moderate intensity statin plus ezetimibe in elderly

 A recent study found that moderate-intensity statins plus ezetimibe in the elderly was associated with similar LDL reduction to a high-intensity statin but decreased adverse effects (see lipids elderly mod statin plus ezetimibe JIntMed2025 in dropbox, or doi: 10.1111/joim.20029)

 

Details:

-- 561 patients who were at least 70yo with documented atherosclerotic cardiovascular disease (ASCVD) in South Korea were randomized to high-intensity statin therapy (rosuvastatin 20mg) vs moderate-intensity statin along with ezetimibe (rosuvastatin 5mg with ezetimibe 10mg) for 6 months in the SaveSAMS trial, a prospective, multicenter, open-label, randomized comparison at 11 sites

-- mean age 77, 67% male, 62kg, BMI 24

-- hypertension in 74%, diabetes in 46%, chronic kidney disease in 21% (none of these were further defined: no info on actual BP, A1c, level of CKD)

-- coronary artery disease in 92%, comprising  prior MI in 9%, percutaneous coronary intervention in 81%, and previous CABG in 2%

-- cerebrovascular disease 6%, peripheral artery disease 6%

-- baseline LDL 117 mg/dL

-- at each visit (baseline, one month, a phone visit, and six-months), patients were interviewed about statin-associated muscle symptoms (SAMS), using a validated SAMS clinical index questionnaire with a score of seven or higher being indicative of SAMS https://pubmed.ncbi.nlm.nih.gov/24793443/

-- myopathy was defined as a CK level at least 10 times the normal value in the setting of muscle symptoms (rhabdomyolysis was defined as a CK level at least 40 times the normal value accompanied by a myoglobulinuria or acute renal failure)

-- new onset diabetes was just defined as a hemoglobin A1c reaching 6.5% or higher, or a fasting plasma glucose of at least 126 mg/dL

 

-- Primary endpoint: comparing the interventions for the  incidence of SAMS and their effect on LDL-cholesterol levels

-- secondary endpoints: achievement of target LDL of <70mg/dL within 6 months; also the development of changes in an array of laboratory tests including CK, AST, ALT, total cholesterol, LDL, HDL, triglycerides, hsCRP, and A1c at least 6.5% (ie, developing diabetes)

 

Results:

--The occurrence of SAMS (primary endpoint):

    -- high intensity statin group: 16 of 282 patients

    -- combination therapy group: 2 of 279 patients

        -- 0.7% versus 5.7%, odds ratio 0.12 (0.03- 0.53), p=0.005 favoring combination therapy

-- Achieving target LDL <70 mg/dL (key secondary endpoint):

    -- high intensity statin group: 68.7%

    -- combination therapy group: 75.4%

        -- results were not statistically significant, with OR 1.40 (0.93-2.12), p=0.110

-- other significant secondary endpoints:

    -- combination therapy was associated with:

        -- significantly lower total cholesterol at six months: 124 mg/dL versus 129 mg/dL (odds ratio not provided)

        -- significantly decreased incidence of new onset diabetes: 7.1% versus 15.9%, OR 0.41 (0.19-0.86), p=0.027

        -- zero patients in the combo of myopathy and rhabdomyolysis in either treatment group

  

Commentary:

-- this is the first trial looking at statin-related myalgias in patients over 70 years old, comparing a high-intensity statin versus a moderate-intensity statin with ezetimibe, supporting the safety and efficacy of 5 mg of rosuvastatin (versus 20 mg) but with additional therapy with ezetimibe 10 mg

    -- it was notable in the study that the safety and efficacy of this combination therapy was impressive, with similar effects on LDL cholesterol levels at six months (both were 59 mg/dL), as well as in achieving an LDL cholesterol level less than 70 mg/dL.

