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Keywords:

  • antidiabetic drug;
  • meta-analysis;
  • type 2 diabetes

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References
  9. Supporting Information

Aim

Some observational studies reporting an increased risk of pancreatitis in association with Dipeptidyl Peptidase-4 inhibitors (DPP4i) have raised concerns on the overall safety of this class. Aim of the present meta-analysis is the systematic collection of information on pancreatitis in randomized clinical trials with DPP4i.

Methods

Data Sources: an extensive Medline, Embase and Cochrane Database search for ‘vildagliptin’, ‘sitagliptin’, ‘saxagliptin’, ‘alogliptin’, ‘linagliptin’ and ‘dutogliptin’ was performed up to 1 March 2013. Study Selection: studies were included if they satisfied the following criteria: (i) randomized trials, (ii) duration ≥12 weeks, (iii) on type 2 diabetes and (iv) comparison of DPP4i with placebo or active drugs. The identification and the selection of studies, and the subsequent data extraction were performed independently by two authors. Mantel-Haenszel odds ratio with 95% Confidence Interval (MH-OR) was calculated for all the adverse events defined below. The principal outcome was the effect of DPP4i on the incidence of pancreatitis.

Results

A total of 134 eligible trials were identified. The overall risk of pancreatitis and pancreatic cancer was not different between DPP4i and comparators (MH-OR: 0.93[0.51–1.69]; p = 0.82).

Conclusions

It should be recognized that the number of observed cases of incident pancreatitis is small and the confidence intervals of risk estimates are wide. However, the present meta-analysis do not suggest any increase in the risk of pancreatitis with DPP4i.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References
  9. Supporting Information

Dipeptidyl peptidase 4 inhibitors (DPP4i) are one of the therapeutic options for the treatment of type 2 diabetes [1]. Due to the lack of hypoglycaemic risk and the apparently satisfactory tolerability profile [2], these drugs are increasingly used in current clinical practice. However, some observational studies reporting an increased risk of pancreatitis in association with DPP4i have raised concerns on the overall safety of this class [3, 4].

Epidemiological studies have the advantage of collecting a vast amount of information in routine clinical setting; conversely, randomized trials involve only a limited number of patients who are not necessarily representative of those receiving prescriptions in the real world. On the other hand, the interpretation of results of observational studies is problematic, because of the inevitable effect of confounders. When assessing safety of new drugs, results of both epidemiologic studies and randomized trials should be critically considered. Aim of the present meta-analysis is the systematic collection and synthesis of information on treatment-emergent cases of pancreatitis described in randomized clinical trials with DPP4i.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References
  9. Supporting Information

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 1 March 2013, with a duration of at least 12 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 12 weeks; trials with a shorter duration were excluded, because of the fact that they could not yield relevant information on the incidence of pancreatitis, which was the principal outcome variable.
  3. Enrolment of patients with type 2 diabetes only (in accord with the approved clinical use of the drugs); trials enrolling non-diabetic, or type 1 diabetic, subjects 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, from www.clinicaltrials.gov, www.merck.com/mrl/clinical_trials/results.html, www.novartisclinicaltrials.com, or www.clinicalstudyresults.org; 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. [5]. The score was not used as a criterion for the selection of trials, whereas some items were used only for descriptive purposes.

Data Synthesis and Analysis

We tested for heterogeneity across trials by using a I2 test with a significance threshold for α of 0.10 or less [6]. We report the results of the random-effects models because the validity of tests of heterogeneity can be limited with a small number of component studies. To estimate possible publication or disclosure bias we used funnel plots (Figure S1), the Begg adjusted rank correlation test [7, 8], including published and unpublished, but disclosed, trials. Mantel-Haenszel odds ratio with 95% confidence interval (MH-OR) was calculated for all the adverse events defined below, on an intention-to-treat basis, excluding trials with zero events. A sensitivity analysis was performed with continuity correction, in order to avoid distortions because of the exclusion of trials with zero events.

