Diabetes and Coronary Artery Disease

Ranjit  Unnikrishnan; Viswanathan  Mohan

Diabetes and Coronary Artery DiseaseCHAPTER 1

Ranjit Unnikrishnan,

Viswanathan Mohan

INTRODUCTION

Cardiovascular disease (CVD) is the leading cause of mortality in all continents across the world except Africa.¹ Coronary artery disease (CAD) accounts for more than two-thirds of the mortality attributable to CVD. It is estimated that CAD was responsible for more than 8 million deaths worldwide as of 2013.² CAD is multifactorial in origin, with some of the risk factors being nonmodifiable (age, sex, ethnicity, etc.), whereas others can be modified by means of lifestyle changes with or without pharmacotherapy (hyperglycemia, hypertension, dyslipidemia, tobacco use, stress).³ Type 2 diabetes mellitus (T2DM) shares a unique relationship with CVD; not only is hyperglycemia a risk factor for CVD per se, but people with diabetes are also more likely to have other risk factors such as hypertension and dyslipidemia, with a multiplicative effect on their overall risk of CVD. In fact, it has been suggested that an individual with diabetes has an equivalent age and sex-adjusted mortality risk to an individual without diabetes who has already suffered from a prior event.⁴ In other words, diabetes is considered as a “coronary risk equivalent.”

SCENARIO OF CORONARY ARTERY DISEASE AND DIABETES IN INDIA

The epidemic of CAD is fast spreading to developing countries. South Asians (Asian Indians), in particular, have one of the highest prevalence rates of CAD in the world. It is estimated that more than 60% of the world's CVD burden will occur in South Asia, despite the region accounting for only 20% of the world's population.⁵ The increased predilection of South Asians to CAD was first reported among migrant Asian Indians in Uganda and later confirmed in studies in various parts of the world.^6–12 This phenomenon has occurred in spite of the South Asian population being younger, and having lower levels of most of the conventional risk factors than other ethnic groups.¹³ This raises the probability of either a higher ethnic susceptibility to CAD, or poorer risk factor control, among members of this ethnic group. The prevalence rates of CAD in India have increased from 2.5% to 10.5% in the urban areas and from 2% to 4.5% in the rural areas between 1960 and 2000.¹⁴

One possible explanation for the predilection of South Asians to CAD might be the higher prevalence of T2DM and its associated metabolic abnormalities in them. Similar to CVD, studies on migrant Asian Indians in the UK and elsewhere have shown higher prevalence rates of diabetes compared to the native white population. The increased predisposition of Asian Indians to T2DM has been explained on the basis of the “Asian Indian Phenotype,” wherein, for any given body mass index, Asian Indians have more abdominal (visceral) fat and more insulin resistance (IR) compared to white Caucasians (Fig. 1).¹⁵ The relative role of genetics and environment in the development of this phenotype remains to be elucidated, but the rapid increase in the prevalence of T2DM in India over the past three decades indicates that 10the latter have a major say. Indeed, the latest studies from southern India show that native Asian Indians now have higher prevalence rates of diabetes compared to their counterparts who have migrated to the US.¹⁶

FIG. 1: Asian Indian phenotype.¹⁵

Notwithstanding these developments, the double burden of CAD and T2DM in India remains a cause for concern, if only on account of the enormous numbers of individuals affected. It is estimated that more than 65 million individuals have diabetes in India [International Diabetes Federation (IDF) Atlas] and that more than 77 million have prediabetes.¹⁷ This translates into a vast population at risk of morbidity and mortality due to CAD. It has also been noted that Asian Indians develop T2DM and CAD at much younger ages than white Caucasians, a finding that has considerable socioeconomic implications.^17,18

