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Dipeptidyl peptidase-4 inhibitors and fracture risk: an updated meta-analysis of randomized clinical trials.

ABSTRACT: Data on the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on fracture risk are conflicting. Here, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the effects of DPP-4 inhibitors. Electronic databases were searched for relevant published articles, and unpublished studies presented at ClinicalTrials.gov were searched for relevant clinical data. Eligible studies included prospective randomized trials evaluating DPP-4 inhibitors versus placebo or other anti-diabetic medications in patients with type 2 diabetes. Study quality was determined using Jadad scores. Statistical analyses were performed to calculate the risk ratios (RRs) and 95% confidence intervals (CIs) using fixed-effects models. There were 62 eligible RCTs with 62,206 participants, including 33,452 patients treated with DPP-4 inhibitors. The number of fractures was 364 in the exposed group and 358 in the control group. The overall risk of fracture did not differ between patients exposed to DPP-4 inhibitors and controls (RR, 0.95; 95% CI, 0.83-1.10; P = 0.50). The results were consistent across subgroups defined by type of DPP-4 inhibitor, type of control, and length of follow-up. The study showed that DPP-4 inhibitor use does not modify the risk of bone fracture compared with placebo or other anti-diabetic medications in patients with type 2 diabetes.

SUBMITTER: Fu J

PROVIDER: S-EPMC4935882 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Dipeptidyl peptidase-4 inhibitors and fracture risk: an updated meta-analysis of randomized clinical trials.

Fu Jianying J Zhu Jianhong J Hao Yehua Y Guo Chongchong C Zhou Zhikun Z

Scientific reports 20160707

Data on the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on fracture risk are conflicting. Here, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the effects of DPP-4 inhibitors. Electronic databases were searched for relevant published articles, and unpublished studies presented at ClinicalTrials.gov were searched for relevant clinical data. Eligible studies included prospective randomized trials evaluating DPP-4 inhibitors versus place ...[more]

PMID: 27384445

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Project description:AimThe association between dipeptidyl peptidase-4 inhibitors (DPP-4is), a class of anti-diabetes, and bone fracture in patients with type 2 diabetes mellitus (T2DM) is unknown. This meta-analysis aimed to systematically evaluate the effects of DPP-4is on bone fracture in T2DM patients.MethodsWe searched the Cochrane Library, Embase, Medline and ClinicalTrials.gov from inception through April 28th, 2016 to identify randomized controlled trials (RCTs) that compared DPP-4is with placebo or other anti-diabetes in T2DM patients. RCTs lasting more than 12 weeks and having data on bone fracture were included. We conducted random-effects meta-analysis to estimate odds ratios (ORs) and their 95% confidence intervals (CIs), and network meta-analysis (NMA) to supplement direct comparisons. Predictive interval plot and node-splitting method were used to evaluate the heterogeneity and inconsistency for NMA, while the funnel plot was applied to explore publication bias. Besides, study quality was assessed according to Cochrane risk of bias tool.ResultsWe identified 75 RCTs with a total of 70,207 patients and 11 treatments: interventions included 5 DPP-4is (alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin), while controls included placebo and 5 other anti-diabetes (sulfonylureas, glucagon-like peptide-1 receptor agonists, metformin, thiazolidinediones, sodium-glucose co-transporter 2 inhibitors). In the NMA, the risk of fracture for alogliptin tended to decrease when versus placebo (OR, 0.51; 95% CI, 0.29 to 0.88). Besides, aloglitpin had a lower risk compared with linagliptin (OR, 0.45; 95% CI, 0.20 to 0.99) and saxagliption (OR, 0.46; 95%CI, 0.25 to 0.84); the risk was higher with saxagliptin when versus sitagliptin (OR, 1.90; 95% CI, 1.04 to 3.47) and sulfonylureas (OR, 1.98; 95% CI, 1.06 to 3.71). In the direct pairwise meta-analysis, alogliptin was associated with a non-significant tendency to reduction of bone fracture compared with placebo (OR, 0.54; 95% CI, 0.29 to 1.01). Ranking probability analysis indicated alogliptin decreased the risk of bone fracture most with a probability of 76.3%.ConclusionAlogliptin may be associated with a lower risk of bone fracture compared with placebo, linagliptin, or saxagliptin, while other anti-diabetes did not seem to have an association with the risk of bone fracture.

Project description:IntroductionMore and more studies suggest that type 2 diabetes mellitus (T2DM) can lead to an increased fracture risk. Some previous clinical studies and experimental data have shown that some antidiabetic drugs can increase or decrease the incidence of fractures.MethodsWe searched Medline, Embase, Cochrane Library, and the ClinicalTrials.gov website ( https://www.clinicaltrials.gov ) for published or unpublished randomized controlled trials (RCTs) from inception through 2 December 2018 to compare the effects of dipeptidyl peptidase-4 (DDP-4) inhibitors with active control drugs or placebo in T2DM patients. All RCTs had a duration of at least 12 weeks, and the ultimate measure was whether a fracture occurs or not. We calculated odds ratios and their 95% confidence intervals by the fixed effect Mantel-Haenszel model. Publication bias was investigated firstly through visual observation of funnel plot asymmetry and then through Begg's test or Egger's test. The Cochrane bias risk tools were used to assess the quality of included studies.ResultsEighty-seven eligible RCTs were included in this study. Of 93,772 participants, 49,270 patients received therapy and 44,502 were control patients. Five kinds of DDP-4 inhibitors were included: sitagliptin, saxagliptin, alogliptin, linagliptin and vildagliptin. There were 676 fractures in the DDP-4 inhibitor treatment group and 646 in the control group. The median average glycosylated hemoglobin level was 8.2%. DDP-4 inhibitor treatment did not seem to influence the fracture risk, no matter whether compared with placebo or active comparators in T2DM patients (Mantel-Haenszel odds ratio (MH-OR) = 1.01, 95% CI 0.90-1.12, P = 0.92). After three subgroup analyses which were defined by drug type, control regimen and duration, the results were still stable.ConclusionThis systematic review and meta-analysis shows that DDP-4 inhibitors do not affect the fracture risk when compared with antidiabetic drugs or placebo in T2DM patients.

