Over just a decade, sodium-glucose cotransporter-2 (SGLT2) inhibitors have revolutionized the second-line treatment of type 2 diabetes by improving the control of blood sugar, and they're also being used to treat heart failure and chronic kidney disease. Now, there's growing evidence that the medications have the potential to play a role in the treatment of a variety of rheumatologic diseases — gout, systemic lupus erythematosus (SLE), and lupus nephritis.
"I suspect that SGLT2 inhibitors may have a role in multiple rheumatic diseases," said rheumatologist April Jorge, MD, of Harvard Medical School and Massachusetts General Hospital, Boston.
In gout, for example, "SGLT2 inhibitors hold great promise as a multipurpose treatment option," said rheumatologist Chio Yokose, MD, MSc, also of Harvard Medical School and Massachusetts General Hospital. Both Dr Jorge and Dr Yokose spoke at recent medical conferences and in interviews about the potential value of the drugs in rheumatology.
There's a big caveat. For the moment, SGLT2 inhibitors aren't cleared for use in the treatment of rheumatologic conditions, and neither physician is ready to recommend prescribing them off-label outside of their FDA-approved indications.
But studies could pave the way toward more approved uses in rheumatology. And there's good news for now: Many rheumatology patients may already be eligible to take the drugs because of other medical conditions. In gout, for example, "sizable proportions of patients have comorbidities for which they are already indicated," Dr Yokose said.
Research Hints at Gout-Busting Potential
The first SGLT2 inhibitor canagliflozin (Invokana), received FDA approval in 2013, followed by dapagliflozin (Farxiga), empagliflozin (Jardiance), ertugliflozin (Steglatro), and bexagliflozin (Brenzavvy). The drugs "lower blood sugar by causing the kidneys to remove sugar from the body through urine," reports the National Kidney Foundation, and they "help to protect the kidneys and heart in people with CKD [chronic kidney disease]."
As Dr Yokose noted in a presentation at the 2023 Gout Hyperuricemia and Crystal Associated Disease Network research symposium, SGLT2 inhibitors "have really become blockbuster drugs, and they've now been integrated into multiple professional society guidelines and recommendations."
These drugs should not be confused with the wildly popular medications known as glucagon-like peptide-1 (GLP1) agonists, which include medications such as semaglutide (Ozempic and Wegovy). These drugs are generally administered via injection — unlike the oral SGLT2 inhibitors — and they're variously indicated for type 2 diabetes and obesity.
Dr Yokose highlighted research findings about the drugs in gout. A 2020 study, for example, tracked 295,907 US adults with type 2 diabetes who received a new prescription for an SGLT2 inhibitor or GLP1 agonist during 2013-2017. Those in the SGLT2 inhibitor group had a 36% lower risk of newly diagnosed gout (hazard ratio [HR], 0.64; 95% CI, 0.57-0.72), the researchers reported.
A similar study, a 2021 report from Taiwan, also linked SGLT2 inhibitors to improvement in gout incidence vs dipeptidyl peptidase 4 (DPP4) inhibitors, diabetes drugs that are not linked to lower serum urate levels. In an adjusted analysis, the risk of gout was 11% lower in the SGLT2 inhibitor group (adjusted HR, 0.86; 95% CI, 0.78-0.95).
What about recurrent gout? In a 2023 study, Dr Yokose and colleagues tracked patients with type 2 diabetes who began SGLT2 inhibitors or DPP4 inhibitors. Over the period from 2013 to 2017, those who took SGLT2 inhibitors were less likely to have gout flares (rate ratio [RR], 0.66; 95% CI, 0.57-0.75) and gout-primary emergency department visits/hospitalizations (RR, 0.52; 95% CI, 0.32-0.84).
"This finding requires further replication in other populations and compared to other drugs," Dr Yokose cautioned.
Another 2023 study analyzed UK data and reached similar results regarding risk of recurrent gout.
Lower Urate Levels and Less Inflammation Could Be Key
How might SGLT2 inhibitors reduce the risk of gout? Multiple studies have linked the drugs to lower serum urate levels, Dr Yokose said, but researchers often excluded patients with gout.