    -- and, there were significantly fewer cases of SAMS, as the principal finding, as well as decreased development of new-onset diabetes and the total cholesterol level

   -- prior studies have supported this conclusion; the RACING trial of patients over 75 years old confirmed that a lower dose of rosuvastatin 10 mg plus ezetimibe 10mg had decreased statin intolerance vs rosuvastatin 20mg

-- there are not a lot of good data on treating patients of significantly advanced age with statins, though studies that did include patients older than 75 years old did find clinical benefit from satins. This is not surprising given that the absolute ASCVD risk is higher in older patients and ASCVD is a frequent cause of morbidity and mortality

    -- given that atherosclerotic events are so common in the elderly with the attendant morbidity was well as mortality, and that the benefit of statins in general is evident clinically within 6 to 12 months, it seems to me to be a reasonable argument that barring any dramatic increase in adverse effects, statins (and even aggressive statin therapy) would likely be useful in this group (and I personally have prescribed high dose statins in my many 90+ year-old patients with no evident adverse effects and also very infrequent atherosclerotic events). I also think that the ASCVD risk calculators misleadingly focus on mortality, but the reality of bad morbidity (paralysis from a stroke, chronic heart failure…) may well be a scarier endpoint for many patients than mortality…..

 

 -- it should be noted that there do seem to be differences in the incidence of SAMS associated with different statins. In particular, there are articles suggesting that pitavastatin has lower incidence of SAMS than the others:

    -- the articles i can find on pitavastatin are mostly case reports and not rigorous studies. pitavastatin is associated with SAMS at a lower incidence, but there are few direct comparisons with other statins

        -- however, one study comparing pitavastatin 2mg vs atorvastatin 10mg found no difference in development of diabetes, though the A1c actually increased non-significantly more with pitavastatin (5.5%) vs atorvastatin 3.9%): https://pubmed.ncbi.nlm.nih.gov/18640465/; some other comparisons did find pitavastatin seemed better. This study found only 2 cases of myalgia with atorvastatin vs 1 with pitavastatin.

        -- In general, studies have found that pravastatin, fluvastatin, and rosuvastatin also seems to be assoiaiated with less SAMS than simvastatin or atorvastatin

    -- one might think that SAMS might be more associated with the lipid soluble statins (lipophilic and penetrating cell membranes) than those that are hydrophilic, but this is all unclear:

        -- pitavastatin, as atorvastatin and simvastatin, is actually lipophilic: https://pubmed.ncbi.nlm.nih.gov/34095267/

        -- pitavastatin is considered to be "moderate intensity" and less potent than higher doses of atorvastatin or rosuvastatin

           -- my side comment: the designation of "high intensity" vs "moderate intensity" is based on averages (ie "community data"), but many individual patients have quite dramatic LDL lowering from the "moderate intensity" ones (ie, individual responses can vary a lot from the community averages)

        -- and the actual clinical effects of the lipophilic statins(which cross the blood-brain barrier and can decrease neuroinflammation, a potential target to  decrease the risk of dementia) vs the hydrophilic ones (which do not) is quite up in the air, with mixed studies: https://gmodestmedblogs.blogspot.com/2023/11/atorvastatin-vs-rosuvastatin-better-for.html , a blog which comments more on the relationship between statins and dementia

        -- which all reinforces the various options for patients who do develop SAMS

            -- try the above approach of lowering the statin dose and adding ezetimibe

            -- just prescribing ezetimibe may be a reasonable alternative to statins, with some evidence that it has a similar 30% reduction in primary prevention of cardiovascular disease: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.039415 ; this degree of protection, however, has not been found in some other studies, though the level of cardiovascular protection tracks with degree of LDL lowering: https://www.acc.org/Latest-in-Cardiology/Articles/2016/03/09/06/50/Ezetimibe-The-Lower-the-LDLC-the-Better

            -- there are several older studies finding that the relationship between statins and SAMS is a bit murky:

                -- some with severe myopathy even to 3 different statins still had myopathy when then given placebo

