OP0177 COMPARATIVE EFFECTIVENESS OF SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS VS SULFONYLUREAS FOR PRIMARY AND SECONDARY GOUT PREVENTION AMONG PATIENTS WITH TYPE 2 DIABETES RECEIVING METFORMIN MONOTHERAPY: TARGET TRIAL EMULATION STUDIES

Background:

Sodium-Glucose Cotransporter Type 2 Inhibitors (SGLT2i) are a revolutionary second-line treatment for type 2 diabetes (T2D) with cardiovascular, kidney, and serum urate-lowering benefits.

Objectives:

To emulate the idealized target trials examining head-to-head the comparative effectiveness of initiation of SGLT2i vs. sulfonylurea (most common second-line glucose-lowering therapy in the US[1] and Canada[2]), when added to metformin monotherapy, for the risk of incident gout and rate of recurrent flares.

Methods:

We followed the approach proposed by Hernan and Robins [Am J Epidemiol 2016] to emulate two-arm randomized clinical trials (the target trials) that would randomize T2D patients receiving metformin monotherapy to initiate SGLT2i or sulfonylurea, in an unblinded fashion. We used administrative health data covering nearly all residents of British Columbia, Canada from Jan 2014 to June 2022, including all dispensed prescriptions, regardless of funder. Adults with T2D receiving metformin (first-line therapy) were identified from ICD codes and dispensing data. Primary outcome was incident gout diagnosis, ascertained by emergency department (ED), inpatient, outpatient, and medication dispensing records. Secondary outcomes were gout-primary hospitalizations and ED visits (PPV 100% for gout[3]) and major adverse cardiovascular events (MACE), as well as rates of recurrent flares among prevalent gout patients (PPV 95% for identifying at least one flare[4]). We stratified by sex, age, and baseline diuretic use. For target trial emulations, we used Cox proportional hazards and Poisson regressions with 1:1 propensity matching (primary analysis) and overlap weighting (sensitivity analysis). To evaluate reproducibility and for spurious associations, we also assessed risk of heart failure hospitalization (expecting SGLT2i would have a protective association), and for risk of any osteoarthritis encounter, a negative control outcome for which we expected a null association.

Results:

Baseline characteristics among the 34,064 propensity score matched adults with T2D (60% male, mean age 60 years) were well-balanced between treatment groups, with standardized differences < 0.1. Incidence rates for gout were lower among SGLT2i initiators (4.27 events per 1000 person-years) than sulfonylurea initiators (6.91 events per 1000 person-years) (Figure 1), with hazard ratio (HR) 0.62 (95% CI: 0.48, 0.80) and rate difference (RD) -2.64 (-3.99, -1.29) per 1000 person-years. Associations persisted regardless of sex, age, or baseline diuretic use. Corresponding HR and RD for incident gout diagnosed during a hospitalization or ED visit were 0.34 (0.17, 0.69) and -0.9 (-1.4, -0.3), respectively (Table 1). SGLT2i use was also associated with fewer recurrent flares among prevalent gout patients (N=5,388, 76% male, mean age 64 years), with rate ratio, 0.67 (0.55, 0.82) and RD, -20.9 (-31.9, -10.0) per 1000 person-years. HR and RD for MACE associated with SGLT2i use were 0.87 (0.77, 0.98) and -3.58 (-6.19, -0.96) per 1000 person-years. For control outcomes, SGLT2i users had lower risk of HF (HR, 0.53 [0.38, 0.76]), as expected, with no difference in osteoarthritis (HR, 1.11 [0.94, 1.34]). Results were similar when applying propensity score overlap weighting.

Conclusion:

The gout and cardiovascular benefits associated with SGLT2i in these target trial emulations may guide selection of glucose-lowering therapy in T2D patients, at risk for or already with gout.

REFERENCES:

[1] PMID 37395339. [2] PMID 36356988. [3] PMID 24377421. [4] PMID 24664671.

Acknowledgements:

NIL.

Disclosure of Interests:

Natalie McCormick: None declared, Chio Yokose: None declared, Leo Lu: None declared, Deborah Wexler Data Monitoring Committees for Novo Nordisk, J. Antonio Aviña-Zubieta: None declared, Mary De Vera: None declared, Rozalina McCoy Emmi, personal fees for the development of patient education materials about diabetes; Yale New Haven Health System, personal fees for the development of quality measures related to diabetes, Hyon Choi Ani, LG, Horizon, Shanton, and Protalix, Horizon.