The end of the line for nicotinic acid?

Today MSD announced that it will be withdrawing its nicotinic acid preparation called Tredaptive following announcement of results from the long awaitied HPS2-Thrive trial. Tredaptive is a combination of nicotinic acid with laropiprant which reduces flushing, the major side effect of the drug. HPS2-Thrive investigated whether, in patients already treated with statins, addition of tredaptive reduced major vascular events. The trial which followed patients for 4 years did not reach its primary endpoint. This result also follows the early termination of the AIM-HIGH trial in 2011 which investigated another nicotinic acid preparation called Niaspan. This trial was also negative.
There is epidemiological data from the Framingham Study which showed that risk of cardiovascular disease increases by about 1% for every 1% increase in LDL cholesterol. Clinical trials with statins, which potently lower LDL, have consistently demonstrated reduction in cardiovascular endpoints when compared to placebo. However despite widespread treatment with statins some people still go on to have a heart attack or require coronary stents or bypass surgery leaving cardiologist to look for additional treatments to try and reduce risk and targetting patients with a low HDL has always been an attractive for cardiologists.

We recognise that patients with recurrent cardiac events often have low levels of HDL (<1.1mmol/L). This is often seen in patients with type 2 diabetes and in South Indian Asians. People wiht low HDL often have raised triglycerides and small dense LDL particles which are highly atherogenic.  There is good evidence from the Framingham Study that for a 1% increase in HDL there is a 3% reduction in the risk of cardiovascular disease. This led pharmaceutical companies to look search for new drugs which increase HDL also to re-examine old drugs (e.g. nicotinic acid) which also raising HDL.  But there is a catch, we need to remember that Framingham was an epidemiological study which only looks at associations between risk factors. An association of increased HDL with reduced cardiovascular risk does not prove causality and raising HDL may not translate into reduced atherosclerosis and cardiovascular events.

Nicotinic acid also known as vitamin B3 or niacin has been used for 50 years to raise levels of HDL. Early research in the Coronary Drug Project published in the 1970's suggested it might be effective but careful analysis of the study demonstrated only a very modest benefit in decreasing definite non-fatal recurrent myocardial infarction and did not decrease mortality. It was only in a long-term follow up study over 15 years (9 years after medication stopped) that a significant 11% difference in mortality was demonstrated. These results have not been repeated and were performed in non-statin treated patients so the results are not relevant for today's clinical practice. The results of the AIM-HIGH and HPS2-thrive trials are long awaited but clearly demonstrate no benefit of nicotinic acid.

Perhaps its time for us to move on from regarding HDL as a target for pharmacological modification and simply use it as a marker of small dense LDL and increased cardiovascular disease risk.

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