In this video, the presenter critically examines the recent New England Journal of Medicine randomized, double‑blind, placebo‑controlled trial of the PCSK9 inhibitor evolocumab (Repatha). He begins by contrasting sensational headlines that claim a 25% reduction in heart attack and stroke risk with the nuanced reality of the study. He explains PCSK9 biology and how its inhibition lowers LDL‑C and ApoB, then clarifies the distinction between primary and secondary prevention, noting that the trial enrolled high‑risk patients—most already on statins, many with diabetes, hypertension, obesity, and existing cardiovascular disease—so the “primary prevention” label is misleading. He details the trial’s size (12,257 participants), primary composite endpoint (MACE), relative risk reduction (25% HR 0.75) and absolute risk reduction (1.8%), lipid‑lowering results (LDL from 116 → 45 mg/dL, ApoB halved, modest triglyceride and Lp(a) changes), and safety (no significant differences). He flags the industry funding by Amgen as a conflict of interest. The presenter then compares PCSK9 inhibitors to statins, arguing that statins have metabolic downsides (insulin resistance, diabetes risk, mitochondrial effects) while PCSK9 inhibitors have fewer muscle or brain side effects and also lower Lp(a). He states his personal preference for PCSK9 inhibitors over statins. The discussion expands to broader themes: the over‑reliance on drugs for a population that is “fat and sick,” the need to address lifestyle, nutrition, and metabolic health, and the emergence of a new oral cyclic peptide that mimics PCSK9 inhibition. Throughout, he promotes his “Stay Curious Metabolism” newsletter and a collaborative “Heart Health Map” project. The overall message is that evolocumab is a valuable tool for high‑risk patients but is not a cure‑all; true cardiovascular health requires systemic lifestyle changes beyond pharmacology.
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Hidden in this little bottle might be the cardiology breakthrough of the year. Breakthrough! Breakthrough! Breakthrough! Breakthrough! But before we get to this little bottle, and I promise we will, I want to talk to you about a huge new cardiology trial that just dropped. One that the media and experts are calling a breakthrough. A massive breakthrough that will save lives. The headlines ran: PCSK9 inhibitors, which are the bazookas of modern cardiology, they can reduce risk of heart attack and stroke by 25%, including in those who have never had a heart attack or stroke before. Now, when I saw these headlines, I truly was hopeful. But then I opened the actual paper, and that's where things got complicated because it's only a half-truth. And the other half, the one that didn't make the headlines, it's the difference. It's the difference between life on medication and life without. Between a population that is sick and obese and one that's truly healthy. So in this video, we're gonna dig into the nuances. What the headlines don't show you, because this story is far more complicated and interesting than headlines suggest. I wanna open with a promise. These bazookas of modern cardiology is like a guy flexing to a girl at a bar that he's a millionaire, but failing to disclose that he's actually playing with Monopoly money. We keep on innovating ways to smash LDL and ApoB lower, but there's a new innovation that changes the game there. Most of us are sick and fat. The solution isn't in a pill. Health is not built in a pharmacy. And I use them intentionally to get a rise. The foundations of health that drugs can't replace. Now, despite the flashy and hopefully entertaining introduction, which was engineered to get you right where I want you, here and ready to learn, I want to open with a promise. This isn't going to be a shallow gotcha piece. My goal here, as it is always, is to provide a balanced and thoughtful assessment of the latest findings, to shine a spotlight where it doesn't normally get shown, and, just a self-plug, after watching this video, if you're hungry for more knowledge and nuance, I'll flag you can find this in the associated Stay Curious Metabolism newsletter, linked below. There, I include deeper discussions of other medications, the invention of a fascinating cyclic molecule, a cyclic peptide that slashes LDL and ApoB, and what I'm doing myself, an experiment I've been running. But with that, let's get on with these data. The major newsworthy item I want to discuss centers around a double-blinded randomized placebo-controlled trial, a gold standard in modern medicine, recently published in the top clinical medical journal in the world, the New England Journal of Medicine. Now, the headline finding went that evolocumab— I know, long jargony word, it's a PCSK9 inhibitor marketed as Repatha, maybe you've heard that drug name— it was shown to reduce the risk of major adverse cardiovascular events, like heart attack and stroke, by 25%, and importantly, improved outcomes in individuals without a prior heart attack or stroke. In other words, primary prevention. So what is a PCSK9 inhibitor anyway? How do these drugs work? Well, PCSK9 itself is a protein produced mainly in the liver, but other places as well, that binds to LDL receptors on liver cells. These