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The role of diabetes in the pathogenesis of cardiovascular disease (CVD) was unclear until 1979 when Kannel et al used data from the Framingham Heart Study (FHS) to identify diabetes as a major cardiovascular risk factor. It was also one of the first studies to demonstrate the higher risk of CVD in women with diabetes compared to men with diabetes. Since then, multiple studies have been done to recognize and curtail cardiovascular risk factors such as smoking, obesity, hypertension, hyperlipidemia, and insulin resistance. This review will examine the contribution of the Kannel article and subsequent studies in defining the contribution of several risk factors on cardiovascular disease.
In 1949, it was noted that “the proper control of diabetes is obviously desirable even though there is uncertainty as to whether coronary atherosclerosis is more frequent or severe in the uncontrolled diabetic.”1 The role of diabetes in CVD had been uncertain until the prominent article published by Kannel et al in 1979 identified it as a major risk factor based on evidence from the FHS, the seminal prospective study of CVD and its determinants. This study provided an update to the FHS, utilizing data that had been collected for twenty years. The results, hence, changed the way healthcare providers thought about diabetes and paved the way for it’s establishment as a major cardiovascular risk factor. The Kannel article is briefly discussed here with its major implications and contributions to subsequent studies.
Kannel et al used a cohort of 13,861 men and 18,928 women of 45 to 74 years of age at the time of the study who had been followed biennially over a twenty year time period. At each biennial examination, participants diagnosed with the defined cardiovascular end-points were identified. The diagnosis of diabetes in this study was made based on either a history of treatment with oral hypoglycemic agents or insulin, or a random blood glucose level of greater than 150 on two separate occasions; participants with these characteristics and an abnormal glucose tolerance test were classified as having diabetes. Selection was performed at each biennial examination based on age, status of diabetes, and other characteristics of interest. At each subsequent biennial examination incidence of cardiovascular events was documented and the participants were then reclassified.
The authors looked at three variables to determine the effect of diabetes on the incidence of CVD: Absolute rate at which CVD develops; relative risk of developing CVD; and the attributable fraction, which is defined as the percent decrease in the incidence of disease that would occur if the risk factor was not present. Attributable fraction minimizes the effect of rare conditions and therefore identifies risk factors for a particular disease that, if curtailed, would be of significant importance to the population as a whole.
In the 20 years of follow-up there were 957 cases of CVD, which included 732 cases of coronary artery disease (CAD), 138 strokes, 179 intermittent claudication (IC), and 219 cases of congestive heart failure (CHF). Looking at the results comprehensively, men had a higher incidence of CVD than women. Furthermore, comparing the various risk factors, diabetes and Left Ventricular Hypertrophy (LVH) based on EKG abnormalities were the least prevalent risk factors when compared to smoking and hypertension.
Diabetes was then individually examined as a risk factor for CVD. First, the relative risk of CVD was examined for those with and without diabetes. Diabetes seemed to double the risk of total CVD in men, and triple it in women (Figure 1). Furthermore, after age-adjustment relative risks were higher for women than for men for every end-point that the authors had considered in the study (CHF, IC, Stroke, CHD, CVD, and CVD deaths) (Figure 1). More significantly, the risk of CHF and of CVD death was doubled for men and tripled for women with diabetes even after adjustment (Figure 1).2
When comparing gender differences, the incidence was greater for men without diabetes as compared to women without diabetes for every end-point considered. However, women with diabetes had a higher incidence than men without diabetes, and for CHF and Stroke women with diabetes had a higher incidence than men with diabetes.2
Multiple studies have followed the original Kannel publication in 1979 to better define the role of diabetes as a risk factor in cardiovascular disease. Re-examination of the contribution of diabetes is especially important since the definition of diabetes has changed since publication of the original study, and the prevalence of diabetes has increased dramatically.3 Fox et al. in 2006 showed that the incidence of diabetes has also almost doubled between 1970 and 1990.4 Furthermore, even though there has been a 50% reduction in the rate of CVD among participants with diabetes from the FHS, the relative risk of diabetes as a risk factor for CVD has been unchanged.5
Additionally, since the Kannel article other studies have also looked at how the attributable risk (AR) has changed overtime for diabetes and CVD. The AR for diabetes as a risk factor for CVD has increased from 5.4% between 1952 and 1974, to 8.7% between 1975 and 1998.6 The importance of this finding is highlighted when other factors are observed as well; the AR for other factors has either decreased or remained stable (Figure 2).6
Examination of these findings underscores the large contribution of diabetes to CVD. Utilizing data from the FHS, Preis et al examined 4195 participants at 50 years of age and 3495 participants at 60 years of age from 1970 to 2005. Participants with diabetes, as compared to those without diabetes, had a greater increase in BMI, a larger decrease in LDL, and a decline in their systolic blood pressure.7 However, only 14% of participants with diabetes from the FHS had their hypertension optimally controlled and 23.1% had LDL within goal-range for those with diabetes.7 These findings highlight the fact that improvements in risk-factor control for CVD that have occurred in the last three decades are measureable but not sufficient to meet the goals set for participants with diabetes, therefore leading to a persistently elevated CVD-risk in this population.
