Diabetes and Cardiovascular Disease

     Long-term exposure to hyperglycemia that characterizes both type 1 and type 2 diabetes mellitus predisposes the patient to a host of interrelated risks and ensuing complications that affect every organ system. While many and varied, complications can generally be traced back to either microvascular, that affect primarily small vessels and capillary beds, or macrovascular, that affect larger vessels. The distinction between the two begins to blur with various neuropathies and vasculopathies that can affect both to some degree, and the patient experiencing one complication almost invariably experiences others.

Table 1: Common Complications Of Diabetes Atherosclerosis/hypertension/increased risk of cardiovascular complications (congestive heart failure and myocardial infarction)
* Dyslipidemias
* Obesity in type 2
* Peripheral vascular disease
* Neuropathy: Peripheral, autonomic and polyneuropathies
* Retinopathy and other ocular complications
* Gum disease
* Claudication
* Foot ulcers
* Hyperinsulinemia and insulin resistance in type 2
* Hypoglycemia in treated type 2
* Chronic hyperglycemia
* Diabetic ketoacidosis in type1

     While the impact of any of these complications can be devastating, cardiovascular disease is the big killer among them, accounting for 90% of mortalities among diabetic patients. Mortality due to cardiovascular disease is 7.5 times as likely for the type 2 diabetic than the non-diabetic, so reducing the impact of cardiovascular disease should be a primary goal of treatment.1

The Risk Factors
    In order to discuss the risk factors with diabetic patients, one must understand their interrelationships. A cardiometabolic syndrome is increasingly recognized as a collection of risk factors associated with both type 2 diabetes and cardiovascular disease.1

Typical of the syndrome are:
* Insulin resistance and resultant hyperinsulinemia – Type 2 diabetes is considered primarily a function of insulin resistance, where available insulin is unable to interact with appropriate cellular receptors in order to properly facilitate utilization of glucose. In response to inadequate glucose utilization and resulting hyperglycemia, the pancreas is stimulated to produce more insulin. Though this increase in insulin secretion can facilitate transport of glucose into target cells, blood levels of both glucose and insulin commonly persist. The associated dyslipidemias, hypertension, and hyperinsulinemia, collectively referred to as Syndrome X, are considered consequences of insulin resistance.2
* Visceral obesity, more common in men, is also seen in women, particularly diabetic and postmenopausal women.
* Albuminuria – Albumin in the urine is a sign and marker of diabetic nephropathy. As blood flow to the kidneys increases as a result of hypertension and endothelial damage, hyperfiltration through the glomeruli increases levels of albumin in the urine. Progressive kidney damage is not only a result of hypertension, but contributory cause as well.3
* Degree of hypertension usually correlates with degree of insulin resistance. As insulin levels increase, sodium excretion decreases, causing sodium retention and increasing the likelihood of hypertension or exacerbating it. Further, hyperinsulinemia probably impairs intracellular transport of glucose in itself as well as membrane sodium pumps; and it increases levels of norepinephrine, which not only contributes to smooth muscle tone but also affects muscular glucose uptake and hepatic glucose production. Insulin resistance also enhances proliferation of arteriolar smooth muscle and deposition of collagen, cholesterol, and triglycerides to accelerate atherosclerosis and impair vascular elasticity and permeability.2
* Typical diabetic dyslipidemias -- elevated triglycerides levels, predominance of small and dense LDL particle sizes, and reduced levels of HDL cholesterol, tend to accelerate atherosclerotic processes.
* Coagulation abnormalities -- Hypercoagulation is a common finding, with a decrease in fibrinolysis due to elevations in plasminogen activator inhibitor-1,and causing an increase in thrombotic tendency. To compound this problem, platelets show hyperactivity and increased aggregability.1
* Endothelial dysfunction – Vascular endothelium in the diabetic tends to express abnormal amounts of adhesion molecules that attract platelets and inflammatory cells and exacerbate vasculopathies. 1
* Left ventricular hypertrophy is a predictable response to longstanding hypertension.
* Orthostatic hypotension and loss of circadian rhythms in blood pressure are consequences of vasculopathies that impair vascular elasticity and autonomic neuropathy that impairs arterial response.

    Since cardiovascular disease in the diabetic is often considered a direct result of early and aggressive development of atherosclerosis seen in diabetes, early measures should be taken to reduce these risk factors in order to maintain quality of life. The pharmacist can play a key role in therapy by making patients aware of these risk factors and helping to minimize them as much as possible. While the above discussion may be overkill to many patients, most can understand a basic explanation of these primary risk factors that can be recognized and minimized. The following information is provided to help patients understand the problem, steps to help prevent or delay development of cardiovascular disease, and oral antidiabetic options.

Information For The Patient
     The type 2 diabetic is much more prone to development of cardiovascular disease than the non-diabetic and much more likely to suffer its fatal consequences of heart attack and congestive heart failure. Recognizing the risk factors and controlling them is the only way help reduce the likelihood of developing or delaying these cardiovascular complications.

