The glycosuria produced by SGLT2 inhibitors results in secretion of uric acid into the urine and a reduction in serum uric acid levels, but a relationship with gout had not been previously shown.
In this new study, there was a nearly 40% relative risk reduction in gout among adults prescribed SGLT2 inhibitors compared with those prescribed glucagon-like peptide-1 (GLP-1) receptor agonists, which do not decrease uric acid levels. The absolute risk reduction was about three fewer adults with gout per 1000 person-years.
If replicated, the findings suggest “SGLT2 inhibitors might be an effective class of medication for the prevention of gout for patients with diabetes or metabolic disorders,” write Fralick, of the Division of Pharmacoepidemiology and Pharmacoeconomics, at Brigham and Women’s Hospital, Boston, Massachusetts, and coauthors.
New gout treatments are needed, they point out, since the recent randomized CARES (Cardiovascular Safety of Febuxostat and Allopurinol in Participants With Gout and Cardiovascular Comorbidities) trial demonstrated an association between febuxostat (Uloric, Takeda) and an increased risk for cardiovascular death and all-cause mortality compared with allopurinol.
Reduced Gout Risk Seen Across Sensitivity Analyses
From a total of 295,907 patients who had type 2 diabetes without current or previous gout seen between March 2013 and December 2017, one-to-one propensity score matching for confounders yielded 119,530 patients with a new SGLT2 inhibitor prescription and the same number of patients with a new GLP-1 agonist prescription.
Mean follow-up was 302 days for the SGLT2 inhibitor group and 261 days for the GLP-1 agonist group. Subsequent gout diagnoses were made in 486 patients in the SGLT2 inhibitor group versus 685 patients in the GLP-1 agonist group (4.9 vs 7.8 per 1000 person-years, respectively). The corresponding hazard ratio of 0.64 was significant. Results were consistent across age, sex, and baseline diuretic use.
Similarly, significant results were seen in sensitivity analyses of just those with up to 1 year of medication exposure (5.6 vs 7.7 per 1000 person-years; hazard ratio, 0.73) and when SGLT2 inhibitor users were compared with propensity-matched new users of dipeptidyl peptidase-4 (DPP-4) inhibitors (hazard ratio, 0.66).
Fralick and colleagues point out that because individuals with a history of gout were excluded, “subsequent observational studies in patients with prevalent gout and in those with a higher baseline risk for gout (such as those older than 65 years and those with established cardiovascular disease) will be particularly important to determine whether the magnitude of potential benefit we identified represents an underestimate.”
And, they add, “Logically, patients with hyperuricemia and higher serum uric acid levels at baseline have a greater potential for reducing uric acid levels. If proven, this will be relevant for adults with diabetes who also have hyperuricemia, and one day may also be relevant for adults with hyperuricemia who do not have diabetes.”
But the investigators also caution that the potential anti-gout benefit of SGLT2 inhibitors should be weighed against the known risks, including genital infections, and rare cases of diabetic ketoacidosis; an association with lower-limb amputation; and the high cost.
The study was funded by Brigham and Women’s Hospital. Fralick has reported receiving funding from the Eliot Phillipson Clinician-Scientist Training Program at the University of Toronto and the Canadian Institutes of Health Research through the Banting and Best PhD Award.
Ann Intern Med. Published online January 13, 2020. Abstract