Time, And Price, Are Right To Prescribe Statins To the Masses

With cheap, proven statins aplenty, cost constraints are “off the table” when it comes to vastly broadening primary prevention, authors of new cholesterol guidelines say at the 2013 AHA meeting. However, evidence for drugs to lower triglycerides and boost HDL is lacking, and focus should be on lifestyle change, they say.

DALLAS – Discussion of the recently released – and significantly expanded – guidelines for treating cholesterol at the American Heart Association annual meeting suggest that the lower costs associated with statin therapy helped pave the way for aggressive treatment recommendations.

With a heavy emphasis on statins, the new LDL-cholesterol guidelines show that gold-standard proof of reduced risk for major cardiovascular events plus low drug prices can equate to mass treatment across America, including those at relatively low risk (Also see "Cholesterol Guidelines Look High And Low: Statin Market Extended At Both Ends" - Pink Sheet, 13 Nov, 2013.).

Asked during a Nov. 20 plenary session at the AHA meeting about the expense of the new approach, Donald Lloyd-Jones, co-chair of the committee on risk assessment, said that a health economist his group consulted with suggested that in this day and age, with statins costing $4 a month – not $4 a pill – “cost is off the table.” Cost effectiveness has been established, as studies suggest real benefit of statins in people with lower and lower levels of risk, he added.

During a press briefing on Nov. 18, Lloyd-Jones had noted that in 2010, the U.S. spent $273 billion in cardiovascular care costs, a figure projected to triple by 2030 to $819 billion yearly. That’s about the cost of a stimulus package every year just to deal with the epidemic of cardiovascular disease, said Lloyd-Jones, chair of preventive medicine at Northwestern University.

“We must get more serious about prevention in this country. We must change the landscape for lifestyle modification and take advantage of very effective tools – including medications – that help us bend the risk curve and decrease costs,” he said.

Earlier iterations of the cholesterol treatment guidelines, then under the aegis of the National Heart, Lung and Blood Institute’s Adult Treatment Panel (ATP), have also pushed for more aggressive treatment at a time when the market was dominated by costly brand products. But the comments at AHA suggest that the new cost realities made it an easier move.

A Risky Business

Risk Groups Of Patients Who Benefit From 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

Source: ACC/AHA Cholesterol Guidelines, November 2013

Now under the auspices of the American Heart Association and the American College of Cardiology, the guidelines on treatment of blood cholesterol to reduce CV risk move away from numerical LDL-C targets, instead focusing on treating certain groups of adults likely to benefit from treatment, based on the most rigorous evidence from randomized, controlled trials.

The guidelines, published Nov. 12, should expand the statin market from two directions: by pushing aggressive treatment for higher-risk patients and by extending recommendations in primary prevention to include patients at lower risk than previous versions.

They outline four groups who could benefit from statins, the lowest of which have at least a 7.5% risk of having a cardiovascular disease event over 10 years, including strokes and heart attacks (see box). That’s the level where the benefits outweigh the risks, though at the AHA meeting, held Nov. 16-20, guideline authors pointed out that the data support an even lower threshold of risk of 5%. In addition to the guidelines, a new risk calculator has been developed that is better able to estimate risk of stroke and also to assess specific risk in African Americans.

An estimated 33 million American adults would fall into the 7.5%+ risk bracket and another 12.7 million have more than a 5% risk.

Backed by numerous RCTs showing reduced risk, statins emerge as the dominant treatment, whereas other lipid-modifying drugs are discouraged due to the lack of evidence of a clinical benefit (see sidebar).

For the pharmaceutical industry, the expansion comes to a mature market. AstraZeneca PLC’s Crestor (rosuvastatin) is the only statin with patent life left and other non-statin, lipid-modifying drugs are either already genericized or close to it. But new classes are coming with an eye toward picking up where statins leave off – either in patients who cannot take statins or who have extremely high cholesterol that cannot be treated with them (Also see "Branded Life After Lipitor: Pharma Targets Unmet Needs In Dyslipidemia" - In Vivo, 23 Apr, 2012.).

