The discovery of PCSK9’s role began in 2003 when researchers identified gain-of-function mutations in the PCSK9 gene in French families with familial hypercholesterolemia, a condition that causes dangerously high cholesterol from birth. Shortly after, scientists discovered the flip side: people with loss-of-function mutations in PCSK9 had remarkably low LDL cholesterol and dramatically reduced cardiovascular disease risk.
In one landmark 2006 study, participants with these protective mutations had 28% lower LDL cholesterol and an 88% reduction in cardiovascular disease risk.
This genetic evidence was so compelling that it launched a pharmaceutical race to inhibit PCSK9- and remarkably, the first drugs were approved just 12 years after the initial discovery.
PCSK9 Inhibitors prevent PCSK9 from doing its job, which in turn increases the number of receptors available to clear cholesterol, lowering LDL levels. Statins work through different mechanisms by inhibiting HMG CoA reductase as well as other effects. Together the two classes of drugs are synergistic when used in combination.
The PCSK9 longevity gene- therapeutics, heart health, brain health, and supplements
There are some oral PCSK9I drugs under development. I’m looking forward to these as injections are inconvenient.
Enlicitide decanoate (MK-0616), developed by Merck, is a promising oral macrocyclic peptide that has shown significant LDL-C reduction in Phase IIb trials and is currently in Phase III clinical development.
AZD0780 is another oral small molecule PCSK9 inhibitor in Phase II trials that has demonstrated robust efficacy in lowering LDL cholesterol levels.
Other oral candidates, such as DC371739 and CVI-LM001, are also being investigated in earlier phase clinical trials.
The question is, with an APOB of 58, is there any reason to use a PCSK9I to lower it further? Or replace the statin? (5 mg Atorvastatin)
Great news that it was sorted! CTO is not the worst thing, since at least it was stable. But that’s definitely a warning sign of a tendency to build plaque.
I assume they gave you medication to take? (Plavix?)
In 2025, the speaker’s biological age was calculated to be 35.4 years, which is 17 years younger than their chronological age.
The biological age clock, known as pheno age, has its limitations, particularly in its exclusion of cardiovascular disease biomarkers.
Despite this limitation, pheno age is still significantly associated with cardiovascular disease-related mortality, showing a 10% increased risk of death for every one-year increase in biological age.
The speaker intends to analyze their blood test data over the past decade, particularly focusing on cardiovascular disease biomarkers.
Blood Testing Process
The speaker uses altabtest.com to select specific blood tests, which are then processed at Quest Diagnostics.
Results are typically received within five days of testing, allowing for timely analysis.
The speaker emphasizes the importance of frequent testing, averaging six times per year to gather more accurate data over time.
Lipid Panel and HDL Analysis
The speaker’s HDL level was measured at 60 milligrams per deciliter, which falls within the optimal range of 50 to 69 milligrams per deciliter.
Cumulative testing shows that the speaker has maintained an average HDL level of 58 milligrams per deciliter over 19 tests spanning three years.
The speaker previously averaged 45 milligrams per deciliter over 44 tests, indicating a significant improvement in HDL levels.
APO A1 is noted as a potentially better predictor of cardiovascular disease mortality risk, and the speaker has been monitoring this biomarker as well.
APO A1 Measurement
The reference range for APO A1 is above 115 milligrams per deciliter, with an optimal range suggested to be between 150 and 180 milligrams per deciliter.
The speaker’s current APO A1 levels are flagged with an orange arrow, indicating they are below the optimal target.
A strong correlation (0.95) between APO A1 and HDL levels in the speaker’s data suggests that measuring both may not be necessary.
The speaker aims to achieve an optimal HDL level of around 67 milligrams per deciliter to simultaneously optimize both biomarkers.
Lipoprotein Analysis
The speaker discusses the importance of lipoproteins containing APO B, including VLDL, lipoprotein A, and LDL, in assessing cardiovascular risk.
APO B levels below 90 milligrams per deciliter are considered good, with less than 70 being optimal, particularly for those without pre-existing conditions.
The speaker’s APO B level was measured at 59 milligrams per deciliter, which is favorable according to their interpretation of the literature.
