Journal of Cardiovascular Pharmacology Publish Ahead of Print

DOI: 10.1097/FJC.0000000000001397

The Significance of Statin Associated Muscle Symptoms and Its Impact on Patient

Adherence and Outcomes

Alfredo Caturano MD1, Gaetana Albanese MD1, Anna di Martino MD1, Raffaele Galiero

MD1, Ferdinando Carlo Sasso MD PhD1

1
Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi

Vanvitelli", Naples, IT

Conflict of interest disclosures: The author declare that he has no conflict of interest.

Funding: None

Address for correspondence: Alfredo Caturano, MD, University of Campania "Luigi

Vanvitelli"Department of Advanced Medical and Surgical Sciences, Piazza Luigi Miraglia 2,

IT-80138 Naples, Italy. Phone: +39 333 8616985, e-mail: alfredo.caturano@virgilio.it

Keywords: statin, adverse event, muscle symptoms, drug adherence, holistic medicine

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 Statin associated muscle symptoms (SAMS) are defined as a wide spectrum of muscle

symptoms, including muscle aches, weakness, soreness, stiffness, cramping, tenderness, or

general fatigue, associated with statin initiation. SAMS adverse events reports vary from

blinded randomized control trials (1-5%) to observational studies (7-29%) [1-2]. A recent

metanalysis reported that during the first year, statin therapy produced a 7% relative increase

in SAMS, also highlighting that only one out of 15 SAMS adverse event patient reports were

actually due to the statin [3]. These may be also be due to the so-called nocebo effect. In fact,

Gupta and coworkers, in a randomised double-blind placebo-controlled trial and its non-

randomised non-blind extension phase, described an increased rate of adverse events reports

only when both patients and their doctors were aware of statin therapy use and not when they

were blinded [1]. Therefore, it is possible there is adverse event overreporting. As statins play

a major role in cardiovascular disease prevention, it is crucial for physician to partner with

the patient to gain a thorough symptom history and determine if he or she is truly statin

intolerant [2-5].

SAMS usually involve both sides of large muscle groups (e.g., buttocks, calves,

shoulder girdle, thighs) and mostly develop between 4-6 weeks from statin initiation or

increase [6]. Several risk factors have also emerged from several studies that may help to

stratify patients at increased risk of SAMS development, including medicine or food

interactions (e.g., CYP3A4A inhibitors), high-dose statin therapy, history of myopathy with

other lipid-modifying medicines, regular vigorous physical activity, impaired hepatic or renal

function, substance abuse (e.g., alcohol, opioids, cocaine), female gender, and low BMI [6].

However, further studies are needed to better clarify the association between risk factors and

SAMS. In fact, Al-Makhamreh and co-workers, in their observational retrospective cohort

study, did not confirm gender, and both kidney and hepatic impairment association with an

increased risk of SAMS onset, giving more prominence instead to the presence of

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autoimmune diseases [7]. Moreover, a recent metanalysis pointed out that statin therapy

causes about 11 additional reports of any muscle pain or weakness per 1000 patients during

the first year, with only a little increase thereafter, with some evidence of persistent risk for

more intensive regimens [3].

A better detection and definition of SAMS has been addressed in the past as a crucial

point to improve patient treatment adherence [6]. Moreover, in a systematic review, it was

reported that 5-15% of the patients ceased the medication due to adverse events onset. Of

these, some patients complained that they were not properly informed about side effects

before starting statin treatment [8]. Al-Makhamreh and co-workers, in their recent paper,

have reported a non-statistically significant difference between patients experiencing SAMS

and the control group [7]. This finding might be due to the improvement in doctor-patient

relationship, to patient involvement in assessing and managing adverse effects, which rarely

represent a life-threatening condition (myopathy incidence is ~ 1 in 10,000 per year;

rhabdomyolysis incidence ~ 1 in 100,000 per year), and to the increase in patient knowledge

about the risk-benefit ratio of statin therapy use and discontinuation [6-7].

However, if on the one hand Al-Makhamreh and co-workers reported encouraging

data about SAMS, on the other hand they have given an alert to the scientific community for

the urgency of improving drug adherence. In fact, lack of adherence among statin and control

groups were 28.9% and 28.0%, respectively [7]. In this scenario, it becomes clear that

clinicians can still do a lot to improve patient adherence. It has been pointed out that

inquiring about medication-taking behaviour, developing a trusting relationship, improving

continuity of care, understanding the role of family support, identifying non-supportive

family member behaviours, understanding patient’s financial situation, and suggesting the

best treatment for all budgets, could represent a good path on the way to patient adherence

improvement [9-10].

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