In the Chennai Urban Population Study (CUPS) conducted on a population-based sample of two residential areas representing the lower and middle income group in Chennai in South India, the overall prevalence of CAD was found to be 11% and the age-standardized prevalence (standardized to the 1991 census of Chennai) was 9.0%. Documented myocardial infarction (MI) was present in 1.2% of the population, 1.3% had Q wave changes, 1.5% had abnormalities of the ST segment and 7.0% had T wave abnormalities. The overall figure of 11% of CAD in the population represents a 10-fold increase in prevalence of CAD in urban India during the last 40 years.¹⁹ The prevalence of CAD was higher among individuals with diabetes (21.4%) (known diabetes 25.3% and newly diagnosed diabetes 13.1%) compared to 14.9% among subjects with impaired glucose tolerance (IGT) and 9.1% among subjects with normal glucose tolerance. Prevalence of known MI was three times higher in subjects with diabetes compared to those without. At every age point, subjects with diabetes and IGT had higher prevalence of CAD compared to subjects with normal glucose tolerance.

RELATIONSHIP BETWEEN CORONARY ARTERY DISEASE AND DIABETES

Type 2 diabetes mellitus and CAD share several common pathophysiologic mechanisms. The IR, one of the main drivers of dysglycemia in T2DM, has been shown to increase the risk of 11CAD. T2DM is also associated with dyslipidemia and hypertension, both of which are strong predictors of CAD. Certain hemorheological and biochemical factors have also been found to play a role in the increased predilection to CAD in T2DM.

Coronary artery disease in diabetes has certain distinctive features. The disease sets in earlier, is more extensive and recurrence after revascularization is more common. Women with diabetes lose the protection from CAD otherwise afforded by their gender. The immediate outcomes after revascularization procedures are also less favorable.

Insulin Resistance and the Metabolic Syndrome

Insulin resistance refers to a condition in which insulin fails to exert its normal physiological response. IR may occur at the level of the insulin receptor or at locations upstream or downstream to it. All individuals with T2DM have some degree of IR, but not all individuals with IR develop diabetes; a concomitant defect in insulin secretion is also necessary to push the blood glucose levels beyond the thresholds diagnostic of diabetes.

Obesity, particularly visceral obesity, is the main driver of IR. The IR tends to cluster with other cardiometabolic risk factors, and this cluster has been termed the “metabolic syndrome”.²⁰ There are several criteria used for the definition of metabolic syndrome. Irrespective of the definition used, CAD was found to be associated with metabolic syndrome in the population-based Chennai Urban Rural Epidemiological Study (CURES).²¹ In the earlier CUPS, CAD also showed strong association with hyperglycemia, hypertension and dyslipidemia.²²

It has also been shown that IR increases CV risk even in normoglycemic individuals. In the CURES, IR (as measured by the homeostasis model assessment—HOMA) was found to be significantly associated with components of metabolic syndrome even at the stage of normoglycemia.²³ This suggests that the clock starts ticking for CAD much before the onset of clinical diabetes.

Diabetes and Dyslipidemia

Lipid abnormalities, especially those involving the apolipoprotein B (apo-B) containing lipoproteins are among the strongest risk factors for CAD. In addition, the effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (INTERHEART) study showed that low high-density lipoprotein (HDL) cholesterol and high triglycerides significantly contribute to the risk of CAD worldwide.³ T2DM is associated with a myriad of lipid abnormalities, many of which are highly atherogenic. The lipid picture in T2DM has been termed “diabetic dyslipidemia,” and consists of the triad of hypertriglyceridemia, low HDL cholesterol and normal or slightly elevated levels of low-density lipoprotein (LDL) cholesterol with a preponderance of small dense LDL particles. Hyperglycemia has been shown to be associated with adverse lipid profiles even in those Asian Indians without a prior history of diabetes.²⁴

A study from Birmingham (US) has shown that migrant Indians have higher levels of small dense LDL compared to their white counterparts.²⁵ In the CURES, small dense LDL levels were found to be higher in individuals with diabetes and highest in those individuals with diabetes who had CAD.²⁶ Small dense LDL particles are more prone to oxidative modification and conformational changes contributing to atheroma formation.²⁷ Levels of oxidized LDL have been shown to increase with increase in severity of glucose intolerance.²⁸