The meta-analysis was reported following the PRISMA checklist [9]. All analyses were performed using Comprehensive Meta-analysis Version 2, Biostat, (Englewood, NJ, USA).

This research was performed independently of any funding, as part of the institutional activity of the investigators.

Main Outcomes and Measures

The principal outcome was the effect of DPP4i, compared either with placebo or active drugs, on the incidence of pancreatitis. Secondary outcomes included overall incidence of treatment-emergent serious adverse events (TSAE) and pancreatic cancer.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References
  9. Supporting Information

The trial flow is summarized in Figure S2. A total of 134 eligible trials were identified. Of these, four (NCT01602003, NCT01046110, NCT00707993, NCT00856284), although completed, reported no results. The remaining 129 trials enrolled 68 318 patients, with a total exposure of 52 464 patient*years (29 920 and 22 544 patient*years for DPP4i and comparators, respectively). The characteristics of the trials included in the meta-analysis are summarized in Table 1, their quality assessment in Table S1. Twenty of those 129 trials did not report any information on the incidence of pancreatitis and were excluded from the analysis. The principal analysis was therefore performed on 109 trials (26 732 and 18 507 patient*years for DPP4i and comparators, respectively), reporting 20 and 15 cases of pancreatitis reported as TSAE in DPP4i and comparator groups, respectively; the yearly incidence was therefore 0.075 and 0.086% for pancreatitis in DPP4i and comparator groups, respectively. Eighty-four trials reported zero events.

Table 1. Main characteristics of the trials included
First author (Reference)NCT code§ComparatorTrial duration (weeks)Number of patientsPancreatitisPancreatic cancer
DPP4iCompDPP4iCompDPP4iComp
  1. DPP4i, dipeptidyl peptidase-4 inhibitors; Comp., comparators; NR, not reported.

  2. *Trial ongoing.

  3. §See www.clinicaltrials.gov website.

