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1. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials

Author

Swerdlow, Daniel I, Preiss, David, Kuchenbaecker, Karoline B, Holmes, Michael V, Engmann, Jorgen EL, Shah, Tina, Sofat, Reecha, Stender, Stefan, Johnson, Paul CD, Scott, Robert A, Leusink, Maarten, Verweij, Niek, Sharp, Stephen J, Guo, Yiran, Giambartolomei, Claudia, Chung, Christina, Peasey, Anne, Amuzu, Antoinette, Li, KaWah, Palmen, Jutta, Howard, Philip, Cooper, Jackie A, Drenos, Fotios, Li, Yun R, Lowe, Gordon, Gallacher, John, Stewart, Marlene CW, Tzoulaki, Ioanna, Buxbaum, Sarah G, van der A, Daphne L, Forouhi, Nita G, Onland-Moret, N Charlotte, van der Schouw, Yvonne T, Schnabel, Renate B, Hubacek, Jaroslav A, Kubinova, Ruzena, Baceviciene, Migle, Tamosiunas, Abdonas, Pajak, Andrzej, Topor-Madry, Romanvan, Stepaniak, Urszula, Malyutina, Sofia, Baldassarre, Damiano, Sennblad, Bengt, Tremoli, Elena, de Faire, Ulf, Veglia, Fabrizio, Ford, Ian, Jukema, J Wouter, Westendorp, Rudi GJ, de Borst, Gert Jan, de Jong, Pim A, Algra, Ale, Spiering, Wilko, der Zee, Anke H Maitland-van, Klungel, Olaf H, de Boer, Anthonius, Doevendans, Pieter A, Eaton, Charles B, Robinson, Jennifer G, Duggan, David, DIAGRAM Consortium, MAGIC Consortium, Kjekshus, John, Downs, John R, Gotto, Antonio M, Keech, Anthony C, Marchioli, Roberto, Tognoni, Gianni, Sever, Peter S, Poulter, Neil R, Waters, David D, Pedersen, Terje R, Amarenco, Pierre, Nakamura, Haruo, McMurray, John JV, Lewsey, James D, Chasman, Daniel I, Ridker, Paul M, Maggioni, Aldo P, Tavazzi, Luigi, Ray, Kausik K, Seshasai, Sreenivasa Rao Kondapally, Manson, JoAnn E, Price, Jackie F, Whincup, Peter H, Morris, Richard W, Lawlor, Debbie A, Smith, George Davey, Ben-Shlomo, Yoav, Schreiner, Pamela J, Fornage, Myriam, Siscovick, David S, Cushman, Mary, Kumari, Meena, Wareham, Nick J, Verschuren, WM Monique, Redline, Susan, Patel, Sanjay R, Whittaker, John C, and Hamsten, Anders

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Clinical Trials and Supportive Activities, Clinical Research, Genetics, Nutrition, Diabetes, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Metabolic and endocrine, Aged, Body Mass Index, Body Weight, Cholesterol, HDL, Cholesterol, LDL, Diabetes Mellitus, Type 2, Female, Genetic Testing, Humans, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Middle Aged, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic, Risk Factors, DIAGRAM Consortium, MAGIC Consortium, InterAct Consortium, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundStatins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.MethodsWe used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.FindingsData were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials).InterpretationThe increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.FundingThe funding sources are cited at the end of the paper.

Published
2015

8. Real world estimates of adrenal insufficiency related adverse events in children with congenital adrenal hyperplasia

Author

Ali, Salma R., Bryce, Jillian, Haghpanahan, Houra, Lewsey, James D., Tan, Li En, Atapattu, Navoda, Birkebaek, Niels H., Blankenstein, Oliver, Neumann, Uta, Balsamo, Antonio, Ortolano, Rita, Bonfig, Walter, Claahsen-van der Grinten, Hedi L., Cools, Martine, Correa Costa, Eduardo, Darendeliler, Feyza, Poyrazoglu, Sukran, Elsedfy, Heba, Finken, Martijn J.J., Fluck, Christa E., Gevers, Evelien, Korbonits, Márta, Guaragna-Filho, Guilherme, Guran, Tulay, Guven, Ayla, Hannema, Sabine E., Higham, Claire, Hughes, Ieuan A., Tadokoro-Cuccaro, Rieko, Thankamony, Ajay, Iotova, Violeta, Krone, Nils P., Krone, Ruth, Lichiardopol, Corina, Luczay, Andrea, Mendonca, Berenice B., Bachega, Tania A.S.S., Miranda, Mirela C., Milenkovic, Tatjana, Mohnike, Klaus, Nordenstrom, Anna, Einaudi, Silvia, van der Kamp, Hetty, Vieites, Ana, Vries, Liat de, Ross, Richard J.M., and Ahmed, S. Faisal

Abstract

Background:\ud Although congenital adrenal hyperplasia (CAH) is known to be associated with adrenal crises (AC), its association with patient or clinician reported sick day episodes (SDE) is less clear.\ud \ud Methods:\ud Data on children with classic 21-hydroxylase deficiency CAH from 34 centers in 18 countries, of which 7 were Low or Middle Income (LMIC) and 11 were High Income (HIC), were collected from the International CAH Registry and analysed to examine the clinical factors associated with SDE and AC.\ud \ud Results:\ud 518 children with a median of 11 children (range 1, 53) per center had 5,388 visits evaluated over a total of 2,300 patient years. The median number of AC and SDE per patient year per center was 0 (0, 3) and 0.4 (0.0, 13.3), respectively. Of the 1,544 SDE, an AC was reported in 62 (4%), with no fatalities. Infectious illness was the most frequent precipitating event, reported in 1,105 (72%) and 29 (47%) of SDE and AC, respectively. On comparing cases from LMIC and HIC, the median SDE per patient year was 0.75 (0, 13.3) vs 0.11 (0, 12.0) (p

Published
2021

9. Real-World Estimates of Adrenal Insufficiency-Related Adverse Events in Children With Congenital Adrenal Hyperplasia

Author

Ali, S., Bryce, J., Haghpanahan, Houra, Lewsey, James D., Tan, Li En, Atapattu, Navoda, Claahsen-van der Grinten, H.L., Vries, Liat, Ross, R., Faisal Ahmed, S., Ali, S., Bryce, J., Haghpanahan, Houra, Lewsey, James D., Tan, Li En, Atapattu, Navoda, Claahsen-van der Grinten, H.L., Vries, Liat, Ross, R., and Faisal Ahmed, S.

