Introduction
Subjects and methods
Subjects and trial design
Hyperinsulinemic–euglycemic clamp procedure
Glucose tolerance testing and assays of serum or plasma
Blood pressure determinations
CIMT assessments
MRI assessments
Monocyte protein preparation, JNK assays, and oxysterol determinations
Statistical analyses
Results
Metabolic effects of increasing doses of chloroquine
Variable | Results |
---|---|
Number | 25 |
Gender (F/M) | 18/7 |
Race | |
Black | 2 |
Non-hispanic white | 23 |
Weight (kg) | 101 ± 17 |
BMI (kg/m2) | 35.0 ± 4.4 |
Waist circumference (cm) | 109 ± 13 |
Fasting glucose (mmol/L) | 5.27 ± 0.61 |
Systolic blood pressure (mmHg) | 135 ± 16 |
Diastolic blood pressure (mmHg) | 80 ± 10 |
Total cholesterol (mmol/L) | 5.25 ± 0.67 |
Non-HDL cholesterol (mmol/L) | 4.11 ± 0.62 |
LDL cholesterol (mmol/L) | 3.23 ± 0.57 |
Triglycerides (mmol/L) | 1.85 ± 0.61 |
HDL cholesterol (mmol/L) | 1.19 ± 0.26 |
Variable | Placebo | 80 mg/week | 80 mg/day | 250 mg/day | P value |
---|---|---|---|---|---|
SBP (mmHg) | 121 ± 12 | 121 ± 10 | 123 ± 12 | 123 ± 12 | 0.5607 |
DBP (mmHg) | 70 ± 7 | 71 ± 7 | 73 ± 8 | 73 ± 9 | 0.1107 |
MAP (mmHg) | 87 ± 8 | 88 ± 7 | 89 ± 9 | 90 ± 9 | 0.1944 |
Overnight MAP dip | 8.8 ± 4.2 | 9.5 ± 5.3 | 9.5 ± 8.8 | 9.6 ± 5.0 | 0.9878 |
Fasting glucose clamp | 5.77 ± 0.53 | 5.83 ± 0.52 | 5.83 ± 0.53 | 5.44 ± 0.65 | 0.0010* |
Fasting glucose OGTT | 5.49 ± 0.57 | 5.77 ± 0.56 | 5.72 ± 0.62 | 5.66 ± 0.62 | 0.0805 |
OGTT AUC (mmol/L/h) | 16.93 ± 3.05 | 17.65 ± 3.00 | 17.87 ± 3.22 | 17.26 ± 3.61 | 0.3585 |
Weight (kg) | 104 ± 18 | 103 ± 18 | 104 ± 19 | 103 ± 19 | 0.6041 |
BMI | 35.9 ± 4.3 | 35.9 ± 4.2 | 35.9 ± 4.5 | 35.5 ± 4.6 | 0.5964 |
A1c (%) | 5.8 ± 0.4 | ND | ND | 5.8 ± 0.4 | 0.9493 |
Insulin (pmol/L) | 153 ± 94 | 138 ± 62 | 166 ± 107 | 148 ± 80 | 0.4260 |
C peptide (nmol/L) | 1.16 ± 0.44 | 1.20 ± 0.38 | 1.26 ± 0.44 | 1.25 ± 0.36 | 0.5473 |
Glucagon (pg/mL) | 110 ± 41 | 101 ± 26 | 111 ± 54 | 102 ± 50 | 0.3646 |
Leptin (μg/L) | 27.5 ± 11.6 | 27.2 ± 11.1 | 31.0 ± 16.4 | 27.2 ± 11.9 | 0.2134 |
NEFA (mmol/L) | 0.56 ± 0.15 | 0.55 ± 0.10 | 0.58 ± 0.19 | 0.55 ± 0.16 | 0.8776 |
TNFα (pg/mL) | 12.9 ± 1.8 | 13.0 ± 1.7 | 12.2 ± 1.9 | 12.4 ± 2.0 | 0.0890 |
Fibrinogen (μmol/L) | 8.44 ± 1.32 | 8.38 ± 1.47 | 8.14 ± 1.09 | 7.94 ± 1.44 | 0.3563 |
IL-6 (pg/mL) | 1.0 ± 1.6 | 1.4 ± 1.5 | 1.2 ± 1.6 | 0.96 ± 1.3 | 0.4282 |
Lp(a) (mg/dL) | 22.9 ± 17.5 | 20.9 ± 16.0 | 22.5 ± 17.2 | 22.8 ± 18.1 | 0.1454 |
CRP (mg/L) | 8.3 ± 10.8 | 7.9 ± 10.6 | 6.4 ± 7.2 | 7.5 ± 8.0 | 0.7455 |
Adiponectin (μg/mL) | 21.6 ± 8.1 | ND | ND | 20.6 ± 5.6 | 0.3503 |
Iron (μmol/L) | 12.3 ± 4.1 | ND | ND | 11.4 ± 5.5 | 0.5311 |
