Monday, March 27, 2017

Dear Mark: That New Cholesterol-Lowering Drug Study

Inline_Dear_MarkFor today’s edition of Dear Mark, I’m answering one question. It’s a good one. A reader (many, actually) wrote in to get my opinion on the latest blockbuster cholesterol-lowering drug. A new study appears to show that the drug in question—Repatha—reduced LDL to unprecedented levels and protected patients against the primary cardiovascular disease endpoints they were measuring. What does it all mean? Should we all start taking Repatha?

Let’s dig into it:

Hi Mark,

What’s your take on this study of a new heart disease drug called Repatha? Apparently it was able to reduce LDL levels to an unprecedented degree, and the lower the LDL the lower the heart attack risk.

Yeah, I saw this. Here’s an article about it in the NY Times. Here’s the actual study. The Times article is positively gushing, recounting that the drug “significantly reduced the chance” of a “heart attack or stroke” in “men and women who had exhausted all other options.”

What’d they take? Repatha is an PCSK9 inhibitor. PCSK9 binds to LDL receptors and prevents them from taking up LDL particles. More PCSK9 activity, fewer available LDL receptors, more LDL particles in the blood.

Given that I’ve spoken about the importance of having good LDL receptor availability and the likely causative role of oxidized LDL particles in heart disease, this doesn’t sound too bad. After all, all else being equal, shouldn’t we want fewer LDL particles? At least Repatha isn’t cutting off a major enzymatic pathway with multiple downstream effects, which is what statins do.

Who took it? High-risk patients with heart disease, about 27.5k of them split into two groups. One got Repatha. One got placebo. Everyone was on statins, so there was no true placebo.

What happened? As the NY Times mentions, the drug did lower the chance of the primary endpoint.

Except the endpoint wasn’t just one event. The endpoint was a composite endpoint. That is, they grouped different events together. The endpoint wasn’t just “did the person have a stroke?” It was “did the person have a stroke, heart attack, hospitalization due to unstable angina or coronary revascularization, or cardiovascular death?”

There’s a big problem with composite endpoints: they assume the constituent events are of equal signifiance. Everyone can agree that death deserves “primary endpoint status.” I’d rather not die of a heart attack (or anything). I imagine most people feel the same way. Not everyone would put “ended up in the hospital because of chest pain” on equal footing as “died from a heart attack”—particularly the people taking the drug. But the success of the Repatha study depends on the two being equally undesirable.

Other “benefits” included reducing LDL levels to an average of 30. A quarter of subjects taking Repatha got their LDL levels down to 19! You’d think with LDL that low they’d be totally impervious to heart attacks and fast approaching demi-god status if not outright immortality.

They weren’t. When you shatter the composite endpoints and examine the individual events, you notice that Repatha didn’t actually help people avoid fatal heart attacks or death from other causes. In fact, the Repatha group had slightly higher death rates from heart attacks (251 vs 240) and other causes (444 vs 426), though it didn’t reach statistical significance.

Furthermore, this study was supposed to last 4 years. They ended it after a little more than 2 years. Drug companies don’t cut studies short if they’re going great. They cut studies short when things start trending south. Were the deaths piling up? Were the initial gains in primary endpoints showing signs of reversal? We just don’t know. But it looks bad if you ask me.

What’s the purpose of PCSK9, though? It can’t be “to give us heart disease.” It’s got to be there for some reason or another, even if that reason is an “outdated relic” of our ancestral past.

It probably evolved as an anti-infectious disease adaptation. LDL is anti-microbial; it can protect against viruses, bacteria, and parasites. In environments with high parasite loads or rampant infectious disease, high PCSK9 activity could enable protective levels of LDL to circulate. 

Another role of LDL is to “soak up” oxidants and other inflammatory agents in the blood. Sure enough, inflammation also increases PCSK9 activity.

Are there any other ways to inhibit PCSK9 that don’t involve spending thousands a month on a potentially-risky drug?

Berberine inhibits PCSK9. It even performs favorably against cholesterol-lowering drugs.

Fasting inhibits PCSK9. In one study, fasting humans achieved the lowest levels of PCSK9 at the 36 hour mark.

Those appear to be safer options. They at least have more history than Repatha.

Overall, I’m not sure what to say. Clearly, the gushing media coverage is misleading. The drug helped reduce non-fatal cardiovascular events, but failed to reduce fatal ones (and even slightly increased them). Furthermore, they cut the study short, which suggests the possibility of worsening mortality and/or other undesirable trends.

I’m not writing it off completely. PCSK9 inhibition might help certain people with confirmed heart disease at high risk of having another attack, like those with familial hypercholesterolemia. Maybe they work better if you’re not taking a statin. Maybe PCSK9-inhibitor+statin is just too much LDL reduction. And maybe there are other, safer ways to inhibit the enzyme.

