The International Network of Cholesterol Skeptics



Discussions July 2003  About the polypill


Uffe Ravnskov
Eddie Vos

Malcolm Kendrick

Eric Freedland

Peter Langsjoen

J°rgen Vesti-Nielsen




Uffe Ravnskov
Medical Science┤s Laurel and Hardy, alias Law and Wald, has done it again -
read to-day┤s BMJ (28. June 2003) These two
British epidemiologists suggest that every human being above age 55 should take a polypill containing statin, a thiazide, a betablocker, an angiotensin converting enzyme inhibitor, folic acid, and aspirin every day for the rest of their life. Say Law and Wald, a pill with these ingredients could prevent 80% of heart attacks and strokes Their daring suggestion made the editor Richard Smith to suggest that we "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 other."

Is this a wise suggestion??? Of course not. Beneath follows a selection of comments from members of our group. 


 Eddie Vos
Before we all run out to get PolyPill [tm], let's not forget past medical intervention trials like:

MRFIT [multiple risk factor intervention] n=12,866, 7 years; half Special Intervention, i.e. stepped hypertension treatment, cholesterol counseling, other. Non significant cardio mortality benefit yet a slight OVERALL MORTALITY DETRIMENT. Five more deaths after ~45,000 years of special medical intervention. PMID 7050440

The Miettinen trial. Long-term mortality in 1222 high-risk Finnish male business executives. Half randomized to 15 doctor visits each over 5 years + "frequently" blood pressure and pre-statin cholesterol lowering drugs. Cardio "risk factors" reduced at 5 years. However, mortality over study + 10 year follow-up (1974-1989): 67 deaths in intervention vs. 46 in control group [RR mortality 1.45 p=0.048]. Here's another kicker: cardio mortality was more than double: 34 vs. only 14 deaths in the control group [RR=2.42 p=0.001] PMID 1870247

Now, 12 years later, realize that the latest 3 statin trials PROSPER, ALLHAT and ASCOT saved exactly nobody at great expense [combined patient- years on statin ~55,000], patient inconvenience and long-term unknown risk. The wonders of meta analysis Ó la Wald and Law never cease.


Malcolm Kendrick
It is almost impossible to know where to start in responding to this article.

I will restrict myself to one part of their polypill concept, namely the benefits of blood pressure reduction. I will quote, highlights, from the European Heart Journal.

'Stamler stated 'the relation of SBP to risk of death is continuous, graded and strong, and there is no evidence of a threshold... The formulation of this 'lower the better' principle, in terms of the linear logistic model is the paradigm for the relationship of all cardiovascular risks to blood pressure and forms the foundation for the current guidelines for hypertension... 

Twenty years ago Keys, using simple graphical methods, concluded that the linear model, in terms of the relationship of overall and coronary heart disease death to blood pressure was unjustified. Could Keys be correct? To see, we reexamined data from the Framingham Heart Study. That carefully conducted and most widely cited study played a seminal role in firmly entrenching the current linear thinking on blood pressure....

We limited our analysis to the 18 year follow-up data. The use of the full (34 year) data would have introduced serious confounding in the natural relationship of cardiovascular risk to blood pressure, which was our primary interest. 

Shockingly, we have found that the Framingham data in no way supported the current paradigm to which they gave birth. In fact, these data actually statistically rejected the linear model. This fact has major consequences. Statistical theory now tells us that the paradigm MUST be false for the target population of the study.' Port S et al 'There is a non-linear relationship between mortality and blood pressure'  European Heart Journal (2000) 21 1635 - 1638

 In the area of blood pressure reduction Law and Wald are using a model of blood pressure reduction that is almost certainly wrong. I believe that their other models are also wrong, but this is a rapid response, not a PhD thesis. 

Yet, on the basis of a horribly flawed analysis Law and Wald recommend that everyone in the Western World should be taking six different drugs for the rest of their lives. Any moment now I am expecting an article to appear in the BMJ written by the Red Queen, entitled 'Everyone is ill, and all shall have medication.' 

