Review: SGLT2 Inhibitors Hold Promise in Improving Renal Outcomes

Sodium-glucose co-transporter-2 inhibitors (SGLT2is) can improve cardiovascular and renal outcomes in patients with type 2 diabetes (T2D) , but the mechanisms by which it confers that protection remain the subject of investigation.

In a new review article published in Frontiers in Medicine, corresponding author Franco Arturi, MD, PhD, of the University Magna Graecia of Catanzaro in Italy, and colleagues outlined the results of major trials examining the renal and cardiovascular (CV) effects of the therapy and hypothesized about future directions of research.

Drugs like SGLT2is are important, Arturi and colleagues wrote, because patients with T2D face a significant risk of developing chronic kidney disease (CKD), which can then lead to end-stage kidney disease (ESKD).

“Control of blood glucose and blood pressure (BP) reduces the risk of developing this complication, but once diabetic nephropathy is established, it is then only possible to slow its progression,” they said.

SGLT2is have been shown to lower glycated hemoglobin (A1C), induce weight loss and improve BP, lipid profile, albuminuria, and uric acid, the investigators wrote.

Clinical trials have been conducted on a handful of SGLT2is, including empagliflozin (Jardiance), dapagliflozin (Farxiga), canagliflozin (Invokana), and ertugliflozin (Steglatro). Yet, Arturi and colleagues said most of the early major trials left key questions unresolved.

“The nephroprotective effects of SGLT2is have been demonstrated in several major intervention studies,” they wrote. “However, all these trials were designed to investigate CV outcomes in patients with T2D and established atherosclerotic CV disease or multiple CV risk and the renal endpoints were evaluated only as a secondary outcome.”

More recent trials have looked at renal outcomes as a primary endpoint, they said.

The CREDENCE trial, for instance, showed that when paired with standard nephroprotective treatment, canagliflozin led to a 30% reduction in the risk of severe renal outcomes.

“More importantly, this effect was independent of the baseline estimated glomerular filtration rate, being true also for patients with more advanced CKD,” the investigators wrote.

Meanwhile, the DAPA-CKD trial of dapagliflozin examined CKD in patients with or without diabetes and found that SGLT2is significantly reduced the risk of outcomes such as ESKD or death from renal or cardiovascular causes.

The investigators then turned their attention to SGLT2is’ place in the wider treatment landscape, arguing that they could play an interesting role in bringing about more personalized therapies.

One possibility, they said, “would be to start more studies testing whether the combination of more drugs (including SGLT2is) with different mechanisms of action would warrant a better prognosis in CKD patients and what type of CKD patients would benefit from these combinations.” Such studies could create the possibility of tailoring therapeutic combinations to patients with specific characteristics.

Arturi and colleagues said new types of trials, such as basket trials and platform trials—where patients can be started on or withdrawn from specific treatments without leaving the testing protocol—may aid in better understanding how personalization might work in this therapeutic category.

The investigators said future studies should be directed at better understanding the mechanisms of cardiorenal protection of SGLT2is, and how the combination of SGLT2is with other nephroprotective treatments might improve outcomes.

Reference:

Provenzano M, Pelle MC, Zaffina I, et al. Sodium-Glucose co-transporter-2 inhibitors and nephroprotection in diabetic patients: more than a challenge. Front Med (Lausanne). Published online June 4, 2021. doi:10.3389/fmed.2021.654557