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Research

Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies

BMJ 2016; 352 doi: https://doi.org/10.1136/bmj.i610 (Published 17 February 2016) Cite this as: BMJ 2016;352:i610
  1. Ling Li, research associate1,
  2. Sheyu Li, attending physician2,
  3. Ke Deng, postgraduate3,
  4. Jiali Liu, postgraduate1,
  5. Per Olav Vandvik, associate professor4 5,
  6. Pujing Zhao, postgraduate1,
  7. Longhao Zhang, postgraduate1,
  8. Jiantong Shen, lecturer1,
  9. Malgorzata M Bala, assistant professor6,
  10. Zahra N Sohani, medical student7 8,
  11. Evelyn Wong, resident physician9,
  12. Jason W Busse, assistant professor7 10 11,
  13. Shanil Ebrahim, assistant professor7 10 12 13,
  14. German Malaga, professor14,
  15. Lorena P Rios, endocrinologist15,
  16. Yingqiang Wang, research associate16,
  17. Qunfei Chen, assistant researcher17,
  18. Gordon H Guyatt, distinguished professor7 18,
  19. Xin Sun, professor1
  1. 1Chinese Evidence-based Medicine Centre, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
  2. 2Department of Endocrinology and Metabolism, West China Hospita, Chengdu
  3. 3West China School of Pharmacy, Sichuan University, Chengdu
  4. 4Norwegian Knowledge Centre for the Health Services, Oslo, Norway
  5. 5Department of Medicine, Innlandet Hospital Trust, Gjøvik, Norway
  6. 6Department of Hygiene and Dietetics, Jagiellonian University Medical College, Krakow, Poland
  7. 7Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada
  8. 8Faculty of Medicine, University of Toronto, Toronto, ON, Canada
  9. 9Department of Medicine, University of British Columbia, Vancouver, BC, Canada
  10. 10Department of Anesthesia, McMaster University, Hamilton
  11. 11Michael G DeGroote Institute for Pain Research and Care, McMaster University, Hamilton
  12. 12Stanford Prevention Research Center, Department of Medicine, Stanford University, Stanford, CA, USA
  13. 13Department of Anaesthesia and Pain Medicine, Hospital for Sick Children, Toronto, ON Canada
  14. 14Department of Medicine, Universidad Peruana Cayetano Heredia, Lima, Peru
  15. 15Internal Medicine Unit, Hospital Clinico FUSAT, Rancagua, Chile
  16. 16Department of Medical Administration, 363 Hospital, Chengdu, Sichuan, China
  17. 17Second Hospital of Lanzhou University, Lanzhou, Gansu, China
  18. 18Department of Medicine, McMaster University, Hamilton
  1. Correspondence to: X Sun sunx26{at}gmail.com
  • Accepted 11 January 2016

Abstract

Objectives To examine the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of heart failure or hospital admission for heart failure in patients with type 2 diabetes.

Design Systematic review and meta-analysis of randomised and observational studies.

Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov searched up to 25 June 2015, and communication with experts.

Eligibility criteria Randomised controlled trials, non-randomised controlled trials, cohort studies, and case-control studies that compared DPP-4 inhibitors against placebo, lifestyle modification, or active antidiabetic drugs in adults with type 2 diabetes, and explicitly reported the outcome of heart failure or hospital admission for heart failure.

Data collection and analysis Teams of paired reviewers independently screened for eligible studies, assessed risk of bias, and extracted data using standardised, pilot tested forms. Data from trials and observational studies were pooled separately; quality of evidence was assessed by the GRADE approach.

Results Eligible studies included 43 trials (n=68 775) and 12 observational studies (nine cohort studies, three nested case-control studies; n=1 777 358). Pooling of 38 trials reporting heart failure provided low quality evidence for a possible similar risk of heart failure between DPP-4 inhibitor use versus control (42/15 701 v 33/12 591; odds ratio 0.97 (95% confidence interval 0.61 to 1.56); risk difference 2 fewer (19 fewer to 28 more) events per 1000 patients with type 2 diabetes over five years). The observational studies provided effect estimates generally consistent with trial findings, but with very low quality evidence. Pooling of the five trials reporting admission for heart failure provided moderate quality evidence for an increased risk in patients treated with DPP-4 inhibitors versus control (622/18 554 v 552/18 474; 1.13 (1.00 to 1.26); 8 more (0 more to 16 more)). The pooling of adjusted estimates from observational studies similarly suggested (with very low quality evidence) a possible increased risk of admission for heart failure (adjusted odds ratio 1.41, 95% confidence interval 0.95 to 2.09) in patients treated with DPP-4 inhibitors (exclusively sitagliptin) versus no use.

Conclusions The relative effect of DPP-4 inhibitors on the risk of heart failure in patients with type 2 diabetes is uncertain, given the relatively short follow-up and low quality of evidence. Both randomised controlled trials and observational studies, however, suggest that these drugs may increase the risk of hospital admission for heart failure in those patients with existing cardiovascular diseases or multiple risk factors for vascular diseases, compared with no use.

Footnotes

  • We thank Daphne Plaut for developing the search strategy and conducting the initial literature search.

  • Contributors: XS and SL conceived the study. XS acquired the funding. XS and LL had full access to all of the data in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis. XS and LL designed the study. XS and LL developed and tested the data collection forms. LL, KD, JL, PZ, LZ, JS, MMB, ZNS, EW, JWB, SE, GM, LPR, POV, YW, QC, and XS acquired the data. LL and XS conducted the analysis, interpreted the data, and drafted the manuscript. LL, XS, GHG, POV, SL, MMB, ZNS, EW, JWB, SE, GM, LPR, KD, JL, PZ, LZ, JS, YW, and QC critically revised the manuscript. XS is the guarantor.

  • Funding: This study was supported by the National Natural Science Foundation of China (grant no 71573183), “Thousand Youth Talents Plan” of China (grant no D1024002) and Sichuan Province, and Young Investigator Award of Sichuan University (grant no. 2013SCU04A37). These funders had no role in the study design, writing of the manuscript, or decision to submit this or future manuscripts for publication. SL is funded by the National Natural Science Foundation of China (grant No 81400811 and 21534008). ZNS is funded by the Canadian Diabetes Association. JWB is funded by a New Investigator Award from the Canadian Institutes of Health Research and Canadian Chiropractic Research Foundation. SE is funded by MITACS Elevate and Restracomp Postdoctoral Awards.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the National Natural Science Foundation of China, “Thousand Youth Talents Plan” of China and Sichuan Province, and Young Investigator Award of Sichuan University for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

  • The lead author (the manuscript’s guarantor) 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 Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/.

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