Endotrophin Levels Could Signal Elevated Kidney Risk in Type 1 Diabetes

Peter Rossing, MD
Credit: Novo Nordisk

A new analysis suggests serum endotrophin levels could prove useful as a predictor of negative kidney outcomes in people with type 1 diabetes.

Using data from a cohort of more than 1400 people with type 1 diabetes, results of the study indicate a doubling of serum endorphin was associated with an increased risk of all-cause mortality and more than 3-fold increase in risk of kidney disease progression, but no increase in risk for either outcome was observed for increased levels of urinary endotrophin.¹

“We validated the previous findings of endotrophin in type 1 diabetes in a large and unselected cohort. Higher levels of serum endotrophin, released during collagen type VI formation, were independently associated with a higher risk of mortality and development or progression of [chronic kidney disease] in persons with type 1 diabetes,” wrote investigators.¹

Although type 1 diabetes is often over-looked as a public health crisis because it is not associated with the same magnitude of risk for negative outcomes as type 2 diabetes, the increasing prevalence of type 1 diabetes poses a significant threat to health systems.² With this serving as a backdrop, identification of biomarkers for predicting risk of various negative outcomes in this patient population has become a focal point of many ongoing research efforts. In the current study, a team led by Peter Rossing, MD, of Steno Copenhagen Diabetes Center, sought to build on previous research purporting endotrophin could predict decline in renal function and adverse outcomes in people with type 1 diabetes.¹

To do so, investigators designed the current study as an analysis of data obtained from the StenoDot cohort, which recruited patients from an outpatient clinical at the Steno Diabetes Center in Denmark from 2012 through 2016. From this cohort, investigators identified 1468 individuals with type 1 diabetes with available measurements of endotrophin for inclusion in their analysis.¹

Overall, 99% of the cohort had serum samples available for endotrophin levels and 85% had urine samples available. The total cohort had a mean age of 51 (Standard deviation [SD], 16) years, a mean diabetes duration of 26 (SD, 15) years, and . Among the 1446 persons with serum samples, 75% had normoalbuminuria, 18% had microalbuminuria, and 7% with macroalbuminuria. For the purpose of analysis, these patients were stratified by turtles of serum and urinary endorphin levels.¹

The study included multiple outcomes of interest. Outcomes of interest included but were not limited to a composite kidney endpoint, first major adverse cardiovascular event (MACE), all-cause mortality, progression of albuminuria, incident heart failure, and vision-threatening diabetic eye disease. The composite kidney endpoint used in the study was defined as a decline of 40% or greater in eGFR confirmed after minimum 1 month or unconfirmed if the measurement was the last before end-of-follow-up, development of CKD stage 5, chronic dialysis, kidney transplantation, or kidney failure as cause of death.¹

Investigators pointed out the median follow-up was 6.4 years for the composite kidney endpoint, 6.3 years for MACE, 5.3 years for all-cause mortality, 6.3 years for albuminuria progression, 6.4 years for incident heart failure, and 3.1 years for sight-threatening diabetic eye disease.¹

Upon analysis, results suggested elevated levels of serum endotrophin were significantly associated with the kidney endpoint and all-cause mortality in both unadjusted and adjusted analyses. In analysis adjusted for traditional risk factors, a double of serum endotrophin was associated with a more than 3-fold increase in risk of the composite kidney endpoint (Hazard ratio [HR], 3.39; 95% Confidence Interval [CI], 1.98-5.82) as well as an increase in risk for first MACE (HR, 1.28; 95% CI, 0.90-1.28) and all-cause mortality (HR, 1.44; 95% CI, 1.03-2.0). Further analysis revealed an association between a doubling of serum endotrophin and progression of albuminuria (HR, 1.82; 95% CI, 1.32-2.52), but not with incident heart failure or vision-threatening diabetic eye disease.¹

Investigators highlighted there were no associations observed between urine endotrophin levels and any of the outcomes of interest.¹

“Further investigation proving the utility of circulating endotrophin as a risk marker and potentially as an actor in disease progression will be important for designing and monitoring intervention strategies to reduce fibrosis and consequent organ function loss,” investigators wrote.¹ “Furthermore, it will be interesting to determine whether changes in endotrophin can predict a clinically meaningful response to therapies with kidney and cardiovascular outcomes benefit.”

References:

1. Møller AL, Tougaard NH, Rasmussen DGK, et al. Endotrophin as a risk marker of mortality and kidney complications in a type 1 diabetes cohort. Front Mol Biosci. 2023;10:1229579. Published 2023 Sep 1. doi:10.3389/fmolb.2023.1229579
2. Campbell P. Rates of type 1, type 2 diabetes expected to balloon in US by 2060. HCP Live. January 12, 2023. Accessed September 20, 2023. https://www.hcplive.com/view/rates-of-type-1-type-2-diabetes-expected-to-balloon-in-us-by-2060.