Overcoming Obstacles In First-Line Cholesterol Treatment

Although statins are the standard of care for treating low-density lipoprotein cholesterol (LDL-C) for patients with atherosclerotic cardiovascular disease (ASCVD), they are limited by their reputation for side effects. Likewise, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have shown high levels of efficacy, but costs can be preclusive.

Many statin treatments have cheaper, generic options available. Their safety data are backed by numerous organizations’ recommendations that they serve as the “optimal first-line therapy” in patients at high-risk for ASCVD. Still, adverse events and patient biases persist.

It’s a complex conversation for doctors, but as James Underberg, MD, pointed out at the 2017 New York Cardio-Endo-Renal Collaborative (CERC), perception is reality for patients. If they refuse statins, alternative treatment is required. “The important thing for patients to understand is that while there is certainly a lot of information out there about potential side effects of statins, that has to be countered by the benefits,” said Underberg, president of the National Lipid Association (NLA), and a clinical assistant professor of medicine at New York University School of Medicine. “In general, statins are safe and effective.”

CONNECTING ASCVD AND LDL-C

For doctors, explaining the risks of refraining from statin therapy is as crucial as explaining the risks of the therapy itself. For example, patients with ASCVD who are unable to continue statin therapy are more susceptible to heart attack and other cardiovascular events, Underberg, said.

Moreover, for patients with high-risk ASCVD, early and efficacious treatment is crucial. Ongoing research has helped to better define the condition and give doctors improved treatment protocols.

LDL-C is proven to have a distinct connection to ASCVD. In a presentation at CERC, Underberg detailed lines of evidence indicating LDL-C’s role in causing ASCVD.

Generic data has established that patients with low LDL-C rates have lower heart disease rates than those born with inherited high LDL-C, who often have early and accelerated cases of ASCVD. Experimental animal-model data show a similar association between higher LDL-C and an increased ASCVD disease burden, Underberg said.

The same association has been documented in observational cohort studies, Underberg added, as well as in interventional data involving pharmacological agents designed to safely lower LDL-C rates and the risk of ASCVD.

Despite this proven correlation, there are open issues in reaching desired treatment rates for LDL-C.

“One of the things that surfaces over and over again is that in high-risk cohorts, the number of patients who get on an appropriate dose of statins, or those who get to the desired low LDL cholesterol levels, is far less than one would like—anywhere between 30% and 40%,” Underberg told MD Magazine®.

A major reason for this rate is patients’ inabilities to tolerate statin therapy, Underberg said. The adverse effects of statin therapy, predominately those stemming from statin-associated muscle symptoms—which include myalgia, myositis, and rhabdomyolysis—are capable of keeping patients with cardiovascular risk from initiating or continuing the primary therapy.

“What most groups determined is that whether statin-associated side effects are real or perceived, they limit a patient’s ability to take the appropriate dose of statins and thereby limit their ability to effectively lower LDL cholesterol to the degree the current recommendations and guidelines would suggest,” Underberg said.

Underberg discussed the results of the USAGE survey conducted by the NLA and Kowa Pharmaceuticals America, Inc. The Internet survey collected input from more than 10,000 statin users from 2007-2011. About 88% of participants had been continuing statin use at the time, while the remainder (12%) had used the therapy previously but had since discontinued.

Regardless of reasons for discontinuing the therapy, former users reported an average LDL cholesterol rate of 223 mg/dL. Current users reported a lower 173 mg/dL rate on average.

PCSK9 iNHIBITOR DATA IMPRESS

Evolocumab (Repatha) and alirocumab (Praluent) were both approved by the FDA as an adjunct to diet and statin therapy in 2015 for treating adults with clinical ASCVD or heterozygous familial hypercholesterolemia, or for lowering LDL-C. Evolocumab is additionally approved to treat homozygous familial hypercholesterolemia.

In the ODYSSEY LONG TERM trial, the inhibitor showed substantial efficacy in lowering LDL-C in a large patient group. The trial reported that 1553 patients administered 150 mg alirocumab every 2 weeks for 78 weeks had reduced LDL-C rates at an average of 61%, from baseline to week 24.

The early clinical benefits of PCSK9 inhibitors are dogged by the treatment’s current prices, according to Kevin Maki, PhD, CLS, FNLA. Maki, president and chief scientist of MB Clinical Research, LLC, detailed the fiscal barriers to PCSK9 inhibitors in a presentation at CERC. He outlined a process that clinicians must go through to get payers’ access to the promising therapy.

“The degree of risk reduction is about what you would expect for the degree of LDL cholesterol lowering, but they’re very expensive,” Maki told MD Magazine.

Not only do doctors have to learn how to expedite the process to get PCSK9 inhibitors approved for their patients, but they may also have to apply again after rejection. Though about half of patients prescribed PCSK9 inhibitors receive access, about 80% of all initial applications for the therapy are rejected on first attempt, Maki said.

Patients with ASCVD have a better chance of receiving PCSK9 inhibitors if they have first tried their share of statin therapies. Among the checkmarks that payers look for in inhibitor applications is whether patients have first taken at least 2 statin regimens without LDL-C reduction, Maki said.

“They’re looking for clear documentation of the indication, so the indication is atherosclerotic cardiovascular disease with a need for additional LDL cholesterol lowering or familial hypercholesterolemia with a need for additional cholesterol lowering,” Maki said.

Along with proof of statin treatment and often adjunct therapy, payers want to see a recent patient lipid profile and a proof of treatment insufficiency, possibly through documented evidence from a family member, Maki said.

For all the hurdles that clinicians must overcome to access the expensive therapy, Maki advocated for an organized application process. “The people who have worked out the systems with their office staff and really understand what the payers are looking for have to go through fewer iterations to get approval,” he said.

As therapies and research progress rapidly in cardiovascular care, clinicians are still hindered by coverage and adherence limitations. Underberg noted that treatment decisions are not as linear as one would think—for better or worse.

“Often at many decision points going forward, we have multiple options,” Underberg said. “While there are issues with regard to new drugs and costs, they also create myriad options that give us some alternatives in the management of these patients.”