SGLT2 inhibitors reduced gout incidence by 11% in patients with type 2 diabetes
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Patients with type 2 diabetes who receive sodium-glucose transport protein 2 inhibitors may have a lower risk for gout compared with those using dipeptidyl peptidase 4 inhibitors, according to data published in JAMA Network Open.
“Sodium-glucose transport protein 2 (SGLT2) inhibitor administration reduces blood glucose levels and is currently the standard intervention for preventing diabetic kidney disease progression and cardiovascular disease in patients with T2DM,” Mu-Chi Chung, MD, of Taichung Veterans General Hospital and National Chung Hsing University, in Taiwan, and colleagues wrote. “In a previous trial, different SGLT2 inhibitor medications consistently lowered blood urate levels to 0.3-0.9 mg/dL.”
“In general, the kidney accounts for approximately 70% of urate elimination, and SGLT2 inhibitors could facilitate glucose transporter 9 excretion of more urine uric acid in exchange for glucose reuptake by increasing glucose concentrations in glomerular filtrate,” they added. “Because hyperuricemia is accepted as the most important risk factor for development of gout, we speculated whether SGLT2 inhibitor use influences the risk of gout. To date, no association between SGLT2 inhibitor use and the incidence of gout have been established.”
To analyze whether SGLT2 inhibition is associated with a lower risk for gout in patients with type 2 diabetes, Chung and colleagues conducted a retrospective cohort study of patients in the Taiwan National Health Institution databases. All 231,208 patients with incident type 2 diabetes between May 1, 2016, and Dec. 31, 2018, were included.
Among these patients, the researchers assessed data from 7,905 individuals receiving SGLT2 inhibitors and 183,303 patients treated with dipeptidyl peptidase 4 (DPP4) inhibitors, as a comparator group, as well as 47,405 pairs using an SGLT2 or DPP4 inhibitor in 1:1 propensity score-matched analyses. The primary outcome was a diagnosis of gout. Chung and colleagues performed multiple Cox proportional hazards regression models to calculate hazard ratios and confidence intervals.
According to the researchers, the overall gout incidence was 20.26 per 1,000 patient-years among those who received SGLT2 inhibition, compared with 24.30 per 1,000 patient-years for DPP4 inhibitors. After adjusting for potential risk factors in the propensity score-matched population, SGLT2 inhibitors were associated with an 11% lower risk for gout (HR = 0.89; 95% CI, 0.82-0.96) compared with DPP4 inhibitors, especially for patients who received dapagliflozin (HR = 0.86; 95% CI, 0.78-0.95).
In a sensitivity analysis — performed in the event of a confirmed gout diagnosis with gout-related medication — SGLT2 inhibitors were associated with %15 lower risk for gout (HR = 0.85; 95% CI, 0.74-0.97). Meanwhile, a subgroup analysis demonstrated that the lower gout risk associated with SGLT2 inhibitors was similar across subgroups.
“The findings of this study suggest that use of SGLT2 inhibitors in patients with T2DM is associated with a lowered gout incidence of 11% compared with DPP4 inhibitors,” Chung and colleagues wrote. “The SGLT2 inhibitors appeared to protect patients with T2DM patients from gout, even across subgroups.”
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David A. McLain, MD, MACR, FACP, FRCP
Studies from America, Denmark, and now Taiwan show that sodium-glucose transport protein 2 inhibitors used for type 2 diabetes lower the risk of gout.
Phlorizin, discovered from apple tree bark in 1835, was the first identified SGLT1 and SGLT2 inhibitor. It was deemed unsuitable for development for use in humans due to very poor bioavailability (metabolized in the intestines) and excessive gastrointestinal adverse events, but its structure was modified to produce three SGLT2 inhibitors that are now in clinical use — canagliflozin (Invokana, Janssen), dapagliflozin (Farxiga; AstraZeneca) and empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly).
The benefits of SGLT2 inhibitors extend beyond type 2 diabetes. The inhibition of the proximal tubular absorption of glucose causes increased glycosuria with resultant improved glycemic control, decreased body mass, reduced adipose tissue deposition and inflammation (decreased leptin), decreased albuminuria and decreased liver steatosis.
Other consequences from lower serum glucose levels and the osmotic diuresis and natriuresis are improved endothelial cell function, decreased systemic blood pressure, improved vascular resistance, decreased oxidative stress and improvement in congestive heart failure (with or without type 2 diabetes). Increased hematocrit due to increased erythropoietin is seen due to reversal of tubular cell injury that was induced by hyperglycemia. There is also increased uric acid excretion with a decrease in the risk of gout (as reported here).
However, glucagon-like peptide-1 agonists — liraglutide (Victoza, Saxenda), dulaglutide (Trulicity, Eli Lilly), exenatide (Bydureon, AstraZeneca and semaglutide (Rybelsus, Novo Nordisk) — and dipeptidyl peptidase-4 inhibitors — sitagliptin (Januvia, Merck) and saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca) — have not been shown to decrease the risk of gout.
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