When Medical Guidelines are Not Enough

This article uses Repatha (evolocumab), a conventional cholesterol medication, to highlight something that comes up constantly in longevity medicine: the gap between general medical guidelines and what actually makes sense for one specific person.

Understanding Repatha

Repatha is an injectable medication that inhibits PCSK9, a protein involved in how the body clears LDL particles from the blood. And it’s extremely effective. At standard dosing, it can lower ApoB somewhere around 40–50% or more - compared to the highest dose of a statin which lowers it by only 30-40%. And ApoB is generally the cholesterol-related number I care most about because it gives us a good estimate of how many atherogenic particles are circulating in your blood and potentially contributing to plaque over time.

Repatha also lowers Lp(a) by roughly 20–30%, which gets my attention because Lp(a) is highly genetic and there are still very few things we can do today to meaningfully lower it (although the recent headline results from the Lp(a)HORIZON trial call into question the value of lowering Lp(a)).

And there are a few other reasons PCSK9 inhibitors get me excited:

• Glycemic control: Statins can slightly worsen glycemic control, particularly at higher doses. We haven’t seen the same effect with Repatha.
• Plaque: We have human data showing favorable changes in coronary plaque (less inflammation, more plaque stability) when Repatha is added to lipid-lowering therapy.
• Mitochondria: There are some interesting differences here too. Statins can negatively affect mitochondrial function, while we haven’t seen the same signal with Repatha. This is likely partly due to the fact that Repatha acts outside of the cell, while statins act intracellularly and, thus, have high potential for off-target consequences.
• Then there’s the potential direct, molecular anti-aging impact: PCSK9 inhibition is also being studied for effects on cellular aging pathways such as directly lowering senescence through a SIRT3 mediated pathway.

Now, the caveat to all these extra potential benefits, particularly the anti-aging and mitochondrial ones, is that they have either only been studied pre-clinically or we are just unclear of their long-term clinical significance. And then on top of that, Repatha has very little end outcome data in studies where it is used alone. Compared to statins which of course have a ton of long-term outcome data as monotherapy. That said, when Repatha is added on to existing statin therapy (as is done in most all its end outcome studies), it does still improve end outcomes above what statins alone do.

So given that, the potential extra longevity benefits, and the amazing lipid lowering efficacy, I like Repatha. A lot. And I think there are people who could benefit from it who probably aren’t currently considering it.

So we have a promising drug with strong results. Which raises the question: 

If it works this well, why aren’t more people on it?

The Role of Medical Guidelines

A lot of conventional medicine is practiced using guidelines created by groups of experts (think the American Heart Association or American College of Cardiology) who look at the overall body of evidence and try to answer, essentially: For the general population of people in this situation, what should we generally do? That means weighing how strong the evidence is, how big the benefit is, how safe and practical the treatment is, what it costs, and whether there's a cheaper way to get most of the same benefit.

Which helps explain the Repatha question. The traditional first-line medication for lowering cholesterol is a statin. Statins are inexpensive, easy to take, very effective and, again, have decades of outcomes data behind them. Repatha hasn’t been used for as long so there is less data, it’s an injection, and has historically been much more expensive. So at a population level, starting with a statin makes a ton of sense.

But when you zoom in on an individual, this is where population-level, cost-effective guideline thinking may fall short.

Where Medical Guidelines Fall Short

Consider the following:

1. Person A ApoB in the “normal” range, but high Lp(a) and a family history of early heart disease. Prevention is their top priority, and they’re willing to add a medication and spend more to lower their risk.
2. Person B Already low-risk, but focused on longevity and minimizing lifetime cardiovascular risk. Comfortable with an injection every couple of weeks and acting on evidence that isn’t perfect for someone exactly like them.
3. Person C High ApoB, but managing several prescriptions already and prioritizing fewer daily pills over marginal gains.

None of them fit the standard guideline. That doesn't mean Repatha wouldn't potentially help them more than a statin. What it does mean is that their provider should be asking whether the potential additional benefit of this drug makes sense for each person (A vs B vs C). But the provider can't answer that very well if they don't know what you actually care about.

KEY TAKEAWAY:

None of this means you should walk into your next appointment demanding Repatha (please don't). But if you care about optimizing beyond the standard guideline, it does mean being direct with your provider about your goals and priorities. 

And it’s always worth asking: Given my risk, my goals and what I'm willing to do, is there any reason we should be thinking beyond the standard approach? Because the ultimate goal is to make sure you're getting an answer based on you, versus what makes sense for the average person.

(Not sure where to start that conversation? See the cheat sheet below):

Cheat Sheet: What your doctor should know about you

If you’re interested in going beyond the standard guideline recommendation, your provider needs more than your lab results. They should understand:

• How aggressive you want to be. Some people want to do everything reasonably possible to lower long-term risk. Other people would rather accept a little more risk if it means taking fewer medications.
• What you’re willing to spend. Cost matters at the population level, but price sensitivity can vary wildly person to person. And sometimes a treatment that is unreasonable at full price may become a very different conversation if insurance covers it.
• How comfortable you are with uncertainty. There are places in longevity medicine where the mechanism is compelling and the evidence is promising, but we don’t have the same level of long-term data we would want for a universal recommendation. Some people are comfortable acting there while others aren’t.
• What treatment burden matters to you. Maybe an injection every couple weeks is nothing. Maybe you absolutely hate needles. Maybe adding another medication feels like a much bigger deal than it would to somebody else. Making your preferences known can help guide treatment plans and protocols.

Bring those four things into your next appointment and you'll get a much better answer than "is this indicated for me," because now your provider actually knows what you're solving for.