Another Study Confirms Gout Benefit With SGLT2 Inhibitors

Patients with type 2 diabetes taking sodium-glucose cotransporter-2 (SGLT2) inhibitors saw a lower risk for gout, a Taiwanese cohort study found.

Compared with patients taking DPP-4 inhibitors, those on an SGLT2 inhibitor had an 11% reduced risk for gout after adjusting for potential risk factors (HR 0.89, 95% CI 0.82-0.96), according to Chi-Jung Chung, PhD, of China Medical University in Taiwan, and colleagues.

Reporting in JAMA Network Open, Chung’s group said the interaction was strongest in patients younger than 65 versus those 65 and older (P=0.02), but this reduced gout risk was largely maintained across all patient subgroups.

“The findings of this study suggest that use of SGLT2 inhibitors may help to decrease the incidence of gout in patients with type 2 diabetes,” the researchers affirmed.

Patients with diabetes have a higher risk of hyperuricemia, a chief risk factor for gout due to insulin resistance or hyperinsulinemia. However, there are several mechanisms by which SGLT2 inhibitors could reduce risk, the researchers suggested.

First, this class of drugs has been shown to increase urine urate secretion in tubular fluid, possibly by inhibiting kidney tubular urate transporters. Second, SGLT2 inhibitors likely enhance sirtuin-1, which inhibits xanthine oxidase and also decreases blood urate levels. Finally, SGLT2 inhibitors significantly suppress activation of the inflammasome NLRP3 and the resulting secretion of interleukin 1β, which are associated with acute flares of gout, the researchers explained.

The retrospective analysis focused on patients in Taiwan’s National Health Institution database who were taking an SGLT2 inhibitor (n=47,905) or DPP-4 inhibitor (n=183,303) from 2016 to 2018, including 47,405 pairs from each group for a propensity-score matched analysis. Most patients were also on metformin and a statin. Approximately half were women, and the mean age was 61. Gout was identified according to ICD-9-CM and ICD-10-CM codes.

SGLT2 inhibitors represented in the cohort included dapagliflozin (Farxiga), empagliflozin (Jardiance), and canagliflozin (Invokana), and the DPP-4 inhibitors included alogliptin (Nesina, Vipidia), linagliptin (Tradjenta), sitagliptin (Januvia), saxagliptin (Onglyza), and vildagliptin (Galvus).

The researchers also performed an additional sensitivity analysis, in which a gout diagnosis was confirmed using records for the prescription of a gout-related medication, in addition to the ICD-9-CM or ICD-10-CM codes. This analysis found a 15% reduction in risk associated with SGLT2 inhibitors versus DPP-4 inhibitors (HR 0.85, 95% CI 0.74-0.97).

In subgroup analyses, the researchers noted there was no reduction of gout risk in patients with diabetes and chronic kidney disease (CKD) taking SGLT2 inhibitors (HR 1.01, 95% CI 0.86-1.19). This may be explained by previous research showing that SGLT2 inhibitors do not lower blood urate levels in patients with CKD, they explained.

A previous U.S.-based study in Annals of Internal Medicine reported a 36% reduction in gout risk for patients taking SGLT2 inhibitors compared with GLP-1 receptor agonists. One explanation for the difference in risk reduction compared with their own study, Chung’s group explained, is that GLP-1 receptor agonists do not affect blood urate levels, but some DPP-4 inhibitors have been reported to inhibit them. “As a positive control in our study, DPP-4 inhibitors may mitigate the SGLT2 inhibitor association with gout reduction,” they said.

When asked for his perspective, Robert Eckel, MD, of the University of Colorado Anschutz Medical Campus in Aurora, who was not involved with the study, noted that observational data based on electronic medical records doesn’t carry the weight of a randomized clinical trial.

“Urate levels were not measured, and the interaction analysis for CKD showed a P-value of 0.07, suggesting an important contribution, which is not surprising,” Eckel said in an email to MedPage Today. “This is not the first such observation, but the comparator here was DPP-4s, not GLP-1 receptor agonists. Overall, an important contribution that adds to this pleiotropic effect of SGLT2 inhibitors.”

Strengths of the study included its large sample size and nationwide scope, the researchers said. However, some limitations included a lack of detailed laboratory values in the national database. In addition, SGLT2 inhibitors were first introduced in Taiwan in 2016, which means the sample size of patients prescribed them was relatively small. Paired with this, there was a relatively short 2-year follow-up period.

Chung’s group concluded by calling for additional studies with longer-term follow-up. “We would expect this incidence difference to grow with longer follow-up periods because reductions in blood urate levels should translate to lower incident gout risks over time.”