Nutrition, Metabolism & Cardiovascular Diseases (2014) xx, 1e9

Available online at www.sciencedirect.com

Nutrition, Metabolism & Cardiovascular Diseases journal homepage: www.elsevier.com/locate/nmcd

Meta-analysis

Dipeptidyl peptidase-4 inhibitors and heart failure: A meta-analysis of randomized clinical trials M. Monami a, I. Dicembrini b,c, E. Mannucci c,* a b c

Section of Geriatric and Medicine, Careggi Teaching Hospital, Via delle Oblate 4, 50141 Florence, Italy Obesity Agency, Careggi Teaching Hospital, Via delle Oblate 4, 50141 Florence, Italy Diabetes Agency, Careggi Teaching Hospital, Via delle Oblate 4, 50141 Florence, Italy

Received 14 November 2013; received in revised form 16 January 2014; accepted 24 January 2014 Available online - - -

KEYWORDS Meta-analysis; DPP-4 inhibitors; Heart failure

Abstract Background & aims: Recently, the SAVOR TIMI-53 (Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus e Thrombolysis in Myocardial Infarction53) reported a significant increase in the risk of hospitalizations for heart failure in patients treated with saxagliptin in comparison with placebo. Aim of the present meta-analysis is the systematic collection and synthesis of information on treatment-emergent cases of acute heart failure described in randomized clinical trials with DPP4. Methods & results: Data sources: An extensive Medline, Embase, and Cochrane Database search for “vildagliptin”, “sitagliptin”, “saxagliptin”, “alogliptin”, “linagliptin”, and “dutogliptin” was performed, collecting all randomized clinical trials on humans up to October 1st, 2013. Studies were included if they satisfied the following criteria: i) randomized trials, ii) duration 24 weeks; iii) on type 2 diabetes; iv) comparison of DPP4i with placebo or active drugs. The principal outcome was the effect of DPP4i on the incidence of acute heart failure. A total of 84 eligible trials was identified. The overall risk of acute heart failure was higher in patients treated with DPP4i in comparison with those treated with placebo/active comparators (MHeOR: 1.19[1.03; 1.37]; p Z 0.015). When trials with non-cardiovascular outcomes were analysed separately no signal of risk was detectable. Conclusion: Available data from RCTs suggest that DPP4i could be associated with an increased risk of heart failure, without any clear evidence of differences among drugs of the class. Although it is plausible that the risk is greater in some sub-populations of patients, current evidence is not yet sufficient to identify susceptible patients. ª 2014 Elsevier B.V. All rights reserved.

Introduction New glucose-lowering agents for the treatment of type 2 diabetes are requested to demonstrate their cardiovascular safety through pooled analyses of adjudicated events in phase IIeIII trials, or through specifically designed

* Corresponding author. E-mail address: edoardo.mannucci@unifi.it (E. Mannucci).

cardiovascular outcome trials [1]. Recently, two large-scale trials designed for this purpose have been published [2,3], showing no significant increase in major cardiovascular events during treatment with DPP4 inhibitors (DPP4i). However, unexpectedly, one of the two trials, the SAVOR TIMI-53 (Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus e Thrombolysis in Myocardial Infarction-53) reported a significant increase in the risk of hospitalizations for heart failure in patients treated with saxagliptin in comparison with

0939-4753/$ - see front matter ª 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.numecd.2014.01.017

Please cite this article in press as: Monami M, et al., Dipeptidyl peptidase-4 inhibitors and heart failure: A meta-analysis of randomized clinical trials, Nutrition, Metabolism & Cardiovascular Diseases (2014), http://dx.doi.org/10.1016/j.numecd.2014.01.017

2

M. Monami et al.

placebo [3]. The authors of the trial remarked that this could have been a false positive result due to multiple testing. Although this is certainly a possibility, the hypothesis of a real detrimental effect of DPP4i on this specific outcome should also be considered. A careful analysis of the results of other randomized trials with drugs of the same class could provide some further insights on this point. Aim of the present meta-analysis is the systematic collection and synthesis of information on treatmentemergent cases of acute heart failure described in randomized clinical trials with DPP4i. Methods Data sources and searches An extensive Medline, Embase, and Cochrane Central Register of Controlled Trials search for “vildagliptin”, “sitagliptin”, “saxagliptin”, “alogliptin”, “linagliptin”, and “dutogliptin” was performed, collecting all randomized clinical trials on humans up to October 1st, 2013, with a duration of at least 24 weeks, enrolling patients with type 2 diabetes, comparing DPP4i with placebo or active drugs (oral hypoglycaemic agents and/or insulin) different from other DPP4i. The identification of relevant abstracts, the selection of studies based on the criteria described above, and the subsequent data extraction were performed independently by two of the authors (I.D., M.M.), and conflicts resolved by the third investigator (E.M.). Completed but still unpublished trials were identified through a search of www.clinicaltrials.gov website. FDA (www.fda.gov) and European Medicines Agency (EMA, www.ema.europa.eu) reviews of approved drugs, as well as published information provided to FDA in response to queries during the approval process, were also searched for retrieval of unpublished trials. Study selection Studies were included in the meta-analysis if they satisfied the following inclusion criteria: 1) Designed as randomized clinical trials. 2) Duration of at least 24 weeks. 3) Enrolment of patients with type 2 diabetes only (in accord with the approved clinical use of the drugs); trials enrolling subjects without diabetes, or with type 1 diabetes, were therefore excluded. 4) Comparison of DPP4i with placebo or active drugs (oral hypoglycaemic agents and/or insulin) different from other DPP4i. No review protocol was published elsewhere. Data extraction and quality assessment Results of unpublished trials were retrieved, if available, on www.clinicaltrials.gov, or www.novartisclinicaltrials.com;

