Can SGLT2 Inhibitors Protect Our SLE Patients?

Plenary Session 2 Highlights Sodium-Glucose Co-Transporter-2 Inhibitors at ACR Convergence 2023

Dr. April Jorge

SAN DIEGO—The ACR Convergence Plenary Sessions highlight selected abstracts of interest to the general ACR audience. In the second plenary session this year, April M. Jorge, MD, assistant professor of medicine, Harvard Medical School and director of the lupus program, Massachusetts General Hospital, Boston, shared fascinating results on the potential cardio- and renal-protective benefits of sodium-glucose co-transporter-2 inhibitors (SGLT2i) in patients with systemic lupus erythematosus (SLE) and lupus nephritis.¹

Background

Dr. Jorge commenced her talk with some sobering facts. “Despite recent improvements in SLE treatment, patients with SLE and [lupus nephritis] have an increased risk of cardiovascular (CV) events and kidney failure,” Dr. Jorge said. “In fact, the CV risk is more than double that of the general population. Up to 50% of patients with SLE will develop [lupus nephritis], and 10–30% of these patients will progress to end-stage renal disease (ESRD). There is a major unmet need to improve these outcomes.”

Sodium-glucose co-transporter-2 inhibitors are a class of oral hypoglycemic agents that have been found to reduce the progression of chronic kidney disease and prevent major adverse cardiovascular events (MACE), independent of glycemic control. There are multiple proposed mechanisms of action for these benefits, including anti-inflammatory effects.² The trouble is that patients with SLE have been excluded from trials that demonstrated these benefits—until now.

Objective & Study Design

Jorge et al. sought to determine the impact of SGLT2i vs. a comparator oral hypoglycemic agent (dipeptidyl peptidase 4 inhibitors [DPP4i]) on kidney and CV outcomes in patients with SLE and lupus nephritis. They used a target trial emulation framework. ³

The target trial emulation framework is essentially a hypothetical randomized controlled trial (RCT) using real-world observational data. Dr. Jorge explained, “With this framework, it’s important to state all the key protocol components and specify how you will emulate each using your observational data.”

Randomization of treatment assignment was emulated with propensity score overlap weighting such that baseline patient characteristics were balanced between groups.

The researchers used observational data from a multi-center electronic health records database that included patient information from 46 healthcare organizations across the U.S. Given the use of oral hypoglycemics, these were patients with SLE, as well as a subgroup with lupus nephritis, who also had type 2 diabetes (DM2) and were initiated on any of the FDA-approved SGLT2i (e.g., canagliflozin) and DPP4i (e.g., sitagliptin) in the U.S. Patients with ESRD were excluded.

Results

As for efficacy outcomes, Jorge et al. examined the following:

1. Renal progression, defined as a decrease in estimated glomerular filtration rate (eGFR) by less than or equal to 30%, or new ESRD
2. MACE, defined as ischemic stroke, myocardial infarction, venous thrombosis, cardiovascular death or heart failure.

Regarding safety outcomes, they examined genital infections (e.g., candidiasis), because these are a known potential side effect of SGLT2i, and serious infections (e.g., pyelonephritis).

For patients with SLE, SGLT2i was associated with lower risk of MACE (HR 0.69, 95% CI 0.48–0.99) and renal progression (HR 0.71, 95% CI 0.52–0.98) than DPP4i use.

“This translates to an absolute risk reduction (ARR) of 4.1 MACE events and 4.7 renal progression events per 100 person years in people with SLE,” explained Dr. Jorge.

For patients with SLE and lupus nephritis, there was a larger ARR of 10.2 MACE per 100 person years, but no statistically significant difference in renal progression. “This may be due to the fact that this was a smaller group,” Dr. Jorge noted.

The cumulative incidence of MACE and renal progression over three years of follow-up was also lower in patients who received SGLTi.

As expected, there was an increased risk of genital infection in the SGLT2i group. “Most of these are benign, easily treated yeast infections,” Dr. Jorge explained. There was no increase in the risk of severe infections.

Of note, Dr. Jorge clarified, “Because these patients also had DM2, we cannot necessarily say how much of the component of kidney progression we prevented was related to SLE as opposed to DM2. But I think it’s really important that this is some of first real-world data we have in patients with SLE. We definitely need more data.”

Are we now beyond needing randomized controlled trials?

An audience member asked about the need for RCTs now that the target trial emulation framework is available.

Dr. Jorge responded, “I think there is definitely a role for RCTs. A limitation of this study is that the patients also had to have DM2. An RCT would be needed to study this medication in people without another indication for SGLT2i. Also, the target trial emulation framework is most useful when comparing two different treatment options. It’s a bit more difficult to emulate a placebo-controlled trial. The benefit here is that you can compare the effectiveness of treatment in populations who would otherwise be excluded from RCTs.”

Conclusion

In this cohort of patients with SLE and DM2 who initiated SGLT2i or DPP4i, Jorge et al. found that SGLT2i use was associated with a lower risk of MACE and renal progression. Dr. Jorge concluded, “Our findings suggest a potential role for SGLT2i to improve outcomes in our SLE and LN patients. Further research is warranted. Next steps would include mechanistic studies of SGLT2i, as well as prospective studies and RCTs in patients with SLE and lupus nephritis, ideally without a separate indication of DM2, to confirm these findings.”

Samantha C. Shapiro, MD, is the executive editor of Harrison’s Principles of Internal Medicine. As a clinician educator, she practices telerheumatology and writes for both medical and lay audiences.

References

1. Jorge A, Zhou B, McCormick N, et al. Sodium-glucose co-transporter-2 inhibitors and the risk of cardiac and renal outcomes in systemic lupus erythematosus [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9).
2. Cowie MR, Fisher M. SGLT2 inhibitors: Mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol. 2020 Dec;17(12):761–772.
3. Hernán MA, Wang W, Leaf DE. Target trial emulation: A framework for causal inference from observational data. JAMA. 2022;328(24):2446–2447.