A recorded monologue (YouTube transcript) by Jeffrey Bland, PhD reviewing evolving research on dyslipidemia and lipid-modulating therapies. He critiques the simplistic view that lowering blood cholesterol always reduces vascular disease risk, highlights reports of higher-than-expected statin-induced myopathy (24–50%), genetic susceptibility related to CoQ10 and membrane transport SNPs, disappointing results with CETP inhibitors, complex findings about triglyceride-related SNPs versus animal models, and raised caution about expensive PCSK9 inhibitors lacking long-term clinical outcome data.
Chapters
Dyslipidemia. What an incredible topic of controversy this has been in medicine all these many years. Dyslipidemia, dysfunctional lipids floating around the body. So we started off, didn't we, thinking that high cholesterol was the major risk factor and if we could just block the synthesis of cholesterol in a rate limiting way through the inhibition of hydroxymethylgluteril, coenzyme A, HMG CoA reductase, that we could then affect a positive outcome in lowering the incidence of vascular disease, the major killer diseases in our society. And that model led ultimately to the development of a whole range of compounds that came out of fungal metabolites, starting with Lovastatin, Mevacor and ultimately moving on into a whole family of other statin related molecules. Some are more fat soluble than others. And we started to develop this wide body of clinical expertise, experience and probably the most studied drugs in the history of pharmacology. And also those that were the most profitable drugs for a long period of time, the number one sellers and the number one driver of profit for the companies that had these drugs in their arsenal. Now, however, we're starting to take a deep breath because new information is coming in. First of all, what about statin induced myopathy? We were told that this is very infrequent and is not something to worry about in the general sense, that only a small percentage of people end up with and these very serious muscle problems. But there was still the report from clinical anecdote of no, there's a lot of these chronic muscle neuromuscular problems that occur with statins. So lo and behold, what do we find? A study has just been done, published, and yes, it is true that there's a lot more statin induced myopathy than was previously thought. Somewhere between 24 and 50% of people on various statins end up with these neuromuscular symptoms. So that's number one. Number two is we found that there were certain genetic types, and I spoke about this In a previous September 2015 little video blog, that are more genetically susceptible to myopathy from statins. These are people that have the genes that are SNPs and are related to coenzyme Q10 and membrane transport uniquenesses. And if they have a slow CoQ10 synthesizing SNP, then they are more susceptible to statin induced myopathy. So those are people that should probably take more CoQ10 and are more concerned about statins, particularly these more fat soluble, lipid soluble statins and now we have a new report, and this new report is the third report of its type around what are called cholesterol ester transport protein inhibitors, CETP inhibitors that dramatically lower cholesterol in the blood and do so in ways that modulate the way that cholesterol is packaged into its little carrier molecules, things like VLDLs, IDLs, LDLs and HDLs. And we find that these CETP inhibitors actually reduce the amount of cholesterol that's found in one of those packages, the HDL molecules, so they change the density of hdl. So what are the results of this most recent study? Well, for the third time now with the CETP inhibitors, it's found the results are not good. Yes, they dramatically lowered the cholesterol in the blood, but they were associated with increased incidence of heart disease. This is a similar thing that was seen with Perceptipid in the trial with Pfizer just a few years ago. And therefore what we are starting to see is it's not just cholesterol in the blood, but it's how it's packaged and how it's transported. Then you add on top of this, another very interesting study that was just published recently about triglycerides in the blood. It turns out that there is a genetic SNP related to a specific protein that is involved with triglycerides metabolism. Finding that people had this SNP are individuals who were not breaking down their triglycerides as rapidly and not releasing the fats into cells as quickly, and they had a lower incidence of vascular disease, suggesting that maybe this would be a desirable characteristic. If we could block this particular process with a drug, we could produce the same positive benefit as people who have this genetic uniqueness. But yet when animal models were done in which they intentionally block this particular to lower their triglycerides and alter their metabolism, that lo and behold, they found that actually these animals ended up getting more fulminant problems with regard to vascular disease and early death. So now we start saying, well, is it really the fat in the blood that's the problem, or is it the form of the fat that's in the blood? Does it relate to how it's transported, how it's delivered, how it's ultimately metabolized? And once we start mucking around with this system, by synthetically modulating the level, by blocking something like statin drug does, or one of these other new forms of medication that modulate fat synthesis or fat metabolism, that we end up not producing a favorable effect. But maybe in certain individuals, an unfavorable effect. So that takes us to the last kind of part of this evolving story. What about these new PSCK9 inhibiting drugs? Now? Were you as surprised as I to see now on television and mass media these being advertised for the treatment of high cholesterol in the general population, when they're really been only approved by the FDA for a specific class of people that have very high cholesterol levels and.
Are statin resistant and cannot get their particular cholesterols down effectively. So it's a very small percentage of the population that would get these injectable PSCK9 inhibiting drugs that cost about $15,000 a year, I might add. And there is no Clin outcome trials yet available as to whether they actually do lower the incidence of vascular disease. They do lower lipids, cholesterol, and specifically LDL quite dramatically. But we don't know yet whether the outcome of these patients has been successfully improved in terms of vascular disease protection. And what we are learning is the more we futz around with this system, the more likely we are to produce an untoward or unexpected side effect. Because this is a very complex part of our metabolism. It's regulated by many hormones, regulated by various transport proteins, has a very significant role to play in cell surface physiology through signaling, and that cholesterol in and of itself is a very important precursor for many things like steroid hormones and cholesterol within membranes and bile salts. So all of this complexity sometimes weaves it down into what we think is a simple answer. Just block or inhibit a specific enzyme or a specific funct. So what's the story say to us right now? The story says if you can stay away from cholesterol modulating drugs, you're better if you have to take them. Take those that have minimum side effects, those that have longer term clinical outcome trials, and those that avoid these lipid solubility problems that are associated with the inhibition of coenzyme Q10, the myopicies that are often seen in 24 to 50% of patients, and that you then are on the safe side of the dose response curve. So, evolving story? Yes. As simple as we were told 20 years ago? No. And more. To learn about how to really modulate successfully using an effective functional medicine program, cardiovascular risk.
