High Follistatin Predicts Poor Cardiometabolic Outcomes

The study covered by this research summary was published on Preprints With The Lancet as a preprint and has not yet been peer reviewed.

Key Takeaways

• Higher plasma levels of the protein follistatin (primarily made in the liver) were significantly and independently associated with an increased risk of all-cause mortality and heart failure, both apparently partly mediated by diabetes, in a study of more than 4700 middle-aged Swedish adults who were followed for an average of 23 years.

• Higher follistatin levels were also significantly linked with an increased risk of chronic kidney disease (CKD), stroke, and ischemic stroke, and these associations remained consistent regardless of diabetes status.

Why This Matters

• CKD is often clinically silent for many years before it is diagnosed. Early detection of CKD risk could allow at-risk patients to take steps for prevention. Follistatin may be a potential biomarker for detecting CKD risk years before disease onset.

• The same research team previously reported that plasma follistatin was elevated up to 19 years prior to the onset of type 2 diabetes, independently of established risk markers for diabetes. The current study suggests that follistatin may also serve as an independent biomarker for early detection of CKD risk and also of risk for certain other adverse cardiometabolic events.

Study Design

• The researchers analyzed data from the Malmö Diet Cancer Study, which enrolled 30,446 adults from Malmö, Sweden, from 1991 to 1994. From this pool, researchers randomly sampled 6103 people who underwent a cardiovascular assessment. In this subgroup, 4742 people had a recorded measure of their plasma follistatin. Excluding those for whom data for covariates were missing left a study cohort of 4733 men (40%) and women (60%). The average age of participants was about 58 years.

• At enrollment, these study participants underwent a physical examination, completed a health questionnaire, and underwent blood tests, including follistatin measurement. Their average body mass index (BMI) was 25.7 kg/m², and 7.6% had diabetes.

• Study outcomes were events that occurred from study entry until the end of 2018, including all-cause mortality and various incident comorbidities: all-cause stroke, ischemic stroke, coronary events (fatal or nonfatal myocardial infarction or death due to ischemic heart disease), heart failure, and CKD. Event data came from Swedish national registries.

Key Results

• At entry, the patients' mean follistatin level was 4.78 arbitrary units. Higher levels were significantly associated with older age, diabetes, and higher BMI, systolic blood pressure, waist circumference, total cholesterol, fasting glucose, insulin, and triglycerides.

• During average follow-up of 23 years, incident events included stroke (in 526 participants), ischemic stroke (432), coronary events (530), heart failure (339), and CKD (320). All-cause death occurred in 1843 (874 men and 969 women).

• During follow-up, for each standard deviation increase in baseline follistatin level, patients had the following significantly increased risks (hazard ratios) for various incident events after full adjustment for multiple potential confounders:

  • All-cause death: 1.05

  • All-cause stroke: 1.10

  • Ischemic stroke: 1.13

  • Heart failure: 1.16

  • CKD: 1.38

• However, there was no significant increase in risk for coronary events associated with increasing follistatin levels at baseline.

• Excluding study participants who had diabetes either at baseline or were diagnosed during follow-up changed the adjusted hazard ratios to being not significant for mortality and for heart failure with each standard deviation increase in baseline follistatin, suggesting that diabetes may partly mediate this association. But the risks for the other outcomes remained largely similar and significant, suggesting that diabetes did not play a substantial role in these outcomes.

Limitations

• Cardiovascular risk factors such as obesity and smoking probably changed in some participants during the long follow-up, but this likely had minimal impact and would have been likely to bias the findings toward neutral associations.

• In measuring follistatin levels, an arbitrary scale, rather than an absolute scale, was used, but because the study included a relatively large number of people drawn from the general adult population, it can be presumed that the observed range reflects a normal distribution.

Disclosures

• The study did not receive commercial funding.

• One senior author of the study, Yang De Marinis, is the founder of Lundoch Diagnostics (www.lundoch.com), which developed and markets a blood test for early detection of risk for type 2 diabetes based on levels of plasma follistatin and other measurements. A second senior author, Gunnar Engström, is a member of the scientific advisory board of Lundoch Diagnostics.

This is a summary of a preprint research study, "Elevated Circulating Follistatin Associates With Increased Risk of Mortality and Cardiometabolic Disorders," written by researchers from Lund University, Malmö, Sweden, published on Preprints With The Lancet, andprovided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on Preprints with The Lancet.

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Cite this: High Follistatin Predicts Poor Cardiometabolic Outcomes - Medscape - May 08, 2023.