Tumor Necrosis Factor-α Inhibitor Use Reduces the Risk of Diabetes in Patients with Rheumatoid Arthritis

Objectives

• Tumor necrosis factor-alpha (TNF-α) inhibitors may improve insulin sensitivity and thus would be expected to reduce the risk of diabetes mellitus (diabetes) in patients with rheumatoid arthritis (RA).
• This study examined the association of TNF-α inhibitor use and the risk of developing diabetes in an RA inception cohort in a tertiary health system using Electronic Health Records (EHR).

Methods

• All adult individuals diagnosed with RA between 1/1/2001 – 3/31/2008 were identified (n=1539). RA was defined as ICD-9 code 714.0 at >e; 2 outpatient encounters with a rheumatologist, and diagnosis was validated against the American College of Rheumatology criteria by manual review of 100 random charts (97% concordance).
• Prevalentcasesof diabetes,definedas1ormoreoutpatientvisits with ICD-9 250, a non-fasting blood glucose >e; 200 mg/dl, hemoglobin A1C≥7,orahypoglycemicmedicationorder, wereexcluded(n=252).
• Information on demographic data, medical history, body mass index (BMI), laboratory measures and medications were collected at office visits TNF-α inhibitor use was modeled as time-varying but for descriptive comparison purposes classified into ever or never usage.
• The outcome was incident diabetes, defined by the 2010 American Diabetes Association criteria.
• Time-varying Cox Proportional Hazard regression models were used to adjust for gender, age, race, hypertension, BMI, positive rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP), erythrocyte sedimentation rate, C- reactive protein (CRP), non-steroidal anti-inflammatory drugs (NSAID), glucocorticoid, hydroxychloroquine and methotrexate use. Medication use was considered continuous for lapses <e; 90 days.

Results

• 1287 non-diabetic incident RA patients were included in the analysis. Patients were predominantly women (73%), and 97% were Caucasian, with median age of 61 years and BMI 28.6 kg/m². RF and anti-CCP were positive in 80% and 53%, respectively.
• Patients in the ever TNF-α inhibitor use group (n=403) had a lower median age but higher median BMI and CRP levels and were more likely to have positive anti-CCP antibodies and to have taken NSAIDs, glucocorticoids or methotrexate and less likey to have been on hydroxychloroquine.
• Median follow-up time (last visit or diabetes diagnosis date) for the ever- and never-TNF-α inhibitor users was 36.3 months and 23.9 months, respectively (p < .001). The median duration of TNF-α inhibitor exposure was 35.2 months.
• Of the 56 cases developing diabetes during observation, 15 were ever and 41 were never TNF-α inhibitor users, yielding incidence rates of 10.5 and 22.0 per 1000 person-years (p=0.020), respectively.
• Adjusting for covariates, the hazard ratio for incident diabetes for TNF-α inhibitor usage was 0.40 (95% confidence interval 0.16-0.99, p=0.046) compared to non-use.

Characteristics of RA Patients by TNF-α Inhibitor Usage

Conclusion

• In this inception RA cohort, the use of TNF-α inhibitors was associated with a 60% reduction in risk of developing diabetes after adjusting for confounders.
• These novel findings have important implications in the treatment of this group of patients at high risk for cardiovascular disease.

References

1. Gonzalez-Gay MA et al. Anti-tumor necrosis factor-alpha blockade improvesinsulin resistance in patients with rheumatoid arthritis. Clin Exp Rheumatol 2006;24(1):83-6.
2. Seriolo B et al Effects of etanercept or infliximab treatment on lipid profile and insulin resistance in patients with refractory rheumatoid arthritis. Clin Rheumatol 2007;26(10):1799-800
3. Rosenvinge A et al. Insulin resistance inpatients with rheumatoid arthritis: effect of anti-TNFalpha therapy. Scand J Rheumatol 2007;36(2):91-6
4. Kiortsis DNet al. Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis 2005; 64(5):765-6
5. Tam LS et al. Impact of TNF inhibition on insulin resistance and lipids levels in patients with rheumatoid arthritis. Clin Rheumatol 2007;26(9):1495-8.