Diabetes and Cardiovascular Disease

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Chapter 42

Diabetes and Cardiovascular Disease

1. What is the current global burden of diabetes, and what is its impact on the epidemiology of cardiovascular disease (CVD)?

    The global burden of diabetes mellitus (DM) in 1985 was an estimated 30 million people. By 2003, it was estimated that there were around 194 million people with diabetes, and this figure is expected to rise to almost 350 million by 2025. At present, the prevalence of DM is much higher in developed countries, but because of urbanization and adoption of western diets and lifestyles, developing countries are rapidly catching up with their developed counterparts. The disease affects a disproportionately higher number of young people in the developing world. The lifetime risk of diabetes is estimated at 32.8% for U.S. males and 38.5% for U.S. females.

    Knowledge of the epidemiology of DM is important to place the expected contribution of DM to the global CVD burden into perspective. The relationship between DM type 1 and type 2 and CVD is well established. In particular, DM is a very strong risk factor for the development of coronary artery disease (CAD) and stroke. The hazard ratio for CAD death in diabetic patients is considered as high as 2.03 (95% confidence interval [CI], 1.60 to 2.59) for men and 2.54 (95% CI, 1.84 to 3.49) for women. Atherosclerosis accounts for 80% of all deaths in diabetic persons, compared with about 30% among nondiabetic persons. Atherosclerotic disease also accounts for greater than 75% of hospitalizations for diabetes-related complications. Patients with diabetes but without previous myocardial infarction (MI) carry the same level of risk for subsequent acute coronary events as nondiabetic patients with previous MI. These results have prompted the Adult Treatment Panel III of the National Cholesterol Education Program to establish diabetes as a CAD risk equivalent, mandating aggressive antiatherosclerotic therapy.

2. What is the impact of diabetes on CVD outcomes?

    In addition to its salutary effects on stable atherosclerotic disease, diabetic patients experience an increased rate of early and late complications following acute coronary syndrome (ACS). Diabetic patients with non–ST segment elevation ACS also experience more in-hospital MIs, associated complications and higher death rates. Diabetic patients also respond less optimally to fibrinolytic therapy, an effect that is sex-dependent—diabetic women fare worse than men. In patients with ACS complicated by hypotension and cardiogenic shock, diabetes is an independent risk variable for adverse outcomes, including death. In the short and long terms, diabetic patients with ACS experience higher rates of heart failure, death, and repeat infarction and require more frequent coronary revascularization.

3. What effect, if any, does diabetes have on the clinical manifestations and prognosis of peripheral arterial disease (PAD) and cerebrovascular disease?

    Diabetes increases the risk of PAD about two- to fourfold. It is more commonly associated with femoral bruits and absent pedal pulses and with a high rate of abnormal ankle-brachial indices, ranging from 11% to 16% in different studies. The duration and severity of diabetes correlates with the incidence and extent of PAD. The pattern of PAD in diabetic patients is characterized by a preponderance of infrapopliteal occlusive disease and vascular calcification. Clinically, PAD in diabetic patients manifests more commonly with claudication and also a higher rate of amputation—the most common cause of nontraumatic amputations.

    Diabetic patients also have a higher rate of intracranial and extracranial cerebrovascular atherosclerosis and calcifications. Patients with a history of stroke have a threefold higher likelihood of being diabetic than do controls, with a risk of stroke that may be up to three- to fourfold higher than that of nondiabetic patients. Compared with nondiabetic subjects, the mortality from stroke in diabetic patients is almost threefold higher. Diabetes also results in a disproportionately higher stroke rate in younger patients and increases the risk of severe carotid disease. In patients younger than 55 years, diabetes increases the risk of stroke about 10 times according to one study. Diabetic patients also suffer worse poststroke outcomes, including a higher mortality rate and recurrence risk and a greater probability of vascular dementia.

4. What is the overall impact of diabetes on the vascular tree?

    Cardiovascular (CV) complications in diabetic patients can be the result of macrovascular disease, including CAD, peripheral arterial disease, and cerebrovascular disease, or can be due to microvascular disease that can result in nephropathy, retinopathy, and neuropathy. Many regard diabetic cardiomyopathy as a distinct entity that is thought to result primarily from hyperglycemia-induced myocardial adverse effects.

