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

doi:10.1136/bmj.i610

Review

. 2016 Feb 17:352:i610.

doi: 10.1136/bmj.i610.

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

Ling Li¹, Sheyu Li², Ke Deng³, Jiali Liu¹, Per Olav Vandvik⁴, Pujing Zhao¹, Longhao Zhang¹, Jiantong Shen¹, Malgorzata M Bala⁵, Zahra N Sohani⁶, Evelyn Wong⁷, Jason W Busse⁸, Shanil Ebrahim⁹, German Malaga¹⁰, Lorena P Rios¹¹, Yingqiang Wang¹², Qunfei Chen¹³, Gordon H Guyatt¹⁴, Xin Sun¹⁵

Affiliations

¹ Chinese Evidence-based Medicine Centre, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
² Department of Endocrinology and Metabolism, West China Hospita, Chengdu.
³ West China School of Pharmacy, Sichuan University, Chengdu.
⁴ Norwegian Knowledge Centre for the Health Services, Oslo, Norway Department of Medicine, Innlandet Hospital Trust, Gjøvik, Norway.
⁵ Department of Hygiene and Dietetics, Jagiellonian University Medical College, Krakow, Poland.
⁶ Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁷ Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
⁸ Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada Department of Anesthesia, McMaster University, Hamilton Michael G DeGroote Institute for Pain Research and Care, McMaster University, Hamilton.
⁹ Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada Department of Anesthesia, McMaster University, Hamilton Stanford Prevention Research Center, Department of Medicine, Stanford University, Stanford, CA, USA Department of Anaesthesia and Pain Medicine, Hospital for Sick Children, Toronto, ON Canada.
¹⁰ Department of Medicine, Universidad Peruana Cayetano Heredia, Lima, Peru.
¹¹ Internal Medicine Unit, Hospital Clinico FUSAT, Rancagua, Chile.
¹² Department of Medical Administration, 363 Hospital, Chengdu, Sichuan, China.
¹³ Second Hospital of Lanzhou University, Lanzhou, Gansu, China.
¹⁴ Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada Department of Medicine, McMaster University, Hamilton.
¹⁵ Chinese Evidence-based Medicine Centre, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China sunx26@gmail.com.

PMID: 26888822
PMCID: PMC4772781
DOI: 10.1136/bmj.i610

Review

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

Ling Li et al. BMJ. 2016.

. 2016 Feb 17:352:i610.

doi: 10.1136/bmj.i610.

Authors

Affiliations

¹ Chinese Evidence-based Medicine Centre, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
² Department of Endocrinology and Metabolism, West China Hospita, Chengdu.
³ West China School of Pharmacy, Sichuan University, Chengdu.
⁴ Norwegian Knowledge Centre for the Health Services, Oslo, Norway Department of Medicine, Innlandet Hospital Trust, Gjøvik, Norway.
⁵ Department of Hygiene and Dietetics, Jagiellonian University Medical College, Krakow, Poland.
⁶ Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁷ Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
⁸ Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada Department of Anesthesia, McMaster University, Hamilton Michael G DeGroote Institute for Pain Research and Care, McMaster University, Hamilton.
⁹ Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada Department of Anesthesia, McMaster University, Hamilton Stanford Prevention Research Center, Department of Medicine, Stanford University, Stanford, CA, USA Department of Anaesthesia and Pain Medicine, Hospital for Sick Children, Toronto, ON Canada.
¹⁰ Department of Medicine, Universidad Peruana Cayetano Heredia, Lima, Peru.
¹¹ Internal Medicine Unit, Hospital Clinico FUSAT, Rancagua, Chile.
¹² Department of Medical Administration, 363 Hospital, Chengdu, Sichuan, China.
¹³ Second Hospital of Lanzhou University, Lanzhou, Gansu, China.
¹⁴ Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada Department of Medicine, McMaster University, Hamilton.
¹⁵ Chinese Evidence-based Medicine Centre, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China sunx26@gmail.com.

PMID: 26888822
PMCID: PMC4772781
DOI: 10.1136/bmj.i610

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.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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Conflict of interest statement

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.

