Potential Effect of Hydroxychloroquine in Diabetes Mellitus: A Systematic Review on Preclinical and Clinical Trial Studies
Table 3
Therapeutic effect of hydroxychloroquine in human study.
Study design
Method and intervention
Main findings
References
Population-based cohort study
Excluding patients with prior history of RA, DM, and PSA, 8628 newly identified SLE patients who are taking HCQ and glucocorticoids were deemed to be eligible for the study.
HCQ reduces the risk of DM in a dose-dependent manner. Compared to groups that took HCQ dose less than 129 g, those who took HCQ greater than 129 g had a significantly lower probability of developing DM.
Eligible 15 nondiabetic rheumatic arteries patients were allocated to placebo and 13 to HCQ groups (400 mg) for 13 weeks.
ISI is increased in HCQ but not in the placebo group. The beta-cell function also improved in the HCQ group, not in placebo. HCQ showed modest improvement in fasting plasma glucose concentration and HbA1c level. No significant change has been observed in circulatory biomarkers, but adiponectin was increased in the HCQ group.
A sum of 20 prediabetic patients who meet the inclusion criteria was allocated to the HCQ group and 19 in the placebo group intervened for 12 weeks.
Level of insulin increased from to units in the case group and from to units in the control group, HCQ. Those taking HCQ experience reduction of glucose at 60 minutes of OGTT.
A total of 100 type II DM patients who were uncontrolled with a combination of antidiabetes medication were grouped into group one receiving metformin, glimepiride, and teneligliptin, and the other group were receiving metformin, glimepiride, and HCQ for 24 weeks.
At week 24, the HbA1c level is decreased by -1.6% in group one and by -1.8% in group two from the baseline. Moreover, FBG and PPBG showed a significant reduction in group two who were on HCQ treatment.
36,329 AS, RA, or PS/PSA patients taking those drugs were enrolled into four mutually exclusive groups. (i) anti-TNFα with or without DMARD, (ii) CSA without anti-TNFα or HCQ, (iii) HCQ without anti-TNF or cyclosporine, and (iv) other nonbiologic DMARD without anti-TNF, CSA, or HCQ.
Newly diagnosed DM was not observed among those given anti-TNF+HCQ therapy. In the RA group, anti-TNF+HCQ therapy and HCQ alone had significant protective effects. In the PS/PSA group, HCQ had a significant protective effect.
267 uncontrolled type II DM patients ( and ≤11.5%), post 3 months of treatment with glimepiride/gliclazide and metformin, to additionally receive HCQ 400 mg/day () or pioglitazone 15 mg/day () for 24 weeks. Efficacy of HCQ was compared with pioglitazone by changes in HbA1c, FBG, and PPG blood glucose at week 12 and week 24.
At week 12 and week 24, HbA1c, FBG, and PPG significantly reduced from baseline in both groups. The mean reduction in glycemic parameters at week 12 was not significantly different between the HCQ and pioglitazone groups. Change in total cholesterol (TC) and LDL-C was significant in favor of HCQ. Triglycerides significantly reduced in both groups at week 24. Mean HDL-C remained unchanged.
Multicenter open-labeled comparative observational study
A total of 240 type II DM patients who were on combination treatment of insulin, glimepiride (1 to 4 mg), and metformin (500 to 2,000 mg) with poor glycemic control were randomly allocated to group I, HCQ 200 mg (), or group II, HCQ 400 mg (120) once daily for 24 weeks.
HbA1c level is significantly reduced by 0.8% and 1.3% in groups I and II, respectively, from the baseline, and the total mean daily dose of insulin was significantly reduced. The effect of HCQ in type II DM patients is dose-dependent; the higher the dose of HCQ, the greater reduction in HbA1c level will be achieved. The reduction of hs-CRP by greater than or equal to 1 is correlating with the reduction of HbA1c in a range of 0.8% to 1.3%.
Poorly controlled type II DM patients () treated with teneligliptin-based regimen (20 mg) per day were replaced by 400 mg HCQ along with metformin and glimepiride, and their data were deemed to be eligible for analysis the whole 24 weeks.
