Statin monotherapy vs combination with ezetimibe

#35

New papers, as usual, the ezetimibe combo is non-inferior.

The clinical effectiveness and safety of low/moderate-intensity statins & ezetimibe combination therapy vs. high-intensity statin monotherapy: a systematic review and meta-analysis 2024

15 studies encompassing 251,450 participants were included in our meta-analysis. In our pooled analysis of observational studies, combination therapy was associated with lower rates of the primary composite outcome (HR = 0.76, CI 95% [0.73, 0.80]), cardiovascular death (HR = 0.80, CI 95% [0.74, 0.88]), all-cause death (HR = 0.84, CI 95% [0.78, 0.91]), and non-fatal stroke (HR = 0.81, CI 95% [0.75, 0.87]). However, the pooled analysis of RCTs did not demonstrate a statistically significant difference between both arms concerning clinical endpoints. Combination therapy had a higher number of patients with LDL-C < 70 mg/dL (RR = 1.27, CI 95% [1.21, 1.34]), significantly lowered LDL-C (MD = -7.95, CI 95% [-10.02, -5.89]) and TC (MD = -26.77, CI 95% [-27.64, -25.89]) in the pooled analysis of RCTs. In terms of safety, the combination therapy lowered muscle-related adverse events (RR = 0.52, CI 95% [0.32, 0.85]) and number of patients with liver enzyme elevation (RR = 0.51, CI 95% [0.29, 0.89]) in the pooled analysis of RCTs and was associated with lower rates of new-onset diabetes (HR = 0.80, CI 95% [0.74, 0.87]) in the pooled analysis of observational studies.

Alternative LDL Cholesterol–Lowering Strategy vs High-Intensity Statins in Atherosclerotic Cardiovascular Disease: A Systematic Review and Individual Patient Data Meta-Analysis 2024

Individual patient data from 2 trials including 8180 patients with ASCVD (mean [SD] age, 64.5 [9.8] years; 2182 [26.7%] female; 5998 male [73.3%]) were analyzed. The rate of the primary end point did not differ between the alternative strategy and high-intensity statin strategy groups (7.5% [304 of 4094] vs 7.7% [310 of 4086]; hazard ratio, 0.98; 95% CI, 0.84-1.15; P = .82). The mean (SD) LDL cholesterol level during treatment was 64.8 (19.0) mg/dL in the alternative strategy group and 68.5 (20.7) mg/dL in the high-intensity statin strategy group (P < .001). The alternative strategy group had a lower rate of new-onset diabetes (10.2% [271 of 2658] vs 11.9% [316 of 2656]; P = .047), initiation of antidiabetic medication for new-onset diabetes (6.5% [173 of 2658] vs 8.2% [217 of 2656]; P = .02), and intolerance-related discontinuation or dose reduction of assigned therapy (4.0% [163 of 4094] vs 6.7% [273 of 4086]; P < .001).

4 Likes
#36

Wow, ezetimibe is no joke. For the past four months I took 10mg/day, and then the past few weeks or so I switched to 10mg ezetimibe+10mg atorvastatin combo therapy. Additionally, there were a few weeks where I ran out of ezetimibe and took 5-10mg/day rosuvastatin monotherapy.

Full disclosure, I’ve also been taking anabolic steroids over that time period, which are known to elevate blood lipids. My total testosterone and free testosterone just came back as 2,465 (ref range 264-916) and 190 (ref range 5-21), respectively.

Despite this, my LDL-C and ApoB just came back at 46 and 42, respectively. Triglycerides also look great at 37. Prior to starting my lipids were already pretty good (ApoB of 71), but it’s impressive that they’ve improved relative to that despite the drastic increase in testosterone levels.

A few other results are more concerning, and I’m considering ending the cycle at 16 weeks rather than 20, but it’s at least good to see that my blood lipids have remained in check.

15 Likes
#37

Do you mind sharing the more concerning results? Do they have to do with elevated liver and/ or kidney values?

1 Like
#38

  • Probably my biggest concern is the increase in RBC, hemoglobin, and hematocrit. My hematocrit is now out of range at 52.3%, whereas before it was only 43.9% (19.1% increase). My RBC only increased from 5.67 to 4.9 (15.7% increase), so probably with increased water intake I can get my hematocrit a little lower.

  • I’m getting conflicting answers on whether secondary erythrocytosis from testosterone is actually dangerous, so that’s something I’d like to ask the experts here. I haven’t noticed any obvious symptoms throughout the cycle, other than increased redness for awhile (which went away) and some shortness of breath (which also mostly went away). I have had a sense of chest heaviness the past couple days ever since I read these results, which perhaps is just psychosomatic.

  • Aspartate aminotransferase (AST) increased from 47 to 32 and is now out of range, and eGFR decreased from 119 to 99. Other liver and kidney markers have remained within range. Urine pH was elevated at 8.0 (previous test was 7.0).