For a small new study presented at the 2023 annual meeting of the American College of Rheumatology but not yet published, Dr Yokose and colleagues reported that patients with gout who began SGLT2 inhibitors had lower urate levels than those who began a sulfonylurea, another second-line agent for type 2 diabetes. During the study period, up to 3 months before and after initiation, 43.5% of patients in the SGLT2 inhibitor group reached a target serum urate of < 6 mg/dL vs 4.2% of sulfonylurea initiators.
"The magnitude of this reduction, while not as large as what can be achieved with appropriately titrated urate-lowering therapy such as allopurinol or febuxostat, is also not negligible. It's believed to be between 1.5-2.0 mg/dL among patients with gout," Dr Yokose said. "Also, SGLT2 inhibitors are purported to have some anti-inflammatory effects that may target the same pathways responsible for the profound inflammation associated with acute gout flares. However, both the exact mechanisms underlying the serum urate-lowering and anti-inflammatory effects of SGLT2 [inhibitors] require further research and clarification."
Moving forward, she said, "I would love to see some prospective studies of SGLT2 inhibitor use among patients with gout, looking at serum urate and clinical gout endpoints, as well as biomarkers to understand better the beneficial effects of SGLT2 inhibitors as it pertains to patients with gout."
In Lupus, Findings Are More Mixed
Studies of SGLT2 inhibitors have excluded patients with lupus, limiting insight into their benefits in that specific population, said Dr Jorge of Massachusetts General Hospital and Harvard Medical School. However, " one small phase I/II trial showed an acceptable safety profile of dapagliflozin add-on therapy in adult patients with SLE," she said.
Her team is working to expand understanding about the drugs in people with lupus. At the 2023 ACR annual meeting, she presented the findings of a study that tracked patients with SLE who took SGLT2 inhibitors (n = 426, including 154 with lupus nephritis) or DPP4 inhibitors (n = 865, including 270 with lupus nephritis). Patients who took SGLT2 inhibitors had lower risks of major adverse cardiac events (HR, 0.69; 95% CI, 0.48-0.99) and renal progression (HR, 0.71; 95% CI, 0.51-0.98).
"Our results are promising, but the majority of patient with lupus who had received SGLT2 inhibitors also had the comorbidity of type 2 diabetes as a separate indication for SGLT2 inhibitor use," Dr Jorge said. "We still need to study the impact of SGLT2 inhibitors in patients with SLE and lupus nephritis who do not have a separate indication for the medication."
Dr Jorge added that "we do not yet know the ideal time to initiate SGLT2 inhibitors in the treatment of lupus nephritis. Specifically, it is not yet known whether these medications should be used in patients with persistent proteinuria due to damage from lupus nephritis or whether there is also a role to start these medications in patients with active lupus nephritis who are undergoing induction immunosuppression regimens."
However, another study released at the 2023 ACR annual meeting suggested that SGLT2 inhibitors may not have a beneficial effect in lupus nephritis: "We observed a reduction in decline in eGFR [estimated glomerular filtration rate] after starting SGLT2 inhibitors; however, this reduction was not statistically significant…early experience suggested marginal benefit of SGLT2 inhibitors in SLE," researchers from Johns Hopkins University, and the University of Maryland, Baltimore, reported.
"My cohort is not showing miracles from SGLT2 inhibitors," study lead author Michelle Petri, MD, MPH, of Johns Hopkins, said in an interview.
Still, new European Alliance of Associations for Rheumatology recommendations for SLE now advise to consider the use of the drugs in patients with lupus nephritis who have reduced eGFR. Meanwhile, "the American College of Rheumatology is currently developing new treatment guidelines for SLE and for lupus nephritis, and SGLT2 inhibitors will likely be a topic of consideration," Dr Jorge added.
