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Sodium-glucose cotransporter 2 inhibitors and cancer: a systematic review and meta-analysis

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Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Background

The effect of sodium–glucose cotransporter 2 (SGLT2) inhibitors on cancer has yet to be fully elucidated.

Objective

This systematic review and meta-analysis investigated the effects of SGLT2 inhibitors on cancer.

Methods

We searched the PubMed and ClinicalTrials.gov databases up to July 15, 2023, to identify eligible randomized, double-blind, placebo-controlled trials that lasted at least ≥24 weeks. The primary outcome was the overall cancer incidence, and the secondary outcomes were the incidences of various types of cancer. We used the Mantel–Haenszel method, fixed effects model, risk ratio (RR) and 95% confidence interval (CI) to analyze dichotomous variables. Subgroup analysis was performed based on the SGLT2 inhibitor type, baseline conditions, and follow-up duration. All meta-analyses were performed using RevMan5.4.1 and Stata MP 16.0.

Results

A total of 58 publications (59 trials) were included, comprising 113,909 participants with type 2 diabetes mellitus and/or chronic kidney disease and/or high cardiovascular risk and/or heart failure (SGLT2 inhibitor group, 63864; placebo group, 50045). Compared to the placebo SGLT2 inhibitors did not significantly increase the overall incidence of cancer (RR 1.01; 95% CI 0.94–1.08; p = 0.82). However, ertugliflozin did significantly increase the overall incidence of cancer (RR 1.29; 95% CI 1.01–1.64; p = 0.04). SGLT2 inhibitors did not increase the risks of bladder or breast cancer. However, dapagliflozin did significantly reduce the risk of bladder cancer by 47% (RR 0.53; 95% CI 0.35–0.81; p = 0.003). SGLT2 inhibitors had no significant effect on the risks of gastrointestinal, thyroid, skin, respiratory, prostate, uterine/endometrial, hepatic and pancreatic cancers. Dapagliflozin reduced the risk of respiratory cancer by 26% (RR 0.74; 95% CI 0.55–1.00; p = 0.05). SGLT2 inhibitors (particularly mediated by dapagliflozin and ertugliflozin but not statistically significant) were associated with a greater risk of renal cancer than the placebo (RR 1.39; 95% CI 1.04–1.87; p = 0.03).

Conclusion

SGLT2 inhibitors did not significantly increase the overall risk of cancer or the risks of bladder and breast cancers. However, the higher risk of renal cancer associated with SGLT2 inhibitors warrants concern.

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Abbreviations

T2DM:

Type 2 diabetes mellitus

SGLT2:

Sodium-glucose cotransporter 2

RR:

Risk ratio

CI:

Confidence interval

CKD:

Chronic kidney disease

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Funding

This study was supported by the NSFC (82003872), Natural Science Foundation of Hunan Province (2022JJ50163, 2023JJ20034), Scientific Research Fund Project of Hunan Provincial Health Commission (20201973), Central government funds for guiding local scientific and Technological Development (2021QZY016), Hunan Province Clinical Medical Technology Innovation Guidance Project (2020SK51823, 2021SK51828, 2021SK51823), Hunan Provincial Clinical Medical Research Center for Drug Evaluation of major chronic diseases (2023SK4040). The science and technology innovation Program of Hunan Province (2023RC3173).

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Authors and Affiliations

  1. The First Affiliated Hospital, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China

    B. Xu, B. Kang, S. Li, S. Fan & J. Zhou

  2. The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China

    B. Xu, B. Kang, S. Li, S. Fan & J. Zhou

  3. The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China

    B. Xu, B. Kang, S. Li, S. Fan & J. Zhou

  4. The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China

    B. Xu, B. Kang, S. Li, S. Fan & J. Zhou

  5. School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China

    B. Xu & J. Zhou

  6. The Affiliated Nanhua Hospital, Department of Docimasiology, Hengyang Medical School, University of South China, Hengyang, 421002, Hunan, China

    S. Li

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Contributions

Bo Xu and Jiecan Zhou provided topics and methods, while Bo Xu and Bo Kang completed literature search and data extraction. Bo Xu, Shaoqian Li, Shangzhi Fan completed the study selection. Bo Xu and Jiecan Zhou identified the outcome of interest. Bo Xu, Bo Kang, and Jiecan Zhou jointly completed the methodological quality assessment. Bo Xu is responsible for data analysis of the entire manuscript, providing tables and figures, and writing the article. All authors have undergone manuscript review. All authors have finally approved the manuscript and submitted it.

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Correspondence to J. Zhou.

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Xu, B., Kang, B., Li, S. et al. Sodium-glucose cotransporter 2 inhibitors and cancer: a systematic review and meta-analysis. J Endocrinol Invest (2024). https://doi.org/10.1007/s40618-024-02351-0

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