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. 2016 Jul 7;6:29104. doi: 10.1038/srep29104

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

Jianying Fu 1,*, Jianhong Zhu 2,*, Yehua Hao 1, Chongchong Guo 1, Zhikun Zhou 1,a
PMCID: PMC4935882  PMID: 27384445

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 Electronic databases were searched for relevant published articles, and unpublished studies presented at ClinicalTrials.gov were searched for relevant clinical data.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.

Type 2 diabetes is a highly prevalent disease, especially in elderly and obese patients. Cumulative evidence shows that type 2 diabetes is associated with an increased risk of bone fracture1,2. Several anti-diabetes drugs have been reported to increase the incidence of fractures3,4.

Dipeptidyl peptidase-4 (DPP-4) inhibitors, a class of incretin based agents for the treatment of type 2 diabetes, have intermediate efficacy regarding glucose control with a satisfactory tolerability profile5,6,7. Data on the effects of DPP-4 inhibitors on fracture risk are conflicting. A meta-analysis of randomized controlled trials (RCTs) suggested that DPP-4 inhibitors reduced the risk of bone fracture8. However, a recent retrospective population-based cohort study concluded that DPP-4 inhibitors were not associated with fracture risk compared with controls and other non-insulin anti-diabetic drugs (NIADs)9.

The association between DPP-4 inhibitors and the risk of fracture in patients with type 2 diabetes has not been well established. We therefore performed a meta-analysis of randomized trials to provide a more robust answer regarding the risk of fracture in patients with type 2 diabetes treated with DPP-4 inhibitors.

Results

Search results

A total of 3092 unique titles and abstracts were identified in initial searches of the electronic database. After screening titles and abstracts, we retrieved 343 reports for full text screening. A total of 62 RCTs, including 13 from journals10,11,12,13,14,15,16,17,18,19,20,21,22,23 and 49 from the trial registry (available from https://clinicaltrials.gov) were included in the final analysis. The details of the study selection flow are described in Fig. 1.

Figure 1. Trial flow diagram.

Figure 1

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Study characteristics

The baseline characteristics of trials are included in Table 1 and the quality assessment results are listed in Table S1. A total of 62,206 patients (33,452 in the experimental group and 28,754 in the control group) were included in this analysis, of which 722 had fractures (364 in the experimental group and 358 in the control group). The age of the included patients ranged from 49.7 to 74.9 years. The inhibitors tested in the trials were alogliptin in 7, linagliptin in 13, saxagliptin in 9, sitagliptin in 27, anagliptin in 1, and vildagliptin in 5. The duration of treatment ranged from 12 weeks to 40 months. Forty-three trials were placebo-controlled and 28 used an active comparator, while nine trials included both placebo and active comparator arms. Active comparators included albiglutide, canagliflozin, empagliflozin, glipizide, glimepiride, metformin, voglibose, or thiazolidinediones. Of the 62 trials included in the meta-analysis, 61 were double blind trials.

Table 1. Characteristics of studies included in primary analysis.