Abstract

Contains fulltext : 230378.pdf (Publisher’s version ) (Open Access)

Published
2021

10. Real-World Estimates of Adrenal Insufficiency-Related Adverse Events in Children with Congenital Adrenal Hyperplasia

Author

Utrecht Palliatie Centrum, Endocrinologie patientenzorg, Child Health, Ali, Salma R, Bryce, Jillian, Haghpanahan, Houra, Lewsey, James D, Tan, Li En, Atapattu, Navoda, Birkebaek, Niels H, Blankenstein, Oliver, Neumann, Uta, Balsamo, Antonio, Ortolano, Rita, Bonfig, Walter, Claahsen-van der Grinten, Hedi L, Cools, Martine, Costa, Eduardo Correa, Darendeliler, Feyza, Poyrazoglu, Sukran, Elsedfy, Heba, Finken, Martijn J J, Fluck, Christa E, Gevers, Evelien, Korbonits, Márta, Guaragna-Filho, Guilherme, Guran, Tulay, Guven, Ayla, Hannema, Sabine E, Higham, Claire, Hughes, Ieuan A, Tadokoro-Cuccaro, Rieko, Thankamony, Ajay, Iotova, Violeta, Krone, Nils P, Krone, Ruth, Lichiardopol, Corina, Luczay, Andrea, Mendonca, Berenice B, Bachega, Tania A S S, Miranda, Mirela C, Milenkovic, Tatjana, Mohnike, Klaus, Nordenstrom, Anna, Einaudi, Silvia, van der Kamp, Hetty, Vieites, Ana, de Vries, Liat, Ross, Richard J M, Ahmed, S Faisal, Utrecht Palliatie Centrum, Endocrinologie patientenzorg, Child Health, Ali, Salma R, Bryce, Jillian, Haghpanahan, Houra, Lewsey, James D, Tan, Li En, Atapattu, Navoda, Birkebaek, Niels H, Blankenstein, Oliver, Neumann, Uta, Balsamo, Antonio, Ortolano, Rita, Bonfig, Walter, Claahsen-van der Grinten, Hedi L, Cools, Martine, Costa, Eduardo Correa, Darendeliler, Feyza, Poyrazoglu, Sukran, Elsedfy, Heba, Finken, Martijn J J, Fluck, Christa E, Gevers, Evelien, Korbonits, Márta, Guaragna-Filho, Guilherme, Guran, Tulay, Guven, Ayla, Hannema, Sabine E, Higham, Claire, Hughes, Ieuan A, Tadokoro-Cuccaro, Rieko, Thankamony, Ajay, Iotova, Violeta, Krone, Nils P, Krone, Ruth, Lichiardopol, Corina, Luczay, Andrea, Mendonca, Berenice B, Bachega, Tania A S S, Miranda, Mirela C, Milenkovic, Tatjana, Mohnike, Klaus, Nordenstrom, Anna, Einaudi, Silvia, van der Kamp, Hetty, Vieites, Ana, de Vries, Liat, Ross, Richard J M, and Ahmed, S Faisal

Published
2021

11. Estimating the impact of stroke unit care in a whole population: an epidemiological study using routine data

Author

Langhorne, Peter, Lewsey, James D., Jhund, Pardeep S., Gillies, Michelle, Chalmers, Jim W.T., Redpath, Adam, Briggs, Andrew, Walters, Matthew, Capewell, Simon, McMurray, John J.V., and MacIntyre, Kate

Subjects
Stroke (Disease) -- Care and treatment, Stroke (Disease) -- Distribution, Stroke (Disease) -- Patient outcomes, Stroke (Disease) -- Research, Hospital wards -- Management, Hospital wards -- Influence, Hospital wards -- Research, Outcome and process assessment (Health Care) -- Research, Company distribution practices, Company business management, Health, Psychology and mental health
Published
2010

12. Real-World Estimates of Adrenal Insufficiency–Related Adverse Events in Children With Congenital Adrenal Hyperplasia

Author

Ali, Salma R, primary, Bryce, Jillian, additional, Haghpanahan, Houra, additional, Lewsey, James D, additional, Tan, Li En, additional, Atapattu, Navoda, additional, Birkebaek, Niels H, additional, Blankenstein, Oliver, additional, Neumann, Uta, additional, Balsamo, Antonio, additional, Ortolano, Rita, additional, Bonfig, Walter, additional, Claahsen-van der Grinten, Hedi L, additional, Cools, Martine, additional, Costa, Eduardo Correa, additional, Darendeliler, Feyza, additional, Poyrazoglu, Sukran, additional, Elsedfy, Heba, additional, Finken, Martijn J J, additional, Fluck, Christa E, additional, Gevers, Evelien, additional, Korbonits, Márta, additional, Guaragna-Filho, Guilherme, additional, Guran, Tulay, additional, Guven, Ayla, additional, Hannema, Sabine E, additional, Higham, Claire, additional, Hughes, Ieuan A, additional, Tadokoro-Cuccaro, Rieko, additional, Thankamony, Ajay, additional, Iotova, Violeta, additional, Krone, Nils P, additional, Krone, Ruth, additional, Lichiardopol, Corina, additional, Luczay, Andrea, additional, Mendonca, Berenice B, additional, Bachega, Tania A S S, additional, Miranda, Mirela C, additional, Milenkovic, Tatjana, additional, Mohnike, Klaus, additional, Nordenstrom, Anna, additional, Einaudi, Silvia, additional, van der Kamp, Hetty, additional, Vieites, Ana, additional, de Vries, Liat, additional, Ross, Richard J M, additional, and Ahmed, S Faisal, additional

Published
2020
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15. Improved survival with bisoprolol in patients with heart failure and renal impairment: an analysis of the cardiac insufficiency bisoprolol study II (CIBIS-II) trial

Author

Castagno, Davide, Jhund, Pardeep S., McMurray, John J.V., Lewsey, James D., Erdmann, Erland, Zannad, Faiez, Remme, Willem J., Lopez-Sendon, José L., Lechat, Philippe, Follath, Ferenc, Höglund, Christer, Mareev, Viacheslav, Sadowski, Zygmunt, Seabra-Gomes, Ricardo J., and Dargie, Henry J.

