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Dipeptidyl peptidase-4 inhibitors, pancreatic cancer and acute pancreatitis: A meta-analysis with trial sequential analysis.

ABSTRACT: The use of dipeptidyl peptidase-4 (DPP-4) inhibitors may be associated with pancreatic cancer and acute pancreatitis. Recent meta-analyses have reported conflicting findings. Therefore, we performed a meta-analysis to assess the risk of both pancreatic cancer and acute pancreatitis associated with the use of DPP-4 inhibitors. We also used trial sequential analysis to evaluate whether the number of patients included was enough to reach conclusions. We included randomised controlled trials lasting 24 weeks or more that compared DPP-4 inhibitors with placebo or other antihyperglycaemic agents. A total of 59,404 patients were included. There was no relationship between the use of DPP-4 inhibitors and pancreatic cancer (Peto odds ratio 0.65; 95% CI 0.35-1.21), and the optimal sample size was reached to determine a number needed to harm (NNH) of 1000 patients. DPP-4 inhibitors were associated with increased risk for acute pancreatitis (Peto odds ratio 1.72; 95% CI 1.18-2.53), with an NNH of 1066 patients, but the optimal sample size for this outcome was not reached. In conclusion, there is no association between DPP-4 inhibitors and pancreatic cancer, and a small risk for acute pancreatitis was observed with DPP-4 inhibitor use, although the latter finding is not definitive.

SUBMITTER: Pinto LC

PROVIDER: S-EPMC5768864 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other

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Dipeptidyl peptidase-4 inhibitors, pancreatic cancer and acute pancreatitis: A meta-analysis with trial sequential analysis.

Pinto Lana C LC Rados Dimitris V DV Barkan Sabrina S SS Leitão Cristiane B CB Gross Jorge L JL

Scientific reports 20180115 1

The use of dipeptidyl peptidase-4 (DPP-4) inhibitors may be associated with pancreatic cancer and acute pancreatitis. Recent meta-analyses have reported conflicting findings. Therefore, we performed a meta-analysis to assess the risk of both pancreatic cancer and acute pancreatitis associated with the use of DPP-4 inhibitors. We also used trial sequential analysis to evaluate whether the number of patients included was enough to reach conclusions. We included randomised controlled trials lasting ...[more]

PMID: 29335646

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Project description:BackgroundGiven recent discrepant results from randomized controlled trials (RCTs), we examined the totality of RCT evidence assessing the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and heart failure.MethodsMEDLINE, Embase and ClinicalTrials.gov were searched without language restrictions to August 2016 for RCTs comparing DPP-4 inhibitors to placebo or no therapy for a period of 24 weeks or more. We included all heart failure outcomes when listed either as a serious adverse event or adverse event. Pooled analyses used random-effects.ResultsWe identified 100 RCTs (n = 79 867) - 3 large cardiovascular-safety RCTs (SAVOR-TIMI 53[saxagliptin]/n = 16 492, EXAMINE[alogliptin]/n = 5380, and TECOS[sitagliptin]/n = 14 735), and 97 smaller RCTs with a primary outcome that was usually change in glycated hemoglobin. Virtually all RCTs were high-quality, multicentre, placebo-controlled trials. A total of 96% (1192/1244) of heart failure events were prespecified, blindly adjudicated and required hospital admission. Pooled results suggested a 13% increase in heart failure (relative risk [RR] 1.13, 95% confidence interval [CI] 1.01-1.26, I2 = 0%; 32 RCTs, n = 54 640, 1244 events). When including only the 3 large RCTs, the increase was similar, but not significant (RR 1.14, 95% CI 0.97-1.32; 3 RCTs, n = 36 543, 1169 adjudicated events; number needed to harm 246) owing to heterogeneity (I2 = 42%), which lead to wider CIs, because SAVOR-TIMI 53 showed increased heart failure (RR 1.26, 95% CI 1.06-1.49) and TECOS showed no effect (RR 1.00, 95% CI 0.83-1.19).InterpretationDespite pooled data from 79 867 patients, whether DPP-4 inhibitors increase heart failure overall or exhibit within-class differences remains unresolved. Our results highlight the importance of ongoing trials that are comparing DPP-4 inhibitors to placebo, although no large cardiovascular-safety RCTs are comparing different DPP-4 inhibitors to each other; consequently, these will address the overall but not class-difference question.