Food and Drug Administration (FDA, www.fda.gov) and European Medicines Agency (EMEA, www.ema.europa.eu) reviews of approved drugs were also searched for retrieval of unpublished trials. All those sources were also used to complete information on results of published trials, when not reported in publications (including the primary trial publications, and subsequent reviews and/or pooled analyses reporting data on individual trials). For all published trials, results reported in papers were used as the primary source of information, when available. When available in the primary or subsequent publications, data with adjudication of events were preferred. The quality of trials was assessed using some of the parameters proposed by Jadad et al. [4]. The score was not used as a criterion for the selection of trials, whereas some items were used only for descriptive purposes. Principal outcomes The principal outcome was the effect of DPP4i, compared either with placebo or active drugs, on the incidence of acute heart failure reported as treatment-emergent serious adverse event. This definition includes any event of acute heart failure which required hospitalization and/ or was life-threatening or posing a permanent threat to patient’s integrity. Data synthesis and analysis Heterogeneity across trials was tested by using a I2 test with a significance threshold for b of 0.10 or less [5]. The results of the random-effects models were reported because the validity of tests of heterogeneity can be limited with a small number of events in each component study. To estimate possible publication/disclosure bias funnel plots (Fig. e1) and the Begg adjusted rank correlation test [6,7], including published and unpublished, but disclosed, trials, were used. Mantel-Haenszel odds ratio with 95% Confidence Interval (MHeOR) was calculated for acute heart failure, on an intention-to-treat basis, excluding trials with zero events. A sensitivity analysis was performed with continuity correction, in order to avoid distortions due to the exclusion of trials with zero events. Whenever possible, subgroup analyses were also performed considering separately trials in which DPP4i were co-administered with insulin, sulphonylureas, or thiazolidinediones; further subgroup analyses were also performed on trials enrolling only elderly patients, or patients with acute heart failure or renal failure. Meta-regression analyses were performed to identify moderators of the effects of DPP4i on the incidence of acute heart failure. Putative moderators included baseline mean age, BMI, HbA1c, duration of diabetes, and proportion of enrolled patients with a previous diagnosis of renal insufficiency or heart failure. The meta-analysis was reported following the PRISMA checklist [8]. All analyses were performed using Comprehensive Meta-analysis Version 2, Biostat, (Englewood, NJ, USA).

Please cite this article in press as: Monami M, et al., Dipeptidyl peptidase-4 inhibitors and heart failure: A meta-analysis of randomized clinical trials, Nutrition, Metabolism & Cardiovascular Diseases (2014), http://dx.doi.org/10.1016/j.numecd.2014.01.017