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: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.

Project description:BackgroundPrevious studies have shown inconsistent conclusions regarding the association between incretin-based therapies and the risk of developing gallbladder or biliary diseases. We conducted a meta-analysis to evaluate the risk of gallbladder or biliary diseases associated with dipeptidyl peptidase 4 inhibitors (DPP4i) in patients with type 2 diabetes.MethodsThe PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched (from inception up to March 14, 2022) for published randomized controlled trials (RCTs) that compared DPP4i with placebo or other glucose-lowering drugs in patients with type 2 diabetes. The outcomes of interest were cholecystitis, cholangitis, cholelithiasis, bile duct stones, and biliary colic. Relative risks (RRs) and 95% confidence intervals (CI) were pooled using a random-effects model. Subgroup analyses were performed according to patient age, trial duration, and types of DPP4i.ResultsIn total, 97,150 participants from 75 eligible RCTs were included in the meta-analysis. DPP4i were associated with an increased risk of composite of gallbladder or biliary diseases (RR 1.20 [95% CI 1.01-1.42]) and cholecystitis (RR 1.38 [95% CI 1.08-1.75]). Among all included trials, DPP4i showed no association with the following manifestations of gallbladder or biliary diseases: cholelithiasis (RR 1.00 [95% CI 0.76-1.32]), cholangitis (RR 0.81 [95% CI 0.39-1.66]), bile duct stones (RR 1.08 [95% CI 0.57-2.05]), and biliary colic (RR 0.72 [95% CI 0.23-2.25]). Subgroup analyses showed that DPP4i were associated with a higher risk of cholecystitis in older patients (RR 1.37 [95% CI 1.03-1.83]) compared with younger patients (RR 1.08 [95% CI 0.89-2.18]) and in those with a longer duration of drug use (RR 1.43 [95% CI 1.08-1.89]) compared with shorter use (RR 1.23 [95% CI 0.74-2.03]).ConclusionsThis systematic review and meta-analysis of RCTs found that the use of DPP4i was associated with an increased risk of cholecystitis, especially in patients of advanced age or in those who were exposed to the drugs for a long period of time.

Project description:Thiazide diuretics are commonly used antihypertensive agents. Until today, whether their use reduces fracture risk remains unclear. Our objective was to conduct a systematic review of thiazide diuretics' effects on fractures and bone mineral density (BMD) in randomized clinical trials (RCT) of adults. MEDLINE, EMBASE, CENTRAL, and the WHO's ICTRP registry were searched from inception to July 31, 2019. Two reviewers assessed studies for eligibility criteria: (i) RCTs; (ii) including adults; (iii) comparing thiazides, alone or in combination; (iv) to placebo or another medication; and (v) reporting fractures or BMD. Conference abstracts and studies comparing thiazides to antiresorptive or anabolic bone therapy were excluded. Bias was assessed using Cochrane Collaboration's Risk of Bias Tool-2. The primary outcome was fracture at any anatomical site. Secondary outcomes were osteoporotic fractures, hip fractures, and BMD at femoral neck, lumbar spine, and/or total hip. Fractures were pooled as risk ratios (RRs) using random-effect models. Prespecified subgroup analyses and post hoc sensitivity analyses were conducted. From 15,712 unique records screened, 32 trials (68,273 patients) met eligibility criteria. Thiazides were associated with decreased fractures at any site (RR = 0.87, 95% confidence interval [CI] 0.77-0.98; I 2 = 0%) and osteoporotic fractures (RR = 0.80; 95% CI 0.69-0.94; I 2 = 0%). Results were consistent in most subgroups and sensitivity analyses. Few studies reported hip fractures, and no association was found between thiazides and this outcome (RR = 0.84; 95% CI 0.67-1.04; I 2 = 0%). Only four studies reported BMD; a meta-analysis was not conducted because BMD reporting was inconsistent. Trials were deemed at low (3 studies, weight = 3%), some concerns (16 studies; 71%), or high (11 studies; 26%) risk of bias for the primary outcome. In conclusion, thiazide diuretics decreases the risk of fractures at any and at osteoporotic sites in a meta-analysis of RCTs. Additional studies are warranted in patients with high fracture risk. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Dipeptidyl peptidase-4 inhibitors and fracture risk: an updated meta-analysis of randomized clinical trials.

Publications

Dipeptidyl peptidase-4 inhibitors and fracture risk: an updated meta-analysis of randomized clinical trials.

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