by cthalupa | 2025-10-02 06:41:30+00:00
> 1. Lowest mortality is with ldl of 140, not lower/. https://www.bmj.com/content/371/bmj.m4266

I guess we're on repeat here. U and J shaped curves in observational studies are notorious for being confounded by reverse causality. They did attempt to control for some of the common factors, but cancer often goes undiagnosed, general frailty matches the age group and results in lower LDL levels, and some chronic inflammatory diseases also lower LDL and are not accounted for. CKD often lowers LDL levels due to malnutrition and decreased ability for the production of enzymes involved in lipid breakdown.

But let's dig deeper. Thankfully, we have other studies that help control for all of these factors and give us better evidence.

We have very large meta-analysis of high quality RCTs on statin use such as this one:

https://www.thelancet.com/journals/lancet/article/PIIS0140-6...

All cause mortality dropped on top of cardiovascular related events and deaths. This is * alot* of data points showing a lack of increased mortality at LDL levels well below the 140 number in your linked study.

Let's go deeper still. The PCSK9 inhibitors are getting us to lower LDL via treatment than ever before:

https://pubmed.ncbi.nlm.nih.gov/36779348/

https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/201...

Evolocumab got LDL down below 20 with better and better CVD related outcomes and no increased in all-cause mortality. Alirocumab taking LDL again, well below the 140 level, decreased all-cause mortality.

But we don't have to stop there. We can look at mendelian randomization studies - while RCTs are the gold standard for determining causal links, well designed MR are far far far superior to observational studies, and particularly when coupled with multiple signals they can be quite good at showing causal links. And that is the case here:

https://pubmed.ncbi.nlm.nih.gov/34729547/

https://pubmed.ncbi.nlm.nih.gov/33704808/

Increasing LDL-C levels = Decreasing lifespan

Observational studies in general are just not good evidence when it comes to all-cause mortality. It's too difficult to control for all of the different confounding factors and the amount of them with J and U shaped curves that do not match RCTs and MRs just shows that. It's the same with bf% - there are observational studies that show 25% bf is lower all-cause mortality than 15%, but there are no proposed mechanisms for that to be the case, no RCTs or MRs that show it to be the case, and for every confounding factor you eliminate the all-cause mortality rate increases at higher bf%.

> 2. Guess what the relative risk of myotoxicity is with statins.

Honestly? Basically not worth mentioning

https://pubmed.ncbi.nlm.nih.gov/36049498/

Blinded RCT/Meta-analysis shows about 11 complaints per 1k patient years, with 90% of them not actually being due to the statin. But because people act like they're common, they mistakenly believe it was the statin, which just reinforces this idea. And that's for muscle pain.

https://www.ahajournals.org/doi/10.1161/atv.0000000000000073

https://academic.oup.com/eurjpc/article-abstract/26/5/512/59...

https://pubmed.ncbi.nlm.nih.gov/15572716/

For actual significant muscle injury? Even lower. 1 or less per 10,000 patient years.

Effectively, you might get one muscle ache per year per 100 people and at most a 1 in 10,000 chance of serious myotoxicity.

The real risk with some statins is increasing your risk of diabetes - some of the older statins impair insulin resistance. But pitavastatin and rosuvastatin actually improve insulin sensitivity, and pravastatin is neutral. Pitavastatin in general has a significantly better side effect profile than other statins in basically every way. It is fairly under-prescribed in the US, though, due to the fact it has just recently become generic, and before that it was difficult to get insurance to cover it with the widespread availability of generic statins that were, honestly, already good enough for the overwhelming majority of use cases.

Additionally, the default treatment option is shifting more and more to combo therapy rather than ramping up statin doses. Most of the beneficial effect of statins comes relatively early on in the dosing curve, and the risk of side effects on the high end of it. You are more and more likely to see a low-dose statin and ezetimibe, which will generally have better LDL-C lowering capability with fewer side effects than a higher dose statin monotherapy. There are also additional options, such as the previously mentioned PCSK9 inhibitors and bempedoic acid that are not available as generics but can be added to therapy if necessary.