Published
2010
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21. Trends in incidence and in short term survival following a subarachnoid haemorrhage in Scotland, 1986 - 2005: a retrospective cohort study

Author

Walters Matthew, Briggs Andrew, Redpath Adam, Chalmers Jim WT, Gillies Michelle, Jhund Pardeep S, Lewsey James D, Macpherson Karen J, Langhorne Peter, Capewell Simon, McMurray John JV, and MacIntyre Kate

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background To examine age and sex specific incidence and 30 day case fatality for subarachnoid haemorrhage (SAH) in Scotland over a 20 year period. Methods A retrospective cohort study using routine hospital discharge data linked to death records. Results Between 1986 and 2005, 12,056 individuals experienced an incident SAH. Of these 10,113 (84%) survived to reach hospital. Overall age-standardised incidence rates were greater in women than men and remained relatively stable over the study period. In 2005, incidence in women was 12.8 (95% CI 11.5 to 14.2) and in men 7.9 (95% CI 6.9 to 9.1). 30 day case fatality in individuals hospitalised with SAH declined substantially, falling from 30.0% in men and 33.9% in women in 1986-1990 to 24.5% in men and 29.1% in women in 2001-2005. For both men and women, the largest reductions were observed in those aged between 40 to 59 years. After adjustment for age, socio-economic status and co-morbidity, the odds of death at 30 days in 2005 compared to odds of death in 1986 was 0.64 (0.54 to 0.76), p < 0.001 for those below 70 years, and 1.14 (0.83 to 1.56), p = 0.4 in those 70 years and above. Conclusions Incidence rates for SAH remained stable between 1986 and 2005 suggesting that a better understanding of SAH risk factors and their reduction is needed. 30 day case fatality rates have declined substantially, particularly in middle-age. However, they remain high and it is important to ensure that this is not due to under-diagnosis or under-treatment.

Published
2011
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22. Cost-effectiveness analysis in R using a multi-state modelling survival analysis framework: a tutorial

Author

Williams, Claire, Lewsey, James D., Briggs, Andrew H., and Mackay, Daniel F.

Abstract

This tutorial provides a step-by-step guide to performing cost-effectiveness analysis using a multi-state modelling approach. Alongside the tutorial we provide easy-to-use functions in the statistics package R. We argue this multi-state modelling approach using a package such as R has advantages over approaches where models are built in a spreadsheet package. In particular, using a syntax-based approach means there is a written record of what was done and the calculations are transparent. Reproducing the analysis is straightforward as the syntax just needs to be run again. The approach can be thought of as an alternative way to build a Markov decision analytic model, which also has the option to use a state-arrival extended approach if the Markov property does not hold. In the state-arrival extended multi-state model a covariate that represents patients’ history is included allowing the Markov property to be tested. We illustrate the building of multi-state survival models, making predictions from the models and assessing fits. We then proceed to perform a cost-effectiveness analysis including deterministic and probabilistic sensitivity analyses. Finally, we show how to create two common methods of visualising the results, namely cost-effectiveness planes and cost-effectiveness acceptability curves. The analysis is implemented entirely within R. It is based on adaptions to functions in the existing R package mstate, to accommodate parametric multi-state modelling which facilitates extrapolation of survival curves.

Published
2017

23. Estimation of survival probabilities for use in cost-effectiveness analysis: a comparison of a multi-state modelling survival analysis approach with partitioned survival and Markov decision-analytic modelling

Author

Williams, Claire, Lewsey, James D., Mackay, Daniel F., and Briggs, Andrew H.

Abstract

Modelling of clinical-effectiveness in cost-effectiveness analysis typically involves some form of partitioned survival or Markov decision-analytic modelling. The health states progression-free, progression and death and the transitions between them are frequently of interest. With partitioned survival, progression is not modelled directly as a state; instead time in that state is derived from the difference in area between overall survival and progression-free survival curves. With Markov decision-analytic modelling, a priori assumptions are often made with regard to the transitions rather than using the individual patient data directly to model them. This article compares a multi-state modelling survival regression approach to these two common methods. As a case study, we use a trial comparing rituximab in combination with fludarabine and cyclophosphamide versus fludarabine and cyclophosphamide alone for the first line treatment of chronic lymphocytic leukaemia. We calculated mean Life Years and QALYs that involved extrapolation of survival outcomes in a trial. We adapted an existing multi-state modelling approach to incorporate parametric distributions for transition hazards, to allow extrapolation. The comparison showed that, due to the different assumptions used in the different approaches, a discrepancy in results was evident. The partitioned survival and Markov decision-analytic modelling deemed the treatment cost-effective with ICERs of just over £16,000 and £13,000 respectively. However, the results with the multi-state modelling were less conclusive with an ICER of just over £29,000. This work has illustrated that it is imperative to check whether assumptions are realistic as different model choices can influence clinical and cost-effectiveness results.

Published
2017

24. Evidence synthesis for constructing directed acyclic graphs (ESC-DAGs): a novel and systematic method for building directed acyclic graphs.

Author

Ferguson, Karl D, McCann, Mark, Katikireddi, Srinivasa Vittal, Thomson, Hilary, Green, Michael J, Smith, Daniel J, and Lewsey, James D

Subjects
DIRECTED acyclic graphs, PARENTAL influences, LIQUOR stores, META-analysis, MODULAR design, STATISTICS, RESEARCH, RESEARCH methodology, SELF-evaluation, EVALUATION research, MEDICAL cooperation, COMPARATIVE studies, CAUSAL inference, RESEARCH funding, STATISTICAL models, DATA analysis, MEDICAL research, HEALTH self-care
Abstract

Background: Directed acyclic graphs (DAGs) are popular tools for identifying appropriate adjustment strategies for epidemiological analysis. However, a lack of direction on how to build them is problematic. As a solution, we propose using a combination of evidence synthesis strategies and causal inference principles to integrate the DAG-building exercise within the review stages of research projects. We demonstrate this idea by introducing a novel protocol: 'Evidence Synthesis for Constructing Directed Acyclic Graphs' (ESC-DAGs)'.Methods: ESC-DAGs operates on empirical studies identified by a literature search, ideally a novel systematic review or review of systematic reviews. It involves three key stages: (i) the conclusions of each study are 'mapped' into a DAG; (ii) the causal structures in these DAGs are systematically assessed using several causal inference principles and are corrected accordingly; (iii) the resulting DAGs are then synthesised into one or more 'integrated DAGs'. This demonstration article didactically applies ESC-DAGs to the literature on parental influences on offspring alcohol use during adolescence.Conclusions: ESC-DAGs is a practical, systematic and transparent approach for developing DAGs from background knowledge. These DAGs can then direct primary data analysis and DAG-based sensitivity analysis. ESC-DAGs has a modular design to allow researchers who are experienced DAG users to both use and improve upon the approach. It is also accessible to researchers with limited experience of DAGs or evidence synthesis. [ABSTRACT FROM AUTHOR]

Published
2020
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25. Fatigue as a predictor of outcome in patients with heart failure: Analysis of CORONA (Controlled rosuvastatin multinational trial in heart failure)

Author

Perez-Moreno, Ana Cristina, Jhund, Pardeep S., Macdonald, Michael R., Petrie, Mark C., Cleland, John G. F., Böhm, Michael, van Veldhuisen, Dirk J., Gullestad, Lars, Wikstrand, John, Kjekshus, John, Lewsey, James D., and McMurray, John J.V.

