Elevated Liver Enzyme Linked With Poor Outcomes in Type 2 Diabetes

Mitchel L. Zoler, PhD, for Medscape

December 10, 2021

Key Takeaways

  • Higher levels of alkaline phosphatase (ALP), as well as variability in serum levels of ALP, are associated with increased risk of all-cause mortality, cardiovascular mortality, and new-onset heart failure in patients with type 2 diabetes.

  • ALP is an enzyme found in the liver, bone, bile duct, kidney, intestinal mucosa, and placenta (in women).

  • Determining the underlying mechanisms of these associations and validating the predictive value of ALP and its variability will require further study.

  • This study is currently a preprint and has not been peer-reviewed.

Why This Matters

  • Results from prior studies showed that elevated ALP levels are independently associated with an increased risk of adverse outcomes in patients with chronic kidney disease or a history of stroke, myocardial infarction, or percutaneous coronary intervention.

  • The present study aimed to evaluate the predictive value of ALP levels and variability in patients with type 2 diabetes for development of incident heart failure, cardiovascular death, and all-cause death.

  • According to the authors, this is the first study to investigate the possible association of new-onset heart failure with higher tertiles of ALP in patients with type 2 diabetes.

Study Design

  • Retrospective analysis of data from 14,289 patients with type 2 diabetes who presented to the Hong Kong Hospital Authority from January 1, 2000 to December 31, 2019.

  • The analysis excluded patients with fewer than three ALP measurements before they developed relevant outcomes. 

  • The primary outcomes were new-onset heart failure, cardiovascular mortality, and all-cause mortality.

  • The analysis included incident outcomes through December 31, 2019.

Key Results

  • Over a mean follow-up of 2513 days (6.9 years), 10,182 patients (71%) died from any cause, 1966 patients (14%) died from cardiovascular causes, and 1171 patients (8%) developed new-onset heart failure.

  • The analysis divided patients into tertiles of baseline ALP levels: less than 72 U/L, 72-90 U/L, and greater than 90 U/L.

  • The cumulative incidences of all-cause death, cardiovascular death, and new-onset heart failure were each significantly higher in the tertile of patients with the highest ALP levels compared with patients in the middle- and low-ALP level tertiles.

  • In a multivariate model that adjusted for baseline differences in demographics, past comorbidities, and medications, patients in the tertile with the highest ALP levels had significantly increased rates of all-cause death (hazard ratio [HR], 1.32), cardiovascular death (HR, 1.22), and incident heart failure (HR, 1.35).

  • However, after further adjustment for subclinical biomarkers, the hazard ratios for all three outcomes were no longer significant.


  • This observational study is susceptible to observational bias, including under-coding and coding errors.

  • The medical-records database used for this study did not include information on cardiovascular risk factors such as smoking and sedentary lifestyle.

  • Data on serum phosphorus, vitamin D, and parathyroid hormone levels were not available.

  • Echocardiographic data were unavailable, and hence, patients' left ventricular ejection fraction was not known.


  • The preprint currently does not include a statement about the source of the study's funding.

  • The authors have reported no relevant financial relationships.

This is a summary of a preprint research study written by a group of researchers based at various centers in the UK and China on MedRxiv provided to you by Medscape. This study has not yet been peer-reviewed. The full text of the study can be found on MedRxiv.org.

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