Study NCT code DPP-4 Comparator(s) N. of patients Duration (weeks) Age (years) HbA1c (%) Fracture
DPP-4 Control DPP-4 Control
Bosi10 NCT00432276 ALOG Pioglitazone 404 399 52 55 8.3 6 4
NCT00286468 NCT00286468 ALOG Placebo 401 99 26 57 8 1 0
NCT01023581 NCT01023581 ALOG Placebo/metformin 450 334 26 53.5 8.5 0 1
NCT00856284 NCT00856284 ALOG Glipizide 1765 874 104 55.4 7.6 6 4
NCT00328627 NCT00328627 ALOG Placebo/pioglitazone 1037 517 26 54.4 8.6 0 1
NCT00707993 NCT00707993 ALOG Glipizide 222 219 52 69.9 NR 2 1
White11 NCT00968708 ALOG Placebo 2701 2679 40 months 60.9 8 38 50
NCT01183013 NCT01183013 LINA Placebo 392 409 54 57.1 8.11 1 0
NCT00915772 NCT00915772 LINA Placebo/metformin 171 170 54 55.8 7.5 1 1
NCT00798161 NCT00798161 LINA Placebo/metformin 428 363 24 55.2 8.91 1 1
NCT01438814 NCT01438814 LINA Placebo 344 345 14 53 NR 0 1
NCT00601250 NCT00601250 LINA Placebo 523 177 24 56.5 8.08 2 0
NCT01084005 NCT01084005 LINA Placebo 162 79 24 74.9 7.78 2 0
NCT00954447 NCT00954447 LINA Placebo 631 630 52 60 8.3 6 5
NCT00602472 NCT00602472 LINA Placebo 792 263 24 58.1 8.14 3 0
NCT00800683 NCT00800683 LINA Placebo 68 65 52 64.4 8.2 2 0
NCT00621140 NCT00621140 LINA Placebo 336 167 24 55.7 8 1 2
NCT01204294 NCT01204294 LINA Metformin 228 124 52 60.9 NR 1 0
NCT01215097 NCT01215097 LINA Placebo 205 100 24 55.5 7.99 1 0
Barnett12 NCT01084005 LINA Placebo 162 79 24 74.9 7.78 2 0
Barnett13 NCT00757588 SAXA Placebo 304 151 52 57.2 8.7 2 3
Hollander14 NCT00295633 SAXA Placebo 381 184 24 54 8 5 1
Scirica15 NCT01107886 SAXA Placebo 8280 8212 2.9 years 65 NR 241 240
NCT01006603 NCT01006603 SAXA Glimepiride 359 359 52 72.6 NR 4 1
NCT00121667 NCT00121667 SAXA Placebo 564 179 206 54.57 8.1 4 0
NCT00575588 NCT00575588 SAXA Glipizide 428 430 52 57.55 7.7 4 2
NCT00614939 NCT00614939 SAXA Placebo 85 85 52 66.5 NR 0 1
NCT00327015 NCT00327015 SAXA Placebo/metformin 643 328 76 52 9.5 3 0
NCT00661362 NCT00661362 SAXA Placebo 283 287 24 54 7.9 3 0
NCT00509236 NCT00509236 SITA Glipizide 64 65 54 59.5 NR 2 0
NCT01076088 NCT01076088 SITA Placebo/metformin 367 377 24 52.7 8.7 0 3
NCT00509262 NCT00509262 SITA Glipizide 211 212 54 64.2 7.8 1 1
NCT01076075 NCT01076075 SITA Pioglitazone 210 212 54 54.9 8.4 0 1
NCT00885352 NCT00885352 SITA Placebo 157 156 26 56.1 8.7 0 1
NCT00395343 NCT00395343 SITA Placebo 322 319 24 57.8 8.7 1 0
NCT00722371 NCT00722371 SITA Placebo/pioglitazone 691 693 54 57 NR 3 1
NCT01462266 NCT01462266 SITA Placebo 329 329 24 58.8 NR 0 1
NCT00305604 NCT00305604 SITA Placebo 102 104 24 71.9 7.8 0 2
NCT00411554 NCT00411554 SITA Voglibose 163 156 12 60.7 7.8 0 1
NCT00103857 NCT00103857 SITA Placebo/ metformin 372 540 104 53.4 9 1 3
NCT01177813 NCT01177813 SITA Empagliflozin 223 448 31 55 NR 0 1
NCT00449930 NCT00449930 SITA Metformin 528 522 24 56 7.3 1 0
NCT00701090 NCT00701090 SITA Glimepiride 516 519 30 56.3 7.5 2 1
NCT00086515 NCT00086515 SITA Glipizide 464 237 24 54.5 8 0 1
NCT01098539 NCT01098539 SITA Albiglutide 246 249 26 63.3 NR 0 2
NCT00086502 NCT00086502 SITA Placebo 175 178 24 56.2 8 0 1
NCT00094770 NCT00094770 SITA Glipizide 588 584 104 56.7 7.7 3 3
NCT01289990 NCT01289990 SITA Placebo/empagliflozin 223 223 76 55.6 NR 0 2
NCT00482729 NCT00482729 SITA Placebo 625 621 44 49.7 9.87 1 2
NCT00397631 NCT00397631 SITA Placebo 261 259 24 50.9 9.5 1 0
NCT01106677 NCT01106677 SITA Canagliflozin 366 735 52 55.4 NR 0 1
NCT01137812 NCT01137812 SITA Canagliflozin 378 377 52 56.5 NR 1 2
NCT01106690 NCT01106690 SITA Canagliflozin 115 227 52 57.4 NR 0 2
NCT00881530 NCT00881530 SITA Placebo 56 56 78 58.6 NR 0 1
Iwamoto16 NR SITA Voglibose 163 156 12 60.7 7.8 0 1
Raz17 NCT00337610 SITA Placebo 96 94 30 54.8 9.2 0 1
Bosi18 NCT00468039 NCT00382096 VILDA Placebo 292 292 24 52.8 8.65 1 0
Fonseca19 NCT00099931 VILDA Placebo 144 152 24 59.2 8.4 0 1
Iwamoto20 NR VILDA Voglibose 188 192 12 60.3 7.5 0 2
Pan21 NR VILDA Placebo 294 144 24 54.2 8.05 1 0
Scherbaum22 NCT00101712 VILDA Placebo 156 155 52 63.3 6.7 0 1
Yang23 NR ANAG Placebo 60 48 24 56.2 7.14 3 0
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ALOG, alogliptin; LINA, linagliptin; SAXA, saxagliptin; SITA, sitagliptin; VILDA, vildagliptin; ANAG, anagliptin;NR, nor reported.

