eCommons@AKU eCommons@AKU
Section of Orthopaedic Surgery Department of Surgery
7-2019
Can alternate-day statin regimen minimize its adverse effects on Can alternate-day statin regimen minimize its adverse effects on
muscle and tendon?: A systematic review muscle and tendon?: A systematic review
Zehra Abdul Muhammad
Aga Khan University
Tashfeen Ahmad
Aga Khan University
Naveed Baloch
Aga Khan University
Follow this and additional works at: https://ecommons.aku.edu/pakistan_fhs_mc_surg_orthop
Part of the Orthopedics Commons, and the Surgery Commons
Recommended Citation Recommended Citation
Muhammad, Z. A., Ahmad, T., Baloch, N. (2019). Can alternate-day statin regimen minimize its adverse
effects on muscle and tendon?: A systematic review.
Journal of the Pakistan Medical Association, 69
(7),
1006-1013.
Available at:Available at: https://ecommons.aku.edu/pakistan_fhs_mc_surg_orthop/109
J Pak Med Assoc
1006
Can alternate-day Statin regimen minimize its adverse effects on muscle
and tendon? A systematic review
Zehra Abdul Muhammad, Tashfeen Ahmad, Naveed Baloch
Introduction
Statins are lipid-lowering drugs by competitively
inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A
reductase enzyme (HMGCR) and thus limiting cholesterol
biosynthesis.
1
Statins are administered daily as standard
therapy for primary and secondary prevention of
coronary heart disease (CHD), stroke and peripheral
arterial disease (PAD).
2
Commonly used statins are
rosuvastatin, atorvastatin, fluvastatin, lovastatin,
simvastatin, pravastatin and pitavastatin. Despite their
clinical benefits, several patients discontinue these drugs
due to intolerance, increasing the risk of cardiovascular
morbidity and mortality. Most common side effects of
statin are myopathy, tendinopathy, hepatotoxicity, type
2 diabetes, cataract, polyneuropathy, memory loss,
behavioural changes and, rarely, headache,
gastrointestinal disturbance, rash etc.
3
In 1987, lovastatin, the first statin drug, was approved
by the Food and Drug Administration (FDA) and was
released for marketing. Later, except with the least potent
fluvastatin, it was identified that statin, in combination
with gemfibrosil, produced severe myopathy and
rhabdomyolysis.
Statins can lead to myalgia (muscle pain), myopathy,
elevated creatinine kinase (myonecrosis) and
rhabdomyolysis.
4,5
Studies have reported that muscle
and tendon related side effects were most commonly
noticed in patients treated with rosuvastatin while
pravastatin and lovastatin have the lowest rate of side
effects.
6
Onset of myalgia varies from patient to patient and starts
after a few weeks to years of statin therapy.
7
Myalgia
could be generalised or localised, and persists for more
than 3 months after discontinuation of statin therapy
with average duration of six-and-a-half months.
8
While
on statins, up to 10% of the patients, specifically older
Abstract
Objective:
To review evidence-based data with respect to safety and efficacy of alternate-day statin
therapy in dyslipidaemia compared to the standard daily dose.
Methods:
The literature review was conducted at Aga Khan University Hospital, Karachi from July,
2016 to August, 2017. Electronic database search was carried out to compile available literature using
PubMed, Excerpta Medica database and Google Scholar. The most relevant evidence-based research
articles published over 10 years were selected. The latest search was dated August 03, 2017.
Results:
A total of 2,074 articles were initially located. Alternate day statin regimen was reported in
53% of articles. Adverse effects on muscle and tendon were reported in 69% of articles. After scrutiny,
19(0.9%) studies covering alternate-day statin-mediated muscle and tendon disorders and 9(0.4%)
studies encompassing the potential pathophysiological mechanisms of statin-associated muscle and
tendon injury were selected. Except pravastatin and lovastatin, alternate-day statin therapy was
almost as effective in lowering total cholesterol, low-density lipoprotein cholesterol and triglycerides
as the daily dosing with low incidence of muscle toxicity and tendinopathy.
Conclusion:
Alternate-day statin regimen was found to be very well tolerated and might be an
effective and safe remedy in clinical practice.
Keywords:
Statin, Alternate-day regimen, Muscle disorders, Tendon disorders, Adverse effects. Cancer.
(JPMA 69: 1006 2019)
Aga Khan University Hospital, Karachi-Pakistan.
Correspondence: Zehra Abdul Muhammad. e-mail: [email protected]
patients and females, experienced muscle pain.
9
Risk factors for statin-induced myopathy include
concomitant drugs, diabetes, old age, female gender,
hepatic and renal insufficiency, hypertension and
hypothyroidism.