Project description:BACKGROUND AND OBJECTIVE:Dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have pancreatic beta-cell preserving effect according to studies using homeostatic model of assessment for beta-cell function (HOMA-?). However, whether HOMA-? is a suitable biomarker for comparisons between hypoglycemic drugs with different mechanisms of action remains unclear. Therefore, we conducted a meta-analysis to compare the effects of DPP-4 inhibitors and other classes of hypoglycemic drugs on HOMA-? and proinsulin-to-insulin ratio (PIR). METHODS:We searched MEDLINE, CENTRAL, and Ichushi-web for the period of 1966 to May 2020. We collected randomized, controlled clinical trials in patients with type 2 diabetes mellitus comparing DPP-4 inhibitors and other classes of hypoglycemic agents [?-glucosidase inhibitors (?-GIs), glucagon-like peptide-1 (GLP-1) analogues, metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, sulfonylureas, or thiazolidinediones]. Weighted mean differences and 95% confidence intervals of changes in HOMA-? or PIR during study periods were calculated for pairwise comparisons. RESULTS:Thirty-seven and 21 relevant trials were retrieved for comparisons of HOMA-? and PIR, respectively. HOMA-? and PIR consistently showed superiority of DPP-4 inhibitors compared with ?-GIs. Both biomarkers consistently supported inferiority of DPP-4 inhibitors compared with GLP-1 analogues. However, PIR showed inferiority of DPP-4 inhibitors compared with metformin, and superiority compared with SGLT2 inhibitors, whereas HOMA-? showed no significant differences between DPP-4 inhibitors and the two other agents. CONCLUSION:DPP-4 inhibitors appear to be superior to ?-GIs but inferior to GLP-1 analogues in preservation of beta-cell function assessed by either HOMA-? or PIR. DPP-4 inhibitors seem to be superior to SGLT2 inhibitors but inferior to metformin on islet function assessed only by PIR. Because HOMA-? and PIR may indicate different aspects of beta-cell function, results of beta-cell function preserving effects of hypoglycemic agents should be interpreted with caution.

Project description:ObjectiveTo quantify the risk of hypoglycaemia associated with the concomitant use of dipeptidyl peptidase-4 (DPP-4) inhibitors and sulphonylureas compared with placebo and sulphonylureas.DesignSystematic review and meta-analysis.Data sourcesMedline, ISI Web of Science, SCOPUS, Cochrane Central Register of Controlled Trials, and clinicaltrial.gov were searched without any language restriction.Study selectionPlacebo controlled randomised trials comprising at least 50 participants with type 2 diabetes treated with DPP-4 inhibitors and sulphonylureas.Review methodsRisk of bias in each trial was assessed using the Cochrane Collaboration tool. The risk ratio of hypoglycaemia with 95% confidence intervals was computed for each study and then pooled using fixed effect models (Mantel Haenszel method) or random effect models, when appropriate. Subgroup analyses were also performed (eg, dose of DPP-4 inhibitors). The number needed to harm (NNH) was estimated according to treatment duration.Results10 studies were included, representing a total of 6546 participants (4020 received DPP-4 inhibitors plus sulphonylureas, 2526 placebo plus sulphonylureas). The risk ratio of hypoglycaemia was 1.52 (95% confidence interval 1.29 to 1.80). The NNH was 17 (95% confidence interval 11 to 30) for a treatment duration of six months or less, 15 (9 to 26) for 6.1 to 12 months, and 8 (5 to 15) for more than one year. In subgroup analysis, no difference was found between full and low doses of DPP-4 inhibitors: the risk ratio related to full dose DPP-4 inhibitors was 1.66 (1.34 to 2.06), whereas the increased risk ratio related to low dose DPP-4 inhibitors did not reach statistical significance (1.33, 0.92 to 1.94).ConclusionsAddition of DPP-4 inhibitors to sulphonylurea to treat people with type 2 diabetes is associated with a 50% increased risk of hypoglycaemia and to one excess case of hypoglycaemia for every 17 patients in the first six months of treatment. This highlights the need to respect recommendations for a decrease in sulphonylureas dose when initiating DPP-4 inhibitors and to assess the effectiveness of this risk minimisation strategy.

Dataset Information

Dipeptidyl peptidase-4 inhibitors, pancreatic cancer and acute pancreatitis: A meta-analysis with trial sequential analysis.

Publications

Dipeptidyl peptidase-4 inhibitors, pancreatic cancer and acute pancreatitis: A meta-analysis with trial sequential analysis.

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