Macrovascular Disease in Elderly Patients with Diabetes

This article is the sixth in a continuing series on diabetes in the elderly. The fifth article in the series, “Microangiopathic Complications of Diabetes: Diabetic Peripheral Neuropathies,” was published in the September issue of the Journal. The remaining article in the series will discuss the role of exercise and dietary supplements in the management of diabetes.

Diabetes mellitus is a group of chronic diseases that share the common manifestation of hyperglycemia, which, along with other comorbidities, considerably increases the risk of developing vascular disease. Due to changes in lifestyle and the increasing prevalence of overweight and obesity (primarily contributing to type 2 diabetes), the prevalence of diabetes in the U.S. population is increasing rapidly. Diabetes mellitus is also an age-related disease, with prevalence increasing as age increases.¹ It now affects approximately 18-30% of the elderly population in the United States.^2,3 Of these individuals, approximately two-thirds have evidence of macrovascular complications from their diabetes.⁴ These complications include coronary heart disease (CHD), cerebrovascular disease, dyslipidemia, and peripheral vascular disease (PVD). Additionally, hypertension, metabolic syndrome, obesity, and smoking substantially increase the risk of these complications.

Atherosclerosis

Atherosclerosis is the main underlying pathological mechanism responsible for CHD, PVD, and cerebrovascular diseases. In the process of atherosclerosis, production of inflammatory cytokines stimulates monocytes to invade the subendothelial space of vessels and ingest oxidized low-density lipoprotein (LDL) via scavenger receptors. The resulting cells develop a characteristic “foamy” appearance, and therefore are referred to as “foam cells.” Foam cells coalesce to form a fatty streak (indicator of early atherosclerosis) in the walls of arteries. Continued inflammation attracts more monocytes, causing the plaque to progress. The plaque eventually consists of collagen, proteoglycans, fibronectin elastic fibers, crystalline cholesterol, cholesterol esters, phospholipids, monocyte-derived macrophages (foam cells), T lymphocytes, smooth muscle cells, and blood vessels from neovascularization.⁵ Inflammatory cytokines also promote smooth muscle cell migration and proliferation, which will provide the collagen used to stabilize the plaque.⁶ Normally, the endothelial cells produce nitric oxide, which is a potent vasodilator, but nitric oxide also plays a role in inhibiting platelet activation and decreasing inflammation by decreasing leukocyte adhesion and migration into the wall of the vessel. Additionally, nitric oxide reduces smooth muscle cell proliferation and migration.⁷ Nitric oxide changes may play a part in vascular dysfunction in patients with diabetes.

There are multiple mechanisms by which diabetes is thought to promote atherosclerosis. Hyperglycemia inhibits endothelial nitric oxide production by blocking nitric oxide synthase activity as well as increasing oxidative stress. Insulin resistance causes excess free fatty acid liberation from adipose tissue, which can also interfere in the nitric oxide synthesis pathway. Diabetes also increases matrix metalloproteinase activity, which leads to collagen breakdown. This may subsequently destabilize the fibrous cap of plaques, making them more prone to rupture and to form thrombi. Hyperglycemia also causes platelet impairment by disrupting intraplatelet calcium homeostasis. Finally, diabetes promotes tissue factor and factor VII production, in addition to lowering antithrombin III and protein C levels, causing a more hypercoagulable state.⁸

Cardiovascular Complications

CHD is the number one cause of mortality in people with diabetes in the United States, accounting for up to 70% of deaths in this population.⁹ Specifically, diabetes has been shown to be an independent risk factor for cardiovascular events—both fatal and nonfatal—in elderly patients.¹⁰ In fact, patients with diabetes have a two- to fourfold increased risk of experiencing cardiovascular events as compared with their nondiabetic counterparts.¹¹ Cardiovascular events include myocardial infarction (MI), stroke, heart failure, need for cardiovascular revascularization, and cardiac-related death. It has been shown previously that with tight glycemic control there is a significant improvement in risk of microvascular complications of diabetes,¹² but until recently there have been few studies on the effects on macrovascular complications, specifically CHD.

