SGLT2 inhibitors slash risks for lupus nephritis, heart failure in SLE, type 2 diabetes
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Key takeaways:
- SGLT2 inhibitors reduce the risks for adverse kidney and cardiac outcomes in patients with lupus and type 2 diabetes.
- SGLT2 inhibitor users were just over half as likely to develop lupus nephritis vs. non-users.
Treatment with sodium-glucose cotransporter-2 inhibitors significantly lowered risks for lupus nephritis, dialysis and kidney transplant for patients with systemic lupus erythematosus and type 2 diabetes, according to data.
The study, published in JAMA Network Open, also found that sodium-glucose cotransporter-2 (SGLT2) inhibitors reduced risks for heart failure and all-cause mortality.
“Although several randomized trials of sodium-glucose cotransporter-2 inhibitors have suggested their potential to reduce the incidence and progression of chronic kidney disease, patients with SLE and lupus nephritis are often excluded from these trials,” Fu-Shun Yen, MD, of Dr. Yen’s Clinic, in Taoyuan, Taiwan, told Healio. “This is due to the frequent use of steroids and other immunosuppressive treatments, which can affect blood glucose control and complicate outcome assessments.”
To examine whether SGLT2 inhibition is associated with the onset or progression of lupus nephritis, as well as other kidney and cardiac outcomes, in SLE and type 2 diabetes, Yen and colleagues conducted a retrospective cohort study of data from 59 U.S. health care organizations using the TriNetX clinical database. The researchers estimated the 5-year adjusted HRs for lupus nephritis, dialysis and other outcomes using Kaplan-Meier analysis and Cox proportional hazards regression models.
To be eligible for inclusion, participants had to have been diagnosed with SLE and comorbid type 2 diabetes. Although the two conditions “do not commonly occur together,” patients with both “may have greater risk of poor outcomes because both conditions are associated with kidney and cardiovascular disease,” the researchers wrote.
The study included 1,775 SGLT2 inhibitor users, defined as those prescribed an SGLT2 inhibitor at least once during the study, who were matched with an equal number of non-users through a propensity score matching process. The participants’ overall mean age was 56.8 years.
Compared with non-users, SGLT2 inhibitor users demonstrated significantly lower risks for lupus nephritis (aHR = 0.55; 95% CI, 0.4-0.77), dialysis (aHR = 0.29; 95% CI, 0.17-0.48), kidney transplant (aHR = 0.14; 95% CI, 0.03-0.62), heart failure (aHR = 0.65; 95% CI, 0.53-0.78), and all-cause mortality (aHR = 0.35; 95% CI, 0.26-0.47), according to the researchers.
Yen highlighted that the reduced risk for heart failure was particularly surprising.
“Given that patients with SLE are at increased risk for cardiovascular disease due to systemic inflammation, it appears that SLGT2 inhibitors may offer the added benefit of reducing the risk for heart failure in this patient population,” he said.
“For clinicians, the significance of our study lies in its novel finding that the use of SGLT2 inhibitors in patients with SLE may potentially reduce the incidence for lupus nephritis, the need for dialysis and kidney transplant, and the risk for all-cause mortality compared to not using SGLT2 inhibitors,” Yen added. “Future research is needed to investigate whether SGLT2 inhibitors can help slow the progression of lupus nephritis. Future rigorous prospective studies and randomized trials are needed to confirm our findings and enable their application in clinical practice for patients.
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
SGLT2 inhibitors are a class of medications that inhibit sodium-glucose transport proteins in the nephron. They have been approved for diabetes mellitus type 2, but have also been approved for heart failure, regardless of left ventricular ejection fraction, and chronic kidney disease. These drugs work by inhibiting reabsorption of glucose in the kidney, thereby lowering blood sugar.
There are now 18 of these medications worldwide, with six approved by the FDA. Reported adverse events include genital infections, fungal infections, urinary tract infections and osmotic diuresis, all linked to the inhibition of reabsorption of glucose with the subsequent load of glucose in the urine.
Another unusual side effect, which one of my patients has experienced, is euglycemic diabetic ketoacidosis (EDKA). This is due to carbohydrate deficit from glucosuria, with decreased insulin and elevated glucagon. The increased glucagon-insulin ratio leads to increased lipolysis, increased free fatty acids and ketoacidosis. There is also volume depletion from the osmotic diuresis.
SGLT2 inhibitors also directly stimulate glucagon release and increase reabsorption of ketones. There is a high risk for this form of DKA in the perioperative period, and the FDA now recommends that these drugs be stopped before surgery. Other causes of EDKA include infection, trauma, a major illness, reduced food intake, gastroparesis, persistent vomiting, pregnancy, dehydration and reduced insulin dosages.
In the present study, SGLT2-inhibitor users consistently had a lower risk for lupus nephritis, dialysis, heart failure and all-cause mortality vs. nonusers. We look forward to further developments in this area.
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