new medications

Is It Finally Time to Consider a Polypill Approach to Cardiovascular Disease Risk Reduction?

Michael J. Bloch, MD
Associate Professor, University of Nevada School of Medicine
Medical Director, Renown Vascular Care, Renown Institute for Heart and Vascular Health
President, Blue Spruce Medical Consultants, PLLC

Bloch MJ. Is it finally time to consider a polypill approach to cardiovascular disease risk reduction? Consultant360. Published online March 8, 2021.


Over the past few decades, we have consistently moved away from a primary prevention approach that looks at individual risk factors in isolation and toward an evaluation of global cardiovascular disease (CVD) risk. Clearly this approach has significant advantages in identifying patients who get the greatest benefit from pharmacological interventions that lower CVD risk, such as lipid-lowering, antihypertensive, and antiplatelet agents. However, when it comes to treatment, we still tend to offer therapies aimed at each CVD risk factor individually. While this strategy can lead to fine-tuning each risk factor and achievement of aggressive control in isolation, it does tend to lead to increases in pill count, a reliance on frequent provider access, and issues with adherence.

Advocates of a “polypill” strategy have long advocated for a simplified approach whereby once elevated CVD risk is identified, most patients can be treated with a single pill with moderate doses of multiple, well-tolerated, and inexpensive medications. The latest in a series of polypill studies was recently published in the New England Journal of Medicine.1 In the TIPS-3 study, 5713 participants—mostly in India and the Philippines—who did not have CVD but had elevated CVD risk (INTERHEART risk score, at least 10) at baseline were randomly assigned 2:2 to a fixed-dose combination of simvastatin, 40 mg; atenolol, 100 mg; hydrochlorothiazide, 25 mg; and ramipril, 10 mg, once daily or matching placebo +/- aspirin, 75 mg, or matching placebo.

Overall, the blood pressure-lipid polypill reduced the incidence of CVD events from 5.5% to 4.4%, and aspirin reduced the risk of myocardial infarction, death, or stroke from 4.7% to 4.1% over 4.6 years. While significant, this effect was lower than expected, likely due to issues with the supply chain of study medications and lower-than-expected adherence during the COVID-19 pandemic. Not surprisingly, participants taking the polypill had a higher incidence of dizziness or hypotension, but otherwise, it was well tolerated. These results are consistent with previous studies that have used similar methodology.2,3

Since it combines multiple low-cost generic medications in one pill and decreases the need for multiple follow-up visits to up-titrate therapy, the polypill approach has been thought to be an attractive option for lower socioeconomic countries. Indeed, the authors suggest that based on the results of the TIPS-3 trial, wide utilization of a polypill intervention plus low-dose aspirin could lead to 3 to 5 million fewer CVD events globally per year. Recently, it has even been suggested that this may also be a reasonable approach to consider in more developed economies. In the United States, we tend to discount this type of universal approach and instead believe that an individualized approach is best for each of our patients. But this “reinvention of the wheel” with each patient is not only expensive, but it may not be substantially effective. Certainly, many patients in the United States are faced with chronic issues with access to providers, and therapeutic inertia, medication expense, and low adherence to individually prescribed medications remain significant problems in this country. These factors are largely responsible for the recent decrease in blood pressure control rates that have been reported in national observational studies.

One could imagine that a polypill could be developed for use in this country that was more consistent with our guidelines. A combination of angiotensin receptor blockers, thiazide, high-intensity statins, and low-dose aspirin could be easily and inexpensively formulated in both low and moderate doses. A population-based strategy could be employed where all primary prevention patients with calculated atherosclerotic CVD risk of more than 10% were offered this polypill. Only after adherence to the polypill is achieved would individualized intensification of therapy be used to achieve blood pressure and lipid goals. For example, add a dihydropyridine calcium channel blocker or ezetimibe as needed.

As TIPS-3 shows us, use of a polypill does not entirely decrease the risk of nonadherence or solve all access issues, but this could be an attractive alternative strategy in certain at-risk populations. In fact, a recent small study4 in an underserved population in rural Alabama demonstrated that a similar polypill was more effective in decreasing blood pressure and improving lipid control than standard care. While it is certainly not ready for widespread utilization in the United States, we should not dismiss the concept of the polypill outright and instead take a thoughtful approach to where it might make sense to study further in certain at-risk populations.


  1. Yusuf S, Joseph P, Dans A, et al; International Polycap Study 3 Investigators. Polypill with or without aspirin in persons without cardiovascular disease. N Eng J Med. 2021;384(3):216-228.
  2. Yusuf S, Pais P, Afzal R, et al; Indian Polycap Study (TIPS). Effect of a polypill (polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomized trial. Lancet. 2009;373(9672):1341-1351.
  3. Yusuf S, Pais P, Sigamani A, et al. Comparison of risk factor reduction and tolerability of a full-dose polypill (with potassium) versus low-dose polypill (polycap) in individuals at high risk of cardiovascular diseases: the Second Indian Polycap Study (TIPS-2). Circ Cardiovasc Qual Outcomes. 2012:5(4):463-471.
  4. Muñoz D, Uzoije P, Reynolds C, et al. Polypill for cardiovascular disease prevention in an underserved population. N Eng J Med. 2019;381(12):1114-1123.