A study to examine additional diabetes and cardiovascular risk variables and determine whether people on disease-modifying anti-rheumatic medications may be at varying risk for the disorder
Main Article Content
Abstract
Objective and Aim: Rheumatoid arthritis patients are at risk for diabetes, which can result in a number of aftereffects and even cardiovascular disease, which is the leading cause of mortality for these individuals. According to earlier studies, certain rheumatoid arthritis medications may help stop diabetes from developing. The purpose of this study was to examine additional diabetes risk factors and determine whether people on disease-modifying anti-rheumatic medications (DMARDs) may be at varying risk for developing diabetes.
Materials & Methods: The analysis included 5530 adults without diabetes who had rheumatoid arthritis. An HbA1c score of ≥7% at follow-up was considered new-onset diabetes, which was the study's endpoint.
Result: When compared to Methotrexate monotherapy, the risk of diabetes was considerably lower during the bDMARD (HR 0.51; 95% CI 0.32 to 0.83), Methotrexate combination (HR 0.50; 95% CI 0.32 to 0.78), and other cDMARD (HR 0.56; 95% CI 0.37 to 0.84) periods. According to individual drug analysis, hydroxychloroquine decreased the incidence of diabetes (HR 0.52; 95% CI 0.42 to 0.65). Inhibitors of tumor necrosis factor-α tended to be protective (HR 0.69; 95% CI 0.46 to 1.03).
Conclusion: Patients with rheumatoid arthritis may have different levels of risk of diabetes depending on the treatment options.
Keywords:
Diabetes, Rheumatoid arthritis, DMARDs, cardiovascular risk.
Article Details
How to Cite
RAY, Dr Saswati et al.
A study to examine additional diabetes and cardiovascular risk variables and determine whether people on disease-modifying anti-rheumatic medications may be at varying risk for the disorder.
Medical Research Archives, [S.l.], v. 13, n. 11, nov. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6965>. Date accessed: 26 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i11.6965.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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6. del Rincón I, Freeman GL, Haas RW, O’Leary DH, Escalante A. Relative contribution of cardiovascular risk factors and rheumatoid arthritis clinical manifestations to atherosclerosis. Arthritis Rheum. 2005;52(11):3413-342316255018
7. Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE. Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2005;52(3):722-73215751097
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10. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115(5):1111-111915864338
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12. Liu S, Tinker L, Song Y, et al. A prospective study of inflammatory cytokines and diabetes mellitus in a multiethnic cohort of postmenopausal women. Arch InternMed. 2007;167(15):1676-168517698692
13. Meigs JB, O’donnell CJ, Tofler GH, et al. Hemostatic markers of endothelial dysfunction and risk of incident type 2 diabetes: the Framingham Offspring Study. Diabetes. 2006;55(2):530-53716 443791
14. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286(3):327-33411466099
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16. Qureshi AA, Choi HK, Setty AR, Curhan GC. Psoriasis and the risk of diabetes and hypertension: a prospective study of US female nurses. Arch Dermatol. 2009;145(4):379-38219380659
17. 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):2114-211720584807
18. Gonzalez-Gay MA, De Matias JM, Gonzalez-Juanatey C, et al. Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2006; 24(1):83-8616539824
19. Kiortsis DN, Mavridis AK, Vasakos S, Nikas SN, Drosos AA. Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis. 2005;64(5):765-76615458960
20. Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356(15):1517-15261 7429083
21. Wasko MC, Hubert HB, Lingala VB, et al. Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis. JAMA. 2007;298(2):187-19317622600.
22. Lillegraven S, Greenberg JD, Reed GW, et al. Immunosuppressive treatment and the risk of diabetes in rheumatoid arthritis. PLoS One 2019;14: e0210459.
23. Ferraz-Amaro I, Arce-Franco M, Muñiz J, et al. Systemic blockade of TNF-Α does not improve insulin resistance in humans. Horm Metab Res 2011; 43:801–8.
24. Stagakis I, Bertsias G, Karvounaris S, et al. Anti-tumor necrosis factor therapy improves insulin resistance, beta cell function and insulin signaling in active rheumatoid arthritis patients with high insulin resistance. Arthritis Res Ther 2012;14.
25. Tsai M-S, Lin M-H, Lee C-P, et al. Chang Gung research database: A multi-institutional database consisting of original medical records. Biomed J 2017;40:263–9.
26. Shao S-C, Chan Y-Y, Kao Yang Y-H, et al. The Chang Gung research database-A multi-institutional electronic medical records database for real-world Epidemiological studies in Taiwan. Pharmacoepidemiol Drug Saf 2019;28:593–600.
