Table 2.

Representative completed or ongoing clinical trials and/or published clinical studies concerning the therapeutic effects of hydroxychloroquine (HCQ) on type 2 diabetes (T2D)

Trial ID and other information	Number of T2D Patients and their health conditions	HCQ dosage, protocol, endpoints	Key clinical and basic research findings	Current status
1 Prospective, randomized, placebo-controlled, double-blind trial (6 months) PI: Giugliano, D., University of Naples, Italy Completed: 1990	38 T2D patients resistant to commonly used therapies (oral drugs, insulin, and their combination (17 in HCQ group, 15 in placebo group); 18 to 85 years, either gender group; Fasting glucose 100–125 mg/dL; BMI > 25; Fasting serum insulin > 7 uU/mL	HCQ 400 mg p.o. once daily for 3 months vs. placebo; Primary Endpoints: Insulin sensitivity (by glucose tolerance test) at the baseline and 3 months post-drug; Secondary Endpoints: Pancreatic beta cell function	At 6 months, significant improvement occurred in the 11 patients who received the insulin and HCQ (glucose profile decrease, − 11.7 mmol/L; 95% CI, − 13.9 to − 9.5, p < 0.01; glycated hemoglobin A1c decrease, − 3.3%; 95% CI, − 3.9 to − 2.7, p < 0.01). No significant changes were seen in patients on placebo. The daily insulin dose in patients treated with the combined insulin and HCQ therapy had to be reduced an average of 30%. No important side effects were detected	Completed and results published in Quatraro A et al. 1990 [58]
2 Randomized double-blind placebo-controlled trial of 3 days of oral drug treatment PI: Powrie, J.K., United Medical and Dental Schools of Guy’s and St. Thomas’s Hospital, London, U.K Completed: August 1990	20 T2D patients controlled by diet; 10 in Chloroquine group and 10 in placebo group (8 males, 2 females in each group); 43 to 65 years	Chloroquine phosphate, 250 mg four times daily; Primary Endpoints: Rates of glucose appearance (Ra) and disappearance (Rd) were evaluated by infusion of stable isotopically labeled D-glucose ([6,6-2H2]glucose) during hyperinsulinemic euglycemic clamps before and after treatment with chloroquine or placebo	Chloroquine treatment significantly improved fasting plasma glucose from 199.8 ± 8.6 to 165.6 ± 7.6 mg/dl (p < 0.01). Total exogenous glucose infusion required to maintain euglycemia significantly increased due to an increase in Rd without change in Ra. Metabolic clearance rate of insulin decreased by 39%. Chloroquine increased fasting C-peptide secretion by 17% and reduced feedback inhibition of C-peptide	Completed and results published in Powrie JK et al. 1991 [140]
3 Randomized, double-blind, parallel-arm trial NCT01326533 Reducing Risk of Type 2 Diabetes: Hydroxychloroquine Use in Pre-Diabetes PI: Toledo, F., University of Pittsburgh, USA Started: March 2011 Completed: March 2013	32 pre-diabetes participants (17 in HCQ group, 15 in placebo group); 18 to 85 years, either gender, any ethnic group; Fasting glucose 100–125 mg/dL; BMI > 25; Fasting serum insulin > 7 uU/mL	HCQ 400 mg p.o. once daily for 3 months vs. placebo; Primary Endpoints: Insulin sensitivity (by glucose tolerance test) at the baseline and 3 months post-drug; Secondary Endpoints: Pancreatic beta cell function	Insulin sensitivity ↑ HCQ + 20.0 ± 7.1% vs. Placebo − 18.4 ± 7.9%, p < 0.01; Beta cell function ↑ HCQ + 45.4 ± 12.3% vs. Placebo 19.7 ± 13.6%, p < 0.01; Fasting plasma glucose and HbA1c ↓ HCQ vs. Placebo, p < 0.05; Circulating markers of inflammation (IL-6, IL-1, TNF-α, soluble intercellular adhesion molecule) →  Adiponectin levels ↑ HCQ + 18.7% vs. Placebo + 0.7%, pp< 0.001 No serious/unexpected adverse effects	Completed and results published in Wasko MC et al. 2015 [60]