Alogliptin         
NCT01263483 [16]NCT01263483Voglibose12155750000
NCT01263470 [16]NCT01263470Placebo/Voglibose123221580000
NCT01318109 [16]NCT01318109Placebo121881000000
NCT01318083 [16]NCT01318083Placebo122091030000
NCT00755846 [16]NCT00755846Placebo12222430000
NCT01318070 [16]NCT01318070Placebo122241150000
Kutoh 2012 [17]NRNone1225260000
NCT01289119 [16]NCT01289119Placebo162522530100
Eliasson 2012 [18]NCT00655863Placebo162524NRNRNRNR
NCT00968708 [16]*NCT00968708Placebo191,0581,076NRNRNRNR
Pratley 2009 [19]NCT00286494Placebo24396970000
DeFronzo 2012 [20]NCT00328627Placebo2610385171000
Rosenstock 2009 [21]NCT00286429Placebo262601301000
DeFronzo 2008 [22]NCT00286455Placebo26264640000
Pratley 2009 [23]NCT00286468Placebo26302990000
Nauck 2009 [24]NCT00286442Placebo264231040000
NCT01023581 [16]NCT01023581Placebo264503340000
Rosenstock 2010 [25]NCT00395512Pioglitazone/Placebo264911631000
Bosi 2011 [26]NCT00432276Pioglitazone524043990000
Dutogliptin         
Pattzi 2010 [27]NCT00482950Placebo12337860000
Linagliptin         
Kawamori 2012 [28]NCT00654381Voglibose2631916200NRNR
NCT01012037 [16]NCT01012037Placebo12447440000
Lewin 2012 [29]NCT00819091Placebo18161840000
NCT01194830 [16]NCT01194830Placebo241061200000
NCT01084005 [16]NCT01084005Placebo24162790000
NCT00996658 [16]NCT00996658Placebo24186921000
Gomis 2011 [30]NCT00641043Placebo242591300000
Del Prato 2010 [31]NCT00621140Placebo243361670000
NCT00601250 [16]NCT00601250Placebo245241770000
Owens 2011 [32]NCT00602472Placebo247922630000
NCT00800683 [16]NCT00800683Placebo5268650000
NCT00954447 [16]NCT00954447Placebo526316302100
NCT00915772 [16]NCT00915772Placebo543961700000
Gallwitz 2012 [33]NCT00622284Glimepiride1047767750021
NCT00328172 [16]NCT00328172Placebo/Metformin121701321000
NCT00309608 [16]NCT00309608Placebo/Glimepiride121971360000
Haak 2012 [34]NCT00798161Placebo/Metformin244382190000
NCT00740051 [16]NCT00740051Placebo/Glimepiride52171760000
NCT01204294 [16]NCT01204294Mixed524501241000
Saxagliptin         
Fonseca 2012 [35]NCT00960076Metformin181381440000
NCT01006590 [16]NCT01006590Metformin241471390000
Pfutzner 2011 [36]NCT00327015Metformin769783281101
NCT00918879 [16]NCT00918879Placebo241071060000
Yang 2011 [37]NCT00661362Placebo242832870000
Pan 2012 [38]NCT00698932Placebo242842840000
NCT00316082 [16]NCT00316082Placebo24291740010
Rosenstock 2009 [39]NCT00121641Placebo24306950000
NCT00614939 [16]NCT00614939Placebo5285850100
Barnett 2012 [40]NCT00757588Placebo523041510001
Hollander 2011 [41]NCT00295633Placebo763811841000
NCT00121667 [16]NCT00121667Placebo2085641790000
NCT00575588 [16]NCT00575588Glipizide1044284300200
Chacra 2011 [42]NCT00313313Placebo/Glyburide765012670000
Sitagliptin         
NCT00411554 [16]NCT00411554Voglibose121631560000
Aschner 2012 [43]NCT00751114Glargine242642370000
NCT00700817 [1]NCT00700817Detemir782194460101
NCT00449930 [16]NCT00449930Metformin245285220000
Derosa 2010 [44]NRMetformin527576NRNRNRNR
Rosenstock 2012 [45]NCT00642278Canagliflozin/Placebo126538600NRNR
NCT01092663 [16]NCT01092663None1230310000
Iwamoto 2010 [46]NRPlacebo12290730000
NCT00127192 [16]NCT00127192Placebo12290730000
NCT00870194 [16]NCT00870194Placebo16111970010
NCT00289848 [16]NCT00289848Placebo183521780000
NCT00875394 [16]NCT00875394None2436320000
