Curr Cardiol Rep (2015) 17:54 DOI 10.1007/s11886-015-0607-7
DIABETES AND CARDIOVASCULAR DISEASE (S MALIK, SECTION EDITOR)
Predicting Cardiovascular Risk in Type 2 Diabetes: the Heterogeneity Challenges M. Odette Gore 1 & Darren K. McGuire 1 & Ildiko Lingvay 2 & Julio Rosenstock 3
# Springer Science+Business Media New York 2015
Abstract Type 2 diabetes mellitus has reached epidemic proportions around the world, and the increase in cardiovascular risk attributable to diabetes estimated to range from 2- to 4-fold poses grave public health concern. Though in some contexts type 2 diabetes has been equated with coronary heart disease equivalent risk, there is considerable evidence that incremental cardiovascular risk does not uniformly affect all people with type 2 diabetes. This heterogeneity in cardiovascular risk is multifactorial and only partially understood but is a key consideration for our understanding of the nexus of diabetes and cardiovascular disease and for the development of optimal and individualized cardiovascular risk reduction strategies. This review provides a brief synopsis of the concept of cardiovascular risk heterogeneity in diabetes, including epidemiologic evidence, discussion of established and potential determinants of heterogeneity, and clinical, research, and regulatory implications.
This article is part of the Topical Collection on Diabetes and Cardiovascular Disease
Keywords Cardiovascular disease . Diabetes mellitus . Cardiovascular risk factors . Macrovascular complications
Introduction More than 29 million people in the USA have diabetes mellitus, either diagnosed or undiagnosed, representing 9.3 % of the entire US population [1]. Worldwide, diabetes affects an estimated 347 million individuals [2]. This represents more than double the global prevalence estimate of 171 million for the year 2000, an increase almost entirely attributable to the growing pandemic of type 2 diabetes (T2DM) and obesity [3]. In turn, T2DM is a major independent risk factor for cardiovascular disease (CVD), including coronary heart disease (CHD) [4], heart failure [5], and stroke [6]. Although in the last two decades rates of diabetes-related acute myocardial infarction (MI) and stroke have been reduced in the US by 68 and 53 %, respectively, presumably due to better blood pressure and lipid interventions and perhaps better glucose control, still significant residual CV risk remains [7•]. Estimates of cardiovascular (CV) risk range from 2-fold to 4-fold in subjects with vs. without T2DM, but there is considerable and mounting evidence that incremental CV risk is not uniformly distributed among people with T2DM.
* M. Odette Gore [email protected] 1
Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
2
Department of Clinical Sciences and Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX, USA
3
Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA
Factors Contributing to Heterogeneity of CV Risk in T2DM A little more than a decade ago, the National Cholesterol Education Program (NCEP) Expert Panel recommended that T2DM be managed as a Bcoronary heart disease risk equivalent^ for the purpose of LDL cholesterol control [8, 9]. This concept was based in part on results from the Finnish
54
Curr Cardiol Rep (2015) 17:54
Page 2 of 9
population-based East–West study comparing 1059 adult individuals with T2DM and 1373 subjects without diabetes, with the 7-year incidence of myocardial infarction (MI) in those with diabetes and no prior MI similar to the incidence of recurrent MI in participants without diabetes (20.2 vs. 18.8 %) [10]. This was confirmed by some [11, 12] but not all subsequent studies, with data from major clinical trials (discussed later in this review) suggesting that 10-year CV risk in selected cohorts of T2DM varies between 8 and 20 % even when enriched for CV risk by trial eligibility criteria, compared with the Bcoronary disease equivalent^ risk that is typically greater than 20 % [13–19]. Such apparent discrepancies between studies are at least in part attributable to differences in population characteristics, with considerable heterogeneity in CV risk among subjects with T2DM. Multiple factors can theoretically contribute to this heterogeneity in CV risk, including sociodemographics (sex, age, race/ethnicity, socioeconomic status, health care access), genetic factors, concomitant CV risk factors and comorbidities (hypertension, dyslipidemia, obesity, physical inactivity, smoking, and others), possible diabetes-specific factors (T2DM duration, degree of glucose control, type of antihyperglycemic therapy), and the increasingly penetrant treatment with evidence-based CV risk modifying therapies such as statins, blood pressure control, and antiplatelet therapy. Many of these factors (discussed below) are highly intertwined, with assessment of their independent contribution to CV risk variability either missing or relying on imperfect statistical adjustment.
