Studies have shown that breast cancer (BC) increases the risk of developing type 2 diabetes mellitus (T2DM) 1.07- to 4.27-fold depending on demographic and treatment-related factors. Tamoxifen, which is used to treat hormone receptor–positive (HR+) BC, is associated with a 1.24- to 2.25-fold increased risk of developing T2DM, whereas the risk is 4.27-fold higher for BC patients receiving aromatase inhibitors. The risk of developing T2DM is greatest within the first 2 years after diagnosis and is higher than the general population for at least 10 to 15 years. Further, BC regimens that include the use of anthracyclines, taxanes, or trastuzumab have been associated with an increased risk of BC therapy–related cardiac dysfunction (BCTRCD). When BCTRCD occurs, oncologic therapy is often interrupted or discontinued, which can lead to poor patient outcomes.
SGLT-2 inhibitors, namely dapagliflozin and empagliflozin, are approved for both the management of T2DM and for the reduction of cardiovascular mortality and hospitalization due to heart failure in patients with or without diabetes; canagliflozin and ertugliflozin are only approved for the management of T2DM. In 2011, the FDA warned that SGLT-2 inhibitors could be associated with an increased risk of BC. Evidence since then has supported this finding.
To assist in further clarifying this issue, researchers used claims data from Optum’s deidentified Clinformatics Data Mart Database to assess the association between SGLT-2 inhibitor use and the risk of BC. Patient data were excluded for male patients; those aged <18 years; those with a history of cancer; those with end-stage renal disease, on dialysis, or who have had kidney transplantation; those who used both SGLT-2 inhibitors and dipeptidyl peptidase-4 (DDP-4) inhibitors; those for whom <1 year of medical history data were available prior to starting SGLT-2-inhibitor therapy; and those with missing data.
The primary outcome was invasive BC incidence during follow-up. Survival time was defined as the date from the first prescription to the date of BC diagnosis, date of end of follow-up, or date of withdrawal from the study. A descriptive analysis was performed that categorized women as aged <51 years and >51 years. Propensity score matching was conducted at the time of medication initiation. Short-term use of SGLT-2 inhibitor was considered <2 years, whereas long-term use was defined as 2 to 9 years.
Researchers analyzed data from 1,112,991 people who were newly started on a SGLT-2 inhibitor or DDP-4 inhibitor between January 1, 2013, and March 31, 2022. They found that over a 2.2-year follow-up period among those with diabetes (N = 158,483), there were 2,154 cases of BC. Of these, 727 occurred in those receiving SGLT-2 inhibitors and 1,427 occurred in those on DDP-4 inhibitors. This resulted in a hazard ratio of 0.84 (95% CI, 0.77-0.92), demonstrating a protective effect of SGLT-2 inhibitors against BC. There was no difference in outcome based on age or with duration of use of the SGLT-2 inhibitor. The authors concluded that there was no association between the use of SGLT-2 inhibitors and the development of BC. Most studies are needed to explore the possible protective effect of SGLT-2-inhibitors against the development of BC.
Other investigators conducted a systematic review of Embase, Medline, the Cochrane Central Register of Controlled Trials, and the Cliicaltrials.gov website to objectively assess published literature on the cardioprotective effects of SGLT-2 inhibitors in BCTRCD. Nineteen studies were included in the systematic review, which were in the forms of basic science research, Clinicaltrials.gov randomized, controlled trial submission, conference abstracts, case reports, reviews, editorial comments, and clinical guidelines. Preliminary evidence suggested a potential cardioprotective effect of SGLT-2 inhibitors against BCTRCD, which may be due to upregulation of adenosine monophosphate-activated protein kinase (AMPK). It is thought that AMPK regulates mitochondrial biogenesis, increases oxidative mitochondrial metabolism, and decreases apoptosis and fibrosis.
Pharmacists should be aware of these evolving developments regarding the use of SGLT-2 inhibitors in BC and may recommend the use of an SGLT-2 inhibitor in patients with BC who also have diabetes. As more data becomes available, this class of hypoglycemic agents may play a role in preventing BCTRCD.
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