  • Prolactin has shot up from 10.9 to 50.6, which is quite elevated. My libido has remained quite stable and I suspect this is why. I’ve also been taking the MOR agonist 7-HO-mitragynine daily for the past few months which could be contributing. Have some cabergoline on the way (which is no joke of a drug) because I would like to briefly see how I feel with low prolactin levels.

  • Estradiol has increased from 28.9 to 86.5, which is quite elevated. Not so worried about this as I haven’t had any bothersome symptoms, although probably it’s contributing to the elevated prolactin.

  • My DHEA-S has always ran high, and it’s taken a hit, going from 533 to 338.

  • Glucose control appears stable considering HbA1c hasn’t changed, but insulin sensitivity has dipped a bit (fasting insulin from 4.7 to 7.3

  • I was surprised to see Vitamin D (25-Hydroxy) take a hit, going from 50.8 to 32.2, which is the very low end of the range.

  • T3 (free) is elevated now also, as it’s gone from 4.5 to 4.2. My thyroid signaling knowledge is elementary, so I would appreciate input on that one.

  • Lastly, systemic inflammation has perhaps gone down, as CRP went from 1.16 to 0.55. I also tested TNF-A as a novel inflammation biomarker, and it’s at 0.8 pg/mL (range 0.0-2.2). Neutrophil-to-lymphocyte ratio did increase from 1.27 to 1.7, which seems unfavorable.

Would really appreciate input on any of these. If you think I’m an idiot for continuing this cycle, please tell me. Likewise if there’s some obvious intervention that might help any of these biomarkers. Although I’ve definitely improved my physique, I haven’t made as many gains as I would like, which is why I want to run it a little longer. Mostly it comes down to not eating enough I think, which is the hardest part for me. But I’m already shut down so figure it’s better to try and really lock in for a few more weeks for some incremental gains.

3 Likes
#39

Worded kind of funny, like you mixed up the from and to. You mean it used to be 32, which was in range, and now it’s 47? You could try TUDCA for this. It works like magic on these numbers and I’ve taken it for a while and there really aren’t any side effects that I’ve noticed.

2 Likes
#40

I mixed those up, my bad. I’ll look into TUDCA, thanks for the recommendation!

1 Like
#41

Check this thread for TUDCA: UDCA (ursodiol) / TUDCA for healthspan and lifespan?

I don’t take it but for high AST and other liver markers it seems to work well and to be safe.

1 Like
#42

No, not an idiot, but I don’t think you’ll get good cycle advice here and this forum isn’t friendly towards PED use, so advice will be skewed and tends to be over cautious and uninformed on this subject. I’d suggest joining Chase Iron’s discord or at least hanging out on meso-rx, professional muscle, t-nation, steroid source talk, enhance genetics etc.

That said, 52.3% with that RBC sounds like a hydration issue (what is the hemoglobin level?), and most manage it also with daily cardio that includes at least some HIIT. That’s considered mandatory if you’re going to use gear. But nobody doing cycles is worried about 52.3%. There’s a lot of discussion on this topic on excel male dot com and by YouTube doctors. None are worried about erythrocytosis causing clotting, but some worry about arterial shear stress over time. But 52.3 isn’t enough to worry about regardless.

Your liver enzymes aren’t bad for what you’re doing. Add NAC. Take som astragalus for your kidneys, but your eGFR probably dropped because of muscle turnover and mass. Get a cystatin C and use the national kidney foundation calculator.

Estradiol is fine for your T levels, but does put you in gynecomastia territory. Same comment on the prolactin. I’d knock the estradiol down below 60, maybe to 40.

It seems like your biggest issue is that you’re wasting time doing this and stressing yourself body for no good reason if you’re not eating enough. You can’t be afraid to gain some fat. I’d discontinue if you can’t maintain a surplus and train very hard because otherwise you’re just spinning your wheels.

4 Likes
#43

Thank you, this is all very helpful information. @AgentSmith

1 Like
#44

@jnorm ezetimibe will bump your liver enzymes. An AST of 42 isn’t too bad but if you are concerned you can take 1/2 or even a 1/3 of that 10 mg dose and get pretty much the same effect on your lipids. That will likely allow your AST to return to normal. I’d do that before I added TUDCA.

3 Likes
#45

What dosage are you taking to get total T of ~2400, if you don’t mind me asking?

#46

400/week of the cypionate ester. IM’ing EoD.
That was my trough iirc.

#47

I’ve always wondered how it scales. Does T go up linearly with dose, or is there a curve? Probably individual.

#48

One more piece of evidence: Cardiovascular Health - #1725 by RapAdmin

Pooled analysis revealed that combination LLT significantly more effectively reduced the LDL-C level from baseline (mean difference, −12.96 mg/dL; 95% CI, −17.27 to −8.65; P<.001) and significantly reduced all-cause mortality (OR, 0.81; 95% CI, 0.67 to 0.97; P=.02), major adverse cardiovascular events (OR, 0.82; 95% CI, 0.69 to 0.97; P=.02), and stroke incidence (OR, 0.83; 95% CI, 0.75 to 0.91; P<.001), with an insignificant effect on cardiovascular mortality (OR, 0.86; 95% CI, 0.65 to 1.12; P=.26) when compared with statin monotherapy. The risk of adverse events and the therapy discontinuation rate were comparable between groups.

