Preventing Heart Disease in Patients with Diabetes

US Pharm. 2006;11:15-18.

According to statistics from the American Diabetes Association (ADA), approximately 21 million children and adults in the United States have diabetes.¹ In 2005, 1.5 million new cases of diabetes were diagnosed in patients older than 20.¹ Additionally, diabetes may be undiagnosed in approximately one third of patients with the condition. Many patients are unaware of the symptoms of diabetes, such as polydypsia (thirst), polyuria (frequent urination), fatigue, and blurry vision. Unfortunately, some patients who seek medical attention after the development of symptoms may already have heart disease. Thus, more attention has been given recently to earlier diagnosis of diabetes, as well as to prevention and control of complications such as heart disease.

Pharmacists have become increasingly involved in the care of patients with diabetes and may have important roles in the prevention and treatment of diabetes and its complications.

Heart Disease as a Complication of Diabetes
Complications that occur as a result of diabetes progression are grouped into two major categories: macrovascular and microvascular. Macrovascular complications include coronary artery disease, cerebral vascular accident (stroke), and peripheral vascular disease. Microvascular complications include nephropathy, retinopathy, peripheral neuropathy, and autonomic neuropathies. Autonomic neuropathies consist of gastroparesis, urinary retention, and male impotence. 

Having diabetes increases a patient's risk for heart attack, stroke, and other complications related to poor circulation. A major cause of death in patients with diabetes is cardiovascular disease.^1,2 When a patient has several risk factors, such as high blood pressure, hyperlipidemia, and diabetes, he or she is at increased risk for a cardiovascular event.^1,2 A twofold to fourfold increased risk for coronary heart disease and stroke is seen in patients with type 2 diabetes.¹ Aggressive control of blood lipids can decrease cardiovascular complications by 20% to 50%.^2,3 Typically, individuals with diabetes have hyperlipidemia characterized by increased triglyceride levels and low HDL chlesterol levels.³ LDL or total cholesterol levels may or may not be elevated. The term metabolic syndrome has been given to patients with abnormal lipid levels, obesity, hypertension, and hyperglycemia. Patients with hyperglycemia may have diabetes or impaired glucose tolerance, the latter of which may actually represent a prediabetic state.

The drug class properly known as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG Co-A) inhibitors are commonly referred to as statins and include agents such as atorvastatin, pravastatin, simvastatin and rosuvastatin. Statins have become the drugs of first choice for treating dyslipidemia in diabetic patients. Although some high-risk patients may develop muscle toxicity, statins are generally well tolerated by most  people with diabetes. However, statins should not be used in women of childbearing potential since they are known teratogens (pregnancy category X).

Statins appear to have beneficial cardiovascular pleiotropic effects (i.e., actions of a drug other than those for which the drug was originally developed. These effects are usually not anticipated and may or may not be related to the primary mechanism of action of the drug. One might even view pleiotropic effects as a surprising but beneficial side effect of a drug). General pleiotropic effects of statins include improvement of endothelial dysfunction, antioxidant properties, inhibition of inflammatory responses, and stabilization of atherosclerotic plaques.⁴ These properties, in combination with the lipid-lowering effects of statins, can lead to long-lasting cardiovascular protective effects.  

Endothelial injury has an important role in the initiation of the atherogenic process within blood vessels. Endothelial dysfunction is an early manifestation of vascular injury and can lead to vasoconstriction because of impaired synthesis, release, and activity of endothelium-derived nitric oxide.⁴ Clinical trials have demonstrated that statins exert these beneficial effects on the endothelium, regardless of the degree of lipid-lowering effects; however, the exact magnitude of endothelial benefit in patients with diabetes remains unclear. 

C-reactive protein (CRP) is a relatively nonspecific marker of inflammation. Some clinicians and researchers consider elevated CRP levels to be a positive risk factor for coronary artery disease, heart attack, and cardiovascular events, in general.⁴ However, the exact role of CRP in coronary artery disease remains unclear. It is not known whether CRP is merely a marker of disease or whether it actually plays a role in causing atherosclerotic disease. Statin therapy has been thought to reduce vascular inflammation by reducing CRP levels and lowering the risk of cardiovascular events.⁴ Other pleiotropic vascular effects attributed to statins include inhibition of thrombus formation (antithrombotic activity), enhancement of plaque stability, and decreasing oxidative stress.⁵ The pleiotropic effects of statins have been brought into the spotlight in recent years, and many clinical trials are being conducted to determine the significance, if any, of these effects.

