In their commentary, Holmes and Bhalla1 discussed the polypill reframing it as a sort of ‘vaccine’ for cardiovascular disease (CVD) primary prevention.

The idea of polypill is more than a decade old. In 2003, Wald and Law claimed that ischaemic heart disease could be reduced by 88% and strokes by 80% if all those over 55 years of age were given a polypill, a fixed-dose combination containing three low-dose blood pressure (BP) lowering medications (a β-blocker, an antidiuretic and an ACE inhibitor), a statin, low-dose aspirin and folic acid, without monitoring risk factor levels or biochemical safety parameters.2 They suggested that such a polypill would reduce diastolic BP by 11 mm Hg and low-density lipoprotein (LDL)-cholesterol by 70 mg/dL. However, their estimated reduction in LDL-cholesterol used a baseline of 4.8 mmol/L, which is very high according to the recent guidelines.3 ,4 This already indicates one of the possible problems with polypill concept. A clinical trial in patients at low cardiovascular risk found that polypill reduced diastolic BP only by 1.6 mm Hg and LDL-cholesterol only by 17.7 mg/dL, so that a recently published critical review stated that the results with polypill have been much more modest than originally hypothesised.5 Somewhat better results were obtained in another trial which was, however, performed on moderate-to-high–risk individuals—systolic BP decreased by 9.9 mm Hg and LDL-cholesterol by 0.8 mmol/L.6

Another problem with polypill is dosage. The idea that by using half standard doses of drugs in the polypill the adverse effects would be minimised has not been proven in large clinical trials. Indeed, in a meta-analysis, tolerability was lower among those on polypill than those on placebo or one-drug component.7 Anyhow, the issue of primary CVD prevention with statins, even when given in full doses, seems still to be open. This is particularly true when, for instance, the use of statins for primary prevention in subjects at low cardiovascular risk is addressed, but some problems also exist with those at moderate or high risk.8

Several randomised clinical trials with various formulations of polypill were performed. Polypill used in most of them differed from the one suggested by Wald and Law (omission of folic acid), as the supposed beneficial effects of folic acid on serum homocysteine have not been confirmed. Recently it has been shown that such a polypill, even if given in double dose, can reduce BP only by a further 2.8 mm Hg systolic and 1.7 mm Hg diastolic, while the difference in LDL-cholesterol was only 6.6 mg/dL.9

One should also not neglect another concern regarding the polypill concept: it might be seen by users as a replacement for moderating the intake of saturated fat, avoiding smoking and dietary salt, limiting alcohol consumption and doing regular exercise, and thus, detracting them from necessary lifestyle changes.

The idea of polypill is also a reflection of a pharmaceutical approach to reduce barriers to non-adherence to chronic drug treatment, since it is well known that adherence with antihypertensives and statins is very low—only about 40% at 12 months; a phenomenon that does not exist with vaccines. However, there is no proof that using a polypill can really improve the compliance. The problem of non-adherence is much more complex and depends not only on individuals’ attitudes, particularly if apparently healthy. For example, although the majority of physicians support the concept of preventive cardiology, this still does not always reflect in their current practice, and the general public perceptions, knowledge and awareness of CVD risk factors are insufficient, which all also influence non-adherence.10 ,11 A recently published study showed that although US physicians’ acceptance of using polypill for CVD prevention appeared fairly high, they were not ready to support a population level polypill approach in which a polypill would be recommended for everyone, available either over the counter or after minimally cumbersome screening by a pharmacist, without ongoing clinical monitoring and without possibility to modify the doses of statins or antihypertensives.12 Such an approach of medicalising a major part of population without physicians’ control is considered by many as not optimal. This is especially true for developed countries where the accessibility of physicians and medical care in general is not an issue, so that individualised treatment of cardiovascular risk factors and the possibility of drugs titration is undoubtedly a better solution. Polypill might be useful and cost-effective, having a potential to be accessible to those in underserved healthcare sectors of the world, primarily in lowest-income countries where problems concerning accessibility to treatment and affordability of medical services are serious obstacles for adequate primary prevention of CVD. Nevertheless, it has to be clearly stated that so far there are no published clinical outcome trials with polypill and no evidence exists that treatment with polypill really prevents cardiovascular events (myocardial infarctions, acute coronary syndromes, strokes etc) and/or saves lives.