Sociodemographics Sociodemographic factors associated with CV risk heterogeneity in T2DM include sex, age, race/ethnicity, health care access, and socioeconomic status. Sex A recent meta-analysis of 64 cohorts including over 850,000 individuals (>36,000 with diabetes) and more than 28,000 coronary events reported a 44 % greater relative risk [relative risk ratio (RRR) 1.44 (95 % confidence interval (CI) 1.27, 1.63)] of incident CHD in women compared with men with diabetes, after adjustment for age and at least one other risk factor for each study [20]. A similar meta-analysis from the same authors also reported a less but still greater relative risk [RRR 1.27 (95 % CI 1.10, 1.46)] of stroke in women vs. men with diabetes [21]. These findings are compatible with prior studies that found greater CVD incidence among women with diabetes [4, 22, 23]. However, a smaller meta-analysis with more rigorous adjustment for classic CV risk factors (including age, hypertension, hypercholesterolemia, and smoking)
found that sex differences in CV risk were no longer significant after adjustment [24]. This apparent discrepancy could be attributable at least in part to variable inclusion of older postmenopausal women, who have a higher prevalence of CV risk factors irrespective of their diabetes status. When analyses were restricted to participants younger than 60 in a recent study of three large US cohorts, nondiabetic women had significantly lower risk of CHD compared with nondiabetic men, but CHD risk was equivalent in both sexes in the presence of T2DM, even after extensive adjustment [25•]. Similar results were reported by a retrospective analysis of a population-wide registry in Ontario, Canada, with diabetes narrowing the gap in CV risk between the sexes [26]. It is possible that relative CV risk is higher in women with diabetes because of persisting sex disparities in the treatment and control of CV risk factors, with women less likely to have their blood pressure and LDL cholesterol controlled in a number of US and European cohorts [27–30]. However, sex differences in disease pathophysiology, including altered hormonal profiles, inflammatory factors, and adipose tissue distribution, could also play a role. Age Older age is a significant risk factor for CVD, irrespective of diabetes status, but the presence of diabetes has been suggested to confer a risk equivalent to ageing of approximately 15 years [26]. In most studies, the independent association between patient age and diabetes complications is confounded by diabetes duration (discussed separately in this review). To eliminate this confounding variable, a population-based study enrolled 7844 subjects with newly diagnosed T2DM and established membership ≥1 year in a US prepaid health plan [31]. Although absolute risk of CVD in T2DM was much lower in young adults (18–44 years) compared with middleaged and older adults (≥45 years), young adults had a 14-fold increased risk of MI vs. age- and sex-matched control subjects [hazard ratio (HR) 14.0 (95 % CI 6.2–31.4)], compared with a 3.7-fold increased risk of MI [HR 3.7 (95 % CI 3.2–4.2)] conferred by T2DM in middle-aged and older individuals [31]. It should be noted however that given the retrospective design of this study, the criterion of prior health plan membership for ≥1 year does not guarantee exclusive inclusion of subjects with true incident T2DM rather than subjects with previously undiagnosed T2DM of unknown duration. Race/Ethnicity Among 62,432 individuals with T2DM enrolled in a US prepaid health plan, and thus less susceptible to confounding by factors such as health care access and utilization, the multivariable-adjusted risk of MI was lower in minorities compared with white Americans [adjusted HR 0.56 for
Curr Cardiol Rep (2015) 17:54
