McGill Janet B, Johnson Mariko, Hurst Stacy, Cade William T, Yarasheski Kevin E, Ostlund Richard E, Schechtman Kenneth B, Razani Babak, Kastan Michael B, McClain Donald A, de las Fuentes Lisa, Davila-Roman Victor G, Ory Daniel S, Wickline Samuel A, Semenkovich Clay F
1Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Box 8127, St. Louis, MO 63110 USA.
2Program in Physical Therapy, Washington University, St. Louis, MO USA.
Diabetol Metab Syndr. 2019 Jul 29;11:61. doi: 10.1186/s13098-019-0456-4. eCollection 2019.
Metabolic 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.
Eligibility 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.
For 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.
These 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. ClinicalTrials.gov (NCT00455325, NCT00455403), both posted 03 April 2007.
代谢综合征是一种与肥胖相关的病症，与胰岛素抵抗和低度炎症相关，可导致糖尿病、心血管疾病、癌症、骨关节炎及其他疾病。最佳治疗方法尚不清楚。抗疟药物氯喹可激活共济失调毛细血管扩张症突变激酶（ATM），改善小鼠的代谢综合征并减轻动脉粥样硬化。为将这一观察结果应用于人类，我们对氯喹在代谢综合征患者中进行了两项临床试验。
纳入标准包括患有至少3项代谢综合征标准但未患糖尿病的成年人。受试者在单一学术健康中心进行研究。具体假设为：氯喹可改善胰岛素敏感性并降低动脉粥样硬化。在试验1中，干预措施为每隔3周递增氯喹剂量，随后进行高胰岛素正常血糖钳夹试验。试验2为平行设计的随机临床试验，干预措施为每日80毫克氯喹或安慰剂，为期1年。试验1的主要结局为钳夹试验测定的胰岛素敏感性，试验2的主要结局为颈动脉内膜中层厚度（CIMT）。对于试验2，受试者根据随机序列按8人一组的方案进行分配。参与者、护理人员及评估结局的人员均对分组情况不知情。
试验1研究了25例患者。氯喹可提高肝脏胰岛素敏感性，但不影响葡萄糖代谢，并改善血脂。试验2中，116例患者被随机分组，59例接受氯喹治疗（56例进行分析），57例接受安慰剂治疗（51例进行分析）。氯喹对CIMT或MRI测定的颈动脉造影增强无影响，MRI测定的颈动脉造影增强是一项预先设定的次要结局。氯喹可降低预先设定的次要结局血压、血脂及JNK（一种与糖尿病和动脉粥样硬化有关的应激激酶）的激活水平。两组不良事件相似。
这些发现表明，低剂量氯喹虽可通过依赖ATM的机制改善小鼠的代谢综合征，但对人类代谢综合征的各项指标仅有适度改善，在这种情况下不太可能具有临床实用性。ClinicalTrials.gov（NCT00455325，NCT00455403），均于2007年4月3日发布。
