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Endotrophin as a risk marker of mortality and kidney complications in a type 1 diabetes cohort.

ABSTRACT: Hyperglycemia triggers pathological pathways leading to fibrosis, where extracellular matrix (ECM) components are accumulated. We investigated the potential of endotrophin, a pro-fibrotic molecule generated during collagen type VI formation, as a risk marker for complications to type 1 diabetes. Endotrophin was measured in serum and urine from 1,468 persons with type 1 diabetes. Outcomes included a composite kidney endpoint, first major adverse cardiovascular event (MACE), all-cause mortality, progression of albuminuria, incident heart failure, and sight-threatening diabetic eye disease. Cox proportional hazards models adjusted for conventional risk factors were applied. A doubling of serum endotrophin was independently associated with the kidney endpoint (n = 30/1,462; hazard ratio 3.39 [95% CI: 1.98-5.82]), all-cause mortality (n = 93/1,468; 1.44 [1.03-2.0]), and progression of albuminuria (n = 80/1,359; 1.82 [1.32-2.52]), but not with first MACE, heart failure, or sight-threatening diabetic eye disease after adjustment. Urinary endotrophin was not associated with any outcome after adjustment. Serum endotrophin was a risk marker for mortality and kidney complications in type 1 diabetes. Biomarkers of ECM remodeling, such as serum endotrophin, may identify persons with active pro-fibrotic processes at risk for complications in diabetes and where antifibrotic agents may reduce this risk.

SUBMITTER: Moller AL

PROVIDER: S-EPMC10505392 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Endotrophin as a risk marker of mortality and kidney complications in a type 1 diabetes cohort.

Møller Alexandra Louise AL Tougaard Ninna Hahn NH Rasmussen Daniel Guldager Kring DGK Genovese Federica F Rønn Pernille Falberg PF Hansen Tine Willum TW Karsdal Morten Asser MA Rossing Peter P

Frontiers in molecular biosciences 20230901

Hyperglycemia triggers pathological pathways leading to fibrosis, where extracellular matrix (ECM) components are accumulated. We investigated the potential of endotrophin, a pro-fibrotic molecule generated during collagen type VI formation, as a risk marker for complications to type 1 diabetes. Endotrophin was measured in serum and urine from 1,468 persons with type 1 diabetes. Outcomes included a composite kidney endpoint, first major adverse cardiovascular event (MACE), all-cause mortality, p ...[more]

PMID: 37724129

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Project description:BackgroundEnhanced de-novo collagen type VI (COL VI) formation has been associated with kidney and cardiovascular fibrosis. We hypothesized that endotrophin (ETP), a product specifically generated during collagen type VI formation, may be prognostic for heart failure (HF), cardiovascular death (CVD), kidney endpoints, and all-cause mortality in patients with type 2 diabetes.MethodsWe measured ETP in plasma (P-ETP) and urine (U-ETP) samples collected at baseline and follow-up (year 3) from the randomized controlled trial, CANagliflozin cardioVascular Assessment Study (CANVAS), by use of the PRO-C6 ELISA measuring COL VI formation and ETP. At baseline, plasma and urine samples were available for 3531 and 3423 patients, respectively. At year 3, plasma and urine samples were available for 2178 (61.7%) and 2070 (60.5%) patients, respectively Patients were followed for a median of 6.1 years, and endpoints included: incident HF, CVD, three kidney composite endpoints, and all-cause mortality. Backward selection was used to identify variables to be included in the analyses. Robustness of the association with outcome was assessed by bootstrap analyses.ResultsIn univariable analysis, P-ETP predicted all investigated outcomes (all p < 0.0001), remained independently associated with all outcomes after adjustment for conventional risk factors (all p < 0.004), and increased C-statistics of the models for the outcomes HF, CVD, HFCVD, all-cause mortality, and kidney composite 2 (ΔC ≥ 0.002). In bootstrap analysis, P-ETP was retained with a frequency ranging from 41.0 to 98.4% for all outcomes. Levels of U-ETP were associated with outcomes in univariable analysis, but associations with most outcomes were lost after adjustment for conventional risk factors. The increase in P-ETP over time was greater with increasing albuminuria stage (p < 0.0001) and was independently associated with the kidney endpoints (p < 0.03). In the placebo arm, the increase in P-ETP was prognostic for all-cause mortality (HR [95% CI]; 1.14 [1.05-1.23], p = 0.003). Whereas levels of P-ETP were not impacted by treatment, levels of U-ETP significantly increased with canagliflozin treatment.ConclusionsP-ETP generated during COL VI formation predicts cardiovascular, kidney and mortality outcomes in patients with type 2 diabetes. As ETP identifies patients at increased risk of experiencing relevant outcomes, it may be used for patient enrichment in future clinical trials. Trial Registry Number (ClinicalTrials.gov Identifier): NCT01032629.

