Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
dLAB and Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
Orphanet J Rare Dis. 2022 Jul 8;17(1):252. doi: 10.1186/s13023-022-02385-8.
MTOR inhibition is an effective treatment for many manifestations of tuberous sclerosis complex. Because mTOR inhibition is a disease modifying therapy, lifelong use will most likely be necessary. This study addresses the long-term effects of mTOR inhibitors on lipid and glucose metabolism and aims to provide better insight in the incidence and time course of these metabolic adverse effects in treated TSC patients.
All patients who gave informed consent for the nationwide TSC Registry and were ever treated with mTOR inhibitors (sirolimus and/or everolimus) were included. Lipid profiles, HbA1c and medication were analysed in all patients before and during mTOR inhibitor treatment.
We included 141 patients, the median age was 36 years, median use of mTOR inhibitors 5.1 years (aimed serum levels 3.0-5.0 µg/l). Total cholesterol, LDL- and HDL-cholesterol levels at baseline were similar to healthy reference data. After start of mTOR inhibition therapy, total cholesterol, LDL-cholesterol and triglycerides increased significantly and were higher compared to healthy reference population. Mean total cholesterol levels increased by 1.0 mmol/L after 3-6 months of mTOR inhibition therapy but did not increase further during follow-up. In this study, 2.5% (3/118) of patients developed diabetes (defined as an HbA1c ≥ 48 mmol/mol) during a median follow-up of 5 years.
Hypercholesterolemia is a frequent side effect of mTOR inhibition in TSC patients, and predominantly occurs within the first year of treatment. Although hyperglycemia is a frequent side effect in other indications for mTOR inhibition, incidence of diabetes mellitus in TSC patients was only 2.5%. This may reflect the difference of mTOR inhibition in patients with normal mTOR complex pathway function versus patients with overactive mTOR complex signaling due to a genetic defect (TSC patients).
mTOR 抑制剂是治疗结节性硬化症多种表现的有效方法。由于 mTOR 抑制剂是一种疾病修饰疗法，因此很可能需要终身使用。本研究旨在探讨 mTOR 抑制剂对脂代谢和糖代谢的长期影响，并旨在更深入地了解接受治疗的 TSC 患者发生这些代谢不良事件的发生率和时间过程。
所有同意参加全国性 TSC 登记处并曾接受 mTOR 抑制剂（西罗莫司和/或依维莫司）治疗的患者均纳入本研究。在接受 mTOR 抑制剂治疗之前和治疗期间，对所有患者的血脂谱、HbA1c 和药物进行了分析。
我们共纳入了 141 名患者，中位年龄为 36 岁，中位 mTOR 抑制剂使用时间为 5.1 年（目标血清浓度为 3.0-5.0μg/l）。基线时总胆固醇、LDL-和 HDL-胆固醇水平与健康参考数据相似。开始 mTOR 抑制治疗后，总胆固醇、LDL 胆固醇和甘油三酯水平显著升高，且高于健康参考人群。mTOR 抑制治疗 3-6 个月后，总胆固醇平均水平升高 1.0mmol/L，但在随访期间未进一步升高。在本研究中，118 例患者中有 2.5%（3/118）在中位随访 5 年内发生糖尿病（定义为 HbA1c≥48mmol/mol）。
高胆固醇血症是 TSC 患者接受 mTOR 抑制剂治疗的常见副作用，主要发生在治疗的第一年。尽管高血糖是 mTOR 抑制剂治疗其他适应证的常见副作用，但 TSC 患者中糖尿病的发生率仅为 2.5%。这可能反映了正常 mTOR 复合物途径功能的患者与由于遗传缺陷（TSC 患者）而导致 mTOR 复合物信号过度激活的患者之间 mTOR 抑制剂的差异。