DPP-4 inhibitors and heart failure

This research was performed independently of any funding, as part of the institutional activity of the investigators. Results The trial flow is summarized in Fig. e2. A total of 109 eligible trials was identified. Of these, eight (NCT01582230, NCT01545388, NCT01462266, NCT01356381, NCT012899 90, NCT01177384, NCT01107886, NCT00875394), although completed, reported no results; in addition, 17 published trials for which main results were published or otherwise disclosed did not report information on cases of heart failure classified as serious adverse events. The remaining 82 trials enrolled 69,615 patients, with a total exposure of 90,731 patient*years (48,714 and 42,017 patient*years for DPP4i and comparators, respectively). The characteristics of the trials included in the meta-analysis are summarized in Table 1, and their quality assessment in eTable 1. Among those trials, 45 reported zero events; therefore, the principal analysis was performed on 37 trials, reporting 448 and 361 cases of acute heart failure in DPP4i and comparator groups, respectively. No heterogeneity was detected (I2 0.0, p Z 0.89; Begg’s tau 0.14, p Z 0.22). The overall risk of acute heart failure was higher in patients treated with DPP4i in comparison with those treated with placebo or other active comparators (MHeOR: 1.19[1.03; 1.37]; p Z 0.015; Fig. 1). The sensitivity analysis with continuity correction estimated an MHeOR with DPP4 inhibitors of 1.14[0.99; 1.29] (P Z 0.062). Considering all trials which reported information, including those with zero events, the yearly incidence of heart failure reported as serious adverse event was 0.9 and 0.9% in DPP4i and comparator groups, respectively. The large majority of events was reported in the two cardiovascular outcome trials, SAVOR-TIMI53 [3] and EXAMINE [2], which accounted for 64 and 25% of the overall result, respectively. When those two trials were analysed separately, a significant increase in risk was observed, whereas no signal of risk was detectable in the other trials, which had been designed for noncardiovascular outcomes. Similar results were obtained when excluding trials comparing DPP4i either with thiazolidinediones or sulphonylureas (Fig. 2). The risk of acute heart failure (MHeOR) with individual DPP4 inhibitors is reported in Fig. 2. A significant increase in risk was found only for saxagliptin; the result did not maintain statistical significance when excluding SAVORTIMI53 [3] (MHeOR: 0.50[0.21; 1.18], p Z 0.11). Linagliptin was associated with a non-significant increase in risk, which was largely due to one trial (NCT00800683) with five events in active drug versus one for control; this was a placebo-controlled 52-week study on patients with severe chronic renal impairment, in which linagliptin was used either as monotherapy or as add-on to sulfonylurea and/or insulin [17]. When trials enrolling only patients with renal failure (n Z 3) were analysed separately, the MHeOR was 0.71 [0.10; 5.09], p Z 0.73. The corresponding figures for trials

3

in which DPP4i were co-administered with sulphonylureas (n Z 2) or thiazolidinediones (n Z 2) were 0.42[0.03; 5.86] and 0.47[0.05; 4.27], respectively, all p > 0.50. Only one trial with events was available for add-on to insulin and for elderly patients, not allowing any formal meta-analysis. Metaregression analyses did not show any effect of age, duration of diabetes, baseline HbA1c, and BMI on the risk of acute heart failure, as shown in Table 2.

Discussion The unexpected increase of incidence of hospitalizations for heart failure in the SAVOR-TIMI53 trial [3] could be interpreted either as a causal result due to multiple testing, or as a real effect of the drug. The other available cardiovascular outcome trial, EXAMINE, did not provide conclusive results, with an estimated OR of 1.19 (pointing to a possible increase in risk), but with no statistically significant difference between treatment groups [2]. On the contrary, earlier non-cardiovascular trials, either with saxagliptin or with other DPP4i, did not show any signal of risk. When all available trials were analysed together, the increase in risk was statistically significant. This result suggests that treatment with DPP4i could be associated with an increased incidence of hospitalizations for heart failure. The association of DPP4i with heart failure was detected in a trial with saxagliptin [3]; however, available data do not support the hypothesis of a drug-specific effect, but rather that of a class effect. In non-cardiovascular trials, none of the DPP4i showed any signal of risk, whereas the combination of two available cardiovascular outcome trials reported a clearly increased risk. This suggests that characteristics of patients enrolled could be more relevant than the choice of individual molecules of the class. Patients enrolled in cardiovascular outcome trials are quite different from those participating to earlier noncardiovascular studies: they are older, with a longer duration of diabetes, higher cardiovascular risk and comorbidity, poorer renal function, and often treated with insulin and other hypoglycemic drugs. It can be speculated that some of these features could explain differences in drug-associated risk of heart failure. However, attempts at identifying sub-populations with a greater susceptibility to this negative effect of DPP4i, either through metaregression or subgroup meta-analyses, failed because of paucity of available data. In fact, a much larger number of events in trials with non-cardiovascular endpoint would have been necessary to explore more efficiently potential predictors of heart failure associated with DPP4i treatment. Therefore, it was not possible to establish whether combined treatment with insulin, sulphonylurea, or thiazolidinediones, as well as advanced age, renal failure or pre-existing heart failure were associated with a greater drug-induced risk. In this respect, post-hoc analyses of results of SAVOR-TIMI53 also failed to detect any significant moderator of the effect of saxagliptin on hospitalization for heart failure [9]; however, the relatively small

Please cite this article in press as: Monami M, et al., Dipeptidyl peptidase-4 inhibitors and heart failure: A meta-analysis of randomized clinical trials, Nutrition, Metabolism & Cardiovascular Diseases (2014), http://dx.doi.org/10.1016/j.numecd.2014.01.017

4

M. Monami et al.

Table 1 Main characteristics of the trials included. First author (reference)

NCT code

Comparator

Trial duration (weeks) Number of pts

Acute heart failure

DPP-4i

Comp.