Diabetes duration was also suggested as an important factor in assessing risk for CVD. In 2004 Fox et al looked at the effect that the duration of diabetes had on CVD by using data from the original FHS cohort as well as their offspring. The results showed that after adjusting for age, CAD risk factors, and sex for every 10 years of diabetes the risk of CAD event was 1.38 times higher and the risk of CAD-related death was 1.86 times higher. This study was important as it showed that CAD and CAD-related deaths are directly related to the duration of diabetes.8 This study has important implications for primary prevention of diabetes mellitus to delay or stop it’s onset and in effect decrease CAD and CAD-related deaths.
There have been multiple studies looking at the effect of diabetes on cardiovascular mortality since the Kannel study, which was able to show an increase in mortality from CVD in participants with diabetes compared to those without diabetes. With more emphasis on preventive medicine and better understanding of treatment of diabetes, there has been a decline in cardiovascular mortality in patients with diabetes over the last few decades.9 However, diabetes continues to be a strong risk factor for CVD and with a four-fold increase in mortality.6, 10 Fox et al were able to show in 2004 that there has been a decrease in the rate of CVD both among those with and without diabetes,5 and multiple other studies have shown decreased mortality rates in both sub-groups as well.11, 12 Upon further exploration, the NHANES study found that this decrease in mortality is mostly for males, and does not apply to females; there was, in fact, an increase in mortality in females with diabetes.10 All of these studies presented conflicting evidence about changes in cardiovascular mortality, especially among the fraction of the population with diabetes.
Preis et al were able to utilize data from the FHS from 1950 to 2005 to look at trends in all-cause and CVD mortality in both men and women with and without diabetes. In contrast to the NHANES study, this study showed a decline in all-cause and CVD mortality in both men and women with diabetes. It also showed that men and women with diabetes continued to be at higher risk of CVD and all-cause mortality than those without diabetes.7 These findings have been supported and replicated in other studies as well, showing a decrease in CVD mortality in men and women with diabetes (Figure 3)12, 7.
In 1998 Haffner et al were able to show that diabetic patients without a prior myocardial infarction (MI) were at a similar risk of developing MI as those patients without diabetes and a history of MI.13 Furthermore, in 2005 Whiteley et al were able to show that middle-aged men and women with diabetes but no CAD were at a lifetime vascular risk as high as individuals with CAD but no diabetes.14 However, one of the most important studies identifying diabetes as a CAD risk-equivalent was conducted by Schramm et al in 3.3 million Danish residents, which showed that patients with diabetes had a CVD risk comparable to those individuals without diabetes.15 All of these studies highlighted the notion that diabetes should be considered a CAD risk-equivalent.
The Framingham Offspring studies (FOS) have also provided further insight into insulin resistance as well as diabetes as CVD risk factors. In 2002 Meigs et al examined 3370 subjects from the Framingham Offspring Cohort and found post-challenge hyperglycemia as an independent risk factor for CVD.16 This is especially important since fasting hyperglycemia has largely replaced post-challenge hyperglycemia for diagnosing diabetes17 and several studies have shown that fasting hyperglycemia overlooks a significant number of people at risk for CVD who are identified using post-challenge hyperglycemia.18, 19
Additionally, other FOS have used data to identify surrogate markers for CVD in diabetics. Meigs et al found that participants with diabetes had more coronary artery calcification than those without diabetes, indicating a higher burden of subclinical CVD not detected by conventional testing.20 Similarly, other studies have shown that elevated levels of C-Reactive Protein21 and Homocysteine16 are both associated with insulin resistance and an increased risk of CVD.
