New cholesterol guidelines should expand the statin market from two directions: by pushing aggressive treatment for higher-risk patients and by extending recommendations for treatment to include patients at lower risk than previous versions.

Developed by the American Heart Association and the American College of Cardiology, the guidelines move away from numerical LDL cholesterol targets, instead focusing on reducing risk in groups of adults likely to benefit from treatment, based on evidence from randomized clinical trials.

A panel of experts chaired by Northwestern University’s Neil Stone published the guidelines on Nov. 12 in the journal Circulation and the Journal of the American College of Cardiology. The expert group had been appointed by the National Heart, Lung and Blood Institute to revise Adult Treatment Panel (ATP) guidelines for the detection, evaluation and treatment of high blood cholesterol in adults.

The guidelines place heavy emphasis on statins as a proven mainstay of treatment and note the lack of evidence for using other lipid-modifying drugs to reach treatment goals.

For the pharmaceutical industry, that translates into a boost for a part of the market that is largely genericized and a harsh blow for other segments – though the negative study results in recent years have taken a toll on non-statin therapies already.

Even after the 2011 patent expiry of Pfizer Inc.’s Lipitor (atorvastatin), AstraZeneca PLC says its Crestor (rosuvastatin) – the sole remaining branded statin – has been holding its own in terms of market share and the drug still has a few years left of branded life to reap the benefits of expanded use of statins. The company reported $1.3 billion in Crestor sales in the third quarter. AstraZeneca released a statement applauding the new recommendations. Crestor has already moved into the lower risk category: in 2010, its label was expanded in 2010 to include treatment of people with lower cholesterol levels based on results from the JUPITER study Also see "Crestor Label Lends Validity To Controversial C-Reactive Protein Test" - Pink Sheet, 15 February, 2010..

Moving Away From Add-On Therapy

The last full version of the guidelines – dubbed ATP III – had been released in 2002, with an update in 2004. That too marked an aggressive expansion of cholesterol management and practitioners turned to alternative therapies to add to statins in hopes of further improving the lipid profile, such as fenofibrates and niacin. However, in recent years mounting evidence has shown that add-on therapies have failed to demonstrate an added benefit in cardiovascular outcomes trials, such as AbbVie Inc.’s Niaspan (extended-release niacin) in AIM-HIGH and TriCor (fenofibrate) in ACCORD Also see "More Disheartening News For Abbott Cholesterol Franchise: Niaspan/Statin Study Halted Due To Lack Of Added Benefit" - Pink Sheet, 26 May, 2011.. Failed trials have also damaged the hypothesis that raising HDL cholesterol would be a way to improve management beyond statins Also see "Dalcetrapib Failure Raises Yet More Questions On Value Of Tinkering With HDL Cholesterol" - Pink Sheet, 14 May, 2012..

In light of these developments, the guidelines prefer more intensive use of statins to reduce LDL in patients at risk for CV events over adding on drugs from other classes. Though products like Niaspan and TriCor have already taken hits, the official recommendations could do further damage.

Merck & Co. Inc. is vulnerable as well with Zetia (ezetimibe), a cholesterol absorption inhibitor positioned as an add-on therapy or as an alternative for people who can’t tolerate statins. Zetia too has been struck by poor trial results with the 2008 of the ENHANCE study of Vytorin, the Zetia/Zocor combination, though Zetia brought in $2.5 billion in sales in 2012, with another $1.7 billion from Vytorin. Merck has another shot at supporting the franchise with the ongoing IMPROVE-IT outcomes trial, which is expected to report out in 2014 ([A#14130312002]). Vytorin has patent protection through early 2017.

Moving Away From Targets

The previous recommendations advised treating patients to specific goals based on a combination of baseline LDL level and cardiovascular risk factors, for example, those at very high risk had an optional target of 70 mg/dL and high-risk patients were advised to get their LDL lower than 100 mg/dL. In the past, new incarnations of the guidelines meant lower optimal LDL targets, which helped drive sales of the more effective statins and created a demand for new drugs with more potency than statins – notably the PCSK9 inhibitors Also see "2012 Wild Card: Will Guideline Revisions Drive Demand For Better Drugs?" - In Vivo, 23 April, 2012.. Though the initial targets are for rare genetic high cholesterol populations, companies working in the space have hopes for statin-intolerant patients and high-risk patients who can’t get at or below the ideal LDL level of 70 mg/dL.

For the latest recommendations, the expert panel had stressed that it would be relying on the highest-quality evidence from randomized clinical trials, with far less openness to use of more subjective expert opinion than in the past. In the end, the revised guidelines ditch treatment targets in favor of tailoring of treatment closely to risk level, with a focus on LDL reduction as a percentage of baseline. They also dispense with the idea that lower cholesterol is always better. Explaining their rationale, the panelists acknowledged that moving away from the treatment-to-target approach “represents a significant departure from current strategies,” but reflects a careful review of the evidence.

The guidelines identify four groups of patients who could benefit from treatment with statins at moderate to high intensity:

individuals with cardiovascular disease (CVD);
those with LDL-C ≥190 mg/dL;
adults aged 40-75 with diabetes and LDL-C ranging from 70-189 mg/dL;
adults aged 40-75 and no clinical CVD or diabetes, with LDL-C from 70 to 189 mg/dL and an estimated 10-year CVD risk of 7.5% or higher.

The benefit for prevention is less clear in other groups and the guidelines advise that for those who don’t fall into the four categories above, prescribers should consider the benefits versus risk for adverse events, patient preferences and drug-drug interactions.

