The Safety of Statins

Ben - Also this week, a study published in the Lancet has confirmed the safety of the widely used class of drugs known as statins.  These are the most commonly used drugs worldwide for heart disease and are taken by millions of people globally.  A randomised heart protection study back in the mid-1990s found the drugs to be highly effective against heart disease but subsequent epidemiological studies did raise some fears of an increased risk of cancer associated with taking them.  Now Richard Bulbulia from the University of Oxford has followed up the participants in that study from the '90s to have a look at any long term effects.  Richard, thank you ever so much for joining us.

Richard -   Good evening, Ben.

Ben -   What were they really looking at back in the '90s?  Were they just confirming that statins did work and did do what we think they should?

Richard -   Observational studies made it clear, 30 or 40 years ago, that people with higher levels of bad cholesterol had increased risk of vascular disease and to test whether this association was causal, people did large, randomised trials such as the Heart Protection Study which lowered cholesterol and consequently lowered vascular risk by around one quarter.  But the same epidemiological studies that highlighted the relationship between cholesterol and vascular risk also showed an increased risk of certain cancers and other causes of non-vascular death with lower cholesterol levels, and those of us who sort of responsibly interpreted that data suggested that these findings were due to something called reverse causality whereby it's the disease such as the cancer which causes the low cholesterol rather than the converse.  But the concerns were out there and they substantially delayed the widespread use of statins. 

Now, the Heart Protection Study which reported its main results in 2001 had reassurance in that there were no excess risks of cancer or other non-vascular deaths associated with taking simvastatin 40 mg for around 5 years.  But that 5-year period was really too short to reliably address the prevalent concerns about the risks and safety of lowering cholesterol in many millions of people.  And for that reason, we carried on following up all 17,000 surviving Heart Protection Study participants for a further 6 years.

Ben -   So what have you actually been doing to follow them up or are you just looking at medical records and incidences of different diseases or are you continuing to investigate more deeply what the lifestyle factors are?

Richard -   We followed up the survivors in two ways.  We asked them to complete postal questionnaires and the vast majority of the participants did so, and on these postal questionnaires, they told us certain things about their statin use after the trial period, whether or not they've been to a hospital, had any clinical events, and also indicated whether or not they'd be happy to receive a subsequent questionnaire the following year.  That questionnaire procedure was augmented by accessing national registries for cancer incidents and they're death certification for people who either had cancers or died during the follow up period.

Ben -   Surely, after the original trial, the people who had been taking placebo, as it was a controlled trial, they must've then been offered the statins.  So surely, actually, the conditions have changed.  How do you take account for that?

Richard -   That's a very important point.  At the end of the trial, it was clear that everybody in the Heart Protection Study would benefit from at least discussing whether or not they should take the statin with their GP and all were encouraged to do so.  Gratifyingly, over the 6-year period, more and more people in both treatment groups have began taking the statin therapy, so by the end of the trial, the average use of statins was around 75% in both original treatment groups.  So, our long term follow up results, which were in the Lancet this week, actually assessed the effect of the initial 5-year randomisation to either simvastatin or placebo over an 11-year period.

Ben -   I guess the fact that people did start taking them after, also means that you could actually stratify your results and show that people have been taking it for this long, you see the following effects, but if people have been taking it for twice as long, then either you see more effects or you still don't see any effect which should help you to be able to say the concerns about cancer were in fact not actually applicable.

Richard -   That's correct and there were three main findings in our study. The first two connected are looking at benefits.   I mean, it's important to remember that statins are incredibly effective form of treatment. During the randomised phase of the trial, the absolute benefits of statin therapy increased as treatment continued.  With year on year reductions of around one quarter, after the first in trial year, and second, the absolute benefits that those originally allocated simvastatin accrued during the in trial period persisted in the post trial period.  That is to say, the people who were originally on placebo and then switched to statin therapy after the trial had closed, never caught up with the original simvastatin group.  And those two findings do show that starting statins early and continuing them long term is necessary to maximise the reductions in major vascular events. 

And following on from that clear message, it's also very reassuring to note that over an 11-year period, there was no suggestion of an emergence of hazard on cancer either globally or in certain specific subtypes of cancer or indeed other forms of non-vascular disease and specifically non-vascular death emerging in this large cohort of trial participants.