Heavy attention is being paid to how the new guidelines will affect the regulatory prospects for the promising class of PCSK9 inhibitors – where Amgen Inc. and Sanofi/Regeneron Pharmaceuticals Inc.are jockeying to be first to market. Both groups have extensive Phase III programs in a variety of populations, leading with the rare genetic condition of familial hypercholesterolemia (Also see "PCSK9 Developers Cover All The Phase III Bases In Post-Lipitor Era" - Pink Sheet, 1 Apr, 2013.).

Those programs include outcomes trials – a long-time practical necessity of CV drug development – and the sponsors and FDA have been clear that those trials should be ongoing at the time of regulatory submission but do not need to be completed prior to approval, though payers are a different story (Also see "Wary Of Surrogates, Payers Seek Outcomes Data For PCSK9 Class" - Pink Sheet, 1 Apr, 2013.). Pfizer Inc., however, raised concern by announcing in October that it intends to wait for outcomes data before filing its PCSK9 candidate (Also see "Pfizer Initiates Phase III Trial For PCSK9; Raises Doubts About Regulatory Pathway" - Pink Sheet, 29 Oct, 2013.). But, having taken a huge hit from the failed torcetrapib program, Pfizer has more reason than most to be conservative.

The cholesterol guidelines put a heavy emphasis on the importance of outcomes assessment to demonstrate the value of cholesterol interventions, leading to speculation that the agency may revise its assessment. FDA, of course, has had the same data as the panel all along.

Amgen Exec VP-R&D Sean Harper addressed these concerns at an AHA briefing (Also see "Amgen Positions Ivabradine As A Foot In The Door Ahead Of PCSK9 Launch" - Pink Sheet, 20 Nov, 2013.). “Ultimately, it is, of course, up to the regulatory authorities whether they approve the product and then what populations they approve it in at the time of the initial LDL base submission and prior to the availability of outcomes data, but we remain, as we have all along, planning to submit based on LDL lowering,” he said. The comprehensive Phase III programs should give Amgen and Sanofi/Regeneron plenty of flexibility in crafting data packages.

Room To Grow, Over The Counter?

The guidelines also suggest a growing comfort with statins’ benefit-risk profile. Widely accepted for their benefits in reducing risk for major cardiovascular events, the class has also been associated with some troubling side effects, like muscle pain and diabetes (Also see "Today’s Statin Debate Bears Lessons For Tomorrow’s Cholesterol Drugs" - Pink Sheet, 23 Apr, 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 Jun, 2011.). Bayer AG’s Baycol (cerivastatin) was withdrawn due to safety reasons, and AstraZeneca dropped development of a high dose of Crestor for similar reasons.

Neil Stone, chair of the expert panel that drafted the guidelines and professor of medicine at Northwestern University, noted that the incidence of drug-induced rhabdomyolysis has been low in clinical trials. Patients often complain of muscle symptoms even when not on statins, and doctors should take a detailed history to identify this issue prior to prescribing statins. It’s also important to check for drug-drug interactions, a common cause of muscle pain side effects, he said.

Acceptance of the risk-benefit profile in lower risk populations could have important ramifications for the prospects for an Rx/over-the-counter statin switch.

Entering the market with the first OTC statin still represents an attractive consumer opportunity, as initially big pharmas could take advantage of a period of exclusivity (Also see "Pfizer Consumer Chief Sees Chronic Conditions In OTC Future" - Pink Sheet, 1 Jun, 2011.). But the regulatory bar for switches in the U.S. is high; FDA advisory committees rejected Merck & Co. Inc.’s Mevacor (lovastatin) three times in the past, citing concerns about patients over-estimating their risk and need for treatment, among other things (Also see "FDA Advisors Say Greater Insight Needed On Self-Selection Of OTC Statins" - Pink Sheet, 17 Dec, 2007.). In the U.K., low-dose statins have been available over-the-counter to those at moderate risk since 2004, but with pharmacists’ monitoring and screening. At the time of the change, U.K. health officials stressed the importance of patient choice in reducing risk.