10
Statin-mediated myopathy with more
than 10 times elevation of creatinine kinase level is a
serious side effect and, according to one study, one per
1,000 patients to one per 10,000 patients may be effected
each year depending on statin dose administered.
11
Therefore, FDA recommends lowest effective dose of
statins to reduce statin-associated myopathies.
12
In most of the statin treated patients, anti-HMGCR
antibodies are not detected and their myopathy resolve
after statin dose adjustment or discontinuation. However,
it is recently identified that statin may induce such
antibodies and cause immune-mediated myopathy.
Antibody-positive patients are most likely having an
autoimmune myopathy that is progressive and persists
after drug withdrawal. These patients require
immunosuppressive drugs, preferably oral prednisolone
(1 mg/kg/day) and sometimes other immuno-
suppressants like azathioprine, methotrexate,
intravenous (IV ) immunoglobulin (Ig) after
confirmation.
13
Statins can also lead to rhabdomyolysis, and release of
muscle intracellular constituents due to muscle injury
could lead to renal failure. After several reports of
cerivastatin-associated rhabdomyolysis and deaths, the
drug was withdrawn from the market.
14
According to
new safety updates; FDA does not recommend
simvastatin administration at the starting dose of 80mg
due to serious myopathies and rhabdomyolysis.
15
Tendinopathy is another side effect related to statin
treatment and is frequent in patients with diabetes,
hyperuricaemia, history of tendon disorders, and in
persons involved in active sports.
6,16
Tendinopathy was first reported in four patients in 2001.
Two patients were on simvastatin. One patient was at a
dose of 10 mg/d (co-administered with enalapril and
nifedipine-atenolol) and one patient at a dose of 20
mg/d. Two patients were treated with atorvastatin. One
patient was at a dose of 20 mg/d and one patient at a
dose of 40 mg/d initially which increased to 80 mg/d
respectively. Out of four patients, one developed
extensor tenosynovitis at the hands, one developed
tenosynovitis of the tibialis anterior tendon and two had
Achilles tendinopathy. The tendinopathy developed 1
to 2 months after treatment initiation.
Tendons mostly involved in statin therapy are Achilles,
rotator cuff, biceps brachii, extensor carpi radialis brevis,
gluteus medius, quadriceps, patellar tendon, tibialis
anterior and finger extensor and flexor tendons.
17,18
Tendinitis or inflammation of a tendon was reported in
patients on statin therapy particularly involving tendons
like Achilles, quadriceps, deltoid etc.
17,19
According to FDA-based eHealthMe report, 0.01%
patients on statin therapy have enthesopathy, a disorder
involving the attachment of a tendon or ligament to a
bone.
20
Several animal studies have been conducted to elucidate
the mechanism of myotoxicity and tendon injury, and
multiple mechanisms have been shown to be
involved.
4,18
In clinical practice, statin dose is adjusted from 5mg to
40mg once daily according to blood lipid profile and
statin type. FDA recommends discontinuation of the
drug if patient experiences statin-associated muscle or
tendon adverse effects.
6
To overcome statin-induced muscle toxicity and
tendinopathy and to determine efficacy and safety,
several studies administered alternate-day statins
compared to standard daily regimen. It was evaluated
that except pravastatin and lovastatin, alternate-day
therapy was as effective in lowering total cholesterol
(TC), low density lipoprotein (LDL) cholesterol and
triglycerides (TG) as the standard daily dosing. Overall
incidence of adverse drug reactions were lower in
alternate-day regimen, particularly rosuvastatin and
atorvastatin were very well tolerated in patients who
were intolerant to these statins on a daily dose.
21
Grounded on all ascertained statin-related adverse
reactions, statin compliance is a major concern for
treating physicians. Alternate-day statin regimen has
been proposed by studies to reduce adverse effects from
statin therapy compared to the daily dose. The current
study was planned to focus on statin-mediated muscle
and tendon disorders, mechanism of tissue injury and
safety and effectiveness of alternate0day statin regimen
reported to date.
Can alternate-day Statin regimen minimize its adverse effects on muscle......
Vol. 69, No. 07, July 2019
1007
Materials and Methods
The literature review was conducted by the research
team from Aga Khan University Hospital, Karachi. Initial
scoping review was conducted in July-August, 2016 and
comprehensive focussed literature search was
undertaken till August, 2017. Electronic database search
was carried out to compile available literature using
PubMed, Excerpta Medica database (EMBASE) and
Google Scholar. The most relevant evidence-based
research articles published over 10 years were selected.