Controllable Risk Factors of Cardiovascular Disease in the Type 2 Diabetic
* Hyperglycemia (high blood glucose levels)
* Hyperinsulinemia (high levels of insulin)
* Hypertension (high blood pressure)
* Dyslipidemias (abnormalities in levels of blood lipids)
* Obesity
* Smoking

How To Minimize Your Risks
    Close glycemic control has been demonstrated conclusively to reduce the risks of developing the microvascular complications of diabetes; and though clinical studies have yet to prove the same concerning macrovascular complications, it is logical to conclude that similar benefit is to be gained in preventing or delaying cardiovascular disease. Since hyperinsulinemia, hypertension, and dyslipidemias are generally noted as more problematic in the diabetic with poor glycemic control, improving glycemic control commonly makes these other problems more manageable.4
    Smoking should be eliminated from the diabetic’s lifestyle if at all possible, as it tremendously increases the effects of most other risk factors. Obesity produces similar effects on the other risk factors, so exercise and weight control are essential components of any diabetic treatment plan. This can make glycemic control more manageable and thus reduce other risks. Hypertension and dyslipidemias must often be treated aggressively with medication in the diabetic in order to bring them into acceptable ranges in spite of successful lifestyle changes and close glycemic control, and aspirin therapy is now recommended for most type 2 diabetics when not contraindicated.5,6 Studies have shown that elevated blood pressure is more profoundly associated with cardiovascular disease in the diabetic than in the non-diabetic and that controlling blood pressure is actually more effective at reducing the risk of cardiovascular disease in the diabetic than is controlling blood glucose levels.1

Oral Antidiabetic Medications7,8
    Five types of antidiabetic medications are currently available to help the type 2 diabetic control levels of blood glucose and thus reduce the other risk factors for cardiovascular disease. Oral medications are used for patients unable to adequately control blood glucose levels by management of diet, exercise, weight control, and smoking cessation. Most can be used alone or with various others in certain situations, and the various differences in absorption, elimination, side effects, and dosing among these medications make each more or less appropriate for individual patients.
Sulfonylureas increase production of insulin by the pancreas. For diabetics whose insulin production has declined, these medications can be very beneficial; but pancreatic function is essential. Irregularities in diet or exercise can allow them to cause episodes of hypoglycemia, and they can cause or worsen hyperinsulinemia.

Sulfonylureas
Chlorpropamide
Tolbutamide
Tolazamide
Acetohexamide
Glyburide
Glipizide
Glimepiride

    Repaglinide is the only meglitinide currently available, and it too enhances insulin production by a functioning pancreas. It is given before each meal to reduce the sharp increase of blood glucose levels that follow a meal. It can be skipped if one misses a meal and an additional dose is taken when additional meals are eaten.
     Metformin is currently the only biguanide used in this country, and a functioning pancreas is not essential for it to reduce the amount of glucose produced by the liver and absorbed by the intestines and to improve uptake by muscles (improves insulin sensitivity). When used alone, it does not cause hypoglycemia, cause hyperinsulinemia, or weight gain.
     Alpha-glucosidase inhibitors impair the function of intestinal enzymes necessary for absorption of ingested starches and sugars. The resulting slower absorption delays and diminishes sharp rises in blood glucose that otherwise follow meals, so they are taken with meals. Their action does not depend upon a functioning pancreas, and hypoglycemia is rare when these agents are used alone.

Alpha-glucosidase inhibitors
Acarbose
Miglitol

    Thiazolidinediones, the latest developments in oral antidiabetic medication, have no direct effect on pancreatic insulin production, but work instead by improving insulin sensitivity, enhancing uptake of blood glucose by reducing insulin resistance to utilize available insulin. They do not cause hypoglycemia when used alone, do not cause weight gain, and can improve blood lipid levels in addition to helping control blood glucose levels.

Thiazolidinediones
Pioglitazone
Rosiglitazone

References
1. Francisco R, Sower J, Diabetes and Hypertension. Medscape Cardiology, 2000. Available at http://www.medscape.com/medscape/cardiology/2000/v04.n04/mc0719.fran/mc0719.fran-01.html. Accessed July 25, 2000.
2. Orzek E. Insulin Resistance: Understanding its association with Syndrome X. Available at: http://www.orzeck.com/con2.html. Accessed July 24, 2000.
3. Kidney Disease of Diabetes. National Diabetes Information Clearinghouse. Available at: http://www.niddk.nih.gov/health/diabetes/pubs/kdd/kdd.htm#thecourse. Accessed July 20, 2000.
4. Kim D, Prevention of Cardiovascular Disease in Diabetes. 60th Scientific Sessions of the American Diabetes Association. Available at: http://www.medscape.com/medscape/cno/2000/ADA/Story.cfm?story_id=1382. Accessed July 22, 2000. 5. Research spots major opportunity to reduce diabetes complications. Press release. American Diabetes Association Press Release. Available at: http://www.diabetes.org/am99/pressreleases/aspirin. Accessed July 21, 2000.
6. Actos: Treatment Options for Type 2 Diabetes. Available at: http://www.actos.com/trt_opts/treat.htm. Accessed July 21, 2000.
7. Drug Facts and Comparisons, Electronic edition, June, 2000.