DPP-4i

24 26 26 26 26 26 52 94

396 264 302 423 442 491 222 2701

97 64 99 104 326 163 219 2679

2 0 0 1 0 0 3 106

0 0 1 0 0 0 1 89

Placebo Placebo Placebo Placebo Placebo Placebo Placebo Placebo/Metformin Voglibose Placebo Placebo/Glimepiride Mixed Placebo Glimepiride

24 24 24 24 24 24 24 24 26 52 52 52 52 104

110 186 259 278 336 523 792 438 319 68 171 450 631 776

124 92 130 101 167 177 263 219 162 65 76 124 630 775

0 0 0 0 0 0 0 2 1 5 0 0 5 3

0 0 0 0 0 0 0 0 0 1 0 0 4 3

NCT01006590 NCT00327015 NCT00918879 NCT00661362 NCT00698932 NCT00121641 NCT00316082 NCT00575588 NCT00614939 NCT00295633 NCT00313313 NCT00121667 NCT00575588 NCT01107886

Metformin Metformin Placebo Placebo Placebo Placebo Placebo Placebo Placebo Placebo Placebo/Glyburide Placebo Glipizide Placebo

24 76 24 24 24 24 24 52 52 76 76 208 104 109

147 978 107 283 284 306 291 304 85 381 501 564 428 8.280

139 0 328 1 106 0 287 0 284 0 95 1 74 1 151 2 85 1 184 0 267 1 179 3 430 1 8.212 289

0 2 0 0 0 0 0 0 2 1 0 3 1 228

NCT00875394 NCT00305604 NCT01028391 NCT00813995 NCT00449930 NCT00106704 NCT00397631 NCT00395343 NCT00086515 NCT00086502 NCT00087516 NCT01106690 NCT00885352 NCT00637273 NCT01081834 NCT00337610 NCT01189890 NCT00701090 NCT00532935 NCT00541450 NCT00094757 NCT00482729 NCT00420511

None Placebo Placebo Placebo Metformin Placebo Placebo Placebo Placebo Placebo Placebo Canagliflozin Placebo Pioglitazone/Exenatide Canagliflozin Placebo Glimepiride Glimepiride Pioglitazone Pioglitazone Placebo Placebo Placebo

36 102 164 197 528 222 261 322 464 175 488 90 157 166 192 96 241 516 261 224 411 625 10

32 104 153 198 522 219 259 319 237 178 253 199 156 325 392 94 239 519 256 248 110 621 11

Alogliptin Pratley 2009 [15] DeFronzo 2008 [16] Pratley 2009 [15] Nauck 2009 [17] NCT01023581 [18] Rosenstock 2010 [19] NCT00707993 [18] White 2013 [2]

NCT00286494 NCT00286455 NCT00286468 NCT00286442 NCT01023581 NCT00395512 NCT00707993 NCT00968708

Placebo Placebo Placebo Placebo Placebo Pioglitazone/Placebo Glipizide Placebo

Linagliptin NCT01194830 [18] NCT00996658 [18] Gomis 2011 [20] Taskinen 2011 [21] Del Prato 2011 [22] NCT00601250 [18] Owens 2011 [23] Haak 2012 [24] Kawamori 2012 [25] NCT00800683 [18] NCT00740051 [18] NCT01204294 [18] NCT00954447 [18] Gallwitz 2012 [26]

NCT01194830 NCT00996658 NCT00641043 NCT00601250 NCT00621140 NCT00601250 NCT00602472 NCT00798161 NCT00654381 NCT00800683 NCT00740051 NCT01204294 NCT00954447 NCT00622284

Saxagliptin NCT01006590 [18] Pfutzner 2011 [27] NCT00918879 [18] Yang 2011 [28] Pan 2012 [29] Rosenstock 2009 [30] NCT00316082 [18] NCT00575588 [18] NCT00614939 [18] Hollander 2011 [31] Chacra 2011 [32] NCT00121667 [18] NCT00575588 [18] Scirica 2013 [3] Sitagliptin NCT00875394 [18] Barzilai (2011) [33] NCT01028391 [18] NCT00813995 [18] NCT00449930 [18] Hermansen 2007 [34] Yoon 2011 [35] Visboll 2010 [36] Charbonnel 2006 [37] Rosenstock 2006 [38] Aschner 2006 [39] NCT01106690 [18] Fonseca 2013 [40] Bergenstal 2010 [41] NCT01081834 [18] Raz 2008 [42] NCT01189890 [18] Arechavaleta 2011 [43] Wainstein 2012 [44] NCT00541450 [18] Raz 2006 [45] NCT00482729 [18] NCT00420511 [18]

24 24 24 24 24 24 24 24 24 24 24 24 24 26 26 30 30 30 32 40 44 44 48

0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 1 0

Comp.

