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Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials

BMJ 2011; 343 doi: https://doi.org/10.1136/bmj.d4169 (Published 26 July 2011) Cite this as: BMJ 2011;343:d4169

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  1. Rémy Boussageon, general practitioner and lecturer1,
  2. Theodora Bejan-Angoulvant, cardiologist, pharmacologist, and lecturer234,
  3. Mitra Saadatian-Elahi, epidemiologist2,
  4. Sandrine Lafont, resident in family medicine1,
  5. Claire Bergeonneau, resident in family medicine13,
  6. Behrouz Kassaï, pharmacologist and lecturer2345,
  7. Sylvie Erpeldinger, general practitioner and lecturer1,
  8. James M Wright, anaesthesiologist, pharmacologist, and professor of anaesthesiology and pharmacology6,
  9. François Gueyffier, head of department and clinical investigation centre, cardiologist, and professor2345,
  10. Catherine Cornu, endocrinologist, pharmacologist, and research physician in clinical investigation centre2345
  1. 1Department of General Medicine, Université Claude Bernard Lyon 1, Lyon, France
  2. 2Department of Clinical Pharmacology, Hospices Civils de Lyon, Lyon, France
  3. 3UMR 5558, CNRS, Villeurbanne, France
  4. 4Université Claude Bernard Lyon 1, Lyon, France
  5. 5Clinical Investigation Centre, Louis Pradel Hospital, Bron, France
  6. 6Departments of Anaesthesiology, Pharmacology, and Therapeutics and Medicine, University of British Columbia, Vancouver, BC, Canada
  1. Correspondence to: C Cornu, Centre d’Investigation Clinique, Hôpital Louis Pradel, 48, Avenue du Doyen Lépine, 69500-Bron, France catherine.cornu{at}chu-lyon.fr
  • Accepted 27 May 2011

Abstract

Objective To determine all cause mortality and deaths from cardiovascular events related to intensive glucose lowering treatment in people with type 2 diabetes.

Design Meta-analysis of randomised controlled trials.

Data sources Medline, Embase, and the Cochrane database of systematic reviews.

Study selection Randomised controlled trials that assessed the effect of intensive glucose lowering treatment on cardiovascular events and microvascular complications in adults (≥18 years) with type 2 diabetes.

Data extraction Primary end points were all cause mortality and death from cardiovascular causes. Secondary end points were severe hypoglycaemia and macrovascular and microvascular events.

Synthesis of results Results are reported as risk ratios with 99% confidence intervals. Statistical heterogeneity between trials was assessed with χ², τ², and I2 statistics. A fixed effect model was used to assess the effect on the outcomes of intensive glucose lowering versus standard treatment. The quality of clinical trials was assessed by the Jadad score.

Results 13 studies were included. Of 34 533 patients, 18 315 received intensive glucose lowering treatment and 16 218 standard treatment. Intensive treatment did not significantly affect all cause mortality (risk ratio 1.04, 99% confidence interval 0.91 to 1.19) or cardiovascular death (1.11, 0.86 to 1.43). Intensive therapy was, however, associated with reductions in the risk of non-fatal myocardial infarction (0.85, 0.74 to 0.96, P<0.001), and microalbuminuria (0.90, 0.85 to 0.96, P<0.001) but a more than twofold increase in the risk of severe hypoglycaemia (2.33, 21.62 to 3.36, P<0.001). Over a treatment period of five years, 117 to 150 patients would need to be treated to avoid one myocardial infarction and 32 to 142 patients to avoid one episode of microalbuminuria, whereas one severe episode of hypoglycaemia would occur for every 15 to 52 patients. In analysis restricted to high quality studies (Jadad score >3), intensive treatment was not associated with any significant risk of reductions but resulted in a 47% increase in risk of congestive heart failure (P<0.001).

Conclusions The overall results of this meta-analysis show limited benefits of intensive glucose lowering treatment on all cause mortality and deaths from cardiovascular causes. We cannot exclude a 9% reduction or a 19% increase in all cause mortality and a 14% reduction or a 43% increase in cardiovascular death. The benefit:risk ratio of intensive glucose lowering treatment in the prevention of macrovascular and microvascular events remains uncertain. The harm associated with severe hypoglycaemia might counterbalance the potential benefit of intensive glucose lowering treatment. More double blind randomised controlled trials are needed to establish the best therapeutic approach in people with type 2 diabetes.

Footnotes

  • We thank Philippe Canet and Renée Cardoso from the French Health Authority for their contribution to bibliographical research and Kent Neal (supported by the French Cochrane Center) for reading the manuscript.

  • Contributors: RB, TBA, CC, ES, and FG conceived the study. RB, SL, and BC extracted the data. RB, SL, and CC reviewed the selected papers. RB and TBA did the statistical analyses. RB, TBA, FG, CC, and MSE drafted the manuscript. WJM and BK assisted in the interpretation of the results. All authors read and approved the final manuscript. RB, TBA, and CC are guarantors.

  • Funding: No specific funding.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

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