Subjects
heart failure, symptoms, fatigue, dyspnea, outcomes
Abstract

Objectives The purpose of this study was to examine the relationship between fatigue and clinical outcomes, using dyspnea as a comparator, in patients with left ventricular ejection fraction (LVEF) ≤35% enrolled in the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study. Background Although fatigue is a common symptom in heart failure (HF), little is known about its association with prognosis. Methods At baseline in CORONA, fatigue “during the past few days” was measured using a 5-point exertion scale (0 = none, 1 = heavy exertion, 2 = moderate exertion, 3 = slight exertion, 4 = rest); a 4-point scale was used for dyspnea (1 to 4 as for fatigue). Patients were grouped into 3 categories: a fatigue score 0 to 1 (n = 535), fatigue score 2 (n = 1,632), and fatigue score 3 to 4 (n = 1,663); and a dyspnea score of 1 (n = 292), dyspnea score of 2 (n = 1,695), and dyspnea score of 3 to 4 (n = 1,843). The association between fatigue and dyspnea and the composite outcome of cardiovascular (CV) death or HF hospital stay and each component separately was examined using Kaplan-Meier analysis and Cox proportional-hazard models. We also examined all-cause mortality. Results In univariate analyses, symptom severity was associated with a higher risk of CV death or HF hospital stay (fatigue: group 3, 49% [n = 810], vs. group 1, 30% [n = 160]; dyspnea: group 3, 50% [n = 918], vs. group 1, 28% [n = 82]) and all-cause mortality (fatigue: group 3, 38% [n = 623], vs. group 1, 24% [n = 130]; dyspnea: group 3, 38% [n = 697], vs. group 1, 23% [n = 66], log-rank p < 0.0001 for all). After adjusting for other prognostic variables, including LVEF, New York Heart Association class, and N-terminal pro-B-type natriuretic peptide level, worse fatigue remained associated with higher risk of HF hospital stay but not mortality (worse dyspnea remained associated with a higher risk of both). An increase in fatigue (or dyspnea) between baseline and 6 months was also associated with worse outcomes. Conclusions In HF, greater fatigue is associated with worse clinical outcomes. Closer attention should be paid to this symptom in clinical practice, with more done to standardize its measurement and understand its origins, with a view to improving treatment.

Published
2014

28. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight : Evidence from genetic analysis and randomised trials

Author

Swerdlow, Daniel I., Preiss, David, Kuchenbaecker, Karoline B., Holmes, Michael V., Engmann, Jorgen E L, Shah, Tina, Sofat, Reecha, Stender, Stefan, Johnson, Paul C D, Scott, Robert A., Leusink, Maarten, Verweij, Niek, Sharp, Stephen J., Guo, Yiran, Giambartolomei, Claudia, Chung, Christina, Peasey, Anne, Amuzu, Antoinette, Li, Kawah, Palmen, Jutta, Howard, Philip, Cooper, Jackie A., Drenos, Fotios, Li, Yun R., Lowe, Gordon, Gallacher, John, Stewart, Marlene C W, Tzoulaki, Ioanna, Buxbaum, Sarah G., Van Der A, Daphne L., Forouhi, Nita G., Onland-Moret, N. Charlotte, Van Der Schouw, Yvonne T., Schnabel, Renate B., Hubacek, Jaroslav A., Kubinova, Ruzena, Baceviciene, Migle, Tamosiunas, Abdonas, Pajak, Andrzej, Topor-Madry, Romanvan, Stepaniak, Urszula, Malyutina, Sofia, Baldassarre, Damiano, Sennblad, Bengt, Tremoli, Elena, De Faire, Ulf, Veglia, Fabrizio, Ford, Ian, Jukema, J. Wouter, Westendorp, Rudi G J, De Borst, Gert Jan, De Jong, Pim A., Algra, Ale, Spiering, Wilko, Der Zee, Anke H Maitland Van, Klungel, Olaf H., De Boer, Anthonius, Doevendans, Pieter A., Eaton, Charles B., Robinson, Jennifer G., Duggan, David, Kjekshus, John, Downs, John R., Gotto, Antonio M., Keech, Anthony C., Marchioli, Roberto, Tognoni, Gianni, Sever, Peter