Bladder Drug May Raise Risk of Blocked Arteries, Heart Disease, and Stroke

A drug that is commonly used to treat overactive bladder could be putting some patients at increased risk of cardiovascular disease and stroke, according to research in mice carried out by scientists at the Karolinska Institute and Shandong University. Their study results indicate that mirabegron treatment promotes atherosclerosis, which may be a particular risk factor for the 1 in 300 or so people who have low density lipoprotein (LDL) receptor mutations that reduce the body’s ability to clear this type of plaque-promoting cholesterol.

The team’s studies in mouse models of atherosclerosis found that treatment using clinically relevant doses of the β3-adrenoreceptor agonist mirabegron sped atherosclerotic plaque formation, and rendered the plaques more unstable. “Patients with cardiovascular disease or atherosclerosis should be careful when using this drug as it could accelerate the growth of plaque and make it less stable, commented study lead Yihai Cao, PhD, a professor at the department of microbiology, tumor and cell biology, Karolinska Institutet. “People with mutations that make it difficult for the body to get rid of LDL can be particularly sensitive since the drug increases levels of LDL in the blood.”

The team’s experiments showed that mirabegron treatment triggered brown fat (brown adipose tissue; BAT) activation and stimulated the conversion of white fat (white adipose tissue; WAT) to brown fat, a process called browning. Activated brown fat produces heat (thermogenesis), which involves the breakdown of fat molecules, and this increases levels of low density lipoprotein (LDL) and very low density lipoprotein (VLDL) that increase the risk for atherosclerosis-related cardiovascular disease.

Although the reported research was carried out in mouse models, one recently reported study found that mirabegron can also activate BAT and WAT browning in people, and this indicates that the preclinical results may also be relevant to humans, the researchers noted. “We link this drug, via the mechanism in brown fat, to atherosclerosis and from there to the potentially higher risk of cardiovascular disease or of conditions such as stoke that affect the flow of blood to the brain,” Cao stated.

The investigators report their findings in the Proceedings of the National Academy of Sciences (PNAS), in a paper titled, “Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis”.

WAT and BAT have different roles in our bodies. WAT stores energy as fat, whereas activated BAT uses up energy to produce heat, through a process that involves the breakdown of fat molecules, or lipolysis. Under some conditions, such as cold exposure, WAT can also undergo a brown-like transition, and the fat cells in the white adipose tissue also start to consume energy for thermogenesis. Mirabegron is a β3-adrenoreceptor agonist, and activation of the β3-adrenergic receptor is known to induce BAT activation and browning of WAT.

To investigate the potential effects of mirabegron on atherosclerosis-related cardiovascular disease the team turned to two mouse models of atherosclerosis, which lacked either the ApoE gene (ApoE-/-animals) or the LDL receptor (Ldlr-/- mice). This latter strain has clinical relevance given that 1 in 300–500 people have mutations in the LDL receptor gene that can cause familial hypercholesterolemia, a condition associated with high blood cholesterol and LDL, which can lead to early-onset cardiovascular disease, the researchers pointed out.

Their initial results confirmed that treating each of the animal models using human therapy-relevant doses of mirabegron induced brown fat activation and white fat browning. Mirabegron also sped the growth of atherosclerotic plaques in both animal models, although the Ldlr-deficient mice developed more severe atherosclerosis disorders following mirabegron therapy. “Atherosclerotic plaque growth and instability were overwhelmingly increased in Ldlr-/- mice,” the scientists wrote. Both of the mirabegron-treated mouse models, in addition, exhibited greater plaque instability, which can ultimately lead to plaque rupture. The formation of fatty plaques containing cholesterol is the primary cause of cardiovascular disease and stroke. “These results validated the phenotypic changes in mirabegron-treated ApoE deficient mice and may recapitulate clinical settings by which patients with LDLR mutations might receive mirabegron treatment,” the authors stated.

Hypercholesterolemia is linked with high blood levels of LDL-cholesterol and VLDL-cholesterol, and with atherosclerotic plaque formation. The team’s studies also confirmed high serum levels of total cholesterol and LDL in both of the mirabegron-treated mouse strains. “These results show that mirabegron induced hypercholesterolemia and elevated LDL-C in ApoE- and Ldlr-deficient mice through a possible mechanism of increasing cholesterol synthesis,” they stated.

The authors suggest that their findings raise real concerns about whether mirabegron might increase cardiovascular and cerebrovascular diseases by promoting lipolysis-triggered atherosclerotic plaque growth and instability. “Together, our findings suggest that mirabegron may trigger cardiovascular and cerebrovascular diseases in patients who suffer from atherosclerosis,” they concluded. “Our study provides an example that drugs used for treating noncardiovascular and noncerebrovascular diseases have a profound effect on the development of atherosclerosis. The clinical risk of mirabegron-triggered atherosclerotic plaque growth and instability has been overlooked, and the underlying mechanism is obscure … This issue warrants a clinical study to validate the preclinical findings.”

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