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      Statin Therapy and Risk of Developing Type 2 Diabetes: A Meta-Analysis

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          Abstract

          OBJECTIVE

          Although statin therapy reduces cardiovascular risk, its relationship with the development of diabetes is controversial. The first study (West of Scotland Coronary Prevention Study [WOSCOPS]) that evaluated this association reported a small protective effect but used nonstandardized criteria for diabetes diagnosis. However, results from subsequent hypothesis-testing trials have been inconsistent. The aim of this meta-analysis is to evaluate the possible effect of statin therapy on incident diabetes.

          RESEARCH DESIGN AND METHODS

          A systematic literature search for randomized statin trials that reported data on diabetes through February 2009 was conducted using specific search terms. In addition to the hypothesis-generating data from WOSCOPS, hypothesis-testing data were available from the Heart Protection Study (HPS), the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study, the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), and the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA), together including 57,593 patients with mean follow-up of 3.9 years during which 2,082 incident diabetes cases accrued. Weighted averages were reported as risk ratios (RRs) with 95% CIs using a random-effects model. Statistical heterogeneity scores were assessed with the Q and I 2 statistic.

          RESULTS

          In the meta-analysis of the hypothesis-testing trials, we observed a small increase in diabetes risk (RR 1.13 [95% CI 1.03–1.23]) with no evidence of heterogeneity across trials. However, this estimate was attenuated and no longer significant when the hypothesis-generating trial WOSCOPS was included (1.06 [0.93–1.25]) and also resulted in significant heterogeneity ( Q 11.8 [5 d.f.], P = 0.03, I 2 = 57.7%).

          CONCLUSIONS

          Although statin therapy greatly lowers vascular risk, including among those with and at risk for diabetes, the relationship of statin therapy to incident diabetes remains uncertain. Future statin trials should be designed to formally address this issue.

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          Most cited references12

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          MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.

          Individuals with diabetes are at increased risk of cardiovascular morbidity and mortality, although typically their plasma concentrations of LDL cholesterol are similar to those in the general population. Previous evidence about the effects of lowering cholesterol in people with diabetes has been limited, and most diabetic patients do not currently receive cholesterol-lowering therapy despite their increased risk. 5963 UK adults (aged 40-80 years) known to have diabetes, and an additional 14573 with occlusive arterial disease (but no diagnosed diabetes), were randomly allocated to receive 40 mg simvastatin daily or matching placebo. Prespecified analyses in these prior disease subcategories, and other relevant subcategories, were of first major coronary event (ie, non-fatal myocardial infarction or coronary death) and of first major vascular event (ie, major coronary event, stroke or revascularisation). Analyses were also conducted of subsequent vascular events during the scheduled treatment period. Comparisons are of all simvastatin-allocated versus all placebo-allocated participants (ie, intention to treat), which yielded an average difference in LDL cholesterol of 1.0 mmol/L (39 mg/dL) during the 5-year treatment period. Both among the participants who presented with diabetes and among those who did not, there were highly significant reductions of about a quarter in the first event rate for major coronary events, for strokes, and for revascularisations. For the first occurrence of any of these major vascular events among participants with diabetes, there was a definite 22% (95% CI 13-30) reduction in the event rate (601 [20.2%] simvastatin-allocated vs 748 [25.1%] placebo-allocated, p<0.0001), which was similar to that among the other high-risk individuals studied. There were also highly significant reductions of 33% (95% CI 17-46, p=0.0003) among the 2912 diabetic participants who did not have any diagnosed occlusive arterial disease at entry, and of 27% (95% CI 13-40, p=0.0007) among the 2426 diabetic participants whose pretreatment LDL cholesterol concentration was below 3.0 mmol/L (116 mg/dL). The proportional reduction in risk was also about a quarter among various other subcategories of diabetic patient studied, including: those with different duration, type, or control of diabetes; those aged over 65 years at entry or with hypertension; and those with total cholesterol below 5.0 mmol/L (193 mg/dL). In addition, among participants who had a first major vascular event following randomisation, allocation to simvastatin reduced the rate of subsequent events during the scheduled treatment period. The present study provides direct evidence that cholesterol-lowering therapy is beneficial for people with diabetes even if they do not already have manifest coronary disease or high cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rate of first major vascular events by about a quarter in a wide range of diabetic patients studied. After making allowance for non-compliance, actual use of this statin regimen would probably reduce these rates by about a third. For example, among the type of diabetic patient studied without occlusive arterial disease, 5 years of treatment would be expected to prevent about 45 people per 1000 from having at least one major vascular event (and, among these 45 people, to prevent about 70 first or subsequent events during this treatment period). Statin therapy should now be considered routinely for all diabetic patients at sufficiently high risk of major vascular events, irrespective of their initial cholesterol concentrations.
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            C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus.

