The World Health Organization (WHO) added cardiovascular polypills to its 2023 Model List of Essential Medicines, and research continues to show that these medications are effective at preventing atherosclerotic cardiovascular disease (ACD) among various other forms of cardiovascular disease. Yet experts say obstacles remain to the adoption of these medications in high-income developed nations.

“These medications are saving lives,” said Anubha Agarwal, MD, assistant professor of medicine of cardiology and co-director of the program in global cardiovascular health at WashU Medicine in St. Louis. “There is not a financial incentive to produce them, which is an issue in high-income countries like the US and the UK.” 

Agarwal said other issues make the introduction of cardiovascular polypills to high-income markets problematic as well, including providers’ preference to stabilize patients on separate medications, while also having some flexibility with their separate components.

“With older patients, who can be more sensitive to blood pressure-lowering medications, and where clinicians are more liberal with tolerances of the upper ranges of blood pressure, there can be some concern about fixed-dose polypills,” she said.

Anthony Rodgers, PhD, a senior professorial fellow at The George Institute for Global Health at the University of New South Wales Sydney in Sydney, Australia, and chair of clinical epidemiology at Imperial College London, London, England, is another leading researcher in the area of cardiovascular polypills, who has collaborated with Agarwal on several studies. Rodgers added that the innovative uses of established medicines aren’t incentivized enough, even where their potential for health impact is sizable.

“The cost, time, and risk of developing and getting regulatory approval for a polypill are significant, way beyond the norm for standard generic medicine approval but also way less than for a new chemical entity approval, and our reimbursement systems just don’t encourage companies — generics or Big Pharma — to address that need ‘in the middle ground,’” he said.

“We need to enable much more effective and cost-effective methods for prescribers to learn about novel products involving established medicines,” Rodgers said. “Polypills aren’t the only example; this is a problem seen in many therapeutic areas.”

Effects of Polypills in Disease Trials

Agarwal was the lead investigator in a meta-analysis of research between 2016 and 2022 on the effects of fixed-dose combination therapy, also known as polypill therapy, on ACD. Rodgers also participated.

In this analysis, which was published in the April 2024 issue of Nature Medicine, patients in both primary and secondary populations on this form of medication measured lower in low-density lipoprotein cholesterol and systolic blood pressure, and had higher rates of adherence. The study also indicated higher rates of adverse events, including muscle aches, increased liver enzymes, cough, and gastrointestinal irritation and bleeding; however, Agarwal said that these were generally not hugely impactful.

“These side effects weren’t dramatic overall, especially in light of the severity of ACD and its burden,” she said. “Additionally, the adverse effect profile does not differ significantly when taking the medications included in the polypills separately as opposed to in just one fixed-dose medication.”

Agarwal noted that some of the polypills included in the earlier trials included in the meta-analysis included aspirin, which was not included in some of the later medications studied, as the thinking on aspirin has evolved in more recent years, especially as a therapy for primary prevention of cardiovascular events and in people older than 60 years.

What’s Next for the Use of Polypills for CVD?

Unfortunately, neither researcher thinks that the adoption of polypills for the treatment of ACD is likely to take place anytime soon in the US or other high-income developed nations. Rodgers said the inclusion of these medications on the WHO’s essential medicines list is an important step, but one that won’t change outcomes much in these more well-off countries.

“I think most people would regard WHO EML [essential medicines list] inclusion as a necessary but not sufficient step to getting widespread access in low- and middle-income countries,” Rodgers said. “No question it is a hugely important step, which would hopefully stimulate inclusion on national essential medicines lists and procurement; coupled with response by companies to make (them) affordable and available.”

However, these researchers and others continue to show the efficacy of polypills in the battle against various kinds of cardiovascular disease.

“We are currently running trials in Sri Lanka using a polypill against heart failure with reduced ejection fraction that is showing a lot of promise, and we have an application filed for similar trial here in the US,” Agarwal said. “We will also be running trials on heart failure without reduced ejection fraction.” 

The Bottom Line: Polypills Are Saving Lives

Agarwal, Rodgers, and their colleagues continue to demonstrate that polypills save lives in the fight against cardiovascular disease. Agarwal does not give in to frustration over the lack of progress about the adoption of these combination medicines in markets like the US and the UK.

“I certainly hope they will become available over time given the evidence supporting their use in primary and secondary prevention of atherosclerotic cardiovascular disease,” she said.