Recently, the Action to Control CardiOvascular Risk in Diabetes (ACCORD) trial,¹³ Action in Diabetes and Vascular disease: preterAx and diamicroN MR Controlled Evaluation (ADVANCE) trial, ¹⁴ and Veterans Affairs Diabetes Trial (VADT)¹⁵ addressed this. All three studies showed no significant decrease in cardiovascular outcomes with intense glycemic control. In fact, the ACCORD trial was stopped early because the mortality rate in the intense glycemic control group was unacceptably high. It is unclear as to why this was the case. At initial glance, one would think that the intense glycemic control group had more hypoglycemia, and therefore increased morbidity and mortality, but the subgroup analysis did not show this. Although the Diabetes Control and Complications Trial (DCCT) showed that there was a 57% decrease in cardiovascular risk factors with improved glycemic control in young persons with type 1 diabetes, this was only evident after nine years, not in the short term.¹⁶ It has been hypothesized that the cardiovascular benefits of tight glycemic control may not be visible unless followed long-term. Additionally, from these data, there is a suggestion that patients with less insulin resistance, dyslipidemia, and obesity would receive the most cardiovascular risk reduction from tight glycemic control. Although it was not shown to be statistically different, in the VADT study the intense glycemic control group had fewer cardiovascular events, possibly due more to improved blood pressure control, aspirin usage, HMG-CoA reductase inhibitor (statin) usage, and intense smoking cessation counseling rather than glycemic control.¹¹

Based upon this information, the authors speculate that it is important to weigh the risks and benefits of tight glycemic control in elderly patients with diabetes when considering the titration of diabetes medications in older persons. The benefit of statin usage is described further in the “Dyslipidemia” section below. Also, with regard to decreasing cardiovascular risk in patients with diabetes, aspirin has been clearly established to be beneficial in both primary and secondary prevention in elderly patients, and therapy should be considered if there are no contraindications.¹⁷

Cerebrovascular Disease and Hypertension

In 2004, 16% of deaths in elderly patients with diabetes were attributed to stroke.¹⁸ Diabetes increases stroke-related mortality, doubles recurrent stroke risk, and triples the frequency of stroke-related dementia.¹⁹ The relationship between diabetes and stroke is unclear; there have been multiple studies that have examined whether hyperglycemia in and of itself causes an increased risk of stroke, but these studies have been inconclusive.¹⁹ Another proposed diabetic mechanism is that of insulin resistance shown by either basal hyperinsulinemia or impaired glucose tolerance. Studies examining insulin resistance and whether it confers a higher risk of stroke have shown this to be true, though the magnitude of this relationship is unclear; insulin resistance is more strongly correlated in cardiovascular disease.²⁰

Hypertension is present as a comorbid condition in 20-60% of patients with diabetes.²¹ It is well established that the number one risk factor for stroke is hypertension.²² In the Greater Cincinnati/Northern Kentucky Stroke Study,²³ 79% of patients (average age, 70 yr) with diabetes (type 1 or 2) had hypertension. This study showed that the increased prevalence of hypertension among persons with diabetes conferred an increased risk of stroke as compared with nondiabetic counterparts.²³ In the United Kingdom Prospective Diabetes Study (UKPDS),¹² each 10-mm Hg reduction in mean systolic blood pressure was associated with a 12% reduction in any diabetic complication, 15% reduction in deaths related to diabetes, 11% reduction in MI, and 13% reduction in microvascular complications. Furthermore, in the Systolic Hypertension in the Elderly Program (SHEP)²⁴ and the HYpertension in the Very Elderly Trial (HYVET²⁵; both studies exclusively examined the effects of blood pressure in patients age 60+ and 80+ yr, respectively), there was an improvement in morbidity and mortality from blood pressure control. Specifically, the SHEP study showed a significant decrease in cardiovascular events, strokes, and all-cause mortality in patients who had blood pressure control with chlorthalidone at five years, a phenomenon more magnified in their diabetic subpopulation.²⁴ In the HYVET study, in which 6-7% of patients had diabetes, when blood pressure was controlled there was a statistically significant decrease in cardiovascular events and all-cause mortality.²⁵ For this reason, the American Geriatrics Society (AGS)²⁶ and the American Diabetes Association (ADA)²⁷ recommend blood pressure control to be 140/90 mm Hg and 130/80 mm Hg, respectively, if possible, in adults with diabetes age 65 years and older. Additionally, aspirin therapy should be considered, as it also has been shown to reduce recurrent strokes in elderly patients.¹⁷

