Case Grows for SGLT2 Inhibitors as Gout Treatment
by John Gever, Contributing Writer, MedPage Today August 28, 2023
Patients with gout and type 2 diabetes treated with SGLT2 inhibitors not only had reduced numbers of gout flares, but also lived longer compared with other such patients receiving other medications, researchers said.
Among nearly 6,000 British patients with the two conditions followed for a median of almost 3 years, those taking SGLT2 inhibitors experienced an approximately 21% average reduction in gout flare incidence versus people taking agents such as GLP-1 receptor agonists or DPP-4 inhibitors, according to Guanghua Lei, MD, PhD, of Central South University in Changsha, China, and colleagues.
The mortality reduction with SGLT2 inhibitors was even more impressive: about 30%, the group reported in JAMA Network Open.
SGLT2 inhibitors, also known as gliflozins, force glucose excretion and thus first found an application in type 2 diabetes. But studies have also shown that these agents alter physiology beyond merely reducing blood glucose, leading to lower incidence of major cardiovascular events and death, even in individuals without overt diabetes. Importantly, SGLT2 inhibitors also seem to reduce serum urate.
Thus, an application to gout seemed like a good bet, and it's been confirmed in a number of retrospective analyses. One such study in 2021 showed reduced incidence of new-onset gout with SGLT2 inhibitor treatment in people with type 2 diabetes. Another, reported just a few months ago, added to that evidence in a large population-based analysis.
But no study had yet examined the potential to reduce rates of recurrent flares in patients with inadequately controlled gout as well as mortality. Therefore, Lei and colleagues turned to a database extracted from general medicine practices in Great Britain, covering some 19 million people.
The researchers searched these records for patients with both gout and type 2 diabetes (the diseases are often comorbid insofar as they involve many of the same risk factors, particularly diet and excess body weight). Ultimately they identified 5,931 whose records indicated new treatment with either SGLT2 inhibitors (n=1,548) or agents targeting GLP-1 (n=324) or DPP-4 (n=4,059). Median follow-up from drug initiation varied from about 2.5 to 3.0 years depending on which outcome was analyzed. Major outcomes were the first recurrence of gout flare, numbers of such flares, and all-cause mortality.
About 80% across all groups were men (though somewhat more commonly among SGLT2 inhibitor users), mean age was 62, and most were overweight or obese. Mean gout duration was about 11 years, and for diabetes it was about 8 years. Most patients were taking a host of other medications besides anti-diabetics, including blood-pressure reducers, painkillers, and stomach acid inhibitors. Just under half were taking urate-lowering agents.
Dapagliflozin (Farxiga) and empagliflozin (Jardiance) were each used by about 40% of patients taking SGLT2 inhibitors, with canagliflozin (Invokana) accounting for the rest. Distributions of DPP-4 inhibitors and GLP-1 drugs weren't reported.
Risk of first recurrent gout flare was 32.4 per 1,000 person-years with gliflozin treatment versus 41.2 in those taking the anti-diabetic comparators. That translated to a hazard ratio of 0.78 after adjusting for age, sex, and year of drug initiation (95% CI 0.64-0.95), Lei and colleagues reported.
For mortality, the rates per 1,000 person-years were 18.8 and 24.9, respectively, for an adjusted hazard ratio of 0.67 (95% CI 0.51-0.89) favoring SGLT2 inhibitors.
The difference in overall gout flare rates was similar to the other outcomes between the gliflozin users and the comparators. The excess risk with non-gliflozin treatment was most prominent during the first few months of therapy, the researchers observed.
Lei and colleagues noted that the exact mechanism underlying the apparent benefit from gliflozins remains unclear, with a variety of theories proposed. One is that their action to dump glucose into the urine also forces urate excretion; others suggest additional effects not involving sodium-glucose transport. Further studies are needed to fully explain the phenomenon.
Limitations to the study included its reliance on administrative data and its retrospective observational design. As such, unmeasured factors influencing patients' outcomes may have been imbalanced between groups. Drug initiation was identified through prescriptions; actual adherence was unknown. Also, the researchers acknowledged that results cannot be generalized to patients receiving care outside the National Health Service's general practices included in the database. Perhaps most importantly, the study didn't address whether SGLT2 might hold gout or mortality benefits for patients without diabetes.
John Gever was Managing Editor from 2014 to 2021; he is now a regular contributor.
The study was funded by Chinese government grants.
Study authors reported relationships with numerous Chinese and Western pharmaceutical companies and other commercial entities.
JAMA Network Open
Source Reference: Wei J, et al "Gout flares and mortality after sodium-glucose cotransporter-2 inhibitor treatment for gout and type 2 diabetes" JAMA Netw Open 2023; DOI: 10.1001/jamanetworkopen.2023.30885.