The addition of HCQ in place of teneligliptin has led to a significant reduction of HbA1c from baseline to 24 weeks. FBG and PPBG level was also decreased. It has been seen that total cholesterol, triglycerides, and LDL levels were decreased and HDL levels were significantly increased. Apart from providing tight glycemic control, this significant reduction in lipid profile also indicates that HCQ has added an advantage in reducing cardiovascular risk.
Multicenter, open-label, parallel-group observational study
Patients who were on a maximum dose of metformin and glibenclamide inadequately controlled with insulin therapy were deemed to be eligible: 338 type II DM patients were randomly allocated to the HCQ group taking 400 mg QD and 343 to the sitagliptin group taking 100 QD for 24 weeks.
Compared to sitagliptin, combination of insulin and HCQ significantly improves FPG and PPG. HBA1c less than seven was achieved when HCQ was added to insulin therapy. In the HCQ group, a daily dose of insulin was significantly reduced. The rapid deterioration of glycemic control was observed so close monitoring or aggressive therapy for normoglycemic effect is mandatory.
A total of 640 eligible type II DM patients were randomly grouped to HCQ 400 mg/day, metformin 1,000 mg/day and glimepiride 2 mg/day taking groups and to sitagliptin group taking 100 mg/day, 1,000 mg/day metformin, and 2 mg/day glimepiride for 24 weeks.
Significant improvement in PPBG, FBG, and HbA1c level was found. After 24 weeks, 1.4% HbA1c level reduction was observed in the HCQ group, 1.2% with sitagliptin. At week 24, both QUICKI and HOMA-IR were significantly changed, but the favorable effect was observed in the HCQ group. Plasma hs-CRP declines more in the HCQ group than the sitagliptin group. HDL-C was markedly improved, and reduction to T-C and LDL-C was more favorable to the HCQ group. No episode of hypoglycemia exhibited marked severity.
A sum of 165 type II DM patients who meet inclusion criteria was randomized into group I taking metformin 2,000 mg/day with glimepiride 2 mg/day, group II taking 1,000 mg/day metformin with 4 mg glimepiride, and group III taking 1,000 mg/day metformin, 2 mg/day glimepiride with 400 mg/day of HCQ.
HbA1c level was reduced by 1.1, 1.3, and 1.5% from baseline in those taking the maximum doses of metformin, glimepiride, and HCQ, respectively. The risk of hypoglycemia was significantly lower in the first and third groups than the second group. Except for the GI side effect in the first group, no significant adverse effect has been reported in three of the groups.
Eligible 300 type II DM patients were randomly placed to the HCQ group () and to teneligliptin () for 24 weeks.
HbA1c level was reduced by 1.2% and 0.9% from the baseline in HCQ and teneligliptin taking group consecutively. A daily dose of insulin was significantly reduced in the HCQ taking group. Significant reduction in FPG and PPG was pronounced in HCQ taking groups.
A total of 100 eligible patients were randomly allocated to the HCQ group taking 400 mg per day and the other 50 to vildagliptin taking 100 mg per day apart from metformin 1gm/day and glimepiride 2 mg/day for 24 weeks.
At week 24, HbA1c level decreased by 1.3 and 1.1% from baseline on HCQ and vildagliptin taking groups, respectively. There was a significant reduction in FPG and PPPG. Two patients in the HCQ group report for mild hypoglycemia and five patients in vildagliptin arm, but severe hypoglycemia effect has not been reported. There was no incidence of renal and hepatic toxicity.
Poorly controlled type II DM patients () with a combination treatment of gliclazide (80 mg/day) and metformin (1,000 mg/day) along with twice a day basal insulin glargine therapy (≥30 units a day) were given to take a fixed dose of 400 mg HCQ QD for 6 months.
Beginning at one month and reaching maximal effects at six months, a significant decrease in HbA1c, FBG, and PPBG level was observed. There was no clinically significant change in ECG. Transient elevation of AST and ALT levels was not observed. Hypoglycemic symptoms that require hospitalization were not reported.
From a total of 7,774 newly diagnosed Sjögren syndrome (SS), 510 patients who had used HCQ for the first time for at least 90 days and who had been diagnosed with SS for no longer than 180 days were observed.
Patients treated with HCQ had a significantly lower cumulative incidence than those not treated with HCQ. Using HCQ had a significant preventive effect on the development of DM with Sjögren syndrome. The usage of HCQ was associated with a reduced risk of developing DM.
