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Diabetes treatments and risk of heart failure, cardiovascular disease, and all cause mortality: cohort study in primary care

BMJ 2016; 354 doi: https://doi.org/10.1136/bmj.i3477 (Published 13 July 2016) Cite this as: BMJ 2016;354:i3477
  1. Julia Hippisley-Cox, professor of clinical epidemiology and general practice,
  2. Carol Coupland, professor of medical statistics in primary care
  1. Division of Primary Care, University Park, University of Nottingham, Nottingham NG2 7RD, UK
  1. Correspondence to: J Hippisley-Cox Julia.hippisley-cox{at}nottingham.ac.uk
  • Accepted 17 June 2016

Abstract

Objective To assess associations between risks of cardiovascular disease, heart failure, and all cause mortality and different diabetes drugs in people with type 2 diabetes, particularly newer agents, including gliptins and thiazolidinediones (glitazones).

Design Open cohort study.

Setting 1243 general practices contributing data to the QResearch database in England.

Participants 469 688 people with type 2 diabetes aged 25-84 years between 1 April 2007 and 31 January 2015.

Exposures Diabetes drugs (glitazones, gliptins, metformin, sulphonylureas, insulin, other) alone and in combination.

Main outcome measure First recorded diagnoses of cardiovascular disease, heart failure, and all cause mortality recorded on the patients’ primary care, mortality, or hospital record. Cox proportional hazards models were used to estimate hazard ratios for diabetes treatments, adjusting for potential confounders.

Results During follow-up, 21 308 patients (4.5%) received prescriptions for glitazones and 32 533 (6.9%) received prescriptions for gliptins. Compared with non-use, gliptins were significantly associated with an 18% decreased risk of all cause mortality, a 14% decreased risk of heart failure, and no significant change in risk of cardiovascular disease; corresponding values for glitazones were significantly decreased risks of 23% for all cause mortality, 26% for heart failure, and 25% for cardiovascular disease. Compared with no current treatment, there were no significant associations between monotherapy with gliptins and risk of any complications. Dual treatment with gliptins and metformin was associated with a decreased risk of all three outcomes (reductions of 38% for heart failure, 33% for cardiovascular disease, and 48% for all cause mortality). Triple treatment with metformin, sulphonylureas, and gliptins was associated with a decreased risk of all three outcomes (reductions of 40% for heart failure, 30% for cardiovascular disease, and 51% for all cause mortality). Compared with no current treatment, monotherapy with glitazone was associated with a 50% decreased risk of heart failure, and dual treatment with glitazones and metformin was associated with a decreased risk of all three outcomes (reductions of 50% for heart failure, 54% for cardiovascular disease, and 45% for all cause mortality); dual treatment with glitazones and sulphonylureas was associated with risk reductions of 35% for heart failure and 25% for cardiovascular disease; triple treatment with metformin, sulphonylureas, and glitazones was associated with decreased risks of all three outcomes (reductions of 46% for heart failure, 41% for cardiovascular disease, and 56% for all cause mortality).

Conclusions There are clinically important differences in risk of cardiovascular disease, heart failure, and all cause mortality between different diabetes drugs alone and in combination. Overall, use of gliptins or glitazones was associated with decreased risks of heart failure, cardiovascular disease, and all cause mortality compared with non-use of these drugs. These results, which do not account for levels of adherence or dosage information and which are subject to confounding by indication, might have implications for prescribing of diabetes drugs.

Footnotes

  • We acknowledge the contribution of the practices that contribute to QResearch and Egton Medical Information Systems (EMIS), and the University of Nottingham for expertise in establishing, developing, and supporting the database. The data from hospital episode statistics used in this analysis are re-used by permission from the Health and Social Care Information Centre who retain the copyright. We thank the Office for National Statistics for providing the mortality data. ONS bear no responsibility for the analysis or interpretation of the data.

  • Contributors: JH-C initiated the study, undertook the literature review, data extraction, data manipulation, and primary data analysis, and wrote the first draft of the paper. CC contributed to the design, analysis, data manipulation, interpretation, and drafting of the paper. JH-C had access to all the data for this project. JH-C is the guarantor

  • Funding: This study received no external 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: JH-C is professor of clinical epidemiology at the University of Nottingham and codirector of QResearch, a not-for-profit organisation, which is a joint partnership between the University of Nottingham and Egton Medical Information Systems (leading commercial supplier of IT for 60% of general practices in the UK). JH-C is also a paid director of ClinRisk, which produces open and closed source software to ensure the reliable and updatable implementation of clinical risk algorithms within clinical computer systems to help improve patient care. CC is professor of Medical Statistics in Primary Care at the University of Nottingham and a paid consultant statistician for ClinRisk. This work and any views expressed within it are solely those of the coauthors and not of any affiliated bodies or organisations.

  • Ethical approval: This project was reviewed in accordance with the QResearch agreement with Trent MultiCentre Ethics Committee (reference 03/4/021).

  • Data sharing: The patient level data from the QResearch are specifically licensed according to its governance framework. See www.qresearch.org for further details.

  • Transparency: The lead author (JH-C) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported, that no important aspects of the study have been omitted, and that any discrepancies from the study as planned have been explained.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/3.0/.

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