4 Randomized, placebo-control trial NCT02026232 Metabolic Effects of Hydroxychloroquine (MetaHcQ) PI: Semenkovich, C Washington University School of Medicine, USA Started March 2012	30 T2D participants; 18 to 75 years, either gender, any ethnic group; A1c of 6.5–9.0%; BMI > 27 but < 45; Treated with at least 1000 mg of metformin daily with or without a dipeptidyl peptidase-4(DPP4) inhibitor, sulfonylurea, bromocriptine or colesevelam	HCQ 200 mg p.o. twice daily or placebo for 4 weeks; Primary Endpoints: Insulin sensitivity determined by hyperinsulinemic euglycemic clamp; Secondary Endpoints: Fasting blood glucose, low-density lipoprotein (LDL), Serum biomarkers of inflammation	Not yet published	Suspended due to COVID-19
5 Randomized, prospective, open-label comparison trial NCT02303405 Hydroxychloroquine Versus Pioglitazone in Combination Treatment for Type 2 Diabetes Mellitus PI: Hsia, S.H., Charles Drew University of Medicine and Science, USA Started Nov. 2014	17 T2D participants; 18 to 75 years, either gender, any ethnic group; HbA1c of 7.5–11%; BMI < 45; Treated at least 3 months with maximum tolerated doses of metformin and a sulfonylurea	HCQ 400 mg p.o. once daily or Pioglitazone 45 mg p.o. once daily for 4 months; Primary Endpoints: Hemoglobin A1c; Secondary Endpoints: Fasting blood glucose, lipids, Body weight and BMI, Serum biomarkers of inflammation, HOMA-IR, Adverse events	Results submitted, but not yet posted	Terminated (Investigator decision)
6 Randomized, triple-blind, placebo-controlled trial NCT02648464 Hydroxychloroquine for the Prevention of Cardiovascular Events in Myocardial Infarction Patients—a Safety Pilot Trial (OXI) PI: Sinisalo, J., Helsinki University Central Hospital, Finland Started Feb. 2016	125 myocardial infarction patients; 18 to 80 years, either gender, any ethnic group	HCQ 300 mg p.o. once daily for 6 months or placebo p.o. once daily for 6 months; Primary Endpoints: 12-month rate of major cardiovascular adverse events (Myocardial infarction, mortality, hospitalization for unstable angina, and heart failure) Secondary Endpoints: 12-month Rate of the primary endpoint plus stroke and urgent coronary revascularization; 6 month Incidence of T2D and the level of HbA1c, LDL, HDL, total cholesterol, triglyceride, hs-CRP TNFalpha, IL-6, IL-1beta, IL-18	Results submitted, but not yet posted	Completed on December 2019; Protocol published in Hartman O et al. 2017 [141]
7 Randomized, double-blind, placebo-controlled, parallel-arm study PI: Nag, A., Medical College and Hospital, Kolkata, West Bengal, India Published June 2020	304 inadequately controlled T2D patients; 18 to 80 years, either gender, any ethnic group	HCQ 200, 300, 400 mg p.o. once daily or placebo (based on body weight of the subject) In follow-up of 400 mg once daily was once again divided to 200 mg twice daily (BD) to study the effect on tolerability profile for further 12 weeks HCQ 300 mg p.o. once daily for 6 months or placebo p.o. once daily for 6 months; Primary Endpoints: 12-week change of HbA1c Endpoints: 12-week Fasting blood glucose, lipids; Body weight	HbA1c ↓ in 12 weeks HCQ vs. Placebo, p < 0.005, i.e., − 0.78%, − 0.91% and 1.2% for 200, 300, and 400 mg HCQ, respectively, versus 0.13% with placebo; Fasting blood glucose ↓  − 25 to − 38 mg/dl and 34–53 mg/dl; Body weight ↓	Results published in Chakravarti HN & Nag A. 2021 [142]