As for mechanism, Dr Jorge said it's not clear how the drugs may affect lupus. "It's proposed that they have benefits in hemodynamic effects as well as potentially anti-inflammatory effects. The hemodynamic effects, including reducing intraglomerular hyperfiltration and reducing blood pressure, likely have similar benefits in patients with chronic kidney disease due to diabetic nephropathy or due to lupus nephritis with damage/scarring and persistent proteinuria. Patients with SLE and other chronic, systemic rheumatic diseases such as ANCA [antineutrophilic cytoplasmic antibody]-associated vasculitis also develop kidney disease and cardiovascular events mediated by inflammatory processes."
Side Effects and Cost: Where Do They Fit In?
According to Dr Yokose, SGLT2 inhibitors "are generally quite well-tolerated, and very serious adverse effects are rare." Side effects include disrupted urination, increased thirst, genital infections, flu-like symptoms, and swelling.
Urinary-related problems are understandable "because these drugs cause the kidneys to pass more glucose into the urine," University of Hong Kong cardiac specialist Bernard Cheung, MBBCh, PhD, who has studied SGLT2 inhibitors, said in an interview.
In Dr Yokose's 2023 study of SGLT2 inhibitors in recurrent gout, patients who took the drugs were 2.15 times more likely than the comparison group to have genital infections (hazard ratio, 2.15; 95% CI, 1.39-3.30). This finding "was what we'd expect," she said.
She added that genital infection rates were higher among patients with diabetes, women, and uncircumcised men. "Fortunately, most experienced just a single mild episode that can readily be treated with topical therapy. There does not appear to be an increased risk of urinary tract infections."
Dr Cheung added that "doctors should be aware of a rare adverse effect called euglycemic ketoacidosis, in which the patient has increased ketones in the blood causing it to be more acidic than normal, but the blood glucose remains within the normal range."
As for cost, goodrx.com reports that several SGLT2 inhibitors run about $550-$683 per month, making them expensive but still cheaper than GLP-1 agonists, which can cost $1000 or more per month. Unlike the most popular GLP-1 agonists such as Ozempic, none of the SGLT2 inhibitors are in short supply, according to the American Society of Health-System Pharmacists.
"If someone with gout already has a cardiovascular-kidney-metabolic indication for SGLT2 inhibitors and also stands to benefit in terms of lowering serum urate and risk of recurrent gout flares, there is potential for high benefit relative to cost," Dr Yokose said.
She added: "It is well-documented that current gout care is suboptimal, and many patients end up in the emergency room or hospitalized for gout, which in and of itself is quite costly both for the patient and the health care system. Therefore, streamlining or integrating gout and comorbidity care with SGLT2 inhibitors could potentially be quite beneficial for patients with gout."
In regard to lupus, "many patients with lupus undergo multiple hospitalizations related to their disease, which is a source of high health care costs," Dr Jorge said. "Additionally, chronic kidney disease and cardiovascular disease are major causes of disability and premature mortality. Further studies will be needed to better understand whether benefits of SGLT2 inhibitors may outweigh the costs of treatment."
As for prescribing the drugs in lupus now, Dr Jorge said they can be an option in lupus nephritis. "There is not a clear consensus of the ideal timing to initiate SGLT2 inhibitors — e.g., degree of proteinuria or eGFR range," she said. "However, it is less controversial that SGLT2 inhibitors should be considered in particular for patients with lupus nephritis with ongoing proteinuria despite adequate treatment with conventional therapies."
As for gout, Dr Yokose isn't ready to prescribe the drugs to patients who don't have comorbidities that can be treated by the medications. However, she noted that those patients are rare.
"If I see a patient with gout with one or more of these comorbidities, and I see that they are not already on an SGLT2 inhibitor, I definitely take the time to talk to the patient about this exciting class of drugs and will consult with their other physicians about getting them started on an SGLT2 inhibitor."
Dr Yokose, Dr Petri, and Dr Cheung have no relevant disclosures. Dr Jorge disclosed serving as a site investigator for SLE clinical trials funded by Bristol-Myers Squibb and Cabaletta Bio; the trials are not related to SGLT2 inhibitors.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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