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Comment in

The safety of incretin based drug treatments for type 2 diabetes.
Bolen SD, Maruthur NM. Bolen SD, et al. BMJ. 2016 Feb 17;352:i801. doi: 10.1136/bmj.i801. BMJ. 2016. PMID: 26888024 No abstract available.
Authors' reply to Patel and colleagues.
Sun X, Guyatt GH, Li L. Sun X, et al. BMJ. 2016 May 24;353:i2927. doi: 10.1136/bmj.i2927. BMJ. 2016. PMID: 27220956 No abstract available.

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References

1. International Diabetes Federation. IDF DIABETES ATLAS (Sixth edition). http://www.idf.org/files/idf_publications/idf_diabetes_atlas_EN/idf_diab... (accessed May 8 2015).
1. Karagiannis T, Paschos P, Paletas K, Matthews DR, Tsapas A. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 2012;344:e1369. 10.1136/bmj.e1369. 22411919. - DOI - PubMed
1. Esposito K, Chiodini P, Maiorino MI, Bellastella G, Capuano A, Giugliano D. Glycaemic durability with dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of long-term randomised controlled trials. BMJ Open 2014;4:e005442. 10.1136/bmjopen-2014-005442. 24916090. - DOI - PMC - PubMed
1. Kawalec P, Mikrut A, Łopuch S. The safety of dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter 2 (SGLT-2) inhibitors added to metformin background therapy in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Metab Res Rev 2014;30:269-83. 10.1002/dmrr.2494. 24829965. - DOI - PubMed
1. Monami M, Ahrén B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2013;15:112-20. 10.1111/dom.12000. 22925682. - DOI - PubMed

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[1] International Diabetes Federation. IDF DIABETES ATLAS (Sixth edition). http://www.idf.org/files/idf_publications/idf_diabetes_atlas_EN/idf_diab... (accessed May 8 2015).

[2] International Diabetes Federation. IDF DIABETES ATLAS (Sixth edition). http://www.idf.org/files/idf_publications/idf_diabetes_atlas_EN/idf_diab... (accessed May 8 2015).

[3] Karagiannis T, Paschos P, Paletas K, Matthews DR, Tsapas A. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 2012;344:e1369. 10.1136/bmj.e1369. 22411919. - DOI - PubMed

[4] Karagiannis T, Paschos P, Paletas K, Matthews DR, Tsapas A. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 2012;344:e1369. 10.1136/bmj.e1369. 22411919. - DOI - PubMed

[5] Esposito K, Chiodini P, Maiorino MI, Bellastella G, Capuano A, Giugliano D. Glycaemic durability with dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of long-term randomised controlled trials. BMJ Open 2014;4:e005442. 10.1136/bmjopen-2014-005442. 24916090. - DOI - PMC - PubMed

[6] Esposito K, Chiodini P, Maiorino MI, Bellastella G, Capuano A, Giugliano D. Glycaemic durability with dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of long-term randomised controlled trials. BMJ Open 2014;4:e005442. 10.1136/bmjopen-2014-005442. 24916090. - DOI - PMC - PubMed

[7] Kawalec P, Mikrut A, Łopuch S. The safety of dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter 2 (SGLT-2) inhibitors added to metformin background therapy in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Metab Res Rev 2014;30:269-83. 10.1002/dmrr.2494. 24829965. - DOI - PubMed

[8] Kawalec P, Mikrut A, Łopuch S. The safety of dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter 2 (SGLT-2) inhibitors added to metformin background therapy in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Metab Res Rev 2014;30:269-83. 10.1002/dmrr.2494. 24829965. - DOI - PubMed

[9] Monami M, Ahrén B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2013;15:112-20. 10.1111/dom.12000. 22925682. - DOI - PubMed

[10] Monami M, Ahrén B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2013;15:112-20. 10.1111/dom.12000. 22925682. - DOI - PubMed

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

Affiliations

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

Authors

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Abstract

Conflict of interest statement

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