The New Paradigm

A recent FDA advisory panel recommended the approval of 2 new agents in a novel class of cholesterol lowering drugs known as PCSK-9 inhibitors. What makes this remarkable is that these drugs illustrate all the promise and pitfalls of modern pharmaceutical development.

First, a little science. The target of the new drugs – a protein named proprotein convertase subtilisin/kexin type 9 (PCSK-9) – was discovered in 2001. Two years later, investigators reported that “gain-of-function” mutations in the gene that codes for PCSK-9 were associated with familial hypercholesterolemia and high rates of atherosclerotic vascular disease. Mutations of the gene that led to reductions in the function of PCSK-9 were associated with low LDL-cholesterol levels, and a lower incidence of vascular disease. That made the compelling case that PCSK-9 had a counter-regulatory function in LDL-cholesterol metabolism, so that interfering with its function would lead to lower cholesterol levels.

The pharmaceutical industry used this insight to design drugs based on monoclonal antibodies that specifically target PCSK-9. Early clinical trials found the agents to be safe and effective at lowering LDL-cholesterol levels, even in individuals who had persistently elevated levels on high dose statins. It was on the basis of these trials that the advisory panel recommended approval. Larger clinical trials are now underway to determine the impact of the drugs on clinical endpoints such as heart attack and death.

So what’s not to like? On the face of it, this is the story of a remarkable achievement of rapidly turning a “bench” discovery into a “bedside” tool by utilizing modern molecular genetics.

Here’s the rub. We are about to have a new “genie” released from the bottle. Because these agents are “biologics,” they must be administered by injection, and (like other biologics) they are likely to be very expensive. Among the as-yet unanswered questions are:

  • How do these agents “fit in” with statin treatment? Should they be reserved for patients who “fail” statin treatment, and if so, what exactly constitutes a statin failure? Does it get added to statins or replace it?
  • Should they be used only for patients with familial hypercholesterolemia? What about other high risk populations?
  • How much money are these drugs worth? The recent controversies over the pricing of anti-cancer drugs is soon to play out in the cardiovascular field

All this boils down to the fact that we have a potentially wonderful new tool, but have no idea how best to use it or how much we should be willing to pay for it, or even if it improves clinical outcomes. This seems to me to be the problematic paradigm of new medical technology, and a significant driver of our ever-higher health care costs.

What do you think?

1 thought on “The New Paradigm

  1. considering the blase attitude that doctors often have towards the side effects of statin (statin toxicity), I don’t think that this will help patients that much. You asked excellent questions that need to be answered.

    My PCP that I got in Oct. was very happy, as unlike the 3 previous PCPs she got my TSH up and my BP down. It just took her reading the labs, and making adjustments to my thyroid hormone supplement, and some kindness on her part. She decided that it was time to make me a compliant patient, so she could meet her patient quota of preventing diabetes and cholesterol diseases. I won’t even take those tests.

    The PCP that poisoned me with statin for prevention and his compliance in the war, at least had the decency to put statin in my EHR as an allergy with seizures as a side effect. I took 10 mg once a day of Simvastatin. In 90 days, I had BLACK urine- not blackish- black like India ink. I also had cramps, seizures, swollen ankles, my Achilles tendons were affected, and the right one ruptured, headaches, constipation, blotchy sores on my face and in my mouth, great pain in my joints, spells of dehydration. peripheral neuropathy up past my knees. I didn’t write well, and I lost my ability for line and copy editing. I still have fatigue. The look on her face was horrible, as she read the EHR.

    Then my ENT requested that a scan check my plaque. None on the left side, and negligible to minimal on the right side. His nurses told me that I was 72, and I didn’t have chronic pain-well-no treatment for that, no sleeping pills- only stomach and GERD meds, and my thyroid hormones. They said that I’ve done a good job of taking care of myself-and don’t let the doctors bully me anymore.

    A French friend, in the Sudan, recommended that I eat a small amount of potato chips each day, hydration salts, like he gave to refugees. It’s amazing how my body started straightening out. I began flooding my body with water and cranberry juice, when I saw the black urine, and while it flushed out my kidneys, my electrolytes were messed up.

    I had a specialist that also suffers from statin toxicity. He asked me why I had turned down all sorts of meds for the neuropathy. I told him that meds caused this- so I didn’t see how meds would cure this–He sent me to PT, and I did hamstring exercises and packed my legs with ice 4 times a day. I got over that. I have feeling in my feet- not pain. My Achilles do get tired rather quickly,

    Thank you for listening to me.

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