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Commentaries on both new and classic studies of importance for the treatment of diabetes are posted here monthly.
CARDS (Collaborative Atorvastatin Diabetes Study)
| Ruediger Landgraf Klinikum University of Munich Munich, Germany |
Click here to download PowerPoint slides of this commentary. |
Comment on:
Background
Diabetes is known to play a major role in vascular complications. Reducing rates of end-organ damage has been a key objective of many clinical trials. In addition to the roles of glycaemic and blood pressure control, lipid reduction via statin therapy independently helps to reduce the risk of vascular events. This effect seems to remain across a broad range of lipid levels, suggesting additional mechanisms for efficacy of statin treatment beyond cholesterol reduction. Until recently, the role of statin treatment in individuals with diabetes without clinical signs or symptoms of coronary heart disease has been inadequately defined. CARDS was therefore designed to assess the effectiveness of statin therapy for primary prevention of major cardiovascular events in individuals with Type 2 diabetes.
Methods and Key Results
CARDS was a multicentre, randomized, double-blind, placebo-controlled trial of atorvastatin, 10 mg/day, in the primary prevention of cardiovascular disease in 2838 individuals with Type 2 diabetes aged 40 to 75 years at randomization (n=1129 adults aged 65-75 years and n=1709 adults aged 40-64 years). Participants had low-density lipoprotein (LDL) cholesterol concentrations ≤4.14 mmol/l (≤160 mg/dl) and triglyceride levels ≤6.78 mmol/l (≤600 mg/dl)). In addition, participants had to have at least one of the following: retinopathy, albuminuria, hypertension, or current smoker status. The primary end point was time to first occurrence of acute coronary heart disease events, coronary revascularization, or stroke. Secondary objectives included the effect of atorvastatin on death and individual cardiovascular events and on serum lipid and lipoprotein concentrations as well as the long-term safety of atorvastatin. Although designed as a 5-year prospective trial, CARDS was terminated 2 years earlier than expected because of the significant benefit already present at the second interim analysis. The median duration of follow-up was 3.9 years.
This journal article reports the results of a post hoc analysis conducted to compare the efficacy and safety of atorvastatin in the older and younger groups.
Atorvastatin therapy resulted in a 38% reduction in the relative risk (95% CI: –58 to –8; P=0.017) of first major cardiovascular events in the older group and a 37% reduction (95% CI: –57 to –7; P=0.019) in the younger group. The corresponding absolute risk reductions were 3.9% and 2.7%, respectively (95% CI: –2.8 to 5.3; P=0.546). The numbers needed to treat for 4 years to avoid one event were 21 for the older group and 33 for the younger group. Atorvastatin led to a relative risk reduction of 48% for fatal and non-fatal strokes in the total population (P<0.05 versus placebo). All-cause mortality was reduced non-significantly by 22% (95% CI: –49 to 18; P=0.245) in the older group and 37% (95 CI: –64 to 9; P=0.98) in the younger group.
For both age groups, there were no differences between atorvastatin and placebo in the rates of all-cause adverse events. Treatment-associated serious adverse events occurred in 1.2% of atorvastatin-treated and 1.6% of placebo-treated individuals aged ≥65 years. Corresponding figures were 0.9% and 0.8% in the younger age group. Treatment-associated adverse events led to discontinuations in 3.0% of atorvastatin-treated and 3.9% of placebo-treated individuals in the older age group. In the younger age group, these numbers were 2.8% for atorvastatin-treated and 3.0% for placebo-treated individuals. Myalgia was reported in 3.5% and 4.3%, respectively, of older and younger individuals treated with atorvastatin and 4.8% and 4.7%, respectively, of older and younger individuals in the placebo group. Creatine kinase elevations >10 times upper limits of normal were seen in four younger individuals on placebo. Rhabdomyolysis was not seen at all.
Clinical Implications
Subgroup analysis of secondary prevention trials has established that statins reduce major cardiovascular events in those with diabetes, including data from the Heart Protection Study (HPS), the Scandinavian Simvastatin Survival Study (4S), the Cholesterol and Recurrent Events (CARE) trial, and the Long-term Intervention With Pravastatin in Ischemic Disease (LIPID) trial. The benefit of lipid lowering for primary prevention of cardiovascular disease in diabetes has been less clear. Subgroup analysis of 2912 individuals with diabetes but without previous occlusive disease in the HPS showed a significant reduction in 33% of events, but the 16% reduction in coronary heart disease in the subgroup of 2532 hypertensive individuals with diabetes observed in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA ) did not achieve statistical significance.
CARDS is the first trial designed and powered to evaluate clinical outcomes specifically in individuals with Type 2 diabetes with one or more cardiovascular risk factors. CARDS supports the findings of HPS, namely that cardiovascular risk and not elevated LDL cholesterol predicts the benefit of statin therapy for those with diabetes. Similar beneficial outcomes were seen irrespective of initial LDL cholesterol and high-density lipoprotein cholesterol levels.
Current guidelines on lipid-lowering therapy for primary prevention of cardiovascular disease in Type 2 diabetes recommend lipid-lowering treatment in individuals with Type 2 diabetes. They include the American Heart Association together with the American Diabetes Association, the Joint European Societies, and the National Cholesterol Education Program Adult Treatment Panel III.
CARDS showed that the treatment of individuals with Type 2 diabetes with a fixed dose of atorvastatin (10 mg/day) significantly reduced cardiovascular events. These results emphasize the importance of a statin as first-line therapy for all individuals ≥40 years of age with Type 2 diabetes, including the elderly, regardless of their baseline LDL cholesterol for primary prevention of cardiovascular disease. This recommendation has a high cost-benefit and should have a high treatment adherence, for as demonstrated by CARDS, the rate of treatment-associated adverse events which did not differ from the placebo treatment was low and atorvastatin at the dose studied was safe even in elderly individuals with diabetes.
References
Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2007;30:162-172.
Collins R, Armitage J, Parish S, Sleigh P, Peto R; 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.
De Backer G, Ambrosioni E, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J. 2003;24:1601-1610.
Goldberg RB, Mellies MJ, Sacks FM, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators. Circulation. 1998;98:2513-2519.
Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.
Haffner SM, Alexander CM, Cook TJ, et al. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med. 1999;159:2661-2667.
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.
Keech A, Colquhoun D, Best J, et al. Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial. Diabetes Care. 2003;26:2713-2721.
Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149-1158.
This Website Feature is funded by an unrestricted educational grant from Pfizer Inc.
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