Can Empagliflozin Also Act Against Gout?
Gliflozins, or sodium-glucose cotransporter 2 inhibitors (SGLT2i), are not only effective antidiabetic agents but also exhibit cardio- and renoprotective effects. It now appears that in type 2 diabetics, they may lower serum uric acid levels and help prevent the development of gout. This was suggested by a post hoc analysis of data from the EMPA-REG OUTCOME study in the case of empagliflozin.
Introduction
Patients with type 2 diabetes mellitus (T2DM) often have elevated uric acid levels, which are associated with increased cardiovascular (CV) risk and can also lead to gouty arthritis, nephrolithiasis, tubulointerstitial fibrosis, and progression of kidney disease. Uric acid is primarily produced during the metabolism of purines and is eliminated by the kidneys. The use of SGLT2i can lead to a decrease in uric acid levels through increased renal excretion or by reducing oxidative stress.
The authors of the cited work built upon the results of the CANVAS clinical trial program, where canagliflozin reduced the number of gout episodes in type 2 diabetics compared to placebo, and in a post hoc analysis of the well-known EMPA-REG OUTCOME study, they tested a similar capability for empagliflozin.
Post Hoc Analysis of the EMPA-REG OUTCOME Study
The population in the EMPA‐REG OUTCOME study comprised 7,020 patients with T2DM and confirmed atherosclerotic CV disease. The estimated glomerular filtration rate (eGFR) among them was ≥ 30 ml/min/1.73 m2.
After randomization into 3 arms in a 1:1:1 ratio, participants received standard care plus empagliflozin at doses of 10 mg (n = 2,345) or 25 mg (n = 2,342) or placebo (n = 2,333). The composite primary endpoint in the EMPA-REG OUTCOME study included the time to the first major CV event involving CV death, non-fatal myocardial infarction (MI), or non-fatal stroke. The median treatment duration was 2.6 years.
The main endpoint of this post hoc analysis was also composite and included the first occurrence of a gout episode (gout, gouty arthritis, gouty tophi) or newly initiated gout medication (allopurinol, benzbromarone, febuxostat, probenecid, or colchicine). The individual components of this composite endpoint were also evaluated separately. Serum uric acid levels were measured at weeks 12, 28, 52, and 66 and then every 14 days until week 206.
Reduction of Uric Acid Levels with Empagliflozin Treatment
Gout medication was used at study entry by 5.9% (413) of participants, who were generally older (median age 65.3 vs. 63.0 years), male (86.4 vs. 70.5%), had higher BMI (median 32.5 vs. 30.5 kg/m2), longer duration of T2DM (more than 10 years in 60.5 vs. 56.9%), worse renal function (median eGFR 60.0 vs. 74.9 ml/min/1.73 m2), higher urinary albumin/creatinine ratio (ACR) (median 30.9 vs. 16.8 mg/g), a history of heart failure (13.3 vs. 9.9%), and were using diuretics (loop diuretics 36.3 vs. 14.2%; thiazides 25.7 vs. 20.9%).
At week 12, the median serum concentration of uric acid was lower in patients treated with empagliflozin compared to the placebo group, and this difference persisted at all subsequent measurements. At week 52, the adjusted difference was –0.37 mg/dl (95% CI –0.42 to –0.31). The effect on uric acid levels compared to placebo was similar for both doses of empagliflozin. At a baseline uric acid level ≥ 6.0 mg/dl, the effect of empagliflozin was more pronounced (at week 52: –0.46 vs. –0.28 mg/dl), similarly for baseline concentrations ≥ 7.0 vs. < 7.0 mg/dl (at week 52: –0.56 vs. –0.30 mg/dl).
At every measurement, there was a higher proportion of patients in the empagliflozin groups with serum uric acid levels < 6.0 mg/dl (e.g., in week 52: 21.8 vs. 11.1%; odds ratio [OR] 2.36) and < 7.0 mg/dl (e.g., in week 52: 28.5 vs. 15.8%; OR 2.22) compared to the placebo group.
Impact of Empagliflozin on Gout Development
Among the 6,607 patients who were not on gout medication at study entry, a gout episode or initiation of gout treatment occurred in 5.2% of the placebo group and 3.6% in both empagliflozin arms, corresponding to an incidence of 21.6 vs. 14.1 events per 1,000 patient-years (hazard ratio [HR] 0.67; p = 0.001). The risk reduction was similar for both doses of empagliflozin and for patients with baseline uric acid levels below or above 6.0 and 7.0 mg/dl (p > 0.1 for all comparisons).
The reduction in the risk of the composite endpoint with empagliflozin was significantly contributed by both its components: HR 0.81 for gout episodes and HR 0.63 for new gout medication initiation. The effect of empagliflozin on reducing the risk of gout or initiation of gout medication cannot be attributed to more frequent use of diuretics in patients with empagliflozin compared to the placebo group, as the proportion of the treatment effect mediated by loop and thiazide diuretics did not exceed 11%.
Conclusion and Discussion
As shown by the post hoc analysis of the EMPA‐REG OUTCOME study, empagliflozin compared to placebo can reduce uric acid levels in patients with T2DM and CV risk, and in patients not previously treated with gout medications, it can also reduce the incidence of gout episodes and the need to initiate gout pharmacotherapy. According to the authors of the cited work, these clinically important findings broaden its utility as a potential adjunct therapy for gout in patients with T2DM. Similar findings for canagliflozin in the CANVAS program suggest this is likely a class effect of SGLT2i. However, further research is needed to precisely understand the mechanism.
(esr)
Source: Ferreira J. P., Inzucchi S. E., Mattheus M. et al. Empagliflozin and uric acid metabolism in diabetes: a post hoc analysis of the EMPA‐REG OUTCOME trial. Diabetes Obes Metab 2022 Jan; 24 (1): 135–141, doi: 10.1111/dom.14559.
Did you like this article? Would you like to comment on it? Write to us. We are interested in your opinion. We will not publish it, but we will gladly answer you.