Multiple mechanisms, multiple benefits: SGLT2 inhibition shows promise in lupus, gout
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Last November, at the American College of Rheumatology Convergence 2023, several faculty members presented new data on how a class of drugs used in type 2 diabetes may also be beneficial in patients with lupus and gout.
This class, known as sodium-glucose cotransporter 2 (SGLT2) inhibitors, are typically prescribed to help improve glycemic control, as well as reduce the risks for major adverse cardiovascular events (MACE) and end-stage kidney disease, in patients with type 2 diabetes. However, many trials have also found SGLT2 inhibitors lower serum urate levels. In addition, a study presented at ACR Convergence 2023 suggested they may have a “potential role” in improving outcomes in systemic lupus erythematosus and lupus nephritis, according to April Jorge, MD, who presented the data in question.
“Although gout and lupus are very different diseases, they share the commonalities of recurrent and/or persistent inflammation and increased risks for kidney disease and cardiovascular disease,” Jorge, a member of the Rheumatology & Allergy Clinical Epidemiology Research Center at Massachusetts General Hospital, and assistant professor of medicine in the division of rheumatology, allergy and immunology at Harvard Medical School, told Healio.
“Further research into the anti-inflammatory mechanisms of SGLT2 inhibitors, and of the risks of these medications in patients who receive immunosuppressant medications, would likely have broad implications for better understanding the role of SGLT2 inhibitors in the treatment of multiple potential indications,” she added.
Emily G. Oakes, BA, a research assistant at Brigham and Women’s Hospital, also presented data on SGLT2 inhibition during the last ACR Convergence. However, her conclusions served more as a warning than a potential hope — that women with autoimmune and rheumatic conditions are at a significant risk for urinary and genital infections while using SGLT2 inhibitors. During her presentation, she added that these findings warrant additional study of SGLT2 inhibitors in patients with rheumatic disease, to provide a cost-benefit analysis of SGLT2-inhibitor use.
Despite the potential risks, Oakes stated that randomized, controlled trials investigating SGLT2 inhibition could in fact pay dividends in lupus nephritis.
“In observational studies of lupus nephritis patients taking SGLT2 inhibitors, it would be interesting to see changes in renal metrics such as eGFR and creatinine over time,” she told Healio. “But what we really need are RCTs in this population to see just how useful and safe SGLT2 inhibition may be.”
In the absence of RCTs, retrospective analyses have pointed the way forward for the research community, according to Natalie McCormick, PhD, of the Rheumatology & Allergy Clinical Epidemiology Research Center at Massachusetts General Hospital, and instructor in medicine in the division of rheumatology, allergy and immunology at Harvard Medical School.
McCormick also presented SGLT2-inhibition data at last November’s ACR Convergence, reporting to attendees that the drug class may reduce the risk for gout by as much as 40% to 60% among certain patients with type 2 diabetes treated with metformin.
“Our work demonstrates there is value in leveraging high quality, real-world data from diverse patient populations to evaluate the comparative effectiveness and safety of approved medications like SGLT2 inhibitors,” she told Healio.
A closer look at these data sets may provide a foundation for a new generation of therapies in the rheumatology space.
Mechanisms ‘not fully understood’
In a pragmatic target trial, Jorge and colleagues aimed to compare the impact of SGLT2 inhibitors with dipeptidyl peptidase (DPP4)-4 inhibitors on kidney and cardiovascular outcomes in patients with SLE and lupus nephritis. The researchers included patients diagnosed with SLE between March 2013 and August 2021 from a large, U.S. multicenter EHR-based cohort of 96,511 individuals. They identified 426 patients who used SGLT2 inhibitors and 865 who used DPP4 inhibitors after SLE diagnosis. A subset included 154 and 270 patients with lupus nephritis in the SGLT2- and DPP4-inhibitor arms, respectively.
