Harvard scientists studied why HDL increasing drug failed to deliver (istock image)& |  Photo Credit: Representative Image
- Two types of lipoproteins carry cholesterol to and from cells.
- One is low-density lipoprotein or LDL.
- One is low-density lipoprotein or LDL. The other is high-density lipoprotein or HDL.
When you get your Lipid Profile report, what do you lookup? Primarily, the levels of low-density lipoprotein (LDL) and high-density lipoprotein (HDL), of course! The lower (or within normal) the range of LDL and the higher (or within normal) the range of HDL — you feel like you have control in the game.
For decades, when it comes to heart disease risk, we have been tutored that the LDL can clog up the artery walls — and “good cholesterol,” or HDL helps clear cholesterol out of the system.
That is what sent scientists setting to work on interventionist drugs that can help in enhancing the “LDL-mopping” HDL. Michael Blanding writes in Harvard Health that recently, drugs have been developed that increase the amount of HDL in the blood, but disappointingly failed to reduce the risk of cardiovascular disease and were never brought to market.
(Michael Blanding is currently a senior fellow at the Schuster Institute for Investigative Journalism at Brandeis University and has previously been a fellow at the Edmond J Safra Center for Ethics at Harvard University; a senior writer at Harvard Business School.)
Blanding interviewed Harvard TH Chan School of Public Health researcher Jeremy Furtado who has co-authored a scientific paper in December along with Professor Frank Sacks, and colleagues. Jeremy Furtado explains why the drugs didn’t work and what the researchers discovered.
“In the middle of the last century, total cholesterol was an important biomarker used to assess heart disease risk. Then, in the 1970s and 1980s, researchers discovered that total cholesterol is actually made up of two very different systems, the LDL and HDL, with opposing relationships with heart disease risk,” Furtado told Blanding.
“Generally speaking, cholesterol in LDL is linked to increased risk while cholesterol in HDL is associated with protection against heart disease. More recently, our group here at Harvard Chan School found that within HDL there are different subspecies that have different types of proteins on their surfaces that make them function differently from each other in the body. Given these functional differences, why should we expect that they are all protective or operate the same way?
“Recently, we’ve been studying 16 out of the potentially 200 or so different protein-defined HDL subspecies and found that while some are associated with a reduced risk of cardiovascular disease as you’d expect, some show no association or are even associated with increased risk. In particular, we found that HDL that contains a protein called apolipoprotein C3 (apoC3) is associated with a higher risk of cardiovascular disease, including stroke and heart attack, and type 2 diabetes. We also found that HDL that contains Complement C3 or alpha-2-Macroglobulin (α2M) is also associated with higher risk. HDLs that lack these proteins are more protective than total HDL. Conversely, HDL that contains apolipoprotein E (apoE) or apolipoprotein C1 (apoC1) is more protective against heart disease,” Furtado told Blanding.
Blanding then asked him about how in the study, the researchers at Harvard looked at a class of drugs called CETP inhibitors, specifically evacetrapib (Eli Lilly) and torcetrapib (Pfizer). “What happened to cholesterol levels and cardiovascular disease when people took these medications?” Blanding asked Professor Furtado.
“CETP is a protein that moves cholesterol from HDL into LDL, so these CETP inhibitor drugs increase HDL cholesterol. While they succeeded in this, phase three clinical trials showed that there wasn’t a significant decrease in cardiovascular disease outcomes, including heart attack.
CETP inhibitors designed to increase “good” cholesterol: Did they work?
“So CETP inhibition wasn’t having the intended effect of reducing mortality and heart disease. The failure of these trials and trials like them, coupled with other studies that showed that naturally occurring genetic mutations that resulted in high HDL cholesterol also did not confer any protection against heart disease, implied to some that HDL was not truly an actor in the disease.
“Our hypothesis was that maybe the different protein-defined subspecies have different relationships with the disease, some bad and some good, and perhaps these drugs didn’t work because even though they increased overall HDL cholesterol, it was the bad kinds that went up.
Shocking discovery: The worst kind of HDL showed a sharper increase!
“And, in fact, we found the types of HDL that went up the most were the ones that were the worst, including those that contained apoC3,” Professor Jeremy Furtado replied.
Blanding asked the Harvard researchers if the pharma companies could retool these drugs or other things that people can do to increase their good cholesterol.
Professor Furtado explained: “One of the most important things to come out of this study is to underscore the need to learn more about HDL subspecies to find out what functions these proteins perform. HDL isn’t just a cholesterol transporter. It also has anti-inflammatory, antioxidant, immunological, and other actions that affect disease risk.
Not the end of the road: More research on, Good news soon!
“We need to find out which HDL subspecies are protective and which ones are detrimental. Once we know that, we can work to produce therapies that will target increases of the good types of HDL or reductions of the bad.
“And it’s not just drug therapies. Our group will soon publish new research on the effects of healthy diets associated with reduced risk of heart disease that increases HDL cholesterol and does so by increasing the good HDL subspecies and not the bad. Stay tuned!” said Professor Furtado.
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