0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0

Please cite this article in press as: Monami M, et al., Dipeptidyl peptidase-4 inhibitors and heart failure: A meta-analysis of randomized clinical trials, Nutrition, Metabolism & Cardiovascular Diseases (2014), http://dx.doi.org/10.1016/j.numecd.2014.01.017

DPP-4 inhibitors and heart failure

5

Table 1 (continued ) First author (reference)

NCT code

Comparator

Trial duration (weeks) Number of pts

Acute heart failure

DPP-4i

Comp.

DPP-4i

Comp.

NCT01137812 [18] Arjona Ferreira 2013 [46] Dobs 2013 [47] Chan 2008 [48] NCT01076075 [18] NCT00509262 [18] NCT01106677 [18] NCT00722371 [18] NCT00700817 [18] WilliamseHerman 2010 [49] Seck 2010 [50]

NCT01137812 NCT00509236 NCT00350779 NCT00095056 NCT01076075 NCT00509262 NCT01106677 NCT00722371 NCT00700817 NCT00103857 NCT00094770

Canagliflozin Glipizide Placebo Placebo Placebo/Pioglitazone Glipizide Canagliflozin Pioglitazone Detemir Placebo Glipizide

52 54 54 54 54 54 54 54 78 104 104

378 64 170 65 210 211 366 922 219 551 588

377 65 92 26 212 212 735 693 446 540 584

0 3 0 4 0 0 0 2 0 1 2

0 3 0 0 0 6 0 0 2 0 1

Vildagliptin Strain 2013 [51] Fonseca 2007 [52] NCT00494884 [18] Pan 2012 [53] Pan 2008 [54] Dejager 2007 [55] Scherbaum 2008 [56] Bolli 2009 [57] Ferranini 2009 [58] NCT00099866 [18] Rosenstock 2009 [59] Foley 2009 [60]

NCT01257451 NCT00099931 NCT00494884 NCT00822211 NCT00110240 NCT00099905 NCT00300287 NCT00237237 NCT00106340 NCT00099866 NCT00099918 NCT00102388

Placebo Placebo Placebo Placebo Acarbose Placebo Placebo Piogitazone Glimepiride Metformin Rosiglitazone Placebo

24 24 24 24 24 24 52 52 52 104 104 104

139 144 268 294 440 472 156 295 1396 305 396 546

137 152 134 144 220 160 150 281 1393 158 202 546

0 0 0 0 0 2 0 0 3 0 1 0

1 0 0 0 0 0 0 0 3 1 1 4

DPP-4i: Dipeptydil Peptidase-4 inhibitors; Comp.: Comparators; n Z number; Pts: patients.

Figure 1 MHeOR for acute heart failure with 95% CI. DPP4i: Dipeptidyl Peptidase-4 inhibitors.

Please cite this article in press as: Monami M, et al., Dipeptidyl peptidase-4 inhibitors and heart failure: A meta-analysis of randomized clinical trials, Nutrition, Metabolism & Cardiovascular Diseases (2014), http://dx.doi.org/10.1016/j.numecd.2014.01.017

6

M. Monami et al.

Figure 2 Subgroup analyses considering trials with and without cardiovascular (CV) endpoints (end.), and trials performed with individual DPP-4 inhibitors (DPP-4i). N Z Number; TZDs: Thiazolidinediones; SUs: sulfonylureas, MH: Mantel-Haenszel Odds Ratio; LL: Lower Limits; UL: Upper Limits.

number of events could have limited the statistical power of those analyses. The possible mechanisms underlying the association of DPP4i with heart failure remain elusive. In fact, experimental studies in vivo and ex vivo have shown that active GLP-1, which is increased during DPP4i treatment, improves cardiac function in animal models and in humans [10e12]. In addition, a single-dose study with sitagliptin in non-diabetic patients with myocardial ischemia reported an increase in stress-induced left ventricular ejection fraction [13]. However, it is possible that prolonged treatment has divergent effect from an acute administration. Speculatively, the reduction of inactivated GLP-1, which has some positive effects on myocardial function [14], or the increase in other vasoactive substrates of DPP4 (e.g., Brain Natriuretic Peptide), could produce detrimental actions during DPP4i treatment. Some limitations of this meta-analysis should be recognized. First of all, cardiovascular outcome trials are responsible for a large fraction of the overall result, with SAVOR-TIMI53 [3] accounting for almost two thirds of all events. In addition, cases of heart failure in earlier (non-cardiovascular) trials include all those that were reported as serious adverse events; the possibility that some events of acute heart failure were considered lifethreatening and/or a threat for permanent integrity (and therefore classified as serious adverse events) without leading to hospitalization, although unlikely, should be considered. On the other hand, SAVOR-TIMI53 [3] and EXAMINE [2] did not report all severe cases of heart failure, but only those leading to hospitalization, which is an investigator-driven event. Furthermore, no formal adjudication of heart failure was performed in the majority of non-cardiovascular trials, allowing for misclassifications.