African Americans, 0.68 for Asians, and 0.68 for Hispanics], and the adjusted risk of stroke and chronic heart failure (CHF) was lower in Asians and Hispanics compared with whites (HR 0.76 and 0.72, respectively, for stroke; 0.70 and 0.61, respectively, for CHF) [32]. A subsequent analysis from the same population showed that Pacific Islanders had significantly higher adjusted risk (HR 1.29) of MI compared with whites but no difference in the risk of stroke of CHF [33]. In addition, when the data were disaggregated by Asian subgroups, the adjusted risk of MI remained lower in Chinese, Filipino, and Japanese Americans compared with whites but was not different between whites and South Asians [33]. Largely similar findings were reported by the UK Prospective Diabetes Study, with lower risk of MI in UK Afro-Caribbean subjects vs. whites with T2DM but no difference between whites and South Asians [34]. Importantly, ethnic differences in CV risk in people with diabetes persist even after adjustment for traditional CV risk factors [32–34, 35•]. Health Care Access and Socioeconomic Status People without health insurance, a key determinant of health care access, are more likely to have undiagnosed and untreated diabetes [36], which is commonly associated with higher CV risk. Even after adjustment for health care access and demographic factors, data from National Health Interview Surveys 1997–2003 with mortality follow-up through 2006 suggested that lower education and lower financial wealth remain associated with higher mortality among adults with T2DM [37]. These findings appear to be consistent across health care systems. For example, in the UK, despite universal health care with minimal out-of-pocket costs for patients, those with T2DM living in areas of lower socioeconomic status are at increased risk for CVD, associated with increased prevalence and clustering of CV risk factors in such populations such as smoking, physical inactivity, obesity, and poor nutrition [38].
Genetic Factors Genome-wide association studies (GWAS) and other largescale genotyping studies have started to uncover gene variants that could partly explain the heritability and inter-individual variation in disease risk for both CHD [39] and T2DM [40]. However, the extent to which genetic factors underlie the heterogeneity of CV risk specifically in people with T2DM, or in other words whether there is an interaction between genetic factors and diabetes status for CV risk, is presently unknown. One example of such interaction may be related to haptoglobin gene type, which was more predictive of CVD in participants with vs. without diabetes in the Strong Heart Study of Native Americans [41]. However, more recent studies in other
Page 3 of 9 54
cohorts yielded contradictory results [42, 43], possibly attributable to the low number of events analyzed. Whether haptoglobin genotype is a true predictor of CV risk in T2DM remains an open question, only answerable by larger studies. Another potential genetic determinant of CV risk in diabetes could be the cosegregation of gene variants located in physical proximity on the same chromosome. For example, at least two single nucleotide polymorphisms (SNPs) that were separately associated with susceptibility to CHD and T2DM respectively, with findings replicated in four European populations, have been mapped in close proximity in a nonprotein coding region of chromosome 9p [44]. This same region was recently studied in over 7000 participants in the Framingham Heart Study and found to be associated with increased risk for MI and markers of subclinical CVD (coronary artery calcium and abdominal aorta diameter), in the absence of association with traditional CV risk factors [45]. However, the potential pathophysiological implications of these findings are unclear, and the same region on chromosome 9p appears to be a GWAS Bhot spot^, also associated with some cancers and with the risk of intracranial aneurysms [46]. How genes influence the course of T2DM and its complications remains a critical and largely unanswered question, but one for which the future holds great promise. In addition, novel interactions between T2DM and CV risk could theoretically be uncovered in the future by advances in epigenetics [47].
Concomitant CV Risk Factors and Comorbidities Traditional major CV risk factors, including hypertension, hypercholesterolemia, and smoking, remain independently associated with CVD in people with diabetes [48], and CV risk heterogeneity in T2DM is in part attributable to variability in the prevalence, treatment, and control of these risk factors. In addition, predisposing risk factors such as increased adiposity and body fat distribution, physical inactivity, and poor diet may modulate CV risk in part through overlapping effects on hypertension, dyslipidemia, and diabetes itself and possibly via other mechanisms. Finally, comorbidities especially kidney disease that doubles the already increased CV risk [49] but also sleep disorders [50], depression [51], and even cancers treated with potentially cardiotoxic drugs [52] may compound CV risk of diabetes.
