Imprecise definitions impair accurate diagnosis of statin-associated adverse events

The major cause of statin intolerance is adverse muscle-related events. However, imprecise definitions have impaired accurate diagnosis of statin-associated adverse events, a speaker said at the National Lipid Association Scientific Sessions.

“The issue of statin-induced adverse muscle complaints is one that is very confused by the patients and the clinicians, and this has tremendous implications for the use of approved therapies that may be options for individuals who cannot tolerate a statin after multiple re-challenges,” Robert S. Rosenson, MD, director of cardiometabolic disorders at Mount Sinai Heart and professor of medicine at Icahn School of Medicine at Mount Sinai, New York, said during a presentation. “Identifying a nomenclature that everyone can understand, one that separates different forms of statin-associated muscle events from each other, is critically important.”

Definitions

The spectrum of statin-associated muscle toxicity includes:

myalgia: unexplained muscle discomfort often described as muscle ache, soreness, stiffness, tenderness or flu-like symptoms with normal creatine kinase;
myopathy: muscle weakness not attributed to pain or associated with elevated creatine kinase;
myositis: muscle inflammation often with muscle enzyme elevations;
myonecrosis: elevation in muscle enzymes, severity graded by elevation of creatine kinase level above pretreatment baseline levels or the upper limit of normal; and
clinical rhabdomyolysis: muscle injury with myoglobinuria and/or acute renal failure.

Tests available to support or confirm the diagnosis of statin-associated adverse muscle events include a proposed clinical index score; muscle enzymes; urinary myoglobin if creatine kinase levels are greater than 50 times the upper limit of normal and/or dark brown; pain questionnaires; strength and aerobic testing; metabolic tests; and pharmacogenetic testing.

“The need for a validated clinical myalgia index is a crucial step for accurate diagnosis,” Rosenson said. He discussed a clinical scoring index that could be used for diagnosis of statin-related myalgia in clinical practice and involved: evaluation of clinical symptoms such as new or increased unexplained muscle complains; the regional distribution and pattern of symptoms, including symmetric pelvic, thigh, calf or upper proximal aches; results of a de-challenge; and results of a re-challenge. As part of an ongoing study collaboration, Rosenson and fellow investigators are looking at this score and attempting to validate it prospectively.

“It is critical to challenge [a patient] — remove the agent and then re-challenge at a lower dose or switch to a different statin. One may have to do this at least twice [based on NLA recommendations] or three times [based on European Society of Cardiology recommendations],” Rosenson said.

Actual rates of myopathy

The prevalence of statin-related myopathy is under debate, Rosenson said.

One reason for the underlying debate is differences in rates in clinical trials vs. clinical practice. According to a systematic review of statin-induced muscle problems in clinical trials by Ganga and colleagues (Am Heart J. 2014;doi:10.1016/j.ahj.2014.03.019), 26 of 42 trials (62%) reported the number of participants with muscle complaints. Only one study specifically solicited muscle complains. Detailed criteria for evaluating mild-to-moderate muscle complains were not presented in 98% of studies included in the review.

“In clinical practice, or the real world, complaints of muscle adverse events are much higher,” Rosenson said. In the PRIMO trial, the prevalence of mild-to-moderate muscle adverse events among patients in France on moderate- to high-dose statin therapy was 10.5%. In the STOMP trial, the prevalence of muscle adverse events was 9.4%; 4.6% of participants assigned placebo met the study definition of myalgia, but the true incidence of statin myalgia was 4.8%. The median time of onset in both studies was 1 month. In a cross-sectional analysis of the National Health and Nutrition Examination Study 1999-2002 data, 22% of 402 statin users reported musculoskeletal pain and 16.7% of nonstatin users reported pain.

PAGE BREAK

The prevalence is “high and nonspecific,” Rosenson said. “This is why we need a validated tool to evaluate these symptoms.”

Differences in rates between clinical trials and clinical practice may be attributable to the placebo effect, the impact of a run-in phase, varying patient populations and different statin types. For example, fewer muscle complaints have been reported with fluvastatin, according to Rosenson.

Predictors of risk

Rosenson identified several clinical predictors of risk for statin-associated muscle adverse events:

older age;
Asian race/ethnicity;
female gender;
exercise;
comorbidities such as hypothyroidism, hyperuricemia, alcohol overconsumption;
statin dose;
history of muscle pain with another lipid-lowering therapy;
family history of muscular symptoms with lipid-lowering agents; and
concomitant medications such as CYP3A4 with simvastatin, inhibitors of CYP3A4 and SLCO1B1 including azole antifungals, ritonavir, verapamil and diltiazem.

Alternative treatments investigated

Several alternative treatments have been or are currently being investigated for use in patients with statin-associated muscle adverse events.

These therapies include ezetimibe (Zetia, Merck), bile acid sequestrants, niacin, red yeast rice, PCSK9 inhibitors, cholesteryl ester transfer protein (CETP) inhibitors and AMP kinase inhibitors.

The role of coenzyme Q10 supplementation also has been explored. “There is a lot of debate about the use of this expensive supplement. The studies are inconsistent,” Rosenson said.

Some studies show benefit of coenzyme Q10 and others show no effect. “I think one would be hard pressed to make this recommendation for patients due to the cost of the therapy. [However], no effect does not necessarily exclude the possibility that some individuals have genetic traits that make them more responsive to supplementation,” he said.

Tips for clinical practice

“One may underestimate the magnitude of [statin-associated muscle adverse events] if you don’t ask the questions,” Rosenson said.

Increased communication with patients and providers also is important because there may be other health care specialists involved in the care of a patient with statin-associated muscle adverse events or complaints, according to Rosenson. He recommended informing patients that if there are major changes in medication with certain therapies, they should notify their lipidologists.

“Research into diagnostic studies and procedures will further improve accurate diagnosis of statin-associated adverse events and provide the basis for evaluating other myopathic disorders and justifying alternative cholesterol-lowering therapies,” he said.

Reference:

Rosenson RS. Risk underlying statin-induced adverse muscle complaints. Presented at: National Lipid Association Scientific Sessions; June 11-14, 2015; Chicago.

Disclosure: Rosenson reports receiving research grants to his institution from Amgen, AstraZeneca and Sanofi; consulting/serving on advisory boards for Aegerion, Amgen, AstraZeneca, GlaxoSmithKline, Eli Lilly, Kowa Pharmaceuticals, Novartis, Regeneron and Sanofi; and royalties from UpToDate Inc.