Project description:OBJECTIVES:This study aimed to evaluate the effectiveness of multiple risk factor control (MRFC) at reducing mortality and cardiovascular events in diabetes and chronic kidney disease (CKD) in clinical practice. DESIGN:Population-based cohort study. SETTING:Primary care database in the UK, linked with inpatient and mortality data. PARTICIPANTS:Participants aged 40-79 years with type 2 diabetes and valid serum creatinine measurements, including 11 431 participants with CKD (estimated glomerular filtration rate: eGFR 15-59 mL/min/1.73 m2) and 36 429 participants with non-CKD (eGFR ≥60 mL/min/1.73 m2). EXPOSURES:MRFC consisted of four components: Haemoglobin A1c (HbA1c) <53 mmol/mol (<7.0%), blood pressure <140/90 mm Hg, total cholesterol <5 mmol/L and no smoking. The main exposure variable was the number of risk factors controlled at baseline. OUTCOME MEASURES:All-cause and cardiovascular mortality in the overall participants. Cardiovascular events, including coronary heart disease and stroke, in participants limited to those without a history of cardiovascular diseases at baseline. RESULTS:In participants with CKD, 37% or 13% met three or four MRFC criteria, respectively. Increasing numbers of risk factors controlled were associated with lower relative hazards for all outcomes studied compared with those meeting no or one criterion. For participants with CKD meeting four criteria, the adjusted HR for all-cause mortality was 0.60 (95% CI 0.53 to 0.69) and the adjusted subdistribution HR for cardiovascular mortality was 0.60 (95% CI 0.50 to 0.70), considering a competing risk of non-cardiovascular death. Participants meeting four criteria also had lower relative hazards for coronary heart disease (adjusted subdistribution HR 0.73, 95% CI 0.59 to 0.91) and stroke (0.63, 95% CI 0.45 to 0.89), considering death as a competing risk. CONCLUSIONS:MRFC may lower the increased risks for mortality and cardiovascular events in people with diabetes and CKD. Further research is needed to evaluate appropriateness of MRFC according to individual participants' health status for improved management of cardiovascular risks in this population.

Project description:BackgroundCross-sectional studies found that frailty was associated with prevalent diabetic microvascular complications (DMC). Longitudinal evidence in this regard is inconclusive and insufficient. We aimed to prospectively evaluate the association of pre-frailty and frailty with DMC in patients with type 2 diabetes (T2D).MethodsWe included 18,062 adults (mean age 59.4 ± 7.2 years, 37.4% female) with T2D at baseline in the UK Biobank. Frailty was defined using the frailty phenotype according to five components (weight loss, exhaustion, low physical activity, slow gait speed, and low grip strength). DMC, defined as diabetic nephropathy, diabetic neuropathy, or diabetic retinopathy, was identified using hospital inpatient records and death registries. Cox proportional hazard regression models considering competing risks were used to evaluate the associations of frailty phenotype with overall DMC events and subtypes.ResultsAmong all participants, 6101 (33.8%) were classified as non-frail, 10,073 (55.8%) were classified as pre-frail, and 1888 (10.4%) were classified as frail. During a median follow-up of 12.0 years, 3678 DMC cases were documented, including 2213 diabetic nephropathy, 1520 diabetic retinopathy, and 673 diabetic neuropathy events. In the multivariable-adjusted model, compared with participants with non-frail, both pre-frailty and frailty were significantly associated with increased risk of overall DMC (HR 1.10, 95% CI: [1.02, 1.18] for pre-frailty and HR 1.52 [95% CI: 1.36, 1.69] for frailty). Similar results were observed in the subtypes of DMC. For each one-point increase in frailty phenotype score, the risk of overall DMC, diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy event increased by 13%, 16%, 10%, and 20%, respectively.ConclusionsBoth pre-frailty and frailty were associated with an increased risk of DMC in patients with T2D. These findings have important implications for integrating early assessment and surveillance of frailty in diabetes and may favor the identification of at-risk patients.

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Endotrophin as a risk marker of mortality and kidney complications in a type 1 diabetes cohort.

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Endotrophin as a risk marker of mortality and kidney complications in a type 1 diabetes cohort.

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