Wilding J P H, Overgaard R V, Jacobsen L V, Jensen C B, le Roux C W
Department of Obesity and Endocrinology, University of Liverpool, Liverpool, UK.
Medical Affairs, GLP-1 and Obesity, Novo Nordisk A/S, Søborg, Denmark.
Diabetes Obes Metab. 2016 May;18(5):491-9. doi: 10.1111/dom.12639. Epub 2016 Mar 1.
Liraglutide 3.0 mg, an acylated GLP-1 analogue approved for weight management, lowers body weight through decreased energy intake. We conducted exposure-response analyses to provide important information on individual responses to given drug doses, reflecting inter-individual variations in drug metabolism, absorption and excretion.
We report efficacy and safety responses across a wide range of exposure levels, using data from one phase II (liraglutide doses 1.2, 1.8, 2.4 and 3.0 mg), and two phase IIIa [SCALE Obesity and Prediabetes (3.0 mg); SCALE Diabetes (1.8; 3.0 mg)] randomized, placebo-controlled trials (n = 4372).
There was a clear exposure-weight loss response. Weight loss increased with greater exposure and appeared to level off at the highest exposures associated with liraglutide 3.0 mg in most individuals, but did not fully plateau in men. In individuals with overweight/obesity and comorbid type 2 diabetes, there was a clear exposure-glycated haemoglobin (HbA1c) relationship. HbA1c reduction increased with higher plasma liraglutide concentration (plateauing at ∼21 nM); however, for individuals with baseline HbA1c >8.5%, HbA1c reduction did not fully plateau. No exposure-response relationship was identified for any safety outcome, with the exception of gastrointestinal adverse events (AEs). Individuals with gallbladder AEs, acute pancreatitis or malignant/breast/benign colorectal neoplasms did not have higher liraglutide exposure compared with the overall population.
These analyses support the use of liraglutide 3.0 mg for weight management in all subgroups investigated; weight loss increased with higher drug exposure, with no concomitant deterioration in safety/tolerability besides previously known gastrointestinal side effects.
利拉鲁肽3.0毫克是一种已被批准用于体重管理的酰化胰高血糖素样肽-1类似物，它通过减少能量摄入来降低体重。我们进行了暴露-反应分析，以提供关于个体对特定药物剂量反应的重要信息，反映药物代谢、吸收和排泄的个体差异。
我们使用来自一项II期试验（利拉鲁肽剂量为1.2、1.8、2.4和3.0毫克）以及两项IIIa期试验[SCALE肥胖与糖尿病前期（3.0毫克）；SCALE糖尿病（1.8；3.0毫克）]的随机、安慰剂对照试验（n = 4372）的数据，报告了广泛暴露水平下的疗效和安全性反应。
存在明显的暴露-体重减轻反应。体重减轻随着暴露增加而增加，在大多数个体中，与利拉鲁肽3.0毫克相关的最高暴露水平时似乎趋于平稳，但在男性中并未完全达到平台期。在超重/肥胖合并2型糖尿病的个体中，存在明显的暴露-糖化血红蛋白（HbA1c）关系。HbA1c降低随着血浆利拉鲁肽浓度升高而增加（在约21 nM时达到平台期）；然而，对于基线HbA1c>8.5%的个体，HbA1c降低并未完全达到平台期。除胃肠道不良事件（AE）外，未发现任何安全性结局的暴露-反应关系。与总体人群相比，患有胆囊AE、急性胰腺炎或恶性/乳腺/良性结直肠肿瘤的个体利拉鲁肽暴露水平并未更高。
这些分析支持在所有研究的亚组中使用利拉鲁肽3.0毫克进行体重管理；体重减轻随着药物暴露增加而增加，除了先前已知的胃肠道副作用外，安全性/耐受性并未随之恶化。