Risk ratio of fracture

A meta-analysis was performed to calculate the overall risk ratio (RR) of fracture associated with DPP-4 inhibitors versus control. Analysis of 62 trials showed that DPP-4 inhibitors were not associated with a significantly increased risk of fracture. The RR of fracture for patients treated with DPP-4 inhibitors compared with that for controls was 0.95 [95% confidence interval (CI) 0.83–1.10, P = 0.50), with insignificant heterogeneity (I2 = 0%) (Fig. 2). The evidence quality was moderate to high (Table S2).

Figure 2. Risk of fractures between patients with type 2 diabetes treated with DPP-4 inhibitors or control.

Figure 2

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Subgroup analysis according to drug type

Subgroup analysis was performed to determine whether drug type had an effect on the RR of fracture with DPP-4 inhibitors. The RR of fracture with individual DPP-4 inhibitors was 0.79 (95% CI: 0.55–1.13, P = 0.19) for alogliptin (seven trials with 12,085 individuals, enrolling 53 patients with fracture in the experimental group and 61 patients with fracture in the control group), 1.25 (0.66–2.38, P = 0.50) for linagliptin (13 trials with 7638 individuals, enrolling 23 patients with fracture in the experimental group and 10 patients with fracture in the control group), 1.03 (0.87–1.22, P = 0.73) for saxagliptin (nine trials with 21,877 individuals, enrolling 266 patients with fracture in the experimental group and 248 patients with fracture in the control group), 0.66 (0.41–1.06, P = 0.08) for sitagliptin (27 trials with 17,907 individuals, enrolling 17 patients with fracture in the experimental group and 35 patients with fracture in the control group), 4.16 (0.22–78.51, P = 0.34) for anagliptin (one trial with 108 individuals, enrolling three patients with fracture in the experimental group and 0 patients with fracture in the control group) and 0.47 (0.13–1.78, P = 0.27) for vildagliptin (five trials with 2591 individuals, enrolling two patients with fracture in the experimental group and four patients with fracture in the control group). There were no statistically significant differences in the risk of fracture between individual DPP-4 inhibitors (P = 0.22) (Table 2). The evidence quality was moderate to high (Table S2).

Table 2. Risk ratio of fracture by subgroup analyses.

Subgroup Studies n No. of fracture No. of participants Risk ratio (95% CI) P Value
DPP-4 Control DPP-4 Control RR Group difference
Overall Individual DPP-4 62 364 358 33452 28754 0.95 (0.82, 1.10) 0.50 NA
Alogliptin 7 53 61 6972 5113 0.79 (0.55, 1.14) 0.20 0.37
Linagliptin 13 23 10 4667 2971 1.19 (0.60, 2.38) 0.62  
Saxagliptin 9 266 248 11662 10215 1.02 (0.86, 1.21) 0.84  
Sitagliptin 27 17 35 8422 9485 0.67 (0.39, 1.15) 0.15  
Anagliptin 1 3 0 68 40 4.16 (0.22, 78.51) 0.34  
Vildagliptin 5 2 4 1661 930 0.50 (0.12, 2.05) 0.33  
Duration
 ≥52 weeks 28 332 330 21645 19996 0.97 (0.83, 1.13) 0.69 0.37
 <52 weeks 34 32 28 11807 8758 0.76 (0.46, 1.27) 0.29  
Comparators
 Active drug 28 24 35 7594 9179 0.91 (0.54, 1.52) 0.71 0.88
 Placebo 43 340 334 26235 21718 0.95 (0.81, 1.10) 0.44  
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NA, not applicable.