In conclusion, available data from RCTs suggest that DPP4i could be associated with an increased risk of heart failure, without any clear evidence of differences among drugs of the class. Although it is plausible that the risk is greater in some sub-populations of patients, current evidence is not yet sufficient to identify susceptible patients.

Table 2 Metaregression analyses in type 2 diabetic patients treated with DPP4 inhibitors (DPP4i). Variables Baseline HbA1c (%) Baseline HbA1c (%) excluding SAVORTIMI53 and EXAMINE Age (years) Age (years) excluding SAVORTIMI53 and EXAMINE BMI (kg/m2) BMI (kg/m2) excluding SAVORTIMI53 and EXAMINE Diabetes duration (years) Diabetes duration (years) excluding SAVORTIMI53 and EXAMINE

Slope

p

0.45[ 1.28; 0.38] 0.38 0.28[ 1.14; 0.57] 0.51 0.04[0.00; 0.09] 0.04[ 0.05; 0.12]

0.09 0.39

0.00[ 0.12; 0.13] 0.90 0.06[ 0.35; 0.23] 0.70 0.04[ 0.02; 0.09] 0.04[ 0.08; 0.16]

0.16 0.50

Authors’ disclosure Matteo Monami has received speaking fees from Bristol Myers Squibb, Merck, and Takeda, and research grants from Astra Zeneca. Ilaria Dicembrini has no relevant financial relationships and/or potential conflict of interest to declare. Edoardo Mannucci has received consultancy fees from Merck and Novartis, speaking fees from Astra Zeneca, Bristol Myers Squibb, Merck, and Novartis, and research grants from Merck, Novartis, and Takeda.

Please cite this article in press as: Monami M, et al., Dipeptidyl peptidase-4 inhibitors and heart failure: A meta-analysis of randomized clinical trials, Nutrition, Metabolism & Cardiovascular Diseases (2014), http://dx.doi.org/10.1016/j.numecd.2014.01.017

DPP-4 inhibitors and heart failure

Authors’ contribution Matteo Monami was involved in each of the following points: 1. 2. 3. 4.

Design Data Collection Analysis Writing manuscript

Ilaria Dicembrini was involved in each of the following points: 1. Data Collection 2. Analysis Edoardo Mannucci was involved in each of the following points: 1. 2. 3. 4.

Design Data Collection Analysis Writing manuscript

All the authors approved the final version of this manuscript. Data access and responsibility E.M. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Appendix A. Supplementary material Supplementary material related to this article can be found at http://dx.doi.org/10.1016/j.numecd.2014.01.017. References [1] Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35(6):1364e79. [2] White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, , et alEXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327e35. [3] Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317e26. [4] Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17(1):1e12. [5] Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557e60. [6] Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50(4):1088e101. [7] Egger M, Davey Smith G, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ 1997; 315(7109):629e34.

7 [8] Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009;151(4):264e9. W64. [9] Scirica BM, Raz I, Cavender MA, Steg PG, Hirshberg B, Davidson J, et al., on behalf of the SAVOR-TIMI 53 Steering Committee and Investigators. Outcomes of patients with type 2 diabetes and known congestive heart failure treated with saxagliptin: Analyses of the SAVOR-TIMI 53 Study. Poster number 5082 presented at American Heart Association 2013, Dallas, Texas, USA on 17th November 2013. [10] Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail 2006;12:694e9. [11] Nikolaidis LA, Elahi D, Shen YT, Shannon RP. Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 2005;289:H2401e8. [12] Read PA, Hoole SP, White PA, Khan FZ, O’Sullivan M, West NE, et al. A pilot study to assess whether glucagon-like peptide-1 protects the heart from ischemic dysfunction and attenuates stunning after coronary balloon occlusion in humans. Circ Cardiovasc Interv 2011;4(3):266e72. [13] Read PA, Khan FZ, Heck PM, Hoole SP, Dutka DP. DPP-4 inhibition by sitagliptin improves the myocardial response to dobutamine stress and mitigates stunning in a pilot study of patients with coronary artery disease. Circ Cardiovasc Imaging 2010;3:195e201. [14] Ban K, Kim KH, Cho CK, Sauvé M, Diamandis EP, Backx PH, et al. Glucagon-like peptide (GLP)-1(9-36)amide-mediated cytoprotection is blocked by exendin(9-39) yet does not require the known GLP-1 receptor. Endocrinology 2010;151:1520e31. [15] Pratley RE, Kipnes MS, Fleck PR, Wilson C, Mekki Q. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Obes Metab 2009;11:167e76. [16] DeFronzo RA, Fleck PR, Wilson CA, Mekki Q. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, doubleblind, placebo-controlled study. Diabetes Care 2008;31:2315e7. [17] Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q, Alogliptin Study 008 Group. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebocontrolled study. Int J Clin Pract 2009;63(1):46e55. [18] http://clinicaltrials.gov/. [19] Rosenstock J, Inzucchi SE, Seufert J, Fleck PR, Wilson CA, Mekki Q. Initial combination therapy with alogliptin and pioglitazone in drug-naïve patients with type 2 diabetes. Diabetes Care 2010; 33(11):2406e8. [20] Gomis R, Espadero RM, Jones R, Woerle HJ, Dugi KA. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2011;13(7):653e61. [21] Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA, et al. Safety and efficacy of linagliptin as add- on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2011;13:65e74. [22] Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of b-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab 2011;13(3):258e67. [23] Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med 2011;28(11):1352e61. [24] Haak T, Meinicke T, Jones R, Weber S, von Eynatten M, Woerle HJ. Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2012;14(6): 565e74. [25] Kawamori R, Inagaki N, Araki E, Watada H, Hayashi N, Horie Y, et al. Linagliptin monotherapy provides superior glycaemic

