disease and those with cardiovascular disease but without diabetes were examined through a systematic review of articles that provided gender-specific hazard ratios for mortality. The authors found that cardiovascular disease and CHD mortality in men was lower for diabetes alone. In contrast, rates appeared to be higher in women with diabetes alone, although wide credible intervals precluded definitive conclusions. All-cause mortality in men was similar for diabetes and previous cardiovascular disease whereas, among women, it was at least as high and possibly higher for diabetes alone. The authors concluded that, compared with previously established cardiovascular disease, diabetes alone leads to lower cardiovascular disease and CHD mortality risk and similar all-cause mortality in men. In contrast, it appeared possible that diabetes leads to higher cardiovascular disease, CHD and all-cause mortality in women.

4. Attempts at explaining the discrepancies in the literature Taken together, ten published observations (Haffner et al., 1998; Malmberg et al., 2000; Mukamal et al., 2001; Ho et al., 2003; Natarajan et al., 2005; Whiteley et al., 2005; Juutilainen et al., 2005; Gowdak et al., 2007; Rashidi et al., 2008; Hadaegh et al., 2010) support the concept of CHD risk equivalence of diabetes or at least in subgroups find an even higher cardiovascular risk associated with diabetes, and eleven do not support this concept (Simons and Simons, 1998; Lotufo et al., 2001; Evans et al., 2002; Eberly et al., 2003; Lee et al., 2004; Vaccaro et al., 2004; Booth et al., 2006; Buyken et al., 2007; Saely et al., 2012, 2010, 2004). One meta-analysis (Bulugahapitiya et al., 2009) comes to the conclusion that patients with diabetes but without prior myocardial infarction are at only about half the risk of developing fatal or non-fatal myocardial infarction compared with patients without diabetes but with previous myocardial infarction; another meta-analysis (Lee et al., 2012) reports that diabetes confers a lower cardiovascular death risk than previous cardiovascular disease in men, whereas the opposite might be true in women. Importantly, from the original publications nine refrain from giving an easy yes-or-no answer to the question whether diabetes is a CHD risk equivalent (Natarajan et al., 2003; Becker et al., 2003; Hu et al., 2005; Pajunen et al., 2005; Hu et al., 2001; Cho et al., 2002; Wannamethee et al., 2004; Carnethon et al., 2010; Howard et al., 2006). Of these studies, four (Natarajan et al., 2003; Becker et al., 2003; Hu et al., 2005; Pajunen et al., 2005) found that diabetes is a CHD risk equivalent or even confers a higher cardiovascular event risk than pre-existing CHD in women but not in men, three found that cardiovascular risk increases with diabetes duration (Hu et al., 2001; Cho et al., 2002; Wannamethee et al., 2004) so that diabetes becomes a CHD risk equivalent only when diabetes duration is sufficiently long, one reported that number of risk factors in patients with diabetes decides whether diabetes is a CHD risk equivalent (Howard et al., 2006), and two found that whether diabetes confers event risk equivalent to that baseline CHD depends on the definition of baseline CHD (Wannamethee et al., 2004; Carnethon et al., 2010). The observation regarding the greater relative risk increase conferred by diabetes among women than among men is well established, and has been recently reviewed comprehensively (Norhammar and Schenck-Gustafsson, 2013). Also, it has long been recognized that patients with a longer diabetes duration are at a higher risk of cardiovascular events. This is obviously what can be expected from pathophysiology given the firmly established role of type 2 diabetes as a causal risk factor in the development of cardiovascular disease. It also appears somewhat common sense that not all manifestations of baseline CHD indicate the same risk of future cardiovascular events and, finally, it is no real surprise that patients with diabetes who have multiple risk factors are at

a higher cardiovascular event risk than those with few additional risk factors. The bottom line from the discussion on whether diabetes is a CHD risk equivalent or not therefore is that not all patients with diabetes who do not have a history of CHD – and, also not all patients with CHD who do not have diabetes – are equal. Most importantly, being asymptomatic does not at all exclude the presence of subclinical cardiovascular disease. The presence or absence of hitherto undiagnosed cardiovascular disease characterizes prognostically distinct categories of patients who are somewhat inaccurately grouped together as primary prevention cohorts. This is illustrated by an observation that our group could contribute to the discussion on the CHD risk equivalence of type 2 diabetes. We found that those patients with diabetes who also have significant baseline coronary artery disease are at an extremely high risk of cardiovascular events whereas diabetic patients without significant baseline coronary artery disease have a similarly benign prognosis as non-diabetic subjects without significant baseline coronary artery disease: moderate-risk diabetic patients without significant coronary artery disease and very high-risk diabetic patients with significant coronary artery disease add up to a grand total of high-risk diabetic patients, with the consequence that diabetes seems to be a CHD risk equivalent in many epidemiological studies. Finally, it should not be overlooked that the inability of a study to detect a difference between two groups of patients does not necessarily indicate that there in fact is no difference: absence of evidence is not evidence of absence in epidemiology, because statistical power inevitably is limited to a greater or lesser degree. Indeed, considering the issue of CHD equivalence of diabetes, some investigations concluding that diabetes is a CHD risk equivalent are quite obviously underpowered. With regard to cardiovascular risk estimation, it is both scientifically and clinically inadequate to pursue a one-size-fits-all strategy for patients with diabetes. If we nevertheless choose to do so, we find that the cardiovascular risk conferred by diabetes overall is not as high as that conferred by CHD—while in fact there are diabetic patients without clinically evident CHD whose cardiovascular event risk even exceeds the event risk of subjects with established stable coronary artery disease.

