Statin monotherapy vs combination with ezetimibe

#1

Several articles were published this week in the prestigious European Heart Journal on (mostly high-dose) statin monotherapy vs (mostly low-dose) statin + ezetimibe combination (or some variations). I thought a dedicated thread could be useful.

Efficacy of lipid lowering therapy beyond statins to prevent cardiovascular events (Germany)

Treatment with ezetimibe or a PCSK-9 inhibitor was associated with a 19% risk reduction in cardiovascular events (OR [95%CI]: 0.81 [0.75; 0.86]). Effect sizes were similar for myocardial infarction (0.81 [0.74; 0.89]) and even more pronounced for ischemic stroke (0.77 [0.70; 0.84]). In contrast, all-cause mortality was not improved by the intensified lipid lowering therapy (0.99 [0.93; 1.04]). Stratifying by follow-up duration of < vs. ā‰„ 3 years, no improvement in all-cause mortality was observed in both groups (<3 years: 1.04 [0.93; 1.17]; ā‰„3 years: 0.97 (0.88; 1.06).

Safety and Efficacy of Moderate-intensity statin plus ezetimibe versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease: a meta-analysis (Brazil)

Analysis revealed significant MIS+EZT-associated with greater percentages in Low Density Lipoprotein (LDL) < 70 (Odds Ratio (OR) 1.76; 95% CI [1.26; 2.45]; p=0.001; IĀ²=73%), LDL reduction (Mean Difference (MD) -5.05 mg/dL; 95% CI [-9.02;-1.07]; p<0.013; IĀ²=56%;); Total Cholesterol reduction (MD -7.91 mg/ dL; 95% CI [-14.90; -0.91]; p<0.027; IĀ²=60%); Triglycerides reduction (MD -8.20 mg/ dL; 95% CI [-13.05; -3.35]; p<0.001; IĀ²=2%;); There was no statistical difference between groups in Drug Adverse reaction (Risk Ratio (RR) 1.19; 95% CI [0.79; 1.78]; p=0.404; IĀ²=0%); and Drug intolerance (RR 0.78 ; 95% CI [0.32; 1.92]; p=0.584; IĀ²=35%).

The upfront lipid-lowering combination therapy of statins and ezetimibe vs statin monotherapy in the reduction of cardiovascular outcomes. A meta-analysis. (US, UK, India, Poland)

Pooled analysis shows that combination LLT significantly reduces the LDL-C level from the baseline (MD, -12.13 mg/dl [0.31 mmol/l] (95%CI: -18.26 to -5.99 mg/dl), p<0.001), all-cause mortality (ACM) (OR, 0.75, 95%CI: 0.62 to 0.92, p=0.01), cardiovascular mortality (CVM) (OR 0.75, 95%CI: 0.66 to 0.84, p<0.001), major adverse cardiovascular events (MACE) (OR, 0.72 95%CI: 0.63 to 0.82, p<0.001), non-significant reduction in the incidence of stroke (OR 0.82, 95%CI: 0.66 to 1.01, p=0.06) when compared with statin monotherapy alone. Similarly, the therapy discontinuation rate was comparable between combination LLT and statin monotherapy groups (OR, 0.87 (95%CI: 0.53 to 1.40), p=0.56). The risk of adverse events related to the gastrointestinal tract (OR, 1.12 (95%CI: 0.93 to 1.36), p=0.23) and musculoskeletal system (OR, 0.88 (95%CI: 0.52 to 1.50), p=0.65) was comparable between both the groups of patients.

Ezetimibe use and mortality after myocardial infarction: a nationwide cohort study (Finland)

Patients with early ezetimibe after MI had lower all-cause mortality during follow-up (33.6% vs. 45.1%; adj. HR 0.77; CI 0.69-0.86; p<0.0001). Early ezetimibe use was associated with lower mortality irrespective of sex, age, atrial fibrillation, diabetes, heart failure, malignancy, revascularization, or statin use. Ongoing ezetimibe therapy during follow-up was associated with lower mortality in time-dependent analysis (adj. HR 0.53; CI 0.48-0.59; p<0.0001).