S., Poulter, Neil R., Waters, David D., Pedersen, Terje R., Amarenco, Pierre, Nakamura, Haruo, McMurray, John J V, Lewsey, James D., Chasman, Daniel I., Ridker, Paul M., Maggioni, Aldo P., Tavazzi, Luigi, Ray, Kausik K., Seshasai, Sreenivasa Rao Kondapally, Manson, Joann E., Price, Jackie F., Whincup, Peter H., Morris, Richard W., Lawlor, Debbie A., Smith, George Davey, Ben-Shlomo, Yoav, Schreiner, Pamela J., Fornage, Myriam, Siscovick, David S., Cushman, Mary, Kumari, Meena, Wareham, Nick J., Verschuren, W. M Monique, Redline, Susan, Patel, Sanjay R., Whittaker, John C., Hamsten, Anders, Delaney, Joseph A., Dale, Caroline, Gaunt, Tom R., Wong, Andrew, Kuh, Diana, Hardy, Rebecca, Kathiresan, Sekar, Castillo, Berta A., Van Der Harst, Pim, Brunner, Eric J., Tybjaerg-Hansen, Anne, Marmot, Michael G., Krauss, Ronald M., Tsai, Michael, Coresh, Josef, Hoogeveen, Ronald C., Psaty, Bruce M., Lange, Leslie A., Hakonarson, Hakon, Dudbridge, Frank, Humphries, Steve E., Talmud, Philippa J., Kivimäki, Mika, Timpson, Nicholas J., Langenberg, Claudia, Asselbergs, Folkert W., Voevoda, Mikhail, Bobak, Martin, Pikhart, Hynek, Wilson, James G., Reiner, Alex P., Keating, Brendan J., Hingorani, Aroon D., Sattar, Naveed, Swerdlow, Daniel I., Preiss, David, Kuchenbaecker, Karoline B., Holmes, Michael V., Engmann, Jorgen E L, Shah, Tina, Sofat, Reecha, Stender, Stefan, Johnson, Paul C D, Scott, Robert A., Leusink, Maarten, Verweij, Niek, Sharp, Stephen J., Guo, Yiran, Giambartolomei, Claudia, Chung, Christina, Peasey, Anne, Amuzu, Antoinette, Li, Kawah, Palmen, Jutta, Howard, Philip, Cooper, Jackie A., Drenos, Fotios, Li, Yun R., Lowe, Gordon, Gallacher, John, Stewart, Marlene C W, Tzoulaki, Ioanna, Buxbaum, Sarah G., Van Der A, Daphne L., Forouhi, Nita G., Onland-Moret, N. Charlotte, Van Der Schouw, Yvonne T., Schnabel, Renate B., Hubacek, Jaroslav A., Kubinova, Ruzena, Baceviciene, Migle, Tamosiunas, Abdonas, Pajak, Andrzej, Topor-Madry, Romanvan, Stepaniak, Urszula, Malyutina, Sofia, Baldassarre, Damiano, Sennblad, Bengt, Tremoli, Elena, De Faire, Ulf, Veglia, Fabrizio, Ford, Ian, Jukema, J. Wouter, Westendorp, Rudi G J, De Borst, Gert Jan, De Jong, Pim A., Algra, Ale, Spiering, Wilko, Der Zee, Anke H Maitland Van, Klungel, Olaf H., De Boer, Anthonius, Doevendans, Pieter A., Eaton, Charles B., Robinson, Jennifer G., Duggan, David, Kjekshus, John, Downs, John R., Gotto, Antonio M., Keech, Anthony C., Marchioli, Roberto, Tognoni, Gianni, Sever, Peter S., Poulter, Neil R., Waters, David D., Pedersen, Terje R., Amarenco, Pierre, Nakamura, Haruo, McMurray, John J V, Lewsey, James D., Chasman, Daniel I., Ridker, Paul M., Maggioni, Aldo P., Tavazzi, Luigi, Ray, Kausik K., Seshasai, Sreenivasa Rao Kondapally, Manson, Joann E., Price, Jackie F., Whincup, Peter H., Morris, Richard W., Lawlor, Debbie A., Smith, George Davey, Ben-Shlomo, Yoav, Schreiner, Pamela J., Fornage, Myriam, Siscovick, David S., Cushman, Mary, Kumari, Meena, Wareham, Nick J., Verschuren, W. M Monique, Redline, Susan, Patel, Sanjay R., Whittaker, John C., Hamsten, Anders, Delaney, Joseph A., Dale, Caroline, Gaunt, Tom R., Wong, Andrew, Kuh, Diana, Hardy, Rebecca, Kathiresan, Sekar, Castillo, Berta A., Van Der Harst, Pim, Brunner, Eric J., Tybjaerg-Hansen, Anne, Marmot, Michael G., Krauss, Ronald M., Tsai, Michael, Coresh, Josef, Hoogeveen, Ronald C., Psaty, Bruce M., Lange, Leslie A., Hakonarson, Hakon, Dudbridge, Frank, Humphries, Steve E., Talmud, Philippa J., Kivimäki, Mika, Timpson, Nicholas J., Langenberg, Claudia, Asselbergs, Folkert W., Voevoda, Mikhail, Bobak, Martin, Pikhart, Hynek, Wilson, James G., Reiner, Alex P., Keating, Brendan J., Hingorani, Aroon D., and Sattar, Naveed

