University of Minnesota

The Polypill

One of the more remarkable events in the history of medical scientific publication was the appearance of the June 28, 2003 issue of the British Medical Journal (BMJ).

Two bright, reputable, card-carrying epidemiologists, Nick Wald and Malcolm Law of London, proposed The Polypill, “a strategy to reduce cardiovascular disease by more than 80%.” They recommended that a pill, a polytherapy of 6 anti-risk ingredients, be administered to all adults age 55 or over. It would have, they claimed, “… a greater impact on the prevention of disease in the Western world than any other single intervention.”

More remarkable still was the extension of this grandiloquent concept by the prime editorial of Anthony Rogers accompanying the article: “Realizing this enormous potential should be a major goal especially for developing countries[ed’s italics]. Today the West, tomorrow the world!

And most remarkable of all this hoopla, was the near-ecstatic endorsement of The Polypill by the journal editor, Richard Smith, in his personal column, “Editor’s Choice:” “I suggest, gentle (or even angry) reader, that you keep this issue of the BMJ. It may well become a collector’s item. It’s perhaps more than 50 years since we published something as important as the cluster of papers from Nick Wald, Malcolm Law, and others.”

Smith raves on: “And what will happen to cardiologists and cardiac surgeons? . . . Maybe too we could buy the pills in supermarkets and pubs¬—perhaps even washing them down with a glass of red wine and preventing still more deaths.”

It seems unlikely that any editor of a reputable journal has ever departed medical decorum so totally or swallowed whole an idea with greater abandon. Reactions, of course, occupied the correspondence column of the BMJ for months afterward. Recently, ProCor editors reignited arguments pro and con. And our own U.S. Centers for Disease Control and Prevention has held meetings of advisors to consider seriously implementing The Polypill as a mass public health measure, worldwide.

What can be said about, and what can be learned, from this phenomenon? I suspect a great deal:

The question whether such a “one-pill-fits-all” polytherapy should be prescribed to all cardiovascular disease (CVD) patients or those at high risk is a medical, not a public health question, and I shall not address it. Recent FDA approval of the first combination of a statin and a blood pressure-lowering medication indicates that we are already going down this road rapidly, for both expedient and marketing reasons.

Public health, ethical, and practical issues are raised, however, by the unqualified proposition to administer The Polypill of 6 active ingredients, in fixed dosages, to all persons age 55 or over. Medicalized prevention by this unqualified proposition is in fact a public health strategy that we need to examine and debate in depth. That debate has at least two components, the evidence and assumptions of the proposal in regard to benefit, safety, cost, and feasibility on one hand, and on the other, the ecologic and ethical issues of a preventive strategy for general populations based on any pill, not least a polypill. I address primarily the second component.

Wald and Law propose that feasibility, acceptance, and adherence are all that need be tested, since The Polypill’s individual components (1 statin, 3 classes of anti-hypertensives at low dosage, and low-dose folic acid and aspirin) have been adequately tested for safety and efficacy. Our FDA would, of course, require the demonstration of benefit/safety of the combination, not just feasibility and adherence. It would likely require testing what formulations of Polypill components are effective and safe for primary and what for secondary prevention and in what age, sex, and ethnic populations.

Polypill proponents argue, however, that an “epidemiological transition” in societal structures is needed for more appropriate testing of drug preventives based on global risk projections rather than combined risk ratios of short-term effects. We might find common ground with their challenge of current paradigms of drug testing. But requirements for the demonstrated safety of preventive interventions in the “healthy” or general population are of a different order than that in patients.

Many have insisted, Geoffrey Rose among the more articulate, that any mass strategy of primary prevention must first be safe. Man-made approaches, pills, beyond the range of human evolutionary experience, always carry risk of adverse long-term consequences. He proposed just such an evolutionary criterion. Mucking about with pills that affect fundamental syntheses, transfers, and feedbacks in the metabolism of whole peoples would not meet his evolutionary criteria.

