Angimar Uriepero-Palma, MD, on CLL: Impact of SGLT2 Inhibitors on Patients With Diabetes

As we know, patients with CLL are usually over 65 years old, and they tend to have other comorbidities, including diabetes, hypertension, and heart failure. They also have a higher risk of developing infection, given the immunodepression that usually patients with CLL have. Taking this into consideration, when we give them a BTK inhibitor, all these can be assembled or developed for the first time. So we hypothesized that if the patients receive SGLT2 as a part of diabetes treatment, we can decrease the risk of developing these toxicities. To evaluate the hypothesis, we designed a retrospective study using a database called TriNetX. This is a real-world database, and we divided our patients into cohorts. One cohort was patients with CLL, diabetes, and on a BTK inhibitor who were receiving an SGLT2 as part of diabetes treatment. And the second cohort was the same patients with CLL, diabetes, and on a BTK inhibitor, but they were not receiving an SGLT2. We ran a propensity score match, adjusting by sex, comorbidity, and medications, and then we evaluated clinical outcomes at 3 years. The first thing that we looked for was overall survival, and we found that patients who were receiving concurrent SGLT2 and BTK inhibitors had a longer overall survival at 3 years: 77% versus 62%. Additionally, we looked for adverse events. We found that grade 3 cytopenias, as well as severe infections, including pneumonia, sepsis, and neutropenic fever, were lower in the patients who received the SGLT2. But what was actually a little bit surprising for us is that we didn't find a significant difference in the development of new-onset heart failure, hypertension, or atrial fibrillation because we know that these are one of the main toxicities associated with BTK inhibitors, and SGLT2 inhibitors have some cardioprotective effect. However, we have to take into consideration that our study was a propensity score-matched study, and although we tried to decrease the confounding, there can still be some unmeasurable variables that we couldn't control. We also couldn't divide our patients by clinical stratification or molecular stratification. This can also be taken into consideration for future studies. However, despite those limitations, we still think that our data are relevant. Even we are finding that there is a benefit of overall survival when we use SGLT2 and BTK inhibitors in patients with diabetes and CLL. We also found, as said before, a decrease in grade 3 cytopenia and a decrease in severe infections. We don't have an explanation right now for the mechanism behind this. But there are some preclinical studies, mostly in solid tumors, showing that SGLT2 inhibitors can be immunomodulatory. So maybe that can be the reason, but we will need to do more prospective studies to confirm these data, and that's what we are planning moving forward.