Risk of dipeptidyl peptidase‐4 (DPP‐4) inhibitors on site‐specific cancer: A systematic review and meta‐analysis

Overbeek, Jetty A.; Bakker, Michael den; Heijden, Amber A. W. A. van der; Herk‐Sukel, Myrthe P. P. van; Herings, Ron M. C.; Nijpels, Giel

doi:10.1002/dmrr.3004

Cited by 55 publications

(33 citation statements)

References 53 publications

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“…The interest in the incident malignancy with DPP-4 inhibitor use received its attention when 223 cases of pancreatic cancer were reported from sitagliptin use in Food and Drug Administration Adverse Event Reporting System (FAERS) from 2007 to 2011 36. Nonetheless, a large number of studies including meta-analyses revealed no increased risk of site-specific malignancy with DPP-4 inhibitors 22,37–40. In accordance with the previous results, this study also displayed the evidence of low risk for malignancy with DPP-4 inhibitors in T2DM patients.…”

Section: Discussionsupporting

confidence: 91%

<p>Incident cancer risk in dipeptidyl peptidase-4 inhibitor-treated patients with type 2 diabetes mellitus</p>

Choi

Kim

Shin

2019

CMAR

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Objective It is known that patients with diabetes are susceptible to cancer development due to long-standing diabetic conditions. This study aimed to investigate new-onset cancer risk associated with dipeptidyl peptidase-4 (DPP-4) inhibitors as compared to metformin, the first-line antidiabetic agent with promising anticancer activity, in patients with type 2 diabetes mellitus (T2DM). Methods A retrospective cohort study of adult T2DM patients was performed at a tertiary care hospital in Korea. Patients who received comparison therapies during 2008–2017 were propensity score (PS)-matched in a 1:1 ratio either to the DPP-4 inhibitors group or to the metformin group in accordance with their primary antidiabetic therapy. Results A total of 1538 patients (769 in each group) were found eligible for study entry. Although the rate of newly diagnosed malignancy, irrespective of specific sites or types, was numerically less frequent in the DPP-4 inhibitors group, the difference in overall cancer risk between groups was not statistically significant (HR=1.00, 95% CI=0.56–1.80, P =0.998). The PS-matched patients were further stratified by relevant patient factors and diabetes severity. No signal of increased risk of malignant complications among DPP-4 inhibitor-receiving diabetic patients was detected in any of the individual strata, nor in the subgroup patients where insulin-exposed patients were excluded from study analyses in consideration of its carcinogenic properties. Patient death or incident pancreatitis events were seldom encountered in both treatment groups; hence such risks were assessed as negligible with the use of either antidiabetic therapy. Conclusion This PS-matched cohort study demonstrated no elevated risk of malignant complications with DPP-4 inhibitor treatment relative to metformin treatment among T2DM patients, irrespective of patient sex, age, comorbid conditions, and diabetes severity status. Similar results were confirmed in the subgroup analyses where a potential confounding effect due to the between-group disparity in insulin co-therapy was eliminated by excluding insulin-exposed patients from risk assessments.

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Section: Discussionsupporting

confidence: 91%

<p>Incident cancer risk in dipeptidyl peptidase-4 inhibitor-treated patients with type 2 diabetes mellitus</p>

Choi

Kim

Shin

2019

CMAR

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“…Research about dipeptidyl peptidase-4 (DPP-4) inhibitors, which function via a similar mechanism as GLP-1 receptor agonists, failed to verify an association between the use of these drugs and an increased risk of site-specific cancer, and this was attributed to the small number of studies for each cancer type and their relatively short duration [50]. Another meta-analysis published in 2017 that included four large-scale studies indicated that GLP-1 receptor agonists did not increase the risk of pancreatic cancer [51], and our study further demonstrated that GLP-1 receptor agonist therapy was not associated with an increased risk of any of the malignant neoplasms studied.…”

Section: Discussionmentioning

confidence: 99%

Risk of Malignant Neoplasia with Glucagon-Like Peptide-1 Receptor Agonist Treatment in Patients with Type 2 Diabetes: A Meta-Analysis