Iron Bind. Cap. (μmol/L) | 64.9 ± 8.7 | ND | ND | 65.8 ± 10.0 | 0.6385 |
Transferrin (mg/dL) | 300.3 ± 47.5 | ND | ND | 303.8 ± 48.5 | 0.6899 |
Transferrin Sat. (%) | 19.1 ± 6.4 | ND | ND | 17.2 ± 6.9 | 0.3413 |
Ferritin (pmol/L) | 170 ± 191 | ND | ND | 105 ± 88 | 0.0155* |
Vascular effects of chloroquine treatment
Variable | Chloroquine group | Placebo group | P value |
---|---|---|---|
Gender (F/M) | 44/12 | 33/18 | 0.1108 |
Age | 55 ± 12 | 55 ± 9 | 0.9999 |
Race (AA/NHW/H/NA) | 9/45/1/1 | 6/45/0/0 | 0.4990 |
Smoking status | |||
Current | 8 | 10 | 0.4341 |
Past | 21 | 23 | 0.2962 |
Statin treatment | 15 | 15 | 0.8310 |
Hypertension treatment | 20 | 19 | 0.9999 |
Fish oil treatment | 5 | 10 | 0.1632 |
Waist circumference | 110.4 ± 10.5 | 108.9 ± 11.8 | 0.6538 |
BMI | 36.2 ± 5.0 | 34.2 ± 5.0 | 0.0433* |
SBP | |||
Screen | 137.1 ± 14.3 | 140.2 ± 13.2 | 0.2385 |
Randomization | 129.2 ± 11.4 | 134.0 ± 10.1 | 0.0237* |
DBP | |||
Screen | 82.8 ± 9.5 | 83.0 ± 9.7 | 0.9483 |
Randomization | 78.3 ± 7.4 | 79.7 ± 7.2 | 0.3244 |
Glucose | 5.48 ± 0.53 | 5.52 ± 0.64 | 0.6960 |
Triglycerides | 1.84 ± 1.04 | 1.82 ± 0.93 | 0.9155 |
HDL-C | 1.14 ± 0.26 | 1.14 ± 0.27 | 0.9603 |
Cholesterol | 5.00 ± 0.85 | 5.18 ± 1.15 | 0.3834 |
LDL-C | 3.04 ± 0.68 | 3.28 ± 0.82 | 0.1073 |
Effects of chloroquine on blood pressure, lipids, and other variables
Variable | Baseline | 6 months | 12 months | 24 months | P value |
---|---|---|---|---|---|
Waist (cm) | |||||
Chloroquine | 110.4 ± 10.5 | 112.5 ± 12.6 | 112.6 ± 13.6 | 113.2 ± 16.6 | 0.5578 (12 m) |
Placebo | 108.9 ± 11.8 | 110.4 ± 13.8 | 109.8 ± 12.4 | 108.9 ± 15.9 | |
Weight (kg) | |||||
Chloroquine | 102.9 ± 16.7 | 102.9 ± 16.7 | 103.1 ± 19.2 | 105.9 ± 20.4 | 0.1323 |
Placebo | 99.7 ± 18.5 | 98.7 ± 18.5 | 99.2 ± 17.8 | 100.5 ± 21.2 | 0.1909 (t test 24 m) |
Fasting glucose | |||||
Chloroquine | 5.48 ± 0.53 | 5.36 ± 0.55 | 5.30 ± 0.51 | 5.58 ± 0.73 | 0.2741 (12 m) |
Placebo | 5.52 ± 0.64 | 5.52 ± 0.62 | 5.51 ± 0.71 | 5.63 ± 0.74 | 0.0930 (t test 12 m) |
Glucose AUC | |||||
Chloroquine | 16.32 ± 2.46 | 15.94 ± 2.24 | 16.17 ± 2.58 | 16.97 ± 3.20 | 0.2537 |
Placebo | 16.54 ± 3.49 | 16.87 ± 3.29 | 16.43 ± 3.34 | 17.50 ± 3.85 | |
Insulin AUC | |||||
Chloroquine | 1202 ± 681 | 1118 ± 542 | 1143 ± 603 | 1213 ± 716 | 0.2479 |
Placebo | 1003 ± 524 | 1054 ± 588 | 995 ± 570 | 1022 ± 613 | |
C peptide AUC | |||||
Chloroquine | 7.46 ± 2.33 | 7.23 ± 2.10 | 7.16 ± 2.20 | 7.39 ± 2.43 | 0.2918 |
Placebo | 6.49 ± 1.80 | 6.69 ± 2.06 | 6.46 ± 2.00 | 6.79 ± 2.06 | |
HOMA-IR | |||||
Chloroquine | 3.89 ± 2.23 | 3.85 ± 2.21 | 3.57 ± 2.12 | 3.72 ± 3.53 | 0.8421 |
