Immunosuppressive agents in diabetes treatment: Hope or despair?

Table 3 Clinical research of immunosuppressive agents involved in type 2 diabetes mellitus or insulin resistance

Ref.	Study type	Disease	Treated drugs	Numbers of drug treated patients	Drug administration	Clinical outcome	Adverse events
Gupta-Ganguli et al[62]	Retrospective study	T2DM with rheumatoid arthritis or Crohn’s disease	Etanercept and infliximab	8	Etanercept: 50 mg each week by injection; Infliximab: Large intravenous bolus every 6-8 weeks	Average FBG decreased from 142 to 121 mg/dL; average HbA1c decreased from 6.5% to 5.5%; average TG decreased from 350 to 200 mg/dL	NA
Yazdani-Biuki et al[64]	Case series	Insulin resistance	Infliximab	5	Infliximab was administered at a dosage of 5 mg/kg every 8 weeks via Intravenous injection	Improvement in insulin sensitivity observed, particularly in obese patients; remission of type-II diabetes in the index case	NA
Yazdani-Biuki et al[65]	Case report	T2DM with psoriatic arthritis	Infliximab	1	Infliximab discontinued and then restarted due to disease activity. No accurate dose	Relapse of diabetes after stopping infliximab; normalization after resuming	NA
Ursini et al[66]	Case report	Psoriasis, psoriatic arthritis and impaired fasting glucose and impaired glucose tolerance	Infliximab	1	Infliximab was administered at a dosage of 5 mg/kg every 8 weeks via Intravenous injection	Developed to T2DM after discontinuation of infliximab	NA
Bissell et al[67]	Randomized controlled trial	Early rheumatoid arthritis	Infliximab	79	3 mg/kg (maximal dose 1000 mg) standard regime (weeks 0, 2, 6, 14, 22)	Greater improvement in HOMA-IR with the addition of infliximab to a methotrexate regimen	NA
Bonilla et al[68]	ADR case report	T2DM with rheumatoid arthritis	Etanercept	1	25 mg subcutaneously twice weekly	Hypoglycemia: Decrease in glycemia to 40-50 mg/dL in the morning after etanercept injection	Hypoglycemia
Cheung and Bryer-Ash[69]	ADR case report	T2DM with Psoriasis	Etanercept	1	25 mg twice weekly	Decrease in fasting blood glucose and HbA1c	Persistent hypoglycemia
Wambier et al[70]	ADR case report	T2DM with generalized pustular psoriasis	Etanercept	1	50 mg on day 33 and day 39	Decrease in blood glucose	Severe hypoglycemia after initiation of etanercept
Farrokhi et al[71]	ADR case report	T2DM with Psoriasis	Etanercept	1	Etanercept 50 mg twice weekly, subcutaneously	Improved glycemic control with decreased HbA1c and insulin requirements	Hypoglycemia
Corrao et al[72]	Case reports	Polymyalgia rheumatica with T2DM	Etanercept	9	25 mg twice weekly	Complete remission at 1-year follow-up	NA
Dominguez et al[73]	Randomized Double-Blind Clinical Trial	Psoriasis with risk factors for T2DM	Etanercept	6	Etanercept 25 mg twice weekly for 2 weeks	No significant difference in insulin secretion and sensitivity compared with control; fasting serum insulin levels decreased in etanercept group	Mild erythema at injection site in one patient
Martínez-Abundis et al[74]	Randomized, Placebo-Controlled Study	Metabolic Syndrome	Etanercept	28	Etanercept 50 mg subcutaneously once a week for 4 weeks	Significant decrease in C-reactive protein levels and increase in adiponectin levels	Well tolerated with no serious adverse events
Bernstein et al[75]	Randomized, Open-Label Study	T2DM with obese	Etanercept	10	Etanercept 25 mg subcutaneously twice weekly for 4 weeks	No improvement in vascular or metabolic insulin sensitivity despite decreased inflammatory markers	One case of cutaneous infection resolved with antibiotics
Pina et al[76]	Prospective Study	Non-diabetic patients with Psoriasis	Adalimumab	29	80 mg at week 0 followed by 40 mg every other week	Significant improvement of insulin sensitivity	NA
van Eijk et al[77]	Case report	Rheumatoid arthritis with T2DM	Adalimumab	2	No accurate dose	Decrease in fructosamine levels, indicating improved glycemic control	NA
Wu and Tsai[78]	Case report	T2DM with psoriasis	Adalimumab	1	40 mg every other week	Elevated blood glucose levels after adalimumab administration	Elevated serum sugar levels
Martinez-Molina et al[79]	Observational, Retrospective, Single-Center Study	T2DM with rheumatoid arthritis	Tofacitinib and baricitinib	Tofacitinib: 6; Baricitinib: 7	Various dosages based on patient needs	Baricitinib significant reduced HbA1c. Tofacitinib showed no significant difference in HbA1c at 6 months	Due to the increased risk of infections, special caution should be taken
Di Muzio et al[80]	6-month proof-of-concept, open, prospective, clinical study	T2DM with rheumatoid arthritis	Tofacitinib	40	No accurate dose	Progressive reduction of HOMA2-IR[80] and improving trend in insulin sensitivity[81]	No life-threatening adverse events, no cardiovascular or thromboembolic events
Terrec et al[82]	Retrospective, noncontrolled, single-center study	Kidney transplant recipients with T2DM	Belatacept	103	Conversion from CNIs to belatacept at least 6 months post-transplant. Initiation of belatacept consisted of 5 mg/kg on day 1, a second injection on day 14, a third on day 28, and then 1 injection every 4 weeks	HbA1c significantly decreased in patients	Two patients experienced acute cellular rejection; no patient suffered from graft loss. No specific adverse events related to the switch to belatacept
Klubo-Gwiezdzinska et al[84]	Prospective cohort study	Type B insulin resistance	Rituximab, steroids and cyclophosphamide	22	Rituximab: Two doses 2 weeks apart at 750 mg/m2	19 of 22 of patients achieved remission after 5 months	Two patients required therapy to prevent reactivation of latent viral hepatitis; one patient treated for latent tuberculosis; Neutropenia observed in 38.1% of patients
Osanami et al[85]	Case report	Type B insulin resistance	Rituximab, Hydroxychloroquine	1	Rituximab: 375 mg/m2 once weekly for 4 weeks	Remission of diabetes; Negative conversion of circulating insulin receptor antibodies after 7 months	NA

FBG: Fasting blood glucose; TG: Triglyceride; HOMA-IR: Homeostasis model assessment for insulin resistance; T2DM: Type 2 diabetes mellitus; HbA1c: Glycated hemoglobin; ADR: Adverse drug reaction; NA: Not available; CNIs: Calcineurin inhibitors.