Wednesday, June 10, 2015

PCSK9 inhibitors and upper limb amputations

Another one liner, this time from Heartwire:

The two new drugs, both of which are proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, effectively lower LDL-cholesterol levels.

"If you're a cardiologist, you must not have a pulse if you're not excited" about the potential availability of the two new agents, Dr Amit Khera (University of Texas Southwestern Medical Center, Dallas) told heartwire from Medscape.

"For those of us who take care of patients with familial hypercholesterolemia [FH], this is just an amazing option," he said. "I know this seems like a small group of patients—one in 500—but it's really not all that small. There's also the advanced coronary artery disease patient who still has high lipids. It almost seems arcane in this modern era that we're just watching patients who have recurrent events and our hands are tied. I think this offers an incredible option for those people."

The hands tied option which caught my eye. I’m not sure if it was Pat Wall or Ronald Melzack, writing about chronic pain, who came up with the gem that “The best surgeon to consult for a chronic pain problem was one who had no arms”.

Nothing changes. We’ll have to wait to see the body counts.



Unknown said...

"Many panel members, including chair Dr Robert J Smith (Alpert Medical School of Brown University, Providence, RI), did not agree that LDL-C lowering is sufficient for establishing effectiveness for reducing CV risk. "I just don't think it predicts clinical outcomes. I would need to see the clinical outcomes," he said."

"Overall, the committee agreed that there were no major risk "signals," but many voiced concerns that these could develop into something stronger with broader use. This included events involving glucose control, liver, and unstable angina—especially because there are currently no data on long-term exposure."

"Another question brought up was whether alirocumab will increase risk of diabetes, based on concerns whether statin use was associated with diabetes risk in the JUPITER trial. Although there has been no strong evidence so far of this for alirocumab, a representative for Sanofi noted that a CV-outcomes study will need to be done to officially rule this out—and noted that that is one of the things that ODYSSEY-Outcomes will examine. That trial is reported to complete enrollment by the end of this year, with results scheduled to be released by the end of 2017."

Unknown said...

To Peter's 'body count' point, this from cholesterol non-skeptic Gina Kolata today in NY Times:

"The F.D.A. usually follows the recommendations of its advisory panels, but not always. The agency says that if it approves the drugs based on their effects on cholesterol, the approval will not be rescinded even if trials now underway fail to show the drugs reduce the risk of heart attacks and deaths."

Raises the fun specter of these drugs killing lots of folks in the trials yet retaining approval because "...the approval will not be rescinded..."

Ash Simmonds said...

@Matt - that simply means the patients weren't taking enough of their drugs, or were supplementing their diet with too much evil saturated fat and red meat.

Red Sphynx said...

But we already have outcome data on PCSK9 inhibitors. Look at Naveresse et al's meta-analysis of 59 PCSK9-inhibitor human trials, . Results? Big decreases in all-cause mortality, cardiovascular mortality, heart attacks.

Skepticism is always warranted, but you have to at least address the most compelling evidence out there.

Actually, statins are PCSK9 *promoters*, so the PCSK9 inhibitors, when co-adminnistered with statins, are undoing some of the harm of statins.

As for me, I'm real interested in trying the PCSK9-inhibitors. But before I get injected with monoclonal antibodies, at $10000+/yr, I think I'll give berberine a try. It's only about $350/yr, and it is a PCSK9-inhibitor, too. Plus it also loweres my insulin resistance.

Boundless said...

re: I think I'll give berberine a try.

Suspect gut biome antagonist (antibiotic), possible adverse metabolic and immunological consequences for chronic use. An LC doctor, on a subscription forum, is highly suspicious due to the majority of glowing studies on it being from China. Another responder on another forum claimed that even traditional Chinese medicine advises that it's for temporary use.

But Dr. Oz endorses it, so there's that.

Peter said...

Red, yes, it will be fascinating if a cholesterol lowering drug is found to have an all cause mortality benefit. The mechanism would have to be very unanticipated, but these things do happen occasionally! I'm not suggesting the benefit will be found for PCSK9 inhibitors, but I guess it's not completely impossible. I think the J-LIT study picked up the excess cancer deaths in patients with TC below 160mg/dl, at a RR of 3.16 at 6 years and the elevated risk was unchanged at 10 years. And the RR of cardiac death was 6.23 at 6 years. These hiccups may not have been evident at a year... We'll see.


karl said...

This one is quite personal to me (Quad CABG - LP(a)), I was encouraged to be part of this study. I don't have FHC. I turned it down. To many possibly hidden risks

Part of this makes my head hurt. We know that the statins have many effects beyond lowering cholesterol - in particular lowering some inflammation markers. Death by all causes is still a disappointing number for Statin users.

Then there is the trouble with other drugs that lower Cholesterol that don't help - which means the theory of using cholesterol levels as a treatment proxy HAS to be wrong.

My best understanding at present is it is NOT LDL, but rather oxLDL that matters - (immune system misidentifies as a bacteria to engulf). There are other ways to reduce oxLDL.

The cholesterol mantra has been repeated too many times out of confirmation bias. We did not evolve LDL to cause CAD.

spfldo said...

Red Sphynx, interesting that berberine is a PCKS9 inhibitor. I tried that stuff for a short period of time. It did lower my TC number some, maybe 10% or so as I remember, but most of the reduction was in HDL. The "good" cholesterol. I'm a prime candidate for PCKS9, with FH type IIa and a TC of 417, give or take, and statin intolerant. My cardiologist, a man I respect and one who is anything but the typical cardiologist has been recommending it for me. I think I'll wait and see, because as Karl says, I think oxLDL is a more promising avenue to pursue.

cavenewt said...

I'm on Peter Attia's email list, and today this one came over the transom:

"In the world of lipidology, remarkable stories about a remarkable therapy: PCSK9 inhibitors. From the early clues provided by the hyperfunction of this proprotein convertase (i.e., a family of proteins that activate other proteins) in gain-of-function mutations in the PCSK9 gene linked with hypercholesterolemia — to the flipside — rare people with loss-of-function mutations linked with big reductions in CHD risk, and low cholesterol levels, particularly LDL-C. How low? Around 15 mg/dL! What might be more remarkable is how quickly everything has unfolded. PCSK9 was unheard of prior to the 21st century (2003, in fact). It’s humbling and heroic (and, currently, expensive). To witness these kinds of scientific insights translate into effective treatments in little over a decade almost feels superhuman. But it’s also as if biology is looking at us, winking, as if to say, ‘you have no idea just how little you know about me.’"

I would not have thought of Attia as being a fan of LDL-lowering drugs. Perhaps I'm misreading his comments. But if not, the final sentence takes on some unintended irony.

The article in Circulation Research that Attia is raving about is at Currently the fulltext is available.

Peter said...

Cave, Peter Attia has always come over as a true cholesterol believer, absolutely. I stopped reading him years ago as I couldn't see any insight coming that sort of mindset. I had Dr Davis in the same camp when he was saturophobic but I have the feeling he has reformed from saturophobia. But I've no idea what he thinks about LDL nowadays...