Chronic Kidney Disease and SGLT2 Inhibitors: A Review of the Evolving Treatment Landscape

Abstract

There is currently an unmet need for effective treatment of chronic kidney disease (CKD) that slows disease progression, prevents development of end-stage kidney disease and cardiovascular disease, and prolongs survival of patients with CKD. In the last 20 years, the only agents to show a reduction in the risk of CKD progression in patients with and without type 2 diabetes (T2D) were angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, but neither drug class has provided a decreased risk of all-cause mortality in patients with CKD and evidence for their use in patients with CKD without T2D is relatively limited. This review discusses the mechanisms underlying the progression of CKD, its associated risk factors, and summarizes the potential therapeutic approaches for managing CKD. There is increasing evidence to support the role of sodium–glucose cotransporter 2 (SGLT2) inhibitor therapy in patients with CKD, including data from the designated kidney outcome trials in patients with T2D (CREDENCE) and in patients with or without T2D (DAPA-CKD). These studies showed a significant reduction in the risk of CKD progression with canagliflozin (in patients with T2D) or dapagliflozin (in patients with or without T2D), respectively, with DAPA-CKD being the first trial to show a reduced risk of all-cause mortality. On the basis of these data, individualized treatment with SGLT2 inhibitors represents a promising therapeutic option for patients with diabetic and nondiabetic CKD to slow disease progression.

Plain Language Summary

Chronic kidney disease is a common condition in which the ability of the kidneys to work correctly gradually decreases over time. It is a major risk factor for a number of other serious conditions, including cardiovascular disease and end-stage kidney disease, and for early death. Several treatments have been shown to reduce the risk of chronic kidney disease progressing (particularly in patients with type 2 diabetes), but there have been no treatments that slow chronic kidney disease progression, prevent the development of end-stage kidney disease and cardiovascular disease, and prolong survival. However, evidence is now accumulating to suggest that some drugs initially developed to treat other diseases may be potential treatments for chronic kidney disease. The sodium–glucose cotransporter 2 inhibitors, which are commonly used to lower blood sugar levels in people with type 2 diabetes, are examples of such drugs. Data from two studies of sodium–glucose cotransporter 2 inhibitors—the CREDENCE study of canagliflozin in patients with chronic kidney disease and type 2 diabetes and the DAPA-CKD study of dapagliflozin in patients with chronic kidney disease with or without type 2 diabetes—have shown that these drugs reduce the risk of chronic kidney disease progression in these patients. More importantly, the DAPA-CKD study showed that patients with chronic kidney disease who were taking dapagliflozin had a reduced risk of death compared with placebo. These results show that sodium–glucose cotransporter 2 inhibitors are slowing the progression of chronic kidney disease and improve overall outcomes for properly selected patients.