Abstract
BackgroundMetabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome.MethodsEligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment.ResultsFor Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups.ConclusionsThese findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting.Trial registration ClinicalTrials.gov (NCT00455325, NCT00455403), both posted 03 April 2007
Highlights
A combination of increased triglycerides, low high density lipoprotein (HDL) cholesterol, hypertension, above normal fasting glucose, and increased waist circumference constitutes the metabolic syndrome [1], which predisposes to diabetes, cardiovascular disease, and all-cause mortality [2]
These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ataxia telangiectasia mutated (ATM)-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting
Mice deficient in ataxia telangiectasia mutated (ATM), the kinase mutated in ataxia telangiectasia, have increased activation of Jun N-terminal kinase (JNK) in macrophages, insulin resistance, hypertension, and increased atherosclerosis [6,7,8]
Summary
A combination of increased triglycerides, low HDL cholesterol, hypertension, above normal fasting glucose, and increased waist circumference constitutes the metabolic syndrome [1], which predisposes to diabetes, cardiovascular disease, and all-cause mortality [2]. Obesity-related insulin resistance is associated with low-grade systemic inflammation characterized by increased activation of a stress kinase known to induce insulin resistance, c-Jun N-terminal kinase (JNK) [3]. Mice deficient in ataxia telangiectasia mutated (ATM), the kinase mutated in ataxia telangiectasia, have increased activation of JNK in macrophages, insulin resistance, hypertension, and increased atherosclerosis [6,7,8]. An obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome
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