POS0669 HYPOGLYCAEMIA FOLLOWING JAK INHIBITOR TREATMENT IN DIABETES MELLITUS PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: J. van Lint, F. Van Hunsel, S. Tas, M. Nurmohamed, H. Vonkeman, R. Hebing, F. Hoentjen, M. van Doorn, B. van den Bemt, E. van Puijenbroek, N. Jessurun
Journal: Annals of the Rheumatic Diseases (2021)

Background: Janus kinase (JAK) inhibitors are effective small molecular drugs for rheumatoid arthritis (RA) and other immune mediated inflammatory diseases (IMIDs). JAK inhibitors exert their immunosuppressive effects by suppressing the action of JAK, an intracellular tyrosine. Although infections are the most reported side effects, potential glucose lowering effects in patients with diabetes mellitus (DM) have been described in literature and have also been reported as suspected adverse drug reactions (ADRs) to the National Pharmacovigilance Centre Lareb in the Netherlands (1). Objectives: To assess and describe suspected adverse effects of JAK inhibitors on glucose levels in diabetic patients with rheumatic diseases and other IMIDs, as reported in daily practice. Methods: We describe ADR reports of tofacitinib and baricitinib in the European pharmacovigilance Eudravigiliance (EV) database from initiation to 12 January 2021. All ADRs in EV are coded according to the Medical Dictionary for Regulatory Activities (MedDRA). We included all reports indicating hypoglycaemia in patients with reported DM type 1 and 2 or with antidiabetic drugs as concomitant medication. This could include oral antidiabetics as well as insulins. Results: On 12 January 2021 the EV database included 32 ADR reports, concerning 32 diabetic patients, indicating hypoglycaemia associated with the use of JAK inhibitors (15 tofacitinib, 17 baricitinib), out of 32,484 ADR reports in total concerning tofacitinib or baricitinb (Table 1). Most patients (25 patients, 78%) used the JAK inhibitor for rheumatoid arthritis. The suspected ADR with MedDRA Preferred Term ‘Hypoglycaemia’ was reported for 16 patients and MedDRA Preferred Term ‘Decreased blood glucose’ was reported for 15 patients. In one case, increased insulin sensitivity was described as suspected ADR of baricitinib. In this case, the insulin dose had to be reduced to prevent hypoglycaemia. Of note, the insulin dose had to be increased after temporary discontinuation of baricitinib and was reduced again after baricitinib was restarted. Additionally, in six cases improvements of glycaemic control were described after discontinuation or dose reduction of the JAK inhibitor or antidiabetic drug. Improvements were also described after unknown action or unchanged treatment with JAK inhibitor in eight cases. Conclusion: JAK inhibitors may induce hypoglycaemia by increasing insulin sensitivity, and consequently may reduce the need for antidiabetic medication (2-3). Healthcare professionals should be alert for these potential ADRs when starting a JAK inhibitor in patients with DM as comorbidity. More research is needed to support our findings and elucidate the underlying pharmacological mechanisms of this potentially beneficial effect of JAK inhibitors. Table 1. Suspected adverse drug reaction reports indicating hypoglycaemia in diabetic patients using tofacitinib or baricitinib in the Eudravigilance database Tofacitinib N (%) Baricitinib N (%) No. of reports 15 (100) 17 (100) Mean age years (range) 65 (56 - 78) 62.2 (48 - 78) Female gender 13 (87) 13 (76) Indication for JAK inhibitor Rheumatoid arthritis 11 (73) 14 (82) Unknown 3 (20) 3 (18) Arthritis 1 (7) Reported adverse drug reaction Hypoglycaemia 6 (40) 11 (65) a Decreased blood glucose 9 (60) 6 (35) a Time to onset after start JAK inhibitor b Within 1 month 6 (40) 3 (18) 2-6months 2 (13) 2 (12) More than 6 months 1 (7) Improvement after action: Drug withdrawal 3 (20) c 1 (6) d Dose adjustments 1 (6) e Other 1 (7) f a.In one case of baricitinib hypoglycaemia as well as decreased blood glucose were reported as adverse drug reactions. b.Time to onset was unknown in 6 reports of tofacitinib and 12 reports of baricitinib c.Tofacitinib withdrawal: 1, sitagliptin withdrawal: 1, tofacitinib and insulin withdrawal: 1 d.Baricitinib withdrawal: 1 e.Baricitinib: after insulin dose adjustments: 1 f.After tofacitinib withdrawal and insulin dose adjustments References: [1]Fujita Y, et al. Case Rep Rheumatol. 2019. [2]Bako HY, et al. Life Sci. 2019. [3]Chaimowitz NS, et al. N Engl J Med. 2020. Disclosure of Interests: Jette van Lint: None declared, Florence van Hunsel: None declared, Sander Tas Consultant of: Gebro, GSK, AbbVie, Galvani, Arthrogen, Galapagos, Grant/research support from: Pfizer, GSK, Celgene, BMS, Sanofi, AstraZeneca, Michael Nurmohamed Speakers bureau: speaker’s fees from AbbVie, Bristol-Myers Squibb, Eli Lilly, Roche, and Sanofi, Consultant of: consulting fees from AbbVie, Celgene, Celltrion, Eli Lilly, Janssen, and Sanofi, Grant/research support from: research funding from AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, MSD, Mundipharma, Novartis, Pfizer, Roche, and Sanofi, Harald Vonkeman Grant/research support from: AbbVie, Amgen, AstraZeneca, BMS, Celgene, Celltrion, Galapagos, Gilead, GSK, Janssen-Cilag, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi-Genzyme, all outside the submitted work., Renske Hebing: None declared, Frank Hoentjen Speakers bureau: served on advisory boards or as speaker for Abbvie, Janssen-Cilag, MSD, Takeda, Celltrion, Teva, Sandoz and Dr Falk, Consultant of: Celgene, Janssen-Cilag, Grant/research support from: Dr Falk, Janssen-Cilag, Abbvie, Takeda, Martijn van Doorn Grant/research support from: reports personal fees from Leopharma, grants and personal fees from Novartis, personal fees from Abbvie, personal fees from BMS, personal fees from Celgene, personal fees from Lilly, personal fees from MSD, personal fees from Pfizer, personal fees from Sanofi-Genzyme, personal fees from Janssen Cilag, outside the submitted work., Bart van den Bemt: None declared, Eugène van Puijenbroek: None declared, Naomi Jessurun: None declared