Statin Intolerance—Individualizing Drug Therapy for Best Patient Outcomes

A stepwise approach may improve detection of statin intolerance and better cholesterol-lowering management in patients who have had poor medication compliance despite their increased risk of both CVD and type 2 diabetes.

with Alicia Jenkins, MBBS, MD, Dennis Bruemmer, MD, PhD, and Elena Christofides, MD

Statins have been first-line therapy for hypercholesterolemia for decades. Evidence from a meta-analysis of the Cholesterol Treatment Trials indicated that—for every 40 mg/dL decline in low-density lipoprotein cholesterol (LDL-C) produced after one year of statin therapy, achieving a 25% reduction in risk of major cardiovascular events with a doubling of that lipid reduction over five years; and a decrease in all-cause mortality of 9% may be achieved.1

Asian patients show different response to certain statins, making culture a necessary consideration in heart disease management.Statin-induced muscle pain is but one reason that patients with diabetes and heart disease may respond more favorably to one statin over another. Photo: geargodz@iStock .

Muscle Pain is Only One Consideration When Selecting a Statin  

There is often one overriding obstacle presenting in patients when they are first advised to begin taking a statin; it often boils down to side effects, and the most frequent reason for poor adherence is muscle pain.2 Despite a 5% occurrence of explicit muscle pain from statin use when compared to placebo, up to one in three patients still report discontinuing their statin medication because of perceived muscle achiness. This may be explained by widespread reporting of a rarely occurring, necrotizing autoimmune myositis.

In seeking to address patients’ hesitations to fill their prescription for a statin or adhere to their medication regimen, a team of researchers from Australia and the University of Tennessee published a clinical approach to aid in the diagnosis and management of statin intolerance, with an emphasis on muscle-related side-effects.2

Statin cessation due to side effects exposes patients to increased risks of both vascular events and death. The goal of this paper, said co-author Alice Jenkins MD, MBBS, FRACP,FRCP, professor of diabetes and vascular medicine at the University of Sydney, indicated is to offer a stepwise approach in addressing the unlikely event of statin intolerance while discussing consistent definitions and presenting a simple flow chart to guide clinicians through diagnosis and management.2

A key impetus driving development of this approach was the inadequate utilization of statin medications among at-risk patients. "We believe there is still under-use of statins in some groups of people who may benefit from statins; such as those at high absolute risk of CVD, for the primary prevention of CVD in women, older people, those with type 1 diabetes and Indigenous people,” Dr. Jenkins told EndocrineWeb.

“Regarding statin intolerance, clinicians are concerned that there may be detrimental long-term outcomes unless statins are avoided, but this is rarely the case. There are therapeutic compromises that may be offered to reticent patients, in most cases, nearly all patients can take a smaller, but effective dose of statin," or a more moderate intensity statin, she said.

How Common is Muscle-Related Pain from Statins?

Everyone agrees muscle-related pain is a valid concern, but exactly how much of an issue is a matter of ongoing debate. In general practice, the authors pointed to an incidence of about 10%, despite a rate of about 1.5 to 5% of those who participated in statin-focused randomized controlled trials (RCTs).3 Still, those numbers are considered to be low, since the RCTs excluded anyone reporting a history of statin intolerance.4

A more recent association with an increased risk of new onset diabetes has been reported in findings out of the Prevention of Cardiovascular Events (JUPITER) trial,5 in which investigators reported a 25% higher incidence of new onset type 2 diabetes in those taking a statin versus placebo.

While the researchers also referred to other less common side effects such as memory impairment, the emphasis of this clinical practice approach focused on the most common barrier raised by patients—muscle-related side effects.

In actual clinical practice in the United States, the debate regarding the frequency of this adverse effect continues. For example, about 30 or 40% of patients report muscle pain, said Elena Christofides, MD, FACE, chief executive officer of Endocrinology Associates in Columbus, Ohio, in reviewing the paper for EndocrineWeb.

Another expert, Dennis Bruemmer, MD, director of cardiometabolic health at Cleveland Clinic, had found that the overall number from his experience was much lower, closer to one in 100 patients.  

Combating Statin Intolerance with a Clear Definition of Muscle Pain

Regardless of questions swirling around the exact number of patients affected by this adverse effect, the more crucial concern is establishing a reasonable method to address this complaint when posed when presented by a patient.

To establish an apparent muscle-related adverse effect, here are two strategies proposed by this research team:2

Define statin intolerance as a crucial first step.  It is ''an inability to tolerate a recommended statin dose to attain the desired CVD risk reduction" because of symptoms, signs and/or tests that indicate statin intolerance, affecting the patient's inability to take the medication.2

Discontinue the statin and see if symptoms resolve and concerns dissipate. First, encourage the patient to give the therapy a few weeks as their body may adjust such that any muscle aches or discomfort will dissapate. Second, contraindications to statins, such as rhabdomyolysis, must be ruled out. Then, when a rechallenge is attempted, the same or similar symptoms recur over days to weeks. All of these steps should be completed for two different statins. A comprehensive history, exam and relevant investigations should be carried out to exclude any other reasons for this adverse effect.2