Results showed that SGLT2 inhibitor use was associated with a lower risk for MACE (HR = 0.69; 95% CI, 0.48-0.99) and renal progression (HR = 0.71; 95% CI, 0.51-0.98), compared with DPP4 inhibition. In the lupus nephritis subgroup, SGLT2 inhibitor use also improved on MACE risk compared with DPP4 inhibitors (HR = 0.58; 95% CI, 0.34-0.99). Also in the lupus nephritis group, renal progression improved with SGLT2 inhibition compared with DPP4 inhibitors, but the difference failed to reach statistical significance, according to the findings.
“There are multiple proposed mechanisms of the kidney and cardiac protective benefits for SGLT2 inhibitors, and this is not completely understood,” Jorge said. “At least part of the kidney benefits are thought to be due to reduced intraglomerular hyperfiltration and reduction of proteinuria. However, it has also been proposed that SGLT2 inhibition may have other anti-inflammatory and anti-fibrotic effects that may impact kidney disease progression.”
She added that the cardiovascular protective benefits are similarly likely due to multiple mechanisms that remain not fully understood.
“In part, this may be mediated by reduction in blood pressure as well as anti-inflammatory effects that lead to reduced endothelial dysfunction and oxidative stress, inhibition of leukocyte adhesion and transmigration, and increased stability of atherosclerotic plaques,” Jorge said, noting findings from de Montages and colleagues published in Frontiers in Pharmacology. “An additional proposed mechanism of cardiovascular benefit is the reduction of AGE-RAGE signaling which is implicated in arterial stiffness.”
According to Jorge, this uncertainty surrounding this mechanism raises the issue of future directions for research.
“We need to better understand when in the course of SLE or lupus nephritis patients will be most likely to benefit from this treatment and which patients are most likely to benefit,” she said. “This will include better understanding the risks for infection and acute kidney injury when patients are undergoing treatment with immunosuppression.”
It is also necessary to determine whether to initiate SGLT2 inhibition in patients with active lupus nephritis or whether these medications should be used in patients with persistent proteinuria related to damage from nephritis.
“This is likely the area with the most immediate treatment implications, because SGLT2 inhibitors have already been included in the recent 2023 EULAR guidelines in the treatment of lupus nephritis,” Jorge said. “In addition to the role of SGLT2 inhibitors in the treatment of lupus nephritis, future research also needs to investigate the potential cardiovascular benefits of SGLT2 inhibitors in patients with lupus more broadly. These studies should include mechanistic studies to better understand the mechanisms of cardiovascular benefits, as well as larger outcomes studies of cardiovascular events.”
As researchers explore these questions, they may gain further understanding by looking at other data sets on this drug class presented at ACR.
‘Multiple benefits’ for gout
In their own study presented at ACR Convergence, McCormick and colleagues compared SGLT2 inhibition with DPP-4 inhibitors, glucagon-like peptide-1 receptor agonists (GLP1-RA) or sulfonylureas regarding the risk for gout in patients with type 2 diabetes who received metformin.
Results showed that SGLT2 inhibition reduced incident gout risk (weighted HR = 0.54; 95% CI, 0.39-0.74) compared with DPP-4i initiation. In addition, similar reductions in gout risk were observed in the comparisons between SGLT2 inhibition and GLP1-RA (weighted HR = 0.39; 95% CI, 0.24-0.62) and SGLT2 inhibitors vs. sulfonylureas (weighted HR = 0.61; 95% CI, 0.46-0.8).
“SGLT2 inhibitors have been shown in randomized trials to lower serum urate levels, and this is the primary hypothesized mechanism for the reduced risk of incident and recurrent gout that we have reported,” McCormick said.
She added that medications in this class exert their primary glucose-lowering effects in the renal proximal tubule — in the kidney — where they induce glucosuria, and this increased urinary glucose is thought to compete with urate for reabsorption by the GLUT9 transporter, thus enhancing urinary excretion of uric acid.
“However, there are likely multiple mechanisms underlying the gout benefits, as SGLT2 inhibitors may also decrease insulin resistance,” McCormick said. “They are believed to affect inflammatory pathways, including interleukin-1ß, a mediator of the inflammatory cascade involved with gout flares.”
At the end of her presentation at ACR Convergence, McCormick suggested that SGLT2 inhibitors could help reduce the overall disease burden of gout in the United States.
