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Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials.

ABSTRACT: OBJECTIVE: Thiazolidinediones and insulin are associated with a higher risk of fractures in type 2 diabetic patients. Incretin hormones increase bone density in experimental models, but the effect of dipeptidyl peptidase-4 (DPP-4) inhibitors on bone fractures has not been reported so far. RESEARCH DESIGN AND METHODS: A meta-analysis was performed including all randomized clinical trials with a duration of at least 24 weeks, enrolling patients with type 2 diabetes, comparing DPP-4 inhibitors with placebo or active drugs. RESULTS: Twenty-eight trials enrolling 11,880 and 9,175 patients for DPP-4 inhibitors and comparators, respectively, were included, reporting 63 fractures. DPP-4 inhibitors, compared with placebo or other treatments, were associated with a reduced risk of fractures (Mantel-Haenszel odds ratio [MH-OR] 0.60, 95% CI 0.37-0.99, P = 0.045), even after the exclusion of comparisons with thiazolidinediones or sulfonylureas (MH-OR 0.56, 0.33-0.93, P = 0.026). CONCLUSIONS: The present meta-analysis suggests that treatment with DPP-4 inhibitors could be associated with a reduced risk of bone fractures.

SUBMITTER: Monami M

PROVIDER: S-EPMC3198283 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials.

Monami Matteo M Dicembrini Ilaria I Antenore Alessandro A Mannucci Edoardo E

Diabetes care 20111101 11

<h4>Objective</h4>Thiazolidinediones and insulin are associated with a higher risk of fractures in type 2 diabetic patients. Incretin hormones increase bone density in experimental models, but the effect of dipeptidyl peptidase-4 (DPP-4) inhibitors on bone fractures has not been reported so far.<h4>Research design and methods</h4>A meta-analysis was performed including all randomized clinical trials with a duration of at least 24 weeks, enrolling patients with type 2 diabetes, comparing DPP-4 in ...[more]

PMID: 22025784

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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:The 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.We 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.We 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%.Alogliptin 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:Background: Acarbose and dipeptidyl peptidase-4 inhibitors (DPP-4is) have several similarities regarding their efficacy. Assessing the hypoglycemic and weight-loss effects, as well as the tolerability between them at their optimal dosages, could provide a better management of adult type 2 diabetics. Methods: We performed a systematic review and network meta-analysis (NMA) on randomized controlled trials that were identified from the databases of EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, Conference Proceedings Citation Index, ClinicalTrials.gov, China National Knowledge Infrastructure, Wan Fang, and SinoMed. The trials with 300 mg/day of acarbose or the recommended doses of DPP-4is were the most optimal for our NMA. The mean differences (MD) and relative risk (RR) derived from eligible studies were used. Results: Among the 15,411 obtained potential studies, 13 pair-wise trials and 48 monotherapy studies were included in the meta-analysis and NMA, respectively. DPP-4is had a greater glucose-lowering effect, but a weaker weight-loss effect than acarbose in pair-wise meta-analysis (p < 0.05). However, NMA with 11,877 participants showed that, at their optimal doses, acarbose and DPP-4is had similar glucose-lowering effects on the 2-h postprandial glucose (MD 0.96 mmol/L, 95% credible interval -0.56 to 2.54), HbA1c (0.05%, -0.25 to 0.33), fasting plasma glucose reductions (-0.27 mmol/L, -0.76 to 0.24), and HbA1c < 7.0% target goal achievement (RR 1.33, 0.51 to 3.64). Acarbose was superior to DPP-4is regarding weight loss (MD -1.23 kg, -2.08 to -0.33). Acarbose had more withdrawal, gastrointestinal, and overall adverse events than DPP-4is (p < 0.05), but the differences disappeared after longer treatment (p > 0.05). Conclusions: Acarbose and DPP-4is have similar glucose-lowering effects, but the weight-loss effects of acarbose are superior. Therefore, in the use of the most optimal dosages, overweight/obese type 2 diabetics might benefit more from a treatment with acarbose than DPP-4is.

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.

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Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials.

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Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials.

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