Use of statins has been debated in recent years in light of the side effects Also see "Today’s Statin Debate Bears Lessons For Tomorrow’s Cholesterol Drugs" - Pink Sheet, 23 April, 2012.. FDA added a class-wide warning on statin labeling about increases in blood sugar, among other changes, in early 2012 Also see "Statin Labeling Changes Include Class Warning About Glucose Effects" - Pink Sheet, 28 February, 2012.. Rhabdomyolysis has been a long-time concern, with high-dose statins posing a particular risk for muscle toxicity Also see "SEARCH Ends Badly For Simvastatin 80 Mg; FDA Restricts Use To Existing Patients" - Pink Sheet, 8 June, 2011..

University of California San Francisco cardiologist Rita Redberg, who has publicly voiced concerns about statin overuse in recent years, said that in her opinion, it’s good that the guidelines do away with LDL targets. But the fourth group cited in the guidelines is at low risk for events (7.5%) and the new guidelines open the door for treating more healthy people between the ages of 40 and 75, she said. Running at 85 pages, the guideline document is complicated and likely to be difficult to put into practice, but the simplest interpretation would be to put people between the ages of 40 and 75 on statins for as long as they can tolerate treatment, she said. In a Nov. 13 article in the New York Times with Harvard Medical School’s John Abramson, Redberg estimated that eliminating the LDL criteria “will mean a vast increase in prescriptions,” boosting the number of healthy people recommended to take statins by almost 70%.

Danger Of Down-titration

The guidelines express concerns about under-treatment and over-treatment if prescribers are overly focused on reaching particular LDL targets. In some cases, prescribers may have used a “suboptimal dose” of a statin because a numerical target was reached. In other cases, they reached treatment goals using an add-on non-statin therapy to allow down-titration of statins for safety reasons, but the non-statins have not been proven to reduce events in randomized controlled trials so patients may not be getting the full benefit of statin therapy. Guidelines advise high-intensity treatment for people at high risk, notably those with CVD, but high-intensity treatment is also an option for those in the lowest risk group, that is in those with no CVD or diabetes, LDL from 70 to 189 mg/dL and with a 7.5% 10-year risk of CVD (see table).

ACC/AHA Guidelines For Intensity Of Statin Therapy, Based On Risk

High-intensity statin therapy

Moderate-intensity statin therapy

Low-intensity statin therapy

Average degree of LDL-C lowering per daily dose

≥50%

30% to <>

<>

Examples of drug options

Lipitor 80 mg, Crestor 40 mg

Lipitor 20 mg, Crestor 10 mg, Zocor 20-40 mg

Zocor 10 mg, Pravachol (pravastatin) 10-20 mg, Mevacor (lovastatin) 20 mg

Appropriate patient populations

Adults ≤75 years of age with clinical CVD. Adults with LDL ≥190 mg/dL – guidelines note it’s reasonable to intensify statin therapy to maximum tolerated statin dose to achieve 50% LDL reduction and to consider non-statin therapies if max statin doses are not enough. Adults with diabetes and ≥7.5% 10-year CVD risk. Adults with LDL from 70-189 mg/dL, no CVD or diabetes and 10-year CVD risk of ≥7.5%.

Adults ≤75 years of age with CVD who can’t tolerate high-intensity statins. Adults with diabetes and between ages 40 and 75. Adults with LDL from 70 to 189 mg/dL, no CVD or diabetes and 10-year CVD risk of ≥7.5%.

Not included in recommendations for four patient groups outlined in guidelines.

Source: Neil Stone et al., Circulation, Nov. 12, 2013

The new guidelines seem likely to raise expectation for new cholesterol drugs, with the recommendation against non-statin therapies underscoring the importance of cardiovascular outcomes trials rather than relying on cholesterol levels alone.

Though the sponsors of the PCSK9 drugs have incorporated outcomes trials into their development plans, up to this point FDA has held that the LDL surrogate is still valid and outcomes trials should be started but do not need to be completed prior to approval. Pfizer has announced its intention to wait for the outcomes data before submission ([A#14131029004]). But even assuming PCSK9 inhibitors are approved ahead of outcomes trial results, this could potentially slow adoption until outcomes data are available in late 2017 or early 2018, ISI Group analyst Mark Schoenebaum suggested in a Nov. 12 note.

Mount Sinai Hospital cardiologist Robert Rosenson, who has been investigator in many PSCK9 trials, said that the guidelines leave unanswered practical questions about how to treat people who can’t tolerate statins. Rosenson said that he’s concerned that use of high-dose statin therapy in patients more likely to experience side effects, such as older people, will result in statin intolerance. And when patients experience intolerance at a high dose, they tend to be reluctant to use lower doses, he said.

In light of the known safety issues, the recommendations for more intense therapy are somewhat surprising, but on the other hand, they are in line with some recently published studies that suggest the risks are outweighed by the benefit of preventing cardiovascular events. A meta-analysis of studies with more than 174,000 patients from the Cholesterol Treatment Trialists collaboration touted the benefits of lowering LDL with statins, even in those at low cardiovascular risk, to help prevent events. In the meta-analysis, which was published in the Lancet in May 2012, statins reduced risk by about 21% regardless of age, sex, baseline LDL or previous disease Also see "Bad News/Good News For Cholesterol: Another Strike Against HDL, But Support For Stricter LDL Targets" - Pink Sheet, 21 May, 2012.. CTT investigators concluded that if statins were used in the lowest risk categories, from six and 15 major vascular events could be avoided per 1,000 patients treated over five years.

Cholesterol Guidelines Look High And Low: Statin Market Extended At Both Ends

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