General Recommendations for Patients with Diabetes
The ADA's 2006 practice guidelines recommend the following clinical targets for adults with diabetes: HbA1c below 7%, blood pressure  below 130/80 mmHg, fasting blood glucose at 90 to 130 mg/dL, LDL cholesterol level below 100 mg/dL, triglycerides below 150 mg/dL, and HDL cholesterol level greater than 40 mg/dL. ¹ Alcohol consumption should be limited to no more than one drink per day for adult women and two drinks per day for adult men. All patients with diabetes and hypertension should be treatedwith either an angiotensin-converting enzyme inhibitor (e.g., lisinopril) or an angiotensin receptor antagonist (e.g., losartan). Dosages should be increased as tolerated to achieve blood pressure targets, and a thiazide diuretic should be added to the treatment regimen if patients require a second agent.

Management of coexisting conditions other than hypertension (e.g., obesity, tobacco dependence) must be a top priority when taking steps to prevent heart disease in patients with diabetes. Some interventions to reduce cardiovascular risks in patients with diabetes include smoking cessation, weight loss, appropriate dietary changes (e.g., caloric restriction; reduced intake of saturated fats, sodium, and sugars), and regular exercise. In addition, prophylactic aspirin may reduce the risk of heart disease in individuals with diabetes. The following is recommended by the ADA: aspirin 75 to 162 mg/day (roughly equivalent to 1 to 2 "baby aspirin" per day) as a secondary prevention strategy in those with diabetes with established coronary disease. The same regimen is recommended as primary prevention in patients with diabetes who are at increased cardiovascular risk, including those older than 40 or those who have additional risk factors (e.g., family history of coronary disease, hypertension, smoking, dyslipidemia, or albuminuria).

Based on recent clinical trials, the National Cholesterol Education Program Adult Treatment Panel III revised its 2001 guidelines to include a reduction in LDL cholesterol levels to below 70 mg/dL as an option in very high-risk patients with overt cardiovascular disease (e.g., patients with established heart disease). ⁶ The combination of a statin drug with other lipid-lowering drugs (e.g., ezetimibe, nicotinic acid) may allow achievement of lower LDL cholesterol level targets in such patients.

Preventing Heart Disease in Patients with Diabetes
ASCOT-LLA: The objective of the Anglo-Scandinavian Cardiac Outcome Trial–Lipid-Lowering Arm (ASCOT-LLA) was to determine the benefit of lowering cholesterol in diabetic patients without coronary disease but with well-controlled hypertension and cholesterol levels at or below average values.⁷ The parent study, the ASCOT trial, evaluated hypertension but did not focus exclusively on patients with diabetes; however, a large subset of patients with diabetes were enrolled, and lipid-lowering effects were studied. ASCOT-LLA can be considered a primary prevention study, since participants had not yet had a stroke or a major coronary event, such as a myocardial infarction or coronary artery bypass surgery.

In ASCOT-LLA, 10,305 hypertensive patients with no history of coronary heart disease but at least three cardiovascular risk factors were randomized to receive placebo or atorvastatin 10 mg once daily. Risk factors included current cigarette smoking, albumin or protein in the urine, type 2 diabetes, male gender, and family history of premature heart disease. Cardiovascular outcomes in a subgroup of 2,532 patients with type 2 diabetes were assessed. 

Findings demonstrated that, among patients with diabetes, total and LDL cholesterol levels were significantly lower in the atorvastatin group than in the placebo group. More significantly, during an average follow-up period of 3.3 years, 116 (9.2%) major cardiovascular events occurred in the atorvastatin group, compared with 151 (11.9%) events in the placebo group (hazards ratio, 0.77; 95% CI, 0.61 to 0.98; P = .036).⁷ The use of atorvastatin was associated with a 16% reduction in coronary heart disease in patients with hypertension and type 2 diabetes who did not have a history of heart disease or significantly elevated cholesterol levels.⁷ This study showed that atorvastatin reduced the risk of major cardiovascular events by 23% (hazard ratio, 0.77; 95% CI, 0.61 to 0.98; P = .036) in the group of diabetic patients with well-controlled hypertension and no history of heart disease or elevated cholesterol levels. It is important to note that the patients in this study had hypertension and may not be representative of the general diabetes population. 

The CARDS Trial: The Collaborative Atorvastatin Diabetes Study (CARDS) assessed the use of 10 mg of atorvastatin compared to placebo for primary prevention of cardiovascular disease in patients with type 2 diabetes.⁸ A total of 2,838 patients with type 2 diabetes were randomized to receive either placebo or atorvastatin 10 mg once daily. The patients had no previous history of cardiovascular disease, LDL cholesterol levels below 160 mg/dL, triglyceride levels below 600 mg/dL, and at least one of the following: retinopathy, albuminuria, positive current smoking status, or hypertension. Primary end points were time to acute coronary heart disease event, coronary revascularization, or stroke.⁸

Compared with the placebo group, the atorvastatin group had a 36% reduction in acute coronary events, a 31% reduction in coronary revascularization events, and a 48% reduction in stroke. The CARDS trial showed that atorvastatin 10 mg once daily leads to an overall 37% reduction in major cardiovascular events in patients with type 2 diabetes with no previous history of cardiovascular disease and without highly elevated LDL cholesterol levels. Also, atorvastatin reduced the all-cause mortality rate by 27%. Adverse events in the trial were similar in the atorvastatin and placebo groups. 