With the massively positive response from the industry, I’m sure we’ll be getting more research in the coming years. Hopefully, it pans out. But don’t be too surprised if it doesn’t.

That’s it for today, folks. Did you hear about the study? What do you think about the results?

Take care.


The post Dear Mark: That New Cholesterol-Lowering Drug Study appeared first on Mark's Daily Apple.

from Mark's Daily Apple

Clean Eating Cabbage Hash Recipe

Clean Eating Cabbage Hash Recipe

I recently went on a field trip with Mini Chef and his class. We went to a local farm where they raise sheep. One thing I love about this area is how picturesque it is. Everywhere you look there is something beautiful to see. From farms to vineyards and coastlines, this part of Northern California is definitely blessed.

Clean Eating Cabbage Hash Recipe

When we got out of the car, all we saw was beautifully green fields (thanks to all those storms we just survived) and sheep as far as the eye could see. We were introduced to the farmer (who’s daughter is in Mini Chef’s class and the reason we were able to visit this family farm in the first place), and then we met the sheep and other animals who live here.Clean Eating Cabbage Hash Recipe

The dogs who help around the farm were incredibly cute. One was named Shamus and the other (pictured here) was named Sandy.
Clean Eating Cabbage Hash Recipe

And then, there was Freckles. Freckles the “ba-sheep” as Mini Chef and I still refer to them (some toddler terms never go away). Freckles accompanied us for very nearly the entire field trip and pretty much ate his way through the entire experience. It was marvelous.Clean Eating Cabbage Hash Recipe

The kids got to play with some of the wool that is produced and sold on the farm and even take a few tufts home with them.
Clean Eating Cabbage Hash Recipe

And somewhere along the way, we passed this humble little patch of veggies they had growing. I saw that marvelous head of cabbage and immediately started craving some. But I didn’t want to make my usual German Cabbage Soup, so I got to spend the rest of the field trip thinking about what I’d do with the head of cabbage I had at home in the fridge.

Clean Eating Cabbage Hash Recipe

I was tired after the field trip and didn’t want to do a lot of cooking when I got home because I still had other things to do that day and the day was disappearing quickly at that point. So I needed something fast.
Clean Eating Cabbage Hash Recipe

This is hands down one of the easiest recipes I’ve made in a long time. It was so easy to make with just a few ingredients and was the perfect ending after spending a day on the farm.


Clean Eating Cabbage Hash RecipeCopyright Information For The Gracious Pantry

Clean Eating Cabbage Hash Recipe



Yield: 3 servings


  • 1-2 tbsp. good quality oil
  • 1 small head green cabbage, sliced small and thin, core removed
  • 1 lb. ground turkey
  • ¼ medium, yellow onion
  • Chicken broth as needed for cooking
  • Salt to taste after cooking


  1. Warm the oil in a large skillet.
  2. Add the cabbage and allow to cook down just enough to make room for the ground turkey.
  3. Add the turkey and onion and stir continuously until the meat is fully cooked (approx. 15 min)
  4. If the pan dries out, you can add chicken broth as needed.
  5. Allow to cool slightly, season with salt and serve.


Clean Eating Cabbage Hash Recipe

from The Gracious Pantry

A Horse Is A Horse Of Course, Of Course

We had such a fun weekend OUTSIDE! The weather was great, and we packed in a lot of fun activities.

On Friday Mazen didn’t have school, so we walked downtown and met Thomas for lunch at Rev Soup. The Gulf Salad is always my favorite! Plus a few bites of Mazen’s spinach and cheese quesadilla 😉

Post lunch ice cream treat!

Mazen spent Friday night with Matt, and we headed out to the Struckmann’s for a bonfire.

T and I had dinner at Keswick Hall’s bar beforehand.

We shared the mussels to start:

And I had a kale salad with salmon on top. Ate every last bite!

Dessert was s’mores with giant marshmallows!!

On Saturday morning I had a quick breakfast before heading out to pick up Mazen and take him to his first soccer practice of the season!

He did really well, and he’s definitely getting a better feel for the game.

We had lunch at home. Salad for me!

After lunch we joined a bunch of friends – and pretty much all of Charlottesville – at King Family Vineyard for the afternoon.

We rode the pretend horse three times, petted one of the beautiful polo horses, and played with the cutest little puppy named Annie!

We drove back to town to reset and headed to a friend’s house for a cookout.

So much great food!

Mazen was overheard calling his new friend “honey!”

On Sunday I played in 1.5 soccer games, so I fueled up with this bacon, egg, and cheese sandwich.

New cleats!!

Hope y’all are thawing out too!

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from Kath Eats Real Food