The speaker emphasizes that diet and exercise, rather than medication, have contributed to their favorable APO B levels.
Lipoprotein A and Cardiovascular Risk
Lipoprotein A levels for the speaker were measured at 81 nanomoles, which is outside the normal range, indicating a potential risk factor for cardiovascular disease.
The speaker has a history of variable lipoprotein A levels, with past results ranging from 70 to 145 nanomoles.
The speaker notes that lipoprotein A is resistant to reduction, but they are working on finding effective methods to lower it.
High-sensitivity C-reactive protein (hsCRP) levels were significantly lower than the threshold associated with increased cardiovascular disease risk, suggesting a favorable outcome.
Triglycerides and VLDL
The speaker’s triglyceride level was measured at 78 milligrams per deciliter, which is within a generally acceptable range but higher than their optimal target of less than 45 milligrams per deciliter.
Over 63 tests in the past decade, the speaker’s average triglycerides were 60 milligrams per deciliter, although recent tests show a slight upward trend.
The speaker expresses concern about the implications of rising triglyceride levels on cardiovascular health as they age.
LDL Levels and Optimization Strategies
The speaker’s LDL level was measured at 57 milligrams per deciliter, which is considered low and could be associated with increased coronary heart disease mortality risk.
The speaker aims to balance their lipid profile by potentially allowing for a higher LDL level while decreasing lipoprotein A and triglycerides.
The speaker emphasizes the importance of tracking multiple biomarkers together to achieve an optimal cardiovascular health profile.
Dietary Correlations with Biomarkers
The speaker tracks dietary intake meticulously to analyze correlations between diet and biomarkers, specifically lipoprotein A.
There is a significant positive correlation between net carbohydrate intake and lipoprotein A levels, indicating that higher carb intake is associated with higher lipoprotein A.
The speaker has reduced their average daily net carb intake in hopes of lowering lipoprotein A levels in future tests.
Total fat intake showed an inverse correlation with lipoprotein A, suggesting that higher fat intake may help lower lipoprotein A levels.
Future Testing and Monitoring
The speaker plans to conduct another blood test on October 27th to assess the effects of dietary changes on their biomarkers.
New Pill From Merck Could Slash Cholesterol Levels, Trials Show
The drug targets the PCSK9 protein, and could give millions of people a more affordable option to reduce their heart disease risk.
Merck, the company that introduced statins to the world nearly 40 years ago, has a new, intensely powerful pill that can slash levels of dangerous LDL cholesterol to levels almost never seen in adults.
The new pill, enlicitide, blocks a liver protein, PCSK9, that slows the body’s ability to clear cholesterol. With most PCSK9 blocked, LDL levels plummet and rates of heart attacks and strokes in high risk patients fall by up to 20 percent in just the first year.
At least six million adults in the United States are eligible for drugs that block PCSK 9.
Merck’s head of research said the goal is to make the pill affordable. It would be an alternative to expensive biweekly or monthly injections of monoclonal antibodies that do the same thing. But only around one percent of eligible patients take the injections, which include Praluent by Regeneron and Sanofi, and Repatha by Amgen. Many patients don’t want to inject themselves, and insurers put up obstacles to paying, cardiologists say. The drugs’ list prices are more than $500 a month.
Multiple studies over the years have shown that the lower the LDL level, the better — heart attack and stroke rates drop as LDL levels fall. And there appears to be no downside to having an astonishingly low LDL level, including one in the teens or twenties. Adults who are not taking cholesterol-lowering drugs usually have levels above 100.).
“Lower is better for sure,” said Dr. Daniel Soffer, a cardiologist at the University of Pennsylvania.
It’s going to be interesting to see the pricing (and prescription requirements… do you need to “fail” on a cheaper statin before they’ll pay for a PCSK9 Pill?).
In theory the market for pills is much, much larger than the injections (people hate injections, generally) and they have refrigeration requirements. So the price can be much lower and still generate vast revenues… we’ll see.