Hong 2012 [47]NCT01100125Placebo246163NRNRNRNR
Barzilai (2011) [48]NCT00305604Placebo241021040000
NCT01028391 [16]NCT01028391Placebo241641530000
Rosenstock 2006 [49]NCT00086502Placebo241751780000
NCT00813995 [16]NCT00813995Placebo241971980000
Hermansen 2007 [50]NCT00106704Placebo242222190000
Yoon 2011 [51]NCT00397631Placebo242612590000
Visboll 2010 [52]NCT00395343Placebo243223190000
Charbonnel 2006 [53]NCT00086515Placebo244642370010
Aschner 2006 [54]NCT00087516Placebo244882530000
NCT00860288 [16]NCT00860288Placebo24608616NRNRNRNR
NCT00885352 [16]NCT00885352Placebo261571560000
Raz 2008 [55]NCT00337610Placebo3096940001
Raz 2006 [56]NCT00094757Placebo444111100101
NCT00482729 [16]NCT00482729Placebo446256211100
NCT00420511 [16]NCT00420511Placebo4810110000
Makdissi 2012 [57]NRPlacebo521210NRNRNRNR
Derosa 2012 [58]NRPlacebo529187NRNRNRNR
Chan 2008 [59]NCT00095056Placebo5465260010
NCT00350779 [16]NCT00350779Placebo54170920000
Williams-Herman 2010 [60]NCT00103857Placebo1045515401101
Koren 2012 [61]NRGlibenclamide124040NRNRNRNR
Sivrastava 2012 [62]NRGlimepiride1825250000
Arechavaleta 2011 [63]NCT00701090Glimepiride305165190010
NCT00509236 [16]NCT00509236Glipizide5464650000
NCT00509262 [16]NCT00509262Glipizide542112120010
Seck 2010 [64]NCT00094770Glipizide1045885841000
NCT01195090 [16]NCT01195090Pioglitazone2460600000
Wainstein 2012 [65]NCT00532935Pioglitazone322612561000
NCT00541450 [16]NCT00541450Pioglitazone402242480000
NCT00722371 [16]NCT00722371Pioglitazone549226930101
NCT00511108 [16]NCT00511108Pioglitazone/Placebo121041070000
NCT00484419 [16]NCT00484419Rosiglitazone /None16561130000
NCT00541775 [16]NCT00541775Rosiglitazone /Placebo18941790000
Russell-Jones 2012 [66]NCT00676338Pioglitazone/Metformin241634091000
Bergenstal 2010 [67]NCT00637273Pioglitazone/Exe261663250200
NCT01076075 [16]NCT01076075Placebo/Pioglitazone542132140000
Vildagliptin         
Pan 2008 [68]NCT00110240Acarbose244402201000
Schweizer 2009 [69]NCT00383578Metformin24169166NRNRNRNR
NCT00099866 [16]NCT00099866Metformin1043051580000
Kikuchi 2010 [70]NCT00325117Placebo121021000000
Fonseca 2007 [71]NCT00099931Placebo24144152NRNRNRNR
Goodman 2009 [72]NCT00351884Placebo24248122NRNRNRNR
Pi-Sunyer 2007 [73]NCT00120536Placebo2426292NRNRNRNR
NCT00494884 [16]NCT00494884Placebo242681340000
Pan 2012 [74]NCT00822211Placebo242941440000
NCT00821977 [16]NCT00821977Placebo24300150NRNRNRNR
Garber 2008 [75]NCT00099853Placebo243051581000
Bosi 2007 [76]NCT00099892Placebo243621820000
NCT00396357 [16]NCT00396357Placebo24456458NRNRNRNR
Dejager 2007 [77]NCT00099905Placebo244721600000
NCT00860288 [16]NCT00860288Placebo241,217616NRNRNRNR
Bunck 2012 [78]NRPlacebo5229300000
NCT00260156 [16]NCT00260156Placebo524544NRNRNRNR
Derosa 2012 [79]NRPlacebo5284830000
Scherbaum 2008 [80]NCT00300287Placebo521561500100
Kothny 2012 [81]NCT00646542Placebo5221615300NRNR
Foley 2009 [82]NCT00102388Placebo104546546NRNRNRNR
Filozof 2010 [83]NCT00102466Gliclazide52513494NRNRNRNR
Ferrannini 2009 [84]NCT00106340Glimepiride52139613933200
Bolli 2009 [85]NCT00237237Piogitazone522952810000
Rosenstock 2009 [86]NCT00099918Rosiglitazone1043962020010
Rosenstock 2007 [87]NCT00101803Placebo/Pioglitazone24446161NRNRNRNR
Bosi 2009 [88]NCT00468039Placebo/Metformin24885294NRNRNRNR

