Dysregulated immune function and chronic systemic inflammation are the hallmarks of rheumatic autoimmune diseases, such as rheumatoid arthritis (RA).1 The association between RA and increased risk for cardiovascular mortality associated with chronic systemic inflammation, including cardiovascular disease (CVD) risk reduction after treatment with biologic disease-modifying antirheumatic drugs (bDMARDs), has been well documented.2,3
Researchers have observed an association between chronic systemic inflammation and increased CVD risk in RA and diabetes, suggesting a link between the 2 diseases.4-6 The increased risk for type 2 diabetes (T2D) in patients with RA has been documented; research results presented at the 2020 European Association for the Study of Diabetes (EASD) meeting showed that adults with vs without RA were 23% more likely to develop T2D.4 Previous research has also suggested that chronic inflammation associated with uncontrolled RA may be a pathophysiologic driver in the development of diabetes.5,6
Considering that bDMARDs may have a protective effect against CVD, the question arises whether bDMARDs are also protective against the risk for T2D in patients with RA and other rheumatic diseases.
Rheumatic Diseases and T2D Share Similar Risk Factors
The prevalence of rheumatic diseases, such as RA, psoriatic arthritis (PsA), and osteoarthritis (OA), increases with age.7 Metabolic disorders, such as impaired fasting glucose and T2D, have also been observed to increase with age.8 The Centers for Disease Control and Prevention (CDC) reported that approximately 50% of individuals with heart disease and diabetes in the United States also have arthritis,7 but the evidence has been limited to confirm the association between rheumatic diseases and T2D.
“Since T2D and RA share multiple risk factors, for those patients with T2D and developing [RA] later (or patients with RA who develop T2D later), they are likely to have a high risk hereditary background predisposed to persistent inflammation and dysregulated metabolism,” noted Linong Ji MD, professor of medicine and director at the Peking University Diabetes Center Department of Endocrinology and Metabolism at the Peking University People’s Hospital in Beijing, China. “The inhibition of chronic inflammation may ease the harmful stimuli to achieve disease remission and even prevention of the second disease,” Dr Ji added.
Recent clinical studies and pathophysiologic mechanisms provide reasonable evidence of the link between rheumatic diseases and diabetes.5,6 A meta-analysis of pooled risk estimate of 11 case-control studies showed a statistically significant increased prevalence of diabetes in patients with RA.9 Similarly, health care utilization data from British Columbia indicated an increased risk for T2D among a cohort of patients with RA and PsA/psoriasis compared with patients without rheumatic diseases.10 Further, a retrospective analysis of the Danish National Health Survey indicated that diabetes was associated with increased risk for RA, OA, and osteoporosis.11
Pathophysiologically, systemic inflammation in RA induced by proinflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin (IL)-6 are known to contribute to the progression of atherosclerosis and CVD.12,13 In a similar light, TNF-α and IL-6 have been found to be increased in inflamed β cells in the diabetic state. Elevated levels of TNF-α and IL-6 are thought to inhibit glucose transporters to induce insulin resistance.14 Interestingly, treatment of RA with nonbiologic and bDMARDs, including hydroxychloroquine, methotrexate, TNFα and IL-1β antagonists, improve the markers of glucose metabolism.15
Although current evidence shows a link between rheumatic diseases and T2D, it remains to be determined whether rheumatic diseases are a risk or a comorbidity of T2D. A study by Dong and colleagues suggests that T2D is likely to be comorbidity of arthritis rather than a risk factor; however, the authors acknowledged that more studies are needed to clarify this association.16
Patients with RA with coexisting diabetes are at an even higher CVD risk, the leading cause of death in this population.17 In patients with RA, the reduction in inflammation and improvements in cardiovascular abnormality with bDMARDs,17-19 raises the question of whether the elevated risk of T2D in patients with RA and other arthritic diseases can also be decreased with bDMARDs and if differences in risk reduction exist between the different bDMARDs.
Rheumatic Diseases and T2D Share a Common Pathway and Treatment
Whether the elevated risk for T2D in patients with RA can be attenuated to DMARDs has been explored in several studies.
“Considering that T2D and RA may share similar inflammatory mechanisms in their pathogenesis, the [bDMARD], which targets the critical mutual inflammatory pathways, is anticipated to confer similar clinical benefits,” Dr Ji noted.
In their study, Wasko and colleagues found that TNFα inhibitors controlled RA inflammation and improved insulin sensitivity, reducing the risk of developing T2D.20 Another study including 13,905 patients diagnosed with RA or psoriasis compared the risk of new cases of T2D among patients who received TNFα inhibitors, methotrexate, hydroxychloroquine, or other nonbiologic DMARDs.21 Results showed a reduced risk for new T2D diagnosis among individuals starting a TNFα inhibitor or hydroxychloroquine. However, the study did not explore risk reduction with other bDMARDs.
