Are protein inhibitors really the next big cholesterol killers?

Heart disease is the leading cause of death in India and the proportion of people losing their lives to the ailment is only rising. If you are one of many Indians diagnosed with cardiovascular disease and high cholesterol, your doctor has probably put you on a statin, in addition to advising a better diet and a healthier lifestyle.

Statins have been the first line of treatment for excessive cholesterol for nearly three decades. Over the last couple of years, however, medical researchers have been testing a new class of drugs to help those patients who do not respond well to statins. Preliminary research of these compounds called PCSK9 inhibitors showed that they reduced cholesterol levels in the body dramatically.

But are PCSK9 inhibitors really effective in preventing heart attacks and deaths due to cardiac disease?

PCSK9 is a naturally occurring protein in the human body that binds to low density lipoprotein, better known as LDL cholesterol or “bad cholesterol”, in the bloodstream and stops it from being cleared away. If unchecked, this leads to an increase in levels of LDL cholesterol in the body. “A PCSK9 inhibitor is a drug that produces antibodies to block the production of this protein, thereby allowing the liver to perform its task of removing LDL cholesterol effectively from the bloodstream,” said Dr Subhash Chandra, consultant cardiologist at Manipal Hospital in Bengaluru.

The first PCSK9 inhibitor called alirocumab was approved for use by the United States Food and Drug Administration in July 2015. A second drug, evolocumab, was approved a month later.

Statins are derived from synthetic sources as well as microorganisms. Statins decrease levels of LDL cholesterol by inhibiting an enzyme called HMG-CoA reductase that plays a key role in the metabolic pathway that produces cholesterol. Statins also make the body produce more lipid receptors, which are proteins that transport LDL cholesterol to the liver and removes it from circulation.

Statins have been known to lower cardiovascular events such as heart attacks. But they are not without side effects. For instance, about 10% of cardiac patients suffer from myalgia, a condition characterised by severe muscle aches and cramps, with even small doses of statins. Use of statins also increases the risk of developing type 2 diabetes – some studies say by as much as 46% – due to decreases in insulin sensitivity and insulin secretion. Besides, between three and four percent of cardiac patients do not respond because of genetic conditions.

Medical researchers have been hoping that PCSK9 inhibitors can work where statins come up short. For instance, some patients have genetically-linked high cholesterol – a condition known as familial hypercholesterolemia. Their bodies do not produce lipid receptors and so statins, which work by boosting lipid receptor production, do not help them. PCSK9 inhibitors’ protein-binding mechanism helps lower LDL-cholesterol in such cases.

“These drugs are being used to treat familial hypercholesterolemia and for patients intolerant of statins or those with a major risk of cardiovascular disease but unable to lower their LDL cholesterol to optimal levels with statins,” said Dr Anoop Misra, specialist in internal medicine and chairman of Fortis Hospital’s Centre of Excellence for Diabetes, Metabolic Diseases and Endocrinology in New Delhi. “However, as experience with these drugs increases, it would be used outside these clinical scenarios.”

They are prescribed as add-on medication to patients who are already on the maximum dose of statins that they can tolerate, according to Dr Vijay Divakaran, the section chief of cardiology at the Baylor Scott & White Medical Center at College Station in Texas, US.

On March 17, the New England Journal of Medicine published results of the longest PCSK9 inhibitor clinical trial so far, testing an injectable form of the PSCK9 inhibitor evolocumab for its role in lowering levels of LDL cholesterol. The study involved a multi-country clinical trial with 27,564 patients with atherosclerotic cardiovascular disease on which arteries become hardened and blocked. These patients were already taking high doses of statins and many of them had suffered heart attacks. One group of patients was randomly assigned to receive 140 mg of evolocumab as an injection every two weeks in addition to their standard statins medication. The other, control group was not given the additional dose of evolocumab. Both groups were studied for a period of over two years.

The study showed that evolocumab reduced LDL cholesterol levels by 60 milligrams per decilitre on average – a reduction not seen with any other therapy. The drug also reduced the risk of heart attack and stroke by about 15% in the two years over which the study was conducted.

While these results indicate that the drug works, doctors remain sceptical about hailing evolocumab or other PCSK9 inhibitors as the big cure for heart disease. The short time frame of the trial also leaves the question of long-term side effects open. Another major concern is that the drug’s impact on mortality rates are yet to be established. While medical researchers are sure that PCSK9 inhibitors reduce LDL cholesterol drastically, they are not certain that this translates into saving more lives.

“The studies that were designed to test the efficacy of the drug showed some signal of reduced mortality, but that hasn’t been conclusive,” said Divakaran. “Some meta analysis have shown lower mortality. There are studies ongoing that are looking at this outcome. I don’t think this drug is going to replace statins as the first-line treatment of high cholesterol.”

Moreover, the study was funded fully by Amgen, the company manufacturing this drug. Most doctors are holding off on deciding the role of PCSK9 inhibitors like ecolucumab till there is more in-depth and independent research.

Divakaran says he prescribes evolocumab to a small group of his patients who do not respond well to statins. “It does lower LDL above and beyond what statins do,” he said.

Misra pointed out that PCSK9 inhibitors not only lower levels of LDL cholesterol but also the level of the potentially harmful lipid subclass called lipoprotein(a) that contributes to heart disease. PCSK9 inhibitors play a role in prevention of heart disease as well, said Dr Girish B Navasundi, senior consultant and interventional cardiologist at Apollo Hospitals in Bengaluru. “When you’ve already had a heart attack, preventing a second attack that can further weaken your heart becomes critical,” he said. “For this, you need significantly lower LDL levels which may not be possible for everyone to achieve. Drugs like this, taken in addition to statins are significant in slowing the progression of cardiovascular disease and stroke, making a population less vulnerable to multiple attacks.”

The uncertainties

Despite the hype and hope around evolocumab and other PCSK9 inhibitors, there are several questions for which researchers and clinicians are awaiting answers.

All PCSK9 drugs are only available as injections, used every two weeks. “Side-effects produced by injectible drugs tend to be more severe as these are difficult to reverse right away and may last over 10-12 days,” said Navasundi. He feels that recorded side-effects like inattentiveness and cognitive impairment from use of the drug are not alarming but need further observation.

“In any new drug which involves an entirely new mechanism of action, we need more time, at least three-five years, to study its side-effects and to see which patients are more sensitive to it,” he said.

Medical researchers would also have to look deeper into the performance of PCSK9 inhibitors in different racial and ethnic populations. “More studies are needed to ascertain its effect on Indian origin people,” said Misra

The drug is also very expensive at the moment. “In the US, it costs around $14,000 per year,” said Divakaran. “This is a limitation, as most patients cannot afford this without medical insurance.”

In India, far fewer people have access to medical insurance. “Until a more cost-effective solution is found to market it, it would be hard to see this having much impact on public health,” said Chandra. “At least for the next five-ten years, a healthy lifestyle coupled with statin therapy is still going to be the norm.”