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
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Dear Editor,
We read with interest the systematic review and meta-analysis by Li et al [1], and congratulate the authors on their thorough, informative and timely review. The inclusion of a large number of studies and diverse diabetic patient populations represents the major strength of this research report. However, certain limitations make it difficult to interpret the results. First, the trials included different exposure durations and follow-up periods, limiting the ability to adequately assess the effect of treatment duration on the occurrence of heart failure events. Second, DPP-4 inhibitors were used both as monotherapy and in combination with other antihyperglycemic agents, making it challenging to determine a direct causal association between DPP-4 inhibition and heart failure. Third, heart failure events were not always prespecified, well-defined, or adjudicated across trials. Finally, study-level meta-analyses and/or systematic reviews lack the ability to identify or confirm predictors of heart failure events.
An emerging signal for an increased risk of hospitalisation for heart failure was observed in several recent diabetes clinical trials [2, 3]. Due to the high morbidity and mortality associated with these events [2, 4], as well as increasing health care costs, hospitalisation for heart failure has become a major cardiovascular concern. In this systematic review, the authors conclude that DPP-4 inhibitors may increase the risk of hospital admission for heart failure in patients with existing cardiovascular disease or multiple risk factors for vascular diseases. Based on the limitations listed above, the evidence provided by study-level data for “a borderline increase in the risk of hospital admission for heart failure” is inconclusive. Furthermore, individual patient demographics and clinical characteristics could not be used to identify subgroups at greatest risk for these serious, life-threatening adverse events. In a previous DPP-4 inhibitor cardiovascular outcomes trial, the risk of hospitalisation for heart failure was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease [2]. Since patient-level data were not available to Li et al [1], further delineation of these potential effect-modifying risk factors across the clinical trials included in their review was not possible. Millions of diabetic patients worldwide are taking DPP-4 inhibitors, and a substantial number of patients hospitalized for heart failure are readmitted with recurrent heart failure episodes or die [2, 5-7]. Therefore, identifying sub-populations at greatest risk for these heart failure events is crucial to enable safe use of DPP-4 inhibitors.
Secondary analyses of large well-controlled clinical trials using pooled patient-level rather than study-level data, as used by Li et al, may offer a more definitive answer. Such analyses can offer better guidance in planning future randomised controlled trials. Alternatively, they may provide supporting evidence when these trials are not feasible. The large data repositories of the National Institutes of Health (e.g., dbGaP) [8], including those from the National Heart, Lung, and Blood Institute (e.g., BioLINCC) [9], are options to address this need. These repositories include individual patient-level data from institute-supported clinical trials, as well as observational studies, providing opportunities for researchers to conduct secondary analyses of existing data. Similar data also are available from several pharmaceutical companies [10] and the European Medicines Agency [11]. Despite the availability to outside investigators, patient-level data sources to a great extent remain underutilized [12].
Tejas Patel, MD, MPH
Bereket Tesfaldet, MS
Charu Gandotra, MD, MS
For the Meta-AnalyTical Interagency Group (MATIG)*
REFERENCES:
1. Li, L., et al., 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: p. i610.
2. Scirica, B.M., et al., Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation, 2014. 130(18): p. 1579-88.
3. Zannad, F., et al., Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet, 2015. 385(9982): p. 2067-76.
4. Cavender, M.A., et al., Impact of Diabetes Mellitus on Hospitalization for Heart Failure, Cardiovascular Events, and Death: Outcomes at 4 Years From the Reduction of Atherothrombosis for Continued Health (REACH) Registry. Circulation, 2015. 132(10): p. 923-31.
5. Bernheim, S.M., et al., National patterns of risk-standardized mortality and readmission for acute myocardial infarction and heart failure. Update on publicly reported outcomes measures based on the 2010 release. Circ Cardiovasc Qual Outcomes, 2010. 3(5): p. 459-67.
6. Gheorghiade, M., et al., Rehospitalization for heart failure: problems and perspectives. J Am Coll Cardiol, 2013. 61(4): p. 391-403.
7. Kulkarni, V.T., et al., Regional density of cardiologists and rates of mortality for acute myocardial infarction and heart failure. Circ Cardiovasc Qual Outcomes, 2013. 6(3): p. 352-9.
8. Mailman, M.D., et al., The NCBI dbGaP database of genotypes and phenotypes. Nat Genet, 2007. 39(10): p. 1181-6.
9. Coady, S.A. and E. Wagner, Sharing individual level data from observational studies and clinical trials: a perspective from NHLBI. Trials, 2013. 14: p. 201.
10. Strom , B.L., et al., Data Sharing, Year 1 — Access to Data from Industry-Sponsored Clinical Trials. New England Journal of Medicine, 2014. 371(22): p. 2052-2054.
11. European Medicines Agency (EMA). Clinical data publication. EMA website. 2016. http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general... (accessed March 22 2016).
12. Navar, A.M., et al., Use of Open Access Platforms for Clinical Trial Data. JAMA, 2016. 315(12): p. 1283-4.
* Keith Burkhart, MD; Henry Chang, MD; Jue Chen, MS, PhD; Sean Coady, MS; Lawton Cooper, MD; Gyorgy Csako, MD; Michelle Fennessy, RN, PhD; Jerome Fleg, MD; Charu Gandotra, MD, MS; Ahmed Hasan, MD, PhD, FACC; Ruth Kirby, BS, RN; Eileen Navarro Almario, MD, MS, FACP; Tejas Patel, MD, MPH; Frank Pucino, PharmD, MPH; Subha Raman, MD; Yves Rosenberg, MD, MPH; George Sopko, MD; Helena Sviglin, MPH; Bereket Tesfaldet, MS; Robert Wesley, PhD.
Competing interests: No competing interests
Disclaimer: The contents of this letter are solely the responsibility of the authors, and do not represent the official views of the National Institutes of Health, the Food and Drug Administration, Howard University, or Ohio State University.
Competing interests: No competing interests
Re: Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies
Dear Editor,
We appreciate the comments made by Patel et al with regard to our systematic review and meta-analysis[1]. In our study, we reported results of DPP-4 inhibitors on heart failure and hospitalization for heart failure. We concluded that the relative effect on heart failure was uncertain, given the limitations of current evidence (e.g. short and varying length of follow up, inability to adjudicate heart failure, small number of events, heterogeneity of results, inability to define individual patient risk factors), and limitations noted by Patel et al. Thus, our conclusion is completely consistent with those of the letter authors.
We further agree with Patel et al that individual participant data (IPD) meta-analyses may offer complementary sources of information to the study level analyses that we have undertaken. Such analyses may provide important insights for clinical care, and for planning of future trials.
However, the availability of individual participant data is challenging in most circumstances, particularly given that the data holders are usually the drug manufacturers. The resistance to share data is the critical obstacle to undertake useful IPD meta-analyses. We therefore call for the sharing of individual participant data to address important unanswered questions regarding intervention effects.
Sharing must, however, be done in such a way that it does not compromise the conduct of large, academic initiated clinical trials. Requirements for premature sharing could result in inappropriate analyses and undermining the motivation for the very trials that are necessary to answer major questions.
REFERENCES:
1. Li L, Li S, Deng K, Liu J, Vandvik PO, Zhao P, et al. 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:i610.
Competing interests: No competing interests