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British Medical Bulletin 59:159-172 (2001)
© 2001 Oxford University Press
Diabetes
Relationship to ischaemic heart disease
Department of Cardiology, London Chest Hospital, London, UK
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Abstract |
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Abstract
IntroductionThe causes of accelerated atherogenesis in diabetes are unclear but the consequences in terms of cardiovascular morbidity and mortality are profound. Thus diabetes not only increases the risk of coronary heart disease but also increases the case fatality rate, ensuring that the majority of patients die of cardiovascular causes, often before the age of 50 years. The problem is compounded by autonomic neuropathy which alters the perception of cardiac pain, attenuating symptoms which are often atypical or absent. This may delay presentation or lead to inappropriate triage decisions such that access to defibrillators and specific treatment is denied. Central to the cardiovascular management of diabetes is vigorous risk factor modification although clear evidence that this leads to extra protection against coronary heart disease beyond that achieved in non-diabetic individuals has not been forthcoming. In other respects too, the management of diabetic patients with heart disease is underpinned by the same evidence-base as applies to non-diabetic patients, and it is noteworthy that 15–20% of the patients in most of the landmark clinical trials have been diabetic. Recently, however, trials such as the United Kingdom Prospective Diabetes Study (UKPDS), the Heart Outcomes Prevention Evaluation (HOPE) study, and the Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study have identified novel strategies for reducing cardiovascular risk in diabetes. These trials have already had a major impact on cardiological practice, emphasising the prime importance of blood pressure control and converting enzyme inhibition for reducing cardiovascular risk in diabetes as well as the value of insulin therapy for reducing mortality in diabetic myocardial infarction. Additional trials, already in progress, are expected to refine further the cardiovascular management of patients with diabetes in order to provide an effective challenge for a problem that shows no signs of going away.
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Introduction |
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Much of the excess morbidity and mortality among diabetic patients is attributable to accelerated atherogenesis. Indeed, 75% of all deaths in patients with diabetes are from this cause1
. With our ageing, sedentary and increasingly obese population, the number of affected individuals will continue to rise with major knock-on effects for cardiological practice. |
Accelerated atherogenesis |
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Conventional risk factors, particularly hypertension and dyslipidaemia, occur more commonly in diabetes, but account for less than 25% of the excess risk of coronary heart disease2
. Thus, most of the excess risk is attributable directly or indirectly to diabetes itself. Mechanisms are unclear although it is generally accepted that, in common with all other major risk factors, diabetes promotes atherogenesis by increasing oxidative stress and lipid peroxidation in the arterial endothelium.
Hyperglycaemia
Because hyperglycaemia is a late event in the process leading from insulin resistance to frank diabetes, it is often regarded as a minor player in the pathogenesis of accelerated atherosclerosis3. Nevertheless, it has recently been implicated in mechanisms of increased oxidative stress by reversible glycosylation of protein amino groups. This has no direct pathological consequences, but leads to irreversible oxidation of fructoselysine which produces a variety of advanced glycation end products (AGEs)4. These react with a specific receptor (RAGE) at the vascular endothelium, increasing vascular endothelial production of superoxide anion and other oxidative products which accelerate atherogenesis5. Recent data indicate that reducing vascular exposure to AGEs by injection of soluble RAGE (which 'mops up' circulating AGEs) suppresses accelerated atherosclerosis in diabetic mice. Whether RAGE scavenging drugs will have a clinical role, however, is not known6.
Hyperinsulinaemia, and insulin resistance
Metabolic characteristics of the cardiovascular dysmetabolic syndrome include hyperinsulinaemia and insulin resistance7. Hyperinsulinaemia promotes smooth muscle proliferation in the vessel wall and stimulates production of plasminogen activator inhibitor. These adverse proliferative and thrombogenic actions, however, must be set against the vasculoprotective effects of insulin which include stimulation of endothelial nitric oxide production, such that net effects on atherogenesis are hard to quantify8. Epidemiological studies have been contradictory9, and taken together suggest that hyperinsulinaemia is only weakly predictive of accelerated atherogenesis without necessarily implying a causal relationship10. Insulin resistance correlates better with coronary artery disease, and in the Insulin Resistance Atherosclerosis Study had an independent effect on carotid intimal medial wall thickness that persisted following adjustment for smoking, lipid levels, hypertension, diabetes and gender11.