are the same LDL receptors that clear LDL particles and cholesterol from your blood. So when PCSK9 binds to an LDL receptor, it promotes the receptor's degradation. You can think of it as, if the LDL receptor were like paper, PCSK9 throws it in the shredder. Thus, by inhibiting PCSK9 with these drugs, these PCSK9 inhibitors, these bazookas of modern cardiology, it prevents the LDL receptor from being degraded, leading to more LDL receptors, leading to more LDL and cholesterol pulling out of your bloodstream, thus plummeting your LDL cholesterol and ApoB levels. And I'll get on Lp later if that's something of interest, I promise. Anyway, I promise the data is worth the wait. I'm going to get to that in a moment. Hold on with me for just one more moment while I tell you something else that is critically important: the difference between primary prevention and secondary prevention. Primary prevention refers to reducing cardiovascular risk in individuals without a history of heart disease, heart attack, or stroke. And secondary prevention targets those who have already had events like heart attack and stroke or who have cardiovascular disease established in their vessels. Now, and this is important, these results were touted by headlines as massive news because they proved a benefit for primary prevention. That's new. Maybe. But here's the nuance that was missing, and it really matters. This trial was not in low-risk patients. It wasn't even really a primary prevention trial. In fact, the trial's registration The title itself, "The Effects of Evulocumab"—this PCSK9 inhibitor—in Patients at High Risk of Cardiovascular Disease, makes that explicit. These were high-risk patients. To qualify for this trial, participants actually had to have—this was inclusion criteria—at least one of the following: coronary artery disease already established, or vascular disease, or high-risk diabetes. And at baseline, 87% of participants were on statins, 59% had diabetes, 27% were smokers, 87% had high blood pressure, and the median BMI was 30, indicating that half of participants had obesity. So to be crystal clear, this was not a study on healthy, low-risk individuals. Some doctors, and AI for that matter, would even argue that this wasn't a primary prevention trial after all, since many of the participants had evidence of preexisting cardiovascular disease. In fact, established cardiovascular disease was literally an inclusion criteria in this study. So naming this a primary prevention trial in the headlines without these extra details is like a guy flexing to a girl at a bar that he's a millionaire, but failing to disclose that he's actually playing with Monopoly money. Now, with all that behind us, let's actually look at what the trial showed. This was a double-blinded randomized placebo-controlled trial that enrolled 12,257 participants, who were then randomized to have the drug, the PCSK9 inhibitor called evolocumab, or a placebo. Now, the primary endpoint was a composite score of death from heart disease, heart attack, or stroke. This is clustered as the major adverse cardiovascular events, MACE, or 3-point MACE. And the results were impressive. They showed a 25% relative risk reduction, so that's a hazard ratio of 0.75, that's what that means. And in this case, the absolute risk reduction was from 8% of events in the placebo group to 6.2% of events in the treatment group, the PCSK9 inhibitor group. So a drop of 1.8%. Now, 1.8% is smaller than 25%, but these are major outcomes, so I wouldn't dismiss that out of hand. It's still meaningful. And in terms of lipid-lowering effects, in a substudy of 2,000 participants examining the detailed lipid-lowering patterns after 48 weeks, the findings were as follows: LDL dropped from 116 to 45, ApoB was halved from 102 to 52, HDL cholesterol remained stable, triglycerides dropped a bit from 160 to 136, and lipoprotein little a, Lp, did drop from 34 to 19. So yes, for those interested, Lp did change, and if that's of interest, I have much more on Lp that I'm linking below. Anyway, as for safety, The trial's safety assessment found minimal side effects, with no differences between the treatment group and the placebo group. Now, take that with a grain of salt if you want, because as a nuanced note, this was an industry-funded trial, supported by Amgen, the manufacturer of the drug in question. As with all industry-sponsored research, financial conflicts of interest— I don't think they negate the results, but they should be transparently communicated, so you can take that for what it's worth. So, wrapping up, where does this leave us? At a high level, I think a fair and balanced summary is as follows: this trial demonstrates that the PCSK9 inhibitor, evolocumab, it does improve cardiovascular outcomes in high-risk patients—patients with pre-existing cardiovascular disease or high-risk diabetes. However, this paper, these headlines, provide no data on risk reduction in low-risk, otherwise healthy populations. That is a qualification, an important one, but not a dismissal. So to recap, the drug works, but the context is being oversold. That said, we've only just begun because there's a lot more you need to know. So now I want to pivot and compare these drugs, these bazookas of