Personalized Medicine Is “The Way To Go”

Outside of the four risk groups identified in the new ACC/AHA guidelines, the benefit for prevention is less clear and prescribers are advised to consider the benefits versus risk for adverse events, patient preferences and drug-drug interactions.

Stone stressed during the Nov. 20 plenary session at the AHA meeting the importance of a thorough discussion between the patient and physician. The appropriateness of drug therapy needs to be determined for each individual, he said. For example, if a young patient has LDL-C of 160 mg/dL and a strong family history of heart disease, he or she might be a candidate for statin therapy. Personalized medicine is the way to go, Stone said.

“This is not some gimmick designed to push medicines on people. This is a patient-centered report designed to allow the physician his or her judgment and the patients’ preferences. … I think that’s a strong point, I’d like to see more guidelines do that as opposed to one size fits all,” Stone said, to a round of applause.

“This is not some gimmick designed to push medicines on people. This is a patient-centered report,” guidelines chair Neil Stone said.

Stone and fellow guideline panelists had found themselves very much on the defensive at the start of the AHA meeting following bad press.

On Nov. 17, the New York Times alerted the country that Harvard Medical School’s Paul Ridker and Nancy Cook would be publishing an article in the Lancet criticizing the calculator used to determine risk. In their article, which the Lancet published on Nov. 20, Ridker and Cook claim that based on their analysis of trial cohorts, the risk calculator accompanying the guidelines vastly over-predicted risk by 75% to 150%. This means that 40%-50% of the 33 million in the target primary prevention population, according to the calculator, do not actually have more than a 7.5% risk, they argued.

At the AHA meeting, guideline authors pointed out that the trial populations analyzed by Ridker and Cook were at lower risk for events than the general American population and argued that the advice for primary prevention must be put into context of high risk and high costs to society associated with cardiovascular disease.

About one-third of Americans will die from heart disease or stroke, and 60% will have a major event, noted David Goff, who worked on the risk assessment portion of the guidelines, during the Nov. 18 press briefing. Under the new guidelines, about one-third of Americans aged 40-75 would get statins for primary prevention. That’s on par with the total number that would have been eligible under the old ATP guidelines, but the populations are different, he said. In comparison, 70 million Americans are recommended to have treatment for high blood pressure, said Goff, dean and professor of medicine at the Colorado School of Public Health.

Among other studies, guideline authors referenced data from the Cholesterol Treatment Trialists Collaboration demonstrating that lowering LDL with statins, even in those at low cardiovascular risk, helps prevent events. In a meta-analysis of studies covering more than 174,000 patients, 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, six to 15 major vascular events could be avoided per 1,000 patients treated over five years.

During the Nov. 20 plenary session, Lloyd-Jones said that far too many events occur suddenly in asymptomatic people – the guidelines help clinicians get a ballpark idea of which patients are most likely to have an event, but these are probabilities, not certainties. The guidelines reflect a risk-screening as opposed to a disease-screening approach to atherosclerosis, he explained.

Is There Life For Add-On Drugs In The Margins?

Pharmaceutical companies developing new drugs for dyslipidemia have noted the high number of patients who don’t reach LDL-C targets, despite the availability of high-potency statins, as a sign of high unmet need. During the plenary session, Stone said that if the usual lowering of risk is not happening on statin treatment, clinicians should first make sure patients have been adhering to the medication regimen rather than “adding on other therapies indiscriminately.”

A range of drugs have been used as add-on therapies to help patients reach the LDL-C targets of the past, when statins were not doing the trick or could not be tolerated due to side effects, or to alter other lipid levels like triglycerides and HDL. These include fibrates, niacin, Merck’s cholesterol absorption inhibitor Zetia (ezetimibe) and prescription and over-the-counter omega-3 fatty acids.