Diabetes-Specific Factors Potential determinants of CV risk heterogeneity that are specific to T2DM include diabetes duration, degree of glucose control, and type of antihyperglycemic drug(s) used.
54
Page 4 of 9
Diabetes Duration Compounding the well-established age-related increase in CV risk, longer diabetes duration appears to be associated with adverse CV outcomes independent of patient age. For example, in a recent study of 72,310 older adults with T2DM stratified by age group (60–69, 70–79, and ≥80 years) and duration of diabetes (short 0–9 years vs. long≥10 years), the sex- and race-adjusted incidence of CV complications increased markedly with longer diabetes duration within each age stratum [53•]. In the Framingham Heart Study, where incident diabetes was assessed every 2–4 years and therefore diabetes duration could be accurately assessed, it was estimated that after adjusting for age, sex, and CHD risk factors, every 10 years of diabetes increased the risk of CVD by 38 % and the risk of CHD death by 86 % [54].
Degree of Glucose Control The influence of glucose control on CV risk and outcomes remains unclear. The United Kingdom Prospective Diabetes Study (UKPDS) comprising a patient population with newly diagnosed T2DM at study entry randomized to a diet policy vs. active policy consisting of insulin, sulfonylurea (chlorpropamide or glibenclamide—a.k.a. glyburide in the USA), and eventually metformin demonstrated the value of improved glucose control on reducing microvascular complications but only tended to favorably affect CVoutcomes [55, 56]. Though beneficial effects on CV outcomes with insulin or sulfonylureas did not achieve statistical differences during the trial, the event curves continued to diverge during long-term post-trial passive follow-up [16]. After a median of 17 years of total observation, in what was called the Blegacy effect,^ the group treated for a median of 10 years on trial protocol in the more vs. less intensive glycemic control groups, achieving initially a median on-study HbA1c of 7.0 vs. 7.9 % that subsequently converged in 8 % range, had statistically lower risk for death (26.8 vs. 30.3 %; P=0.007) and for MI (16.8 vs. 19.6 %; P= 0.01). In the group of patients overweight or obese at study entry and eligible for randomization to metformin in the intensive treatment arm, though just achieving an HbA1c contrast of 0.4 % (7.5 vs. 7.1 %) during the trial, metformin was associated with statistically lower risk for MI (11.4 vs. 17.8 %; P=0.01) and for coronary death (4.7 vs. 8.8 %; P=0.02)[55]. However, the validity of such findings remains uncertain in view of the relatively low number of subjects on metformin (n=342) and low number of events. In the wake of UKPDS, recent CV outcome trials testing the impact of glucose control or the multiple regulatoryrequired CV safety trials testing new diabetes drugs have shed some light on the multiple risk factors that drive CV event rates in people with T2DM
Curr Cardiol Rep (2015) 17:54
Three key clinical trials—ADVANCE [13], ACCORD [14], and VADT [15] (Table 1), each designed to specifically assess the CVeffects of more vs. less intensive glucose control with specific HbA1c targets for each randomized group, all failed to demonstrate incremental CV benefits of intensive glucose control. Each of these three trials were designed based on the epidemiologic analyses and the long-term legacy effect showing associations between HbA1c and CV risk observed in UKPDS [57], with the assumption that robust pharmacologic reductions of HbA1c along the observed continuum of CV risk, linearly associated with HbA1c, would result in commensurate CV risk reduction. However, as summarized in Table 1, none of the three trials achieved statistical difference in their primary outcomes of major adverse CV events between the two groups, despite absolute delta HbA1c reductions achieved between groups in the 0.8–1.5 % range. Furthermore, the ACCORD study was prematurely stopped in view of the unexpected increased overall and CV mortality in the intensive group. The explanation for such unfortunate finding remains unknown, and multiple analyses have excluded hypoglycemia or any specific use of antidiabetic agents. The key finding of major clinical relevance was that increased mortality occurred mainly in those intensively treated subjects who failed to achieve HbA1c
DIABETES AND CARDIOVASCULAR DISEASE (S MALIK, SECTION EDITOR)
Predicting Cardiovascular Risk in Type 2 Diabetes: the Heterogeneity Challenges M. Odette Gore 1 & Darren K. McGuire 1 & Ildiko Lingvay 2 & Julio Rosenstock 3