Published
2015

29. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: Evidence from genetic analysis and randomised trials

Author

Cardiovasculaire Epi Team 3, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, JC onderzoeksprogramma Kanker, Cardiovasculaire Epidemiologie, Circulatory Health, Zorgeenheid Vaatchirurgie Medisch, ZL Cerebrovasculaire Ziekten Medisch, MS Infectieziekten, Global Health, JC onderzoeksprogramma Methodologie, Cardiologie, Public Health Epidemiologie, Swerdlow, Daniel I., Preiss, David, Kuchenbaecker, Karoline B., Holmes, Michael V., Engmann, Jorgen E L, Shah, Tina, Sofat, Reecha, Stender, Stefan, Johnson, Paul C D, Scott, Robert A., Leusink, Maarten, Verweij, Niek, Sharp, Stephen J., Guo, Yiran, Giambartolomei, Claudia, Chung, Christina, Peasey, Anne, Amuzu, Antoinette, Li, Kawah, Palmen, Jutta, Howard, Philip, Cooper, Jackie A., Drenos, Fotios, Li, Yun R., Lowe, Gordon, Gallacher, John, Stewart, Marlene C W, Tzoulaki, Ioanna, Buxbaum, Sarah G., Van Der A, Daphne L., Forouhi, Nita G., Onland-Moret, N. Charlotte, Van Der Schouw, Yvonne T., Schnabel, Renate B., Hubacek, Jaroslav A., Kubinova, Ruzena, Baceviciene, Migle, Tamosiunas, Abdonas, Pajak, Andrzej, Topor-Madry, Romanvan, Stepaniak, Urszula, Malyutina, Sofia, Baldassarre, Damiano, Sennblad, Bengt, Tremoli, Elena, De Faire, Ulf, Veglia, Fabrizio, Ford, Ian, Jukema, J. Wouter, Westendorp, Rudi G J, De Borst, Gert Jan, De Jong, Pim A., Algra, Ale, Spiering, Wilko, Der Zee, Anke H Maitland Van, Klungel, Olaf H., De Boer, Anthonius, Doevendans, Pieter A., Eaton, Charles B., Robinson, Jennifer G., Duggan, David, Kjekshus, John, Downs, John R., Gotto, Antonio M., Keech, Anthony C., Marchioli, Roberto, Tognoni, Gianni, Sever, Peter S., Poulter, Neil R., Waters, David D., Pedersen, Terje R., Amarenco, Pierre, Nakamura, Haruo, McMurray, John J V, Lewsey, James D., Chasman, Daniel I., Ridker, Paul M., Maggioni, Aldo P., Tavazzi, Luigi, Ray, Kausik K., Seshasai, Sreenivasa Rao Kondapally, Manson, Joann E., Price, Jackie F., Whincup, Peter H., Morris, Richard W., Lawlor, Debbie A., Smith, George Davey, Ben-Shlomo, Yoav, Schreiner, Pamela J., Fornage, Myriam, Siscovick, David S., Cushman, Mary, Kumari, Meena, Wareham, Nick J., Verschuren, W. M Monique, Redline, Susan, Patel, Sanjay R., Whittaker, John C., Hamsten, Anders, Delaney, Joseph A., Dale, Caroline, Gaunt, Tom R., Wong, Andrew, Kuh, Diana, Hardy, Rebecca, Kathiresan, Sekar, Castillo, Berta A., Van Der Harst, Pim, Brunner, Eric J., Tybjaerg-Hansen, Anne, Marmot, Michael G., Krauss, Ronald M., Tsai, Michael, Coresh, Josef, Hoogeveen, Ronald C., Psaty, Bruce M., Lange, Leslie A., Hakonarson, Hakon, Dudbridge, Frank, Humphries, Steve E., Talmud, Philippa J., Kivimäki, Mika, Timpson, Nicholas J., Langenberg, Claudia, Asselbergs, Folkert W., Voevoda, Mikhail, Bobak, Martin, Pikhart, Hynek, Wilson, James G., Reiner, Alex P., Keating, Brendan J., Hingorani, Aroon D., Sattar, Naveed, Cardiovasculaire Epi Team 3, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, JC onderzoeksprogramma Kanker, Cardiovasculaire Epidemiologie, Circulatory Health, Zorgeenheid Vaatchirurgie Medisch, ZL Cerebrovasculaire Ziekten Medisch, MS Infectieziekten, Global Health, JC onderzoeksprogramma Methodologie, Cardiologie, Public Health Epidemiologie, Swerdlow, Daniel I., Preiss, David, Kuchenbaecker, Karoline B., Holmes, Michael V., Engmann, Jorgen E L, Shah, Tina, Sofat, Reecha, Stender, Stefan, Johnson, Paul C D, Scott, Robert A., Leusink, Maarten, Verweij, Niek, Sharp, Stephen J., Guo, Yiran, Giambartolomei, Claudia, Chung, Christina, Peasey, Anne, Amuzu, Antoinette, Li, Kawah, Palmen, Jutta, Howard, Philip, Cooper, Jackie A., Drenos, Fotios, Li, Yun R., Lowe, Gordon, Gallacher, John, Stewart, Marlene C W, Tzoulaki, Ioanna, Buxbaum, Sarah G., Van Der A, Daphne L., Forouhi, Nita G., Onland-Moret, N. Charlotte, Van Der Schouw, Yvonne T., Schnabel, Renate B., Hubacek, Jaroslav A., Kubinova, Ruzena, Baceviciene, Migle, Tamosiunas, Abdonas, Pajak, Andrzej, Topor-Madry, Romanvan, Stepaniak, Urszula, Malyutina, Sofia, Baldassarre, Damiano, Sennblad, Bengt, Tremoli, Elena, De Faire, Ulf, Veglia, Fabrizio, Ford, Ian, Jukema, J. Wouter, Westendorp, Rudi G J, De Borst, Gert Jan, De Jong, Pim A., Algra, Ale, Spiering, Wilko, Der Zee, Anke H Maitland Van, Klungel, Olaf H., De Boer, Anthonius, Doevendans, Pieter A., Eaton, Charles B., Robinson, Jennifer G., Duggan, David, Kjekshus, John, Downs, John R., Gotto, Antonio M., Keech, Anthony C., Marchioli, Roberto, Tognoni, Gianni, Sever, Peter S., Poulter, Neil R., Waters, David D., Pedersen, Terje R., Amarenco, Pierre, Nakamura, Haruo, McMurray, John J V, Lewsey, James D., Chasman, Daniel I., Ridker, Paul M., Maggioni, Aldo P., Tavazzi, Luigi, Ray, Kausik K., Seshasai, Sreenivasa Rao Kondapally, Manson, Joann E., Price, Jackie F., Whincup, Peter H., Morris, Richard W., Lawlor, Debbie A., Smith, George Davey, Ben-Shlomo, Yoav, Schreiner, Pamela J., Fornage, Myriam, Siscovick, David S., Cushman, Mary, Kumari, Meena, Wareham, Nick J., Verschuren, W. M Monique, Redline, Susan, Patel, Sanjay R., Whittaker, John C., Hamsten, Anders, Delaney, Joseph A., Dale, Caroline, Gaunt, Tom R., Wong, Andrew, Kuh, Diana, Hardy, Rebecca, Kathiresan, Sekar, Castillo, Berta A., Van Der Harst, Pim, Brunner, Eric J., Tybjaerg-Hansen, Anne, Marmot, Michael G., Krauss, Ronald M., Tsai, Michael, Coresh, Josef, Hoogeveen, Ronald C., Psaty, Bruce M., Lange, Leslie A., Hakonarson, Hakon, Dudbridge, Frank, Humphries, Steve E., Talmud, Philippa J., Kivimäki, Mika, Timpson, Nicholas J., Langenberg, Claudia, Asselbergs, Folkert W., Voevoda, Mikhail, Bobak, Martin, Pikhart, Hynek, Wilson, James G., Reiner, Alex P., Keating, Brendan J., Hingorani, Aroon D., and Sattar, Naveed

Published
2015

30. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight:evidence from genetic analysis and randomised trials