Dyslipidaemia
In type 2 diabetes, chylomicrons and atherogenic very low density lipoprotein (VLDL) remnants accumulate12–14. Hypertriglyceridaemia causes high density lipoprotein (HDL) levels to diminish and low density lipoprotein (LDL) particles to become smaller and denser, increasing their ability to penetrate the arterial intima and their susceptibility to oxidation. Thus, while total cholesterol levels may be normal, the atherogenicity of LDL and VLDL is enhanced, and circulating levels of protective HDL are reduced. Nevertheless, dyslipidaemia probably accounts for only a part of the increased susceptibility to coronary heart disease in diabetes, since treatment does not reduce risk to the level seen in patients without diabetes.
Procoagulant factors
Oxidative stress and endothelial dysfunction in diabetes results in deficient production of prostacyclin and plasminogen activator inhibitor, and is also responsible for increased platelet production of thromboxane A215. The net effect of these changes is to enhance vasoconstrictor and thrombotic responses to plaque rupture in diabetes, increasing plaque burden and the risk of myocardial infarction.
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Cardiovascular risk |
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The Framingham study showed that diabetes independently increased the relative risk of coronary heart disease by 66% in men and 203% in women followed-up for 20 years2
. The heightened risk in women has since been confirmed by a large volume of clinical data, most recently the report that diabetes abolishes gender differences in coronary calcification measured by ultrafast computed tomography16. The Whitehall study of male civil servants extended the Framingham observations by showing that subclinical glucose intolerance, in addition to frank diabetes, also increased coronary risk17. The Multiple Risk Factor Interventional Trial (MRFIT) with its very large population of middle-aged men was able to provide more detailed information about the interaction between diabetes and other risk factors in determining coronary risk18. This trial confirmed the heightened risk attributable to diabetes, and also the independent effects of serum cholesterol, blood pressure and smoking in men with and without diabetes. MRFIT showed that in men with diabetes, 12-year cardiovascular mortality was much higher at every level of these major risk factors considered singly and in combination, and that with progressively more unfavourable risk factor status the mortality rate rose much more steeply than in men without diabetes. |
Protecting against coronary heart disease |
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The MRFIT investigators recommended 'rigorous sustained intervention in people with diabetes to control blood pressure, lower serum cholesterol, and abolish cigarette smoking...', recommendations that remain central to the cardiovascular management of diabetes today. Disappointingly, however, there is not yet clear evidence that these recommendations lead to extra protection against coronary heart disease beyond that achieved in non-diabetic individuals, although important protection against microvascular complications (retinopathy, renal disease) does occur. Nevertheless, as practice evolves from single to multifactorial risk assessment, in which absolute coronary risk can be readily assessed from colour-coded charts, the clinical impact of risk factor modification can be expected to increase19
.
Lowering blood pressure
Hypertension commonly occurs in type 2 diabetes, and contributes importantly to the heightened risk of macrovascular and microvascular disease20–23. Trial data have suggested that the benefits of treating hypertension apply equally to diabetic and non-diabetic patients, a suggestion emphatically confirmed in the hypertensive cohort of the UK Prospective Diabetes Study (UKPDS)24. Comparison of patients allocated either to tight blood pressure control (<150/85 mmHg) using captopril or atenolol, or to less-tight control showed that tight control for a mean of 8.4 years was associated with significant reduction in the risk of death related to diabetes, and with reductions in all microvascular end-points. Predictably, reductions in the risk of heart failure and stroke also occurred, but the 21% reduction in the risk of myocardial infarction was not significant. The Hypertension Optimal Treatment (HOT) study also reported reductions in myocardial infarction in patients treated to a target diastolic blood pressure of 
80 mmHg compared with targets of 85 or 90 mmHg, but again the changes were not significant25. Based largely on these recent trial data, a target blood pressure of < 130 mmHg systolic and <80 mmHg diastolic is now recommended for diabetic patients26. Lower targets might be appropriate for diabetic patients with micro-albuminuria, in whom considerable data support the use of ACE inhibitors for protecting against deterioration of renal function, a beneficial effect that occurs independently of blood pressure reduction27,28. However, UKPDS reported that captopril or atenolol was similarly effective in reducing the incidence of diabetic complications and concluded that for most patients blood pressure reduction itself is more important than the agent used29.