Please cite this article in press as: Monami M, et al., Dipeptidyl peptidase-4 inhibitors and heart failure: A meta-analysis of randomized clinical trials, Nutrition, Metabolism & Cardiovascular Diseases (2014), http://dx.doi.org/10.1016/j.numecd.2014.01.017

8

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

M. Monami et al. control versus placebo or voglibose with comparable safety in Japanese patients with type 2 diabetes: a randomized, placebo and active comparator-controlled, double-blind study. Diabetes Obes Metab 2012;14(4):348e57. Gallwitz B, Rosenstock J, Rauch T, Bhattacharya S, Patel S, von Eynatten M, et al. 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, doubleblind, non-inferiority trial. Lancet 2012;380(9840):475e83. Pfützner A, Paz-Pacheco E, Allen E, Frederich R, Chen R, CV181039 Investigators. Initial combination therapy with saxagliptin and metformin provides sustained glycaemic control and is well tolerated for up to 76 weeks. Diabetes Obes Metab 2011; 13(6):567e76. Yang W, Pan CY, Tou C, Zhao J, Gause-Nilsson I. Efficacy and safety of saxagliptin added to metformin in Asian people with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Res Clin Pract 2011;94(2):217e24. Pan CY, Yang W, Tou C, Gause-Nilsson I, Zhao J. Efficacy and safety of saxagliptin in drug-naïve Asian patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Metab Res Rev 2012;28(3):268e75. Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R, CV181-011 Study Investigators. Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr Med Res Opin 2009;25(10):2401e11. Hollander PL, Li J, Frederich R, Allen E, Chen R, CV181013 Investigators. Safety and efficacy of saxagliptin added to thiazolidinedione over 76 weeks in patients with type 2 diabetes mellitus. Diab Vasc Dis Res 2011;8(2):125e35. Chacra AR, Tan GH, Ravichandran S, List J, Chen R, CV181040 Investigators. Safety and efficacy of saxagliptin in combination with submaximal sulphonylurea versus up-titrated sulphonylurea over 76 weeks. Diab Vasc Dis Res 2011;8(2):150e9. Barzilai N, Guo H, Mahoney EM, Caporossi S, Golm GT, Langdon RB, et al. Efficacy and tolerability of sitagliptin monotherapy in elderly patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Curr Med Res Opin 2011; 27(5):1049e58. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P, Sitagliptin Study 035 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab 2007;9(5): 733e45. Yoon KH, Shockey GR, Teng R, Golm GT, Thakkar PR, Meehan AG, et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and pioglitazone on glycemic control and measures of beta-cell function in patients with type 2 diabetes. Int J Clin Pract 2011;65:154e64. Vilsbøll T, Rosenstock J, Yki-Järvinen H, Cefalu WT, Chen Y, Luo E, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab 2010;12(2):167e77. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006;29:2638e43. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebocontrolled, parallel-group study. Clin Ther 2006;28:1556e68. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE, Sitagliptin Study 021 Group. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 2006;29(12):2632e7. Fonseca V, Staels B, Morgan 2nd JD, Shentu Y, Golm GT, JohnsonLevonas AO, et al. Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized, placebo-controlled, 26-week trial in patients with type 2 diabetes. J Diabetes Complicat 2013;27(2):177e83.

