PyMOL rendering of the structure of the PCSK9 protein.

PyMOL rendering of the structure of the PCSK9 protein.


Are statins obsolete? Are new drugs more effective and free of side effects? The headlines sound too good to be true:

“New cholesterol drug with no side-effects to replace statins… a new vaccine could replace statins.”

“New cholesterol fighting drug may replace old treatment.”

“New drug cuts ‘bad’ cholesterol by 60% on average, reducing heart attack risk.”

“The new drug for people who suffer side effects from statins.”

Drugs that replace statins but without the side effects approved for use by the NHS.”

As usual, many of the headlines are misleading. Evolucumab and other new PCSK9 inhibitors are effective, but they’re not exactly going to replace statins. The devil is in the details, and the details bring up several concerns.

What is PCSK9?

PCSK9’s long name is proprotein convertase subtilisin/kexin type 9. It is an enzyme, the 9th member of a family of proteins that activate other proteins. PCSK9 binds to the LDL receptors on the liver and keeps them from recycling to remove more LDL particles from the blood; hence, PCSK9 raises LDL cholesterol levels in the blood. Blocking PCSK9 lowers LDL blood levels.

A new class of drugs, PCSK9 inhibitors, are human monoclonal antibodies that bind to PCSK9 and keep it from binding to LDL receptors on the liver, leaving more receptors available to remove LDL cholesterol from the blood. Since antibodies are destroyed by digestion, they can’t be used orally: they must be injected subcutaneously once or twice a month. Evolucumab (Repatha) was approved in 2015. It costs $14,300 per year.

The FOURIER study

Evolocumab had been shown to lower LDL cholesterol levels by 60%, but did it also reduce the rate of cardiovascular events? The FOURIER study, recently published in The New England Journal of Medicine, was designed to answer that question.

  • Randomized, double-blind, placebo-controlled multinational trial
  • 1,242 sites in 49 countries
  • 27,564 patients between the ages of 40 and 85
  • Subjects were all high-risk. They had clinically evident atherosclerotic cardiovascular disease and additional risk factors. Their LDL was 70mg/dL or higher or HDL was 100 or higher while they were on an optimized regimen of statins. 5.2% were also taking ezetimibe, a drug that decreases cholesterol absorption in the small intestine. 92.3% were also taking antiplatelet therapy, 75.6% beta-blockers, 78.2% ACE inhibitors or angiotensin-receptor blockers (ARBs).
  • Median duration was 26 months

Results:

  • Evolucumab lowered LDL cholesterol levels by 59% from baseline levels, to a median of 30mg per deciliter.
  • It reduced LDL to 70 or lower in 87% of patients, 40 or lower in 67%, and 25 or lower in 42%
  • Reductions of 21-27% in myocardial infarction, stroke, and cardiovascular revascularization
  • The benefits increased over time
  • No reduction in rate of hospitalization
  • It reduced cardiovascular events but didn’t save lives; there was no reduction in cardiovascular deaths.
  • Safety: the drug and placebo groups had the same rates of adverse events except that injection-site reactions were slightly more frequent in the evolucumab group.

Interpretation

This study was not about using evolucumab alone, but about adding it to an optimized statin regimen in patients who are at high risk. The results may not be applicable to lower risk patients or to patients treated with evolucumab alone.

Relative risk figures like 21-27% can be misleading when the numbers are small. It is more meaningful to look at absolute risk and the NNT (number needed to treat). 74 of these high-risk patients would have to be treated for 2 years to prevent one incident in the composite outcome of cardiovascular death, heart attack, or stroke.

There was concern that evolucumab might affect cognitive function. That concern was put to rest by a study that showed no difference in cognitive function between evolucumab and placebo groups over a 19-month period. The FOURIER study confirmed the safety of the drug: it found no increase in any adverse events compared to placebo, other than mild injection site reactions.

