BACKGROUND: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. METHODS: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. FINDINGS: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30). INTERPRETATION: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. FUNDING: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.

Anschutz Medical Campus University of Colorado Denver Denver CO USA

Biomedical and Translational Informatics Geisinger Health System Danville PA USA; Department of Biochemistry and Molecular Biology Huck Institutes of the Life Sciences Pennsylvania State University University Park PA USA

Bradford Institute for Health Research Bradford Royal Infirmary Bradford UK

Cancer Epidemiology Unit San Giovanni Battista Hospital Turin Italy; Centre for Oncology Prevention CPO Piemonte Turin Italy

Center for Health Research Geisinger Clinic Danville PA USA

Center for Human Genetics Marshfield Clinic Research Foundation Marshfield WI USA

Centre for Cardiovascular Genetics University College London UK

Centre for Population Health Research Sansom Institute for Health Research University of South Australia Adelaide SA Australia; Population Policy and Practice UCL Great Ormond Street Institute of Child Health London UK; South Australian Health and Medical Research Institute Adelaide SA Australia

Centre for Population Health Sciences Usher Institute of Population Health Sciences and Informatics University of Edinburgh Edinburgh UK

Charité Research Group on Geriatrics Charité Universitätsmedizin Berlin Berlin Germany

Charité Research Group on Geriatrics Charité Universitätsmedizin Berlin Berlin Germany; Institute of Medical and Human Genetics Charité Universitätsmedizin Berlin Berlin Germany

Children's Hospital of Philadelphia Philadelphia PA USA

Clinical Trial Service Unit and Epidemiological Studies Unit Nuffield Department of Population Health University of Oxford Oxford UK; Medical Research Council Population Health Research Unit at the University of Oxford University of Oxford Oxford UK

CNRS UMR 8199 European Genomic Institute for Diabetes Institut Pasteur de Lille University of Lille Lille France

Cyprus International Institute for Environmental and Public Health Cyprus University of Technology Limassol Cyprus

Department of Biomedical Informatics Vanderbilt University School of Medicine Nashville TN USA

Department of Cardiology University Medical Center Groningen University of Groningen Groningen Netherlands

Department of Clinical Epidemiology Leiden University Medical Center Leiden Netherlands

Department of Epidemiology and Public Health UCL Institute of Epidemiology and Health Care University College London UK

Department of Epidemiology Erasmus University Medical Center Rotterdam Netherlands

Department of Epidemiology Fred Hutchinson Cancer Research Center University of Washington Seattle WA USA

Department of Epidemiology University Medical Center Groningen University of Groningen Groningen Netherlands

Department of Genomics of Common Disease Imperial College London London UK; CNRS UMR 8199 European Genomic Institute for Diabetes Institut Pasteur de Lille University of Lille Lille France

Department of Internal Medicine B University Medicine Greifswald Greifswald Germany; German Centre for Cardiovascular Research Greifswald Germany

Department of Internal Medicine Erasmus University Medical Center Rotterdam Netherlands

Department of Medicine A University Medicine Greifswald Greifswald Germany

Department of Neurology Medical University of Innsbruck Innsbruck Austria

Department of Non Communicable Disease Epidemiology London School of Hygiene and Tropical Medicine London UK

Department of Primary Care and Population Health University College London UK

Department of Respiratory Medicine Academic Medical Center Amsterdam Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht Institute of Pharmaceutical Sciences Faculty of Science Utrecht University Utrecht Netherlands

Department of Surgery University of Pennsylvania Philadelphia PA USA

Department of Vascular Medicine Academic Medical Center Amsterdam Netherlands

Department of Vascular Surgery Imperial College London London UK; Department of Surgery Nicosia Medical School University of Nicosia Nicosia Cyprus

Departments of Medicine and Pharmacology Vanderbilt University School of Medicine Nashville TN USA

Division of Biomedical Statistics and Informatics Mayo Clinic Rochester MN USA

Division of Genetic Epidemiology Innsbruck Department of Medical Genetics Molecular and Clinical Pharmacology Medical University of Innsbruck Innsbruck Austria

Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht Institute of Pharmaceutical Sciences Faculty of Science Utrecht University Utrecht Netherlands

Durrer Center for Cardiovascular Research Netherlands Heart Institute Utrecht Netherlands; Department of Cardiology University Medical Center Groningen University of Groningen Groningen Netherlands; Department of Genetics University Medical Center Groningen University of Groningen Groningen Netherlands

Durrer Center for Cardiovascular Research Netherlands Heart Institute Utrecht Netherlands; Department of Clinical Epidemiology Biostatistics and Bioinformatics Academic Medical Center Amsterdam Netherlands

