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      Glycaemic Effects of Non-statin Lipid-Lowering Therapies

      review-article
      1 , 2 ,
      Current Cardiology Reports
      Springer US
      Statins, Hypercholesterolaemia, PCSK9, Ezetimibe, Niacin, Diabetes

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          Abstract

          Since the publication of the JUPITER trial, attention has been focused on the adverse glycemic effects of statin therapy. Although the modest increase in the risk of new diabetes mellitus is outweighed by the reduction in cardiovascular events for statins, emerging biochemical and genetic links between lipid metabolism and glycemic control raise the prospect of a broader diabetogenic effect of lipid-lowering therapies. For the novel and powerful PCSK9-inhibitor class available evidence does not support a major glycaemic effect with the results of large scale trials awaited although preliminary genetic data does suggest a link. In contrast, there is clear evidence of a diabetogenic effect for the now outdated but well-studied niacin. For ezetimibe and fibrates, evidence is scarce but currently broadly unconcerning. For now, the glycemic effects of lipid-lowering therapies should have a limited influence on clinical decision-making. Further study in this topical area is needed.

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          Most cited references14

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          Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.

          Although statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals, their efficacy and safety in elderly people is not fully established. Our aim was to test the benefits of pravastatin treatment in an elderly cohort of men and women with, or at high risk of developing, cardiovascular disease and stroke. We did a randomised controlled trial in which we assigned 5804 men (n=2804) and women (n=3000) aged 70-82 years with a history of, or risk factors for, vascular disease to pravastatin (40 mg per day; n=2891) or placebo (n=2913). Baseline cholesterol concentrations ranged from 4.0 mmol/L to 9.0 mmol/L. Follow-up was 3.2 years on average and our primary endpoint was a composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke. Analysis was by intention-to-treat. Pravastatin lowered LDL cholesterol concentrations by 34% and reduced the incidence of the primary endpoint to 408 events compared with 473 on placebo (hazard ratio 0.85, 95% CI 0.74-0.97, p=0.014). Coronary heart disease death and non-fatal myocardial infarction risk was also reduced (0.81, 0.69-0.94, p=0.006). Stroke risk was unaffected (1.03, 0.81-1.31, p=0.8), but the hazard ratio for transient ischaemic attack was 0.75 (0.55-1.00, p=0.051). New cancer diagnoses were more frequent on pravastatin than on placebo (1.25, 1.04-1.51, p=0.020). However, incorporation of this finding in a meta-analysis of all pravastatin and all statin trials showed no overall increase in risk. Mortality from coronary disease fell by 24% (p=0.043) in the pravastatin group. Pravastatin had no significant effect on cognitive function or disability. Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people.
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            Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus.

            Familial hypercholesterolemia is characterized by impaired uptake of cholesterol in peripheral tissues, including the liver and the pancreas. In contrast, statins increase the cellular cholesterol uptake and are associated with increased risk for type 2 diabetes mellitus. We hypothesize that transmembrane cholesterol transport is linked to the development of type 2 diabetes.
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              Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials.

              Patients with dyslipoproteinemia constitute the largest risk group for development of atherosclerosis and cardiovascular disease (CVD). Despite extensive statin use, many patients with CVD risk do not achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) targets. This pooled analysis of 27 previously published clinical trials conducted between 1999 and 2008 evaluated the lipid-altering efficacy and factors related to treatment response of ezetimibe combined with statin and statin monotherapy. Patient-level data were combined from double-blind, placebo-controlled or active comparator studies randomizing adult subjects to ezetimibe 10mg plus statin (n=11,714) versus statin alone (n=10,517) for 6-24 weeks (mean=9 weeks). Association of factors with treatment response, percent change from baseline LDL-C and other lipids, and attainment of guideline-recommended lipid and lipoprotein targets were evaluated. Higher baseline LDL-C, diabetes mellitus, Black race, greater age, and male gender were associated with small but significantly greater percent reductions in LDL-C regardless of treatment. Treatment influenced efficacy, with ezetimibe plus statin producing significantly greater reductions in LDL-C, total-cholesterol, non-HDL-C, ApoB, triglycerides, lipid ratios, hs-CRP; significantly larger increases in HDL-C and ApoA1; and significantly higher achievement of LDL-C (<70mg/dl, <100mg/dl), non-HDL-C (<100mg/dl, <130mg/dl), and ApoB (<80mg/dl, <90mg/dl) targets than statin monotherapy at statin potencies compared (p<0.0001 for all). Differential treatment effects were seen with first-/second-line therapy and statin potency. These results suggest that patient characteristics have a limited influence on response to lipid-lowering therapy and demonstrate the consistent treatment effect of ezetimibe combined with statin and statin monotherapy across a diverse patient population. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
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                Author and article information

                Contributors
                patrickcollins@nhs.net
                naveed.sattar@glasgow.ac.uk
                Journal
                Curr Cardiol Rep
                Curr Cardiol Rep
                Current Cardiology Reports
                Springer US (New York )
                1523-3782
                1534-3170
                19 November 2016
                19 November 2016
                2016
                : 18
                : 12
                : 133
                Affiliations
                [1 ]University Hospital Lewisham, Lewisham High Street, London, SE13 6LH UK
                [2 ]Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University Of Glasgow, 126 University Place, Glasgow, G12 8TA UK
                Article
                795
                10.1007/s11886-016-0795-9
                5116040
                27864787
                533de812-3a7b-4214-8bb7-5cd192ae9e8f
                © The Author(s) 2016

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Funding
                Funded by: University of Glasgow
                Categories
                Diabetes and Cardiovascular Disease (S Malik, Section Editor)
                Custom metadata
                © Springer Science+Business Media New York 2016

                Cardiovascular Medicine
                statins,hypercholesterolaemia,pcsk9,ezetimibe,niacin,diabetes
                Cardiovascular Medicine
                statins, hypercholesterolaemia, pcsk9, ezetimibe, niacin, diabetes

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