27. Bannwarth B, Péhourcq F, Schaeverbeke T, et al. Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis. Clin Pharmacokinet 1996;30:194–210.
28. Moodley D, Yoshida H, Mostafavi S, et al. Network pharmacology of JAK inhibitors. Proc Natl Acad Sci U S A 2016;113:9852–7.
29. Nestorov I, Zitnik R, DeVries T, et al. Pharmacokinetics of subcutaneously administered Etanercept in subjects with psoriasis. Br J Clin Pharmacol 2006;62:435–45.
30. Lutt JR. Efficacy, safety, and tolerability of Abatacept in the management of rheumatoid arthritis.
Open Access Rheumatol 2009;1:17–35.
31. Ternant D, Ducourau E, Fuzibet P, et al. Pharmacokinetics and concentration-effect relationship of Adalimumab in rheumatoid arthritis. Br J Clin Pharmacol 2015;79:286–97.
32. Blick SKA, Curran MP. Certolizumab Pegol: in Crohn’s disease. BioDrugs 2007;21:195–201;
33. Zhou H, Jang H, Fleischmann RM, et al. Pharmacokinetics and safety of Golimumab, a fully human anti-TNF-alpha Monoclonal antibody, in subjects with rheumatoid arthritis. J Clin Pharmacol 2007;47:383–96.
34. Leung E, Crass RL, Jorgensen SCJ, et al. Pharmacokinetic/ pharmacodynamic considerations of alternate dosing strategies of Tocilizumab in COVID-19. Clin Pharmacokinet 2022;61:155–65.
35. Regazzi MB, Iacona I, Avanzini MA, et al. Pharmacokinetic behavior of Rituximab: a study of different schedules of administration for heterogeneous clinical settings. Ther Drug Monit 2005;27:785–92.
36. Tian Z, Mclaughlin J, Verma A, et al. The relationship between rheumatoid arthritis and diabetes mellitus: a systematic review and meta-analysis. Cardiovasc Endocrinol Metab 2021;10: 125–31.
37. Baker JF, England BR, George M, et al. Disease activity, Cytokines, Chemokines and the risk of incident diabetes in rheumatoid arthritis. Ann Rheum Dis 2021;80:566–72.
38. Kuo T, McQueen A, Chen T-C, et al. Regulation of glucose homeostasis by glucocorticoids. Adv Exp Med Biol 2015;872:99–126.
39. Suh S, Park MK. Glucocorticoid-induced diabetes mellitus: an important but overlooked problem. Endocrinol Metab (Seoul) 2017;32:180–9.
40. Fraenkel L, Bathon JM, England BR, et al. American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 2021;73:1108–23.
41. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 2020;79:685–99.
42. Munro R, Morrison E, McDonald AG, Hunter JA, Madhok R, Capell HA: Effect of disease modifying agents on the lipid profiles of patients with rheumatoid arthritis. Ann Rheum Dis. 1997, 56: 374-377.
43. Landewe RB, Breedveld FC, Dijkmans BA: Methotrexate treatment and mortality in rheumatoid arthritis. Lancet. 2002, 360: 1095-1096. 10.1016/S0 140-6736(02)11157-3.
44. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F: Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet. 2002, 359: 1173-1177. 10.1016/S0140-6736 (02)08213-2.
45. Wallace DJ, Metzger AL, Stecher VJ, Turnbull BA, Kern PA: Cholesterol-lowering effect of hydroxychloroquine in patients with rheumatic disease: reversal of deleterious effects of steroids on lipids. Am J Med. 1990, 89: 322-326. DOI:10.1016/0002-9343(90)90345-E.
46. Nashel DJ: Is atherosclerosis a complication of long-term corticosteroid treatment?. Am J Med. 1986, 80: 925-929. DOI:10.1016/0002-9343(86) 90639-X.
47. van Ede AE, Laan RF, Blom HJ, Boers GH, Haagsma CJ, Thomas CM, de Boo TM, van de Putte LB: Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatology (Oxford). 2002, 41: 658-665. 10.1093/rheumatology/41.6.658.
48. Wondafrash DZ, Desalegn TZ, Yimer EM, et al. Potential effect of hydroxychloroquine in diabetes mellitus: A systematic review on Preclinical and clinical trial studies. J Diabetes Res 2020;2020: 5214751.
