SGLT2 Inhibitors in Heart Failure and Comorbidities: Multidimensional Mechanisms and Clinical Evidence

Heart failure and diabetes mellitus frequently coexist. These two conditions mutually exacerbate each other, significantly increasing the risks of cardiovascular death and rehospitalization. Sodium–glucose cotransporter 2 inhibitors have demonstrated unexpected and profound cardioprotective effects beyond glycemic control in cardiovascular outcome trials, driving a paradigm shift in heart failure treatment. A literature search was conducted to identify key studies, including landmark randomized controlled trials, meta-analyses, and real-world evidence studies. The findings show that sodium–glucose cotransporter 2 inhibitors exert cardioprotective effects through multiple mechanisms including hemodynamic optimization, myocardial energy metabolism reprogramming, ionic homeostasis regulation, anti-inflammatory and antioxidant effects, and renoprotection. Real-world evidence studies validate these findings across broader populations. Clear benefits are also observed in special populations, including elderly and frail patients and patients with cancer therapy-related cardiac dysfunction. Regarding safety, although increased risks of genital infections and volume depletion exist, these are generally manageable, while risks of acute kidney injury are significantly reduced, indicating favorable overall tolerability. In sum, sodium–glucose cotransporter 2 inhibitors have established themselves as a cornerstone therapy for patients with heart failure and type 2 diabetes. Future research should focus on elucidating direct cardiac mechanisms, optimizing implementation in routine care, exploring novel combination strategies, and advancing precision medicine-guided individualized treatment. Type 1 diabetes, by contrast, remains a distinct research question and requires dedicated efficacy and safety studies, with particular attention to ketoacidosis risk.