[41] Bergenstal RM, Wysham C, Macconell L, Malloy J, Walsh B, Yan P, , et alDURATION-2 Study Group. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet 2010;376(9739):431e9. [42] Raz I, Chen Y, Wu M, Hussain S, Kaufman KD, Amatruda JM, et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin 2008;24(2):537e50. [43] Arechavaleta R, Seck T, Chen Y, Krobot KJ, O’Neill EA, Duran L, et al. Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, noninferiority trial. Diabetes Obes Metab 2011;13(2):160e8. [44] Wainstein J, Katz L, Engel SS, Xu L, Golm GT, Hussain S, et al. Initial therapy with the fixed-dose combination of sitagliptin and metformin results in greater improvement in glycaemic control compared with pioglitazone monotherapy in patients with type 2 diabetes. Diabetes Obes Metab 2012;14(5):409e18. [45] Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H, Sitagliptin Study 023 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia 2006;49(11):2564e71. [46] Arjona Ferreira JC, Corry D, Mogensen CE, Sloan L, Xu L, Golm GT, et al. Efficacy and safety of sitagliptin in patients with type 2 diabetes and ESRD receiving dialysis: a 54-week randomized trial. Am J Kidney Dis 2013;61(4):579e87. [47] Dobs AS, Goldstein BJ, Aschner P, Horton ES, Umpierrez GE, Duran L, et al. Efficacy and safety of sitagliptin added to ongoing metformin and rosiglitazone combination therapy in a randomized placebo-controlled 54-week trial in patients with type 2 diabetes. J Diabetes 2013;5(1):68e79. [48] Chan JC, Scott R, Arjona Ferreira JC, Sheng D, Gonzalez E, Davies MJ, et al. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes Metab 2008;10(7):545e55. [49] Williams-Herman D, Johnson J, Teng R, Golm G, Kaufman KD, Goldstein BJ, et al. Efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy over 2 years in patients with type 2 diabetes. Diabetes Obes Metab 2010;12(5):442e51. [50] Seck T, Nauck M, Sheng D, Sunga S, Davies MJ, Stein PP, , et alSitagliptin Study 024 Group. Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year study. Int J Clin Pract 2010;64(5):562e76. [51] Strain WD, Lukashevich V, Kothny W, Hoellinger MJ, Paldánius PM. Individualised treatment targets for elderly patients with type 2 diabetes using vildagliptin add-on or lone therapy (INTERVAL): a 24 week, randomised, double-blind, placebo-controlled study. Lancet 2013;382(9890):409e16. [52] Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia 2007;50(6):1148e55. [53] Pan C, Xing X, Han P, Zheng S, Ma J, Liu J, , et alInstitution Investigators. Efficacy and tolerability of vildagliptin as add-on therapy to metformin in Chinese patients with type 2 diabetes mellitus. Diabetes Obes Metab 2012;14(8):737e44. [54] Pan C, Yang W, Barona JP, Wang Y, Niggli M, Mohideen P, et al. Comparison of vildagliptin and acarbose monotherapy in patients with Type 2 diabetes: a 24-week, double-blind, randomized trial. Diabet Med 2008;25(4):435e41. [55] Dejager S, Razac S, Foley JE, Schweizer A. Vildagliptin in drugnaïve patients with type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled, multiple-dose study. Horm Metab Res 2007;39(3):218e23. [56] Scherbaum WA, Schweizer A, Mari A, Nilsson PM, Lalanne G, Jauffret S, et al. Efficacy and tolerability of vildagliptin in drugnaïve patients with type 2 diabetes and mild hyperglycaemia. Diabetes Obes Metab 2008;10(8):675e82. [57] Bolli G, Dotta F, Colin L, Minic B, Goodman M. Comparison of vildagliptin and pioglitazone in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Obes Metab 2009;11:589e95.

Please cite this article in press as: Monami M, et al., Dipeptidyl peptidase-4 inhibitors and heart failure: A meta-analysis of randomized clinical trials, Nutrition, Metabolism & Cardiovascular Diseases (2014), http://dx.doi.org/10.1016/j.numecd.2014.01.017

DPP-4 inhibitors and heart failure [58] Ferrannini E, Fonseca V, Zinman B, Matthews D, Ahrén B, Byiers S, et al. Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes Obes Metab 2009;11(2):157e66. [59] Rosenstock J, Niggli M, Maldonado-Lutomirsky M. Long-term 2year safety and efficacy of vildagliptin compared with

9 rosiglitazone in drug-naïve patients with type 2 diabetes mellitus. Diabetes Obes Metab 2009;11(6):571e8. [60] Foley JE, Sreenan S. Efficacy and safety comparison between the DPP-4 inhibitor vildagliptin and the sulfonylurea gliclazide after two years of monotherapy in drug-naïve patients with type 2 diabetes. Horm Metab Res 2009;41(12):905e9. http: //dx.doi.org/10.1055/s-0029-1234042.

Please cite this article in press as: Monami M, et al., Dipeptidyl peptidase-4 inhibitors and heart failure: A meta-analysis of randomized clinical trials, Nutrition, Metabolism & Cardiovascular Diseases (2014), http://dx.doi.org/10.1016/j.numecd.2014.01.017