The stance on add-on therapies follows numerous failed outcomes trials for a range of drugs, including marketed drugs like AbbVie Inc.’s Niaspan (extended-release niacin) and TriCor (fenofibrate), and drugs in development, notably the HDL-cholesterol raising CETP inhibitors (Also see "Dalcetrapib Failure Raises Yet More Questions On Value Of Tinkering With HDL Cholesterol" - Pink Sheet, 14 May, 2012.). However, in some failed outcomes studies, certain subgroups still benefited. For example, AbbVie’s TriCor failed a primary composite event reduction endpoint in the National Institutes of Health-funded ACCORD Lipid trial, but the study suggested a benefit for a subgroup with high baseline triglycerides and low HDL-C.

Amid low confidence in surrogate markers apart from LDL-C,Amarin Corp. PLC had a rude awakening recently in its bid to expand the label of its triglyceride-lowering EPA fish oil product Vascepa (icosapent ethyl). The product was approved as an add-on therapy to statins for lowering triglycerides in patients with extremely high triglycerides (over 500 mg/dL) and the company had been looking to branch out into the much larger population of patients with high triglycerides (200 mg/dL to 500 mg/dL). But FDA made clear at an advisory committee review that in the wake of the failed outcomes trials of other drugs targeting triglycerides, the surrogate is too damaged to support approval. The panel voted against label expansion prior to outcomes data (Also see "FDA Makes It Formal, Rescinds SPA For Amarin’s ANCHOR Study" - Pink Sheet, 30 Oct, 2013.).

At least for now, low HDL-C and high triglycerides appear to be risk markers and not necessarily risk targets for drug therapy, Stone argued.

Stone gave a detailed presentation about the evidence against treatment of low HDL-C and high triglycerides in a Nov. 17 session at the AHA meeting. At least for now, low HDL-C and high triglycerides appear to be risk markers and not necessarily risk targets for drug therapy, Stone argued.

It still makes sense to use triglyceride-lowering treatments in those with extremely high triglycerides to prevent pancreatitis, in his view. However, Stone stressed the importance of first ruling out secondary causes of high triglycerides, especially lipoprotein lipase deficiency, which can be managed primarily with a low-fat diet.

Stone generally stressed non-drug management of high triglycerides. For example, alcohol intake and weight need to be kept in check and clinicians need to be alert to drugs that can cause high triglycerides, including beta blockers and estrogens.

He called for new trials of the fibrate class in the patient subgroups most likely to benefit from treatment. And on fish oil, “we have a country that seems obsessed with omega-3 fatty acids,” Stone commented. “You can now buy them in huge jars with all kinds of additives to them. But do we really have strong evidence that we should be taking them, each of us?” he asked.

A few trials showed a signal for benefit with fish oils, he said, but as data accumulated it became harder to show that omega-3s make a difference, for example, if used specifically to lower triglyceride levels from 250 mg/dL to 150 mg/dL, he said. Stone did acknowledge, however, that omega-3 fatty acids could play a role in preventing fatty liver and hepatic insulin resistance.

As for HDL-raising therapies like niacin, the overall benefit is slight, whereas the data for statins show a striking benefit for risk reduction. However, Stone called attention to an article by Brigham and Women’s Samia Mora published online Sept. 3 in Circulation that suggested HDL particle number (HDL-P) may be a better marker of residual risk among those treated to low LDL-C with a potent statin. In the JUPITER trial of the statin Crestor, which established the drug in a relatively low-risk population, HDL-P had a statistically significant and somewhat stronger association with CVD than HDL-C or apoliprotein A1 (apoA-1), Mora and colleagues reported.

HDL-P may prove to be a stronger, more significant risk marker than HDL-C in the future, Stone said. “I am going to be very interested to see next year what we know more about HDL particles.”

HDL subtypes have long been thought to be part of the issue with the CETP inhibitor failures (Also see "Other CETP Inhibitors Could Escape Torcetrapib Trap, ACC Studies Suggest" - Pink Sheet, 2 Apr, 2007.).