Obesity

Obesity is a major risk factor for metabolic dysfunction-associated steatohepatitis (MASH). It is linked to diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF), and is an independent risk factor for chronic kidney disease (CKD). Therefore, there is a current need for novel biomarkers to support personalized care for people with obesity.

BMI alone does not reflect metabolic health. Biomarkers can help with diagnosis and stratification by identifying pre-obesity states or people at high risk before severe weight gain. Biomarkers can guide personalized treatment and identify who will respond to specific interventions, such as lifestyle changes or glucagon-like peptide-1 receptors agonists (GLP-1 RAs). Lastly, biomarkers can help monitor treatment response and predict long-term outcomes, such as cardiovascular disease (CVD).

Increased fibroblast activity in people with obesity promotes excessive extracellular matrix (ECM) production, leading to tissue fibrosis and contributing to the progression of organ dysfunction and related diseases.

Nordic Bioscience’s biomarkers, which reflect ECM turnover, can be used to study and improve our understanding of fibrotic processes in organ systems affected by obesity.

Elevated PRO-C3 levels are strongly associated with increased severity of key liver histological features, including hepatocellular ballooning, lobular inflammation, steatosis, and fibrosis stage. As obesity is a major risk factor for MASH and its progression to MASH and liver fibrosis, these data highlight the importance of NordicPRO-C3™ as a biomarker in the obese population.

With increasing severity of obesity-related liver pathology, NordicPRO-C3™ concentrations rise, reflecting greater fibrogenic activity and tissue remodeling. This relationship underscores the potential of NordicPRO-C3™ to identify and stratify individuals with obesity who are at increased risk of developing advanced liver disease, enabling earlier intervention and more targeted management.

Immunohistological images highlight this organ specificity: non-fibrotic kidneys show minimal or no staining for nordicPRO-C6™, while fibrotic kidneys exhibit strong nordicPRO-C6™ signal, directly correlating with the degree of tissue fibrosis.

This indicates that nordicPRO-C6™ can serve as a non-invasive indicator of renal fibrosis severity, with direct implications for obesity-driven kidney disease.

NordicPRO-C6™ is upregulated in the fibrotic heart, especially in heart failure with preserved ejection fraction (HFpEF), a condition strongly associated with obesity. In fact, nordicPRO-C6 has a received a letter of support by the FDA.

Clinical outcome studies show that higher nordicPRO-C6™ levels independently predict increased mortality, cardiovascular events, even after accounting for traditional risk factors. Individuals with the highest nordicPRO-C6™ concentrations have significantly worse long-term outcomes.

Supporting these findings, data from six independent HFpEF cohort studies demonstrate that elevated nordicPRO-C6™ is prognostic for adverse outcomes. The forest plot from a participant-level meta-analysis shows consistently increased hazard ratios for mortality across all cohorts, confirming the robust relationship between high nordicPRO-C6™ levels and risk of death in patients with HFpEF—a population where obesity is highly prevalent.

NordicPRO-C3™ demonstrates clinical utility in tracking response to intervention. Data show thatNordicPRO-C3™ decreases significantly after bariatric surgery in people with severe obesity who have advanced baseline liver fibrosis (F3–4), independent of changes in adipose tissue fibrosis.

This reduction is not seen in individuals with mild or no liver fibrosis (F0–2), highlighting the marker’s specificity for active fibrogenic processes in the liver

These findings reinforce the value of nordicPRO-C3™ not only for risk prediction but also for monitoring treatment efficacy in obesity-related liver disease.

Change in nordicPRO-C3™ with empagliflozin in heart failure. In a recent study, empagliflozin led to a significant reduction in nordicPRO-C3™ levels after 52 weeks compared to placebo. Data reflect percentage change from baseline.

The graph demonstrates that, while placebo-treated patients showed minimal change, those receiving empagliflozin exhibited a progressive decrease in nordicPRO-C3™ over one year, with statistical significance reached at week 52. For obesity, this is relevant because nordicPRO-C3™ is a biomarker associated with extracellular matrix remodeling, which is implicated in both heart failure and metabolic diseases like obesity. The reduction in nordicPRO-C3™ with empagliflozin suggests potential benefits beyond heart failure, including an impact on fibrotic and metabolic pathways involved in obesity and its complications.

Changes in collagen type III biomarkers with canagliflozin in type 2 diabetes with expected levels of nordicCTX-III™ at follow-up (week 156) are plotted against baseline levels. Conversely, nordicCTX-III™ levels were significantly higher with canagliflozin, with a greater effect in those with elevated baseline levels.

The graph demonstrates that both 100 mg and 300 mg doses of canagliflozin result in higher follow-up nordicCTX-III™ levels compared to placebo, especially in individuals who started with higher baseline values. This indicates that canagliflozin increases collagen type III degradation activity over time.

The implication is that canagliflozin may enhance collagen turnover and tissue remodeling processes in metabolic tissues. Elevated nordicCTX-III™ suggests increased breakdown of type III collagen, which can reflect dynamic changes in extracellular matrix composition. This may have relevance for addressing fibrosis and tissue stiffness often seen in obesity-related metabolic dysfunction, highlighting a potential mechanism by which canagliflozin exerts beneficial metabolic effects beyond glycemic control.