Mechanism of Mirabegron-Induced Cholesterol Elevation
Mirabegron increases cholesterol levels through β3-adrenergic receptor-mediated activation of brown adipose tissue (BAT), which triggers thermogenesis-dependent lipolysis that elevates plasma LDL-cholesterol and VLDL-cholesterol remnants.
Mechanistic Pathway
The cholesterol elevation occurs through a specific cascade:
BAT activation via β3-adrenergic receptors stimulates thermogenesis and browning of white adipose tissue, which increases systemic lipolysis 1, 2
Thermogenesis-triggered lipolysis releases fatty acids and lipoproteins into circulation, specifically increasing both LDL-cholesterol and VLDL-cholesterol remnants 1
This mechanism is thermogenesis-dependent: Studies in mice with genetic deletion of uncoupling protein 1 (UCP1), the critical thermogenesis protein, completely abolished mirabegron's effect on cholesterol and atherosclerosis, confirming the pathway requires active BAT thermogenesis 1
Clinical Evidence of Lipid Effects
The metabolic consequences in humans include:
Increased beneficial lipoproteins: Chronic mirabegron treatment (100 mg for 4 weeks) elevated HDL cholesterol and ApoA1 levels in healthy women, along with increased total bile acids 3
Enhanced lipolysis markers: Non-esterified fatty acids (NEFA) significantly increased with mirabegron treatment, reflecting active lipolysis 2
Increased metabolic activity: BAT activity, resting energy expenditure, and body temperature all rose significantly, confirming active thermogenic lipolysis 3, 2
Important Clinical Caveat
The preclinical atherosclerosis concern: In apolipoprotein E-/- and LDL receptor-/- mice, clinically relevant doses of mirabegron markedly accelerated atherosclerotic plaque growth and instability through this same lipolysis mechanism 1. However, this finding has not been replicated in human cardiovascular outcome studies, where mirabegron showed comparable CV adverse event rates to placebo (0.4%-1.5% vs 0.9%) 4.
The paradox is that while mirabegron increases potentially atherogenic LDL/VLDL particles through BAT-mediated lipolysis, it simultaneously increases protective HDL cholesterol and improves insulin sensitivity 3. The net cardiovascular effect in humans appears neutral based on current safety data 4, though the animal data raises theoretical concerns for patients with pre-existing atherosclerosis 1.