E CA Economics GmbH Berlin Germany

Essentia Institute of Rural Health Duluth MN USA

Faculty of Medicine and Department of Biostatistics and Epidemiology MRC PHE Centre for Environment and Health School of Public Health Imperial College London London UK; Department of Epidemiology Erasmus University Medical Center Rotterdam Netherlands

Farr Institute of Health Informatics Research UCL Institute of Health Informatics University College London UK

George Washington University Washington DC USA

Group Health Research Institute in Seattle WA USA

Group Health Research Institute Seattle WA USA

Harvard Medical School Center for Cardiovascular Disease Prevention Brigham and Women's Hospital Boston MA USA

Human Genetics Foundation HuGeF Turin Italy; Department of Medical Sciences University of Turin Turin Italy

I'institut du Thorax INSERM CNRS University of Nantes CHU de Nantes Nantes France

Institute for Community Medicine University Medicine Greifswald Greifswald Germany; Department of Epidemiology and Preventive Medicine University of Regensburg Regensburg Germany

Institute for Community Medicine University Medicine Greifswald Greifswald Germany; German Centre for Cardiovascular Research Greifswald Germany

Institute for Social and Economic Research University of Essex Colchester Essex UK

Institute of Cardiovascular and Medical Sciences University of Glasgow Glasgow UK

Institute of Cardiovascular Science University College London UK; Department of Medicine Imperial College London London UK

Institute of Cardiovascular Science University College London UK; Farr Institute of Health Informatics Research UCL Institute of Health Informatics University College London UK

Institute of Cardiovascular Science University College London UK; Farr Institute of Health Informatics Research UCL Institute of Health Informatics University College London UK; Durrer Center for Cardiovascular Research Netherlands Heart Institute Utrecht Netherlands; Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht Netherlands; Department of Cardiology Division Heart and Lungs University Medical Center Utrecht Utrecht Netherlands

Institute of Cardiovascular Science University College London UK; Farr Institute of Health Informatics Research UCL Institute of Health Informatics University College London UK; The Barts Heart Centre St Bartholomew's Hospital London UK

Institute of Genetics and Molecular Medicine University of Edinburgh Edinburgh UK

Institute of Health and Wellbeing University of Glasgow Glasgow UK

Interfaculty Institute of Genetics and Functional Genomics University Medicine Greifswald Greifswald Germany; German Centre for Cardiovascular Research Greifswald Germany

Internal Medicine Unit Department of Medicine Lausanne University Hospital Lausanne Switzerland

Jagiellonian University Collegium Medicum Krakow Poland

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht Netherlands

Lithuanian University of Health Sciences Kaunas Lithuania

Max Planck Institute for Human Development Berlin Germany; Max Planck Institute for Molecular Genetics Berlin Germany

Molecular Epidemiology Department of Medical Sciences Uppsala University Uppsala Sweden

Molecular Epidemiology Department of Medical Sciences Uppsala University Uppsala Sweden; Science for Life Laboratory Department of Medical Sciences Uppsala University Uppsala Sweden; Division of Cardiovascular Medicine Department of Medicine Stanford University School of Medicine Stanford CA USA

MRC Epidemiology Unit Institute of Metabolic Science University of Cambridge School of Clinical Medicine Cambridge UK

National Institute of Public Health Prague Czech Republic

Neuroepidemiology and Ageing Research Unit Imperial College London London UK; Lübeck Interdisciplinary Platform for Genome Analytics Institutes of Neurogenetics and Integrative and Experimental Genomics University of Lübeck Lübeck Germany

Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Novosibirsk State Medical University Novosibirsk Russia; Institute of Internal and Preventive Medicine Siberian Branch of the Russian Academy of Medical Sciences Novosibirsk Russia

Population Health Research Institute Hamilton ON Canada

Population Health Research Institute St George's University of London London UK

Population Policy and Practice UCL Great Ormond Street Institute of Child Health London UK

Postgraduate Program in Epidemiology Federal University of Pelotas Pelotas Brazil

Renal and Cardiovascular Epidemiology Centre de Recherche en Epidémiologie et Santé des Populations INSERM U1018 Villejuif France

Research Centre for Prevention and Health Capital Region of Denmark Denmark

Research Centre for Prevention and Health Capital Region of Denmark Denmark; Department of Clinical Experimental Research Rigshospitalet Copenhagen Denmark; Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Robertson Centre for Biostatistics University of Glasgow Glasgow UK

School of Health Sciences University of South Australia Adelaide SA Australia; South Australian Health and Medical Research Institute EMBL Australia Adelaide SA Australia

School of Social and Community Medicine University of Bristol Bristol UK

University of Newcastle Newcastle NSW Australia

Wellcome Trust Centre for Human Genetics University of Oxford Oxford UK

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Lancet Diabetes Endocrinol. 2017 Feb;5(2):78-79. doi: 10.1016/S2213-8587(16)30398-9. PubMed

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