49. Infante M, Padilla N, Alejandro R, et al. Diabetes-modifying Antirheumatic drugs: the roles of Dmards as glucose-lowering agents. Medicina (Kaunas) 2022;58.
50. Alvarez-Nemegyei J, Pacheco-Pantoja E, González-Salazar M, et al. Association between overweight/obesity and clinical activity in rheumatoid arthritis. Reumatol Clin (Engl Ed) 2020;16:462–7.
2. Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003;107(9):1303-130712628952.
doi: 10.1161/01.cir.0000054612.26458.b2.
3. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296(14):1735-174117032986. DOI: 10.1001/jama.296.14.1735
4. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002 Mar 5;105(9):1135-43. doi: 10.1161/hc0902.104353.
5. Sattar N, McCarey DW, Capell H, McInnes IB. Explaining how “high-grade” systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation. 2003;108(24):2957-296314676136
6. del Rincón I, Freeman GL, Haas RW, O’Leary DH, Escalante A. Relative contribution of cardiovascular risk factors and rheumatoid arthritis clinical manifestations to atherosclerosis. Arthritis Rheum. 2005;52(11):3413-342316255018
7. Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE. Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2005;52(3):722-73215751097
8. Solomon DH, Kremer J, Curtis JR, et al. Explaining the cardiovascular risk associated with rheumatoid arthritis: traditional risk factors versus markers of rheumatoid arthritis severity. Ann Rheum Dis. 2010;69(11):1920-192520444756
9. Garg R, Tripathy D, Dandona P. Insulin resistance as a proinflammatory state: mechanisms, mediators, and therapeutic interventions. Curr Drug Targets. 2003;4(6):487-49212866663
10. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115(5):1111-111915864338
11. Festa A, D’Agostino R Jr, Tracy RP, Haffner SM. Insulin Resistance Atherosclerosis Study. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes. 2002;51(4):1131-113711916936
12. Liu S, Tinker L, Song Y, et al. A prospective study of inflammatory cytokines and diabetes mellitus in a multiethnic cohort of postmenopausal women. Arch InternMed. 2007;167(15):1676-168517698692
13. Meigs JB, O’donnell CJ, Tofler GH, et al. Hemostatic markers of endothelial dysfunction and risk of incident type 2 diabetes: the Framingham Offspring Study. Diabetes. 2006;55(2):530-53716 443791
14. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286(3):327-33411466099
15. Han C, Robinson DW Jr, Hackett MV, Paramore LC, Fraeman KH, Bala MV. Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. J Rheumatol. 2006;33(11):2167-217216981296
16. Qureshi AA, Choi HK, Setty AR, Curhan GC. Psoriasis and the risk of diabetes and hypertension: a prospective study of US female nurses. Arch Dermatol. 2009;145(4):379-38219380659
17. 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):2114-211720584807
18. Gonzalez-Gay MA, De Matias JM, Gonzalez-Juanatey C, et al. Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2006; 24(1):83-8616539824
19. Kiortsis DN, Mavridis AK, Vasakos S, Nikas SN, Drosos AA. Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis. 2005;64(5):765-76615458960
20. Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356(15):1517-15261 7429083
21. Wasko MC, Hubert HB, Lingala VB, et al. Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis. JAMA. 2007;298(2):187-19317622600.
22. Lillegraven S, Greenberg JD, Reed GW, et al. Immunosuppressive treatment and the risk of diabetes in rheumatoid arthritis. PLoS One 2019;14: e0210459.
23. Ferraz-Amaro I, Arce-Franco M, Muñiz J, et al. Systemic blockade of TNF-Α does not improve insulin resistance in humans. Horm Metab Res 2011; 43:801–8.
24. Stagakis I, Bertsias G, Karvounaris S, et al. Anti-tumor necrosis factor therapy improves insulin resistance, beta cell function and insulin signaling in active rheumatoid arthritis patients with high insulin resistance. Arthritis Res Ther 2012;14.
25. Tsai M-S, Lin M-H, Lee C-P, et al. Chang Gung research database: A multi-institutional database consisting of original medical records. Biomed J 2017;40:263–9.
26. Shao S-C, Chan Y-Y, Kao Yang Y-H, et al. The Chang Gung research database-A multi-institutional electronic medical records database for real-world Epidemiological studies in Taiwan. Pharmacoepidemiol Drug Saf 2019;28:593–600.
27. Bannwarth B, Péhourcq F, Schaeverbeke T, et al. Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis. Clin Pharmacokinet 1996;30:194–210.
28. Moodley D, Yoshida H, Mostafavi S, et al. Network pharmacology of JAK inhibitors. Proc Natl Acad Sci U S A 2016;113:9852–7.