5. What is the burden of additional CV risk factors in diabetic patients, and what is their cumulative impact on the atherosclerosis morphology and burden?

    Diabetic patients are known to bear a higher burden of CV risk factors, including twice the prevalence of hypertension, and a higher prevalence of dyslipidemia, including lower high-density lipoprotein (HDL) cholesterol, higher triglycerides, and higher small, dense low-density lipoprotein (LDL) cholesterol levels. The clustering of CV risk factors appears to have a multiplicative effect in diabetic patients, who experience a threefold higher CV mortality than do nondiabetic persons for each risk factor present. In addition, CAD in diabetic patients involves a greater number of coronary vessels and more diffuse atherosclerotic lesions, including significantly more severe proximal and distal CAD.

    Atherosclerotic plaque ulceration and thrombosis also occur more often in diabetic patients. Atherosclerotic plaques in diabetic patients are considered high-risk because of a greater propensity for erosion or rupture, which accounts for a higher incidence of ACS in this population. Diabetic plaques are characterized by high levels of inflammatory cell infiltration, large lipid cores, thin fibrous caps, the presence of new vessel formation (neovascularization) and hemorrhage within the plaque.

6. What characteristics of the atherosclerotic plaque in diabetic patients make it unstable compared with plaque in nondiabetic patients?

    Diabetic patients harbor a proinflammatory and prothrombotic milieu with greater C-reactive protein (CRP), matrix metalloproteinase 3 and 9 (MMP-3 and MMP-9), intercellular adhesion molecule (ICAM), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), and superoxide concentrations. In addition to its adverse effects on the endothelium, diabetes promotes processes that lead to monocyte transmigration across the endothelium into the vessel wall and uptake of oxidized LDLs into these cells, resulting in foam cell and fatty streak formation. In addition to plaque initiation, diabetes renders the atherosclerotic plaque unstable. Endothelial cells in diabetic patients release cytokines and enzymes (MMPs) that impair collagen synthesis by vascular smooth muscle cells and also accelerate its breakdown. Because collagen is an essential component of the plaque fibrous cap, weakening it renders the plaque unstable. Plaque rupture or erosion triggers an intense local prothrombotic milieu, resulting in thrombus formation. In addition, following plaque rupture, platelets of diabetic patients aggregate more aggressively and are more likely to disaggregate with more efficacious antiplatelet agents (especially prasugrel and ticagrelor, when compared to clopidogrel), as demonstrated in the diabetic cohorts of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) and Platelet Inhibition and Patient Outcomes (PLATO) trials. Diabetes also results in elevated factor VII levels (procoagulant) and reduced protein C and antithrombin III levels (naturally occurring anticoagulants). Finally, diabetic endothelial cells produce more tissue factor, the major procoagulant found in atherosclerotic plaques.

7. What broad management strategy is advocated for diabetic patients with CVD?

    A multidisciplinary approach is the cornerstone in the successful management of diabetes and CVD. Since the presence of diabetes is considered equivalent to having CAD, aggressive management of all potential risk factors, including hypertension, dyslipidemia, and the hypercoagulable state, are recommended. In addition to measures to promote weight loss by dietary modification and exercise, diabetic patients benefit from aggressively managing conventional risk factors. The strongest evidence supporting a multifaceted and comprehensive approach in the management of diabetic patients comes from the Steno-2 trial. It demonstrated that a strategy including lifestyle and pharmacologic interventions intended to reduce CV risk in type 2 diabetic patients with microalbuminuria was significantly more effective in reducing CV events and mortality than was usual care in the long term.

8. How does the treatment of hyperglycemia and insulin resistance impact outcomes in diabetic patients with CVD?

    Tight glycemic control has been shown to improve microvascular complications, including diabetic nephropathy. The current American Diabetes Association target for HbA1C is less than 7% and for the American College of Clinical Endocrinology less than 6.5%. Diabetic nephropathy occurs in 40% of patients with type 1 and type 2 diabetes, and the main risk factors for its development include poor glycemic control, hypertension, and ethnicity. The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study group trial (UKPDS) demonstrated that the development and progression of microalbuminuria can be prevented through strict glycemic control. This was also demonstrated for type 2 patients in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial.