# Springer Science+Business Media New York 2015
Abstract Type 2 diabetes mellitus has reached epidemic proportions around the world, and the increase in cardiovascular risk attributable to diabetes estimated to range from 2- to 4-fold poses grave public health concern. Though in some contexts type 2 diabetes has been equated with coronary heart disease equivalent risk, there is considerable evidence that incremental cardiovascular risk does not uniformly affect all people with type 2 diabetes. This heterogeneity in cardiovascular risk is multifactorial and only partially understood but is a key consideration for our understanding of the nexus of diabetes and cardiovascular disease and for the development of optimal and individualized cardiovascular risk reduction strategies. This review provides a brief synopsis of the concept of cardiovascular risk heterogeneity in diabetes, including epidemiologic evidence, discussion of established and potential determinants of heterogeneity, and clinical, research, and regulatory implications.
This article is part of the Topical Collection on Diabetes and Cardiovascular Disease
Keywords Cardiovascular disease . Diabetes mellitus . Cardiovascular risk factors . Macrovascular complications
Introduction More than 29 million people in the USA have diabetes mellitus, either diagnosed or undiagnosed, representing 9.3 % of the entire US population [1]. Worldwide, diabetes affects an estimated 347 million individuals [2]. This represents more than double the global prevalence estimate of 171 million for the year 2000, an increase almost entirely attributable to the growing pandemic of type 2 diabetes (T2DM) and obesity [3]. In turn, T2DM is a major independent risk factor for cardiovascular disease (CVD), including coronary heart disease (CHD) [4], heart failure [5], and stroke [6]. Although in the last two decades rates of diabetes-related acute myocardial infarction (MI) and stroke have been reduced in the US by 68 and 53 %, respectively, presumably due to better blood pressure and lipid interventions and perhaps better glucose control, still significant residual CV risk remains [7•]. Estimates of cardiovascular (CV) risk range from 2-fold to 4-fold in subjects with vs. without T2DM, but there is considerable and mounting evidence that incremental CV risk is not uniformly distributed among people with T2DM.
* M. Odette Gore [email protected] 1
Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
2
Department of Clinical Sciences and Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX, USA
3
Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA
Factors Contributing to Heterogeneity of CV Risk in T2DM A little more than a decade ago, the National Cholesterol Education Program (NCEP) Expert Panel recommended that T2DM be managed as a Bcoronary heart disease risk equivalent^ for the purpose of LDL cholesterol control [8, 9]. This concept was based in part on results from the Finnish
54
Curr Cardiol Rep (2015) 17:54
Page 2 of 9
population-based East–West study comparing 1059 adult individuals with T2DM and 1373 subjects without diabetes, with the 7-year incidence of myocardial infarction (MI) in those with diabetes and no prior MI similar to the incidence of recurrent MI in participants without diabetes (20.2 vs. 18.8 %) [10]. This was confirmed by some [11, 12] but not all subsequent studies, with data from major clinical trials (discussed later in this review) suggesting that 10-year CV risk in selected cohorts of T2DM varies between 8 and 20 % even when enriched for CV risk by trial eligibility criteria, compared with the Bcoronary disease equivalent^ risk that is typically greater than 20 % [13–19]. Such apparent discrepancies between studies are at least in part attributable to differences in population characteristics, with considerable heterogeneity in CV risk among subjects with T2DM. Multiple factors can theoretically contribute to this heterogeneity in CV risk, including sociodemographics (sex, age, race/ethnicity, socioeconomic status, health care access), genetic factors, concomitant CV risk factors and comorbidities (hypertension, dyslipidemia, obesity, physical inactivity, smoking, and others), possible diabetes-specific factors (T2DM duration, degree of glucose control, type of antihyperglycemic therapy), and the increasingly penetrant treatment with evidence-based CV risk modifying therapies such as statins, blood pressure control, and antiplatelet therapy. Many of these factors (discussed below) are highly intertwined, with assessment of their independent contribution to CV risk variability either missing or relying on imperfect statistical adjustment.