“SGLT2 inhibitors have been shown to be effective treatments for many of the cardiometabolic-kidney comorbidities that frequently occur in gout patients, including type 2 diabetes, heart failure and chronic kidney disease,” she said. “Our research shows that SGLT2 inhibition could have multiple benefits for gout patients — reducing the burden of gout comorbidities, and now by also lowering the risk for gout flares themselves. Future research should assess the effectiveness of SGLT2 inhibitors in gout patients without diabetes.”
In addition, although researchers exploring novel medications generally should keep potential risks in mind, McCormick said she is optimistic that this will not be a stumbling block for this drug class.
“SGLT2 inhibitors are generally well tolerated,” she said. “Because they act independently of insulin, hypoglycemia is rare, and they are unlikely to cause kidney stones because they ultimately increase osmotic diuresis and urinary flow.”
However, diabetic ketoacidosis is a rare, serious adverse effect that is more common in patients with identifiable precipitants such as surgery, preparation for colonoscopy and other fasting states, and acute illness, according to McCormick.
“The risk for this adverse effect is reduced by withholding SGLT2 inhibition when acutely ill with limited oral intake, or in the 3 to 4 days prior to procedures,” she said.
As experts weigh this risk in patients treated with SGLT2 inhibitors, it may be necessary to review other data showing additional risks observed in patients treated with medications in this class.
Genitourinary infections ‘of concern’
Oakes and colleagues compared adverse events associated with SGLT2-inhibitor use in patients with and without autoimmune rheumatic diseases. The 519 eligible patients in each group included those who had been prescribed either dapagliflozin (Farxiga, AstraZeneca), canagliflozin (Invokana, Janssen) or empagliflozin (Jardiance, Boehringer Ingelheim) — three of the five SGLT2 inhibitors currently approved by the FDA — between Jan. 1, 2016, and Dec. 10, 2021.
Among 12 categories of adverse events and discontinuations, the most common were yeast infections, which occurred in 9.9% of the autoimmune rheumatic disease cohort and in 6.1% of controls (P = .04). Myalgias and weakness were also more common in the patient group, 3.4% vs. 0.9% (P = .01).
Multivariable analysis additionally demonstrated a significant increased risk for adverse events in the patient group compared with controls (HR = 1.74; 95% CI, 1.33-2.29).
However, perhaps the most striking trend was that women were significantly more likely than men to experience adverse events (P < .00001). Moreover, women in the patient group were more than twice as likely as women without an autoimmune rheumatic condition to experience an adverse event, even after adjusting for glucocorticoid and immunosuppressant use (HR = 2.05; 95% CI, 1.47-2.85).
“Outside of infection type, we don’t have much detail about the severity of the infections,” Oakes said. “However, yeast and urinary tract infections were generally relatively mild, especially if treated early. Only a few of the patients in our cohort were hospitalized, with the most serious adverse event being Fournier’s gangrene, which occurred in one patient with rheumatic disease.”
Although Oakes and colleagues suspect that the overall infection risks may be low, a significant proportion of patients who experienced an infection ultimately discontinued or changed their SGLT2 inhibitor prescription.
“This is of concern, especially given the often-recurrent nature of genitourinary infections,” she said. “Thus, prescribers should be aware of the potential increased risks for genitourinary infections in the immunosuppressed.”
Further study is likely to elucidate both the risks and benefits of SGLT2 inhibition.
In the meantime, experts working in this space said they were encouraged by the findings reported thus far.
“It is exciting to see so many different potential benefits of SGLT2 inhibitor utilization in our rheumatic disease patients,” Oakes said.
References:
Jorge A. Abstract 1579. Presented at: ACR Convergence 2023; Nov. 10-15, 2023; San Diego.
McCormick N. Abstract 742. Presented at: ACR Convergence 2023; Nov. 10-15, 2023; San Diego.
Oakes EG, et al. Abstract 741 Presented at: ACR Convergence 2023; Nov. 10-15, 2023; San Diego.
de Mortanges AP, et al. Frontiers in Pharmacology. 2021;doi: 10.3389/fphar.2021.751214.
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