Efficacy of combination lipid lowering therapy in achieving low density lipoprotein cholesterol targets after one month of event in patients with acute coronary syndrome (India)

dual RE (rosuvastatin plus ezetimibe) and triple REB (rosuvastatin plus ezetimibe and bempedoic acid) combination LLT
The percentage reduction in LDL-C level was 44.4%, 55.5%, and 62.2%, respectively (p<0.001). REB enabled 70.8% and 95.2% of patients to achieve the Lipid Association of India, and American College of Cardiology recommended LDL-C targets of <50 mg/dl and <70 mg/dl within 4 weeks. These target levels were achieved in 67.6% and 88.7% of patients on the dual RE therapy and 50% and 81.6% of patients, respectively, on HIS alone.

Efficacy of combination therapy with statin and ezetimibe versus high dose statin monotherapy in secondary prevention in high-risk patients (Romania)

None of the patients had taken lipid-lowering drugs in the previous 12 months. Patients were randomly assigned to one of two treatment groups: Group 1 - rosuvastatin 40 mg (n= 144) and Group 2 - rosuvastatin 40 mg and ezetimibe 10 mg (n= 120).
As expected, the combination therapy reduced LDL-cholesterol at one month significantly higher compared to high-dose statin monotherapy (-59.65% versus -37.54%; p< 0.0001). After one month of treatment, only 47.92% of patients in Group 1 reached the LDL-cholesterol target (<55 mg/dL) compared to 90.00% of the patients in Group 2 (p<0.0001; R.R.= 0.53).

High intensity statin-ezetimibe combination therapy reduces mortality in patients with ischaemic heart disease and elevated Lipoprotein(a) (Singapore)

Compared with a less intensive regimen, HI statin-ezetimibe was associated with reduced risk of all-cause mortality (HR 0.44 [0.21-0.89], P=0.023) and MACE (HR 0.71 [0.52-0.95], P=0.027), with no statistically significant effect on cardiovascular mortality (HR 0.43, P=0.142). Notably, the cardiovascular benefits of HI statin-ezetimibe were more pronounced in patients with elevated Lp(a); a greater reduction in risk of MACE was seen for patients with Lp(a) ā‰„70 nmol/L (HR 0.51, P=0.007) or Lp(a) ā‰„100 nmol/L (HR 0.36, P=0.009), and in all-cause mortality risk for those with Lp(a) ā‰„70 nmol/L (HR 0.24, P=0.025). Although LDL-C reduction >50% was associated with reduced risk of all-cause mortality (p=0.027), this could not fully explain the overall cardiovascular benefit of HI statin-ezetimibe use in patients with or without elevated Lp(a).

Combination of moderate-intensity statins and ezetimibe versus high-intensity statins alone for primary prevention of cardiovascular events (Canada, US)

We included all adults aged ā‰„ 67 years (eligible for drug coverage) with a first prescription of either a combination of moderate-intensity statin with ezetimibe (ā€œcombination therapyā€) or high-intensity statin alone between January 2010 and December 2022. Patients were excluded if they had not received any prior lipid lowering therapies or had a history of myocardial infarction (MI), stroke, heart failure, peripheral vascular disease or prior coronary revascularisation at any time before or within 3 months of treatment initiation.
The cumulative incidence of the primary outcome at 10 years in the weighted cohort was 32.7% in the combination therapy group and 36.1% in the high-intensity statin group (HR: 0.87; 95% CI: 0.82 to 0.92; p<0.001; absolute risk reduction: 3.5%; 95% CI: 0.8 to 6.1; Figure 1). This result was primarily driven by a lower risk of all-cause death (HR: 0.85; 95% CI: 0.80 to 0.91; p<0.001; Figure 2) and stroke (cause-specific [cs] HR: 0.86; 95% CI 0.74 to 0.99; p=0.04), whereas no differences were observed in the risk of MI (csHR: 0.97; 95% CI: 0.82 to 1.15) or coronary revascularization (csHR: 0.97; 95% CI 0.85 to 1.11).

