Background/Purpose: Diabetes mellitus (DM) is an important cardiovascular risk factor in RA. Although a few prior studies reported DM risk reduction with hydroxychloroquine (HCQ) and TNF inhibitors in RA, at present the impact of newer biologics and statins, the timing, dosing and the sustainability of the HCQ effect are unknown. In this study, we examined the incident DM rate and the impact of DMARDs and statins in RA patients.

Methods: We studied patients with RA and ≥1 year participation in the National Data Bank for Rheumatic Diseases without baseline DM from 2000 through 2015. DM was determined by self-report or initiating DM medication. DMARDs were categorized into 4 mutually exclusive groups: (1) MTX monotherapy (reference) (2) any abatacept (ABA) with or without MTX (3) any other DMARD with MTX (4) all other DMARDs without MTX; along with separate statin, glucocorticoids (GC), and HCQ (yes/no) variables. Time-varying Cox proportional hazard models were used to adjust for sociodemographics, comorbidities, BMI, and RA severity measures.

Results: A total of 1,139 incident DM cases were observed during median (IQR) 4.6 (2.5-8.8) years of followup in 13,669 RA patients. The incidence rate in RA patients found to be increased (age and sex-adjusted SIR 1.37 [1.29-1.45]) compared to that of in US adult population (Table 1). Adjusted HR (95% CI) for DM were 0.67 (0.57, 0.80) for HCQ, 0.52 (0.31, 0.89) for ABA, 1.31 (1.15, 1.49) for GC, and 1.56 (1.36, 1.78) for statins. Other synthetic/biologic DMARDs were not associated with any risk change (Table 2). DM risk reduction started after 2 years of HCQ treatment, HR 0.76 (0.58-1.00), and continued to decrease with longer duration, >4 years HR 0.69 (0.59-0.81). HCQ doses of <400mg/day (HR 0.71, 0.52-0.96) and ≥400mg/day (HR 0.66, 0.55-0.81) were both associated with DM risk reduction. Patients who initiated and then discontinued HCQ (N=342) had a nonsignificant risk reduction up to 6 months compared to HCQ never-used patients: HR 0.65 (0.21-2.0) for ≥ 3 months, 0.88 (0.28-2.75) for ≥ 6 months, and 1.27 (0.31-5.10) for ≥ 1 year off-HCQ. Concomitant use of HCQ either with GC (HR 0.69, 0.51-0.93) or statins (HR 0.92, 0.68-1.25) abolished risk increase associated with both drugs.

Conclusion: Incidence of DM in RA patients is increased. HCQ and ABA were associated with decreased risk of DM, and GC and statins with increased risk. HCQ confers a sustainable, dose and treatment duration-dependent DM risk reduction, and also attenuates the increased risk associated with GC or statins. Careful monitoring for DM should be considered in RA patients especially who were on GC or statins.