Subgroup analysis according to duration

Given the potential effect of duration of treatment on the association of DPP-4 inhibitors with risk of fracture, we performed a subgroup analysis stratified according to the length of follow-up. For a duration of ≥52 weeks with 41,641 participants, no statistically significant difference was observed between patients in the DPP4i and control groups (RR = 0.98, 95% CI, 0.84–1.13, P = 0.75), including 662 patients with fracture (332 in the experimental group and 330 in the control group). No significantly increased risk of fracture was observed for a duration of <52 weeks with 20,565 participants (RR = 0.78, 95% CI, 0.51–1.21, P = 0.28) including 60 patients with fracture (32 in the experimental group and 28 in the control group). There were no statistically significant differences in the risk of fracture according to the length of follow-up (P = 0.35) (Table 2). The evidence quality was moderate to high (Table S2).

Subgroup analysis according to control regimen

Investigation of the effect of inhibitors according to the type of control (active treatment vs. placebo) did not suggest apparent differences (P = 0.76). In trials using active drug for comparison with 16,773 participants, the RR was 0.88 (95% CI: 0.56–1.39, P = 0.58), including 59 patients with fracture (24 in the experimental group and 35 in the control group). In trials using placebo for comparison with 47,953 participants, the RR was 0.95 (95% CI: 0.82–1.10, P = 0.48), including 674 patients with fracture (340 in the experimental group and 334 in the control group) (Table 2). The evidence quality was moderate to high (Table S2).

Risk of specific fractures

Individual specific and non-specific fractures were listed in Table S3. There was no significant difference between the two groups in the incidence of specific fractures.

Publication bias

No evidence of publication bias was detected for the RR of fracture in this study (Figure S1).

Discussion

The effects of DPP-4 inhibitors on bone fractures in type 2 diabetes patients have not been well documented. Here, we performed an updated meta-analysis to provide a summary of current data. Analysis of 62 RCTs demonstrated that the use of DPP-4 inhibitors does not affect the risk of bone fracture compared with placebo or other antidiabetic medications in patients with type 2 diabetes. The results were consistent across subgroups defined by type of DPP-4 inhibitor, type of control, and length of follow-up.

Our results were in line with a recently published retrospective population-based cohort study that examined 216,816 patients and suggested that DPP-4 inhibitors were not associated with fracture risk compared with controls or other NIADs9. Our study was inconsistent with that of Monami et al.8, which showed a 40% reduction of fracture risk in DPP4-I users compared with patients taking other anti-diabetic drugs or placebo24,25,26. However, the positive effect observed in this study could be related to the limited number of trials included in the analysis. Compared with the study by Monami et al.8, our study has several strengths. First, we collected data from 62 randomized trials (N = 62,206), which together involved approximately three times as many patients as those included in the study by Monami et al. (N = 21,055)8. Second, we explored sources of heterogeneity with three priori subgroup hypotheses and the results remained robust.

Out results were largely influenced by a large RCT (N = 16,492) that compared saxagliptin with placebo and showed that the incidence of bone fracture was comparable between saxagliptin and placebo users16. However, the results remained robust after omitting that trial.

Glucagon-like peptide-1 (GLP-1) has been suggested to have a beneficial effect on bone27,28. The enzyme DPP-4 is involved in the degradation of GLP-1, and DPP-4 inhibitors are able to inhibit this process9. However, a recent meta-analysis highlighted that the use of GLP-1 receptor agonists does not modify the risk of bone fracture in patients with type 2 diabetes compared with the use of other antidiabetic medications29. Moreover, a recent in vivo study showed that MK-0626, a DPP-4 inhibitor, had neutral effects on cortical and trabecular bone in an animal model of type 2 diabetes, and MK-0626 did not alter osteoblast differentiation30. Thus, bone quality may be more important than bone density in predicting the increased risk for fractures in patients with type 2 diabetes31.

