Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Epidemiology

Sodium-glucose cotransporter 2 (SGLT2) inhibitors and non-small cell lung cancer survival

Abstract

Background

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs with demonstrated renal and cardiovascular disease benefit. This study evaluates the role of SGLT2 inhibitors on the survival of non-small cell lung cancer (NSCLC) patients.

Methods

We used National Surveillance, Epidemiology and End Results (SEER)-Medicare linked data. Twenty four thousand nine hundred fifteen NSCLC patients newly diagnosed between 2014 and 2017 with pre-exiting diabetes and aged 66 years or older were included and followed to the end of 2019. Information on SGLT2 inhibitors use was extracted from the Medicare Part D file.

Results

SGLT2 inhibitor use was associated with significantly reduced mortality risk after adjusting for potential confounders (HR = 0.68, 95% CI = 0.60–0.77) with stronger association for longer duration of use (HR = 0.54, 85% CI = 0.44–0.68). Further, we found that SGLT2 inhibitor use was associated with a significant reduced risk of mortality regardless of patients’ demographic, tumour characteristics and cancer treatments.

Conclusion

Our large SEER-Medicare linked data study indicates that SGLT2 inhibitors use was associated with improved overall survival of NSCLC patients with pre-existing diabetes. Further studies are needed to confirm our findings and elucidate the possible mechanisms behind the association.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2: Forest plot of association between sodium-glucose cotransporter 2 (SGLT2) inhibitor use and mortality by covariates.

Data availability

Data were available from the SEER-Medicare website (https://healthcaredelivery.cancer.gov/seermedicare/obtain/) on reasonable request.

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.

    Article  PubMed  Google Scholar 

  2. Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu, M et al. SEER Cancer Statistics Review, 1975-2016. 2019. https://seer.cancer.gov/csr/1975_2016/. Accessed 15 Oct 2015.

  3. Lin CC, Virgo KS, Robbins AS, Jemal A, Ward EM. Comparison of comorbid medical conditions in the national cancer database and the SEER-medicare database. Ann Surg Oncol. 2016;23:4139–48.

    Article  PubMed  Google Scholar 

  4. Deng HY, Zheng X, Zha P, Peng L, Huang KL, Qiu XM. Diabetes mellitus and survival of non-small cell lung cancer patients after surgery: a comprehensive systematic review and meta-analysis. Thorac Cancer. 2019;10:571–8.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Zhu L, Cao H, Zhang T, Shen H, Dong W, Wang L, et al. The effect of diabetes mellitus on lung cancer prognosis: a PRISMA-compliant meta-analysis of cohort studies. Medicine (Baltim). 2016;95:e3528.

    Article  Google Scholar 

  6. Bi, G, Yao G, Bian Y, Xue L, Zhang Y, Lu T, et al. The effect of diabetes mellitus on prognosis of patients with non-small-cell lung cancer: a systematic review and meta-analysis. Ann Thorac Cardiovasc Surg. 2019. https://doi.org/10.5761/atcs.ra.19-00170.

  7. Blonde L. Current antihyperglycemic treatment guidelines and algorithms for patients with type 2 diabetes mellitus. Am J Med. 2010;123:S12–18.

    Article  CAS  PubMed  Google Scholar 

  8. Tentolouris A, Vlachakis P, Tzeravini E, Eleftheriadou I, Tentolouris N SGLT2 inhibitors: a review of their antidiabetic and cardioprotective effects. Int J Environ Res Public Health. 2019;16:2965.

  9. Nainggolan L FDA approves Canagliflozin, a first-in-class diabetes drug. 2013. https://www.medscape.com/viewarticle/781709 Accessed 30 Sept 2019.

  10. ClinCalc. The top 200 of 2021. Provided by the ClinCalc Drugstats database. 2021. https://clincalc.com/DrugStats/Top200Drugs.aspx Accessed 11 Jan 2021.

  11. CADTH. Canagliflozin (Invokana) for Type 2 Diabetes Mellitus [Internet]. Ottawa: Canadian Agency for Drugs and Technology in Health; 2015.

  12. Zhang XL, Zhu QQ, Chen YH Li, XL Chen F, Huang JA, et al. Cardiovascular safety, long-term noncardiovascular safety, and efficacy of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: a systemic review and meta-analysis with trial sequential analysis. J Am Heart Assoc. 2018;7:e007165.

  13. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91:733–94.

    Article  CAS  PubMed  Google Scholar 

  14. Rosenwasser RF, Sultan S, Sutton D, Choksi R, Epstein BJ. SGLT-2 inhibitors and their potential in the treatment of diabetes. Diabetes Metab Syndr Obes. 2013;6:453–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Gallwitz B. The cardiovascular benefits associated with the use of sodium-glucose cotransporter 2 inhibitors—real-world data. Eur Endocrinol. 2018;14:17–23.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Cavaiola TS, Pettus J. Cardiovascular effects of sodium glucose cotransporter 2 inhibitors. Diabetes Metab Syndr Obes. 2018;11:133–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41:2669–701.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Kaji K, Nishimura N, Seki K, Sato S, Saikawa S, Nakanishi K, et al. Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake. Int J Cancer. 2018;142:1712–22.

    Article  CAS  PubMed  Google Scholar 

  19. Scafoglio CR, Villegas B, Abdelhady G, Bailey ST, Liu J, Shirali AS, et al. Sodium-glucose transporter 2 is a diagnostic and therapeutic target for early-stage lung adenocarcinoma. Sci Transl Med. 2018;10:eaat5933.