    Despite epidemiologic evidence linking poor glycemic control with CVD, aggressive glucose control for reduction of CV risk is controversial and potentially harmful in susceptible populations. This has recently been an area of considerable debate because of the results of two recent large randomized controlled trials: Action to Control Cardiovascular Risk in Diabetes (ACCORD) and ADVANCE. The means used to attain glycemic control have also recently received much scrutiny because of reports suggesting increased risk of CVD, including mortality, MI, and fluid retention and/or heart failure, with thiazolidinediones (TZD), in particular rosiglitazone. Another TZD, pioglitazone, which is believed to have a relatively benign CV profile, has recently been associated with a higher incidence of bladder carcinoma and bone fractures.

    For these reasons, metformin remains the first-line treatment option in most type 2 diabetes patients and seems to have a beneficial effect on insulin resistance without an adverse effect on CVD. The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial has demonstrated that an insulin-sensitizing strategy led by metformin was superior to an insulin provision strategy in reducing CV events in diabetic patients with established coronary disease. This landmark study also demonstrated the efficacy of medical management in diabetic patients with less extensive coronary disease.

9. What are the currently recommended strategies for the management of diabetic dyslipidemia?

    The lipid abnormalities in diabetes improve with lifestyle modifications, including weight loss, exercise, smoking cessation, and dietary changes, which are the first line of treatment. The most effective intervention in the management of diabetic patients with CAD is the use of statin medications, which have proven especially useful in this population. In the Scandinavian Simvastatin Survival Study (4S) and Cholesterol and Recurrent Events (CARE) trials and the Heart Protection Study (HPS), simvastatin demonstrated a significantly greater benefit in mortality and MI of diabetic subjects compared with nondiabetic subjects. The goal for LDL cholesterol is less than 100 mg/dL for patients without CAD and less than 70 mg/dL for those with CAD.

    In addition to statins, fibric acid derivatives may be especially beneficial in diabetic patients because of their effects in lowering triglycerides and raising HDL levels. Treatment with gemfibrozil significantly reduced the risk of MI in the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT). In addition to the lipid-lowering effect, fibric acid derivatives may have antiatherogenic, antithrombogenic, and antiinflammatory effects. However, the role of fibric acid derivatives has been questioned in diabetic patients recently, following the results of the ACCORD lipid study in which adding a fibrate to a statin did not confer additional CV protection. Nicotinic acid also produces a similar favorable effect on the lipid profile in diabetic patients but needs investigation in a large study, following disappointing results from the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial. In addition, diabetic patients on niacin may require close monitoring of their glucose levels.

10. What do the current guidelines recommend for management of hypertension in diabetic patients?

    The goal blood pressure in diabetic patients is less than 130/80 mm Hg. Those with a blood pressure 140/90 mm Hg or more should be given drug therapy in addition to lifestyle and behavioral therapy. However, the effect of blood pressure reduction below 120/70 mm Hg remains unclear. It is not uncommon for diabetic patients to require multiple agents for optimal blood pressure control. Unless contraindicated or not tolerated, either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB) should be included in all blood pressure regimens for diabetic patients. Diuretics, beta-adrenergic blocking agents (β-blockers), ACE inhibitors, ARBs, and calcium channel antagonists all effectively decrease blood pressure in diabetic patients.

    Regardless of the agent chosen, evidence from prior randomized clinical trials overwhelmingly favors good blood pressure control. The recommendations given here are based on the results of trials of hypertension or CV prevention. In the Heart Outcomes and Prevention Evaluation (HOPE) study, ramipril significantly decreased the rates of MI, stroke, and death in patients with diabetes and one additional CV risk factor. The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study demonstrated that losartan was more effective than atenolol for reducing CV mortality in diabetic patients with hypertension and left ventricular hypertrophy (LVH).

11. What are the principles of management of chronic CAD in diabetic patients?

    Diabetic patients are more likely to experience painless cardiac ischemia and suffer more silent MIs and sudden cardiac death. Evidence from observational studies and randomized trials has shown significant mortality benefit with β-blockers in diabetic patients. β-Blockers are well tolerated in diabetic patients; masking or prolongation of hypoglycemic symptoms is infrequent, particularly with cardioselective agents. Recommendations include continuing antiplatelet therapy; ACE inhibitors and ARBs should be used as appropriate for blood pressure control, and β-blockers are recommended in diabetic patients after an MI. However, routine screening for CAD in diabetic patients is not recommended, as demonstrated in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) trial. The multifaceted approach to the diabetic patient is illustrated in Figure 42-1.

