The association between sglt-2 inhibitor use and progression from monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans

Abstract Introduction Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are antidiabetic agents with known cardio- and renoprotective effects. SGLT-2i have demonstrated anti-cancer activity; however, their activity in multiple myeloma (MM) remains unclear. We evaluated the association between SGLT-2i use and progression from MGUS to MM in patients with diabetes mellitus (DM) using population-level data. Methods We identified patients diagnosed with MGUS from 1/1/2014 to 12/31/2024 in the nationwide US Veterans Health Administration (VHA) with preceding DM. Diagnoses of MGUS and MM were confirmed by a natural language processing-based algorithm (NLP; Wang et al. JCO CCI 2023). DM was identified via ICD-9/10 codes and DM prescriptions in the VHA, VHA-purchased care, and the linked Medicare Part D claims. We excluded patients who were diagnosed with MGUS before DM or progressed to MM within 6 months. MGUS patients using SGLT-2i within ±1 year of MGUS were matched on follow-up time (±6 months) in a 1:2 ratio to non-users during the same period. Follow-up was the time from MGUS to MM progression, death, or censoring on 6/3/2025, whichever came first. The exposure was time-varying SGLT-2i use during follow-up, assessed in 30-day intervals based on prescription fill dates. The outcome was time from MGUS to MM progression, confirmed by ≥1 record of MM treatment within ±6 months of NLP-confirmed MM. The association between time-varying SGLT-2i use and MM progression was estimated by multivariable, inverse probability of treatment weighting (IPTW)-adjusted, time-to-competing event analysis using a Fine-Gray model with death as a competing risk. Covariates included age, sex, race (Non-Hispanic Black [NHB], Non-Hispanic White [NHW], Other, and Unknown), MGUS subtype (IgG, IgA, or light-chain), M-protein category (e.g., ≥1.5 g/dL), BMI category (underweight, normal weight, overweight, obese), creatinine level (>1.5 mg/dL), anemia status based on ICD-9/10 codes, Charlson Comorbidity Index (CCI), HbA1c level (>7%), months from DM to MGUS (±6 months), MGUS diagnosis year (2014-2019 vs 2020-2024), and DM medication use (i.e., metformin, insulin, glucagon-like peptide-1 receptor agonist [GLP-1RA], sulfonylureas [SU], thiazolidinediones [TZDs], and dipeptidyl peptidase-4 inhibitor [DPP-4i]), all at MGUS diagnosis. IPTW was used to balance covariates between the SGLT-2i use groups. Propensity scores were generated using logistic regression, with a binary outcome indicating SGLT-2i use within ±6 months of MGUS diagnosis. The model included the covariates above to estimate the probability of using SGLT-2i at baseline. Common support was applied to exclude patients with extreme scores. Results Our matched cohort included 2,069 SGLT-2i ever-users and 4,138 non-users. Among ever-users and non-users, the median age was 74.0 (IQR: 68.1-77.8) vs. 74.2 (IQR: 68.6-79.5; p<0.0001) years; 96.7% vs. 96.6% were male (p=0.96); 31.0% vs. 31.7% were NHB, 57.3% vs. 57.3% NHW, 4.1% vs. 3.8% Hispanic, and 2.3% vs. 1.7% other (p=0.61). Baseline characteristics were significantly different in BMI category (higher obesity and lower proportions of underweight, normal weight, and overweight in the SGLT-2i group), anti-DM medication use (greater use of metformin, insulin, GLP-1RA, SU, TZD, and DPP-4i in the SGLT-2i group), creatinine <1.5 mg/dL (higher in the SGLT-2i use group), HbA1c >7% (higher in the SGLT-2i use group), MGUS diagnosis in 2020-2024 (higher in the SGLT-2i use group), CCI (lower in the SGLT-2i use group), time from DM to MGUS diagnosis (higher in the SGLT-2i use group). At a median follow-up of 23.9 (IQR: 14.8-38.9) months for SGLT-2i users vs. 24.6 (IQR: 14.6-39.2; p=0.93), progression occurred in 2.8% vs. 3.9% of patients, respectively (p<0.0001). In the multivariable IPTW-adjusted analysis, SGLT-2i use was associated with reduced MM progression risk (aHR 0.65, 95% CI 0.43–0.99). Other covariates associated with progression included M-protein ≥1.5 g/dL (aHR 7.72, 95% CI 5.32-11.21), age (aHR 0.96, 95% CI 0.95-0.98), HbA1c >7% (aHR 0.68, 95% CI 0.50-0.93), months from DM to MGUS diagnosis (aHR 0.997, 95% CI 0.995-0.999), and MGUS diagnosis year 2020-2024 (aHR 0.55, 95% CI 0.40-0.75). Conclusion In patients with DM and MGUS, SGLT-2i use was associated with a 35% reduced risk of progression to MM. Prospective studies are needed to evaluate whether SGLT-2i may play a role in MM prevention. B.S. and L.L., co–first; T.T. and S.H., co–senior authors.