PCSK9 inhibitor benefits patients with statin intolerance

Statin intolerance does exist and a PCSK9 inhibitor can lower cholesterol in these patients, according to a study published online in JAMA and presented at the American College of Cardiology's 65th Annual Scientific Session in Chicago.

Read: New cholesterol-lowering drugs draw attention

In the first major trial of its kind, Cleveland Clinic researchers used a blinded rechallenge with atorvastatin or placebo to objectively confirm the presence of muscle-related symptoms in patients with a history of intolerance to multiple statins and found that injectable PCSK9 inhibitor evolocumab (Repatha) was a more effective option to lower cholesterol than ezetimibe in these patients.

Nissen

Currently, statins are the most effective drug to lower LDL-or so called “bad” cholesterol-but patient intolerance to statins has been a challenging issue for physicians because no biomarker exists to definitively document it, according to lead study author Steven Nissen, MD, chairman of Cardiovascular Medicine at Cleveland Clinic.

“[Statin intolerance] has been one of the most controversial areas of medicine for a long time-some great thought leaders believed it didn’t exist, yet clinicians were reporting this a common adverse effect of their patients’ statin use. It is a vexing problem, patients with LDL cholesterol not taking their statin because they have muscle pain or weakness,” Nissen tells Managed Healthcare Executive. 

“Statins are not only the most effective at reducing cardiovascular risk, they are also the least expensive therapeutic option,” he continues. “The alternatives to statins for reducing LDL cholesterol are substantially more expensive than generic statins. This has big implications for the cost of delivering care: How do you manage patients in a cost-effective manner?”

Study overview 

The phase 3 GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3) trial enrolled 511 patients with very high levels of LDL cholesterol, averaging more than 210 mg/dL, and with a history of muscle-related statin intolerance. More than 80% of participants had previously reported intolerance to three or more statins. The study showed that 42.6% of these patients reported muscle pain or weakness on atorvastatin, but not placebo, and 26.5% on the placebo, but not atorvastatin.

Brill

The patients who demonstrated statin intolerance only on atorvastatin were randomly assigned to two alternative treatments to lower LDL cholesterol: evolocumab or ezetimibe. On average, patients showed a 52.8% reduction on evolocumab compared with 16.7% reduction with ezetimibe. Evolocumab was more effective, but had a similar incidence of muscle-related adverse effects compared with ezetimibe, according to the study.

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“Side effects from statins [e.g. muscle aches] are real,” says Managed Healthcare Executive Editorial Advisor Joel Brill, MD, chief medical officer, Predictive Health LLC.  “Some patients need and can benefit from a PSCK9.  But not everybody needs a PSCK9 to treat their hypercholesterolemia.”

Next: Clinical takeaway for managed care executives

The clinical takeaway for managed care executives? Proceed with caution, according to Curant Health CEO Patrick Dunham.

“High LDL is a surrogate marker for cardiovascular events,” Dunham says. “Therefore, on the surface it would appear that a drug class shown to lower LDL levels would benefit patients with high cholesterol by reducing the rate of negative cardiovascular events.”

However, he says that while PSK9 inhibitors show great promise, the referenced study did not show direct causation between taking evolocumab and a lower rate of negative cardiovascular events. 

“Therefore, it would not be prudent to prescribe this drug for the vast majority of patients with high cholesterol,” Dunham says. “For the relatively small niche of patients who absolutely can’t tolerate statins, evolocumab has been proven to be safe and effective in lowering LDL. If the choice for these patients is a PCSK9 inhibitor or no drug to treat high cholesterol, it likely makes clinical and financial sense to prescribe a PCSK9 inhibitor.”

The underlying question that remains is which healthcare stakeholder makes the decision between cost versus benefit: Payer or prescriber, according to Dunham.

Dunham

“If, after additional studies of more patients over longer periods of time, PCSK9 inhibitors are shown to be more effective than statins in lowering LDL cholesterol levels and significantly reducing the rate of negative cardiovascular events, this fundamental question will move to the forefront of the larger discussion on value-based healthcare,” he says.

Nissen advocates for good policies. “Make every conceivable effort to treat patients with statins, but provide a pathway for the high-risk patient to be treated with alternative, more expensive therapies,” he says.

“There is going to be considerable pushback from payers about the use of a specialty drug-the PCSK9 inhibitors-in cases where a generic can keep cholesterol in check for only a few dollars a month,” says Peter Gilmore, principal at KPMG Strategy. “The [study] shows that statin intolerance may be higher than previously thought, but payers will likely include prior authorization or step therapy protocols around the use of PCSK9 inhibitors. The vast majority of the millions of patients needing to lower their cholesterol will be fine with a statin. For a fairly select group of patients who need to lower their LDL levels and don’t tolerate statins, PCSK9 inhibitors could help patients meet their clinical goals.”  

The study was funded by Amgen, manufacturer of evolocumab.