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Comparative Study
. 2024 Jun 1;184(6):650-660.
doi: 10.1001/jamainternmed.2024.0376.

Sodium-Glucose Cotransporter-2 Inhibitors vs Sulfonylureas for Gout Prevention Among Patients With Type 2 Diabetes Receiving Metformin

Natalie McCormick  1   2   3   4 , Chio Yokose  1   2   3 , Na Lu  4 , Deborah J Wexler  3   5 , J Antonio Aviña-Zubieta  4   6 , Mary A De Vera  4   7 , Rozalina G McCoy  8   9   10 , Hyon K Choi  1   2   3   4
Affiliations
Comparative Study

Sodium-Glucose Cotransporter-2 Inhibitors vs Sulfonylureas for Gout Prevention Among Patients With Type 2 Diabetes Receiving Metformin

Natalie McCormick et al. JAMA Intern Med. .

Abstract

Importance: Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) are a revolutionary treatment for type 2 diabetes (T2D) with cardiovascular, kidney, and serum urate-lowering benefits.

Objective: To compare risk of incident gout and rate of recurrent flares between patients with T2D initiating SGLT2i vs sulfonylurea, most common second-line glucose-lowering therapy, when added to metformin monotherapy.

Design, setting, and participants: This sequential, propensity score-matched, new-user comparative effectiveness study using target trial emulation framework included adults with T2D receiving metformin monotherapy in a Canadian general population database from January 1, 2014, to June 30, 2022.

Exposures: Initiation of SGLT2i vs sulfonylurea.

Main outcomes and measures: The primary outcome was incident gout diagnosis, ascertained by emergency department (ED), hospital, outpatient, and medication dispensing records. Secondary outcomes were gout-primary hospitalizations and ED visits and major adverse cardiovascular events (MACE), as well as recurrent flare rates among prevalent gout patients. Heart failure (HF) hospitalization was assessed as positive control outcome and osteoarthritis encounters as negative control. For target trial emulations, we used Cox proportional hazards and Poisson regressions with 1:1 propensity score matching (primary analysis) and overlap weighting (sensitivity analysis). The analysis was conducted from September to December, 2023.

Results: Among 34 604 propensity score matched adults with T2D initiating SGLT2i or sulfonylurea (20 816 [60%] male, mean [SD] age, 60 [12.4] years), incidence of gout was lower among SGLT2i initiators (4.27 events per 1000 person-years) than sulfonylurea initiators (6.91 events per 1000 person-years), with a hazard ratio (HR) of 0.62 (95% CI, 0.48-0.80) and a rate difference (RD) of -2.64 (95% CI, -3.99 to -1.29) per 1000 person-years. Associations persisted regardless of sex, age, or baseline diuretic use. SGLT2i use was also associated with fewer recurrent flares among gout patients (rate ratio, 0.67; 95% CI, 0.55-0.82; and RD, -20.9; 95% CI, -31.9 to -10.0 per 1000 person-years). HR and RD for MACE associated with SGLT2i use were 0.87 (95% CI, 0.77-0.98) and -3.58 (95% CI, -6.19 to -0.96) per 1000 person-years. For control outcomes, SGLT2i users had lower risk of HF (HR, 0.53; 95% CI, 0.38-0.76), as expected, with no difference in osteoarthritis (HR, 1.11; 95% CI, 0.94-1.34). Results were similar when applying propensity score overlap weighting.

Conclusions: In this population-based cohort study, the gout and cardiovascular benefits associated with SGLT2i in these target trial emulations may guide selection of glucose-lowering therapy in patients with T2D, at risk for or already with gout.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr McCormick reported grants from the National Institutes of Health (NIH) (K99-AR080243 Career Development Award) during the conduct of the study. Dr Yokose reported grants from NIH (NIAMS K23-AR081425-01A1) during the conduct of the study. Dr Wexler reported being a part of the Novo Nordisk Data Monitoring Committee for the SOUL and FLOW trials outside the submitted work. Dr Aviña-Zubieta reported grants from Canadian Institutes for Health Research during the conduct of the study. Dr McCoy reported grants from PCORI, grants from NIDDK, grants from NIA, personal fees from Emmi for the development of patient education materials about diabetes, and personal fees from Yale New Haven Health System for the development of quality measures related to diabetes outside the submitted work. Dr Choi reported grants from Horizon for unrelated investigator-initiated research, personal fees from Ani and Protalix for advisory board membership, personal fees from Shanton for DSMB membership, and grants from LG Chem outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Cumulative Incidence of Gout
A, Overall gout and (B) gout requiring hospitalization and emergency department encounters among patients with type 2 diabetes initiating SGLT2i vs sulfonylurea, after propensity score matching. SGLT2i indicates sodium glucose cotransporter-2 inhibitors.
See this image and copyright information in PMC

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