Except for one research article published post-submission
and was added in the revised manuscript, the latest
search was dated August 03, 2017.
Keywords and phrases used for the search were
'alternate-day statin', 'statin-associated myopathy', 'statin-
associated tendinopathy', 'statin-related adverse effects',
'statin-associated enthesopathy', 'statin-related
mechanism of tendon injury', 'statin-related mechanism
of muscle injury', and 'alternate-day statin efficacy and
safety'. Research articles in which alternate-day or daily
statin regimens were used but contained no information
on muscle or tendon disorders were excluded.
Referenced citations from relevant publications were
also considered. Findings of research studies involving
human subjects with study designs such as randomised
double- or single-blind trials, randomised open label
trials, non-randomised before-after comparison trials,
randomised crossover trials and prospective or
retrospective studies comparing the safety and efficacy
of alternate-day statin regimen were primarily included
for analysis. Research studies explaining statin-induced
key pathophysiological mechanisms were also included.
Results
A total of 2,074 articles were initially located. Alternate
day statin regimen was reported in 1,110 (53%) articles.
Adverse effects on muscle and tendon were reported in
1,430 (69%) articles. After scrutiny, 19(0.9%) studies
covering alternate-day statin-mediated muscle and
tendon disorders and 9(0.4%) studies encompassing the
potential pathophysiological mechanisms of statin-
associated muscle and tendon injury were selected.
Drugs analysed included atorvastatin, fluvastatin,
lovastatin, pravastatin, rosuvastatin and simvastatin
(Table).
The review found several studies that were conducted to
assess the safety and efficacy of alternate-day atorvastatin
administration. Most of these studies compared safety of
alternate-day statin regimen to daily regimen. In different
research studies, mixed results for efficacy of alternate-
day atorvastatin regimen were observed.
Few studies reported that in dyslipidaemia with coronary
artery disease, 6-12 week alternate-day regimen treatment
significantly increased LDL cholesterol and TC levels. About
10-20mg alternate-day atorvastatin regimen non-
significantly decreased TG level after 3 months of
treatment. Alternate-day regimen was not as effective as
the daily regimen.
22-26
Contrary to above studies, in some studies, when patients
with dyslipidaemia, with or without type 2 diabetes, were
treated with 10-20 mg alternate-day atorvastatin regimen
there was significant decrease in LDL cholesterol, TC and
TG levels with non-significant increase in high density
lipoprotein (HDL) level after 6-12 weeks treatment.
27-30
Alternate-day atorvastatin regimen was well tolerated in
all studies with few side effects like flu-like symptoms,
somnolence, increase in serum transaminases and muscle
enzymes, myalgia, headache, dyspepsia, dizziness and
paresthesia compared to daily regimen.
In terms of fluvastatin, in one crossover study, patients
with hypercholesterolaemia who were on diet restriction
therapy were first treated with fluvastatin 40 mg daily or
20 mg alternate-day for 6 weeks. Both groups of patients
were then switched to other regimen for further 6 weeks.
LDL cholesterol and TC decreased significantly in both
regimens. There was non-significant decrease in TG and
increase in HDL cholesterol while few adverse effects were
observed.
31
The limiting factor for this study was that
there was no drug washout period in between the drug
regimen switchover.
Regarding lovastatin, in two studies, patients with
dyslipidaemia were treated with 20 mg lovastatin for 6
weeks to 4 months. There was significant decrease in TC
and LDL cholesterol, while non-significant decrease in TC
and increase in HDL cholesterol were observed.
32,33
On
alternate-day lovastatin regimen, angioedema and muscle
cramping were observed in two patients only. Daily
regimen was not administered in these studies, therefore,
alternate-regimen could not be compared for safety.
On the basis of results, although this drug seems to be
effective, there are some limitations in these studies like
the selection of male participants only, small number of
patients, retrospective in nature, lack of external validity
J Pak Med Assoc
1008
Z.A. Muhammad, T. Ahmad, N. Baloch
Vol. 69, No. 07, July 2019
Can alternate-day Statin regimen minimize its adverse effects on muscle......
1009
Table: Research studies on alternate-day statin regimen - precise details.
LDL-C: Low density lipoprotein cholesterol, HDL: High density lipoprotein, TC: Total cholesterol, TG: Triglyceride), N: Number of patients, NS: Not significant, AD: Alternate-day drug
dose, DD: Daily drug dose, Pt: Patient, UL: Upper limit, gp: Group, = decrease, = increase, = no change
26
29
30
28
25
22
23
24
31
32
33
34
35
21
36
37
38
39
1010
etc.
