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. 2016 Dec;7(4):725-742.
doi: 10.1007/s13300-016-0198-3. Epub 2016 Sep 21.

Incretin-Based Therapy and Risk of Pancreatic Cancer in Patients With Type 2 Diabetes Mellitus: A Meta-analysis of Randomized Controlled Trials

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Free PMC article

Incretin-Based Therapy and Risk of Pancreatic Cancer in Patients With Type 2 Diabetes Mellitus: A Meta-analysis of Randomized Controlled Trials

Han Chen et al. Diabetes Ther. .
Free PMC article

Abstract

Introduction: The present study aims to evaluate the risk of pancreatic cancer with incretin-based therapy among patients with type 2 diabetes mellitus (T2DM).

Methods: We searched EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for eligible studies published up to March 06 2016. This meta-analysis includes all studies reporting adverse events of pancreatic cancer with use of incretin-based therapies compared with placebo or non-incretin anti-diabetic drugs in patients with T2DM. We used fixed-effect model to compare pooled relative risk (RR) with related 95% confidence intervals (CI).

Results: A total of 159 randomized trials were identified. Out of these, 135 studies were excluded as pancreatic cancer occurrence had not been included as an end point. The remaining 24 trials enrolling 47,904 participants were further assessed. Overall, no increased risk of pancreatic cancer were detected in association with incretin-based treatment (RR = 0.7, 95% CI 0.37-1.05). The incidence of pancreatic neoplasm was even lower among incretin-based groups than controls (RR = 0.50, 95% CI 0.29-0.87) in trials with duration more than 104 weeks. There was even decreased risk of pancreatic cancer within groups paralleled by incretin-matched placebos (RR = 0.55, 95% CI 0.32-0.93) than by non-incretin anti-diabetic drugs. Neither monotherapy (RR = 0.62, 95% CI 0.38-1.01) nor combination regimen (RR = 0.92, 95% CI 0.45-1.90) of incretin mimetics increased the risk of pancreatic cancer.

Conclusion: This meta-analysis shows that incretin-based therapies are not associated with increase in the risk of pancreatic cancer. Interestingly, subgroup analyses suggested lower risk of pancreatic cancer in incretin groups than placebo in long-term studies (>104 weeks). Considering the inconsistent results among randomized trials and previous epidemiological investigations, more such studies should be conducted to clarify the existence or non-existence of this association.

Funding: This work was supported by grants from the National Natural Science Foundation of China (Nos. 81270476 and 81470830).

Keywords: Anti-diabetic drug; Incretin-based therapy; Meta-analysis; Pancreatic cancer; Type 2 diabetes.