See also Malcolm Kendrick's comment on Red Flags Daily


Eric Freedland
From the get go, the beta blocker and thiazide will raise insulin resistance and the risk of developing type 2 diabetes--28% by the beta blocker alone (according to an NEJM article --Gress et al 2000). Then I was an intern I joked about developing a single prescription pill that would alleviate the long laundry list of PRN and other meds we routinely wrote for elderly patients. This would include: an ant-acid, sleeping
med, Haldol, Tylenol, nitro, a BP med, etc. Maybe I was ahead of my time. My attending told me I would wind up famous one day or in the gutter. When I reminded him of that years later he looked at me and asked, "And...?"


Peter Langsjoen
This is an unbelievable exaggeration of drug benefits and a great minimization of drug side effects.  The "Polypill" idea represents several fallacies:

1.  That risk factors are Since a deep ear lobe crease is a risk factor for CAD, why not cut off all our ear lobes after the age of 55 - for that matter, why not start snipping them off at birth - after all, the sooner the intervention the better and the small inconvenience is certainly worth the millions of lives saved and billions of dollars saved.
Further, since according to Wald and Law risk factors need not even be measured there is no need to look for the crease.  Since we all have ears we are all at risk.

2.  As we all cholesterol skeptics agree, hypercholesterolemia is not causative for CAD and neither is hypertension.  They are numbers, pseudo-diseases against which drugs may be prescribed.

3.  The minimization of adverse drug effects:  It is a basic principle of medicine to start medication (when necessary) one prescription at a time so that when a patient develops an adverse effect it is simple to identify the offending agent. The Polypill proposes three anti-hypertensive drugs: 

- Thiazide diuretic:  may give rash, sun sensitivity, leg cramps and potassium depletion.
- Beta blocker:  may give fatigue, impotence and dyspnea
- ACE inhibitor:  may give cough

Along with that is aspirin which may give allergic reactions, GI distress and iron deficiency anemia and then of course the Polypill would contain the most insidious toxin ever prescribed to man:  a statin drug.

Statins are the most dangerous class of drugs ever promulgated upon man.At least commonly toxic drugs, such as chemotherapeutic agents, are obvious in their rather immediate side effects.  Statins, on the other hand, bring about a gradual, insidious state of fatigue, muscle soreness and eventually heart muscle weakness which comes on after many months or years. Furthermore, there is evidence for statin-related increases in cancer, peripheral neuropathy and cognitive impairment.

4. Folic acid is incredibly safe and the associated homocysteine lowering may indeed be a good idea.  The Polypill proponents may have added this to give the pill an aura of safety.  As Anthony Rodgers laments, "...a third or more of adults in many countries already take natural supplement pills...".  It appears that he would rather that a third of the population swallow a combination of five different drugs.  Folic acid is the only reasonable component to the Polypill but I think it's only put there for marketing purposes.

5. I am dumbstruck by the idea of taking such a pill without need for medical examination and further dumbstruck at the hint that in the future this Polypill may be over-the-counter and, according to Richard Smith, washed down with wine at a pub.  What an insult to good wine.  Can you imagine having a wonderful evening at the pub only later to find out that you're impotent from the beta-blocker, coughing your head off from the ACE inhibitor, having terrible leg cramps from the diuretic and, finally awakening the next morning having forgotten everything due to statin-induced memory loss!

If we, adult members of world society are gullible enough to believe that we are all somehow diseased after age 55 and that to save ourselves we must swallow this toxic garbage pill with blind confidence in the pharmaceutical/medical industry, then perhaps there is more than a little of the lemming in us all.  Maybe in some mysterious way we humans need to run off a cliff from time to time.

Forward!  Fellow lemmings - Polypill, wine and immortality await us all!


J°rgen Vesti-Nielsen
Could anyone explain how the average duration of life gained in Law and Wald's
estimates can become 11-15 years. According to calculations using survival
curves -- the difference in the areas between the two groups -- hardly more
than 1 months per 5 years of treatment with each modality can be expected. At
least according to my source:

Lubsen J, Hoes A, Grobbee D. Implications of trial results: the potentially
misleading notions of number needed to treat and average duration of life
gained. Lancet 2000;356:1757-59


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