In terms of pravastatin, step-down treatment either every
other day or half of the adjusted dose significantly
increased TC and LDL cholesterol levels while TG and HDL
cholesterol increased non-significantly, thus, was
ineffective.
34
Adverse events, like nausea, heart burn,
myalgia, diarrhoea, night sweats were recorded in
alternate-day regimen group.
Regarding rosuvastatin, in some studies when patients
with dyslipidaemia were treated with 2.5-20 mg alternate-
day regimen, there was significant decrease in LDL
cholesterol, TG and TC compared to the baseline values.
In most studies, HDL cholesterol was non-significantly
increased.
21,35-37
Discussion
In the light of these studies, it seems that alternate-day
administration of rosuvastatin is almost as effective as the
daily regimen. Alternate-day rosuvastatin regimen was
well tolerated in all studies with few side effects like
headache, increase in liver enzymes which did not exceed
more than three times the normal upper limit, myalgia,
fatigue, rash, gastrointestibnal tract (GIT) disturbances
and some memory impairment.
Regarding simvastatin, in few studies, simvastatin, with
or without fenofibrate, was administered in alternate days
at dose of 10-80 mg in dyslipidaemia patients. There was
significant decrease in LDL cholesterol, TG and TC and
increase in HDL cholesterol compared to baseline
values.
38,39
Alternate-day regimen of simvastatin was well
tolerated. In one study, simvastatin was co-administered
with fenofibrate, therefore lipid-lowering effect and
incidences of adverse effects were inconclusive for
simvastatin.
Speculated mechanisms involved in statin-induced
myotoxicity and tendon injury.
a. Actual mechanism involved in statin-associated
myotoxicity is still unclear. Several studies, mainly on
rat models, were conducted to explore this
phenomenon (Figure). It seems that several
pathological events are involved in muscle injury
including direct HMGCR,
40,41
decrease in muscle
ubiquinone leve,
42
mitochondrial dysfunction in
skeletal muscle cells leading to impaired cell
membrane functions as well as defect in myocyte
duplication, impaired cell membrane glycoprotein
synthesis, decreased muscle membrane chloride
channel activation and increase in intracellular calcium
concentrations leading to membrane function
impairment resulting in myocyte injury,
4,43
impaired
function of Ras homolog gene family member A due
to lipid synthesis problem with geranylgeranyl
pyrophosphate which is an intermediate in HMGCR
pathway and is involved in the mechanisms of statin-
induced skeletal muscle toxicity
44
b. Genetic factors are also reported to be responsible
for muscle toxicity.
45
J Pak Med Assoc
Z.A. Muhammad, T. Ahmad, N. Baloch
Mevalonate: Cholesterol and coenzyme Q10 precursor, MMP: Metalloproteninase,
MHC: Major Histocompatibility complex, HMGCR: 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase enzyme.
Figure: Possible mechanisms of stain mediated muscle and tendon disorders.
Vol. 69, No. 07, July 2019
Likewise, exact mechanism of immune-mediated
myopathy is unclear, but it is suggested that it could be
due to induction of endoplasmic reticulum stress response,
up-regulation of major histocompatibility complex-I
expression with antigen presentation by muscle fibres,
and up-regulation of HMGCR in regenerating muscle cells
and autoimmune response generation leading to
immune-mediated necrotising myopathy.
13,46
Several
statin-induced mechanisms are deliberated upon to
produce tendon injury. Severity of tendon injury depends
on the dose and type of statin used.
Pleiotropic effect of statins on metalloproteinase activity
leads to tendon pathology. Statins enhance tissue inhibitor
of metalloproteinase-1 expression in macrophages and
thus inhibit metalloproteinase activity resulting in
tendinopathy.
16,47
Statin-associated tendon micro damage is caused by
extracellular matrix components derangement,
particularly in Achilles tendon. These evidences indicate
that statins alter balance between the synthesis and
degradation of several molecules, particularly involving
collagen I which is the main constituent in tendon
extracellular matrix.
18
Statins induce muscular and tendon side effects could be
life-threatening and devastating leading to non-
compliance of the daily statin regimen. Although several
mechanisms at molecular level are detected in animal
models that seem to be involved in myotoxicity, tendon
injury and immune-mediated myopathy but still definite
pathophysiological mechanism of these side effects is still
unclear. This suggests that multifactorial causes are
involved in these adverse effects. To overcome these side
effects and for better adherence to the drug compliance,
studies were conducted in which daily statin regimen was
switched to alternate-day regimen.
Although several studies have been published with the
aim of investigating safety and efficacy of alternate-day
statin regimen, results cannot be generalised for different
patient populations as the studies stated above are mainly
conducted on specific set of patients.