In trials reporting at least one case of pancreatitis (N = 24), no heterogeneity was detected (I2 = 0.0, p = 0.96; Begg's tau = −0.09, p = 0.55). The overall risk of pancreatitis was not different between DPP4i and comparators (MH-OR: 0.93[0.51–1.69]; p = 0.82; figure 1). The sensitivity analysis with continuity correction estimated a MH-OR with DPP4i of 0.70[0.53–0.92] (p = 0.011). The risk of pancreatitis (MH-OR) with individual DPP4i was 0.89[0.32–2.49] (p = 0.83) for sitagliptin (N = 9 trials), 1.18[0.32–4.26] (p = 0.80) for vildagliptin (N = 4 trials), 0.41[0.09–1.87] (p = 0.25) for saxagliptin (N = 4 trials), 0.93[0.19–4.62] (p = 0.93) for alogliptin (N = 4 trials) and 1.62[0.37–7.02] (p = 0.52) for linagliptin. DPP4i were not associated with an increased risk of pancreatic cancer in comparison with comparators (MH-OR: 0.72[0.32–1.61]; p = 0.42). The overall incidence of TSAE with DPP4i was similar to that of comparators (MH-OR: 0.97[0.89–1.04], p = 0.38).

image

Figure 1. MH-OR for pancreatitis with 95% CI. DPP4i: dipeptidyl peptidase-4 inhibitors.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References
  9. Supporting Information

Available randomized controlled trials do not suggest any increase in the risk of pancreatitis during treatment with DPP4i. This result confirms the findings of a previous meta-analysis on a much smaller number of trials [10] and those of a pooled analysis of patient-level data on sitagliptin [11]. Considering the relatively low incidence of pancreatitis, a meta-analytic approach is inevitably needed to collect any sensible information on this event in clinical trials. On the other hand, meta-analyses reduce the role of chance but may introduce bias or confounding based on heterogeneity of the component trials.

Preclinical studies on rodents suggest that glucagon-like peptide-1 based therapies, including DPP4i, can facilitate the onset of pancreatitis [12]. An analysis based on the FDA's database of reported adverse events suggested that sitagliptin could be associated with a 70% increase in the risk of pancreatitis, and a more than twofold increase in the risk of pancreatic cancer [4]. However, that analysis included only those cases that physicians, other health professionals or patients decided to report to the FDA; therefore, reporting bias could have been a major issue. Furthermore, no data on actual overall exposure to the drug were available, so that no incidence ratio could be calculated. Results of epidemiological studies have been contrasting. Two surveys based on administrative data revealed no increase in risk of pancreatitis associated with sitagliptin [13, 14]. However, more recently, a case–control study nested within a much larger cohort revealed a twofold increase in the incidence of hospitalization for pancreatitis associated with incretin-based therapies, after adjusting for confounders [3].

The results of randomized trials seem to be at variance with those of this latter study, showing no signal of risk. The interpretation of observational studies on the effects of drugs is always problematic, because of the possible effect of confounders. Despite the attempt at adjusting analyses for potentially relevant covariates, some parameters are difficult to be measured in a reliable manner in large populations. For example, the definition of alcohol abuse or the exclusion of cases of pre-existing milder forms of chronic pancreatitis is problematic in large datasets. On the other hand, it should be recognized that the size of available trials is still limited; as a consequence, the number of observed cases of incident pancreatitis is small and the confidence intervals of risk estimates are wide. In addition, the limited number of cases does not allow any comparison across individual molecules, which could theoretically be associated with different risks. However, available cases are already sufficient to exclude a risk increase greater than 70%. Although information on pancreatitis was available in the large majority of trials, and specific analyses did not suggest any publication or disclosure bias, it is possible that selective reporting contributed to a more favourable result for DPP4i. In addition, the duration of available trials is still limited; for this reason, a detrimental effect of DPP4i on pancreatitis requiring a longer exposure to the drug cannot be ruled out. Moreover, the duration of studies is inadequate to draw any conclusions on the occurrence of pancreatic cancer. A further limitation is represented by the fact that pancreatitis was not included in the primary endpoint in the majority of trials, and in most instances there was no predefinition of diagnostic criteria or subsequent adjudication of cases, possibly leading to misclassifications. For this reason, no definitive conclusion can be drawn on the causal relationship between DPP4i and pancreatitis on the basis of this meta-analysis, which is only hypothesis-generating. This analysis was restricted to cases of pancreatitis reported as serious adverse events in order to reduce disclosure or publication bias and to exclude milder forms, where diagnostic uncertainty could be greater. The usual definition of serious adverse events in randomized trials include all cases requiring hospitalization, and those determining a risk for survival or physical integrity of the patient. On the other hand, the epidemiological survey cited above [3] collected only information on hospitalization for pancreatitis, using an even more restrictive criterion.