Secondary Phase in Management of Lipid Lowering Therapy After Muscle Pain

Once statin intolerance is indicated (by patient report or clinical confirmation), treatment options to consider:

  • Initiate a different statin—a more moderate-intensity.
  • Return to a lower dose (which may include alternate day dosing).
  • Consider an alternative cholesterol-reducing medication (ie, bile acid-binding resins, ezetimibe, nicotinic acid, proprotein convertase subtilisin/kexin type 9 [PCSK9 inhibitors]).
  • Revisit lifestyle patterns that may be contributory or play a role. It may be that the patient is willing to try a more committed attempt to address diet and exercise behaviors, which would lower LDL-C by 10 to 15%.6

Another important factor, not mentioned in this paper, is the need to consider cultural and ethnic differences. Asians, for example, responded better to rosuvastin compared with atorvastin, as reported in the DISCOVERY trial.7

When reintroducing statin therapy, recommend a different statin be tried or suggest returning to the lower dose of the prescribed statin, especially if there was no problem if started at the lower dose without incident. Slow release fluvasatatin XL 80 mg/day, for example, was tolerated by 97% of those with prior muscle pain intolerance; reducing LDL-C by nearly 33%.8

Alternate day statin use may also prove effective as this approach lowered LDL-C by 34%.9 And, when prescribing alternate day dosing, doing so with atorvastatin and rosuvastatin is preferred given their longer half-lives.10,11

If the patient refuses to consider staying on statin therapy, an excellent alternative is ezetimibe, which reduced both dietary and biliary cholesterol and LDL-C by 15 to 25%.12 Resins and bile acid sequestrants such as colestipol and cholestyramine have achieved a 15-26% lower LDL-C but may also boost  triglycerides.13 .Fibrates lower CVD risk by 35% in those with dyslipidemia.14

A PCK9 inhibitor—given two to four times a week subcutaneously—may reduce high LDL-C by 50-70%.15 Another option: LDL apheresis, twice a week, may improve severe familial hyperlipidemia by 65 to 70%.16 . And, on the horizon is a once-daily oral drug, bempedoic acid that does not accumulate in the liver and may reduce LCL-C by 20-30%.17,18

Related article: Statins Promote Bone Health
Related article: Manaing Complex Lipid Disorders

Given Need for Statin Therapy, Acknowldeged Value in Promoting Guidance

Both experts who commented on this clinical approach at the behest of EndocrineWeb offered different views of proposed protocol.

The summary reflects the approach already adopted by endocrinologists who are up-to-date with cholesterol management, said Dr. Christofides. “Most are already doing this daily.”

Among her critiques of the paper, she pointed out what she considered a glaring omission: the research did not talk about pitavastatin (Livalo), which "doesn't have any of the same muscle-related issues" that other statins may pose.

When her patients complain about a muscle pain after starting a statin, she switches them to pitavastatin. "It's the most beneficial statin in terms of alleviating the myalgia. We use it often.” When pressed, the Australian researchers say they did not include pitavastatin because it was not readily available in Australia.

The new report is not a primary research paper, Dr. Bruemmer says, but rather ''it is more for guidance. It is really important for physicians to identify those patients who really have true statin-induced myalgia," he told EndocrineWeb since word-of-mouth and media reporting about this side effect may affect people who fear this problem or may believe it is occurring but isn’t really.

"When we have a patient who has been started on the medication and comes in with statin-induced myalgia, the first thing we do is stop the medicine and consider possible risk factors," he said. Next, patients are rechallenged on a lower dose or switched to a different statin.

Patients with Diabetes Are Strong Candidates for Effective Lipid-Lowering Therapy

“The authors essential follow this algorithm in their practice guidance," he said. "In all of this discussion, we have to keep in mind that for endocrinologists, most of the patients needing a statin are going to be patients with diabetes." And these individuals, he said, ''should be on a high-intensity statin."

What the new report did not address, is that many patients with diabetes are not being prescribed a statin appropriately, he said, even after a myocardial infarction.19

The previous argument about patients who voice a desire to avoid statin therapy or see cost as a barrier, does not fly these days, according to Dr. Bruemmer. "We need to recognize that there is a disconnect between what is understood about CVD and diabetes and what we are actually doing in our practices."

The researchers agreed that resistance to statin therapy remains a central issue, regardless of the cause. "Non-adherence represents a huge missed opportunity for both patients and clinicians with regard to demonstrated evidence of reduced risk of heart attack and stroke as well as improved survival. Non-adherence to appropriately recommended statin therapy has been associated with significant detrimental outcomes," said Dr. Jenkins. This reality should be clearly stated to these high-risk patients with diabetes, obesity, metabolic disease, and other cardiovascular-related conditions.

Clinical guidance such as the one produced by these researchers certainly will help more clinicians properly diagnose and manage statin intolerance thereby keeping more patients on statin therapy for the long-term, Dr. Jenkins said.

There were no financial conflicts related to this article to disclosure.  

Continue Reading:
Calculating Diabetes Risk in Patients Taking Statins
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