Primary Care Corner with Geoffrey Modest MD: Nonstatin Lipid Lowering Drugs, and Statin Myopathy

By Dr. Geoffrey Modest

The ACC/AHA has just released a therapy guideline for patients who are on a statin but do not achieve the goal LDL (see http://content.onlinejacc.org/article.aspx?articleID=2510936#tab1 for full guideline). The context here is that recent guidelines have suggested that we do not add meds on top of statins, but there are a couple of studies which led them to change these recommendations). Main points:

• If a patient is on a high-intensity statin but not achieving the goal LDL (which in the former guidelines was >50% decrease in LDL, though they are noting that one “may consider LDL <100” as a target)
  • Address statin adherence and intensify lifestyle changes (consider phytosterols)
  • Increase to high-intensity statin if not already on one [as pointed out in prior blogs, there are really pretty broad differences in statin intensity within their groupings: rosuvastatin 40 gets more LDL reduction than atorvastatin 40, so I definitely move within the high-intensity group as my first med change. As a side-issue, I do see many patients who have a really low LDL, in the 40-50 range, even on “low-intensity” statins, and I do not move to more intense ones — see my many prior blogs on this: I am still pretty convinced of the data on treating to a goal LDL and still do so. And I think their “consider LDL<100” suggests that they are moving more in that direction as well]
  • Consider adding non-statin meds:
    • Consider ezetimibe first, or consider adding or replacing with PCSK9 inhibitor second
  • Especially in patients with clinical CAD, and especially in diabetics, it is better to look at non-HDL levels (i.e., total cholesterol minus HDL), which has more predictive value than LDL levels [there are a few studies I have seen on this. In general, for those just on statins, the non-HDL is a better predictor of further clinical events (see JAMA 2012; 307:1302), and the target is non-HDL <100. as per above, they do include as a “may consider” the LDL goal of <70 or non-HDL goal of <100]
  • In high risk patients on a statin who do not achieve the goal, consider adding ezetimibe [though they acknowledge there is an evidence gap there, which is a euphemism for the fact that this has not been studied], or a bile-acid sequestrant if triglycerides <300 as second line [also no clinical outcome data on this….]. And in those with really high risk (documented CAD plus baseline LDL>190 and not achieve >50% LDL reduction or LDL<70), consider adding PCKS9 inhibitor even as a first step
  • They even consider PCKS9 inhibitors in patients without clinical CAD but baseline LDL>190 and not achieve >50% reduction in LDL on high-intensity statin. But no clear role for them for primary prevention or LDL <190, with or without diabetes
  • Can consider a nonstatin add-on in adults 40-75 yo without clinical ASCVD or diabetes, LDL 70-189 and estimated 10-year risk of >7.5% and on a statin for primary prevention but who do not achieve a >=30% reduction in LDL. consider ezetimibe or bile-acid sequestrant
• They are not so clear on what to do if the patient is statin-intolerant. They do suggest that there may be less problem with lower statin dose [and the data are pretty clear that the majority of LDL reduction is with 5-10mg of a statin] or less frequent dosing [I have seen some data long ago suggesting similar lipid effects if take atorvastatin only a few times a week as with every day.]

Interestingly, at about the same time as the AHA came out with their guidelines for using non-statin lipid lowering therapy, JAMA published the GAUSS-3 RCT which found that the commonly-reported statin myopathy is very often not really true, and also found that evolocumab (a PCSK9 inhibitor) is much more effective than ezetimibe (see doi:10.1001/jama.2016.3608).

Details (in pretty brief):

• 511 patients with uncontrolled high LDL levels and a history of intolerance to 2 or more statins (e.g. atorvastatin 10mg or any dose of other statins)
• 2 phases of the study:
  • Phase A: a 24-week crossover trial with atorvastatin 20mg vs placebo, on each drug for 10 weeks
    • 491 patients (mean age 61, 50% women, 35% with CAD, mean LDL of 212. BMI 28, 95% white, 35% with CAD, 10% smokers, 13% diabetic, 63% high risk with 10-yr risk Framingham risk score of >20%. more than 80% were intolerant to 3 or more statins)
    • Results: “intolerable” muscle symptoms in 43% (209 of the 491) in those put on atorvastatin but not on placebo; 130 (27%) had muscle symptoms only on placebo; 48 (10%) had symptoms on both placebo and atorvastatin; and 85 (17%) had symptoms to neither drug
  • Phase B: those with muscle symptoms only on atorvastatin were randomized to ezetimibe 10mg/d vs evolocumab 420 mg subcutaneously per month.
    • Results: mean LDL 220 initially, decreasing to:
      • Ezetimibe: 183 mg/dL, absolute decrease of 31.0 [-16.7% (-20.5 to -12.9%)]; 0% achieved LDL <70 at 24 weeks
      • Evolocumab: 103.6 mg/dL, absolute decrease of 106.8 [-52.8% (-55.8 to -49.8%)]; 27% achieved LDL <70 at 24 weeks
    • Muscle symptoms reported in 28.8% on ezetimibe and 20.7% on evolocumab.