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Moderate-intensity statin combined with ezetimibe versus high-intensity statin monotherapy for secondary cardiovascular risk reduction: a systematic review and meta-analysis (Italy, US, Brazil, Taiwan, India)

Cardiovascular mortality (RR 0.83; CI95% 0.73-0.94; p=0.003), all-cause mortality (RR 0.90; CI95% 0.82-0.98; p=0.02) and non-fatal stroke (RR 0.83; CI95% 0.73-0.93; p=0.002) were significantly lower in patients treated with MIS+EZE compared to those treated with HIS. A significantly higher proportion of patients in the MIS+EZE group reached an LDL-C ā‰¤ 70mg/dL (RR 1.26; CI95% 1.19-1.34; p<0.00001). No statistically significant difference was found for non-fatal myocardial infarction (RR 0.87; CI95% 0.64-1.17; p=0.36), coronary revascularization (RR 1.03; CI95% 0.78-1.35; p=0.83), heart failure (RR 0.95; CI95% 0.86-1.06; p=0.38) and unstable angina (RR 1.52; CI95% 0.62-3.75; p=0.36). A RCT sub-analysis was feasible for cardiovascular mortality and showed no statistically significant difference between the two groups (RR 1.01; CI95% 0.42-2.42; p=0.98).
Regarding safety endpoints, the risk of adverse events (RR 0.84; CI95% 0.74-0.95; p=0.004) and the risk of muscle-related adverse events (RR 0.67; CI95% 0.49-0.92; p=0.01) were significantly lower in MIS+EZE group. The significant reduction in muscle-related adverse events was maintained in the RCT sub-analysis (RR 0.61; CI95% 0.41-0.91; p=0.02). There was no difference between groups in the risk of liver-related adverse events (RR 0.63; CI95% 0.29-1.41; p=0.26) or new-onset malignancy (RR 0.99; CI95% 0.87-1.12; p=0.85).

All the above are from the European Heart Journal, while this one is from a less prestigious journal and research team: Efficacy and safety of double-dose statin monotherapy versus moderate-intensity statin combined with ezetimibe dual therapy in diabetic patients: a systematic review and meta-analysis of randomized controlled trials (India, Pakistan, Bangladesh, Ukraine, US)

Monotherapy showed no significant difference compared with dual therapy for low-density lipoprotein-cholesterol levels [mean difference (MD): āˆ’5.03; P = 0.37], high-density lipoprotein-cholesterol levels (MD: 0.01; P = 0.95), total cholesterol (MD: āˆ’2.38; P = 0.66), and triglycerides (MD: 5.37; P = 0.67) at follow-up compared to baseline. Monotherapy significantly reduced serious clinical adverse events (risk ratio: 0.21; P = 0.04), with no difference in treatment-related adverse effects, discontinuation due to treatment-related or overall adverse events.

Other similar papers published on this topic this year that reached similar conclusions:

To me, the topic is now closed, and low-dose statin + ezetimibe seems superior to high-dose statin. Thoughts @CronosTempi @Neo @AnUser?

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#2

Great collection of papers, Antoine. I have tried to locate the papers I saw which showed a different signal, but so far cannot locate them, which is super frustrating. One paper was focused I think on plaque regression, and it showed that mes+eze was better at plaque regression than mono-his, but surprisingly mono-his was superior in acm; the other paper had a graph with eze showing mild worse acm on its own. This was awhile ago, and I was doing research for myself in picking the best approach to llt for me, and so I only made mental notes to myself ā€œoh, ok, so eze is out for meā€, and never bothered to write down the pmid as I wasnā€™t doing it to present an argument in a forum - but now of course itā€™s come back to bite me when I need those papers again. That said, the papers you came up with present a pretty strong case, whereas what I remember from my papers was that they were only signals (trend lines, close but not significant, minor effect etc.), and not strong results, like yoursā€¦ so unless I can find those papers soon, Iā€™ll concede the point. This is the downside of doing a lot of reading, you notice some point in passing, and donā€™t think to write down the paper and then canā€™t find it.

