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Low‐dose chloroquine is associated with favourable effects on lipoprotein metabolism without significant influence on insulin resistance

Chloroquine and its analogue hydroxychloroquine are commonly prescribed drugs for anti-malarial and immunomodulation indications. At full treatment doses, chloroquine and hydroxychloroquine promote improvement in lipid profiles [1], but can cause substantial side effects and require clinical and laboratory monitoring. However, low-dose chloroquine is given safely without monitoring to millions of people worldwide to prevent malaria. Therefore, we hypothesized that this could safely treat metabolic syndrome. From over 1500 healthy volunteers participating in a randomized clinical trial of chloroquine for the prevention of influenza, we selected plasma samples collected from participants who had fasted overnight for 8 h. All participants were taking either chloroquine (300 mg base weekly for 11 weeks, following an initial loading dose of 300 mg daily for 1 week) or matching placebo. Details of the original clinical trial protocol and participant demographics have been published elsewhere [2]. The trial protocol was approved by the ethics committee of the National Healthcare Group and all participants provided written informed consent. Total cholesterol, HDL cholesterol, triglycerides, glucose and insulin levels were measured by routine clinical chemistry assays. HOMA-IR was calculated using the HOMA2 Oxford calculator. The TyG index was calculated as ln[fasting triglycerides (mg/dl) 9 fasting glucose (mg/dl)/2]. We analysed samples from 277 participants, 134 taking chloroquine and 143 on placebo. Participants were 66% male, mean age = 28 years, mean BMI = 23.1 kg/m and of Asian origin (87% Chinese, 5% Malay, 5% Indian). Table 1 shows the lipid and glucose parameters in the chloroquine and control groups. The cholesterol : HDL ratio was significantly lower in the chloroquine group than in the control group [geometric mean ratio 0.93, 95% confidence interval (CI) 0.89–0.99, P = 0.013]. Plasma triglyceride levels were also significantly reduced in the chloroquine group compared with the control group (geometric mean ratio 0.89, 95% CI 0.80–1.00, P = 0.047). There was a trend towards lower LDL cholesterol (geometric mean ratio 0.95, 95% CI 0.89– 1.01, P = 0.075) and lower TyG index (geometric mean ratio 0.98, 95% CI 0.97–1.00, P = 0.052) in the chloroquine-treated group. There were no significant differences in cholesterol, HDL cholesterol, glucose, insulin and HOMA–IR between the chloroquine and control groups. This study indicated that healthy participants treated with low-dose chloroquine weekly had small, but significantly decreased triglycerides and cholesterol ratio, with lower LDL levels than controls. Recent studies have shown that both increased blood triglyceride and LDL cholesterol levels are potent cardiovascular risk factors in Asian patients with diabetes [3]. Therefore, the small but modest reduction in blood triglyceride levels detected in our healthy chloroquinetreated participants might warrant further studies in patients with metabolic syndrome, where it might have a greater effect. There was also a trend towards lower a TyG index, a measure of insulin sensitivity which correlated well with the euglycaemic–hyperinsulinaemic glucose clamp [4], in the chloroquine-treated participants compared with the control group. It is noteworthy that HOMA–IR did not reveal any significant changes despite the postulated mechanisms that operate in chloroquine-mediated insulin sensitization.