5 Likes
#49

Comparative cardiovascular outcomes of statin monotherapy versus statin plus ezetimibe combination therapy in patients with atherosclerotic cardiovasc

After propensity score matching, baseline characteristics including hypertension (85.4% vs 85.3%), diabetes (46.3% vs 46.3%), and prior myocardial infarction (29.8% vs 29.6%) were well-balanced between groups. The statin plus ezetimibe group showed significantly lower risk across multiple outcomes compared to statin monotherapy: all-cause mortality (HR 1.445, 95% CI 1.412-1.480), dementia (HR 1.498, 95% CI 1.447-1.550), cardiac arrest (HR 1.332, 95% CI 1.263-1.404), and stroke (HR 1.253, 95% CI 1.202-1.306). More modest risk reductions were observed for atrial fibrillation (HR 1.132, 95% CI 1.110-1.154) and heart failure (HR 1.075, 95% CI 1.059-1.091), while ventricular tachycardia showed no significant difference between groups (HR 1.035, 95% CI 0.999-1.072).

4 Likes
#50

Apologies if I missed this. Does anyone have any empirical data on the merit of the generalization that low or normal triglycerides (well below 100) with elevated LDL suggests being a hyper adsorber whereas an elevated lipid profile with high trigs is more suggestive of being a hyperproducer? If one is a hyperproducer is 10 mg/day ezetimibe the ceiling or can it safely be taken at higher doses and to what effect?

#51

Ezetimibe primarily blocks the (NPC1L1) cholesterol transporter in the intestine. The 10mg dose is enough to nearly saturate that effect (blocking 50-60% of cholesterol ingestion) that’s why it’s not dose dependent.

4 Likes
#52

I think you would certainly need to follow Liver function tests if taking more than 10 of ezetimibe. Even at 10 I see my LFT’s bump (with statin on board as well). As @cl-user says you don’t get a lot of benefit above 5 so you are already pretty much maxed out at 10 mg. I try hard not to put pressure on my liver even if the enzyme bumps are clinically minor, they indicate stress on the liver.

1 Like
#53

There isn’t any need to take more than 10 mg of Ezetimibe. It isn’t worth the risk to your liver for any minuscule additive gain.

3 Likes
#54

Might as well share my numbers, since I meet those criteria. These are averages from at lest 3 readings, taken over at least 3 month intervals (i.e. each results is a Jan, April, Sept or similar):

Untreated:
LDL-C: 180 mg/dl
HDL-C: 53 mg/dl
Trigs: 70.4 mg/dl
HBA1C: 5.0%
ALT: 42

I have familial hypercholesterolemia, and likely the “hyper absorption” type. As you can see, my trigs were low, HDL-C was good, metabolic health great, but I had some fatty liver and sky high LDL-C.

After treatment with Rosuvastatin 10mg:
LDL-C: 177 mg/dl
HDL-C: 60 mg/dl
Trigs: 67 mg/dl
HBA1C: 5.2%
ALT: 25.0

So for me, the statin alone did very little for LDL-C, but did seem to help with the liver.

Rosuvastatin 5mg, and Ezetimide 5 mg: (half doses of each. Only 1 time for this result):
LDL-C: 93 mg/dl
HDL-C 58 mg/dl
Trigs 59 mg/dl
HBA1C: 5.0%
ALT: didn’t measure

Rosuvastatin 10 mg, and Ezetimibe 10 mg: (using the proper doses)
LDL-C: 71 mg/dl
HDL-C: 45 mg/dl
Trigs: 56 mg/dl
HBA1C: 5.2%
ALT: 31.4

So addition of Ezetimibe was incredibly effective at LDL-C lowering. The 5mg is definitely very effective, but 10 mg is still better. The statin at 10 mg does seem to add 0.2% onto my HBA1C. You can see when I reduced the statin to 5 mg, my A1C went back down again. None of the medications has any measurable negative effects on the liver either. In fact, all the results are better than pre-treatment, and ultrasound showed that a small amount of fatty liver totally resolved once I started treatment.

And for reference, I now use 10 mg Rosu, 10 mg Ezet, and Repatha (injectable PCSK9i):
LDL-C: 43 mg/dl
HDL-C: 58 mg/dl
Trigs: 62 mg/dl
HBA1C: 5.2%
ALT: 28.3

Pretty happy with this. And I totally agree with the others that 5 mg Ezetimibe is very powerful in combination with a statin, and 10 mg gets you some incremental additional benefit. I can’t see any value in going higher. If you want to lower LDL-C more, just add a different drug.

6 Likes