Similarly, results of a retrospective study of 21,775 DMARD-treated patients from the Consortium of Rheumatology Researchers of North America registry indicated a significantly reduced risk for diabetes among patients with RA who received TNFα inhibitors.22
Abatacept has also been associated with a reduction in risk for T2D among patients with RA.23 Another study showed that IL-1 receptor antagonists improved β-cell function, peripheral glucose sensitivity, and reduction of hemoglobin A1c (HbA1c) levels in patients with T2D.24 Both these studies support the hypothesis that treatment of RA with bDMARDs correlates with a reduced risk for diabetes and CVD in RA.
In a systematic review and meta-analysis of 22 randomized controlled trials and 3 cohort studies, Lin and colleagues examined the effect of bDMARDs on the risk for T2D.25 The study, which included 34,725 patients with systemic inflammatory conditions (such as RA, psoriasis, lupus, gout flares, ankylosing spondylitis, and giant cell arteritis) who received bDMARDs and 101,906 control participants who received nonbiologic DMARDs, compared the use of bDMARDs and incidence of diabetes. Study authors evaluated DMARDs including TNFα inhibitors (infliximab, adalimumab, etanercept, golimumab, and certolizumab), IL receptor inhibitors (anakinra, rilonacept, canakinumab, and tocilizumab), a CD20 inhibitor (rituximab), and a CD80/86 inhibitor (abatacept). The findings of this research were consistent with previous studies showing an overall significant reduction (P <.001) in the incidence of diabetes among bDMARDs users compared with nonbiologic DMARD users across all conditions (P <.001), particularly RA (P <.0005). The risk for new-onset diabetes was significantly reduced with TNFα inhibitors and abatacept (P <.001); however, subgroup analysis did not show differences between specific TNFα inhibitors, and the IL receptor inhibitors did not show a reduction in the incidence of diabetes or new-onset diabetes.25
The study by Lin and colleagues suggests that targeting abnormal T-cell immune responses in patients with systemic inflammatory conditions may improve glucose metabolism and prevent the development of diabetes. These results may also have implications for the clinical management of rheumatic diseases, especially for therapeutic options that can reduce diabetes risk.25
An interesting speculation is whether the systemic inflammation associated with inflammatory rheumatic diseases and T2D may offer a new dual disease management strategy. In a multicenter, open-label, randomized controlled trial – Clinical Study to Evaluate the Efficacy of Anakinra in Patients With RA and Diabetes (TRACK) – the researchers compared anakinra to TNF inhibitors in improving both glycemic and inflammatory parameters in patients with RA and T2D.26 Results showed a reduction in the percentage of HbA1c among patients who received anakinra and TNF inhibitors; however, the reduction reached statistical significance only with anakinra. Although the study was conducted over a period of 6 months with a small sample size of 39 participants, the results may suggest the consideration of IL-1 inhibition for further evaluation as potential treatment for RA and T2D.
“More investigations are needed to assess the potential protective effects of other [bDMARDs],” Dr Ji suggested.
Clinical Implications for Rheumatic Disease Management
Historically, the emphasis on the management of inflammatory joint diseases, such as RA, has been placed on preventing joint destruction. The association between inflammatory rheumatic diseases and risk for T2D suggests that monitoring for diabetes should be part of the routine management of patients with rheumatic diseases. The evidence that TNFα inhibitors and abatacept can reduce the risk for diabetes, including new-onset diabetes in patients with RA, may guide clinicians in treatment selection to optimize RA management and reduce the risk for T2D.
- England BR, Thiele GM, Anderson DR, Mikuls TR. Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications. BMJ. 2018;361:k1036. doi:10.1136/bmj.k1036
- Robert M, Hot A, Mifsud F, Ndongo-Thiam N, Miossec P. Joint destruction is associated with all types of cardiovascular events in French rheumatoid patients: a real-life study with very long follow-up. Front Med (Lausanne). 2020;7:556086. doi:10.3389/fmed.2020.556086
- van Halm VP, Nurmohamed MT, Twisk JW, Dijkmans BA, Voskuyl AE. Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study. Arthritis Res Ther. 2006;8(5):R151. doi:10.1186/ar2045
- Tian Z, McLaughlin J, Verma A, Gibson M, Heald AH. The relation between rheumatoid arthritis and diabetes incidence: a systematic review and meta-analysis. Presented at: EASD Annual Meeting; September, 21-25, 2020, Abstract 271.
- Ruscitti P, Ursini F, Cipriani P et al. Poor clinical response in rheumatoid arthritis is the main risk factor for diabetes development in the short-term: A 1-year, single-centre, longitudinal study. PLoS One. 2017;12(7):e0181203. doi:10.1371/journal.pone.0181203
- Lu MC, Yan ST, Yin WY, Koo M, Lai NS. Risk of rheumatoid arthritis in patients with type 2 diabetes: a nationwide population-based case-control study. PLoS One. 2014;9(7):e101528. doi:10.1371/journal.pone.0101528
- Centers for Disease Control and Prevention. Arthritis in America Time to Take Action! Updated March 7, 2017. Accessed December 19, 2020. https://www.cdc.gov/vitalsigns/arthritis/index.html
- Chia CW, Egan JM, Ferrucci L. Age-related changes in glucose metabolism, hyperglycemia, and cardiovascular risk. Circ Res. 2018;123(7):886-904. doi:10.1161/CIRCRESAHA.118.312806
- Jiang P, Li H, Li X. Diabetes mellitus risk factors in rheumatoid arthritis: a systematic review and meta-analysis. Clin Exp Rheumatol. 2015;33(1):115-21.