  20. Villani LA, Smith BK, Marcinko K, Ford RJ, Broadfield LA, Green AE, et al. The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration. Mol Metab. 2016;5:1048–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Li H, Tong CW, Leung Y, Wong MH, To KK, Leung KS. Identification of clinically approved drugs indacaterol and canagliflozin for repurposing to treat epidermal growth factor tyrosine kinase inhibitor-resistant lung cancer. Front Oncol. 2017;7:288.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lin HW, Tseng CH. A review on the relationship between SGLT2 inhibitors and cancer. Int J Endocrinol. 2014;2014:719578.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tang H, Dai Q, Shi W, Zhai S, Song Y, Han J. SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials. Diabetologia. 2017;60:1862–72.

    Article  CAS  PubMed  Google Scholar 

  24. Molina JR, Yang PG, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83:584–94.

    Article  PubMed  Google Scholar 

  25. SEER. Overview of the SEER Program. https://seer.cancer.gov/about/overview.html. Accessed 2 Nov 2021.

  26. CMS. Medicare Program - General Information. http://www.cms.gov/MedicareGenInfo/. Accessed 24 Nov 2021.

  27. SEER-Medicare:: Brief Description of the SEER-Medicare Database. https://healthcaredelivery.cancer.gov/seermedicare/overview/. Accessed 29 Oct 2021.

  28. Engels EA, Pfeiffer RM, Ricker W, Wheeler W, Parsons R, Warren JL. Use of Surveillance, Epidemiology, and End Results-Medicare Data to Conduct Case-Control Studies of Cancer Among the US Elderly. Am J Epidemiol. 2011;174:860–70.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Noone AM, Lund JL, Mariotto A, Cronin K, McNeel T, Deapen D, et al. Comparison of SEER treatment data with medicare claims. Med Care. 2016;54:e55–64.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Yamamoto L, Yamashita S, Nomiyama T, Kawanami T, Hamaguchi Y, Shigeoka T, et al. Sodium-glucose cotransporter 2 inhibitor canagliflozin attenuates lung cancer cell proliferation in vitro. Diabetol Int. 2021;12:389–98.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Scafoglio C, Hirayama BA, Kepe V, Liu J, Ghezzi C, Satyamurthy N, et al. Functional expression of sodium-glucose transporters in cancer. Proc Natl Acad Sci USA. 2015;112:E4111–4119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Blair SL, Heerdt P, Sachar S, Abolhoda A, Hochwald S, Cheng H, et al. Glutathione metabolism in patients with non-small cell lung cancers. Cancer Res. 1997;57:152–5.

    CAS  PubMed  Google Scholar 

  33. Hochwald SN, Harrison LE, Rose DM, Anderson M, Burt ME. gamma-Glutamyl transpeptidase mediation of tumor glutathione utilization in vivo. J Natl Cancer Inst. 1996;88:193–7.

    Article  CAS  PubMed  Google Scholar 

  34. Kan O, Baldwin SA, Whetton AD. Apoptosis is regulated by the rate of glucose-transport in an interleukin-3 dependent cell-line. J Exp Med. 1994;180:917–23.

    Article  CAS  PubMed  Google Scholar 

  35. Shim H, Chun YS, Lewis BC, Dang CV. A unique glucose-dependent apoptotic pathway induced by c-Myc. Proc Natl Acad Sci USA. 1998;95:1511–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.

    Article  Google Scholar 

  37. Yaribeygi H, Atkin SL, Butler AE, Sahebkar A. Sodium-glucose cotransporter inhibitors and oxidative stress: an update. J Cell Physiol. 2019;234:3231–7.

    Article  CAS  PubMed  Google Scholar 

  38. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010;49:1603–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Multhoff G, Molls M, Radons J. Chronic inflammation in cancer development. Front Immunol. 2011;2:98.

    PubMed  Google Scholar 

  40. Sugizaki T, Zhu S, Guo G, Matsumoto A, Zhao J, Endo M, et al. Treatment of diabetic mice with the SGLT2 inhibitor TA-1887 antagonizes diabetic cachexia and decreases mortality. npj Aging Mech Dis. 2017;3:12.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Ishibashi Y, Matsui T, Yamagishi S. Tofogliflozin, a highly selective inhibitor of SGLT2 blocks proinflammatory and proapoptotic effects of glucose overload on proximal tubular cells partly by suppressing oxidative stress generation. Horm Metab Res. 2016;48:191–5.

    CAS  PubMed  Google Scholar 

  42. Osorio H, Coronel I, Arellano A, Pacheco U, Bautista R, Franco M, et al. Sodium-glucose cotransporter inhibition prevents oxidative stress in the kidney of diabetic rats. Oxid Med Cell Longev. 2012;2012:542042.

  43. Ishikawa N, Oguri T, Isobe T, Fujitaka K, Kohno N. SGLT gene expression in primary lung cancers and their metastatic lesions. Jpn J Cancer Res. 2001;92:874–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study is supported by the National Institutes of Health (R03CA256238).

Author information

Authors and Affiliations

Authors

Contributions

JL: Conceptualisation, methodology, formal analysis, writing–original draft and writing-review and editing. MH: Conceptualisation, methodology and writing-review and editing. YD: Conceptualisation and writing-review and editing.

Corresponding author

Correspondence to Juhua Luo.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study was reviewed and approved by the Human Research Protection Program (HRPP) Office of Research Compliance—Indiana University, Protocol #: 2012984604.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Luo, J., Hendryx, M. & Dong, Y. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and non-small cell lung cancer survival. Br J Cancer (2023). https://doi.org/10.1038/s41416-023-02177-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41416-023-02177-2

Search

Quick links