Whatever. I’ll just wait for those pills to become available in India, one way or another. India has a truly epic size problem with CVD. The government will make it a top priority to get ahold of these meds by hook or by crook, patents be damned. And when they become available, I’m placing my order. I have zero faith in the insurance industry in the US, their willingness to cover them unless you’re on the verge of death if not actually clinically expired, or the pharma companies and PMBs marketing them at anything less than the price of your first born. I have no desire to deal with obstinate doctors, ghoulish companies and other bloodsuckers along the chain. Order from India, done. First however let’s wait until the drugs actually come out and then hit India. Then we’ll talk. YMMV.
I actually disagree. I think the fat jabs show that people aren’t as resistant as you think. Repatha and Praluent are both simple “click pens” which you can do at home.
I think the problem is simply the cost. Antibodies generally cost a lot more to manufacture, since they need to be made by living cells, then purified etc. It’s a big industrial process. By comparison, small molecules can be made by mixing ingredients in the lab.
Still, the overall biggest factor is that price gouging in the US healthcare system, because a Repatha injection might cost $150 in other parts of the world. Not “cheap” but nowhere near as pricey as in the US.
Cronos, I just learned from you that CVD is a particularly bad problem. Do you know what this is attributed to? They don’t eat much cow, but of course they are consuming dairy and other animals. This fact only just leads me to guess their issue is not due to consuming more sat fat, but?
And ARGH on US health insurance. @relaxedmeatball I qualify for repatha and got the pre authorization blah blah blah…. But alas, it’s still subject to my 8k deductible, so I pay for it. Fortunately, repatha offers coupons. For years, it only cost $5 a month, but a couple years ago they started to cap it to a 3k coupon benefit max per year. Still nice, but it doesn’t make me any less bitter
As popular as the injections are now, I think you’ll see how many people have been holding out for a pill once orforglipron (small molecule GLP-1 agonist, no food/water restrictions for absorption) hits the market next year. Eli Lilly already has manufactured literally billions of tablets in preparation for its release, and they pretty much know what they’re doing.
From what I remember (years since I listened), the guest stated that Indian origin people tend to accumulate a lot of visceral fat, tend to not have much muscle mass, and aren’t particularly “athletic” in general. (Side note: consider Indian athletes, Olympic Games performance etc). He posits that they simply don’t handle high calorie diets very well, and they store lots of fat around organs, lots of fat inside muscle tissue etc. So basically they get insulin resistant and get lots of inflammation very easily.
Attia starts the podcast by talking about a patient of his (South Asian) who had insulin resistance that the usual approaches weren’t fixing.
@relaxedmeatball has it. There is a genetic component in the South Asians that predisposes to the TOFI phenotype (Thin Ouside Fat Inside), so already at a BMI of 21 you can have metabolic derangements leading to diabetes and CVD. The diet is problematic, because it’s pretty far from traditional these days, calories are much higher and a ton of regional cuisines have unhealthy components like high levels of SFA, and in the urban setting fried food, fast food and processed foods and sodas. And many urban Indians don’t exercise much or do anything near enough to burn all those excess calories.
The result is a diabetes and CVD epidemic. And while incidence matters, it’s the absolute numbers that are the problem - India has recently overtaken China as the most populous country on earth. There are now tens of millions who are at risk of CVD or already suffering from it. And it’s getting worse, with childhood obesity rising rapidly, setting up a huge challenge for generations to come. Education and lifestyle changes are always going to be a hard path. You’re going to have to add a pharmaceutical component to tackle this, and it has to be affordable for the population. So they’ll follow their playbook when it comes to CVD and diabetes drugs, and scour the world for the most effective drugs that can be easily replicated and either strike a deal with the original manufacturer/marketer, or make a knockoff for the domestic market. That if course is greatly facilitated by a giant pharma industry where generics are made and where a huge amount is also produced as subcontractors for Western pharma companies. That’s where we come in, placing our orders. CVD is not an exotic collection of pathologies, so odds that a drug that’s proven to be safe and effective will eventually appear in India is high, and it should be relatively affordable. We’ll see.
I don’t know. I use repatha every two weeks with the Sureclick pen and it hurts like a MF. I am no stranger to all sorts of injections, and that one I always dread. Its a pretty big volume and a fast flow, so that doesn’t help.