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#3

Thatā€™s why Iā€™m doing this forum as my notes :joy: and I try to post here whenever I find something interesting. Otherwise I have the same problem.

Coming back to the topic: yes, until recently papers were mixed. I think now the case for the combination is stronger.

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#4

Great compilation

I think this supports general conclusion at a Medicine 2.0 level, for Medicine 3.0 / our individual N=1 optimization level Iā€™d have the following questions

  1. Does above hold for both hyper absorber and producers of cholesterol. Above makes it very high probability that the case is yes for the absorber phenotype. For the hyper producer phenotype the jury might still be out - or have you seen any papers where they stratified people along that line? (Itā€™s very easy to find out your time, at least in the U.S. with a home test for 99 bucks).

  2. Would the Eze combo results be even better if a person measured their Omega Index and optimized their actually Omega types and levels their body is experiencing (vs just guessing at what dose to take via food and supplements). This is also quite simple to test.

  3. Usual point about that unless a study was designed and sized in number of patients (huge) and duration (long) to detect differences in all cause mortality an absence of such a signal does not mean evidence that their is no such signal.

  4. To what extent is the statin important here vs the general principle of lower dose combination therapies being better than (higher dose) mono therapies in Apo B and CVD?

  5. Usual issues of people at risk of or with a disease may not be representative of people without the disease and even less so for generally optimized longevity biohacker, etc

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#5

This is consistent with the thinking that these powerful drugs provide most of their benefit and the least of their side effects at low doses. Adding different drugs at low dose is superior to adding more of the same drugs, is the idea. Still it is probably better to take as few of the drugs as necessary to accomplish the goal. So whatā€™s the goal? Thatā€™s a hard question to answer.

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#6

You should start using Obsidian as your note taking app itā€™s very helpful as second degital brain but donā€™t stop the sharing here please hhhhhh

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#7

From what I remember, hyperabsorbers are about 20% of the untreated population. Itā€™s a small group, so if the positive effect were limited to them, then we wouldnā€™t see the great results above.

However, note that statins increase absorption:

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So, are all statin users hyperabsorbers?

Iā€™ve seen papers about statins being useless in hyperabsorbers, but I donā€™t know if papers looked at the opposite.

Ezetimibe has nothing to do with omega 3 so I donā€™t understand your question:

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But here we do have the signal. So whatā€™s your point?

It could be specific to statins and ezetimibe here given the synergies between statins (that block synthesis but unfortunately increase absorption) and ezetimibe (that do the opposite).

However, the difference in LDL-C reduction is minor (and not even clinically significant) between statin monotherapy and the combo (and one paper notes ā€œAlthough LDL-C reduction >50% was associated with reduced risk of all-cause mortality (p=0.027), this could not fully explain the overall cardiovascular benefit of HI statin-ezetimibeā€). So it might be more than just this synergistic effect on cholesterol levels, and, as you say, another example of ā€œgeneral principle of lower dose combination therapies being better than (higher dose) mono therapiesā€. For instance, how much of the positive effect is just driven by the higher risk of diabetes at high-dose statin?

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#8

Iā€™m not sure about that. Think Peter Attia (perhaps on one of his episodes with Dayspring actually, but not sure) suggested that people re-test their absorber/producer status once on a medical protocol to see if it could be either improved in by tweaking how much they are hitting absorption vs production

Also with regards to this balancing both - not sure if one perhaps can swap in other meds that decrease production for example BA vs a statins - into the frame work and pair with Ezetimibe.

Not sure if you are saying that testing for cholesterol balance (degree of absorber vs producer) for optimal N=1 and ā€œprecision medicineā€ may not be helpful?