Lipid modification
Hypertriglyceridaemia with reductions in HDL cholesterol are the typical abnormalities detected on routine laboratory testing in type 2 diabetes12. This provides a logic for fibrate therapy in addition to exercise and weight reduction. The Helsinki study suggested a trend towards reduced coronary events in diabetic patients treated with gemfibrozil for 5 years30, but data from other fibrate studies have generally been inconclusive. Nevertheless, a recent secondary prevention trial of gemfibrozil in men with low HDL cholesterol (<1 mmol/l) followed-up for 5 years, showed that a 6% increase in HDL plus a 31% reduction in triglyceride concentrations were associated with a 22% relative risk reduction in non-fatal myocardial infarction or coronary death31. It is expected that fibrates will have increasing application in diabetic coronary disease but further trials are needed and meanwhile statins will have the major role based on subgroup analyses of major trials32–34 which have shown convincingly that hypercholesterolaemic diabetic patients gain similar relative benefit as non-diabetic patients in the secondary prevention of coronary artery disease, and greater absolute benefit due to their higher event rate. Thus, statin therapy for all diabetics with known atherosclerotic disease (secondary prevention) is now recommended to lower total cholesterol concentrations below 5.0 mmol/l (LDL <3.0 mmol/l) or by 20–25%, whichever is lower. Additional fibrate therapy to correct hypertriglyceridaemia and increase HDL should also be considered as necessary. In diabetic patients without overt atherosclerotic disease (primary prevention), an absolute risk = 30% of developing coronary heart disease over the next 10 years, as deduced from colour-coded risk prediction charts, is sufficiently high to justify drug treatment26.
Smoking cessation
Observational data suggest that the risk of myocardial infarction is reduced by up to 50% within 1 year of quitting smoking. Since the cardiac risk attributable to smoking is magnified considerably in diabetes, as indeed is the risk attributable to all other risk factors, the benefits of quitting are likely to be as great, if not greater in diabetic then non-diabetic patients18.
Glycaemic control
Strict glycaemic control has long been recommended in diabetes, based on epidemiological surveys that have reported more favourable clinical outcomes for groups with lower plasma glucose and glycosylated haemoglobin concentrations35–37. However, whether these more favourable outcomes reflected less severe underlying disease rather than the benefits of glycaemic control remained unresolved until publication of UKPDS in which 3867 newly diagnosed patients with type 2 diabetes were randomly assigned to an intensive (sulphonylurea or insulin) or conventional treatment policy38. After follow-up for 10 years, glycosylated haemoglobin concentrations in the two groups were 7.0% and 7.9%, respectively, a difference of only 11%. Nevertheless, this trial confirmed the close relation between glycaemia and the risk of microvascular and macrovascular complications39, including coronary heart disease, and also dispelled concerns about the potential adverse cardiovascular effects of sulphonylureas. Importantly, in the group randomised to intense glycaemic control, significant protection against microvascular complications occurred although macrovascular complications were not similarly affected, the 16% reduction in the risk of myocardial infarction being of only borderline statistical significance. In short, therefore, UKPDS has confirmed the importance of strict glycaemic control (glycosylated haemoglobin 7% or lower) for protection against microvascular, but not macrovascular, complications of diabetes. Whether the newly available thiazolidinediones (glitazones) prove more effective for reducing cardiovascular risk remains to be seen, but there are grounds for optimism. These drugs improve long-term glycaemic control by increasing insulin sensitivity40. They may, therefore, have a special role for correcting insulin resistance in the cardiovascular dysmetabolic syndrome which is thought to play an important pathogenic role in the accelerated atherogenesis that affects South Asians among others41. Glitazones are well tolerated with good side-effect profiles, problems with hepatotoxicity seen with troglitazone (now withdrawn) not occurring with rosiglitazone or pioglitazone. Their insulin sensitizing effects may also benefit other manifestations of the dysmetabolic syndrome, and preliminary studies with rosiglitazone have shown small reductions in diastolic blood pressure and late increases in HDL cholesterol92,93.
Antiplatelet therapy
An overview of randomised trials has shown that the benefits of antiplatelet therapy for secondary prevention of coronary heart disease are similar for groups with and without diabetes42. Thus patients with diabetic coronary heart disease should all receive a daily aspirin. Though not strictly evidence-based, aspirin is now recommended for diabetic adults without clinical manifestations of atheromatous disease (primary prevention) since platelet dysfunction is common and the prevalence of subclinical disease high. Evidence for non-aspirin platelet inhibitors in diabetic subgroups is unavailable. However, as an adjunct to coronary stenting, glycoprotein IIb/IIIa receptor antagonists have a useful role43, reducing the rate of adverse events in patients with diabetes to a level comparable to that of patients without diabetes.