29. Nestorov I, Zitnik R, DeVries T, et al. Pharmacokinetics of subcutaneously administered Etanercept in subjects with psoriasis. Br J Clin Pharmacol 2006;62:435–45.
30. Lutt JR. Efficacy, safety, and tolerability of Abatacept in the management of rheumatoid arthritis.
Open Access Rheumatol 2009;1:17–35.
31. Ternant D, Ducourau E, Fuzibet P, et al. Pharmacokinetics and concentration-effect relationship of Adalimumab in rheumatoid arthritis. Br J Clin Pharmacol 2015;79:286–97.
32. Blick SKA, Curran MP. Certolizumab Pegol: in Crohn’s disease. BioDrugs 2007;21:195–201;
33. Zhou H, Jang H, Fleischmann RM, et al. Pharmacokinetics and safety of Golimumab, a fully human anti-TNF-alpha Monoclonal antibody, in subjects with rheumatoid arthritis. J Clin Pharmacol 2007;47:383–96.
34. Leung E, Crass RL, Jorgensen SCJ, et al. Pharmacokinetic/ pharmacodynamic considerations of alternate dosing strategies of Tocilizumab in COVID-19. Clin Pharmacokinet 2022;61:155–65.
35. Regazzi MB, Iacona I, Avanzini MA, et al. Pharmacokinetic behavior of Rituximab: a study of different schedules of administration for heterogeneous clinical settings. Ther Drug Monit 2005;27:785–92.
36. Tian Z, Mclaughlin J, Verma A, et al. The relationship between rheumatoid arthritis and diabetes mellitus: a systematic review and meta-analysis. Cardiovasc Endocrinol Metab 2021;10: 125–31.
37. Baker JF, England BR, George M, et al. Disease activity, Cytokines, Chemokines and the risk of incident diabetes in rheumatoid arthritis. Ann Rheum Dis 2021;80:566–72.
38. Kuo T, McQueen A, Chen T-C, et al. Regulation of glucose homeostasis by glucocorticoids. Adv Exp Med Biol 2015;872:99–126.
39. Suh S, Park MK. Glucocorticoid-induced diabetes mellitus: an important but overlooked problem. Endocrinol Metab (Seoul) 2017;32:180–9.
40. Fraenkel L, Bathon JM, England BR, et al. American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 2021;73:1108–23.
41. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 2020;79:685–99.
42. Munro R, Morrison E, McDonald AG, Hunter JA, Madhok R, Capell HA: Effect of disease modifying agents on the lipid profiles of patients with rheumatoid arthritis. Ann Rheum Dis. 1997, 56: 374-377.
43. Landewe RB, Breedveld FC, Dijkmans BA: Methotrexate treatment and mortality in rheumatoid arthritis. Lancet. 2002, 360: 1095-1096. 10.1016/S0 140-6736(02)11157-3.
44. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F: Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet. 2002, 359: 1173-1177. 10.1016/S0140-6736 (02)08213-2.
45. Wallace DJ, Metzger AL, Stecher VJ, Turnbull BA, Kern PA: Cholesterol-lowering effect of hydroxychloroquine in patients with rheumatic disease: reversal of deleterious effects of steroids on lipids. Am J Med. 1990, 89: 322-326. DOI:10.1016/0002-9343(90)90345-E.
46. Nashel DJ: Is atherosclerosis a complication of long-term corticosteroid treatment?. Am J Med. 1986, 80: 925-929. DOI:10.1016/0002-9343(86) 90639-X.
47. van Ede AE, Laan RF, Blom HJ, Boers GH, Haagsma CJ, Thomas CM, de Boo TM, van de Putte LB: Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatology (Oxford). 2002, 41: 658-665. 10.1093/rheumatology/41.6.658.
48. Wondafrash DZ, Desalegn TZ, Yimer EM, et al. Potential effect of hydroxychloroquine in diabetes mellitus: A systematic review on Preclinical and clinical trial studies. J Diabetes Res 2020;2020: 5214751.
49. Infante M, Padilla N, Alejandro R, et al. Diabetes-modifying Antirheumatic drugs: the roles of Dmards as glucose-lowering agents. Medicina (Kaunas) 2022;58.
50. Alvarez-Nemegyei J, Pacheco-Pantoja E, González-Salazar M, et al. Association between overweight/obesity and clinical activity in rheumatoid arthritis. Reumatol Clin (Engl Ed) 2020;16:462–7.