The Evolution of Sodium–Glucose Cotransporter-2 Inhibitors: A Paradigm Shift in Managing Heart Failure and Chronic Kidney Disease

Sodium–glucose cotransporter-2 (SGLT2) are drugs that were primarily developed and employed to address type 2 diabetes mellitus (T2DM) to reduce blood glucose concentrations. One of their main actions, the reduction of glucose reabsorption in the renal proximal tubules,[1] was useful in improving glycemic control. However, within the past few years, the use of the SGLT2 inhibitors has not been limited to a therapeutic function for managing hyperglycemia only. They have now become important treatment modalities in the treatment of heart failure (HF) and chronic kidney disease (CKD),[2] irrespective of diabetes. It is an important revolution in the clinical practice and shifts the paradigm of these chronic diseases. SGLT2 inhibitors have proven benefits beyond glycemic control, with strong evidence supporting their cardioprotective and renoprotective properties. Early pivotal trials, such as the EMPA-REG OUTCOME trial,[3] demonstrated significant reductions in cardiovascular (CV) death and HF hospitalizations in patients with T2DM and established CV disease. Similarly, the CANVAS Program[4] validated these findings by showing reductions in major adverse CV events and HF hospitalizations in high CV-risk T2DM patients. These landmark trials established the foundational role of SGLT2 inhibitors in CV protection and expanded their therapeutic indications. Recent trials, such as dapagliflozin (DAPA)-HF, EMPEROR-Reduced, and DAPA-CKD,[5] further presented a profound reduction in the total CV incidents, hospitalization, and CV death in the patients with HF and nondiabetic or diabetic kidney disease. The results of these trials have quickly translated into changes in practices advocated by some of the most reputable organizations such as the American Heart Association and Kidney disease: Improving Global Outcomes. Recent guidelines from these two organizations have included SGLT2 inhibitors in the management of all patients with HF and CKD, even without diabetes mellitus. These clinical trials are summarized in Table 1.Table 1: Key clinical trials supporting the expanded use of sodium–glucose cotransporter-2 inhibitors in heart failure and chronic kidney diseaseThe benefits of SGLT2 inhibitors are beyond glycemic control, especially in HF and patients with CKD. These agents affect several physiological factors, which make them impart CV and renal medical values. One of them is the decrease of glomerular hyperfiltration,[6] which helps to decrease intraglomerular pressure and thus protect renal function. Third, their weak diuretic properties help control fluid balance and improve the symptoms of a person with HF. SGLT2 inhibitors also possess anti-inflammatory and antioxidant effects, reducing the level of oxidative stress and the risk of CV complications.[7] Furthermore, recent data from newer molecules in the SGLT2 inhibitor class, including sotagliflozin and ertugliflozin, suggest a continued expansion of their therapeutic potential. These newer agents are being investigated in diverse populations and conditions, further solidifying the broad utility of this drug class.[8] These interacting mechanisms suggest that SGLT2 inhibitors are useful in a broad range of patients with any form of diabetes and potentially in nondiabetic patients, providing a spectrum of protective actions beyond glucose lowering [Figure 1].Figure 1: Schematic representation of the mechanisms of action of sodium–glucose cotransporter-2 inhibitorsAn increasing focus on the use of SGLT2 inhibitors is shifting the paradigm of internal medicine, especially in regard to collaborative care with cardiologists, nephrologists, and primary care physicians. It is now possible to prescribe such agents to patients with HF or CKD, which makes the use of these agents significantly extended. The current patient selection is gradually shifting toward patients whose conditions would be improved by the drug’s cardioprotective and renoprotective effects while controlling side effects such as volume depletion and urinary tract infection, especially in the elderly and patients with advanced CKD. Although the current evidence is robust, further studies are required for a better understanding of long-term safety and efficacy, especially in vulnerable populations, including older patients, those with progressive and advanced CKD, and patients of different ethnicities. Moreover, emerging data from ongoing trials are exploring their efficacy in other CV conditions such as coronary artery disease and metabolic disorders, including obesity. These investigations may further expand the therapeutic indications for SGLT2 inhibitors. In conclusion, SGLT2 inhibitors represent a paradigm shift in the management of HF and CKD, offering unprecedented benefits for a broader patient population. Continued research is necessary to unlock their full potential, ensuring safe and effective use across diverse populations and exploring new indications that could further transform clinical practice. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.