12. What strategies for coronary revascularization are currently recommended for the management of multivessel CAD in diabetic patients?

    The optimal revascularization strategy in stable diabetic patients with multivessel coronary disease has been debated extensively in recent years. The Bypass Angioplasty Revascularization Investigation (BARI) trial substudy of diabetic patients indicated that coronary artery bypass grafting (CABG) offered a clinically meaningful and statistically significant survival advantage in diabetic patients when compared to balloon angioplasty. Even in nondiabetic patients, the need for future revascularization has been traditionally higher in the angioplasty group compared with CABG, and these differences are even more pronounced in diabetic patients. However, BARI was conducted in an era when stents were not available. The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D) trial suggested that diabetic patients with three-vessel and severe coronary disease should preferably be managed with open revascularization. Because BARI-2D did not compare percutaneous coronary intervention (PCI) and CABG in patients with multivessel disease, the question was being addressed in the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial. FREEDOM revealed that in diabetic patients with advanced coronary artery disease, CABG was superior to PCI with drug-eluting stents in reducing death and myocardial infarction rates, albeit with a higher stroke risk.

Bibliography, Suggested Readings, and Websites

1. ADVANCE Collaborative Group, Patel, A., MacMahon, S., et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–2572.

2. American Diabetes Association. Standards of medical care in diabetes—2006. Diabetes Care. 2006;29(Suppl 1):S4–S42.

3. Aneja A, Tang WH, Bansilal S, et al: Diabetic cardiomyopathy: insights into pathogenesis, diagnostic challenges, and therapeutic options, Am J Med 121(9):748–757

4. Beckman, J.A., Creager, M.A., Libby, P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002;287:2570–2581.

5. Berry, C., Tardif, J.C., Bourassa, M.G. Coronary heart disease in patients with diabetes. Part I: Recent advances in prevention and noninvasive management. J Am Coll Cardiol. 2007;49:631–642.

6. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253–259.

7. Farkouh, M.E., Domanski, M., Sleeper, L.A., et al. FREEDOM Trial Investigators: Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012;367(25):2375–2384. Dec 20

8. Gaede, P., Lund-Andersen, H., Parving, H.H., et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580–591.

9. Gerstein, H.C., Miller, M.E., Byington, R.P., et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–2559.

10. Goldberg, R.B., Mellies, M.J., Sacks, F.M., et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial: the CARE investigators. Circulation. 1998;98:2513–2519.

11. Grundy, S.M., Cleeman, J.I., Merz, C.N., et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004;44:720–732.

12. Gu, K., Cowie, C.C., Harris, M.I. Diabetes and decline in heart disease mortality in US adults. JAMA. 1999;281:1291–1297.

13. Khardori, R. Diabetes mellitus, type 2. Available at http://emedicine.medscape.com/article/117853-overview. Accessed February 27, 2013

14. Malmberg, K., Yusuf, S., Gerstein, H.C., et al. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) registry. Circulation. 2000;102:1014–1019.

15. McCullock DK: Overview of medical care in adults with diabetes mellitus. In Basow, DS, editor: UpToDate, Waltham, MA, 2013, UpToDate. Available at http://www.uptodate.com/contents/overview-of-medical-care-in-adults-with-diabetes-mellitus. Accessed March 26, 2013

16. Nesto RW: Coronary artery revascularization for angina in patients with diabetes mellitus and multivessel coronary artery disease. In Basow, DS, editor: UpToDate, Waltham, MA, 2013, UpToDate. Available at http://www.uptodate.com/contents/coronary-artery-revascularization-in-patients-with-diabetes-mellitus-and-multivessel-coronary-artery-disease. Accessed March 26, 2013

17. Pyorala, K., Pedersen, T.R., Kjekshus, J., et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. Diabetes Care. 1997;20:614–620.

18. Smith, S.C., Jr., Allen, J., Blair, S.N., et al. ACC/AHA guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113:2363–2372.

19. Skyler, J.S., Bergenstal, R., Bonow, R.O., et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes Trials: a position statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association. J Am Coll Cardiol. 2009;53:298–304.

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