Sociodemographics Sociodemographic factors associated with CV risk heterogeneity in T2DM include sex, age, race/ethnicity, health care access, and socioeconomic status. Sex A recent meta-analysis of 64 cohorts including over 850,000 individuals (>36,000 with diabetes) and more than 28,000 coronary events reported a 44 % greater relative risk [relative risk ratio (RRR) 1.44 (95 % confidence interval (CI) 1.27, 1.63)] of incident CHD in women compared with men with diabetes, after adjustment for age and at least one other risk factor for each study [20]. A similar meta-analysis from the same authors also reported a less but still greater relative risk [RRR 1.27 (95 % CI 1.10, 1.46)] of stroke in women vs. men with diabetes [21]. These findings are compatible with prior studies that found greater CVD incidence among women with diabetes [4, 22, 23]. However, a smaller meta-analysis with more rigorous adjustment for classic CV risk factors (including age, hypertension, hypercholesterolemia, and smoking)
found that sex differences in CV risk were no longer significant after adjustment [24]. This apparent discrepancy could be attributable at least in part to variable inclusion of older postmenopausal women, who have a higher prevalence of CV risk factors irrespective of their diabetes status. When analyses were restricted to participants younger than 60 in a recent study of three large US cohorts, nondiabetic women had significantly lower risk of CHD compared with nondiabetic men, but CHD risk was equivalent in both sexes in the presence of T2DM, even after extensive adjustment [25•]. Similar results were reported by a retrospective analysis of a population-wide registry in Ontario, Canada, with diabetes narrowing the gap in CV risk between the sexes [26]. It is possible that relative CV risk is higher in women with diabetes because of persisting sex disparities in the treatment and control of CV risk factors, with women less likely to have their blood pressure and LDL cholesterol controlled in a number of US and European cohorts [27–30]. However, sex differences in disease pathophysiology, including altered hormonal profiles, inflammatory factors, and adipose tissue distribution, could also play a role. Age Older age is a significant risk factor for CVD, irrespective of diabetes status, but the presence of diabetes has been suggested to confer a risk equivalent to ageing of approximately 15 years [26]. In most studies, the independent association between patient age and diabetes complications is confounded by diabetes duration (discussed separately in this review). To eliminate this confounding variable, a population-based study enrolled 7844 subjects with newly diagnosed T2DM and established membership ≥1 year in a US prepaid health plan [31]. Although absolute risk of CVD in T2DM was much lower in young adults (18–44 years) compared with middleaged and older adults (≥45 years), young adults had a 14-fold increased risk of MI vs. age- and sex-matched control subjects [hazard ratio (HR) 14.0 (95 % CI 6.2–31.4)], compared with a 3.7-fold increased risk of MI [HR 3.7 (95 % CI 3.2–4.2)] conferred by T2DM in middle-aged and older individuals [31]. It should be noted however that given the retrospective design of this study, the criterion of prior health plan membership for ≥1 year does not guarantee exclusive inclusion of subjects with true incident T2DM rather than subjects with previously undiagnosed T2DM of unknown duration. Race/Ethnicity Among 62,432 individuals with T2DM enrolled in a US prepaid health plan, and thus less susceptible to confounding by factors such as health care access and utilization, the multivariable-adjusted risk of MI was lower in minorities compared with white Americans [adjusted HR 0.56 for
Curr Cardiol Rep (2015) 17:54
