Is there a connection between Growth Differentiation Factor-15 (GDF-15) and Glucagon-Like Peptide-1 (GLP-1) analog use, such as liraglutide (Victoza) or semaglutide (Ozempic), in patients with elevated GDF-15 levels?

Connection Between GDF-15 and GLP-1 Receptor Agonist Use

GLP-1 receptor agonist therapy does not alter circulating GDF-15 levels in humans with obesity, despite causing significant weight loss, indicating these are independent pathways rather than directly connected mechanisms. 1

Evidence from Clinical Studies

Direct Investigation of GLP-1 and GDF-15 Relationship

The most definitive evidence comes from a randomized, double-blinded crossover trial examining liraglutide (a GLP-1 receptor agonist) in 20 subjects with obesity over 5 weeks. 1

• Neither total nor intact GDF-15 levels changed in response to liraglutide treatment, despite significant weight loss occurring. 1
• This finding demonstrates that GDF-15 is not directly involved in the metabolic feedback pathways downstream of GLP-1 receptor activation. 1
• The lack of GDF-15 response suggests these biomarkers operate through separate mechanisms in weight regulation and metabolic control. 1

Mechanistic Independence

GDF-15 and GLP-1 appear to work through distinct receptor systems and signaling pathways:

• GDF-15 acts through GFRAL receptors located selectively in the brain, functioning as a stress-responsive cytokine. 2
• GLP-1 receptor agonists work through incretin-based mechanisms affecting insulin secretion, gastric emptying, and appetite centers. 3
• While both can reduce appetite and body weight, they do so via non-overlapping pathways. 1

GDF-15 Elevation in Diabetes Context

Metformin Connection (Not GLP-1)

The primary diabetes medication that increases GDF-15 is metformin, not GLP-1 receptor agonists:

• Metformin administration for 8 weeks significantly upregulated GDF-15 in type 2 diabetes patients, correlating with reduced body mass. 3, 4
• In rats with diet-induced obesity, intragastric metformin for 11 days induced GDF-15 expression in kidneys, resulting in increased circulating GDF-15 and lowered food intake. 3
• This represents a fundamentally different mechanism than GLP-1 therapy. 3

GDF-15 as a Stress Biomarker in Diabetes

• GDF-15 is elevated in type 2 diabetes as a stress-responsive cytokine reflecting systemic inflammation and metabolic dysfunction. 4, 5
• GDF-15 levels are higher in metabolic dysfunction-associated steatotic liver disease compared to healthy controls. 4
• Each 1 SD increase in log2[GDF-15] predicts major adverse cardiovascular events (aHR 1.12) and all-cause mortality (aHR 1.27) in type 2 diabetes patients. 6

Emerging Dual Agonist Research

Experimental GLP-1/GDF-15 Fusion Proteins

Preclinical research has explored engineered dual agonists combining GLP-1 and GDF-15 activities, but these are experimental molecules not available clinically:

• A fusion protein (QL1005) combining GLP-1 and GDF-15 analogs showed superior weight reduction in obese mice compared to semaglutide alone. 7
• In cynomolgus monkeys, this dual agonist reduced body weight, food intake, insulin, and glucose with limited gastrointestinal side effects. 7
• These effects resulted from balanced activities of both GLP-1 and GDF-15 pathways working independently but synergistically. 7
• This research confirms that GLP-1 and GDF-15 are separate pathways that can be therapeutically combined, not that standard GLP-1 agonists affect GDF-15 levels. 7

Clinical Implications for Patients with Elevated GDF-15

When Prescribing GLP-1 Receptor Agonists

Elevated baseline GDF-15 levels should not influence the decision to prescribe GLP-1 receptor agonists, as these pathways are independent:

• GLP-1 receptor agonists (liraglutide, semaglutide, dulaglutide) are recommended for cardiovascular risk reduction in type 2 diabetes regardless of GDF-15 status. 3
• Empagliflozin, canagliflozin, or dapagliflozin (SGLT2 inhibitors, not GLP-1 agonists) are also recommended for cardiovascular event reduction. 3
• Standard monitoring for GLP-1 therapy includes watching for nausea/vomiting, hypoglycemia risk reduction, and diabetic retinopathy complications (particularly with semaglutide). 3

GDF-15 as a Prognostic Marker

• GDF-15 should be interpreted as a marker of systemic stress, inflammation, and cardiovascular risk rather than a target affected by GLP-1 therapy. 4
• GDF-15 is incorporated into the ABC bleeding risk score for patients with atrial fibrillation on anticoagulation. 3, 4
• Elevated GDF-15 predicts all-cause mortality across disease states and reflects adverse cardiac events independent of glucose-lowering therapy choice. 4, 6

Key Clinical Pitfalls to Avoid

• Do not expect GDF-15 levels to decrease with GLP-1 therapy—this is not a mechanism of action or expected benefit. 1
• Do not withhold GLP-1 receptor agonists based on elevated GDF-15—these are independent pathways with separate therapeutic targets. 1
• Do not confuse metformin's effect on GDF-15 with GLP-1 effects—only metformin has been shown to increase GDF-15 in clinical studies. 3, 4
• Recognize that experimental dual GLP-1/GDF-15 agonists are research tools, not reflective of current clinical GLP-1 medications. 7