One criticism of the CARDS trial is that it may not be widely generalized to today's treatment of patients with diabetes; this is because patients in the CARDS trial were enrolled between November 1997 and June 2001, before lower LDL cholesterol level targets had been recommended. In CARDS, the beneficial treatment effect conferred by the statin drug did not vary by pretreatment (baseline) cholesterol level.

The Heart Protection Study: In the Heart Protection Study, 14,573 patients with occlusive arterial disease but without a diabetes diagnosis, as well as an additional 5,963 patients with diabetes, were randomized to receive either simva­ statin 40 mg once daily or placebo. ³ An average reduction of 39 mg/dL in LDL cholesterol level was observed during the five-year period in the simvastatin group compared with the placebo group. 

Among patients with diabetes, there was a 22% (95% CI) reduction in the rate of vascular events (601 events in the simvastatin group vs. 748 events in the placebo group).³ A 33% (95% CI, P = .0003) reduction in vascular events was observed among the 2,912 patients with diabetes who did not have any occlusive arterial disease at study entry, and a 27% reduction (95% CI, P = .0007) in vascular events was observed among the 2,426 patients with diabetes whose pretreatment LDL cholesterol level was below 116 mg/dL.³ This study further proves that cholesterol-lowering therapy is beneficial in patients with diabetes, regardless of whether they have hyperlipidemia or coronary artery disease. The investigators concluded that statin therapy should be used routinely for all patients with diabetes who are at sufficiently high risk for major vascular events, irrespective of their baseline lipid profile. 

Implications for Pharmacy Practice
Preventing heart disease in patients with diabetes should become a major public health initiative. In a study involving more than 8,000 outpatients with diabetes and/or cardiovascular disease, only about 50% of patients were currently being treated to achieve recommended target LDL cholesterol levels.⁹ Investigators concluded that many patients receive suboptimal treatment and do not achieve target cholesterol levels, despite the widespread availability of safe and effective lipidlowering drugs such as statins. Some controversy exists about the routine use of statins for primary prevention in all patients with diabetes who are at low risk of coronary disease.¹⁰ One could argue that diabetes is a progressive disease and that many patients will eventually develop some degree of both microvascular and macrovascular disease. Indeed, the most equivocal case in which to start a statin for primary prevention is in a patient with diabetes who is older than 40, has an LDL cholesterol level below 100 mg/dL, and is at low risk for coronary disease. However, almost all other patients with diabetes should qualify for long-term statin use, based on available evidence. 

Pharmacists have an important role in the management of patients with diabetes and, specifically, in the prevention of heart disease in such patients. Many patients with diabetes are either not receiving a statin or not achieving target LDL cholesterol levels despite statin therapy; therefore, pharmacists should collaborate with physicians and recommend appropriate therapy.⁹ Pharmacists can optimize choles­ terol-lowering therapy by addressing cost and formulary concerns, recommending the drug and dose most likely to achieve target LDL cholesterol levels, screening for potential drug or disease-state interactions, and teaching patients about the early symptoms of statin-induced muscle toxicity and other adverse drug effects.

Pharmacists can also assist patients and physicians by addressing common diabetic comorbidities--such as tobacco dependence, hypertension, and obesity--both with phar­ maco­ therapy and lifestyle advice. Pharmacists can also work to ensure that patients with diabetes are vaccinated for influenza and pneumococcal disease, when appropriate. They can teach patients basic principles of diabetes self-management and work with patients and physicians to ensure that optimal blood glucose levels are achieved. Lastly, pharmacists can help promote patient adherence to the prescribed regimen and can work to remove any barriers to effective treatment that may exist.

REFERENCES
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3. Collins R, Armitage J, Parish S, et al. Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005-2016.
4. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation. 2004;109(23 suppl 1):39-43.
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7. Sever PS, Poulter NR, Dahlof B, et al. Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA). Diabetes Care. 2005;28:1151-1157.
8. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685-696.
9. Yan AT, Yan RT, Tan M, et al. Contemporary management of dyslipidemia in high-risk patients: targets still not met. Am J Med. 2006;119(8):676-683.
10. Costa J, Borges M, David C, Vaz Carneiro A. Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. BMJ. 2006;332:1115-1124.

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