Current treatment guidelines recommend prescribing statins according to risk status and not worrying about the LDL levels achieved. The FOURIER study suggests that there is additional benefit to lowering LDL levels to well below any previous target levels. It will be interesting to see whether official treatment guidelines will change accordingly.

Cost and inconvenience are big concerns. Evolucumab must be injected once or twice a month, and it is very expensive: $14,300 a year. Generic statins cost much less, about 1% of that ($12 a month or less), and they come in convenient once-a-day pill form.

Many patients on statins complain of muscle pain, but their pain is not always caused by statins. In some placebo controlled studies, the incidence of muscle pain was no higher than with placebo. If statin-related muscle symptoms do occur, they can often be managed by reducing the dose or switching to another statin (unless the rare complication of rhabdomyolysis occurs). And evolucumab can cause muscle pain too. Myalgias occur in 4% of patients and musculoskeletal pain in 3.3%, and there are a number of other side effects. Stopping statins and switching to evolucumab might not be the best idea. We don’t yet have studies comparing evolucumab to statins.

In contrast to the positive headlines, one said, “A new drug to replace statins? Don’t believe the hype.” It says it’s not a statin replacement and would only be appropriate when diet and statins haven’t lowered LDL enough.

Other options

Alirocumab (Praluent) is another PCSK9 inhibitor that was shown in a post-hoc analysis to reduce the risk of cardiovascular events. It was the first PCSK9 inhibitor approved by the FDA. It was approved for the treatment of familial hypercholesterolemia and for use along with statin therapy in adults whose cholesterol is still too high after diet and maximally tolerated statins. Like evolucumab, it costs around $14,300 a year.

Another PCSK9 inhibitor, inclisiran, appears to maintain its effectiveness longer and might decrease the number of injections to 3 or 4 a year. The NNT? They estimate that 17 high-risk patients would have to be treated for 5 years to prevent one heart attack or stroke.

Vaccines are being investigated and have shown promise in animal studies, but human trials are only just beginning.

Canakinumab is a human monoclonal antibody targeting a cytokine. It has anti-inflammatory effects and has been approved for the treatment of rheumatologic disorders. Treatment of atherosclerosis has focused on reducing cholesterol levels, but inflammation is involved and statins have an anti-inflammatory effect in addition to their effect on LDL cholesterol levels. The CANTOS trial was a randomized, double blind, placebo-controlled study of patients with a history of a heart attack who had elevated levels of C-reactive protein, a marker of inflammation. Canakinumab reduced inflammatory markers but not cholesterol levels, and it significantly reduced the incidence of recurrent cardiovascular events. This supports the inflammatory hypothesis of cardiovascular events. Canakinumab causes side effects: there was a higher incidence of fatal infection and sepsis, and a reduction in platelet counts. But it also has beneficial side effects: it improves other inflammatory conditions like arthritis and gout. And it significantly lowers the mortality from some cancers. It appears to reduce the occurrence of lung cancer by 67% and death from lung cancer by 77%. It costs $64,000 a year, which some consider a bargain for a drug that prevents lung cancer in high-risk patients

Conclusion: PSCK9 inhibitors are effective but not likely to replace statins

In my opinion, there is a place for limited use of PSCK9 inhibitors, but only in patients who are truly unable to tolerate statins, or along with statins in high risk patients whose cholesterol is not well controlled on statins alone. Other potential treatments for atherosclerosis are promising, but still investigational. Statins have a proven track record; they remain the treatment of choice.

Posted by Harriet Hall

Harriet Hall, MD also known as The SkepDoc, is a retired family physician who writes about pseudoscience and questionable medical practices. She received her BA and MD from the University of Washington, did her internship in the Air Force (the second female ever to do so),  and was the first female graduate of the Air Force family practice residency at Eglin Air Force Base. During a long career as an Air Force physician, she held various positions from flight surgeon to DBMS (Director of Base Medical Services) and did everything from delivering babies to taking the controls of a B-52. She retired with the rank of Colonel.  In 2008 she published her memoirs, Women Aren't Supposed to Fly.