ACE inhibition
ACE inhibition can protect against the development of atherosclerotic plaque in experimental animals fed lipid-rich diets44–46. Potential for similar benefit in humans was reported by the TREND investigators who showed that treatment with quinapril improved coronary endothelial function in patients with coronary disease47. This potential has now been confirmed by the Heart Outcomes Prevention Evaluation (HOPE) study in which significant reductions in the risk of the combined primary outcome (death, myocardial infarction and stroke) occurred in high-risk patients randomised to treatment with ramipril48. Among these high-risk patients were 3577 with diabetes who had a previous cardiac event or at least one other cardiovascular risk factor, but not heart failure or proteinuria. Within this diabetic subgroup, randomisation to ramipril reduced the risk of the combined primary outcome by 25%, with an additional reduction in the risk of overt nephropathy49. Further large trials of ACE inhibition for protecting against cardiovascular end-points are in progress, but meanwhile there is clear indication for ACE inhibition with ramipril in any diabetic patient with multiple risk factors, established vascular disease, or microalbuminuria.
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Screening for coronary heart disease |
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The prevalence of subclinical coronary artery disease in the diabetic population is high50
,51 as reflected by a long-term rate of myocardial infarction and cardiovascular death comparable to that of non-diabetic patients with a documented history of myocardial infarction52. Subclinical disease is commonly non-obstructive due to outward remodelling of the coronary artery53. However, obstructive disease may also be clinically silent, particularly in diabetes when autonomic neuropathy may interfere with the perception of cardiac pain such that symptoms take longer to develop after the onset of myocardial ischaemia (prolonged anginal perceptual threshold54) or do not occur at all (silent ischaemia55).
There has been recent debate about the value of screening programmes to detect subclinical coronary artery disease in patients with diabetes using non-invasive tests56,57. As a universal principal this can scarcely be justified, because there is only a 5–10% incidence of obstructive lesions (> 50% luminal narrowing at angiography) among asymptomatic diabetic cohorts, ensuring that the sensitivity of stress testing (electrocardiographic or perfusion imaging) is very low58–60. Moreover, the mere demonstration of obstructive coronary disease does not usually affect management, there being no evidence to support angioplasty in asymptomatic cases, while the potential prognostic benefits of surgery in the minority with 3 vessel or left main disease needs to be balanced against the heightened procedural risk and less favourable longer term outcome in patients with diabetes (see below). Nevertheless, in certain subgroups, screening for coronary artery disease is recommended because it can lead to treatment strategies that favourably affect prognosis. These include diabetic patients needing renal transplantation or major non-cardiac vascular surgery in whom coronary revascularisation may reduce the procedural risk61–63.
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Angina and revascularisation |
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Angina in diabetes is commonly atypical, perhaps because of abnormalities in the perception of angina caused by autonomic neuropathy54
,55, but a positive stress test indicates a high probability of underlying coronary disease and the need for specific anti-anginal treatment, often with additional angiographic assessment. The disease is typically diffuse affecting both proximal and distal coronary segments and this makes revascularisation by angioplasty or bypass surgery more difficult and more hazardous. Indeed, diabetes has long been recognised as one of the major independent predictors of long-term mortality after surgery64. The results of angioplasty also tend to be less good in diabetic compared with non-diabetic patients. Again, diffuse disease makes for technically more difficult angioplasty procedures and, in addition, re-stenosis rates are consistently higher65. In the recent BARI trial of angioplasty versus bypass surgery, subgroup analysis showed that patients without diabetes had comparable results with either revascularisation modality, in contrast to patients with diabetes who fared significantly worse with angioplasty66. The investigators concluded that, for most diabetics requiring revascularisation, coronary bypass surgery was preferable. More recently, however, a predefined subgroup analysis from the EPISTENT trial showed that angioplasty and stenting combined with infusion of abciximab (a glycoprotein IIb/IIIa receptor inhibitor) improved the long-term outcome in diabetic patients substantially, with a 6 month incidence of ischaemic end-points comparable to that achieved in non-diabetic patients43. The data suggest, therefore, that stenting and IIb/IIIa receptor blockade may have an important role in diabetic angioplasty. |
Acute myocardial infarction |
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The risk of acute myocardial infarction is 50% greater in diabetic men and 150% greater in diabetic women than in non-diabetic individuals2
. Autonomic dysfunction and increased platelet activation combine to attenuate circadian and seasonal rhythms, increasing the risk of acute myocardial infarction throughout the day and the year67. Autonomic dysfunction, by altering the perception of ischaemic cardiac pain, predisposes to 'silent' myocardial infarction68 which has the potential to delay access to emergency facilities early after coronary events, increasing the risk of out-of-hospital sudden death69,70. All the major complications of myocardial infarction occur more commonly in diabetes, particularly heart failure which affects nearly 50% of diabetics compared with under 30% of non-diabetics71. This difference is not accounted for by infarct size, but may reflect the more severe and diffuse disease in diabetes that limits coronary reserve and intensifies ischaemia in non-infarcted segments by a watershed effect72. Diabetes-specific myocardial disease may also have a role, and contractile dysfunction remote from the infarct zone has been reported72. Hospital and long-term mortality rates are increased68,71,72.
