Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge.
Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
JAMA Netw Open. 2021 Jan 4;4(1):e2033457. doi: 10.1001/jamanetworkopen.2020.33457.
Antibody blockade of activin type II receptor (ActRII) signaling stimulates skeletal muscle growth. Previous clinical studies suggest that ActRII inhibition with the monoclonal antibody bimagrumab also promotes excess adipose tissue loss and improves insulin resistance.
To evaluate the efficacy and safety of bimagrumab on body composition and glycemic control in adults with type 2 diabetes and overweight and obesity.
DESIGN, SETTING, AND PARTICIPANTS: This double-masked, placebo-controlled, 48-week, phase 2 randomized clinical trial was conducted among adults with type 2 diabetes, body mass index between 28 and 40, and glycated hemoglobin (HbA1c) levels between 6.5% and 10.0% at 9 US and UK sites. The trial was conducted from February 2017 to May 2019. Only participants who completed a full treatment regimen were included in analysis.
Patients were randomized to intravenous infusion of bimagrumab (10 mg/kg up to 1200 mg in 5% dextrose solution) or placebo (5% dextrose solution) treatment every 4 weeks for 48 weeks; both groups received diet and exercise counseling.
The primary end point was least square mean change from baseline to week 48 in total body fat mass (FM); secondary and exploratory end points were lean mass (LM), waist circumference (WC), HbA1c level, and body weight (BW) changes from baseline to week 48.
A total of 75 patients were randomized to bimagrumab (n = 37; 23 [62.2%] women) or placebo (n = 38; 12 [31.6%] women); 58 (77.3%) completed the 48-week study. Patients at baseline had a mean (SD) age of 60.4 (7.7) years; mean (SD) BMI of 32.9 (3.4); mean (SD) BW of 93.6 (14.9) kg; mean (SD) FM of 35.4 (7.5) kg; and mean (SD) HbA1c level of 7.8% (1.0%). Changes at week 48 for bimagrumab vs placebo were as follows: FM, -20.5% (-7.5 kg [80% CI, -8.3 to -6.6 kg]) vs -0.5% (-0.18 kg [80% CI, -0.99 to 0.63 kg]) (P < .001); LM, 3.6% (1.70 kg [80% CI, 1.1 to 2.3 kg]) vs -0.8% (-0.4 kg [80% CI, -1.0 to 0.1 kg]) (P < .001); WC, -9.0 cm (80% CI, -10.3 to -7.7 cm) vs 0.5 cm (80% CI, -0.8 to 1.7 cm) (P < .001); HbA1c level, -0.76 percentage points (80% CI, -1.05 to -0.48 percentage points) vs -0.04 percentage points (80% CI, -0.23 to 0.31 percentage points) (P = .005); and BW, -6.5% (-5.9 kg [80% CI, -7.1 to -4.7 kg]) vs -0.8% (-0.8 kg [80% CI, -1.9 to 0.3 kg]) (P < .001). Bimagrumab's safety and tolerability profile was consistent with prior studies.
In this phase 2 randomized clinical trial, ActRII blockade with bimagrumab led to significant loss of FM, gain in LM, and metabolic improvements during 48 weeks in patients with overweight or obesity who had type 2 diabetes. ActRII pathway inhibition may provide a novel approach for the pharmacologic management of excess adiposity and accompanying metabolic disturbances.
ClinicalTrials.gov number: NCT03005288.
抗活素 II 型受体（ActRII）信号的抗体阻断刺激骨骼肌生长。先前的临床研究表明，单克隆抗体 bimagrumab 抑制 ActRII 也可促进过多脂肪组织损失和改善胰岛素抵抗。
评估 bimagrumab 对 2 型糖尿病和超重肥胖成人身体成分和血糖控制的疗效和安全性。
设计、设置和参与者：这是一项在美国和英国的 9 个地点进行的双盲、安慰剂对照、48 周、2 期随机临床试验，纳入了 2 型糖尿病、身体质量指数在 28 到 40 之间、糖化血红蛋白（HbA1c）水平在 6.5%到 10.0%之间的成年人。试验于 2017 年 2 月至 2019 年 5 月进行。仅纳入完成完整治疗方案的患者进行分析。
患者随机接受静脉输注 bimagrumab（10 mg/kg，最多 1200 mg 用 5%葡萄糖溶液配制）或安慰剂（5%葡萄糖溶液），每 4 周一次，共 48 周；两组均接受饮食和运动咨询。
主要终点是从基线到第 48 周总脂肪量（FM）的最小平方均数变化；次要和探索性终点是瘦体重（LM）、腰围（WC）、HbA1c 水平和从基线到第 48 周的体重（BW）变化。
共有 75 名患者被随机分为 bimagrumab 组（n = 37；23 [62.2%] 名女性）或安慰剂组（n = 38；12 [31.6%] 名女性）；58 名（77.3%）患者完成了 48 周的研究。患者基线时的平均（SD）年龄为 60.4（7.7）岁；平均（SD）体重指数为 32.9（3.4）；平均（SD）BW 为 93.6（14.9）kg；平均（SD）FM 为 35.4（7.5）kg；平均（SD）HbA1c 水平为 7.8%（1.0%）。bimagrumab 与安慰剂相比，第 48 周的变化如下：FM，-20.5%（-7.5 kg [80% CI，-8.3 至-6.6 kg]）与-0.5%（-0.18 kg [80% CI，-0.99 至 0.63 kg]）（P < .001）；LM，3.6%（1.70 kg [80% CI，1.1 至 2.3 kg]）与-0.8%（-0.4 kg [80% CI，-1.0 至 0.1 kg]）（P < .001）；WC，-9.0 cm（80% CI，-10.3 至-7.7 cm）与 0.5 cm（80% CI，-0.8 至 1.7 cm）（P < .001）；HbA1c 水平，-0.76 个百分点（80% CI，-1.05 至-0.48 个百分点）与-0.04 个百分点（80% CI，-0.23 至 0.31 个百分点）（P = .005）；和 BW，-6.5%（-5.9 kg [80% CI，-7.1 至-4.7 kg]）与-0.8%（-0.8 kg [80% CI，-1.9 至 0.3 kg]）（P < .001）。bimagrumab 的安全性和耐受性与先前的研究一致。
在这项 2 期随机临床试验中，ActRII 阻断剂 bimagrumab 在 48 周内可显著减少肥胖或超重合并 2 型糖尿病患者的 FM，增加 LM，并改善代谢。ActRII 途径抑制可能为肥胖症及其伴随的代谢紊乱的药物治疗提供一种新方法。
ClinicalTrials.gov 编号：NCT03005288。