Liu

Zhang

Chai

et al. 2019

Journal of Diabetes Research

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Background. Glucagon-like peptide-1 (GLP-1) receptor agonists are effective glucose-lowering drugs, but there is concern that they may increase the risk of malignant neoplasia. The present meta-analysis examined the safety of GLP-1 receptor agonists with regard to malignant neoplasia. Methods. We analyzed data from randomized controlled trials with a minimum duration of 24 weeks that assessed the incidence of neoplasms in type 2 diabetes patients receiving GLP-1 receptor agonists compared with placebo or other hypoglycemic drugs. We searched the MEDLINE, Embase, and Cochrane databases with a language restriction of English through October 1, 2018, and carried out a meta-analysis of the available trial data using a fixed effects model to calculate odds ratios (ORs) for neoplasia. Results. Thirty-four relevant articles, providing data for 50452 patients, were included in the meta-analysis. Compared with the incidence of malignant neoplasia with placebo or other interventions, no increase in malignant neoplasm formation was observed with the use of GLP-1 receptor agonists (OR 1.04, 95% confidence interval (CI) 0.94–1.15; p=0.46), liraglutide (OR 1.08, 95% CI 0.91–1.27; p=0.38), exenatide (OR 1.00, 95% CI 0.86–1.16; p=1.00), semaglutide (OR 0.89, 95% CI 0.35–2.22; p=0.80), or albiglutide (OR 1.07, 95% CI 0.23–4.88; p=0.93). A subanalysis of trials lasting longer than 3 years also showed no increase in the neoplasia risk with GLP-1 receptor agonist use (OR 1.03, 95% CI 0.92–1.15; p=0.60). Between-trial statistical heterogeneity was low for all comparisons. Conclusion. GLP-1 receptor agonists can be used without safety concerns related to malignant neoplasia in patients with type 2 diabetes.

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“…However, later years did not confirm these findings. Meta-analysis of site-specific cancers associated with DPP-4 inhibitors use in 12 RCTs and 13 observational studies did not reveal elevated cancer risk in DPP-4 inhibitors' users [103]. The most recent meta-analysis of 157 RCTs, performed by Dicembrini and colleagues, revealed neutral effect of DPP-4 inhibitors on overall cancer risk, irrespective of molecule studied and cancer site, with the exception of colorectal cancer, in which DPP-4 inhibitors use was associated with its significantly reduced risk [104].…”

Section: Dipeptidil-peptidase-4 Inhibitorsmentioning

confidence: 86%

“…The associations between incretin-based therapies and cancer are still not fully elucidated. Although there are some concerns regarding DPP-4 inhibitors and breast cancer and its metastasis risk, it seems that both DPP-4 inhibitors and GLP-1 receptor agonists can be considered neutral, or even beneficial (decreased risk of colorectal cancer in case of DPP-4 inhibitors) [99][100][101][102][103][104][105][106][107][108]. Hopes associated with GLP-1 receptors agonists use in terms of cancer risk were not confirmed, despite their beneficial effect on glycemia, body weight, blood pressure, liver steatosis and insulin sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Diabetes, Antidiabetic Medications and Cancer Risk in Type 2 Diabetes: Focus on SGLT-2 Inhibitors

Dąbrowski

2021

IJMS

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In the last decade, cancer became the leading cause of death in the population under 65 in the European Union. Diabetes is also considered as a factor increasing risk of cancer incidence and mortality. Type 2 diabetes is frequently associated with being overweight and obese, which also plays a role in malignancy. Among biological mechanisms linking diabetes and obesity with cancer hyperglycemia, hyperinsulinemia, insulin resistance, increased levels of growth factors, steroid and peptide hormones, oxidative stress and increased activity of pro-inflammatory cytokines are listed. Antidiabetic medications can modulate cancer risk through directly impacting metabolism of cancer cells as well as indirectly through impact on risk factors of malignancy. Some of them are considered beneficial (metformin and thiazolidinedions—with the exception of bladder cancer); on the other hand, excess of exogenous insulin may be potentially harmful, while other medications seem to have neutral impact on cancer risk. Inhibitors of the sodium-glucose cotransporter-2 (SGLT-2) are increasingly used in the treatment of type 2 diabetes. However, their association with cancer risk is unclear. The aim of this review was to analyze the anticancer potential of this class of drugs, as well as risks of site-specific malignancies associated with their use.

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Risk of dipeptidyl peptidase‐4 (DPP‐4) inhibitors on site‐specific cancer: A systematic review and meta‐analysis

Cited by 55 publications

References 53 publications

<p>Incident cancer risk in dipeptidyl peptidase-4 inhibitor-treated patients with type 2 diabetes mellitus</p>

<p>Incident cancer risk in dipeptidyl peptidase-4 inhibitor-treated patients with type 2 diabetes mellitus</p>

Risk of Malignant Neoplasia with Glucagon-Like Peptide-1 Receptor Agonist Treatment in Patients with Type 2 Diabetes: A Meta-Analysis

Diabetes, Antidiabetic Medications and Cancer Risk in Type 2 Diabetes: Focus on SGLT-2 Inhibitors

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