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Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database

BMJ 2009; 339 doi: (Published 04 December 2009) Cite this as: BMJ 2009;339:b4731
  1. Ioanna Tzoulaki, lecturer1,
  2. Mariam Molokhia, senior lecturer2,
  3. Vasa Curcin, research associate3,
  4. Mark P Little, reader1,
  5. Christopher J Millett, senior lecturer in public health4,
  6. Anthea Ng, research associate4,
  7. Robert I Hughes, research associate5,
  8. Kamlesh Khunti, professor6,
  9. Martin R Wilkins, professor5,
  10. Azeem Majeed, professor4,
  11. Paul Elliott, professor17
  1. 1Department of Epidemiology and Public Health, Faculty of Medicine, Imperial College London, London W2 1PG
  2. 2Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London
  3. 3Department of Computing, Imperial College London, London,
  4. 4Department of Primary Care and Social Medicine, Imperial College London, London
  5. 5Department of Experimental Medicine and Toxicology, Imperial College London, London
  6. 6Department of Health Sciences, University of Leicester, Leicester
  7. 7MRC-HPA Centre for Environment and Health, London
  1. Correspondence to: P Elliott p.elliott{at}
  • Accepted 30 September 2009


Objective To investigate the risk of incident myocardial infarction, congestive heart failure, and all cause mortality associated with prescription of oral antidiabetes drugs.

Design Retrospective cohort study.

Setting UK general practice research database, 1990-2005.

Participants 91 521 people with diabetes.

Main outcome measures Incident myocardial infarction, congestive heart failure, and all cause mortality. Person time intervals for drug treatment were categorised by drug class, excluding non-drug intervals and intervals for insulin.

Results 3588 incident cases of myocardial infarction, 6900 of congestive heart failure, and 18 548 deaths occurred. Compared with metformin, monotherapy with first or second generation sulphonylureas was associated with a significant 24% to 61% excess risk for all cause mortality (P<0.001) and second generation sulphonylureas with an 18% to 30% excess risk for congestive heart failure (P=0.01 and P<0.001). The thiazolidinediones were not associated with risk of myocardial infarction; pioglitazone was associated with a significant 31% to 39% lower risk of all cause mortality (P=0.02 to P<0.001) compared with metformin. Among the thiazolidinediones, rosiglitazone was associated with a 34% to 41% higher risk of all cause mortality (P=0.14 to P=0.01) compared with pioglitazone. A large number of potential confounders were accounted for in the study; however, the possibility of residual confounding or confounding by indication (differences in prognostic factors between drug groups) cannot be excluded.

Conclusions Our findings suggest a relatively unfavourable risk profile of sulphonylureas compared with metformin for all outcomes examined. Pioglitazone was associated with reduced all cause mortality compared with metformin. Pioglitazone also had a favourable risk profile compared with rosiglitazone; although this requires replication in other studies, it may have implications for prescribing within this class of drugs.


  • Imperial College London are supported by the National Institute for Health Research (NIHR) biomedical research centre programme. The Department of Primary Care and Social Medicine, Imperial College, and the Department of Health Science, University of Leicester, are supported by the NIHR collaboration for leadership in applied health research and care programme. MM is funded by an NIHR postdoctoral award and together with VC and AM are investigators for the EU-ADR FP7 project on adverse drug reactions. CM and AN are funded by the NIHR service delivery and organisation programme. PE is an NIHR senior investigator. Imperial College receives a contribution for AM’s salary from the UK Diabetes Research Network. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Deborah Ashby for helpful comments.

  • Contributors: IT and MM contributed equally to the study. PE, MRW, AM, KK, IT, and MM conceived and designed the study. IT, MM, VC, KK, AM, MPL, MRW, and PE analysed and interpreted the data. All authors drafted the manuscript and critically revised the manuscript for important intellectual content. IT and MPL carried out the statistical analysis. VC provided technical support. PE, IT, MM, and AM supervised the study. PE is the guarantor.

  • Funding: No funding was obtained for this study. This study is based on data from the full feature general practice research database funded through the Medical Research Council’s license agreement with the UK Medicines and Healthcare Products Regulatory Agency. The interpretation and conclusions contained in this study are those of the authors alone.

  • Competing interests: PE is a coprincipal investigator on a grant cofunded by the UK Medical Research Council and GlaxoSmithKline. MRW has received consultancy fees from GlaxoSmithKline in the past five years. MM has received grants from Pfizer, AstraZeneca, and the Serious Adverse Events Consortium (collaboration between industry and academia). KK has acted in a consultant capacity or as a speaker for Novo-Nordisk, Sanofi, Lilli, Merck Sharp & Dohme, Tekeda, GSK, and Bayer and has received research grants from Servier, Novartis, Novo-Nordisk, Sanofi-Aventis, Merck Sharp & Dohme, Pfizer, Bayer, Unilever, and Lilly.

  • Ethical approval: The GPRD Group has obtained ethical approval from a multicentre research ethics committee for all purely observational research using anonymised records from the general practice research database. This study was approved by the general practice research database Independent Scientific Advisory Committee.

  • Data sharing: The technical appendix and statistical code (through permission of the general practice research database) are available from the corresponding author.

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