In the CUPS, prevalence of CAD increased with increase in total cholesterol, LDL cholesterol, triglycerides, and total or HDL cholesterol ratio. LDL cholesterol emerged as one of the main risk factors for CAD by logistic regression analysis, along with age.¹⁹ Individuals with CAD in CUPS had lipid levels that were much lower than the thresholds described by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) guidelines, possibly reflecting the preponderance of small dense LDL in this population.¹⁸

Lipoprotein (a) [Lp(a)], is a complex of apo (a) and LDL, which is highly atherogenic. It competitively inhibits plasminogen activity 12and impairs fibrinolysis. In a study on 300 individuals from south India, Lp(a) was found to be independently associated with CAD in T2DM.²⁹

Inflammatory Markers

Chronic subclinical inflammation has been implicated in the pathogenesis of both CAD and T2DM. Cytokines like tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP) and interleukin-6 are strongly associated with CAD. Migrant Asian Indians in the UK have been shown to have higher levels of CRP compared to white Caucasians.³⁰ High levels of CRP are found even in Asian Indian children.³¹ In a study on native Asian Indians in South India, CRP levels were found to be higher in individuals with diabetes compared to those without.³² The CRP showed a strong association with CAD even after adjusting for age and gender; however, the association disappeared when body fat was added to the model. Levels of CRP and TNF-α have been shown to increase with increase in severity of glucose intolerance; even in individuals with normal glucose tolerance, CRP and TNF-α are associated with increased levels of carotid intima-medial thickness (IMT), a preclinical marker of atherosclerosis.³³

Disorders of Coagulation and Fibrinolysis

Insulin resistance is associated with several defects in hemostasis and fibrinolysis. The IR and T2DM are associated with elevated levels of plasminogen activator inhibitor-1 (PAI-1). In experimental models, hyperinsulinemia has been found to stimulate production of PAI-1. In Asian Indians with and without diabetes, fibrinogen and PAI-1 levels have been shown to be associated with angiographically proven CAD.³⁴ T2DM has also been associated with increased expression of tissue factor (TF) and accelerated activation of the coagulation cascade.³⁵ Platelet dysfunction has also been identified in T2DM. Platelets isolated from patients with diabetes show increased adhesiveness and activation (both spontaneous as well as in response to agonists).³⁶

MANAGEMENT OF CORONARY RISK IN DIABETES

Several “risk engines” have been designed to calculate an individual's future risk of developing CAD. These include the Framingham Risk Score, the World Health Organization/International Society for Hypertension Risk Score, the American College of Cardiology/American Heart Association Risk Score and the Joint British Societies risk assessment model. However, none of these have been validated in native Asian Indians, thereby limiting their usefulness in this setting. Nevertheless, since individuals with diabetes represent a subgroup with an elevated risk of CAD, they are candidates for aggressive preventive strategies irrespective of their performance on the risk scores.

Since IR and hyperglycemia are associated with increased coronary risk, aggressive control of blood glucose is theoretically an attractive option for reducing CV risk in patients with diabetes. However, clinical trials have provided conflicting evidence on the desirability of “tighter-than-tight” glycemic control in the prevention of CAD in diabetes. The Diabetes Control and Complications Trial (DCCT) in type 1 diabetes mellitus and the United Kingdom Prospective Diabetes Study (UKPDS) in T2DM have unequivocally shown the benefits of tight glycemic control, aiming for glycosylated hemoglobin (HbA1c) of less than 7% in reducing the risk of microvascular disease (retinopathy and nephropathy).^37,38 However, tight control was not associated with statistically significant reductions in CVD. This led to the hypothesis that even more aggressive treatment of hyperglycemia, aiming for HbA1c of less than 6–6.5% might be needed for CVD prevention in diabetes. Three trials: (1) the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, (2) Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study and (3) the Veterans Affairs Diabetes Trial (VADT) were designed to test this hypothesis. Unfortunately, none of these trials conclusively showed that tighter glycemic control was better as far as CVD was concerned; in fact, ACCORD had to be prematurely terminated on account of excess mortality in the intensive control arm.^39–4¹13