- Solomon DH, Love TJ, Canning C, Schneeweiss S. Risk of diabetes among patients with rheumatoid arthritis, psoriatic arthritis and psoriasis. Ann Rheum Dis. 2010;69(12):2114-7. doi:10.1136/ard.2009.125476
- Rehling T, Bjørkman AD, Andersen MB, Ekholm O, Molsted S. diabetes is associated with musculoskeletal pain, osteoarthritis, osteoporosis, and rheumatoid arthritis. J Diabetes Res. 2019;2019:6324348. doi: 10.1155/2019/6324348.
- Guin A, Sinhamahapatra P, Misra S, Choudhury Mazumder SR, Chatterjee S, Ghosh A. Incidence and effect of insulin resistance on progression of atherosclerosis in rheumatoid arthritis patients of long disease duration. Biomed J. 2019;42(6):394-402. doi:10.1016/j.bj.2019.01.007
- Nicolau J, Lequerré T, Bacquet H, Vittecoq O. Rheumatoid arthritis, insulin resistance, and diabetes. Joint Bone Spine. 2017;84(4):411-416. doi:10.1016/j.jbspin.2016.09.001.
- Mabhida SE, Dludla PV, Johnson R, Ndlovu M, Louw J, Opoku AR, Mosa RA. Protective effect of triterpenes against diabetes-induced β-cell damage: An overview of in vitro and in vivo studies. Pharmacol Res. 2018;137:179-192. doi:10.1016/j.phrs.2018.10.004
- Masuko K. Angiopoietin-like 4: A molecular link between insulin resistance and rheumatoid arthritis. J Orthop Res. 2017;35(5):939-943. doi:10.1002/jor.23507
- Dong Q, Liu H, Yang D, Zhang Y. Diabetes mellitus and arthritis: is it a risk factor or comorbidity? A systematic review and meta-analysis. Medicine (Baltimore). 2017;96(18):e6627. doi:10.1097/MD.0000000000006627
- Ozen G, Pedro S, Michaud K. The risk of cardiovascular events associated with disease-modifying antirheumatic drugs in rheumatoid arthritis. J Rheumatol. Published online August 15, 2020. doi: 10.3899/jrheum.200265
- Singh S, Fumery M, Singh AG, Singh N, Prokop LJ, Dulai PS, Sandborn WJ, Curtis JR. Comparative risk of cardiovascular events with biologic and synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2020;72(4):561-576. doi:10.1002/acr.23875
- Plein S, Erhayiem B, Fent G, et al. Cardiovascular effects of biological versus conventional synthetic disease-modifying antirheumatic drug therapy in treatment-naïve, early rheumatoid arthritis. Ann Rheum Dis. 2020;79(11):1414-1422. doi:10.1136/annrheumdis-2020-217653
- Wasko MC, Kay J, Hsia EC, Rahman MU. Diabetes mellitus and insulin resistance in patients with rheumatoid arthritis: risk reduction in a chronic inflammatory disease. Arthritis Care Res (Hoboken). 2011;63(4):512-21. doi:10.1002/acr.20414
- Solomon DH, Massarotti E, Garg R, Liu J, Canning C, Schneeweiss S. Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis. JAMA. 2011;305(24):2525-31. doi:10.1001/jama.2011.878
- Lillegraven S, Greenberg JD, Reed GW, et al. Immunosuppressive treatment and the risk of diabetes in rheumatoid arthritis. PLoS One. 2019;14(1):e0210459. doi:10.1371/journal.pone.0210459
- Ozen G, Pedro S, Holmqvist ME, Avery M, Wolfe F, Michaud K. Risk of diabetes mellitus associated with disease-modifying antirheumatic drugs and statins in rheumatoid arthritis. Ann Rheum Dis. 2017;76(5):848-854. doi:10.1136/annrheumdis-2016-209954
- Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356(15):1517-26. doi:10.1056/NEJMoa065213
- Lin C, Ji H, Cai X, Yang W, Lv F, Ji L. The association between the biological disease-modifying anti-rheumatic drugs and the incidence of diabetes: A systematic review and meta-analysis. Pharmacol Res. 2020;161:105216. doi:10.1016/j.phrs.2020.105216
- Ruscitti P, Masedu F, Alvaro S et al. Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): a multicentre, open-label, randomised controlled trial. PLoS Med. 2019;16(9):e1002901. doi:10.1371/journal.pmed.1002901