Figures

Fig. 1
Fig. 1
Flow chart. A total of 159 randomized controlled trials were identified. Of these, 135 did not disclose their results or did not report any adverse events of pancreatic cancer. The remaining 24 trials were finally assessed. T2DM type 2 diabetes mellitus
Fig. 2
Fig. 2
Risk of bias graph a reviewer’s judgments about each risk of bias item presented as percentages across all included studies. b Risk of bias summary: reviewer’s judgments about each risk of bias item in each study. (+) low risk of bias, (?) unclear, (−) high risk of bias
Fig. 3
Fig. 3
Funnel plot analysis of 24 studies. Statistical analysis confirmed no evidence of publication bias. RR relative risk
Fig. 4
Fig. 4
Forest plot of incretin-based therapy vs. placebo/NIADs on pancreatic cancer risks. A fixed-effect model was used. No heterogeneity was shown among the studies (I-squared = 0.0%, P = 0.943). There were no increased risks of pancreatic neoplasms associated with incretin-based treatment than control groups (pooled RR = 0.7, 95% CI 0.47–1.05, P = 0.083), irrespective of different types of incretin drugs (GLP-1 receptor agonists: pooled RR = 0.58, 95% CI 0.26–1.33. P = 0.198; DPP-4 inhibitors: pooled RR = 0.74, 95% CI 0.46–1.18, P = 0.210). The triangles represent individual studies and the size of the triangle represents the weight given to each study in the meta-analysis. The diamond represents the combined results. NIDAs incretin-based anti-diabetic drugs, RR relative risk, CI confidence interval, GLP glucagon-like peptide, DPP-4 dipeptidyl peptidase-IV
Fig. 5
Fig. 5
Forest plot of subgroup analysis. a trial duration: within study groups in which trial duration exceeded 104 weeks, there was lower incidence of pancreatic neoplasms in incretin-based groups than those in placebo or NIADs ones (pooled RR = 0.50, 95% CI 0.29–0.87, P = 0.014). No significant difference was detected in risks of pancreatic cancer among trials less than 52 weeks (pooled RR = 1.26, 95% CI 0.54–2.98, P = 0.593) and those with trial duration range from 52 to 104 weeks (pooled RR = 0.93, 95% CI 0.37–2.34, P = 0.879). NIDAs incretin-based anti-diabetic drugs, RR relative risk, CI confidence interval. b Incretin-based medication versus placebo or other anti-diabetic drugs: decreased risks of pancreatic cancer were identified in intervention studies controlled with incretin-matched placebos than those setting non-incretin-based anti-diabetic drugs as control (pooled RR = 0.55, 95% CI 0.32–0.93, P = 0.025). RR relative risk, CI confidence interval. c Incretin-based monotherapy versus combination regimen: incretin mimetics used as either monotherapy (pooled RR = 0.62, 95% CI 0.38–1.01, P = 0.055) or combination regimen (pooled RR = 0.92, 95% CI 0.45–1.90, P = 0.828) did not increase risks of pancreatic cancer than non-incretin-based anti-diabetic drugs (NIADs) or placebos. RR relative risk, CI confidence interval, NIDAs incretin-based anti-diabetic drugs. d Pancreatic cancer as principal outcome or not: studies that considered the incidence of pancreatic cancer to be one of the principal outcome variables did not show an increased risk of pancreatic cancer (pooled RR = 1.17, 95% CI 0.62–2.19, P = 0.630), whereas studies reporting pancreatic cancer events as non-principal outcome (pooled RR = 0.48, 95% CI 0.28–0.84, P = 0.010). RR relative risk, CI confidence interval
Fig. 5
Fig. 5
Forest plot of subgroup analysis. a trial duration: within study groups in which trial duration exceeded 104 weeks, there was lower incidence of pancreatic neoplasms in incretin-based groups than those in placebo or NIADs ones (pooled RR = 0.50, 95% CI 0.29–0.87, P = 0.014). No significant difference was detected in risks of pancreatic cancer among trials less than 52 weeks (pooled RR = 1.26, 95% CI 0.54–2.98, P = 0.593) and those with trial duration range from 52 to 104 weeks (pooled RR = 0.93, 95% CI 0.37–2.34, P = 0.879). NIDAs incretin-based anti-diabetic drugs, RR relative risk, CI confidence interval. b Incretin-based medication versus placebo or other anti-diabetic drugs: decreased risks of pancreatic cancer were identified in intervention studies controlled with incretin-matched placebos than those setting non-incretin-based anti-diabetic drugs as control (pooled RR = 0.55, 95% CI 0.32–0.93, P = 0.025). RR relative risk, CI confidence interval. c Incretin-based monotherapy versus combination regimen: incretin mimetics used as either monotherapy (pooled RR = 0.62, 95% CI 0.38–1.01, P = 0.055) or combination regimen (pooled RR = 0.92, 95% CI 0.45–1.90, P = 0.828) did not increase risks of pancreatic cancer than non-incretin-based anti-diabetic drugs (NIADs) or placebos. RR relative risk, CI confidence interval, NIDAs incretin-based anti-diabetic drugs. d Pancreatic cancer as principal outcome or not: studies that considered the incidence of pancreatic cancer to be one of the principal outcome variables did not show an increased risk of pancreatic cancer (pooled RR = 1.17, 95% CI 0.62–2.19, P = 0.630), whereas studies reporting pancreatic cancer events as non-principal outcome (pooled RR = 0.48, 95% CI 0.28–0.84, P = 0.010). RR relative risk, CI confidence interval

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