Robert S. Rosenson, MD

This study supports that nonadherence to statin therapy is associated with a higher CVD event rate. It showed a higher mortality rate than in patients with a higher adherence to statin therapy.

It supports our work (Serban M-C, et al. J Am Coll Cardiol. 2017;doi: 10.1016/j.jacc.2016.12.036), the first in the literature on this topic that showed that patients who were hospitalized for a MI who downtitrated to discontinue their statins presumably from adverse muscle events had a 50% higher risk for recurrent MI in the next 2 years and a 51% higher risk of being hospitalized for CVD events.

Following our study, there was a trial conducted by the Partners group of Brigham and Women’s Hospital and Massachusetts General that went through case reports (Zhang H, et al. Ann Intern Med. 2013;doi:10.7326/0003-4819-158-7-201304020-00004.). They showed that patients that discontinued or downtitrated their statins had a higher mortality rate.

The current study focuses on people with atherosclerotic CVD, which includes patients with MI and probably patients without MI who have coronary disease or atherosclerotic CVD. It shows that not only are they at a high rate for CVD events, but also have a higher mortality rate.

These three studies are all consistent with regards to the fact that statin nonadherence is a very important predictor of a bad outcome.

These findings have a lot of implications for public health. There are many patients that fear starting a statin because they hear of an adverse event, which may or may not be related to statins. Some patients who have CVD refused to be placed on a statin because they have a fear of muscle aches or weakness that were reported by a relative or a friend. Patients at high risk for CVD events have to realize that statins are the most extensively studied cholesterol-lowering therapy of all time and they consistently reduce risk for MI and stroke and improve survival. The reduction in CVD events is seen in people who are at risk for a CVD event and an even greater impact has been established in patients with known atherosclerotic vascular disease. Patients need to discuss the benefits and risk of statin therapy with their health care providers. They need to understand that discontinuation of statin therapy due to the perception of side effects may or may not be related to the statin and increases the risk for a recurrent MI or stroke and dying.

This study, similar to our study, puts this whole concept into context by saying that it is not just a matter of stopping the statin and your cholesterol goes up. There are consequences that you are more likely to be in the hospital with a debilitating event — a recurrent MI in our study — or it could be a stroke or the risk for dying.

What this study also tells us with support from the previous two studies is that engaging in a conversation with a health care provider about your fears, your concerns about side effects and symptoms that you think are side effects which may or may not be related to the statin is necessary. There are many examples where people may have a problem with one statin but are able to tolerate another statin. There are differences in terms of drug-drug interactions, drug elimination, people with chronic disease or liver disease or pharmacogenomic inherited differences in drug metabolism that may cause one drug to be a problem but not another drug.

We published two papers in this regard. One was a state-of-the-art review on statin-associated muscle events (Rosenson RS, et al. J Am Coll Cardiol. 2017;doi: 10.1016/j.jacc.2017.07.752). We followed that publication with a paper that discussed the contribution of genetics to statin-associated muscle events (Brunham LR, et al. Cardiovasc Res. 2018;doi: 10.1093/cvr/cvy119). The fact that you have a problem with one statin does not mean that you are going to have a problem with a lower dose, or you are going to have a problem with a different statin.

This paper puts into context what happens if you do not adhere to this therapy and you already have vascular disease. This is not a decision that the patient should take lightly by stopping the therapy or not continuing to take the statin therapy every day.

The major side effect of statins are adverse muscle events. Once somebody experiences an adverse event, three out of four people refuse to start a statin. We published that work as well (Mefford MT, et al. Am J Cardiol. 2018;doi:10.1016/j.amjcard.2018.05.016) of 16,000 participants of the REGARDS study who were administered questionnaires.

No. 1, it is very important for the patient to contact their health care professional and discuss these symptoms. No. 2, because the major side effect associated with statin discontinuation are the muscle events, we do not have a simple biological test that can determine whether it is real or not. We are relying on the creatine kinase level, which is a marker of muscle breakdown and may identify people that are at high risk for developing acute kidney injury. People who have a creatine kinase level 10 times or 50 times the upper limits of what is normal are a rare phenomenon. For acute kidney injury, that is one in 100,000.

We developed a scoring tool to identify people that had true statin-associated muscle events (Rosenson RS, et al. Cardiovasc Drugs Ther. 2017;doi: 10.1007/s10557-017-6723-4). This tool is identified based on randomized clinical trials where people crossed over to a placebo or a statin and then treated with either a statin or a placebo, the reverse way. We identified certain characteristics that were reproducible on re-challenge and others that were not. We determined that if you scored low on this tool, there is a 92% chance that it is not related to the statin. It is a very good screening tool.

The health care professional also needs to be educated as to what symptoms are highly likely to be related to an adverse statin effect vs. those that are not. Those symptoms are going to be symmetric muscle aches and weakness typically affecting the hip flexors, found in people who report difficulty climbing stairs, having difficulty getting up from a chair, having difficulty getting up from a toilet and having to lift themselves up because those muscles are weak. It can also occur in the upper arms, where they have difficulty raising their arms above their head or lifting items. Typically, it is a weakness, ache or soreness in both muscles.

Some people report their left arm hurt from carrying groceries and then they assume that it is due to the statin based on the internet. That is an anticipated side effect of carrying groceries with the left arm, but people stop the therapy and they convinced themselves that this is related to the statin. Relying on the internet and not engaging the health care professional could result in adverse consequences (Hill JA, et al. J Cardiovasc Pharmacol. 2019;doi: 10.1097/FJC.0000000000000648). Your life could depend on it.

We have been conducting multiple studies during the past 5 years to gain a better understanding of these effects. We are working on genetic markers, how different metabolic pathways are involved in identifying people that may be at risk for a statin muscle effect. It is ongoing research to develop a biomarker. But right now, diagnosing statin adverse muscle events is a clinical diagnosis.

This was a well-conducted study performed in a Veterans Administration facility where they have electronic medical records, laboratory studies, pharmacy data and encounters with the patients. It is a good-quality study and it supports the two previous studies. All of these three studies are highly consistent with regards to what they have shown using different populations and different states of risk. Ours was post-hospitalization for MI, the current study was people with atherosclerotic vascular disease and then the study from the Partners group was the general population with and without atherosclerotic vascular disease who were treated with a statin. This study falls in the middle and covers the full spectrum of patients who are eligible for statin therapy.