                -- and there are several observational studies finding that vitamin D supplementation in those with low vitamin D levels is associated with a dramatic (eg 95%) lower risk of SAMS on restarting statins: https://gmodestmedblogs.blogspot.com/2017/05/statin-myopathy-and-vitamin-d-deficiency.html (vitamin D receptors are replete on muscle cells)

                    -- and, of course, there is my anecdotal experience, which may or may not mean anything: i have been a pretty rigorous tester of 25(OH)D levels in my patients of all ages for many decades, as well as prescribing vitamin D supplementation to achieve a level of 30 ng/ml. And, i have had a rigorous approach to decreasing LDL levels by nonphramacologic and pharmacologic (statins) for decades. And i have had approximately zero patients who have had SAMS, including my many 90+ year olds with heart disease who are on very aggressive statins to lower their LDL to the 40-50 range, given that in general the lower the LDL, the better: https://gmodestmedblogs.blogspot.com/2018/08/very-low-ldl-levels-benefit-without-harm.html

 

-- the above refers to the typical SAMS. it should be noted that there are the quite uncommon but very severe issues in patients who develop severe rhabdomyolysis (stop the statin and not rechallenge with a different one) or the immune-mediated necrotizing myopathy (needs aggressive treatment with immunosuppressants and never more statins)

 

Limitations:

-- this study was in Korean patients and the results may not be generalizable to other groups. for example, the BMI on average was 24, where in Korean a person with a BMI of 23-25 is considered overweight, a BMI of 25 is considered obese and a BMI of 30 is severely obese

    -- there may  well be related differences in other potential atherosclerotic risk factors, including diet and exercise

-- there are an absence of useful granular data about diet and exercise in this study, which may also have changed during the course of the six-month study, and perhaps differentially with the two group studies (especially since this was an open label study) and any changes might have affected the outcomes

-- this study assessed LDL effects of their interventions, and LDL is a surrogate marker for clinical events and not the actual events themselves. And this is important since, for example, small dense LDL particles are three times more atherogenic than the larger ones and we have no information about that. If there had been a significant difference (perhaps as measured by apolipoprotein B levels), this could influence the results. And there is evidence that lipoprotein (a),  Lp(a), levels are more prognostic for ASCVD risk than LDL: https://gmodestmedblogs.blogspot.com/2024/03/lipoprotein-a-bad-actor.html. and the next blog will have more on the role of Lp(a)

-- the information on the development of new onset diabetes is fraught given that we do not know what the initial A1c levels were prior to meeting the 6.5% cutpoint for defining diabetes. And if the A1c levels were closer to 6.5% in the group on the high intensity statins, a very small increase in A1c could provide a false sense of benefit for the combination therapy

-- also, there was no placebo group and this was an open label study, both of which could affect the quality of the results

-- it turns out that rosuvastatin 40 mg, the highest dose that we can prescribe in the US, is not available in South Korea, so they used the lower 20 mg dosage. (the incidence of SAMS seems to be dose-related, so more likely with the higher dose)

 

So,

-- this study supports the concept of statin therapy in the elderly, with the apparent likelihood of decreasing the risk of statin-associated myopathy with lower dose statin with exetimibe

-- as above, i would argue:

    -- it is worth checking vitamin D levels with 25(OH)D and supplementing if low. this is likely generally beneficial as well as apparently decreasing SAMS

    -- if a problem with SAMS, it might be useful to change to pitavastatin, though this is a moderate intensity statin and not often sufficient in those needing more aggressive LDL lowering

    -- or, as per this study, there seems to be benefit from remaining in the lower statin dosing and using ezetimibe, the latter not related to myalgias

 -- but, my underlying suggestion is that we clinicians should treat hyperlipidemia as aggressively as needed pretty much independent of age if the patient has a life expectancy of at least 1 year or so. And by any ASCVD calculator, older people will have a high absolute risk of an ASCVD event...

geoff

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