Given the strong evidence of cardiovascular and kidney-protective effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in patients with type 2 diabetes, heart failure, and chronic kidney disease (CKD), research is needed to assess the similar effects of SGLT-2 inhibitors in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lupus nephritis, according to a viewpoint published in Annals of the Rheumatic Diseases.1

Although initially studied as antidiabetic drugs, SGLT-2 inhibitors have emerged as potent cardiovascular and kidney protectors, reducing albuminuria and preventing the decline in estimated glomerular filtration rate (eGFR) in patients with CKD.1

The SGLT-2 inhibitors block the reabsorption of glucose and sodium in the proximal tubules of the nephron, which may confer kidney-protective effects by changing the hemodynamics of the glomerulus. Through feedback in the macula densa, the increased sodium and calcium in the tubule leads to vasoconstriction of the afferent arterioles and vasodilation of the efferent arterioles that decreases glomerular pressure, hyperfiltration, and proximal tubule workload.1


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Clinical trials have showed that SGLT-2 inhibitors reduce the progression of CKD and adverse cardiovascular events in patients with type 2 diabetes, heart failure , and CKD, both among those with and without diabetes. The robust effects observed with SGLT-2 inhibitors and their favorable safety profile have led to their inclusion as a therapy recommendation in patients with these conditions.1

However, most clinical trials have excluded patients with autoimmune kidney diseases. An exception that offers a glimpse of the potential of SGLT-2 inhibitors in these patients is the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial (DAPA-CKD; ClinicalTrials.gov Identifier: NCT03036150).1

In DAPA-CKD, the researchers evaluated the effects of SGLT-2 inhibitor dapagliflozin, along with angiotensin-blocking agents, on the progression of kidney disease in patients with CKD, including those with immunoglobulin A (IgA) nephropathy. Overall, the researchers observed a 39% reduction in the primary outcome (≥50% decline in eGFR, end-stage kidney disease, or death from cardiovascular or renal causes).2 Patients with IgA nephropathy showed an unprecedented 71% reduction in the primary outcome,3 suggesting CKD treatment may be more beneficial than immunosuppression.

Patients with AAV and systemic lupus erythematosus have a significantly increased risk for cardiovascular morbidity and mortality, with both inflammation and long-term use of immunosuppressants contributing to this risk. In patients with AAV with kidney involvement and lupus nephritis, CKD is a strong cardiovascular risk factor. Efforts to prevent CKD progression, such as with SGLT-2 inhibitors, may have a positive effect on patient outcomes.1

Inhibition with SGLT-2 was noted to be a simple and cheap therapeutic strategy that could ultimately have organ protection as well as increase the health and lifespan of affected individuals by reducing their cardiovascular risk.1

To better understand SGLT-2 inhibitors and its potential application in autoimmune diseases, we spoke with lead author of the viewpoint, Marcus Säemann, MD, 6th Medical Department, Nephrology and Dialysis, Clinic Ottakring, Vienna, Austria.

Based on the DAPA-CKD study, it is suggested that patients with glomerulonephritis may benefit more from treatment of their CKD than from immunosuppression. Can you explain why that is? Do you think this may hold true for patients with AAV and lupus nephritis? 

Principally, the effect size in terms of nephroprotection with SGLT-2 inhibitors is considerable and far exceeds that of angiotensin-converting enzyme (ACE) inhibition. Hence, SGLT-2 inhibitors should be part of a foundation therapy of any nephroprotective therapy in most forms of CKD. Ideally, in patients with glomerulonephritis, a specific targeted therapy is combined with an SGLT-2 inhibitor to gain a maximal therapeutic effect.

Your paper focuses on AAV and lupus nephritis. Would SGLT-2 inhibitors have a role in the treatment of patients with rheumatoid arthritis and other autoimmune diseases who are also at increased risk for cardiovascular and kidney disease? 

Yes, as mentioned above, SGLT-2 inhibitors should be part of a modern nephroprotective strategy in patients with or at risk for kidney disease or heart failure, or both. Prospective studies among these patients should be performed.

What studies are currently underway to assess SGLT-2 inhibitor therapy in people with AAV and lupus nephritis?

Unfortunately, on www.clinicaltrials.gov, no studies can be found. However, I am aware of 1 study that is in the planning phase with patients with AAV and SGLT-2 inhibitors. More and larger studies should be planned and executed in patients with AAV and lupus nephritis.

Disclosures: The authors of the viewpoint declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

References

1. Säemann M, Kronbichler A. Call for action in ANCA-associated vasculitis and lupus nephritis: promises and challenges of SGLT-2 inhibitors. Ann Rheum Dis. Published online November 29, 2021. doi:10.1136/annrheumdis-2021-221474

2. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. Published online October 8, 2020. doi:10.1056/NEJMoa2024816

3. Wheeler DC, Toto RD, Stefánsson BV, et al; DAPA-CKD Trial Committees and Investigators. A pre-specified analysis of the DAPA-CKG trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int. Published online April 17, 2021. doi.org/10.1016/j.kint.2021.03.033