Other studies conducted throughout the world built on the foundation created by the FHS. The Inter-Heart Study collected data from 52 countries and found diabetes, abdominal obesity, and hypertension to be strong risk factors for CAD after smoking and abnormal lipids.22 Similarly, Stengard et al were able to show in the Finnish cohort of the Seven Countries Study the role of diabetes in CAD.23 Hence, the Framingham Heart Study set a precedence for well-designed longitudinal studies around the world that helped our understanding about the role of diabetes in CVD.
Studying global trends in diabetes, Whiting et al were able to show that the highest diabetes prevalence for 2011 was for Middle East and North Africa; however, the largest increase in adult diabetes by 2030 would be for African nations. Furthermore, even though China and India already have the highest number of people aged 20–79 with diabetes (90 and 61.3 million people respectively), 48% of the predicted increase of 186 million in people with diabetes from 2011 to 2030 would be in these two populous nations.24 Due to the increased risk of CVD in patients with diabetes as seen in the FHS and other subsequent studies, these statistics present a difficult challenge to healthcare and an enormous public health dilemma that needs to be more closely monitored and intercepted.
Since the Kannel article many studies have replicated the increased risk of CAD and CAD-mortality in women with diabetes compared to men with diabetes.25, 26 The Strong Heart Study showed a larger impact of diabetes on CV risk factors in women, but the reason for an increased risk in women is still not completely understood.27 While these studies have replicated most of the findings from the Kannel article, our understanding of pathogenesis of CVD due to diabetes has improved significantly, with hyperinsulinemia, insulin resistance28 and hypercoagulability29 playing a role in the excess CVD-risk in patients with diabetes.
Since the inception of the FHS, researchers have tried to devise a score that would help predict the risk of developing CAD based on risk factors. Truett et al were the first to utilize data from the FHS to develop a risk score for men and women based on seven risk factors: age, systolic blood pressure, relative weight, hemoglobin, cigarette smoking, and EKG evidence of LVH.30 Over time, hemoglobin and LVH were removed31 glucose intolerance was added, and the AHA published a book of risk tables in 1973.32 Eventually, in the 1991 a point scoring system was developed to help clinicians risk-stratify patients33 and in 2008 a tool was developed for primary care physicians.52 Data from the Framingham Heart Study, therefore, were crucial in devising the Framingham Risk Score to determine the 10-year risk of developing CAD.34
Even though our understanding of the pathogenesis of CVD in patients with diabetes has improved, the incidence and prevalence of diabetes has increased significantly as well. Shaw et al showed that the burden of diabetes will increase significantly from 2010 to 2030, with a 69% increase in adult diabetes in developing countries, and a 20% increase in developed countries; the associated population increase is expected to be 36% and 2% respectively.35 Based on these figures, the diabetes burden will lead to increasing morbidity, mortality, stress on healthcare providers, and healthcare-associated costs. A joint statement by the American Heart Association and American Diabetes Association in 2007 said that a multi-faceted approach including risk factor control as well as aggressive life-style changes must be employed to prevent the development of diabetes and its complications, most importantly CVD.36 Using the available data, more individualized plans of action with multifactorial interventions need to be devised to reduce the incidence of CVD as well as CVD-related mortality in patients with diabetes.
The Kannel study was one of the first ones to describe diabetes mellitus as a significant risk factor for cardiovascular disease, especially among women. Multiple studies have subsequently examined the role of diabetes as well as other coexisting risk factors and comorbidities that increase the risk of CVD. Current guidelines address target levels of coexisting risk factors in those with diabetes. However, recent studies suggest that there may be different levels of recommended glycemic controls depending on either the duration of diabetes or comorbidities such as existing CVD. Non-invasive screening techniques such as coronary artery calcium score are also being increasingly utilized in clinical practice to risk stratify individuals who need more expensive and invasive screening modalities. The Kannel article was seminal in identifying an important risk factor for cardiovascular disease, and the findings have been paramount in guiding research that followed. Future research needs to be done to look at surrogate markers for CVD and to see how successful individualization of treatment protocols is in preventing CVD.
Conflict of Interest: None
Financial Disclosures: None
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