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Statins for people with diabetes
Comment
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The Lancet Jan 12, 2008; 371:94-95
Bernard MY Cheung
Department of Clinical Pharmacology, Division of Medical Sciences, University of Birmingham, Birmingham B15 2TH, UK
Statins are among the most notable triumphs of modern medicine. Since the demonstration of reduction in mortality in the Scandinavian
Statins are among the most notable triumphs of modern medicine. Since the demonstration of reduction in mortality in the Scandinavian Simvastatin Survival Study (4S) study in 1994,1 these lipid-lowering drugs have become widely used in people with or without known cardiovascular disease and in people with average as well as high cholesterol concentrations. In recent years, generic formulations have made the drugs affordable for more people.
7% of people in the USA have diabetes mellitus,2 and the prevalence is higher in Asia.3 Patients with diabetes have increased susceptibility to cardiovascular disease. Indeed, the coronary risk of a person with diabetes is similar to that of a person without diabetes who has had a previous myocardial infarction. Guidelines recognise the increased cardiovascular risk in patients with diabetes and endorse the use of statins in people with diabetes at risk of cardiovascular disease.4
Despite the widespread use of statins in patients with diabetes, there are some unanswered questions. For example, do statins confer more or less benefit to patients with diabetes than to people without the disorder? Would glycaemic and blood-pressure control affect the benefit of statins? Are statins beneficial in those with hypertriglyceridaemia, low HDL, or both?
Just when the benefits of statins seemed to be beyond reasonable doubt, two randomised studies found no clear benefit of statins in patients who had diabetes: the German Diabetes and Dialysis Study (4D)5 and the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN).6 In 4D, 1255 patients with diabetes on dialysis were assigned to atorvastatin or placebo for about 4 years. There was an 8% reduction in the primary endpoint of myocardial infarction, cardiac death, or stroke that was not statistically significant. In ASPEN, there was a 10% reduction (again, not statistically significant) in the primary endpoint. Very recently, the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) reported an 8% reduction in the primary endpoint (not statistically significant), despite 45% lower LDL concentrations in those treated with rosuvastatin 10 mg daily.7 In this trial, 30% of the participants had diabetes.
he meta-analysis in today's Lancet by the Cholesterol Treatment Trialists Collaborators8 therefore explores a very important issue: whether statins are as beneficial in patients with diabetes as in those without diabetes with respect to different outcomes, and whether the benefits depend on the type of diabetes, lipid profile, or other factors. The meta-analysis benefited from data on very large numbers of individual trial participants, which enabled detailed and prespecified subgroup analysis. The findings are reassuring: there was a 9% proportional reduction in all-cause mortality per mmol/L reduction in LDL cholesterol in participants with diabetes (rate ratio [RR] 0¥91, 99% CI 0¥82-1¥01), which was similar to the 13% reduction in those without diabetes (0¥87, 0¥82-0¥92). There were significant reductions in the numbers of fatal and non-fatal myocardial infarctions, coronary revascularisations, and strokes. Moreover, the relative-risk reduction was similar irrespective of previous history of vascular disease and baseline characteristics.
However, the meta-analysis did not include the recent negative trials-4D, ASPEN, and CORONA-nor did it include small trials, unpublished trials, or trials published in languages other than English. Nevertheless, the addition of 4D and ASPEN did not affect the estimated rate ratios. Although there were no significant reductions in the composite primary endpoints in 4D, ASPEN, and CORONA, the reductions in fatal and non-fatal myocardial infarction were 15%, 26%, and 17%, respectively. These reductions were not individually statistically significant, but were clearly consistent with the findings of the meta-analysis. Importantly, there was no question of harm. Thus there is no need to change current practice for statins in patients with diabetes. In the near future, trials such as the Study of Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) and Study of Heart and Renal Protection (SHARP) will be completed and shed further light on this issue.
While statins are expected to reduce the incidence of fatal and non-fatal myocardial infarctions, they are not a panacea, and patients on statins are liable to other causes of morbidity and mortality. In any case, treatment decisions should be based not on the reduction in relative risk but on the reduction in absolute risk or its reciprocal, the number needed to treat.9 If a patient has a high absolute cardiovascular risk, even a modest reduction in relative risk gives meaningful clinical benefits. Additionally, one should consider life expectancy, concomitant diseases, and quality of life.10 Apart from drug treatment, one must not forget the importance of lifestyle changes, such as cessation of smoking, healthy diet, and regular exercise.
I have received financial support from drug companies that make statins to organise, attend, or speak at scientific conferences.
REFERENCES
1. The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383-1389. MEDLINE
2. Ong KL, Cheung BM, Wong LY, Wat NM, Tan KC, Lam KS. Prevalence, treatment, and control of diagnosed diabetes in the United States National Health and Nutrition Examination Survey 1999-2004. Ann Epidemiol (in press).
3. Yoon KH, Lee JH, Kim JW, et al. Epidemic obesity and type 2 diabetes in Asia. Lancet 2006; 368: 1681-1688. Abstract | Full Text | Full-Text PDF (180 KB) | CrossRef
4. Grundy SM, Cleeman JI, Merz CNfor the Coordinating Committee of the National Cholesterol Education Program, Endorsed by the National Heart, Lung, and Blood Institute, American College of Cardiology Foundation, and American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004; 110: 227-239. CrossRef
5. Wanner C, Krane V, Marz Wfor the German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353: 238-248. CrossRef
6. Knopp RH, d'Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN). Diabetes Care 2006; 29: 1478-1485. MEDLINE | CrossRef
7. Kjekshus J, Apetrei E, Barrios Vfor the CORONA Group. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007; 357: 2248-2261. CrossRef
8. Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy of cholesterol-lowering therapy in 18 686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008; 371: 117-125
9. Kumana CR, Cheung BM, Lauder IJ. Gauging the impact of statins using number needed to treat. JAMA 1999; 282: 1899-1901. MEDLINE | CrossRef
10. Cheung BM, Kumana CR. Should decisions on treatment be based on absolute benefit rather than absolute risk?. N Z Med J 2001; 114: 214-215. MEDLINE
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