Author

Swerdlow, Daniel I, Preiss, David, Kuchenbaecker, Karoline B, Holmes, Michael V, Engmann, Jorgen E L, Shah, Tina, Sofat, Reecha, Stender, Stefan, Johnson, Paul C D, Scott, Robert A, Leusink, Maarten, Verweij, Niek, Sharp, Stephen J, Guo, Yiran, Giambartolomei, Claudia, Chung, Christina, Peasey, Anne, Amuzu, Antoinette, Li, KaWah, Palmen, Jutta, Howard, Philip, Cooper, Jackie A, Drenos, Fotios, Li, Yun R, Lowe, Gordon, Gallacher, John, Stewart, Marlene C W, Tzoulaki, Ioanna, Buxbaum, Sarah G, van der A, Daphne L, Forouhi, Nita G, Onland-Moret, N Charlotte, van der Schouw, Yvonne T, Schnabel, Renate B, Hubacek, Jaroslav A, Kubinova, Ruzena, Baceviciene, Migle, Tamosiunas, Abdonas, Pajak, Andrzej, Topor-Madry, Roman, Stepaniak, Urszula, Malyutina, Sofia, Baldassarre, Damiano, Sennblad, Bengt, Tremoli, Elena, de Faire, Ulf, Veglia, Fabrizio, Ford, Ian, Jukema, J Wouter, Westendorp, Rudi GJ, de Borst, Gert Jan, de Jong, Pim A, Algra, Ale, Spiering, Wilko, Maitland-van der Zee, Anke H, Klungel, Olaf H, de Boer, Anthonius, Doevendans, Pieter A, Eaton, Charles B, Robinson, Jennifer G, Duggan, David, Kjekshus, John, Downs, John R, Gotto, Antonio M, Keech, Anthony C, Marchioli, Roberto, Tognoni, Gianni, Sever, Peter S, Poulter, Neil R, Waters, David D, Pedersen, Terje R, Amarenco, Pierre, Nakamura, Haruo, McMurray, John J V, Lewsey, James D, Chasman, Daniel I, Ridker, Paul M, Maggioni, Aldo P, Tavazzi, Luigi, Ray, Kausik K, Seshasai, Sreenivasa Rao Kondapally, Manson, JoAnn E, Price, Jackie F, Whincup, Peter H, Morris, Richard W, Lawlor, Debbie A, Smith, George Davey, Ben-Shlomo, Yoav, Schreiner, Pamela J, Fornage, Myriam, Siscovick, David S, Cushman, Mary, Kumari, Meena, Wareham, Nick J, Verschuren, W M Monique, Redline, Susan, Patel, Sanjay R, Whittaker, John C, Hamsten, Anders, Delaney, Joseph A, Dale, Caroline, Gaunt, Tom R, Wong, Andrew, Kuh, Diana, Hardy, Rebecca, Kathiresan, Sekar, Castillo, Berta A, van der Harst, Pim, Brunner, Eric J, Tybjaerg-Hansen, Anne, Marmot, Michael G, Krauss, Ronald M, Tsai, Michael, Coresh, Josef, Hoogeveen, Ronald C, Psaty, Bruce M, Lange, Leslie A, Hakonarson, Hakon, Dudbridge, Frank, Humphries, Steve E, Talmud, Philippa J, Kivimäki, Mika, Timpson, Nicholas J, Langenberg, Claudia, Asselbergs, Folkert W, Voevoda, Mikhail, Bobak, Martin, Pikhart, Hynek, Wilson, James G, Reiner, Alex P, Keating, Brendan J, Hingorani, Aroon D, Sattar, Naveed, Swerdlow, Daniel I, Preiss, David, Kuchenbaecker, Karoline B, Holmes, Michael V, Engmann, Jorgen E L, Shah, Tina, Sofat, Reecha, Stender, Stefan, Johnson, Paul C D, Scott, Robert A, Leusink, Maarten, Verweij, Niek, Sharp, Stephen J, Guo, Yiran, Giambartolomei, Claudia, Chung, Christina, Peasey, Anne, Amuzu, Antoinette, Li, KaWah, Palmen, Jutta, Howard, Philip, Cooper, Jackie A, Drenos, Fotios, Li, Yun R, Lowe, Gordon, Gallacher, John, Stewart, Marlene C W, Tzoulaki, Ioanna, Buxbaum, Sarah G, van der A, Daphne L, Forouhi, Nita G, Onland-Moret, N Charlotte, van der Schouw, Yvonne T, Schnabel, Renate B, Hubacek, Jaroslav A, Kubinova, Ruzena, Baceviciene, Migle, Tamosiunas, Abdonas, Pajak, Andrzej, Topor-Madry, Roman, Stepaniak, Urszula, Malyutina, Sofia, Baldassarre, Damiano, Sennblad, Bengt, Tremoli, Elena, de Faire, Ulf, Veglia, Fabrizio, Ford, Ian, Jukema, J Wouter, Westendorp, Rudi GJ, de Borst, Gert Jan, de Jong, Pim A, Algra, Ale, Spiering, Wilko, Maitland-van der Zee, Anke H, Klungel, Olaf H, de Boer, Anthonius, Doevendans, Pieter A, Eaton, Charles B, Robinson, Jennifer G, Duggan, David, Kjekshus, John, Downs, John R, Gotto, Antonio M, Keech, Anthony C, Marchioli, Roberto, Tognoni, Gianni, Sever, Peter S, Poulter, Neil R, Waters, David D, Pedersen, Terje R, Amarenco, Pierre, Nakamura, Haruo, McMurray, John J V, Lewsey, James D, Chasman, Daniel I, Ridker, Paul M, Maggioni, Aldo P, Tavazzi, Luigi, Ray, Kausik K, Seshasai, Sreenivasa Rao Kondapally, Manson, JoAnn E, Price, Jackie F, Whincup, Peter H, Morris, Richard W, Lawlor, Debbie A, Smith, George Davey, Ben-Shlomo, Yoav, Schreiner, Pamela J, Fornage, Myriam, Siscovick, David S, Cushman, Mary, Kumari, Meena, Wareham, Nick J, Verschuren, W M Monique, Redline, Susan, Patel, Sanjay R, Whittaker, John C, Hamsten, Anders, Delaney, Joseph A, Dale, Caroline, Gaunt, Tom R, Wong, Andrew, Kuh, Diana, Hardy, Rebecca, Kathiresan, Sekar, Castillo, Berta A, van der Harst, Pim, Brunner, Eric J, Tybjaerg-Hansen, Anne, Marmot, Michael G, Krauss, Ronald M, Tsai, Michael, Coresh, Josef, Hoogeveen, Ronald C, Psaty, Bruce M, Lange, Leslie A, Hakonarson, Hakon, Dudbridge, Frank, Humphries, Steve E, Talmud, Philippa J, Kivimäki, Mika, Timpson, Nicholas J, Langenberg, Claudia, Asselbergs, Folkert W, Voevoda, Mikhail, Bobak, Martin, Pikhart, Hynek, Wilson, James G, Reiner, Alex P, Keating, Brendan J, Hingorani, Aroon D, and Sattar, Naveed

Abstract

BACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 year

Published
2015

32. Fatigue as a Predictor of Outcome in Patients With Heart Failure

Author

Perez-Moreno, Ana Cristina, primary, Jhund, Pardeep S., additional, Macdonald, Michael R., additional, Petrie, Mark C., additional, Cleland, John G.F., additional, Böhm, Michael, additional, van Veldhuisen, Dirk J., additional, Gullestad, Lars, additional, Wikstrand, John, additional, Kjekshus, John, additional, Lewsey, James D., additional, and McMurray, John J.V., additional

Published
2014
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34. Abstract 18355: Predictors of Fatigue in Heart Failure

Author

Perez-Moreno, Ana C, primary, Jhund, Pardeep S, additional, Cleland, John G, additional, van Veldhuisen, Dirk J, additional, Gullestad, Lars, additional, Wikstrand, John, additional, Kjekshus, John K, additional, Lewsey, James D, additional, and McMurray, John J, additional