5. Clinical implications 5.1. Aspirin There are robust data supporting the use of aspirin to prevent cardiovascular events in patients who already have suffered cardiovascular events (Anon., 2013). Regarding diabetes as a CHD risk equivalent one therefore may argue for giving aspirin to patients with diabetes also when they are in primary prevention. However, data for aspirin are not very convincing in primary prevention, either among non-diabetic subjects or among patients with diabetes. A meta-analysis did find a moderate 12% event risk reduction with aspirin in primary prevention, which was of similar magnitude both among patients without diabetes and among patients with diabetes (Baigent et al., 2009). However, two trials explicitly aiming at demonstrating a beneficial effect of aspirin on cardiovascular event risk among patients with diabetes failed to conclude in this sense (Ogawa et al., 2008; Belch et al., 2008). From this background, the current American Diabetes Association (ADA) standards of medical care in diabetes communication (Anon., 2013) give a level of evidence C recommendation to consider aspirin therapy as a primary prevention strategy in patients with type 1 or type 2 diabetes who are at increased cardiovascular risk (10-year risk >10%), while it recommends against aspirin for cardiovascular disease prevention for adults with diabetes at low cardiovascular risk (10-year risk b 5%). Thus, with regard to aspirin therapy, current guidelines do not follow

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the inaccurate concept of diabetes as a CHD risk equivalent but pursue a more individualized approach. 5.2. Statins Lowering LDL cholesterol by statins reduces the relative risk of clinical cardiovascular events in patients with diabetes to about the same degree as in non-diabetic individuals (Kearney et al., 2008). Given the higher absolute cardiovascular risk of patients with diabetes, absolute risk reduction in patients with diabetes even exceeds that achieved in non-diabetic subjects. Therefore, the current guidelines on the management of dyslipidemia issued by the European Society of Cardiology/European Atherosclerosis Society allocate all patients with type 2 diabetes, as well as patients with type 1 diabetes who have target organ damage such as microalbuminuria, to the category of very high risk, and here call for a stringent LDL cholesterol goal of b70 mg/dL in such patients (Reiner et al., 2011). The current ADA recommendations (Anon., 2013) have not adopted the b70 mg/dL LDL cholesterol goal for all patients with type 2 diabetes, but do state that patients with diabetes who are aged 40 or older and have one or more other cardiovascular risk factors should take a statin irrespective of baseline lipid values. We feel that it is important to notice that the recommendation to provide patients with diabetes with statin therapy is not dependent on the assumption of CHD risk equivalence of patients with diabetes. First, there is firm direct clinical trial evidence that statins lower cardiovascular event rates significantly, and to a clinically important absolute degree in primary prevention patients with diabetes (Kearney et al., 2008) and even in primary prevention patients without diabetes who are at much lower risk (Mihaylova et al., 2012). Second, preventing the development of coronary artery disease in diabetic patients with statins has the potential to prevent them from entering the extremely high risk stratum of patients who suffer from both diabetes and coronary artery disease. 5.3. Screening for coronary artery disease in asymptomatic patients with diabetes The current ADA standards give a level of evidence A recommendation against screening for coronary artery disease in asymptomatic patients with diabetes, because routine screening for this does not improve outcomes as long as cardiovascular disease risk factors are treated (Anon., 2013). Also this recommendation eventually is based on clinical trial data and not on the concept of CHD risk equivalence of diabetes. 5.4. Psychological consequences The paradigm of diabetes as a CHD risk equivalent in its simplicity is false. Nevertheless, during the past 15 years it may have helped to focus academic and public interest on the cardiovascular risk of individuals affected by diabetes and may have improved risk management in these patients. However, this was at the cost of communicating patients with diabetes a worse prognosis than they actually have. Much psychological discomfort can be removed from patients with diabetes when we tell them the truth, which is that they do not suffer from a CHD risk equivalent. References Anon., 2001. Executive summary of the 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). JAMA 285, 2486–2497. Anon., 2013. Standards of medical care in diabetes—2013. Diabetes Care 36 (Suppl. 1), S11–S66. Baigent, C., Blackwell, L., Collins, R., et al., 2009. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373, 1849–1860.

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