#9

Would love to see more evidence on that black and white ā€œnothing to do withā€ statement from you (and not just another black and white statement in a tweet by something who often is too black and white on twitter, perhaps to drive his followers up or something).

The last I saw the jury is still out, with some support that at least for ALA it does impact it negatively. So N=1 / precision medicine where there is a simple test to check Omega 3 index (which probably is with checking for any health optimizer even if not on Ezetimibe) still seems like something a longevity optimizer on Ezetimibe may want to consider.

See for example:

A randomized trial of the effects of ezetimibe on the absorption of omega-3 fatty acids in cardiac disease patients: A pilot study

Conclusion: Ezetimibe therapy inhibited the absorption of omega-3 fatty acids. Patients receiving ezetimibe therapy may not receive the expected cardiovascular benefits from dietary supplementation with omega-3 fatty acids.

I have read all or most refereed articles reporting clinical research or metanalysis, including the one you posted. The scant research is suggestive of the belief that ezetimibe will not substantially block and adsorption of at least some forms of omega-3 under some conditions but it does not exhaust even the omega-3 questions or close all doubts as to its validity. Beyond that, it says little and we know little. Specifically, we know almost nothing about a large number of related dietary substances that may be blocked (partially or wholly) by this drug. To name a few: pro-resolving mediators, omega-7, astaxanthin, lutein.

Conclusion: Ezetimibe therapy inhibits the absorption of omega-ā€3 fatty acids. Patients receiving ezetimibe therapy will not receive the expected cardiovascular benefits from dietary supplementation with omega-ā€3 fatty acids.

The Effects of Ezetimibe on Omega-ā€3 Fatty Acid Absorption in the Prevention

No interactions were found between ezetimibe and Fish Oil. However, this does not necessarily mean no interactions exist.

https://www.drugs.com ā€ŗ ezetimibe-ā€¦Ezetimibe and Fish Oil Interactions - Drugs.com

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#10

Thought some of the papers did not show all cause mortality and just wanted to help ensure people new to reading study results did not see that as signal of no all cause mortality reduction in those cases

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#11

I just started min dose statin + ezetimibe and i took a complete omega 3 test right before including ala. I will take it again in a few months along with the 99$ test to make sure i dont have too low desmeratol for brain health.

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#12

I donā€™t understand your point. Yes, itā€™s great to test the Omega 3 Index and EPA and DHA fractions (by the way: what do you think about this: Omega 3 makes me depressed: why? - #23 by adssx ?). But how does this relates to ezetimibe? (even if would decrease significantly DPA + EHA absorption, youā€™d just have to increase supplementation, no? Or do you mean someone with a low omega-3 index shouldnā€™t take ezetimibe?)

And I canā€™t find papers showing that ezetimibe impacts EPA or DHA but I found two articles showing the opposite (no effect): Interaction among Omega 3, Ezetimibe and HDL - #23 by adssx

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#13

The effect of statins on absorption seems quite complex: Association between cholesterol synthesis/absorption markers and effects of cholesterol lowering by atorvastatin among patients with high risk of coronary heart disease 2013

The effect of cholesterol lowering by atorvastatin was significantly associated with baseline lathosterol levels but modified bidirectionally by baseline campesterol levels. In patients with the highest baseline campesterol levels, atorvastatin treatment decreased cholesterol absorption by 46.1%, which enhanced the effect of LDL-C lowering. Atorvastatin treatment increased cholesterol absorption by 52.3% in those with the lowest baseline campesterol levels, which attenuated the effect of LDL-C reduction.

They conclude:

Based on these findings, instead of high absorption before statin treatment, patients with low cholesterol absorption, especially in the setting of high cholesterol synthesis, may particularly need combination treatment of a statin and ezetimibe at the beginning of treatment.

If this is correct, then you can indeed test for cholesterol balance:

Conclusion: ezetimibe + statin for everyone andā€¦ precision medicine becomes useless? (I donā€™t know :man_shrugging: )

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#14

@Neo FYI. I have been taking ezetimibe for 2 years. My omega index is 10.3%. N=1. I eat a lot of fish (tuna/ salmon) and walnuts (ALA), and I take fish oil most days. I was worried about ezetimibe but not any longer.