Published
2012
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35. Trends in incidence and in short term survival following a subarachnoid haemorrhage in Scotland, 1986 - 2005: a retrospective cohort study

Author

Macpherson, Karen J, primary, Lewsey, James D, additional, Jhund, Pardeep S, additional, Gillies, Michelle, additional, Chalmers, Jim WT, additional, Redpath, Adam, additional, Briggs, Andrew, additional, Walters, Matthew, additional, Langhorne, Peter, additional, Capewell, Simon, additional, McMurray, John JV, additional, and MacIntyre, Kate, additional

Published
2011
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36. EFFECTS OF THE ORAL DIRECT RENIN INHIBITOR ALISKIREN ON PLASMA BNP CONCENTRATION IN PATIENTS WITH SYMPTOMATIC HEART FAILURE ACCORDING TO BACKGROUND DOSE OF ACE INHIBITOR

Author

McMurray, John JV, primary, Gimpelewicz, Claudio, additional, Latini, Roberto, additional, Maggioni, Aldo P., additional, Pitt, Bertram, additional, Solomon, Scott D., additional, Verma, Anil, additional, Smith, Beverly A., additional, Keefe, Deborah L., additional, Prescott, Margaret F., additional, and Lewsey, James D., additional

Published
2010
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37. Age- and Sex-Specific Trends in Fatal Incidence and Hospitalized Incidence of Stroke in Scotland, 1986 to 2005

Author

Lewsey, James D., primary, Jhund, Pardeep S., additional, Gillies, Michelle, additional, Chalmers, Jim W.T., additional, Redpath, Adam, additional, Kelso, Laura, additional, Briggs, Andrew, additional, Walters, Matthew, additional, Langhorne, Peter, additional, Capewell, Simon, additional, McMurray, John J.V., additional, and MacIntyre, Kate, additional

Published
2009
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40. Discordant Short- and Long-Term Outcomes Associated With Diabetes in Patients With Heart Failure: Importance of Age and Sex

Author

MacDonald, Michael R., primary, Jhund, Pardeep S., additional, Petrie, Mark C., additional, Lewsey, James D., additional, Hawkins, Nathaniel M., additional, Bhagra, Sai, additional, Munoz, Nuria, additional, Varyani, Fumi, additional, Redpath, Adam, additional, Chalmers, Jim, additional, MacIntyre, Kate, additional, and McMurray, John J.V., additional

Published
2008
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50. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials

Author

Swerdlow, Daniel I, Preiss, David, Kuchenbaecker, Karoline B, Holmes, Michael V, Engmann, Jorgen EL, Shah, Tina, Sofat, Reecha, Stender, Stefan, Johnson, Paul CD, Scott, Robert A, Leusink, Maarten, Verweij, Niek, Sharp, Stephen J, Guo, Yiran, Giambartolomei, Claudia, Chung, Christina, Peasey, Anne, Amuzu, Antoinette, Li, KaWah, Palmen, Jutta, Howard, Philip, Cooper, Jackie A, Drenos, Fotios, Li, Yun R, Lowe, Gordon, Gallacher, John, Stewart, Marlene CW, Tzoulaki, Ioanna, Buxbaum, Sarah G, Van Der A, Daphne L, Forouhi, Nita G, Onland-Moret, N Charlotte, Van Der Schouw, Yvonne T, Schnabel, Renate B, Hubacek, Jaroslav A, Kubinova, Ruzena, Baceviciene, Migle, Tamosiunas, Abdonas, Pajak, Andrzej, Topor-Madry, Roman, Stepaniak, Urszula, Malyutina, Sofia, Baldassarre, Damiano, Sennblad, Bengt, Tremoli, Elena, De Faire, Ulf, Veglia, Fabrizio, Ford, Ian, Jukema, J Wouter, Westendorp, Rudi GJ, De Borst, Gert Jan, De Jong, Pim A, Algra, Ale, Spiering, Wilko, Maitland-Van Der Zee, Anke H, Klungel, Olaf H, De Boer, Anthonius, Doevendans, Pieter A, Eaton, Charles B, Robinson, Jennifer G, Duggan, David, DIAGRAM Consortium, MAGIC Consortium, InterAct Consortium, Kjekshus, John, Downs, John R, Gotto, Antonio M, Keech, Anthony C, Marchioli, Roberto, Tognoni, Gianni, Sever, Peter S, Poulter, Neil R, Waters, David D, Pedersen, Terje R, Amarenco, Pierre, Nakamura, Haruo, McMurray, John JV, Lewsey, James D, Chasman, Daniel I, Ridker, Paul M, Maggioni, Aldo P, Tavazzi, Luigi, Ray, Kausik K, Seshasai, Sreenivasa Rao Kondapally, Manson, JoAnn E, Price, Jackie F, Whincup, Peter H, Morris, Richard W, Lawlor, Debbie A, Smith, George Davey, Ben-Shlomo, Yoav, Schreiner, Pamela J, Fornage, Myriam, Siscovick, David S, Cushman, Mary, Kumari, Meena, Wareham, Nick J, Verschuren, WM Monique, Redline, Susan, Patel, Sanjay R, Whittaker, John C, Hamsten, Anders, Delaney, Joseph A, Dale, Caroline, Gaunt, Tom R, Wong, Andrew, Kuh, Diana, Hardy, Rebecca, Kathiresan, Sekar, Castillo, Berta A, Van Der Harst, Pim, Brunner, Eric J, Tybjaerg-Hansen, Anne, Marmot, Michael G, Krauss, Ronald M, Tsai, Michael, Coresh, Josef, Hoogeveen, Ronald C, Psaty, Bruce M, Lange, Leslie A, Hakonarson, Hakon, Dudbridge, Frank, Humphries, Steve E, Talmud, Philippa J, Kivimäki, Mika, Timpson, Nicholas J, Langenberg, Claudia, Asselbergs, Folkert W, Voevoda, Mikhail, Bobak, Martin, Pikhart, Hynek, Wilson, James G, Reiner, Alex P, Keating, Brendan J, Hingorani, Aroon D, and Sattar, Naveed

Subjects
Male, Body Weight, Cholesterol, HDL, Cholesterol, LDL, Middle Aged, Polymorphism, Single Nucleotide, 3. Good health, Body Mass Index, Diabetes Mellitus, Type 2, Risk Factors, Humans, Female, Hydroxymethylglutaryl CoA Reductases, Genetic Testing, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Aged, Randomized Controlled Trials as Topic
Abstract

BACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target. METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis. FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials). INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition. FUNDING: The funding sources are cited at the end of the paper.

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