African Americans, 0.68 for Asians, and 0.68 for Hispanics], and the adjusted risk of stroke and chronic heart failure (CHF) was lower in Asians and Hispanics compared with whites (HR 0.76 and 0.72, respectively, for stroke; 0.70 and 0.61, respectively, for CHF) [32]. A subsequent analysis from the same population showed that Pacific Islanders had significantly higher adjusted risk (HR 1.29) of MI compared with whites but no difference in the risk of stroke of CHF [33]. In addition, when the data were disaggregated by Asian subgroups, the adjusted risk of MI remained lower in Chinese, Filipino, and Japanese Americans compared with whites but was not different between whites and South Asians [33]. Largely similar findings were reported by the UK Prospective Diabetes Study, with lower risk of MI in UK Afro-Caribbean subjects vs. whites with T2DM but no difference between whites and South Asians [34]. Importantly, ethnic differences in CV risk in people with diabetes persist even after adjustment for traditional CV risk factors [32–34, 35•]. Health Care Access and Socioeconomic Status People without health insurance, a key determinant of health care access, are more likely to have undiagnosed and untreated diabetes [36], which is commonly associated with higher CV risk. Even after adjustment for health care access and demographic factors, data from National Health Interview Surveys 1997–2003 with mortality follow-up through 2006 suggested that lower education and lower financial wealth remain associated with higher mortality among adults with T2DM [37]. These findings appear to be consistent across health care systems. For example, in the UK, despite universal health care with minimal out-of-pocket costs for patients, those with T2DM living in areas of lower socioeconomic status are at increased risk for CVD, associated with increased prevalence and clustering of CV risk factors in such populations such as smoking, physical inactivity, obesity, and poor nutrition [38].
Genetic Factors Genome-wide association studies (GWAS) and other largescale genotyping studies have started to uncover gene variants that could partly explain the heritability and inter-individual variation in disease risk for both CHD [39] and T2DM [40]. However, the extent to which genetic factors underlie the heterogeneity of CV risk specifically in people with T2DM, or in other words whether there is an interaction between genetic factors and diabetes status for CV risk, is presently unknown. One example of such interaction may be related to haptoglobin gene type, which was more predictive of CVD in participants with vs. without diabetes in the Strong Heart Study of Native Americans [41]. However, more recent studies in other
Page 3 of 9 54
cohorts yielded contradictory results [42, 43], possibly attributable to the low number of events analyzed. Whether haptoglobin genotype is a true predictor of CV risk in T2DM remains an open question, only answerable by larger studies. Another potential genetic determinant of CV risk in diabetes could be the cosegregation of gene variants located in physical proximity on the same chromosome. For example, at least two single nucleotide polymorphisms (SNPs) that were separately associated with susceptibility to CHD and T2DM respectively, with findings replicated in four European populations, have been mapped in close proximity in a nonprotein coding region of chromosome 9p [44]. This same region was recently studied in over 7000 participants in the Framingham Heart Study and found to be associated with increased risk for MI and markers of subclinical CVD (coronary artery calcium and abdominal aorta diameter), in the absence of association with traditional CV risk factors [45]. However, the potential pathophysiological implications of these findings are unclear, and the same region on chromosome 9p appears to be a GWAS Bhot spot^, also associated with some cancers and with the risk of intracranial aneurysms [46]. How genes influence the course of T2DM and its complications remains a critical and largely unanswered question, but one for which the future holds great promise. In addition, novel interactions between T2DM and CV risk could theoretically be uncovered in the future by advances in epigenetics [47].
Concomitant CV Risk Factors and Comorbidities Traditional major CV risk factors, including hypertension, hypercholesterolemia, and smoking, remain independently associated with CVD in people with diabetes [48], and CV risk heterogeneity in T2DM is in part attributable to variability in the prevalence, treatment, and control of these risk factors. In addition, predisposing risk factors such as increased adiposity and body fat distribution, physical inactivity, and poor diet may modulate CV risk in part through overlapping effects on hypertension, dyslipidemia, and diabetes itself and possibly via other mechanisms. Finally, comorbidities especially kidney disease that doubles the already increased CV risk [49] but also sleep disorders [50], depression [51], and even cancers treated with potentially cardiotoxic drugs [52] may compound CV risk of diabetes.