Moreover, a phase 3 trial of The Polypill in our inefficient system of adverse event reporting would be rampant adventurism. None even today is studying empirically the side effects of the long-term (decades-long) interruption of metabolic pathways in risk-factor-lowering therapies, notwithstanding dreams of an 80 percent reduction in CVD.

Philosophy, ethics, and the ecology

Where informed and respectful debate is most needed is in the area where there is little empiricism or even common wisdom to guide us. The Polypillers and other pharmaceutical interventionists justify mass medicalization of prevention by discounting health promotion strategies as either infeasible or infinitely slow and “paltry” in effect. Their models inadequately reflect the clear effects of hygienic change when applied across the whole population, when integrated into the culture and introduced early in life, or, on the other hand, inadequately consider the long-term costs and ill effects of medical strategies.

Cultural differences mainly account for the virtual absence of atherosclerosis or of hypertension in some populations. Huge population differences in disease rates reflect relatively small differences in levels, distributions, or trends of multiple risk factors. A simple change in direction of risk factors is ecologically associated with early changes in mortality rates, in either direction. It’s the age-old conflict from looking only at individuals, not at populations, and holding different views between a medical and a public health strategy of prevention rather than combining them rationally.

An Evoltionary Legacy?

Epidemics are not mysterious phenomena reflecting profound differences in basic “herd immunity” but rather they arise from rapid changes in mass behaviors and exposures. This herd, our human species, is for the foreseeable future highly vulnerable to environmental tsunamis, a vulnerability probably due to the metabolic legacy of living patterns during the critical phases of human evolution. These adaptations have a history of maximally 500 generations coping, for example, with mass sedentation and fewer with perpetually abundant calories, distorted eating patterns, and noxious exposures such as to tobacco.

Economics and Luddite negativism

The Polypill strategy in a sense assumes and propagates as necessary and desirable a global market system documented to cause ecologic damage and distorted eating and activity patterns, which lead, in turn, to mass metabolic illness. The socioeconomic waves of consumerism and overnutrition wash away intelligent public health goals and ecologic realism.

Questioning any pharmaceutical approach to population-wide primary and primordial prevention, no matter how exciting and attractive, is not blind Luddite negativism. Any polypharmalogic redirection of human metabolic pathways for the long term, and in the mass, calls for profound reflection and solid empiricism.

Lip Service to Healthy Living

The proponents of medicalized prevention in the masses often pay lip service to healthy lifestyle while maintaining that such interventions accomplish too little and take too long, as in this codicil of Dr. Rogers’s Polypill editorial: “. . the [Polypill] strategy should be integrated with population-wide approaches that address the root causes of cardiovascular disease, including reshaping societies so that smoking and development of life-threatening levels of body fat, cholesterol, and blood pressure are not the norm.” Indeed, but we have seen this apologia too often in national campaigns that set out pharmacological recommendations before their population strategies are even prepared, much less promulgated.

Nip the bud before the prototype Polypill flowers?

In one specially positive decision of the Nixon Administration, at a stage in the development of the U.S. version of the supersonic air transport, the building of the prototype was vetoed. Once there is a prototype demonstrating feasibility of production and acceptance, investigator and institutional investment is irreversible, careers and empires are committed, powerful medical-industrial forces are in play. The prototype itself renders no longer feasible the needed rational examinations and social decisions about production, dissemination, and “environmental impact” of the new technology—or new pill.

What positive can come from The Polypill debate?