So, several issues:

• In this last study, the presence of “intolerable” muscle symptoms actually from statins was confirmed in a minority of patients who had failed >= 3 statins in 80% of them. And a large retrospective study looked at people who had discontinued a statin due to adverse effects but were then rechallenged, finding a 92% success in restoring therapy, although not necessarily with the same statin or dose. This brings up the “nocebo” effect, where placebo gives patients either a perceived adverse effect (e.g., myalgias, in the above study) or even a profound measurable physiologic effect (e.g. hypotension in a patient who “overdosed” on placebo) — see prior blog: https://stg-blogs.bmj.com/bmjebmspotlight/2013/11/25/primary-care-corner-with-dr-geoffrey-modest-nocebo/ . And, for better or worse, patients are more focused on adverse effects of meds than before (?? why: related to TV advertising, more distrust of meds given publicity of drug company malfeasance, deterioration in clinician/patient relationship….). But, in my experience, the bottom line is that if a patient is convinced that a med has a bad adverse effect, there is a pretty low probability that changing to another of the same class of drug will work.
• Unfortunately the new guidelines do not really answer a pretty common question: what do I do with patients who are unable to take statins, even after trying several different ones at low doses?  The ACC/AHA guidelines punt on this one, with some vague recommendation that these patients “should be evaluated for statin intolerance and considered for referral to a lipid specialist”. The reality is that there really are limited possibilities, as follows:
  • Ezetimibe: the reason for including ezetimibe as an “add-on” drug in the ACC/AHA guidelines above is based on the IMPROVE-IT trial (see https://stg-blogs.bmj.com/bmjebmspotlight/2015/06/23/primary-care-corner-with-geoffrey-modest-md-improve-it-trial-ezetimibe/for the blog on the IMPROVE-IT trial of simvastatin plus ezetimibe vs just simvastatin on patients with acute coronary syndrome, finding small but significant benefit with the addition of ezetimibe, though this drug-company sponsored trial and, per the blog, raises many questions about how useful ezetimibe really is as an adjuvant (e.g., it might be more useful to raise the statin dose maximally first). There are no studies on other cardiac conditions (primary prevention, those with stable CAD, etc.). And the data on ezetimibe is pretty clear: those with genetic mutations which presumably create the same situation as by ezetimibe (inhibiting the Niemann-Pick C1 like 1 protein) have lower ASCVD risk, ezetimibe lowers LDL cholesterol by about 17% alone, and provides an additional 14% reduction beyond that of simvastatin, but the trials of using ezetimibe are pretty bad (other than IMPROVE-IT): a 14-month trial of people with CAD on a statin were randomized to ezetimibe or 2 g of niacin, finding an increase in carotid intima-media thickness (CIMT) with ezetimibe, vs decrease with niacin. a 2 year study (ENHANCE trial) in patients with familial hypercholesterolemia put on simvastatin 80mg with or without ezetimibe found that ezetimibe lowered LDL a lot, but there was again an increase in CIMT with the addition of ezetimibe and a nonsignificant trend to more cardiac events with ezetimibe. bottom line: I am not so excited about this drug, and in general would not prescribe it alone (without a statin) and would first really push the statin to the maximally effective one (eg rosuvastatin 40) before considering it as an add-on
  • PCSK9-inhibitors: pretty powerful LDL lowering (though in the above study, the 52.8% is on a par with the high-intensity statins). The only clinical study to date is the pretty short 11 month OSLER study (N Engl J Med 2015; 372:1500), which found that evolocumab plus standard therapy (mostly statin, some on just ezetimibe) had a 61% decrease in LDL, and 0.95% cardiovascular events (vs 2.18% in the standard-therapy group). So, really expensive drug, reasonable at this point in patients at very high risk of a clinical event with suboptimal LDL lowering on a maximal statin, bigger studies are ongoing, and no clinical data yet on monotherapy.
  • And the old standbys, with some reasonable clinical data:
    • Cholestyramine: lipid research trial: lowered LDL 10-20%, 2% decrease in ASCVD events for each 1% lowering of LDL. No mortality benefit but study was not powered to achieve than endpoint. I have been using more colesevalam as my preferred bile acid sequestrant, since it is a little stronger in terms of LDL reduction and has additional benefit on LDL when added to a statin, though there are no studies showing it specifically has clinical benefit (and there are some studies showing improved glycemic control in diabetics)
    • Gemfibrozil: Helsinki study: 1% decrease in cholesterol was associated with 4% decrease in ASCVD events. Also underpowered for mortality benefit; VA-HIT trial: 22% decrease in ASCVD in those with mean LDL 111 but low HDL of 32.
    • Niacin (which I have not used for years) at high doses in the Coronary Drug Project was associated with 27% decrease in ASCVD over 6 years, with decreased mortality 9 years after the study stopped

So, bottom line: statins are pretty great overall, with significant reduction in lipids and improvement in clinical events within 6 months or so. And the 2 studies looking at long-term effectiveness have confirmed benefit up to 20 years later. One of my major concerns with statins is the recent observation that those on statins revert to stopping their lifestyle changes (“after all, my cholesterol is so good…..”). And probably we get some blame as well (“your cholesterol is so good”, and then move on to other issues). Lifestyle changes (exercise, healthy diet, losing weight, decreasing stress, stopping smoking, etc. etc.) are so important for many other things besides lipids (diabetes prevention, improved cognition, decreasing ASCVD beyond the effect of decreasing lipids, increasing longevity…) that we as clinicians should make sure to reinforce these issues. And I have had a couple of patients do so well with lifestyle changes that they have come off statins. And these lifestyle changes take on an even more significant role in those who are intolerant of statins