Dyslipidemia

Diabetic dyslipidemia (the most common lipid abnormality in persons with type 2 diabetes) consists of an increased serum triglyceride concentration, an increased small density LDL concentration, and a decreased high-density lipoprotein (HDL) concentration. The plasma LDL levels in these patients are frequently normal. Normally, triglycerides are transferred from very low–density lipoprotein (VLDL) to HDL by cholesterol esterase protease, which creates triglyceride-rich HDL particles. These particles are then hydrolyzed by hepatic lipase, which will lead to rapid plasma clearance. It is thought that increased insulin resistance causes increased free fatty acid flux to the liver, which will then subsequently increase hepatic VLDL secretion and other apolipoprotein B–containing lipoprotein particles. Insulin resistance decreases the suppressive effect of insulin on apolipoprotein B secretion (either at the regulation level of apolipoprotein B degradation or by inhibition of microsomal triglyceride treatment protein activity).²⁸

Previously, it has been shown that elevated serum triglyceride levels and low HDL levels are each independent risk factors for CHD. Therefore, it is hypothesized that the diabetic dyslipidemic syndrome is part of the major driving force of increased incidence of cardiovascular events in persons with diabetes. Although the mainstay of treatment has been statin therapy to reduce cardiovascular risk by reducing LDL concentrations, this is likely inadequate for patients with diabetes, as they may also need therapy for their hypertriglyceridemia and low HDL levels.²⁹

The goal in the elderly patient should be to treat dyslipidemia based on life expectancy. A meta-analysis of recent statin therapy–based trials showed a five-year morbidity and mortality benefit in patients with diabetes taking a statin, irrespective of initial LDL levels; the meta-analysis included a sub-analysis of the elderly participants.³⁰ The Veterans Affairs High-density lipoprotein cholesterol Intervention Trial (VA-HIT)³¹ showed a 6% improvement in HDL levels, 4% reduction in cholesterol levels, and 31% reduction in triglyceride levels in patients treated with gemfibrozil at one year. This subsequently translated to a 22% reduction in cardiovascular events in this patient population at two years.³¹ Based on this study, in which 70% or more of the patients were over 60 years old, the AGS recommends the use of fibrates in patients with hypertriglyceridemia and low HDL levels.²⁶ It is important to note, however, that only 25% of patients had diabetes in the study population. There has recently been some evidence that extended-release niacin therapy could be useful in improving both HDL levels and endothelial function in persons with diabetes, but this has not been extensively studied in the elderly population.³² Additionally, recent studies show that niacin may increase insulin resistance, and therefore transiently worsen glucose control, so this is still somewhat controversial.³³ Unfortunately, there have not been many large studies examining the effects of lipid control in the elderly population with diabetes, so many recommendations are extrapolated from data using younger individuals. There seems to be a clear benefit of lipid control in diabetes, even in the short term, in terms of morbidity and mortality, and so lipid therapy should be considered for all patients with diabetes, regardless of age.

Peripheral Vascular Disease

PVD affects approximately 12 million individuals in the United States, of which 20-30% have diabetes. Diabetes is associated with a two to four times increased incidence of PVD when compared with nondiabetic counterparts. Additionally, an abnormal ankle-brachial index has been found in up to 15% of the diabetic population.¹⁹ Prevalence of PVD increases with age, duration of diabetes, and presence of peripheral neuropathy. The pathogenesis of diabetic PVD was described in the “Atherosclerosis” section above. It is important to note, though, that there is a specific PVD pattern in persons with diabetes. They tend to experience more distal stenosis, with typical affected vessels being popliteal or run-off vessels below the knee, anterior tibial, posterior tibial, and peroneal arteries. Due to the fact that the distal limb vessels are more affected, there are often limited revascular options.¹⁹