Those who have worked among whole populations that live attractive lives free of a major burden of CVD and cancers, and those others who have identified groups of individuals at phenomenally low risk among high CVD-risk industrial societies, can accept with equanimity the authors’ apparently grandiose claim of “80% reduction in CVD risk” from The Polypill. We, and the pioneers of CVD epidemiology and prevention, have maintained such a potential of prevention for nigh-on half a century. One can recognize, as well, a number of helpful concepts in the syntheses of Wald and Law that led to The Polypill and from those who have taken up their banner. One can credit their paradigm challenges and their positive views compatible with epidemiological evidence, without accepting their main argument: to medicalize primary CVD prevention, en masse:


  • for a new paradigm debate, the call for evidence-based decisions in medicine and the public health, and the strong challenge to single-factor screening and threshold treatment values;
  • for recognition that Western risk factor levels overall are high, not “normal,” and that the lower the risk factor levels the better;
  • for the recommended simultaneous reduction of multiple risk factors and the search for cost-effective and widely accessible prevention strategies;
  • for confirming the long-established epidemiological finding that most cases come from the central part of the risk distribution and that prevention effect is proportional to the risk at all levels;
  • for confirming similar evidence that there are no risk “thresholds” and that small changes in average risk levels have large population effects;
  • for calling attention to high risk in transitional societies and to the best measures of actual risk: not screened risk factor levels, but age, sex, geography, social status, and prevalent illness;


  • for the absence of a feasible and complementary population strategy of health promotion, or the recognition that in a healthy society there is no age trend in risk and no epidemic CVD;
  • for the failure to address root social causes of risk; paying only lip service to health promotion and the public health;
  • for the absence of a strategy for primordial prevention in youth and developing countries;
  • for the focus on manipulation of biomechanisms rather than lifestyles;
  • for the search for a “quick fix.”
  • for embrace solely of high-tech approaches to what are mass sociocultural phenomena;
  • for proposing The Polypill for primordial prevention in millions in the developing world;
  • for the patent and copyright pending on Polypill;
  • for the implication that pills make for a healthy society;
  • for the greater furor over a pill than over healthy lives.

A Polypill does not a healthy population make!


Anthony Rogers of New Zealand was editorialist for and strong supporter of the original BMJ article on The Polypill. He was proponent and I antagonist in a debate before the American Heart Association Council on Epidemiology and Prevention, in San Francisco in April 2004. My rebuttal was in the form of this contrived posting on cathedral doors:

Theses Contra

the Papal Indulgence –

“The Polypill.”

Posted on the Portals,

Great Heart Council of

San Francisco,

Four March, Year of Our Lord,

Two Thousand Four.

I. Your Polypill, Sire, is but an

Indulgence, like Pope Leo’s of old,

tied with a crimson ribbon-

promising Salvation and

Eternal Life — for Gold!

II. Your Polypill, Sire, like

16th Century Indulgences,

fosters the Cardinal Sins,

Gluttony, Sloth, and Self-indulgence.

III. Mankind, Sire, can buy His way

neither unto Heaven,

nor unto Health!

IV. Patented Polypill, claim not,

Sans Essential Empiricism, to

“Save Souls and prevent Heart Attack

Among most Peoples On Earth!

V. Ask rather Polypill’s True Purpose:

To Bless Mankind, or

To Restore the Papal Treasury?

VI. Ask whether Polypill,

Interrupting Nature’s Pathways,

Flies in the face of Evolution?

Is it thus the Work of the Devil?

VII. Prithee, Good Doctor,

Fall on Thy Knees for Blasphemy,

That Polypill be called,

“The New Paradigm of Prevention!”

VIII. Good Sire from the Vatican,

Admonish Thy Flock to Healthy Choices:

Meditative Walks in Smoke-free Vales,

Five Daily Servings of Fruits and Vegetables,

Five too, of Legumes and Whole Grains,

Condiments only of Lean Meats, Fishes, and Fowl,

A Spoonful a Day of Oil of Olives,

A Goatskin of Pure Water,

And a Glass of Light Dry Wine.

IX. Good Sire from the Vatican,

Burn Thy Indulgences

Banish Thy Merchant Conspirators

Renounce Thy Polypill Patent.

Embrace the Lord’s Way to Good Works

And Nature’s Way to Good Health!

(Henry Blackburn)