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Risk of cancer in patients treated with dipeptidyl peptidase-4 inhibitors: an extensive meta-analysis of randomized controlled trials

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Abstract

Aims

Observational studies and meta-analyses of randomized trials on dipeptidyl peptidase-4 inhibitors (DPP4i) reported discordant results on the risk of malignancies with this class of drugs. Aim of the present meta-analysis is the assessment of the effect of DPP4i treatment on the incidence of different types of cancer, collecting all available evidence from randomized controlled trials.

Methods

An extensive MEDLINE, EMBASE, and Cochrane database search for sitagliptin or vildagliptin or omarigliptin or saxagliptin or alogliptin or trelagliptin or anagliptin or linagliptin or gemigliptin or evogliptin or teneligliptin was performed up to September 30th, 2019. All trials performed on type 2 diabetes, with duration ≥ 24 weeks, and comparing of DPP4i with placebo or active drugs were collected. The study has been registered on PROSPERO (#153344). Mantel–Haenszel odds ratio (MH-OR) with 95% confidence interval (95% CI) was calculated for all outcomes.

Results

A total of 157 eligible trials were identified. DPP-4i were not associated with an increased risk of overall cancer (MH-OR 0.93 [0.86, 1.00]; p = 0.07), with no significant differences across individual molecules of the class. When compared with placebo/none, a lower risk of cancer with DPP-4i was observed in placebo-controlled trials (MH-OR 0.90 [0.82, 0.99], p = 0.030), whereas no significant differences have been detected with any other comparators. DPP-4i was associated with a significant reduction in colorectal cancer (MH-OR 0.70 [0.53, 0.94], p = 0.020).

Conclusions

Available data do not support the hypothesis of an association of DPP4i treatment with malignancies, with a possible beneficial effect for colon-rectal cancer.

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References

  1. Koo DH, Han KD, Kim HJ, Park CY (2019) Middle-aged men with type 2 diabetes as potential candidates for pancreatic cancer screening: a 10-year nationwide population-based cohort study. Acta Diabetol [Epub ahead of print]

  2. Pasquale V, Dugnani E, Liberati D et al (2019) Glucose metabolism during tumorigenesis in the genetic mouse model of pancreatic cancer. Acta Diabetol 56:1013–1022

    Article  CAS  Google Scholar 

  3. Yang WS, Chen PC, Lin HJ et al (2017) Association between type 2 diabetes and cancer incidence in Taiwan: data from a prospective community-based cohort study. Acta Diabetol 54:455–461

    Article  CAS  Google Scholar 

  4. Monami M, Dicembrini I, Mannucci E (2014) Thiazolidinediones and cancer: results of a meta-analysis of randomized clinical trials. Acta Diabetol 51:91–101

    Article  CAS  Google Scholar 

  5. Monami M, Lamanna C, Balzi D, Marchionni N, Mannucci E (2009) Sulphonylureas and cancer: a case-control study. Acta Diabetol 46:279–284

    Article  CAS  Google Scholar 

  6. Rotella CM, Monami M, Mannucci E (2006) Metformin beyond diabetes: new life for an old drug. Curr Diabetes Rev 2:307–315

    Article  CAS  Google Scholar 

  7. Overbeek JA, Bakker M, van der Heijden A, van Herk-Sukel MPP, Herings RMC, Nijpels G (2018) Risk of dipeptidyl peptidase-4 (DPP-4) inhibitors on site-specific cancer: a systematic review and meta-analysis. Diabetes/Metab Res Rev 34:e3004

    Article  Google Scholar 

  8. Capuano A, Sportiello L, Maiorino MI, Rossi F, Giugliano D, Esposito K (2013) Dipeptidyl peptidase-4 inhibitors in type 2 diabetes therapy–focus on alogliptin. Drug Des Dev Ther 7:989–1001

    Google Scholar 

  9. Wang H, Liu X, Long M et al (2016) NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis. Sci Transl Med 8:334ra51

    Article  Google Scholar 

  10. Lee M, Sun J, Han M et al (2019) Nationwide trends in pancreatitis and pancreatic cancer risk among patients with newly diagnosed type 2 diabetes receiving dipeptidyl peptidase 4 inhibitors. Diabetes Care 42:2057–2064

    Article  Google Scholar 

  11. Abrahami D, Douros A, Yin H et al (2018) Incretin based drugs and risk of cholangiocarcinoma among patients with type 2 diabetes: population based cohort study. BMJ (Clin Res Ed) 363:k4880

    Article  Google Scholar 

  12. Noh Y, Jeon SM, Shin S (2019) Association between glucose-lowering treatment and cancer metastasis among patients with preexisting type 2 diabetes and incident malignancy. Int J Cancer 144:1530–1539

    Article  CAS  Google Scholar 

  13. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC (2011) Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 141:150–156

    Article  CAS  Google Scholar 

  14. Faillie JL, Azoulay L, Patenaude V, Hillaire-Buys D, Suissa S (2014) Incretin based drugs and risk of acute pancreatitis in patients with type 2 diabetes: cohort study. BMJ (Clin Res Ed) 348:g2780

    Google Scholar 

  15. Htoo PT, Buse JB, Gokhale M, Marquis MA, Pate V, Sturmer T (2016) Effect of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors on colorectal cancer incidence and its precursors. Eur J Clin Pharmacol 72:1013–1023

    Article  CAS  Google Scholar 

  16. Tseng CH (2017) Sitagliptin may reduce breast cancer risk in women with type 2 diabetes. Clin Breast Cancer 17:211–218

