Am Fam Physician. 2004;70(4):775-777
The Clinical Efficacy Assessment Subcommittee of the American College of Physicians (ACP) recently published a guideline on the management of dyslipidemia, particularly hypercholesterolemia, in patients with type 2 diabetes mellitus. The guideline appeared in the April 20, 2004, issue of Annals of Internal Medicine, and the full text can be accessed online athttp://www.annals.org.
Vascular complications are the most common cause of adverse outcomes in patients with type 2 diabetes. These complications generally are classified as microvascular (including retinopathy, nephropathy, and neuropathy, although the latter may not be entirely a microvascular disease) or macrovascular (e.g., coronary artery disease, cerebrovascular disease, peripheral vascular disease).
To decrease or prevent the progression of microvascular complications, diabetes management should encompass metabolic control and control of cardiovascular risk factors.
The ACP guideline was based on a systematic review of the evidence, which was presented in a background paper by Vijan and colleagues that appears in the same issue. Only studies that measured clinical end points (i.e., all-cause mortality, cardiovascular mortality, and cardiovascular events) were included. In this guideline, the ACP subcommittee addressed the following questions:
What are the benefits of tight lipid control for primary and secondary prevention in patients with type 2 diabetes?
What is the evidence for treating to certain target levels of low-density lipoprotein (LDL) cholesterol for patients with type 2 diabetes?
For patients with type 2 diabetes, are certain lipid-lowering agents more effective or beneficial?
The ACP guideline was created for all physicians who care for patients with type 2 diabetes. The target patient population is all persons with type 2 diabetes, including those who already have some form of microvascular complication and, especially, premenopausal women.
The systematic review by Vijan and colleagues was stratified into two categories. The first category evaluated the effects of lipid management in primary prevention (i.e., in patients without known coronary disease). The second category evaluated the effects in secondary prevention (i.e., in patients with established coronary disease). A total of 12 lipid-lowering studies presented diabetes-specific data and reported clinical outcomes.
For the background report, Vijan and colleagues conducted a meta-analysis of the trial results for the diabetes subgroups. Six studies of primary prevention in patients with diabetes were identified. For the primary prevention studies, the pooled relative risk for cardiovascular events with lipid-lowering therapy was 0.78 (confidence interval [CI], 0.67 to 0.89) and the pooled absolute risk reduction was 0.03 (CI, 0.01 to 0.04); the pooled estimate of the number needed to treat to prevent an event was 34.5 for a weighted trial average of 4.3 years.
Eight trials reported on secondary prevention in patients with diabetes. For the secondary prevention studies, the pooled relative risk for cardiovascular events with lipid-lowering therapy was similar to that for primary prevention: 0.76 (CI, 0.59 to 0.93). However, because of the greater absolute risk among patients with known coronary artery disease, the pooled absolute risk reduction was more than twice as high (0.07 [CI, 0.03 to 0.12]), and the number needed to treat for benefit was only 13.8 for a weighted trial average of 4.9 years.
In patients who have type 2 diabetes, lipid-lowering agents reduce cardiovascular risk. Most patients, including those whose baseline LDL cholesterol levels are below 115 mg per dL (2.97 mmol per L), and possibly below 100 mg per dL (2.59 mmol per L), benefit from statin therapy. Moderage dosages usually are sufficient.
The ACP subcommittee has made the following recommendations for lipid control in the management of type 2 diabetes:
• Recommendation 1: Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all patients with known coronary artery disease and type 2 diabetes.
While the relative risk reductions were similar for primary and secondary prevention, the average absolute risk reduction was more than twice as high for patients with known coronary artery disease (secondary prevention) than for patients without (primary prevention).
Statins have the most cumulative evidence of benefit and should be the agent of choice for secondary prevention. One exception is for patients who have diabetes and low levels of high-density lipoprotein (HDL) and LDL cholesterol. In one study, treatment with gemfibrozil, in a dosage of 1,200 mg per day, led to an absolute risk reduction of 10 percent. Therefore, these patients may benefit more from gemfibrozil therapy than from use of a statin, but currently there are no studies in the literature comparing the drugs alone or in combination.
• Recommendation 2: Statins should be used for primary prevention against macrovascular complications in patients with type 2 diabetes and other cardiovascular risk factors.
The most benefit with treatment was seen in the primary prevention studies that included patients with other significant cardiovascular risk factors, specifically age older than 55 years, hypertension, smoking, left ventricular hypertrophy, previous cerebrovascular disease, and peripheral arterial disease.
No strong evidence exists to support exact thresholds for initiating treatment or treating to specific target LDL or total cholesterol levels in patients with type 2 diabetes. Deciding to initiate treatment on the basis of thresholds or to treat to a target should be done after discussion with the patient. Clinical trial evidence does not support the use of statins in low-risk persons younger than 55 years who have type 2 diabetes but no other cardiovascular risk factors.
• Recommendation 3: Once lipid-lowering therapy is initiated, patients with type 2 diabetes mellitus should take at least moderate dosages of a statin.
The current literature strongly supports the use of moderate dosages of statins in patients with diabetes (see accompanying table). The benefit of targeted treatment is implied in observational studies. However, the trials that reported experience in patients with diabetes did not set specific target levels for LDL cholesterol or used different target levels than those recommended currently.
While the achieved LDL cholesterol levels in the trials have consistently been below 120 mg per dL (less than 3.1 mmol per L), different studies have shown differing benefit for lower target levels. The primary prevention trials do not provide adequate evidence to guide drug choice because most of the diabetes subgroups were too small. No clinical trials recommend the use of one statin over another. Given the unclear evidence on the benefit of treating to target LDL cholesterol levels, more aggressive titration of statins or use of combination lipid-lowering treatment titrated on the basis of LDL cholesterol levels should be a mutual decision between physician and patient.
• Recommendation 4: For patients with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances.
According to the current literature, statins are extremely safe. While rates of discontinuation and nonadherence are approximately 15 percent or higher in many trials, discontinuation rates usually are similar to those of patients receiving placebo. In recent large-scale trials, the rates of elevated liver or muscle enzyme levels did not differ between the statin and placebo groups. Based on safety data pertaining to these medications, routine monitoring of muscle enzymes and liver function is probably unwarranted except in patients with symptoms, those who have liver enzyme abnormalities at baseline, or those taking medications that interact with statins to increase the risk of adverse events.
Optimal treatment of hypertension, smoking cessation, and control of lipid levels provide substantial benefit, at least to the average patient with type 2 diabetes. However, evidence on targeting specific levels of LDL cholesterol is unclear. Most trials did not set specific target levels or used levels different from those currently recommended. Also, reasonable arguments can be made in favor of using gemfibrozil as first-line therapy (compared with statins) for patients with low levels of HDL and LDL cholesterol. Although the relative risk reductions were similar for primary and secondary prevention, the average absolute risk reduction was more than twice as high for persons with known coronary artery disease (secondary prevention) than for persons without (primary prevention).
Among the secondary prevention trials, the absolute risk reduction was the greatest in the three trials with the highest-risk participants. Only one of the primary prevention studies showed statistically significant benefit in patients with diabetes, and the observed benefits were small or absent in studies of patients with diabetes and low baseline risk. Therefore, physicians should be careful when applying the average results from the primary prevention meta-analysis to patients at lower-than-average risk (e.g., younger patients with diabetes who have no other major cardiovascular risk factors).
Future studies should examine the relative efficacy of specific strategies, such as different targets for LDL cholesterol level versus different dosages of empirical statin therapy and combination therapy, and should also consider the potential effects of statins beyond their lipid-lowering properties.