2型糖尿病血脂指南

Lipid Control in the Management of Type 2 Diabetes Mellitus: A Clinical Practice Guideline from the American College of Physicians Vincenza Snow, MD; Mark D. Aronson, MD; E. Rodney Hornbake, MD; Christel Mottur-Pilson, PhD; and Kevin B. Weiss, MD, for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians* In an effort to provide internists and other primary care physicians with effective management strategies for diabetes care, the Clin- ical Efficacy Assessment Subcommittee (CEAS) of the American College of Physicians (ACP) decided to develop guidelines on the management of dyslipidemia, particularly hypercholesterolemia, in people with type 2 diabetes mellitus. The CEAS commissioned a systematic review of the currently available evidence on the man- agement of lipids in type 2 diabetes mellitus. The evidence review is presented in a background paper in this issue. On the basis of this systematic review, the CEAS developed recommendations that the ACP Board of Regents then approved as policy. The target audience for this guideline is all clinicians who care for patients with type 2 diabetes. The target patient popula- tion is all persons with type 2 diabetes, including those who already have some form of microvascular complication and, of particular importance, premenopausal women. The recommenda- tions are as follows. Recommendation 1: Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all patients (both men and women) with known coronary artery disease and type 2 diabetes. Recommendation 2: Statins should be used for primary pre- vention against macrovascular complications in patients (both men and women) with type 2 diabetes and other cardiovascular risk factors. Recommendation 3: Once lipid-lowering therapy is initiated, patients with type 2 diabetes mellitus should be taking at least moderate doses of a statin. Recommendation 4: For those patients with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circum- stances. Ann Intern Med. 2004;140:644-649. www.annals.org For author affiliations, see end of text. See related article on pp 650-658. Diabetes mellitus is a leading cause of morbidity andmortality in the United States. Type 2 diabetes mel- litus is most common (90% to 95% of persons with dia- betes) and affects older adults, particularly those older than 50 years of age. An estimated 16 million Americans have type 2 diabetes, and up to 800 000 new diagnoses are made each year (1, 2). Most adverse diabetes outcomes are a result of vascular complications, which are generally clas- sified as microvascular (such as retinopathy, nephropathy, and neuropathy, although the latter may not be entirely a microvascular disease) or macrovascular (such as coronary artery disease, cerebrovascular disease, and peripheral vas- cular disease). To prevent or diminish the progression of microvas- cular and macrovascular complications, recommended diabetes management necessarily encompasses both meta- bolic control and control of cardiovascular risk factors (3– 5). The need for good glycemic control is supported by the Diabetes Control and Complications Trial (6) in type 1 diabetes and, more recently, the United Kingdom Prospec- tive Diabetes Study in type 2 diabetes (7). In these studies, tight blood sugar control reduced microvascular complica- tions such as nephropathy and retinopathy but had little effect on macrovascular outcomes. Up to 80% of patients with type 2 diabetes will develop or die of macrovascular disease, underscoring the importance of preventing macro- vascular complications. In an effort to provide internists and other primary care physicians with effective management strategies for diabetes care, the American College of Physicians (ACP) decided to develop guidelines on the management of dys- lipidemia, particularly hypercholesterolemia, in people with type 2 diabetes. A previous College guideline ad- dressed the critical role of tight blood pressure control in type 2 diabetes mellitus (8, 9). The target audience for this guideline is all clinicians 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, of particular im- portance, premenopausal women. In this guideline we ad- dress the following questions. 1. What are the benefits of tight lipid control for both primary and secondary prevention in type 2 diabetes? 2. What is the evidence for treating to certain target levels of low-density lipoprotein (LDL) cholesterol for pa- tients with type 2 diabetes? 