Cholesterol-lowering "statin" drugs taken by millions worldwide may not work well enough for half of those prescribed, research suggests.
UK investigators looked at 165,000 patients on statins and found that for one in two the drugs had too little effect on bad cholesterol - one of the big risk factors for heart disease.
They are not sure why statins appear to help some more than others.
Patients should not stop taking the drugs without seeing their doctor.
One possible explanation is patients not taking their prescribed drugs or doctors giving them at too low doses, experts suggest.
Cardiovascular disease kills about 17 million people worldwide each year.
"Bad" low-density lipoprotein (LDL) cholesterol is a major contributor - it can lead to furring and blockage of blood vessels.
Smoking and obesity
Cutting down on saturated fat can help lower bad cholesterol, but some people will also need medication. Millions of people in the UK are given statins for this reason.
But statins can cause side effects and there is a debate about how many patients should be prescribed them.
The study, published in the journal Heart, included 165,411 patients who had been put on statins to cut their risk of developing heart disease by lowering their cholesterol to a healthy level.
Half of the patients - 84,609 in total - did not see their cholesterol go down by enough - the required 40 percent or more reduction specified by guidelines - even after being on the daily treatment for two years.
Experts say the study findings are somewhat limited because they cannot prove that patients who do not respond well to statins will necessarily fare worse as a consequence. Other factors - like smoking and obesity - also raise cardiovascular risk.
But the work does provide "real life" data and experience to draw on.
Researcher Stephen Weng, from Nottingham University, said: "Our research has shown that in almost half of patients prescribed statins, they are very effective and offer significant protection against cardiovascular disease.
"However, for the other half - whether it's due to your genetic make-up, having side effects, sticking to the treatment or other medications - we don't see that intended benefit."
In the study, a higher proportion of patients with a sub-optimal response to statins were prescribed lower potency doses, compared with those with an optimal response.
"We have to develop better ways to understand differences between patients and how we can tailor more effective treatment for those millions of patients who are simply blanket-prescribed statins," Dr Weng said.
British Heart Foundation associate medical director Metin Avkiran said "statins are an important and proven treatment for lowering cholesterol and reducing the risk of a potentially fatal heart attack or stroke.
"If you have been prescribed statins, you should continue to take them regularly, as prescribed. If you have any concerns you should discuss your medication with your GP. There are now other drugs available to help lower cholesterol levels, and it may be that another type of medication will be an effective addition or alternative for you."
Prof Helen Stokes-Lampard, chairwoman of the Royal College of GPs, said: "When we prescribe medication, we have to rely on patients to make sure that they take it, both at the recommended dose and for the duration of time that we think will benefit them most.
"There is a substantial body of research showing that statins are safe and effective drugs for most people, and can reduce the risk of heart attacks and stroke, when prescribed appropriately - but controversy remains around their widespread use and their potential side-effects.
"There are complex reasons why patients choose not to take their prescribed medication, and mixed messaging around statins could be one of these."