Department of Medicine Solna, Karolinska Institutet, Norrbacka, S1:02, 171 76, Stockholm, Sweden.
Janssen Research & Development, LLC, 920 US-202, Raritan, NJ, 08869, USA.
Cardiovasc Diabetol. 2022 Jul 4;21(1):127. doi: 10.1186/s12933-022-01558-w.
Raised liver function tests (LFTs) have been correlated with multiple metabolic abnormalities and variably associated with cardiorenal outcomes. We sought to systematically test the relationship between LFT levels within the accepted range and major cardiorenal outcomes in a large clinical trial in type 2 diabetes, and the possible impact of placebo-controlled canagliflozin treatment.
We measured serum alanine aminotransferase (ALT), aspartic aminotransferase (AST), gamma-glutamyl transferase (γGT), alkaline phosphatase (ALP), and bilirubin concentrations in 10,142 patients, at baseline and repeatedly over follow-up. The relation of LFTs to first hospitalized heart failure (HHF), cardiovascular (CV) and all-cause mortality, and progression of renal impairment was investigated using multivariate proportional-hazards models.
In univariate association, ALT was reciprocally predictive, and ALP was positively predictive, of all adjudicated outcomes; γGT also was directly associated with CV-but not renal-outcomes. In multivariate models including all 5 LFTs and 19 potential clinical confounders, ALT was independently associated with lower, and γGT with higher, CV outcomes risk. Canagliflozin treatment significantly reduced ALT, AST, and γGT over time. In a fully adjusted model including updated LFT levels and treatment, γGT was independently associated with CV and all-cause mortality, ALP with renal dysfunction progression, and canagliflozin treatment with significant reduction in HHF and renal risk.
Higher γGT levels are top LFT markers of risk of HHF and death in patients with diabetes and high CV risk, while ALT are protective. Canagliflozin lowers the risk of HHF and renal damage independently of LFTs and potential confounders.
升高的肝功能测试（LFT）与多种代谢异常相关，且与心肾结局的关系也各不相同。我们旨在通过一项大型 2 型糖尿病临床试验，系统检测在可接受范围内的 LFT 水平与主要心肾结局之间的关系，以及安慰剂对照的卡格列净治疗的可能影响。
我们在 10142 例患者中测量了基线和随访期间的血清丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、γ-谷氨酰转移酶（γGT）、碱性磷酸酶（ALP）和胆红素浓度。使用多变量比例风险模型研究 LFT 与首次住院心力衰竭（HHF）、心血管（CV）和全因死亡率以及肾功能恶化的关系。
在单变量关联中，ALT 呈反比预测，ALP 呈正相关预测所有判定的结局；γGT 也与 CV 但与肾脏结局无关。在包括 5 种 LFT 和 19 种潜在临床混杂因素的多变量模型中，ALT 与较低的 CV 结局风险独立相关，γGT 与较高的 CV 结局风险独立相关。卡格列净治疗随时间显著降低 ALT、AST 和 γGT。在包括更新的 LFT 水平和治疗的完全调整模型中，γGT 与 CV 和全因死亡率独立相关，ALP 与肾功能障碍进展相关，卡格列净治疗与 HHF 和肾脏风险的显著降低相关。
在具有高 CV 风险的糖尿病患者中，较高的 γGT 水平是 HHF 和死亡风险的最佳 LFT 标志物，而 ALT 则具有保护作用。卡格列净独立于 LFT 和潜在混杂因素降低 HHF 和肾脏损害的风险。
