Available online 28 November 2023, 101500

Author links open overlay panel, , , , , ABSTRACTPurpose

According to the preclinical data, sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is) may exert anticancer effects. Here, we clarified the cancer-specific mortality (primary outcome) and all-cause mortality (secondary outcome) of SGLT2is and their dose-dependency in patients with cancer undergoing standard curative treatments.

Methods

We analyzed data from patients with type 2 diabetes mellitus (T2DM) diagnosed with cancer between January 1, 2016, and December 31, 2018, enrolled from the Taiwan Cancer Registry database. Kaplan-Meier method was used to estimate all-cause mortality and cancer-specific mortality, comparing survival curves between SGLT2i users and nonusers using the stratified log-rank test. Cox proportional hazards regression was conducted to identify independent predictors for all-cause and cancer-specific mortality among the covariates.

Results

We performed 1:2 propensity score matching of our data, which yielded a final cohort of 50,133 patients with cancer; of them, 16,711 and 33,422 were in the SGLT2i user and nonuser groups, respectively. The adjusted hazard ratio (aHR) for cancer-specific and all-cause mortality in SGLT2i users compared with nonusers was 0.21 (95% confidence interval [CI]: 0.20–0.22) and 0.22 (95% CI: 0.21–0.23). We divided the patients into four subgroups stratified by quartiles (Q) of cumulative defined daily doses per year (cDDDs), and all-cause and cancer-specific mortality was noted to significantly decrease with increases in dosage (from Q1 to Q4 cDDDs) in SGLT2i users compared with in nonusers (P < 0.001).

Conclusion

SGLT2is increase overall survival and cancer-specific survival in patients with cancer in a dose-dependent manner.

Section snippetsINTRODUCTION

Diabetes, primarily type 2 diabetes mellitus (T2DM), is associated with an increased risk of cancers such as liver, pancreatic, endometrial, colorectal, breast, and bladder cancers [1]. Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is), developed as antidiabetic drugs [2], target SGLT2 that is expressed in the proximal tubule of the kidneys. This protein mediates reabsorption of approximately 90% of the filtered glucose load [3]. SGLT2is mediate the renal excretion of glucose, thereby

Data Sources and Study Cohort

We extracted data on cancer patients with type 2 diabetes mellitus (T2DM) who were diagnosed with cancer between January 1, 2016 and December 31, 2020 from the Taiwan Cancer Registry database (TCRD) linked to the National Health Insurance Research Database (NHIRD). The date of cancer diagnosis was used as the index date and follow-up extended until December 31, 2020. The study protocol was reviewed and approved by the Institutional Review Board of Tzu-Chi Medical Foundation (IRB109-015-B).

Propensity score matching and Study Cohort

Our propensity score matching process yielded a final cohort of 50,133 eligible patients with cancer: 16,711 SGLT2i users and 33,422 nonusers; their characteristics are summarized in Table I. After head-to-head propensity score matching, the two groups had similar sex, years of cancer diagnosis, cancer types, American Joint Committee on Cancer clinical stages, number of diabetes drugs, antidiabetic medications, adapted Diabetic Complication Severity Index scores, BMI, smoking status, alcohol

DISCUSSION

Preclinical studies have demonstrated that SGLT2is exert anticancer effects through the blocking of the functional activity of SGLT2 in several malignant cancers, including cervical [8], hepatocellular [11], breast [7], prostate [12], and lung [12] cancers. This is because SGLT2 is overexpressed in malignant cancers, including pancreatic and prostate adenocarcinomas [13], lung cancer [10], and breast cancer [9], and SGLT2 overexpression significantly promotes proliferation, migration, and

CONCLUSION

SGLT2is may increase Overall Survival and Cancer-Specific Survival in patients with cancer in a dose-dependent manner, regardless of patient sex, age, cancer type, American Joint Committee on Cancer clinical stage, adapted Diabetic Complication Severity Index score, BMI, and cigarette smoking status.

Declaration of Competing Interest

The authors have no potential conflicts of interest to declare. The data sets supporting the study conclusions are included within the manuscript.

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