New research explains what’s behind these hugely common statin side effects
Canadian researchers at McMaster University are reporting they've uncovered a biological pathway that may explain why certain side-effects, such as muscle pain, weakness and exercise intolerance, occur with statin use.
This new pathway may help open the door to future therapies that could make statins easier to tolerate while maintaining their life-saving cardiovascular benefits.
The study, published in the journal Science Advances, identifies an immune and metabolic mechanism that drives statin-induced muscle damage, challenging longstanding assumptions about how these side-effects develop. Senior study author Jonathan Schertzer, professor in McMaster’s Department of Biochemistry and Biomedical Sciences in Hamilton, Ont., said statins are among the most effective medications available for reducing cardiovascular disease risk and preventing early death.
The study involved broad international collaboration with researchers from the Centre International de Recherche en Infectiologie (CIRI) in Lyon, France; the Centre for Muscle Research at the University of Melbourne, Australia; the Murdoch Children’s Research Institute and The Royal Children’s Hospital in Australia; York University in Canada; and McMaster’s Department of Pathology and Molecular Medicine.
The investigators found statins can disrupt how muscle cells produce energy, triggering an immune response that damages muscle tissue. In experiments using muscle cells and mouse models, the investigators were able to prevent much of that damage by blocking the immune response. Schertzer said one of the most exciting findings is that the mechanism causing muscle side-effects appears to be separate from the mechanism that lowers cholesterol. So, it may be possible to target the side-effects without interfering with the cardiovascular benefits that make statins so valuable.
“We discovered that statins cause a type of metabolic danger which lowers the ability to use sugar in muscle cells, which leads to activation of a very specific immune response that promotes muscle damage directly within muscle cells. Importantly, we found that the pathway to muscle side-effects were completely separate from the cholesterol-lowering benefits of statins,” Schertzer told the Medical Post.
Statin-associated muscle symptoms affect an estimated 7%-to-29% of individuals who take statins. While researchers have long known that statins can sometimes cause muscle problems, the biological mechanisms behind those effects have remained unclear.
“The next step is to try to find a way to specifically block the pathway to side-effects, while maintaining the cholesterol-lowering benefits of statins and to understand how to do this in humans. The limitations are that we only have proven this concept in mice and cells so far,” said Schertzer. “It is not yet clear how soon next-generation statins with lower side effects could be designed, but this is a future goal.”
He noted muscle-related side effects are one of the most commonly reported effects of statins. Severe muscle damage is extremely rare, but low-level muscle weakness, pain, and reduced exercise tolerance are more common. It is not yet clear if certain populations are at increased risk of muscle side effects. The "cost-benefit" of statins is sometimes debated by some individuals who compare the side effects versus proven benefits of statins in cardiovascular disease.
“We are surprised that this debate happens rather than trying to improve statins. Our opinion is that statins are excellent drugs to lower cardiovascular disease risk, but rather than debate the “cost-benefit” why not figure out exactly how they work to remove or limit any potential cost or side effects while maintaining the proven benefits. That is the goal of this research,” Schertzer told the Medical Post.
The research was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC).
Reference:
Nazli R, Nicole G. Barra NG, Kevin P. Foley KP, et al. Statins promote muscle metabolic danger and NLRP3-mediated myopathy via lower protein-prenylation and YAP.Sci. Adv.12,eadz3612(2026). DOI:10.1126/sciadv.adz3612