Sodium-glucose cotransporter-2 (SGLT2) inhibitors, a class of medications primarily used to manage type 2 diabetes, have been found to significantly reduce the risk of lupus nephritis, dialysis, kidney transplant, heart failure, and all-cause mortality in patients with both systemic lupus erythematosus (SLE) and type 2 diabetes. The research, led by Dr. Fu-Shun Yen from Taiwan, utilized data from 59 U.S. healthcare organizations compiled in the TriNetX clinical database. The study evaluated how SGLT2 inhibitors affect kidney and cardiac outcomes in patients with these conditions, which significantly increase the risk of kidney and cardiovascular disease.
Patients with SLE and lupus nephritis are often excluded from randomized trials of SGLT2 inhibitors due to the frequent use of steroids and other immunosuppressive treatments, which can complicate blood glucose control and outcome assessments. This study aimed to address that gap by retrospectively analyzing data to evaluate the potential benefits of SGLT2 inhibitors in this patient population. The multicenter cohort study involved 1,775 SGLT2 inhibitor users matched with non-users. Researchers assessed five-year risks for lupus nephritis, dialysis, kidney transplant, heart failure, and all-cause mortality. Using Kaplan-Meier and Cox regression models, the study found that SGLT2 inhibitor users had significantly reduced risks for lupus nephritis (aHR = 0.55), dialysis (aHR = 0.29), kidney transplant (aHR = 0.14), heart failure (aHR = 0.65), and all-cause mortality (aHR = 0.35).
There are four SGLT2 inhibitors approved by the Food and Drug Administration (FDA) for use in adults: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. All four SGLT2 inhibitors act by reducing the reabsorption of filtered glucose, lowering the renal threshold for glucose (RTG), and promoting urinary glucose excretion. These inhibitors reduce HbA1c by 0.7%. By blocking SGLT2-dependent glucose and sodium reabsorption, they increase the sodium load in the distal tubules, which leads to inhibition of the renin-angiotensin-aldosterone system and a reduction in both afterload and preload, thereby providing cardioprotective benefits.
The researchers emphasized that SGLT2 inhibitors can reduce the risk of heart failure in patients, particularly important for individuals with SLE who are already at an elevated risk of cardiovascular disease due to inflammation. The study suggests that SGLT2 inhibitors could potentially provide dual benefits for managing both kidney and cardiovascular complications in patients with SLE and type 2 diabetes. In a similar study, Heerspink and colleagues found that among patients with chronic kidney disease, regardless of the presence of diabetes, the risk of experiencing a sustained decline in estimated glomerular filtration rate of at least 50%, developing end-stage kidney disease, or experiencing death from renal or cardiovascular causes was significantly lower with the SGLT2 inhibitor dapagliflozin.
The researchers concluded that the study underscores the potential of SGLT2 inhibitors not only to reduce the incidence of lupus nephritis but also to lessen the need for dialysis and kidney transplants and to lower all-cause mortality risks. The researchers also noted that future rigorous prospective studies and randomized controlled trials are necessary to confirm these findings and establish the efficacy of SGLT2 inhibitors in clinical practice for patients with SLE and type 2 diabetes.
In summary, the use of SGLT2 inhibitors in patients with both SLE and type 2 diabetes appears to offer significant protective benefits against kidney and cardiac complications, suggesting a promising therapeutic approach that warrants further investigation.
References
- Yen FS, Wang SI, Hsu CC, Hwu CM, Wei JCC. Sodium-Glucose Cotransporter-2 Inhibitors and Nephritis Among Patients With Systemic Lupus Erythematosus. JAMA Network Open. 2024 Jun 12;7(6):e2416578.
- Padda IS, Mahtani AU, Parmar M. Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Jul 23]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK576405/.
- Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436–46.