Despite a narrower definition, the incidence of pancreatitis in the cohort studied by Singh et al. [3] was probably greater than that reported in the clinical trials summarized in the present meta-analysis and in previous pooled analyses [15]. Although the publication did not report the mean duration of follow-up for the entire cohort, considering that 1269 cases of pancreatitis were collected in about 1 000 000 patients with diabetes, during an overall observation of 4 years, the estimated incidence should be around 1 case per thousand patient*years [3]. Other observational studies based on administrative data, which included also cases not requiring hospitalization, reported even higher incidence estimates [14]. Conversely, in the trials included in the present meta-analysis the incidence of pancreatitis classified as serious adverse event was lower than 1 per thousand patient*years. The difference in the incidence of pancreatitis between patients enrolled in clinical trials and those in routine clinical practice captured by administrative databases points out to the fact that the former cannot be considered representative of the latter. It can be speculated that patients with many comorbidities have a lower chance of being invited to participate to randomized trials, which therefore select a ‘healthier’ population with reduced risk for pancreatitis. For example, alcohol abusers, or those with a previous history of symptoms compatible with pancreatitis, are unlikely to be enrolled in clinical trials. Differences in results between observational studies and randomized trial could therefore be the consequence of diversities in case mix.

It is possible that epidemiological studies overestimate, and clinical trials underestimate, the actual impact of DPP4i on the incidence of pancreatitis. Another possibility is that the increase in risk is limited to some subpopulations, which are included in observational studies but under-represented (or not represented) in clinical trials. Further studies are needed for a better definition of the effects of DPP4i and other incretin-based therapies on pancreatitis. Several large-scale trials designed for cardiovascular outcomes, with either DPP4i or GLP-1 receptor agonists, are currently ongoing; pancreatitis, although it is not within the principal endpoint of those studies, is usually designated as an event ‘of interest’, with specific diagnostic criteria and screening procedures. The results of those trials, which include also patients with relevant comorbidities, will certainly be useful. At the same time, further epidemiological studies would provide additional information; in particular, surveys on populations at high risk of pancreatitis who are unlikely to be enrolled in clinical trials would allow a better definition and delimitation of risk.

In conclusion, when summarizing the results of available randomized clinical trials, the point estimates for the risk of pancreatitis are reassuring but the width of the confidence intervals include small to moderate risks as well as benefits. Thus, these data contribute to the formulation of the hypothesis of no increased risks of pancreatitis with DPP4i.

Conflict of Interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References
  9. Supporting Information

M. M. has received speaking fees from Bristol Myers Squibb, Merck and Takeda, and research grants from AstraZeneca. I. D. has no relevant financial relationships and/or potential conflict of interest to declare. E. M. 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. M. M. and E. M. performed the design, data collection, analysis and writing of the manuscript and I. D. performed the data collection and analysis for the study. All the authors approved the final version of this manuscript. 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.

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  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References
  9. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References
  9. Supporting Information
FilenameFormatSizeDescription
dom12176-sup-0001-TableS1.docWord document239KTable S1. Quality assessment of the trials included in the meta-analysis.
dom12176-sup-0002-FigureS1.docWord document41KFigure S1. Funnel plot of standard error by MH log OR.
dom12176-sup-0003-FigureS2.docWord document71KFigure S2. Trial flow diagram. RCT, Randomized Clinical Trial; T2, Type 2; DPP4, Dipeptidyl Peptidase-4.
dom12176-sup-0004-AppendixS1.docWord document62KAppendix S1. References.

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