Center for Cardiovascular Disease Prevention, Harvard Medical School, Boston, Massachusetts; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Endocrinology, Diabetes & Metabolism, University Hospital Basel, Basel, Switzerland.
J Am Coll Cardiol. 2018 May 29;71(21):2392-2401. doi: 10.1016/j.jacc.2018.03.002. Epub 2018 Mar 12.
Subclinical inflammation mediated in part by interleukin (IL)-1β participates in peripheral insulin resistance and impaired pancreatic insulin secretion.
The authors tested the hypothesis that the IL-1β inhibitor canakinumab reduces incident diabetes.
The authors randomized 10,061 patients with prior myocardial infarction and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/l to placebo or canakinumab at doses of 50 mg, 150 mg, or 300 mg subcutaneously once every 3 months. The authors tested the effects of canakinumab on major cardiovascular events in patients with and without diabetes at baseline, and evaluated as a pre-specified analysis whether canakinumab would reduce the risk of adjudicated cases of new-onset type 2 diabetes among those with protocol-defined pre-diabetes at trial entry. The authors also evaluated the effect of canakinumab on fasting plasma glucose and glycosylated hemoglobin (HbA) in patients with and without established diabetes.
Of the participants, 4,057 (40.3%) had baseline diabetes, 4,960 (49.3%) had pre-diabetes, and 1,044 (10.4%) had normal glucose levels. Among those without diabetes, increasing tertiles of hsCRP at baseline associated with an increased risk of developing diabetes during the median follow-up period of 3.7 years (incidence rates 3.2, 4.1, and 4.4 per 100 person-years; p = 0.003). Canakinumab 150 mg as compared with placebo had similar magnitude effects on major cardiovascular event rates among those with diabetes (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.70 to 1.03), pre-diabetes (HR: 0.86; 95% CI: 0.70 to 1.06), and normoglycemia (HR: 0.81; 95% CI: 0.49 to 1.35). Despite large reductions in hsCRP and IL-6, canakinumab did not reduce the incidence of new-onset diabetes, with rates per 100 person-years in the placebo, 50 mg, 150 mg, and 300 mg canakinumab groups of 4.2, 4.2, 4.4, and 4.1, respectively (log-rank p = 0.84). The HR comparing all canakinumab doses to placebo was 1.02 (95% CI: 0.87 to 1.19; p = 0.82). Canakinumab reduced HbA during the first 6 to 9 months of treatment, but no consistent long-term benefits on HbA or fasting plasma glucose were observed.
Although IL-1β inhibition with canakinumab had similar effects on major cardiovascular events among those with and without diabetes, treatment over a median period of 3.7 years did not reduce incident diabetes. (Canakinumab Anti-inflammatory Thrombosis Outcomes Study [CANTOS]; NCT01327846).
部分由白细胞介素 (IL)-1β介导的亚临床炎症参与外周胰岛素抵抗和受损的胰腺胰岛素分泌。
作者检验了 IL-1β抑制剂卡那奴单抗是否可以降低糖尿病的发生。
作者将 10061 名有心肌梗死病史且高敏 C 反应蛋白 (hsCRP)≥2mg/L的患者随机分为安慰剂或卡那奴单抗组，剂量分别为 50mg、150mg 或 300mg，每 3 个月皮下注射一次。作者检测了卡那奴单抗对基线时有和无糖尿病患者主要心血管事件的影响，并作为预先指定的分析评估卡那奴单抗是否会降低试验入组时存在协议定义的前期糖尿病患者新发生 2 型糖尿病的风险。作者还评估了卡那奴单抗对有和无已确诊糖尿病患者空腹血糖和糖化血红蛋白 (HbA)的影响。
参与者中，4057 人（40.3%）基线时有糖尿病，4960 人（49.3%）有前期糖尿病，1044 人（10.4%）血糖水平正常。在没有糖尿病的患者中，基线时 hsCRP 三分位数升高与中位随访 3.7 年期间发生糖尿病的风险增加相关（发生率分别为 3.2、4.1 和 4.4 例/100 人年；p=0.003）。与安慰剂相比，卡那奴单抗 150mg 对糖尿病患者（风险比 [HR]：0.85；95%置信区间 [CI]：0.70 至 1.03）、前期糖尿病患者（HR：0.86；95%CI：0.70 至 1.06）和血糖正常患者（HR：0.81；95%CI：0.49 至 1.35）的主要心血管事件发生率具有相似的影响。尽管 hsCRP 和 IL-6 有较大程度的降低，但卡那奴单抗并未降低新发生的糖尿病的发生率，安慰剂、50mg、150mg 和 300mg 卡那奴单抗组的发生率分别为每 100 人年 4.2、4.2、4.4 和 4.1（对数秩检验 p=0.84）。与安慰剂相比，所有卡那奴单抗剂量的 HR 为 1.02（95%CI：0.87 至 1.19；p=0.82）。卡那奴单抗在治疗的最初 6 至 9 个月内降低了 HbA，但未观察到 HbA 或空腹血糖的长期一致获益。
尽管卡那奴单抗抑制白细胞介素-1β对有和无糖尿病患者的主要心血管事件有相似的影响，但中位 3.7 年的治疗并未降低糖尿病的发生率。（卡那奴单抗抗炎性血栓结局研究 [CANTOS]；NCT01327846）。
