New cholesterol-lowering medications called PCSK9 inhibitors are likely going to be approved this summer and come to a pharmacy near you soon afterward. This is big news. They will be the first new class of potent LDL-cholesterol-lowering drugs for a potential large population of patients since the first statin came to market in 1987.
Many cardiologists are enthusiastic about the drugs’ potential to treat patients who haven’t responded to statins and other medications. Pharmaceutical companies are ecstatic about a whole new market…especially now that many statins are generic and so less profitable.
Before we jump on the new bandwagon, however, let’s take a close look at these powerful drugs. It pays to be cautious. We often may not know the real story about effectiveness—and harm—until many years later after completion of long-term outcome studies, potentially long after new drugs have been approved and are being used by millions of people. Once approved for very specific uses, as these new drugs are likely to be, they would be available to be prescribed for a much broader population. Others may be tempted to skip the use of currently well-studied drugs such as statins and downplay the lifestyle changes that can go a long way toward preventing heart disease.
To get the inside story on these new weapons in the cholesterol wars, we reviewed the studies and spoke with our two contributing medical editors as well as Michael Rocco, MD, a cardiologist at the Cleveland Clinic in Ohio. He has been involved in clinical trials of two of these new drugs but has no personal financial stake in any of them. Says Dr. Rocco, “We use current cholesterol-lowering drugs not just to make the numbers look pretty, but also to safely reduce adverse events, like heart attacks and strokes. We will need to continue to critically evaluate these new drugs after approval as new data becomes available in terms of their safety profile and ability to further reduce these adverse cardiac events.”
How do PCSK9 inhibitors stack up?
WHAT WE KNOW…NOW
Let’s start out with the nuts and bolts of this new class of drugs that is likely to be hugely promoted when it hits the market…
1. Expect them this summer. An FDA panel voted its recommendation to approve two of these drugs, evolocumab (brand name: Repatha) and alirocumab (brand name: Praluent) in June. By the end of July for Praluent and in August for Repatha, the FDA may formally vote to allow them to be marketed. Yet a third one, bococizumab (a brand name hasn’t been announced yet) is in the wings.
2. They work in a new way. Statins reduce the amount of cholesterol produced by the liver. PCSK9 inhibitors, in contrast, speed up the body’s ability to eliminate LDL, the “bad” cholesterol, from the bloodstream by a different mechanism. They are monoclonal antibodies that target a specific protein that regulates LDL receptors.
3. They lower LDL levels—a lot. “In the recent clinical trials, we’ve seen consistent, significant reduction of LDL in the 50% to 70% range whether used alone or in combination with statin therapies,” said Dr. Rocco. As a point of reference, people who are at elevated risk for heart disease are often told to lower their LDL levels to below 100, sometimes below 70. In studies of the new drugs, the average LDL went down into the 40s.
4. They’re not pills—they are injections. People using PCSK9 inhibitors will need to give themselves injections under the skin (or have someone else do it) every two weeks or every four weeks.
5. They’re likely to be very expensive. Prices won’t be announced until these actually hit the market, but they won’t be cheap—in fact, they may cost $1,000 a month.
6. They’ve been studied in trials so far lasting only up to 20 months. Only longer-term studies, now underway, will be able to establish both potential benefits and risks conclusively.
7. They may prevent heart attacks. In short-term studies, these drugs cut the incidence of cardiovascular events such as heart attack and stroke in half. However, says Dr. Rocco, “These weren’t long-term studies, and the number of actual events was low.” While the results “are encouraging and suggest that we’re headed in the right direction,” he says, before we start using these drugs in a broad population of individuals, “we need to wait for long-term clinical trial results.”
8. Adverse side effects appear to be modest—so far. In the evolocumab study, which compared the drug to standard practice (usually with statins), there was no difference in total serious adverse events including muscle symptoms, although the incidence of “neurocognitive” events (amnesia/memory problems/confusion) was 0.9% with the new drug versus 0.3% without it. “But this wasn’t a blinded, placebo-controlled study,” says Dr. Rocco, “so it’s hard to know what to make of those results.” For example, patients on the new medication saw their doctors more often, so they had more opportunity to lodge complaints. For alirocumab, which compared people on the drug plus statins to those on high-dose statins alone, the total serious adverse events were also about the same, although there was more muscle pain on the alirocumab/statin combo. There were also more neurocognitive events, although this wasn’t statistically significant. Again, these studies are short-term so we won’t know the full story for several years.
9. These drugs won’t replace statins anytime soon. “We already know that statins have proven benefits not only in reducing LDL cholesterol but in reducing cardiovascular risk,” says Dr. Rocco. “Some of that risk reduction may be mediated through the cholesterol-lowering effect, but there are other effects of statins that may also be helpful, such as the anti-inflammatory and antioxidant effects. Replacing statins, a drug with proven benefit, with a drug that right now has potential benefit but while still awaiting definitive long-term outcome studies is something that has to be thought about very seriously.”
10. They may be prescribed for people who just can’t take statins. Up to 10% to 20% of people who take statins stop them or reduce the dose, primarily because of complaints of muscle pain, which is not only unpleasant but can even be debilitating. These people are potential candidates for the new drugs.
11. They may be prescribed for people in addition to statins. Some people who can take statins find that their LDL levels remain stubbornly high. People with an inherited form of high cholesterol and associated very high risk for premature cardiovascular events can have LDL levels of 200 to 300 or higher, and lifestyle changes plus statins may not be able to reduce these enough.
UNANSWERED QUESTIONS ABOUT A REALLY NEW DRUG
Cardiologists are clearly excited about the potential for these new drugs to help prevent heart attacks in hard-to-treat patients. One survey found that they would prescribe them for 18% of their patients if they were available now.
It is reasonable to temper the enthusiasm with caution…and experience. After all, the side effects of statins, which include not only muscle problems but diabetes, are still being uncovered—nearly 30 years after they were first approved. Statins increase the risk of developing diabetes by 9%, according to a meta-analysis of the research, and one study has found an increased risk of 46%.
The long-term studies of these new drugs won’t be completed until 2017. Daily Health News contributing medical editor Richard O’Brien, MD, FACEP, believes these drugs may be appropriate only for a small population. “My own view is that the new injections are under-studied. We have no idea of long-term safety,” he says.
Excitement over a new medication should not obscure the powerful role that a healthy lifestyle needs to play in preventing—and treating—heart disease. Many factors besides cholesterol levels play a role, including blood pressure and inflammation. To learn more, see “Become Heart Attack Proof—Here Are the Tests and Other Strategies You Really Need….” Daily Health News contributing medical editor Andrew Rubman, ND, notes that while statins may provide anti-inflammatory and antioxidant effects, “these are provided to a greater degree by lifestyle changes, better diets, and supplements.
A healthy lifestyle that includes a good diet, exercise, not smoking, maintenance of ideal weight and stress reduction is an essential component of any cardiovascular risk reduction strategy, so it remains the core of a cardiovascular disease prevention program. As Dr. Rocco pointed out, this should be true whether or not you are taking statins—and whether or not you end up trying a new PCSK9 drug.