To our knowledge, this is the first, large, real-world study evaluating the incidence of adverse cardiovascular and renal outcomes among patients with prostate cancer on HT treated with SGLTi compared to other agents for T2DM. We found that among patients with prostate cancer, SGLT2i treatment was associated with a significantly lower risk of developing the composite outcome of all-cause mortality, new onset HF, acute MI and PAD over two years since initiation of HT. In the analysis of individual outcomes, SGLT2i were associated with lower odds of new onset HF, HF exacerbation, PAD, atrial fibrillation/flutter, cardiac arrest, need for RRT, overall ER visits/hospitalizations and all-cause mortality.
Patients with prostate cancer represent a unique patient population with a high burden of comorbid cardiovascular conditions, including T2DM, as well as cardiovascular disease, which is a leading cause of death 2–4. The high prevalence of cardiovascular disease among patients with prostate cancer has been attributed not only to the coexistence of shared risk factors but also the effects of HT. HT is the backbone of prostate cancer therapy and it is used for as many as 50% of patients with prostate cancer at some point in their disease course. In 2006, Keating et al. were one of the first to report an association between GnRH agonists and increased incidence of DM, coronary heart disease, MI, and sudden cardiac death 6. Since then, several studies and clinical trials have confirmed that GnRH agonists, abiraterone, androgen receptor antagonists, and less so GnRH antagonists, are associated with increased incidence of adverse cardiovascular events. The mechanism of HT related cardiotoxicity includes hypogonadism-mediated alterations in body composition, with increase in adiposity and decrease in lean mass, lipid abnormalities (increase in triglycerides and LDL cholesterol) and impaired glucose control with decreased insulin sensitivity and subsequently elevated fasting serum glucose 5. These metabolic derangements lead to an increase in circulating proinflammatory adipokines and prothrombotic markers with subsequent vascular endothelial dysfunction, vascular inflammation, and adverse cardiovascular and renal events 5.
Over the last decade, several large clinical trials have shown that treatment with SGLT2 inhibitors is associated with favorable cardiovascular and renal outcomes in patients with T2DM at risk of or with established cardiovascular disease but also in patients with HF and chronic kidney disease (CKD) without T2DM 9–12. Empagliflozin was the first SGLT2i that received FDA approval in December of 2016 for reduction of cardiovascular death in adults with T2DM 17. Subsequently, in May of 2020 FDA approved dapagliflozin for reducing the risk of cardiovascular death and HF hospitalizations in patients with HF with reduced ejection fraction regardless of diabetes status, 18 and in April of 2021 dapagliflozin was approved to reduce the risk of kidney function decline in adults with CKD 19. More recently, in February of 2022, FDA approved empagliflozin to reduce the risk of cardiovascular death and hospitalizations in adults with HF regardless of ejection fraction 20. In addition to the above benefits, recent evidence suggests that SGLT2i may also reduce the incidence of atrial fibrillation/flutter 21. Our study findings further emphasize the importance of using SGLT2i in patients with T2DM to prevent adverse cardiorenal outcomes.
Considering that cardiovascular disease is a major cause of death among a large portion of men with prostate cancer, treatment with SGLT2i might have a great impact in improving mortality and morbidity. Furthermore, SGLT2i might be able to mitigate the risk of cardiotoxicity mediated by HT. Despite the significant potential benefits, patients with prostate cancer were excluded from the above-mentioned clinical trials and the exact role and size of impact of SGLT2i in preventing adverse cardiovascular and renal outcomes among patients with T2DM and prostate cancer treated with HT has not been examined. Our study is the first one to report a significant reduction in the risk of adverse cardiorenal outcomes among patients with prostate cancer on HT and T2DM treated with vs without SGLT2i. We hypothesize that by inducing glucosuria and natriuresis, SGLT2i improve hyperglycemia and hypertension, the two major risk factors contributing to the development of cardiovascular disease among patients with prostate cancer treated with HT 22,23. Furthermore, similar to patients with HF, it is likely that SGLT2i alter adipokine signaling and reduce inflammation, which could prevent HT-related cardiotoxicity 22,23. Based upon clinical observations and convergent data, our group has also postulated that a subset of prostate cancers is part of an “overlap syndrome” of age-related illnesses, including cardiovascular disease, with shared biology 24. The findings of this study suggest that SGLT2i warrant further investigation in this subset of patients since it has the potential to improve survival.
In addition to the favorable cardiorenal benefits of SGLT2i among patients with prostate cancer, preclinical studies have suggested functional expression of SGLT receptors in prostate adenocarcinomas and that treatment with SGLT2i might lead to favorable oncologic outcomes as well 25. Studies evaluating the role of SGLT2i in prostate cancer-specific outcomes in human subjects are currently underway (NCT04887935). Such trials may also be able to assess the cardiovascular benefits of SGLT2i in patients with prostate cancer irrespective of the presence of T2DM.
Study Limitations:
Our study has several limitations including those inherent to observational studies such as selection bias. Most importantly, despite our efforts to carefully control for baseline differences in the SGLT2i versus non-SGLT2i cohort using propensity matching, unmeasured confounding may still exist. To eliminate this possibility, we performed a sensitivity analysis of patients with prostate cancer treated with vs without SGLT2i, the results of which indicated that the findings are unlikely to be explained by unmeasured confounders. Patients on SGLT2i may have also have socioeconomic differences related to access to medications, which cannot be assessed in this study. Differences in the type of HT that the two patient groups received, and the stage of their prostate cancer could not be assessed either, due to limitations of the database used. Furthermore, retrospective data curated from electronic medical records may be inaccurate or carry the risk of biases. This risk is somewhat mitigated by the large number of patients included in our study and the large effect size. Finally, this study did not assess side effects related to SGLT2i or prostate cancer specific outcomes.