3. Are certain lipid-lowering agents more effective or beneficial in patients with type 2 diabetes? This guideline is based on the systematic review of the evidence presented in the background paper by Vijan and *This paper, written by Vincenza Snow, MD; Mark D. Aronson, MD; E. Rodney Hornbake, MD; Christel Mottur-Pilson, PhD; and Kevin B. Weiss, MD, was developed by the Clinical Efficacy Assessment Subcommittee of the American College of Physicians (ACP): Kevin Weiss, MD (Chair); Mark Aronson, MD; Patricia Barry, MD; Virginia Collier, MD; J. Thomas Cross Jr., MD; Nick Fitterman, MD; E. Rodney Hornbake, MD; Douglas K. Owens, MD; and Katherine D. Sherif, MD. Approved by the ACP Board of Regents in July 2003. Annals of Internal Medicine encourages readers to copy and distribute this paper, providing such distribution is not for profit. Commercial distribution is not permitted without the express permission of the publisher. Clinical Guidelines 644 © 2004 American College of Physicians colleagues in this issue (10). When Vijan and colleagues analyzed benefit or effectiveness, only studies that mea- sured clinical end points were included. The major clinical end points in trials used to support the evidence for these guidelines were all-cause mortality, cardiovascular mortal- ity, and cardiovascular events (that is, myocardial infarc- tion, stroke, and cardiovascular mortality). No studies of lipid-lowering therapy have been conducted solely in pa- tients with diabetes. Moreover, many trials excluded pa- tients with diabetes. The sample sizes of participants with diabetes were often small, and many studies reported re- sults only for the combined groups. Thus, the reports in- cluded in this review are of the subgroup analyses for stud- ies that included patients with diabetes. The review was stratified into 2 categories. The first category evaluated the effects of lipid management in pri- mary prevention (that is, in patients without known coro- nary disease). The second category evaluated the effects in secondary prevention (that is, in patients with established coronary disease). A total of 12 lipid-lowering studies pre- sented diabetes-specific data and reported clinical out- comes. A discussion of this evidence follows (for a more detailed description of methodology, refer to the back- ground paper by Vijan and colleagues [10]). PRIMARY PREVENTION Six studies of primary prevention in patients with di- abetes were identified. The Air Force Coronary Atheroscle- rosis Prevention Study/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) randomly assigned patients with average cholesterol levels and lower than av- erage high-density lipoprotein (HDL) cholesterol levels to lovastatin, 20 to 40 mg/d, or placebo (in addition to a low-fat and low-cholesterol diet) for an average follow-up of 5.2 years (11). Based on data from the Third National Health and Nutrition Examination Survey, mean total cholesterol level was 5.72 mmol/L (221 mg/dL), mean LDL cholesterol level was 3.88 mmol/L (150 mg/dL), and mean HDL cholesterol level was 0.93 mmol/L (36 mg/dL) for men and 1.03 mmol/L (40 mg/dL) for women. One hundred fifty-five patients had diabetes. Lovastatin therapy led to a relative risk of 0.56 (95% CI, 0.17 to 1.92) for any atherosclerotic cardiovascular event (first fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death) and an absolute risk reduction of 0.04 (CI, �0.04 to 0.12), neither of which was statistically significant. The mean LDL cholesterol level at the end of the study was 2.97 mmol/L (115 mg/dL), and the mean HDL choles- terol level was 1.00 mmol/L (39 mg/dL). The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid-Lowering Trial (ALLHAT-LLT) randomly assigned patients 55 years of age and older who had hypertension and at least one other coronary heart disease (CHD) risk factor to pravastatin, 40 mg/d, or placebo (12). In the subgroup analysis of 3638 patients with type 2 diabetes, the relative risk for CHD events was 0.89 (CI, 0.71 to 1.10); the absolute risk reduc- tion was not reported. This study has been criticized be- cause of the smaller difference between LDL cholesterol levels in the control and intervention groups, which is probably due in part to contamination of the control group by publication of several other lipid-lowering trials during the study. The Helsinki Heart Study (13) randomly assigned men age 40 to 55 years with elevated non-HDL cholesterol levels to gemfibrozil, 600 mg 2 times per day, or placebo. The mean total cholesterol level was 7.5 mmol/L (290 mg/dL), and mean HDL cholesterol level was 1.23 mmol/L (47.6 mg/dL). In the 135 patients with diabetes, the incidence of CHD at 5 years was 3.4% in the gem- fibrozil group and 10.5% in the placebo group. The rela- tive risk was 0.32 (CI, 0.07 to 1.46), and the absolute risk reduction was 0.07 (CI, �0.01 to 0.15). None of these differences were statistically significant (14). The Heart Protection Study (HPS) included data on both primary and secondary prevention in patients with diabetes who were at high risk for cardiovascular disease (15). The objective of this study was to examine the effects of therapy to