            Over 20 large-scale prospective studies show that the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) is an independent predictor of future cardiovascular events that additionally predicts risk of incident hypertension and diabetes. In many studies, the relative impact of hsCRP is at least as large as that individually of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, blood pressure, or smoking, and knowledge of hsCRP correctly reclassifies a substantial proportion of "intermediate-risk" individuals into clinically relevant higher- or lower-risk categories. Other studies show the relative benefit of statins to be greater among those with increased hsCRP and that achieved hsCRP levels after statin therapy predict recurrent event rates as much as achieved levels of low-density lipoprotein cholesterol. Nonetheless, it remains controversial whether the time has come to modify traditional algorithms used for global risk detection. As described here, 6 areas of controversy regarding hsCRP are resolvable with a consensus position that focuses in primary prevention on selective use among individuals with 5% to 20% 10-year risk as estimated by Adult Treatment Panel III, and focuses in secondary prevention on high-risk patients being treated with statin therapy. Forthcoming trial data could expand or contract this "screen selectively" policy, and investigators should be open to the possibility that second-generation inflammatory biomarkers may be developed that supplant hsCRP altogether. In the meantime, however, this consensus position on hsCRP should be one to which both advocates and critics of the inflammatory hypothesis of atherosclerosis can adhere because it is one that can immediately improve patient care.
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              Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control.

              Hyperlipidaemia often occurs in patients with type 2 diabetes mellitus. Though HMG-CoA reductase inhibitors (statins) are widely used for controlling hypercholesterolemia, atorvastatin has also been reported to have an adverse effect on glucose metabolism. Based on these findings, the aim of this study was to investigate the effects of statins on adipocytes, which play pivotal roles in glucose metabolism. In 3T3-L1 cells, effects of statins on adipocyte maturation were determined morphologically. Protein and mRNA levels of SLC2A4 and adipocyte marker proteins were determined by immunoblotting and RT-PCR, respectively. Type 2 diabetic NSY mice were treated with atorvastatin for 15 weeks, followed by glucose and insulin tolerance tests and examination of SLC2A4 expression in white adipose tissue (WAT). Seventy-eight Japanese subjects with type 2 diabetes and hypercholesterolaemia were treated with atorvastatin (10 mg/day), and its effects on lipid and glycaemic profiles were measured 12 weeks after treatment initiation. Treatment with atorvastatin inhibited adipocyte maturation, SLC2A4 and C/EBPalpha expressions and insulin action in 3T3-L1 cells. Atorvastatin also attenuated SLC2A4 and C/EBPalpha expressions in differentiated 3T3-L1 adipocytes. These effects were reversed by L. mevalonate or geranylgeranyl pyrophosphate. In NSY mice, atorvastatin accelerated glucose intolerance as a result of insulin resistance and decreased SLC2A4 expression in WAT. In addition to improving hyperlipidaemia, atorvastatin treatment significantly increased HbA(1c) but not fasting glucose levels in diabetic patients, and this effect was greater in the non-obese subgroup. These results demonstrate that atorvastatin attenuates adipocyte maturation and SLC2A4 expression by inhibiting isoprenoid biosynthesis, and impairs glucose tolerance. These actions of atorvastatin could potentially affect the control of type 2 diabetes.
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                Author and article information

                Journal
                Diabetes Care
                diacare
                dcare
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                October 2009
                : 32
                : 10
                : 1924-1929
                Affiliations
                [1] 1Department of Epidemiology and Population Health and Department of Medicine, Albert Einstein College of Medicine, New York, New York;
                [2] 2Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio;
                [3] 3Center for Cardiovascular Disease Prevention and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
                Author notes
                Corresponding author: Swapnil Rajpathak, srajpath@ 123456aecom.yu.edu .
                Article
                0738
                10.2337/dc09-0738
                2752935
                19794004
                a11eb23a-5819-42b7-94cd-84982efb5d3f
                © 2009 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                : 17 April 2009
                : 25 June 2009
                Funding
                Funded by: National Institutes of Health
                Award ID: 5P60DK20541
                Categories
                Reviews/Commentaries/ADA Statements
                Meta-analyses

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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