Insulin and glucose infusion for 24 h followed by subcutaneous insulin for at least 3 months improves survival in patients with myocardial infarction and a presenting blood glucose concentration 
11.0 mmol/l, with or without frank diabetes73. This protects against ischaemic injury and improves left ventricular function74 by preserving the shift to anaerobic myocardial glucose metabolism during acute ischaemia, an insulin-dependent adjustment that may be deficient in diabetes due to absolute or relative lack of insulin75,76.
In other respects, the treatment of acute myocardial infarction in diabetes should be conventional, responses to thrombolytic therapy – judged by patency of the infarct-related artery and mortality reduction – being similar to patients without diabetes72. Similarly, diabetes does not appear to affect the benefits of aspirin42, nor that of ß-blockers77 and statins32. ACE inhibitors, in particular, have a special role and should be given to all diabetic patients with acute myocardial infarction, not only because of the heightened risk of left ventricular failure, for which these drugs are of proven benefit, but also because of the protection they afford against microvascular and macrovascular complications (see previously).
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Sudden death |
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The increased risk of plaque events in patients with diabetes predisposes to sudden death. However, other mechanisms also contribute78
,79, particularly autonomic neuropathy which may be arrhythmogenic through prolongation of QT interval and selective reductions in vagal tone which increases sympathetic activity80–82. Moreover, altered perception of ischaemic cardiac pain may deprive diabetic patients of the signal to stop exercising allowing ischaemia to intensify to the point that arrhythmias are triggered83. Autonomic neuropathy may also interfere with pain perception during plaque events, delaying presentation to hospital or leading to inappropriate triage decisions such that access to defibrillators and specific treatment is denied84. This emphasises the importance of retaining low diagnostic thresholds for coronary heart disease in the diabetic patient presenting with atypical symptoms. |
Heart failure |
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Epidemiological, pathological and haemodynamic data provide the evidence-base for diabetes-specific myocardial disease, commonly called ‘diabetic cardiomyopathy’. Thus the Framingham investigators reported that the annual incidence of heart failure was substantially greater across all age groups in diabetic than non-diabetic individuals, even after controlling for underlying coronary and rheumatic heart disease85
. The inference that diabetes itself might predispose to heart failure was supported by postmortem reports in diabetics with heart failure describing normal coronary arteries and heart valves86. Myocardial histology in diabetic heart failure (myocyte hypertrophy, interstitial fibrosis, increased PAS-positive material and intramyocardial microangiopathy87) is similar to changes found in hypertensive left ventricular disease, emphasising the importance of effective antihypertensive therapy as reported in UKPDS24. Analysis of systolic time intervals has provided evidence of both systolic and diastolic left ventricular dysfunction in diabetic individuals in whom there was no clinical evidence of coronary artery disease88.
The pathogenesis of diabetic cardiomyopathy is unclear, although possible mechanisms include the synergistic impact of hypertension plus chronic derangement of myocardial metabolism, with increased free fatty acid oxidation and decreased glucose utilization89. Treatment strategies are the same as for non-diabetic patients with heart failure, and are directed at controlling provocative factors, particularly arrhythmias and hypertension. Diuretics may adversely influence metabolic control in diabetes but are mandatory for symptomatic treatment, while the efficacy of ACE-inhibition is undiminished, judging by subgroup analyses of the Studies Of Left Ventricular Dysfunction (SOLVD) prevention and treatment trials90,91. ß-Blockers too are recommended, although this is based on generalisation from randomised trials rather than specific data for patients with diabetes.
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Footnotes |
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Correspondence to:Mr Adam D Timmis, Department of Cardiology, London Chest Hospital, Banner Road, London E2 9JX, UK
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