r/ProactiveHealth

My last lipid panel came back with LDL of 60 mg/dL. That's sitting right on the line the new 2026 ACC/AHA dyslipidemia guideline drew for very-high-risk patients: <55 mg/dL. The guideline does not go lower than that.

My May 2026 lipid panel

That bothered me a little. The trial evidence keeps going lower. In FOURIER-OLE, the long-term extension of the evolocumab outcomes trial, achieved LDL kept reducing cardiovascular events all the way down past 20 mg/dL. Lower kept being better. So if 55 is good and 30 is biologically better, why did the guideline stop at 55?

The editorial that accompanies the new guideline answers this. Gregory Schwartz, JACC. The argument is a cost ladder, and I think it's the most useful piece of cardiology economics I've read this year.

The numbers come from PROVE-IT (the post-ACS lipid trial). On atorvastatin 80 mg alone, 35% of patients reach LDL <55. Add ezetimibe (also generic, $20-30 a month), and 55% get there. Roughly half of high-risk patients can hit the guideline target on two generic pills, combined cost of $20-40 a month.

Beyond that, the math gets ugly fast.

https://preview.redd.it/xgfapm4emh2h1.png?width=1536&format=png&auto=webp&s=1a30d9c76382d5a9f5e4ea478d9f4ac7f4c9a4f1

  To push below 55, 45% would need a third drug. That third drug is almost always a PCSK9 inhibitor. List price is around $6,000 a year, but the realistic cash price through GoodRx for Repatha (the most-prescribed one) runs about $2,900 a year right now. To push below 30, more than 90% would need the third drug.

The benefit you're buying for that money? FOURIER-OLE showed about 1 percentage point of absolute reduction in cardiovascular death, MI, or stroke over 5 years when you go from achieved LDL 55 down to 40. That's the trade: thousands of dollars for a year for a 1-point absolute risk reduction at 5 years.

 Schwartz's conclusion: the 55 mg/dL target is "a judicious distillation of current evidence, balancing clinical efficacy with cost and complexity of care." Translation: the guideline picked 55 because that's where two generic drugs land most people, and going lower as a population-level recommendation still costs meaningfully more than the marginal benefit justifies. For someone with high Lp(a) or strong family history of premature ASCVD, the math at $3K/year tilts more toward "yes" than the list-price math used to.

For me at LDL 60, this means I'm still done. The math doesn't support adding a PCSK9 inhibitor unless something else changes. For someone with a high Lp(a), bad family history, or established cardiovascular disease with multiple events, the math is different and the case for the third drug is stronger.

I wrote up the full 2026 guideline (PREVENT calculator, CAC scoring upgrade, ApoB targets, all the drugs in plain English) here: Reading Your Cholesterol Panel at 50. The cost ladder above is one piece of a longer story.

I’m asking this based on Episode #69 of the podcast Live Long and Thrive by Dr. Bobby Dubois. The title is “Physiology Often Beats Insight”.

Here’s a quote that describes the episode: In this episode, I explore a difficult but important idea: when it comes to depression, anxiety, fear, and emotional suffering, changing physiology often works better than understanding the story behind the pain. 
I begin with a simple question: why do we assume insight should heal us? As human beings, we naturally look for patterns and explanations, but explanation is not the same as relief. I share two personal examples—my years of dysthymia that lifted quickly with Wellbutrin, and my exercise-related fears that insight alone never resolved—to show how biology can sometimes succeed where understanding falls short.”

Basically, he had tried therapy, meditation, and many other things to relieve his dysthymia, with no results, but Wellbutrin relieved it and brought him happiness. He’s been on it for 20 years. This had made me consider trying it. I have been extremely skeptical about SSRI drugs and other psychoactive drugs, believing they don’t really work.

I have tried Prozac and Lexapro in the past with no results.
I really respect Dr. Bobby. He’s a real evidence-based doctor, not some influencer or grifter.

Has anyone else ever used Wellbutrin?

If I decide to try it, I’ll set a time limit (maybe one month) and if I see no results, quit (or taper off).

I see at least one of these takes in my feed every couple weeks. The reasoning shifts but the tone doesn’t. Guidelines are wrong, your doctor is hiding something, Big Pharma and the government are pushing statins on everyone, the brave skeptic has cracked the code.
I’ve gone looking for a clean rebuttal more times than I want to admit. James Stein, who ran the UW preventive cardiology program for 21 years.

His core argument is that the U-shaped mortality curve people love to cite, where low cholesterol appears to predict higher death rates, isn’t biology reversing direction. It’s confounding. Low cholesterol can mean low cardiovascular risk. It can also mean cancer, malabsorption, chronic inflammation, or frailty. Mix those people into the data and the left tail goes up. Once you exclude early deaths and adjust for illness markers, the upturn shrinks.