lower LDL cholesterol level across a broad range of lipid levels and risk factors. The HPS enrolled patients 40 to 80 years of age with nonfasting total choles- terol levels of at least 3.49 mmol/L (�135 mg/dL). In the primary prevention group, 3982 patients had diabetes. Treatment with simvastatin, 40 mg, led to reduced risks for CHD events (relative risk, 0.74 [CI, 0.64 to 0.85]; absolute risk reduction, 0.05 [CI, 0.03 to 0.07]). The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) randomly assigned men and women 70 to 82 years of age with a history of cerebral or peripheral vascular disease or risk factors for such disease (such as smoking, hypertension, and diabetes) to pravastatin, 40 mg/d, or placebo (16). In the primary prevention group, 396 patients had diabetes. In these patients, treatment with pravastatin led to a trend toward harm (relative risk, 1.23 [CI, 0.77 to 1.95]; absolute risk reduction, �0.03 [CI, �0.10 to 0.04]). The interaction between diabetes and the treatment group was statistically significant, suggesting that patients with diabetes did substantially worse than those without diabetes. The Anglo-Scandinavian Cardiac Outcome Trial– Lipid Lowering Arm (ASCOT-LLA) randomly assigned patients age 40 to 79 years without CHD but with hyper- tension and at least 3 other cardiovascular risk factors (left ventricular hypertrophy, other electrocardiographic abnor- malities, type 2 diabetes, peripheral arterial disease, previ- ous stroke or transient ischemic attack, male sex, age� 55 years, microalbuminuria, proteinuria, smoking, ratio of plasma total to HDL cholesterol of 6 or higher, or family history of premature CHD) to atorvastatin, 10 mg/d, or placebo (17). The diabetes subgroup, 2532 patients who had hypertension and at least 2 other risk factors, had low Clinical GuidelinesLipid Control in the Management of Type 2 Diabetes Mellitus www.annals.org 20 April 2004 Annals of Internal Medicine Volume 140 • Number 8 645 event rates of 3.6% in the control group and 3.0% in the intervention group. Thus, lipid-lowering treatment, with a relative risk of 0.84 (CI, 0.55 to 1.29) and an absolute risk reduction of 0.006 (CI, �0.008 to 0.019), did not lead to statistically significant improvements in the diabetes group. SECONDARY PREVENTION Eight trials reported on secondary prevention in pa- tients with diabetes. The first, the Scandinavian Simvasta- tin Survival Study (4S), randomly assigned patients with coronary disease to simvastatin, 20 mg, or placebo (18). In a secondary analysis of the 202 patients with diabetes, sim- vastatin led to large benefits (relative risk for cardiovascular events, 0.50 [CI, 0.33 to 0.76]; absolute risk reduction, 0.23 [CI, 0.10 to 0.35]). Of note is the relatively high event rate in the control group (45%) compared with those seen in other trials. The Cholesterol and Recurrent Events (CARE) trial randomly assigned patients with previous myocardial in- farction to pravastatin, 40 mg/d, or placebo (19). Pravasta- tin improved CHD outcomes in the 586 patients with diabetes (relative risk for cardiovascular events, 0.78 [CI, 0.62 to 0.99]; absolute risk reduction, 0.08 [CI, 0.01 to 0.16]). Results were reported as stratified by baseline LDL cholesterol levels and showed that for the overall study sample, those with baseline levels below 3.23 mmol/L (�125 mg/dL) did not benefit from lipid-lowering therapy while those with LDL cholesterol levels of at least 3.23 mmol/L (�125 mg/dL) benefited substantially. The small sample size precluded a similar stratified analysis in the patients with diabetes. The HPS examined the impact of lipid-lowering ther- apy in secondary prevention in 20 536 patients with coro- nary disease, other occlusive arterial disease, or diabetes (15). Treatment was with simvastatin, 40 mg/d, or pla- cebo. There was no dose adjustment by baseline lipid lev- els. Among patients with diabetes, the relative risk for any cardiovascular event was 0.89 (CI, 0.79 to 1.00) in the simvastatin group, and the absolute risk reduction was 0.04 (CI, 0.00 to 0.09). The Long-Term Intervention with Pravastatin in Isch- emic Disease (LIPID) trial randomly assigned patients with known heart disease to pravastatin, 40 mg/d, or placebo (20). In the subgroup of 782 patients with diabetes, the relative risk for a cardiovascular event was 0.84 (CI, 0.64 to 1.11) and the absolute risk reduction was 0.04 (CI, �0.02 to 0.09). Neither of these was statistically significant. The Lescol Intervention Prevention Study (LIPS) was a trial conducted in patients who had undergone percuta- neous coronary intervention (21). Researchers randomly assigned patients to fluvastatin, 80 mg/d, or placebo. In the 202 patients with type 2 diabetes, fluvastatin was effective in preventing CHD events (relative risk, 0.53 [CI, 