Placebo | 3.54 ± 2.03 | 3.64 ± 2.08 | 3.30 ± 2.23 | 3.29 ± 2.26 | |
Matsuda index | |||||
Chloroquine | 2.89 ± 1.72 | 2.88 ± 1.55 | 3.13 ± 2.31 | 3.43 ± 2.84 | 0.8997 |
Placebo | 3.21 ± 1.89 | 3.07 ± 1.64 | 3.50 ± 2.14 | 3.56 ± 2.70 | |
Insulinogenic index | |||||
Chloroquine | 1.40 ± 1.75 | 1.17 ± 0.87 | 1.24 ± 0.87 | 1.12 ± 0.89 | 0.4988 |
Placebo | 1.05 ± 0.77 | 1.03 ± 0.67 | 1.09 ± 0.88 | 1.13 ± 1.62 | |
Glucagon AUC | |||||
Chloroquine | 174.0 ± 63.5 | 152.3 ± 60.3 | 126.8 ± 43.3 | ND | 0.6126 |
Placebo | 168.0 ± 60.6 | 138.7 ± 46.7 | 119.8 ± 36.2 | ND | |
Creatinine (μmol/L) | |||||
Chloroquine | 68 ± 14 | 67 ± 15 | 66 ± 15 | ND | 0.7859 |
Placebo | 66 ± 16 | 65 ± 17 | 65 ± 17 | ||
ALT | |||||
Chloroquine | 26 ± 16 | 26 ± 19 | 26 ± 15 | ND | 0.2056 |
Placebo | 25 ± 12 | 27 ± 16 | 23 ± 9 | ND | |
WBC count | |||||
Chloroquine | 6.7 ± 1.8 | 6.3 ± 1.6 | 6.0 ± 1.5 | ND | 0.7249 |
Placebo | 6.5 ± 1.7 | 6.3 ± 1.8 | 6.1 ± 1.9 | ND | |
Hemoglobin | |||||
Chloroquine | 13.6 ± 1.1 | 13.3 ± 1.1 | 13.2 ± 1.2 | ND | 0.8953 |
Placebo | 13.8 ± 0.8 | 13.5 ± 0.9 | 13.5 ± 0.9 | ND |
Potential mechanistic mediators
Adverse events
Adverse event | Subjects (%) |
---|---|
Total subjects with any event | 24 (69) |
Subjects with a serious adverse event | 0 (0) |
Total adverse events | 57 (100) |
Study related | 14 (25) |
IV placement difficulties | 1 (1.8) |
IV infiltration | 1 (1.8) |
Phlebitis | 1 (1.8) |
Skin reaction to tape | 1 (1.8) |
Extremity erythema due to BP cuff | 1 (1.8) |
Vasovagal episode with IV placement | 1 (1.8) |
Incorrect stable isotope administered | 1 (1.8) |
Nausea | 3 (5) |
Anemia | 4 (7) |
Not study related | 43 (75) |
Infectious | 15 (26) |
Allergy/immunology | 3 (5) |
Musculoskeletal | 8 (14) |
CNS | 3 (5) |
Psychiatric | 5 (9) |
Cardiovascular | 2 (4) |
GI | 4 (7) |
Metabolic | 3 (5) |
Adverse event | Chloroquine subjects (%) | Placebo subjects (%) | P value |
---|---|---|---|
Total subjects with any event | 44 (76) | 39 (67) | 0.4107 |
Subjects with a serious adverse event | 5 (9) | 2 (3) | 0.4385 |
Total adverse events | 109 (100) | 105 (100) | – |
Infectious | 51 (47) | 42 (40) | 0.0609 |
Allergy/immunology | 5 (5) | 10 (10) | 0.2681 |
Musculoskeletal | 17 (16) | 15 (15) | 0.8357 |
CNS | 5 (5) | 3 (3) | – |
Psychiatric | 5 (5) | 6 (6) | – |
Hematologic/neoplasm | 2 (2) | 2 (2) | – |
Cardiovascular | 2 (2) | 3 (3) | – |
GI | 3 (3) | 3 (3) | – |
GU | 2 (2) | 2 (2) | – |
Metabolic | 1 (1) | 6 (6) | – |
Miscellaneous | 0 (0) | 3 (3) | – |
Ocular | 16 (15) | 10 (10) | 0.2654 |
Ocular details | |||
Retinal | 3 | 3 | – |
Lens | 4 | 2 | – |
Vision | 2 | 0 | – |
Infectious | 2 | 0 | – |
Glaucoma | 2 | 2 | – |