The present meta-analysis had several limitations. First, the duration of the trials included was not long enough to analyze the effects of DPP-4 inhibitors on the risk of bone fracture. We performed a subgroup analysis according to duration (≥52 weeks vs. <52 weeks) and found that the risk of fracture in different length of follow up were not significantly different. Second, fractures were not the primary endpoints in any of the included trials and were reported only as serious adverse events. Finally, no data could be obtained about gender and menopausal status. Therefore, trials with a longer follow-up duration and bone fracture as the primary endpoint are needed to further investigate the effects of DPP-4 inhibitors on fracture risk.

In summary, the current analysis suggested that the use of DPP-4 inhibitor does not decrease the risk of fracture in patients with type 2 diabetes. Given the negative effects of certain anti-diabetic drugs on bone, the results of the present study may be disappointing; however, a neutral effect on bone is still reassuring.

Methods

Data Sources and Searches

An extensive search of Medline, Embase, and Cochrane Central Register of Controlled Trials was performed by two of the investigators (J.F. and J.Z.). Data were collected on all randomized clinical trials in humans up to March 2016. Discrepancies in abstracted data between the reviewers were resolved by a third reviewer (Z.Z.). The search terms used were as follows: “DPP-4”, “dipeptidyl peptidase 4”, “alogliptin”, “linagliptin”, “saxagliptin”, “sitagliptin”, “vildagliptin”, “anagliptin”, and “dutogliptin”. The results of unpublished data were identified through a search of the www.clinicaltrials.gov website.

Study Selection

The trials that met the following criteria were included in the analysis: (a) randomized clinical trials in type 2 diabetes patients; (b) duration of at least 12 weeks; (c) patients assigned to treatment with DPP-4 inhibitors compared with placebo or active drugs; (d) data on bone fracture was available; and (f) trials with two zero events were excluded from the analysis.

Data Extraction and Quality Assessment

The following information was extracted independently from eligible RCTs by two of the investigators (Y.H. and C.G.): author’s name, year of publication, study design, sample size, number of treatment groups, length of follow-up, mean age, and registry number. In addition, for trials in which fracture data had not been published previously, the investigators abstracted the relevant numbers from their previously established databases of adverse events. The quality of included trials was assessed using the Jadad score32, which was only used for descriptive purposes. Any discrepancies in abstracted data between the reviewers were resolved by a third reviewer (Z.Z.).

Data analysis

The meta-analysis was performed following the PRISMA checklist33. The main outcome was bone fracture reported as a serious adverse event. Trials were pooled using the Mantel-Haenszel method to calculate RRs and their 95% CIs. P < 0.05 was considered significant. For studies reporting zero fracture events in a treatment or control arm, a classic half-integer continuity correction was used to calculate the RR and variance. Heterogeneity between studies was assessed by using the χ2 test and the I2 statistic. Selection of the fixed- or random-effects model depended on the result of the Cochrane’s Q test. An I2 value of 50% was considered to indicate significant heterogeneity between trials34. A fixed effects model was applied if there was no statistical heterogeneity among the studies; otherwise, the random effects model was used34. Pre-defined subgroup analyses were performed for trials that included different types of DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin, anagliptin, and vildagliptin), different types of control (active treatment vs. placebo), and different lengths of follow-up (≥52 weeks vs. <52 weeks). Finally, publication bias was evaluated through funnel plots. Meta-analyses were performed using Review Manager 5.1 software. The criteria of the Grading of Recommendations Assessment, Development and Evaluation were used to evaluate the quality of evidence by outcome.35

Additional Information

How to cite this article: Fu, J. et al. Dipeptidyl peptidase-4 inhibitors and fracture risk: an updated meta-analysis of randomized clinical trials. Sci. Rep. 6, 29104; doi: 10.1038/srep29104 (2016).

Supplementary Material

Supplementary Information
srep29104-s1.pdf (131.2KB, pdf)

Acknowledgments

We acknowledge Dr. William B. White (Calhoun Cardiology Center, Department of Medicine, University of Connecticut School of Medicine) and Dr Neila Smith (Pharmacovigilence at Takeda Development Center) for providing additional data and substantial support. This study was supported by grants from National Natural Science Foundation of China (81273779). The funders had no role in the study design, writing of the manuscript, or decision to submit this or future manuscripts for publication.

Footnotes

Author Contributions J.F. and J.Z. wrote the manuscript text, searched the library and reviewed all articles, Y.H., C.G. and Z.Z. extracted data and evaluated the bias. All authors reviewed the manuscript.

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