Abstract Body (Do not enter title and authors here): Background:
Cancer therapy–related cardiac dysfunction (CTRCD) is a significant complication among cancer patients, particularly those with type 2 diabetes mellitus (T2DM). While recent observational studies have shown potential cardioprotective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i), these findings may be biased by imprecise cohort definition. This study aimed to evaluate the association between SGLT2i use and the risk of new-onset CTRCD in T2DM patients undergoing potentially cardiotoxic cancer therapy.

Research Question:
Does pretreatment with SGLT2i reduce the incidence of CTRCD in T2DM patients undergoing cardiotoxic cancer therapy?

Methods:
We conducted a retrospective cohort study using the TriNetX US Collaborative Network, which aggregates de-identified electronic health records from healthcare organizations. Adults with T2DM and cancer receiving their first potential cardiotoxic cancer therapy between January 1, 2013, and October 31, 2022, were included. Patients with prior heart failure (HF), cardiomyopathy, or LVEF ≤40% were excluded to preserve a primary prevention framework. Patients were classified as SGLT2i users (≥1 prescription within one year before cancer therapy) and nonusers. The two groups were matched 1:1 using propensity score matching (PSM) across 52 covariates. The primary outcome was 1-year incidence of CTRCD (new-onset HF, cardiomyopathy, LVEF ≤40%, or IV diuretic use). Secondary outcomes included HF hospitalization, all-cause mortality, MI, AF/AFL, and new metastasis. Falsification endpoints included pneumonia and GI bleeding.

Results:
After PSM, 2,656 patients (1,328 SGLT2i users and 1,328 nonusers) were included. Over a 1-year follow-up, the incidence of CTRCD was similar between the two groups (13.5% vs 13.6%; HR 0.99, 95% CI 0.80–1.22; p = 0.91). No significant differences were observed in secondary outcomes or falsification endpoints. A non-significant trend toward lower CTRCD was observed in anthracycline-treated patients (13.9% vs 21.4%; p=0.10).

Conclusion:
Our study shows that in T2DM patients with cancer, SGLT2i pretreatment was not associated with a reduced risk of CTRCD or other adverse cardiovascular outcomes. Our findings differ from those of previous observational studies and highlight the importance of precise cohort definitions and effective confounding control. Additionally, potential benefits within anthracycline subgroups necessitate further investigation in randomized controlled trials.