Ehlers M R, Klaff L J, D'Alessio D A, Brazg R, Kay H D, Harley R E, Mathisen A L, Schneider R
Restoragen, Inc., Lincoln, Nebraska, USA.
Horm Metab Res. 2003 Oct;35(10):611-6. doi: 10.1055/s-2003-43509.
To evaluate the safety and efficacy of various doses of recombinant glucagon-like peptide-1 (7-36) amide (rGLP-1) administered subcutaneously (s. c.) via bolus injection or continuous infusion to lower fasting serum glucose (FSG) levels in subjects with type 2 diabetes treated by diet, hypoglycemic drugs, or insulin injection.
rGLP-1 was administered s. c. to 40 type 2 diabetics currently treated by diet, sulfonylurea (SU), metformin, or insulin in a double-blind, placebo-controlled, cross-over trial; preexisting treatments were continued during the study. In the bolus injection protocol, 32 subjects (8 from each of the 4 treatment groups) received 0.0, 0.5, 1.0, and 1.5 nmol rGLP-1/kg per injection (two injections, two hours apart, beginning one hour after the evening meal) in a randomized order on separate days. In the continuous s. c. infusion protocol, 40 subjects received rGLP-1 at 0.0, 1.5, 2.5, 3.5, and 4.5 pmol/kg/min for 10-12 hours overnight starting one hour after the evening meal. Fasting bloods were taken the morning after for glucose, insulin, and glucagon measurements.
In the diet, SU, and metformin cohorts, bolus rGLP-1 injections produced modest reductions in mean FSG levels, averaging 17.4 mg/dl (7.3-27.5; 95 % CI) at the highest dose (p < 0.001 vs. placebo). Reductions in FSG levels were greater by continuous infusion at up to 30.3 mg/dl (18.8 - 41.8; 95 % CI; p < 0.001 vs. placebo). The greatest reduction in mean FSG occurred in the SU cohort (up to 43.9 mg/dl, 24.7 - 63.1; 95 % CI; p < 0.001). rGLP-1 infusions resulted in significant increases in fasting plasma insulin and decreases in fasting plasma glucagon levels. There were no serious adverse events; GI-related symptoms were dose-related and more commonly associated with injections.
rGLP-1 (7-36) amide dose-dependently lowered FSG in a broad spectrum of type 2 diabetics when added to their existing treatment. Subcutaneous infusion was more effective than injection, and the combination with SU was more effective than with metformin.
评估不同剂量的重组胰高血糖素样肽-1(7-36)酰胺(rGLP-1)通过大剂量注射或持续输注皮下给药,以降低接受饮食、降糖药物或胰岛素注射治疗的2型糖尿病患者空腹血清葡萄糖(FSG)水平的安全性和有效性。
在一项双盲、安慰剂对照、交叉试验中,对40名目前接受饮食、磺脲类药物(SU)、二甲双胍或胰岛素治疗的2型糖尿病患者进行rGLP-1皮下给药;研究期间继续原有治疗。在大剂量注射方案中,32名受试者(4个治疗组每组8名)在不同日期以随机顺序接受每注射0.0、0.5、1.0和1.5 nmol rGLP-1/kg(两次注射,间隔两小时,晚餐后一小时开始)。在持续皮下输注方案中,40名受试者在晚餐后一小时开始,以0.0、1.5、2.5、3.5和4.5 pmol/kg/min的速度接受rGLP-1持续输注10 - 12小时。次日早晨采集空腹血样测量血糖、胰岛素和胰高血糖素。
在饮食、SU和二甲双胍治疗组中,大剂量注射rGLP-1可使平均FSG水平适度降低,最高剂量时平均降低17.4 mg/dl(7.3 - 27.5;95% CI)(与安慰剂相比,p < 0.001)。持续输注降低FSG水平的效果更显著,可达30.3 mg/dl(18.8 - 41.8;95% CI;与安慰剂相比,p < 0.001)。平均FSG降低幅度最大的是SU治疗组(可达43.9 mg/dl,24.7 - 63.1;95% CI;p < 0.001)。rGLP-1输注导致空腹血浆胰岛素显著升高,空腹血浆胰高血糖素水平降低。未出现严重不良事件;胃肠道相关症状与剂量有关,且更常见于注射给药。
在现有治疗基础上添加rGLP-1(7-36)酰胺可使广泛类型的2型糖尿病患者的FSG水平呈剂量依赖性降低。皮下输注比注射更有效,与SU联合使用比与二甲双胍联合使用更有效。