0.29 to 0.97]; absolute risk reduction, 0.16 [CI, 0.03 to 0.29]). The Post–Coronary Artery Bypass Graft (Post-CABG) trial randomly assigned patients who had undergone coro- nary artery bypass grafting to “aggressive” LDL cholesterol targets of 1.55 to 2.20 mmol/L (60 to 85 mg/dL) or “mod- erate” targets of 3.36 to 3.62 mmol/L (130 to 140 mg/dL) (22). Lovastatin was used as the primary agent, and cho- lestyramine was added if goals were not achieved. Most patients did not reach the intensive goal; the mean achieved LDL cholesterol level ranged from 2.40 to 2.51 mmol/L (93 to 97 mg/dL) over the course of the study. One hundred sixteen patients in the trial had diabetes. Aggressive LDL cholesterol lowering led to a relative risk of 0.53 (CI, 0.18 to 1.60) and an absolute risk reduction of 0.12 (CI, �0.03 to 0.27). Neither of these was statistically significant. The Veterans Administration High-Density Lipopro- tein Cholesterol Intervention Trial (VA-HIT) was a sec- ondary prevention study whose intervention and goal were different from the others (23). This study targeted patients with the low-HDL, low-LDL syndrome (HDL cholesterol level � 1.03 mmol/L 40 mg/dL]; LDL cholesterol level � 3.62 mmol/L [�140 mg/dL]), which is very common in patients with diabetes or insulin resistance. The study enrolled men younger than 74 years of age who had doc- umented coronary disease. Treatment was with gemfibro- zil, 1200 mg/d, or placebo. In the diabetes subgroup (n � 627), the relative risk for cardiovascular events was 0.76 (CI, 0.57 to 1.01) and the absolute risk reduction was 0.08 (CI, 0.01 to 0.15). In a follow-up article, inclusion of pa- tients with undiagnosed diabetes in this subgroup reduced the risks further (relative risk, 0.68; absolute risk reduction, 10%) (24). Of interest, these analyses also suggest that much of the benefit in this study was in patients with diabetes and that fasting plasma insulin levels were a major indicator of the success of therapy. META-ANALYSIS Vijan and colleagues conducted a meta-analysis of the trial results for the diabetes subgroups (10). For the pri- mary prevention studies, the pooled relative risk for cardio- vascular events with lipid-lowering therapy was 0.78 (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. Of note, the results of ALLHAT- LLT are included in the pooled estimates of relative risk but not those of absolute risk reduction because the latter data were not available. For the secondary prevention studies, the pooled rela- tive risk for cardiovascular events with lipid-lowering ther- apy was very similar to that for primary prevention: 0.76 (CI, 0.59 to 0.93). However, because of the greater abso- lute risk among patients with known coronary artery dis- ease, 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 Clinical Guidelines Lipid Control in the Management of Type 2 Diabetes Mellitus 646 20 April 2004 Annals of Internal Medicine Volume 140 • Number 8 www.annals.org trial average of 4.9 years. In trials of both primary and secondary prevention, Vijan and colleagues conducted sen- sitivity analyses excluding the trials that used gemfibrozil (the Helsinki Heart Study for primary prevention and VA- HIT for secondary prevention), but this did not change the estimates of relative risk or absolute risk reduction (10). SAFETY OF LIPID-LOWERING AGENTS The current literature suggests that statins are ex- tremely safe. Although rates of discontinuation and non- adherence in clinical trials are approximately 15% or more in many cases, rates of discontinuation typically are not different from those of placebo. Rates of elevated levels of liver or muscle enzymes did not differ between the statin and placebo groups in recent large-scale studies. For exam- ple, in the HPS, rates of elevated alanine aminotransferase levels above twice the upper limit of normal were 1.8% in the simvastatin group and 1.6% in the placebo group, and rates of elevated creatine kinase levels were 0.3% in the simvastatin group and 0.2% in the placebo group (15). Neither of these differences was statistically significant. Similarly, among the 5804 patients in PROSPER, only 1 person in each group had an alanine aminotransferase or aspartate aminotransferase level more than 3 times the up- per limit of normal (16). In addition, no patients had rhab- domyolysis and 36 patients in the pravastatin group had myalgia compared with 32 in the placebo group. Based on the safety of these drugs, routine monitoring of liver or muscle enzymes is probably not warranted except in pa- tients with symptoms, patients who have liver enzyme ab- normalities at baseline, or patients taking drugs that inter- act with statins to increase the risk for adverse events. SUMMARY Given the markedly elevated risk for cardiovascular events in most persons