Elderly patients with diabetes who have PVD and no history of cardiovascular disease are at a 1.5 times higher risk of a cardiovascular event as compared with their nondiabetic counterparts with PVD who have had a MI.³⁴ For this reason, it is important to risk modify as much as tolerated. Studies in younger individuals show a significant benefit from smoking cessation, especially reduced rates of intermittent claudication and symptoms.³⁵ This has not been thoroughly evaluated in the elderly population, however. Blood pressure control, controlling LDL levels, treating hypothyroidism, and moderate exercise have all been shown to reduce cardiovascular events in older patients with preexisting PVD. Most of these treatments have not been shown to improve PVD symptoms or progression in the elderly population. Aspirin has been shown to decrease vascular death, nonfatal stroke, and nonfatal MI in patients with a higher risk for these complications who also have PVD. There has been no evidence that high-dose aspirin provides any more benefits, though it does portend a higher risk of gastrointestinal bleeding than low-dose aspirin. The hematologic side effects of ticlopidine limit its use in the elderly. Aspirin in combination with dipyridamole has shown additional benefit over aspirin alone in secondary stroke prevention.³⁶ Clopidogrel has been shown to be more beneficial than aspirin in reducing vascular complications and cardiovascular and cerebrovascular events, and also carries Food and Drug Administration approval for the treatment of PVD, which aspirin does not. Angiotensin-converting enzyme inhibitors, in patients who do not have a contraindication to their use, have also been shown to reduce cardiovascular events. In one study of patients (mean age, 80 yr) who had PVD and a history of MI, when given a beta blocker (only patients with no contraindication were given this), there was a 53% reduction in new cardiovascular events.³⁷ Statins have been shown in older populations to give significant symptom relief from claudication as well as the cardiovascular benefits mentioned above in the “Dyslipidemia” section. Cilostazol has been shown to increase the distance patients are able to walk, but has a host of contraindications that should be reviewed prior to administration. Surgical revascularization can also be considered in severe cases.³⁷

Metabolic Syndrome and Obesity

No discussion of diabetes is complete without considering the effects of metabolic syndrome and obesity. Metabolic syndrome is considered to be the constellation of dysglycemia, hypertension, hypertriglyceridemia, low HDL levels, and obesity (specifically, central adiposity). Patients with this syndrome have twice the risk of a cardiovascular event as compared with their counterparts without metabolic syndrome. They also carry a five-times increased risk of developing type 2 diabetes.³⁸ Obesity is on the rise in the elderly population. From 1990 to 2000, the prevalence of obesity in the elderly population rose from 24% to 31% in the United States, and is predicted to rise up to 36-42% by 2010.³⁹ Not only do metabolic syndrome and obesity confer a higher risk of morbidity and mortality, they are also associated with more cognitive decline in the elderly. The main pathophysiologic mechanism of the metabolic syndrome is insulin resistance, which is discussed in detail above. It has been shown that weight loss promotes insulin sensitivity, and improves physical performance and quality of life in the elderly. Other treatment options include therapies that increase insulin sensitivity.³⁸

Conclusion

The macrovascular complications of diabetes are the main cause of morbidity and mortality in elderly patients with diabetes. Though there are limited studies devoted to studying these as well as their treatment in the elderly population, some information from studies of younger populations can be extrapolated. Such information has been used in both the ADA and the AGS guidelines for diabetes treatment in the older patient. The confounding variables that limit prevention and treatment of macrovascular complications include the risk/benefit ratio as compared to life expectancy, cost of therapy, and cognitive impairment. It is difficult for elderly individuals to afford healthcare, much less medications and treatments that could improve their comorbidities, so it is important for clinicians to take this into account when prescribing a treatment plan. Additionally, varying degrees of cognitive impairment often make treatment strategies different from that which may be recommended for younger individuals. The focus of treatment, therefore, should be on ensuring the safety of the patient as well as making changes that improve quality of life and possible reduction in mortality whenever possible.

Dr. Gunasekaran is a Fellow, and Dr. Fowler is Assistant Professor of Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN. Dr. Fowler is also Associate Editor of Clinical Diabetes, and Director of the Vanderbilt Diabetes Outreach, Vanderbilt University Medical Center.

The authors report no relevant financial relationships.

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