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Dr Amand F Schmidt, PhD, Daniel I Swerdlow, PhD, Michael V Holmes, PhD, Riyaz S Patel, MD, Zammy Fairhurst-Hunter, MSc, Donald M Lyall, PhD, Fernando Pires Hartwig, MSc, Prof Bernardo Lessa Horta, PhD, Prof Elina Hyppönen, PhD, Prof Christine Power, PhD, Max Moldovan, PhD, Erik van Iperen, MSc, Prof G Kees Hovingh, PhD, Ilja Demuth, PhD, Kristina Norman, PhD, Prof Elisabeth Steinhagen-Thiessen, MD, Juri Demuth, PhD, Prof Lars Bertram, MD, Tian Liu, PhD, Stefan Coassin, PhD, Prof Johann Willeit, PhD, Stefan Kiechl, MD, Karin Willeit, MD, Dan Mason, PhD, Prof John Wright, FRCP, Prof Richard Morris, PhD, Prof Goya Wanamethee, PhD, Prof Peter Whincup, FRCP, Prof Yoav Ben-Shlomo, PhD, Stela McLachlan, PhD, Prof Jackie F Price, MD, Prof Mika Kivimaki, PhD, Catherine Welch, PhD, Adelaida Sanchez-Galvez, PhD, Pedro Marques-Vidal, PhD, Andrew Nicolaides, PhD, Andrie G Panayiotou, PhD, N Charlotte Onland-Moret, PhD, Prof Yvonne T van der Schouw, PhD, Giuseppe Matullo, PhD, Giovanni Fiorito, PhD, Simonetta Guarrera, MSc, Carlotta Sacerdote, PhD, Prof Nicholas J Wareham, PhD, Claudia Langenberg, PhD, Robert Scott, PhD, Jian'an Luan, PhD, Prof Martin Bobak, PhD, Prof Sofia Malyutina, PhD, Andrzej Pająk, PhD, Ruzena Kubinova, PhD, Prof Abdonas Tamosiunas, PhD, Hynek Pikhart, PhD, Lise Lotte Nystrup Husemoen, PhD, Niels Grarup, PhD, Oluf Pedersen, PhD, Torben Hansen, PhD, Prof Allan Linneberg, PhD, Kenneth Starup Simonsen, PhD, Jackie Cooper, MSc, Prof Steve E Humphries, PhD, Murray Brilliant, PhD, Terrie Kitchner, CCRP, Hakon Hakonarson, PhD, David S Carrell, PhD, Catherine A McCarty, PhD, H Lester Kirchner, PhD, Eric B Larson, MD, David R Crosslin, PhD, Prof Mariza de Andrade, PhD, Prof Dan M Roden, MD, Joshua C Denny, MD, Cara Carty, PhD, Stephen Hancock, MSciStud, John Attia, PhD, Elizabeth Holliday, PhD, Martin O'Donnell, PhD, Prof Salim Yusuf, DPhil, Michael Chong, MSc, Prof Guillaume Pare, MD, Prof Pim van der Harst, PhD, M Abdullah Said, BSc, Ruben N Eppinga, PhD, Niek Verweij, PhD, Prof Harold Snieder, PhD for the LifeLines Cohort study group, Tim Christen, MSc, Dennis O Mook-Kanamori, PhD, Stefan Gustafsson, PhD, Prof Lars Lind, PhD, Prof Erik Ingelsson, PhD, Raha Pazoki, PhD, Oscar Franco, PhD, Prof Albert Hofman, PhD, Andre Uitterlinden, PhD, Abbas Dehghan, PhD, Alexander Teumer, PhD, Sebastian Baumeister, PhD, Prof Marcus Dörr, MD, Prof Markus M Lerch, MD, Prof Uwe Völker, PhD, Prof Henry Völzke, MD, Joey Ward, PhD, Jill P Pell, PhD, Daniel J Smith, PhD, Tom Meade, FRS, Prof Anke H Maitland-van der Zee, PhD, Ekaterina V Baranova, MSc, Robin Young, PhD, Ian Ford, PhD, Archie Campbell, MA, Prof Sandosh Padmanabhan, PhD, Prof Michiel L Bots, MD, Prof Diederick E Grobbee, PhD, Prof Philippe Froguel, PhD, Dorothée Thuillier, MSc, Beverley Balkau, PhD, Amélie Bonnefond, PhD, Prof Bertrand Cariou, MD, Melissa Smart, PhD, Yanchun Bao, PhD, Prof Meena Kumari, PhD, Anubha Mahajan, PhD, Prof Paul M Ridker, MD, Daniel I Chasman, PhD, Alex P Reiner, MD, Prof Leslie A Lange, PhD, Marylyn D Ritchie, PhD, Prof Folkert W Asselbergs, MD, Prof Juan-Pablo Casas, PhD, Brendan J Keating, PhD‡, David Preiss, MD, Prof Aroon D Hingorani, PhD, UCLEB consortium, Prof Naveed Sattar, FMedSci
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.
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.
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).
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.