Insulin resistance in rheumatoid arthritis: disease-related indicators and associations with the presence and progression of subclinical atherosclerosis

Abstract

Objective: Systemic inflammation and insulin resistance (IR) are linked, yet the determinants of IR and its impact on atherosclerosis in rheumatoid arthritis (RA) are incompletely understood. The aim of this study was to explore the prevalence of IR in RA and non-RA populations and investigate whether the associations of IR with measures of atherosclerosis differ between these groups.

Methods: IR was quantified using the homeostatic model assessment of IR (HOMA-IR), and was compared between RA patients and demographically matched non-RA controls. Differences in the associations between the HOMA-IR index and the Agatston coronary artery calcium (CAC) score, ultrasound-determined intima-media thickness (IMT) of the common carotid artery (CCA) and internal carotid artery (ICA), and focal plaque in the ICA/carotid bulb were compared according to RA status.

Results: Among the 195 RA patients and 198 controls studied, average HOMA-IR levels were higher in the RA group by 31%, and were consistently higher in the RA group regardless of stratification by demographic or cardiometabolic risk factors. While the HOMA-IR index was strongly and significantly associated with C-reactive protein (CRP) and interleukin-6 (IL-6) levels in the control group, the association was weaker in the RA group. Among RA patients, higher HOMA-IR levels were associated with rheumatoid factor (RF) seropositivity in men and women, and prednisone use in women only. Before adjustment, higher HOMA-IR levels were associated with all assessed measures of subclinical atherosclerosis in the control group only; associations were diminished and lost statistical significance after adjustment for cardiovascular risk factors. Among the RA patients, neither baseline nor average HOMA-IR levels were significantly associated with change in any of the atherosclerosis measures over an average of 3.2 years of followup.

Conclusion: Although IR was higher in RA patients than in non-RA controls, higher levels may not independently impart additional risk of atherosclerosis.

Figure 1

Associations of log-transformed interleukin-6 (IL-6) and C-reactive protein (CRP) levels with the log-transformed homeostatic model assessment of insulin resistance (HOMA-IR) index in the rheumatoid arthritis (RA) group and the non-RA control group. Shown are the least squares estimators for the average association and the 95% confidence intervals (dotted lines). A, A strong linear association between the IL-6 level and the HOMA-IR index was found in the control group (β = 0.381, P = 0.001), although the association was weaker, and not significant, in the RA group (β = 0.064, P = 0.18) (P < 0.001 for the interaction between RA status and IL-6 level). B, The linear association between the CRP level and the HOMA-IR index was significant in both the RA group (β = 0.094, P = 0.007) and the control group (β = 0.169, P < 0.001) (P = 0.15 for the interaction between RA status and CRP level).

Figure 2

Associations of the natural log–transformed homeostatic model assessment of insulin resistance (HOMA-IR) index with coronary artery calcium (CAC) (A), the intima-media thickness (IMT) of the common carotid artery (CCA) (B), and the IMT of the internal carotid artery (ICA) (C). Shown at left are least squares estimators for the average association in the rheumatoid arthritis (RA) group (solid lines) and the non-RA control group (shaded lines) and corresponding 95% confidence intervals (95% CIs) (dotted lines), as well as Spearman’s correlation coefficients for each group. Shown at right are crude and adjusted β coefficients following linear regression with associated 95% CIs for the average association between IR and measures of coronary and carotid atherosclerosis. P values are for the interaction between RA status and the measures of coronary and carotid atherosclerosis. HDL = high-density lipoprotein.