He also picks apart the more sophisticated version. People grab the recent NEJM paper from the Global Cardiovascular Risk Consortium that dichotomized non-HDL cholesterol at 130 mg/dL and showed modest lifetime contrasts. The authors noted the real association is J or U shaped, but the modeling choice flattened it. Read casually, it looks like cholesterol barely matters. Stein’s point: that’s an accounting exercise about one threshold at one age, not a finding about biology.
His closing line, lightly paraphrased: there is no cholesterol debate at the causal level. What keeps coming back isn’t new biology. It’s misreads of risk data.

Worth a read if you’ve ever tried to argue with this stuff: https://jamesstein18.substack.com/p/why-cholesterol-is-debunked-arguments

The “cholesterol is debunked” takes aren’t a scientific position. They’re a content strategy.​​​​​​​​​​​​​​​​

What increasingly strikes me is that the strongest near-term aging interventions may not be one grand therapy.

They may be layered: targeted senolysis, immune surveillance enhancement, tissue repair, and maybe partial reprogramming later on, right?

That is less dramatic than “immortality,” but arguably more plausible.

If that’s the path, then the real milestone isn’t “curing aging” in one shot; it’s building therapies that keep pushing back multiple aging drivers faster than damage accumulates.

Curious whether that feels like a realistic transhumanist path or just a slower version of the same old promises.

I posted about ACHIEVE-3 back in February. That one was the head-to-head of Lilly's oral orforglipron against oral semaglutide in type 2 diabetes. Interesting result, not my question.

My question, after 18 months on Zepbound and now at the weight and body fat I actually want to hold, is the boring and slightly terrifying one. What does maintenance look like, and is it really lifelong.

ATTAIN-MAINTAIN, published May 13 in Nature Medicine, is the first trial that goes after that directly. Patients who finished SURMOUNT-5 on injectable tirzepatide or semaglutide came off the shot and were randomized to daily oral orforglipron or placebo for a year.

The headline says the pill worked. The numbers are more honest. People switching from tirzepatide kept 74.7 percent of their body weight reduction. People switching from semaglutide kept 79.3 percent. The pill mostly holds the line, but you give back roughly 20 to 25 percent of what you lost. The tirzepatide arm gained about 11 pounds back over the year. The semaglutide arm about 2.

For me, stopping is not on the table. The real choice is keep injecting at the current dose, drop to a lower maintenance dose, or move to the pill and accept some giveback. ATTAIN-MAINTAIN does not test a lower-dose injectable arm, which is the comparison I actually want to see. It also does not break out how much of the regain is fat versus muscle and bone.

A Lilly-funded trial at Lilly's preferred academic centers. Definitely interesting, but not the last word.

I have basically no hobbies outside of working out, so I went into this paper ready to dismiss it.

The study looked at 3,556 adults in the UK Household Longitudinal Study and asked whether arts/cultural engagement and physical activity were associated with seven epigenetic aging clocks. Arts/cultural engagement meant things like music, dancing, painting, photography, crafts, museums, galleries, libraries, archives, historic sites, and cultural events. Physical activity was measured separately.

The results were not “art makes you live longer.” The older first-generation clocks showed basically nothing. But the newer clocks — PhenoAge, DunedinPoAm, and DunedinPACE — did show slower epigenetic aging in people who were more engaged in arts/culture and in people who were more physically active. The effect sizes were apparently similar enough that the authors compare arts/cultural engagement to physical activity.

This is where my skepticism kicks in hard.

People who go to museums, sing in choirs, take classes, dance, do photography, make things, or visit historic sites are probably different in a thousand ways from people who do none of that. They may have more money, more free time, better mobility, better mental health, stronger social ties, more education, less loneliness, and fewer life constraints. The authors adjusted for a lot, including socioeconomic factors, smoking, drinking, BMI, and health status, but this is still observational. You cannot model your way into certainty.

Also, epigenetic clocks are not the same thing as hard outcomes. I care much more about whether people avoid heart attacks, dementia, falls, frailty, disability, and early death than whether a methylation algorithm moves a little. Interesting signal, not proof.

But the annoying part is that the result is still plausible.

A lot of “longevity” culture collapses into exercise, sleep, diet, lipids, glucose, supplements, wearables, and lab work. I’m guilty of this too. My default leisure activity is just more training. This paper is a reminder that a healthy life might need something less measurable: hobbies, culture, creativity, social identity, novelty, and reasons to leave the house that are not just zone 2 or errands.

I do not think anyone should read this and force themselves into museum optimization mode. But I am taking it as a nudge that “I lift and do cardio” may not be a complete adult life.

For those of you who actually have hobbies: what has felt health-giving in a way that is not just another workout?

✔ Strong sleep routine

✔ Consistent exercise

✔ Low stress levels

✔ Healthy diet

✔ Good hydration

Most people ignore #3…”