Golfyeti,

Thank you for chiming in. Seems to me that there are a few issues in your post.

1) What are statins approved for?

Statins are not only approved for reducing cardiovascular events, but also for LDL-cholesterol lowering. So statin use for LDL-C is "on-label" not "off-label." LDL-C is a proven and trusted risk factor for cardiovascular disease. Cardiovascular medicine organizations issue guidelines on target goals for LDL-C, and these guidelines get revised over time. LDL-C management is appropriate for both primary and secondary prevention; however, aggressive LDL-C lowering is more common with secondary prevention or for primary prevention in those with other pre-existing cardiovascular risk factors. I'm pretty sure statins were approved for LDL-C lowering prior to any cardiovascular outcomes trials (CVOTs) being completed, but don't quote me on that since I am not 100% sure. More recently, the PCSK9 antibody drugs were approved for LDL-C lowering prior to being approved for cardiovascular event prevention. Esperion (ESPR) filed for FDA/EMA approval for bempedoic acid to lower LDL-C this past February and is seeking marketing approval for LDL-C lowering prior to their ongoing CLEAR Outcomes CVOT trial being completed. Similarly, The Medicines Company (MDCO) is wrapping up their LDL-C lowering program for Inclisiran in H2 2019 and will be filing for LDL-C marketing approval prior to their ongoing ORION CVOT study being completed. 

2) What is the evidence for statins reducing cardiovascular events as secondary prevention in those who have experienced a prior cardiovascular event vs. as primary prevention in those who have not experienced a prior cardiovascular event?

The use of statins for primary prevention is definitely a controversial topic, as you pointed out Golfyeti. There is definitely stronger clinical evidence for secondary prevention than for primary prevention. However, as pointed out in #1 above LDL-C is a proven and trusted risk factor. In this recent review, I like this statement from the conclusion:

"This overview suggests there is mixed evidence on the effectiveness of stains in primary prevention populations; however, this population is heterogeneous with widely ranging baseline risks. For the individual patient and clinician, there are three considerations in the process of informed decision making. First, what is the RR reduction according to the baseline risk of the individual. Second, what is the absolute risk reduction in risk for that person, and finally, what are potential side effects from taking statins in the context of that patient’s preferences."

Along the same lines, this review offers a nice summary:

"No direct evidence from RCTs is available to guide the choice of a specific CVD risk threshold for statin use. However, in the available trials of statin use among adults at increased risk of CVD but without a history of CVD events, benefits have been generally consistent across different clinical and demographic subgroups (even among adults without marked dyslipidemia). As such, the likelihood that patients will benefit from statin use is directly associated with their absolute baseline risk of experiencing a CVD event."

Primary prevention encompasses a wide range of risk levels. Obviously, the CVD risk for a mid-thirties age non-smoking patient with no prior cardiovascular event, normal body weight, normal blood pressure, normal glucose control, normal triglycerides, normal hsCRP, no family history of cardiovascular disease (CVD), but with elevated LDL-C but with is going to be lower than a 50 to 60 year old obese, diabetic or insulin-resistant patient who smokes with elevated blood pressure, elevated LDL-C, elevated hsCRP and elevated triglyerides, a family history of CVD but no prior cardiovascular event. The efficacy and decision making for LDL-C management in primary prevention is highly dependent upon the absolute baseline risk. The evidence for primary prevention benefit of statins for those with minimal other risk factors might be weak, but the evidence of statin benefit for primary prevention in those with substantial CVD risk seems solid.

3) What are the chances of off label use of apabetalone for primary prevention of cardiovascular events if and when approved after BETonMACE for high-risk diabetics with low-HDL and recent ACS event?

 Assuming that BETonMACE succeeds, I won't be surprised if apabetalone gets prescribed off-label for cardiovascular event prevention in lower risk patients for secondary prevention. For example, diabetic with recent ACS but normal HDL. Non-diabetics with recent ACS and low-HDL. Pre-diabetes, but insulin resistant, with recent ACS and low-HDL. And on and on. These are all close, but not exactly the BETonMACE patient criteria. The further one stretches from the BETonMACE population, the less in known about the clinical benefit. Unfortunately, there won't be enough information from BETonMACE to know if apabetalone is effective for primary prevention for those at high-risk for experiencing their first cardiovascular event. But I won't be surprised if some docs would prescribe it for primary prevention in high-risk patients prior to apabetalone being shown in clinical trials to be effective for primary prevention. If BETonMACE succeeds, there will surely be follow up CVOTs in other populations. So the story is to be continued.....

BearDownAZ