    Article  CAS  Google Scholar 

  17. Hicks BM, Yin H, Yu OH, Pollak MN, Platt RW, Azoulay L (2016) Glucagon-like peptide-1 analogues and risk of breast cancer in women with type 2 diabetes: population based cohort study using the UK Clinical Practice Research Datalink. BMJ (Clin Res Ed) 355:i5340

    Google Scholar 

  18. Amritha CA, Kumaravelu P, Chellathai DD (2015) Evaluation of anti cancer effects of DPP-4 inhibitors in colon cancer—an invitro study. J Clin Diagn Research JCDR 9:Fc14-6

    Google Scholar 

  19. Femia AP, Raimondi L, Maglieri G, Lodovici M, Mannucci E, Caderni G (2013) Long-term treatment with Sitagliptin, a dipeptidyl peptidase-4 inhibitor, reduces colon carcinogenesis and reactive oxygen species in 1,2-dimethylhydrazine-induced rats. Int J Cancer 133:2498–2503

    Article  CAS  Google Scholar 

  20. Yorifuji N, Inoue T, Iguchi M et al (2016) The dipeptidyl peptidase-4 inhibitor sitagliptin suppresses mouse colon tumorigenesis in type 2 diabetic mice. Oncol Rep 35:676–682

    Article  CAS  Google Scholar 

  21. Lehrke M, Marx N, Patel S et al (2014) Safety and tolerability of linagliptin in patients with type 2 diabetes: a comprehensive pooled analysis of 22 placebo-controlled studies. Clin Ther 36:1130–1146

    Article  CAS  Google Scholar 

  22. Engel SS, Round E, Golm GT, Kaufman KD, Goldstein BJ (2013) Safety and tolerability of sitagliptin in type 2 diabetes: pooled analysis of 25 clinical studies. Diabetes Ther Res Treat Educ Diabetes Related Disord 4:119–145

    Google Scholar 

  23. Hirshberg B, Parker A, Edelberg H, Donovan M, Iqbal N (2014) Safety of saxagliptin: events of special interest in 9156 patients with type 2 diabetes mellitus. Diabetes/Metab Res Rev 30:556–569

    Article  CAS  Google Scholar 

  24. Pinto LC, Rados DV, Barkan SS, Leitao CB, Gross JL (2018) Dipeptidyl peptidase-4 inhibitors, pancreatic cancer and acute pancreatitis: a meta-analysis with trial sequential analysis. Sci Rep 8:782

    Article  Google Scholar 

  25. Monami M, Dicembrini I, Martelli D, Mannucci E (2011) Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized clinical trials. Curr Med Res Opin 27(Suppl 3):57–64

    Article  CAS  Google Scholar 

  26. Zhao M, Chen J, Yuan Y et al (2017) Dipeptidyl peptidase-4 inhibitors and cancer risk in patients with type 2 diabetes: a meta-analysis of randomized clinical trials. Sci Rep 7:8273

    Article  Google Scholar 

  27. Rosenstock J, Perkovic V, Johansen OE et al (2019) Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA 321:69–79

    Article  CAS  Google Scholar 

  28. Rosenstock J, Kahn SE, Johansen OE et al (2019) Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial. JAMA [Epub ahead of print]

  29. Moses RG, Kalra S, Brook D et al (2014) A randomized controlled trial of the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes and inadequate glycaemic control on metformin plus a sulphonylurea. Diabetes Obes Metab 16:443–450

    Article  CAS  Google Scholar 

  30. Oyama J, Murohara T, Kitakaze M et al (2016) The effect of sitagliptin on carotid artery atherosclerosis in type 2 diabetes: the PROLOGUE randomized controlled trial. PLoS Med 13:e1002051

    Article  Google Scholar 

Download references

Funding

This research was performed as a part of the institutional activity of the unit, with no specific funding. All expenses, including salaries of the investigators, were covered by public research funds assigned to the unit. The manuscript was drafted and revised by the authors in accordance with ICJME standards for authorship. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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Author notes

  1. Ilaria Dicembrini and Besmir Nreu have contributed equally to this work.

Authors and Affiliations

  1. Diabetology, Careggi Hospital and University of Florence, Via delle Oblate 4, 50141, Florence, Italy

    Ilaria Dicembrini, Besmir Nreu, Chiara Montereggi, Edoardo Mannucci & Matteo Monami

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  1. Ilaria Dicembrini
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  2. Besmir Nreu
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  3. Chiara Montereggi
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  4. Edoardo Mannucci
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Contributions

MM and EM were involved in design, data collection, analysis, and writing manuscript. ID, BN, and CM were involved in data collection and manuscript revision.

Corresponding author

Correspondence to Matteo Monami.

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Conflict of interest

ID has received speaking fees from Novonordisk; CM has no conflict of interest; BN is presently employee of Novo Nordisk; FT has no conflicts of interest to declare MM has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb; EM has received consultancy fees from Merck and Novartis speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Merck, Novartis, and Takeda. All the authors approved the final version of this manuscript. Dr. Matteo Monami is the person who takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.

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Dicembrini, I., Nreu, B., Montereggi, C. et al. Risk of cancer in patients treated with dipeptidyl peptidase-4 inhibitors: an extensive meta-analysis of randomized controlled trials. Acta Diabetol 57, 689–696 (2020). https://doi.org/10.1007/s00592-020-01479-8

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  • DOI: https://doi.org/10.1007/s00592-020-01479-8

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