Liver function markers predict cardiovascular and renal outcomes in the CANVAS Program

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Coexistence of sarcopenia and self‐reported weight loss is a powerful predictor of mortality in older patients with heart failure

“…[34][35][36] This is the case in HF patients: subanalyses of large-scaled randomized controlled studies for HF patients showed that a decline in body weight was associated with a higher risk of all-cause mortality, regardless of the treatment. 17,20,22 The importance of timedependent weight loss in adverse clinical outcomes was supported by a recent retrospective observational study with a large number of HF patients and a prospective observational study carried out in Japan. 18,21,23 In other words, the prediction of prognosis by assessment of body weight at a single point might not necessarily be accurate, as it is unclear whether body weight is in the process of increasing or decreasing compared with the previous time point.…”

“…17 The importance of time-dependent weight loss in the prediction of prognosis in HF patients was supported by the results of recent studies. [18][19][20][21][22][23] The untoward impact of weight loss on prognosis is at least partly explained by the progression of muscle wasting, but reduction in fat/bone mass, which is usually seen in patients with cachexia, might play a role. Therefore, the presence of time-dependent weight loss potentially has an additive impact on the prediction of prognosis by sarcopenia through detection of patients who entered the cachexic process.…”

Association between nonalcoholic fatty liver disease and atrial fibrillation and other clinical outcomes: a meta-analysis

“…66,67 However, it is still undetermined whether these markers are specific or sensitive in clinical practice; for instance, a recent study conducted through the CANVAS program found that though raised γGT was associated with the risk of HF, ALT levels were independently associated with lower risk. 68…”

“…66,67 However, it is still undetermined whether these markers are specific or sensitive in clinical practice; for instance, a recent study conducted through the CANVAS program found that though raised gGT was associated with the risk of HF, ALT levels were independently associated with lower risk. 68 Screening protocols should be equipped to identify certain parameters that would indicate increased CVD risk in NAFLD outside of traditional metabolic markers. Currently, the literature has not reached a consensus on the validity of lipid profiles (i.e., LDL-C levels) or liver enzymes in determining CVD risk within the NAFLD population.…”

The Safety Profile of Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-like Peptide 1 Receptor Agonists in the Standard of Care Treatment of Type 2 Diabetes Mellitus

“…Moreover, a slower eGFR rate decline for dapagliflozin in DAPA-HF; a reduction of albuminuria and of the risk of kidney function loss, and a slower decline of the eGFR for canagliflozin in CANVAS are reported as safety parameters. In relation to hepatic function, there is a reported reduction of aminotransferases (GPT > GOT), which are secondary to hepatic fat reduction for empagliflozin in EMPA-REG OUTCOME, and of GOT, GPT, and γ-glutamyl transpeptidase (GGT) for canagliflozin in CANVAS, alongside with classical adverse reactions (AR) such as reducing the incidence of hypoglycemia episodes, volume depletion, arrythmias, amputation, urinary tract infections, and all-cause mortality [ 20 , 26 , 27 , 28 , 29 , 30 ]. On the other hand, GLP-1 RAs are reported to reduce 3-point MACE and the rate of myocardial infarction and non-fatal stroke for semaglutide in PIONNER and SUSTAIN, and for liraglutide in LEADER [ 31 , 32 , 33 ].…”