cardiology, the PCSK9 inhibitors, to statins, frontline therapy, and I'll tell you which I'd choose if I needed to. And why. So, statins. Again, they're frontline therapy for high cholesterol. But, in my opinion, they have significant— not in my opinion, the data show they have significant downsides. As we've previously reviewed on this channel, this includes causing insulin resistance, lowering GLP-1 levels, harming mitochondria, and raising diabetes risk. I'll link more below if you want those details. These are not trivial considerations. Now, that doesn't make statins or any other drug "bad" per se, but it does mean they come with a constellation of physiological consequences that should be acknowledged and often aren't. Now, PCSK9 inhibitors, by contrast, I think they offer several noteworthy advantages. First, they tend to lower LDL and ApoB more, anyway, if that's a goal. Second, PCSK9 expression, that protein, is concentrated in the liver, with minimal expression on muscle, nearly undetectable, which theoretically limits the muscle-related side effects which are present in statins. And while PCSK9 is also expressed in the brain, the antibodies that constitute these PCSK9 inhibitors, they don't cross the blood-brain barrier. They're huge, so they can't. So to the best of my knowledge, thus the theoretical risks on the brain, I think are lower for PCSK9 inhibitors than statins on balance. There is a lot more nuance here, and if you want that, you can check out the newsletter comments for those. Anyway, Another differentiating point between statins and PCSK9 inhibitors is that the PCSK9 inhibitors tend to lower Lp levels, another risk factor for cardiovascular disease, where statins often increase them. Thus, on balance, if I had to choose between one of these two classes of lipid-lowering agents myself, the statin or the PCSK9 inhibitor, I personally would choose the PCSK9 inhibitor over the statin. And for what it's worth, I also discuss the mechanisms of action, pros and cons of other medications and supplements azetamide, bempedoic acid, and berberine in the newsletter below, along with what I'm doing myself in terms of lipid-modifying therapy as an experiment, and I talk through a second breakthrough—a cyclic peptide—this bottle—that does the same as the normal PCSK9 inhibitors but can be taken by mouth rather than by injection, which currently is one benefit of statins over PCSK9. Normally PCSK9 inhibitors are injections, but there's a new innovation that changes the game there. I'll link more context below, but let's summarize. These breakthroughs, the headlines, they come with massive and obvious caveats. And for me, the recurring point of disappointment is how these conversations unfold. There seems to be a growing acceptance that our population is, to put it bluntly, fat and sick, and that we need to design our solutions with that constraint. The narrative becomes, Since we can't fix obesity and the food ecosystem, let's just optimize for drugs. But cardiovascular disease? This is a fact. It remains a world's leading killer. Not simply because we aren't lowering LDL or ApoB enough—we keep on innovating ways to smash LDL and ApoB lower—but because we continue to ignore and under-address the metabolic dysfunction that is the root of cardiovascular disease and other metabolic health disorders. And while PCSK9 inhibitors are valuable tools, they're not the solution to poor metabolic health. The solution isn't in a pill, but in the hard, slower work of addressing lifestyle, nutrition, and movement in the food ecosystem—the foundations of health that drugs can't replace. This broader conversation is a harder conversation, but I'd be remiss if I didn't say this out loud, and I know many of you feel the same. Now that doesn't mean that these medications aren't breakthroughs. Again, I'm not trying to dismiss this paper, I'm qualifying it. These medications can save lives in the right patients because, to be frank, most of us are sick and fat. And I know those are jarring monosyllabic words, and I use them intentionally to get a rise, to point a spotlight, because my aim here, it's not to blame or dismiss, but to raise, via the tools I have at my disposal, the discussion that often gets dismissed by mainstream medicine. Health is not built in a pharmacy. It is built in daily lives by your choices. And my hope is that conversations like this sharpen our understanding, deepen our curiosity, expand our focus beyond numbers on a lab report to the systems and behaviors that actually drive long-term health. And as a final note, if you want much more infinite expanding knowledge, you can check out the Heart Health Map that I'm building with my partners at Hundred Health. Basically what we're doing is we're creating an intricate web, interconnected nodes where each one represents a unique piece of learning around heart health. Like this video will be a single node in the network. So check out the link there. Right now it's totally free to access. I wanna help with your learning and your input really helps develop this intellectual ecosystem we're building around nuance and curiosity that goes beyond the shallow headlines. So stay curious and truly, Thank you for listening and being on board here with me. Peace.
