New US cholesterol guidelines reinforce the importance of outcomes data

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Long-awaited cholesterol guidelines released by an influential panel of US cardiologists yesterday will please those who have been calling for so-called treat-to-target strategies to be abandoned. Recognition of the lack of conclusive evidence to support a specific cholesterol level target reflects a big shift in thinking about how to treat cardiovascular disease.

The implications of these guidelines could go beyond clinical practice. For drugs in development, it emphasises just how important outcomes data have become; the guidelines largely withdraw support from non-statin drugs like fibrates or niacin owing to lack of any evidence that they prolong life. For developers of the PCSK-9 antibodies, three of which are already in huge pivotal programmes, proving that these promising agents can radically lower bad cholesterol levels will not be enough (Pfizer’s outcomes studies for new heart drug will prove a prudent move, October 31, 2013).

Disregarding targets

A person’s level of LDL, or bad cholesterol, is by far the most proven marker of cardiovascular risk. And previous guidelines stated that patients with cardiovascular disease should be treated to bring LDL levels to less than 100mg/dl, or less than 70mg/dl in some cases.

But mounting concerns that these targets were not based on any firm evidence has prompted the panel of US experts to recommend that they be disregarded, and instead physicians are directed to choose an appropriate intensity of statin therapy to achieve relative reductions in LDL cholesterol. Four groups of patients have been describedwho would benefit from cholesterol-lowering therapy, with either moderate or high-intensity statins.

Authors of the guidelines said they were hoping to eradicate over and under-treatment with statins. And one of the biggest impacts on the statin market is likely to be a recommendation to treat much lower-risk patients with moderate-intensity products, which could expand their use to many more people.

This end of the statin market is all generic now; AstraZeneca’s Crestor is the sole brand left standing, and it falls into the high-intensity group.

Some analysts expressed concern today that erasing the 70mg/dl target blunts the company’s message that it is the most potent of the class, but it is hard to see these guidelines having any sudden big impact on prescribing. Treat-to-goal strategies are well entrenched, the panel still advocates regular LDL testing, and a "lower is better" philosophy widely accepted.

Recognising doubts

The new guidelines certainly strongly back statins as a class, and recommend that a patient’s lipid profile be improved through the maximum dose of these drugs, over adding another type of therapy. Statin-intolerant patients are an exception to this, as are those with intractably high LDL cholesterol.

The failure of several trials in the past few years to establish a clear benefit for drugs like niacin, fibrates and Merck & Co’s Zetia has already dented demand for these medicines, and these guidelines will consign them to the last resort. Amarin, which failed to win support for broader approval of its purified fish oil pill Vascepa, has already felt the full force of scepticism in this regard.

It is a pretty safe assumption that regulators share physicians’ doubts about treating relatively low-risk cardiovascular patients with drugs that have yet to prove that they prevent heart attacks and strokes. This confirms that developers of the PCSK-9 antibodies must now be facing a long wait for approval in broad populations, until their outcome studies start to report in 2016.

Whether they can win approval in higher-risk groups earlier based on potent LDL lowering will no doubt depend on squeaky clean safety profiles emerging.

But it is clear that these new guidelines do reflect some of the biggest quandaries facing cardiovascular medicine, and attempt to address the fact that measuring a person’s risk of having a heart attack or stroke is not an exact science.

The explicit lack of backing for the use of other biomarkers such as non-HDL cholesterol and apolipoprotein B or LDL particles demonstrates how it is far from clear what markers physicians should be measuring, and what targets should be treated. The failure of GlaxoSmithKline's darapladib yesterday was a symptom of this uncertainty (Darapladib failure is a disappointment for a field struggling for direction, November 12, 2013)..

For now, LDL cholesterol remains the most reliable warning sign of potential cardiovascular problems, and statins are still the only drugs proven to reduce that risk.

To contact the writer of this story email Amy Brown in London at AmyB@epvantage.com or follow @AmyEPVantage on Twitter.

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