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#15

@Joseph_Lavelle Perfect, and must feel good to have that data vs just hoping that your index was good and living in darkness

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#16

Iā€™m saying the need to measure in order to know whether and to have an estimate of how much to supplement and then to confirm if there supplement choice was working

Without testing people with either overshoot (too much might be bad for a fib, etc)

Iā€™m not following why you ask that, I said

  1. Would the Eze combo results be even better if a person measured their Omega Index and optimized their actually Omega types and levels their body is experiencing (vs just guessing at what dose to take via food and supplements). This is also quite simple to test.

ā€”

(Havenā€™t read the the depression thread yet so donā€™t have the full context to comment on they part)

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#17

One can do it a bit more calibrated if one really wants itā€™s not just Eze = yes/no and Statin = yes/no one can be low dose or high dose of either etc and the cholesterol balance tests can help an health optimizer work on that calibration (even if I understand the average patient may not want to deal with things at that level)

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#18

Putting aside the cost and time required (and therefore the therapeutic lag compared to early combined ā€œkeep it simple stupidā€ statin + ezetimibe intervention), given the complexity and the interplay between the two I donā€™t even know how you could do that. What would be the decision tree/algorithm? There might be an optimum, such an optimized algorithm might be discovered one day (:pray:), but as of today, my conclusion based on the literature is: ezetimibe + low-dose statin for everyone, with the exception of hyperabsorbers who can start with ezetimibe only (thatā€™s my case: ezetimibe lowered my LDL and ApoB by 40%! So I didnā€™t need to add a statin). Alternatively, everyone can start with ezetimibe and if enough (most likely hyperabsorbers) stop there and if not add a low-dose statin. If ezetimibe + statin not enough: add BA or PCSK9i or one day obicetrapib?

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#19

@adssx Personally Iā€™ll simply do the home cholesterol balance test now and then and use that to eg help calibrate whether to be on 3, 5 or 10 mg of the Ezemibe

The cholesterol balance test will also help me decide on how much to bring on any statin at all (assuming Iā€™m continuing with my PCSK9), with regards to not having demosterol go too low since that might have a negative risk profile for neurological

Iā€™m not saying that cholesterol balance test will answer all questions, but combined with detailed lipid panels (I like NMR + Apo A/B + Lp(a)) and a other testing I feel it has begun to help me calibrate in on exact protocols and since lipid management is something expect to be doing for many decades, perhaps the majority of my entire life, it feels like one of the areas that I want to keep calibrating and now and then optimizing as my body might (will?!) change (to some extent is picked up by this and other tests)

Again this approach is not something Iā€™m arguing the average patient should do, but for someone that is devoting to help optimizing it feel like a simple, relatively low cost way to get some extra data that might help a bit more.

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#20

Everyone is in their own unique situation. Statins, like most meds have side effects, and if you are vulnerable (f. ex. PD), it may make sense to avoid them if you can get your lipids to goal by other means. But every statin has its own profile, so it pays to take that into consideration. The other aspect, is that statins have extensive pleiotropic effects. If you are interested in those ā€œpositive side effectsā€, you have to consider the balance of benefits/negatives, that are relevant to your situation. Statins have been studied extensively - thatā€™s a big plus in my book, because I can have more confidence in knowing what Iā€™m getting and making adecision about the overall effects; often people spring for some med or supplement based on fewer sides but thatā€™s because it has been less studied, not because it is better. I have made an assesment that in my case, a statin makes sense, because I like the ā€œpositiveā€ side effects. YMMV.

Throw in ā€œpleiotropic effects of statinsā€ into pubmed, and read until the cows come home! Iā€™m a fan.

To get you started:

https://www.sciencedirect.com/science/article/pii/S0925443920303161?via%3Dihub

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