Diabetes-Specific Factors Potential determinants of CV risk heterogeneity that are specific to T2DM include diabetes duration, degree of glucose control, and type of antihyperglycemic drug(s) used.
54
Page 4 of 9
Diabetes Duration Compounding the well-established age-related increase in CV risk, longer diabetes duration appears to be associated with adverse CV outcomes independent of patient age. For example, in a recent study of 72,310 older adults with T2DM stratified by age group (60–69, 70–79, and ≥80 years) and duration of diabetes (short 0–9 years vs. long≥10 years), the sex- and race-adjusted incidence of CV complications increased markedly with longer diabetes duration within each age stratum [53•]. In the Framingham Heart Study, where incident diabetes was assessed every 2–4 years and therefore diabetes duration could be accurately assessed, it was estimated that after adjusting for age, sex, and CHD risk factors, every 10 years of diabetes increased the risk of CVD by 38 % and the risk of CHD death by 86 % [54].
Degree of Glucose Control The influence of glucose control on CV risk and outcomes remains unclear. The United Kingdom Prospective Diabetes Study (UKPDS) comprising a patient population with newly diagnosed T2DM at study entry randomized to a diet policy vs. active policy consisting of insulin, sulfonylurea (chlorpropamide or glibenclamide—a.k.a. glyburide in the USA), and eventually metformin demonstrated the value of improved glucose control on reducing microvascular complications but only tended to favorably affect CVoutcomes [55, 56]. Though beneficial effects on CV outcomes with insulin or sulfonylureas did not achieve statistical differences during the trial, the event curves continued to diverge during long-term post-trial passive follow-up [16]. After a median of 17 years of total observation, in what was called the Blegacy effect,^ the group treated for a median of 10 years on trial protocol in the more vs. less intensive glycemic control groups, achieving initially a median on-study HbA1c of 7.0 vs. 7.9 % that subsequently converged in 8 % range, had statistically lower risk for death (26.8 vs. 30.3 %; P=0.007) and for MI (16.8 vs. 19.6 %; P= 0.01). In the group of patients overweight or obese at study entry and eligible for randomization to metformin in the intensive treatment arm, though just achieving an HbA1c contrast of 0.4 % (7.5 vs. 7.1 %) during the trial, metformin was associated with statistically lower risk for MI (11.4 vs. 17.8 %; P=0.01) and for coronary death (4.7 vs. 8.8 %; P=0.02)[55]. However, the validity of such findings remains uncertain in view of the relatively low number of subjects on metformin (n=342) and low number of events. In the wake of UKPDS, recent CV outcome trials testing the impact of glucose control or the multiple regulatoryrequired CV safety trials testing new diabetes drugs have shed some light on the multiple risk factors that drive CV event rates in people with T2DM
Curr Cardiol Rep (2015) 17:54
Three key clinical trials—ADVANCE [13], ACCORD [14], and VADT [15] (Table 1), each designed to specifically assess the CVeffects of more vs. less intensive glucose control with specific HbA1c targets for each randomized group, all failed to demonstrate incremental CV benefits of intensive glucose control. Each of these three trials were designed based on the epidemiologic analyses and the long-term legacy effect showing associations between HbA1c and CV risk observed in UKPDS [57], with the assumption that robust pharmacologic reductions of HbA1c along the observed continuum of CV risk, linearly associated with HbA1c, would result in commensurate CV risk reduction. However, as summarized in Table 1, none of the three trials achieved statistical difference in their primary outcomes of major adverse CV events between the two groups, despite absolute delta HbA1c reductions achieved between groups in the 0.8–1.5 % range. Furthermore, the ACCORD study was prematurely stopped in view of the unexpected increased overall and CV mortality in the intensive group. The explanation for such unfortunate finding remains unknown, and multiple analyses have excluded hypoglycemia or any specific use of antidiabetic agents. The key finding of major clinical relevance was that increased mortality occurred mainly in those intensively treated subjects who failed to achieve HbA1c