Does this mean that tight control of glycemia is not beneficial? For the answer, we need to look at the long-term follow-up of the DCCT and the UKPDS. Following the conclusion of the active intervention, participants in both arms of the UKPDS and DCCT returned to usual care. Over time, glycemic control in the erstwhile intensive control arm deteriorated, while that in the conventional control arm, control improved, so that at 10 years post-study termination, the two groups were indistinguishable with respect to current HbA1c. However, individuals formerly assigned to intensive care continued to enjoy its benefits in terms of lower risk of microvascular disease as well as CVD even after deterioration of glycemic control. This phenomenon (termed “metabolic memory” or the “legacy effect”) suggests that the timing of intervention matters almost as much as the intensity of glycemic control in deciding an individual's risk of diabetes complications.^42,43 Also, it is now clear that not all individuals are candidates for tight glycemic control. Older individuals, those with longer diabetes duration and those with established CVD are likely to derive less benefit, or even suffer harm, if tight glycemic control is attempted.

In view of the caveats mentioned above, a holistic approach aimed at comprehensive risk factor reduction rather than aggressive management of glycemia alone appears to be the best bet for prevention of CAD in T2DM. The components of a comprehensive CAD risk factor reduction plan are listed in Box 1 below.

Recent guidelines reiterate that glycemic targets need to be individualized based on patient characteristics. Young individuals with a short duration of diabetes and few or no complications and comorbidities can aim for HbA1c of below 6.5 or even 6%. On the other hand, older individuals and those with long duration of diabetes and established diabetes complications may benefit from more relaxed glycemic targets.⁴⁴

As regards hypertension, the risk of cardiovascular morbidity and mortality starts increasing from systolic blood pressure (SBP) of 115 mm Hg and diastolic BP (DBP) levels of 75 mm Hg. However, there is no evidence that lowering BP below 140/80 mm Hg with pharmacotherapy is beneficial. In fact, some studies have even shown that aggressive reduction of BP may be harmful.⁴⁵ With this in mind, the American Diabetes Association has recently revised BP targets for patients with diabetes upwards to 140/80 mm Hg. However, this does not imply that lower levels of BP should not be tried for, if they are achievable without undue treatment burden and drug side-effects.⁴⁴

The recent publication of the American College of Cardiology or American Heart Association Guidelines has led to considerable controversy in the drug treatment of dyslipidemia in the general population and in diabetes in particular.⁴⁶ These guidelines have lowered the threshold for initiation of statin therapy and have done away with treatment targets. While the early use of HMG-CoA reductase inhibitors (statins) is an attractive concept in Asian Indians considering their high risk of CAD and T2DM, concern has been raised that omission of retesting and abolition of treatment targets might lead to over or undertreatment in a significant proportion of cases.^47,48

CONCLUSION

The South Asian region is the diabetes and CAD capital of the world. The predilection of Asian Indians for diabetes and premature CAD can be explained by the Asian Indian phenotype, a constellation of metabolic abnormalities with excess of visceral (abdominal) fat as the central player. Both T2DM and CAD tend to occur at younger ages in Asian Indians compared to other ethnic groups, leading to considerable morbidity and mortality during the prime of the individual's productive life. Fortunately, a comprehensive risk 14factor reduction program, covering all the known modifiable risk factors of CAD, can prevent the majority of cases in this population. However, true primary prevention of CAD will occur only if the burgeoning epidemic of T2DM in South Asia can be nipped in the bud.

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Chapter Notes

Diabetes and Coronary Artery DiseaseCHAPTER 1

BOX 1 : Comprehensive cardiovascular risk reduction in diabetes.