Studies conducted on alternate-day atorvastatin showed
mixed results in drug efficacy to treat dyslipidaemia and
thus results were inconclusive for drug efficacy although
it was well tolerated. Alternate-day dose of pravastatin
was ineffective in treating dyslipidaemia. The most
favourable results were obtained in studies with alternate-
day rosuvastatin regimen with study design of randomised
and crossover clinical trials. Alternate-day rosuvastatin
was almost as effective as daily regimen and was also well
tolerated. Simvastatin was effective in treating
dyslipidaemia and was also well tolerated by the patients
but either co-administered with other lipid-lowering drug
or was not compared with daily statin dose.
A cross-sectional study was conducted in Pakistan on 400
patients between 40 and 70 years of age. There was
significant difference in the frequency of myalgia in
patients on alternate-day statin that was 4% compared
to every-day statin regimen that was 10%. Lipid-lowering
effect was not evaluated in this study which was one
limiting factor to infer alternate-day drug regimen results.
48
Based on all these facts, the studies cited above were
limited due to study design and patient selection bias as
in the case of alternate-day lovastatin, pravastatin and
simvastatin treatment studies. Therefore, pooled analysis
was not acquiescent. Retrospective studies conducted
have the potential for bias, therefore results are
inconclusive. Further, small sample size, short study
duration, dose adjustments according to lipid level goals
and lack of washout period in some studies did weaken
the findings. As in the above-mentioned studies, no
cardiovascular outcome has been evaluated so far. For
external validity of results, appropriately designed studies
to reach scientifically sound conclusions are required to
be conducted before implementation of alternate-day
regimen in routine practice. Nevertheless, foremost
strength of these studies is that the research was directly
conducted on human subjects with dyslipidaemia. Patients
were generally randomised in identically constituted
groups for comparison. Consequently, the results can
propose new direction for future larger clinical trials.
On the basis of this review it appears that alternate-day
dose may be better due to fewer side effects, but a
systematic review and meta-analysis are required to clearly
define the risk versus benefit.
Conclusion
Weighing statin benefits against statin toxicity, alternate-
day regimen may be a suitable option for those patients
who cannot tolerate statins daily. Clinical trials will help
physicians to consider evidence-based clinical efficacy of
drugs when making safety and resource-allocation
decision while prescribing drugs. It is recommended that
Can alternate-day Statin regimen minimize its adverse effects on muscle......
1011
1012
J Pak Med Assoc
physicians supervise patients on statin therapy by
considering risks associated with statins, particularly
autoimmune myopathy and rhabdomyolysis.
Disclaimer:
A poster of the initial literature review done
between July and August 2016 focussing on safety and
general adverse effects of statins was presented at the
10th Health Sciences Research Assembly, Aga Khan
University, Karachi, on August 23-24, 2016. The current
manuscript differs from that poster as it contains focussed
review on muscle and tendon side effects conducted
thereafter until August 2017.
Conflict of Interest:
None.
Source of Funding:
None.
Acknowledgement:
We are grateful to the Aga Khan
University, Karachi, for allowing the use of services and
support.
References
1. Goldstein JL, Brown MS. A century of cholesterol and coronaries:
from plaques to genes to statins. Cell 2015; 161: 161-72.
2. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB,
Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood
cholesterol to reduce atherosclerotic cardiovascular risk in adults:
a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines. J Am Coll Cardiol
2014; 63: 2889-934.
3. Maji D, Shaikh S, Solanki D, Gaurav K. Safety of statins. Indian J
Endocrinol Metab 2013; 17: 636-46.
4. Camerino GM, De Bellis M, Conte E, Liantonio A, Musaraj K, Cannone
M, et al. Statin-induced myotoxicity is exacerbated by aging: A
biophysical and molecular biology study in rats treated with
atorvastatin. Toxicol Appl Pharmacol 2016; 306: 36-46.
5. Ambapkar SN, Shetty N, Dwivedy A, Malve HO. Statin-induced
rhabdomyolysis in patient with renal failure and underlying
undiagnosed hypothyroidism. Indian J Crit Care Med 2016; 20:
305-7.
6. Hoffman KB, Kraus C, Dimbil M, Golomb BA. A survey of the FDA's
AERS database regarding muscle and tendon adverse events linked
to the statin drug class. PloS One 2012; 7: e42866.
7. Tobert JA. Efficacy and long-term adverse effect pattern of
lovastatin. Am J Cardiol 1988; 62: J28-J34.
8. Echaniz-Laguna A, Mohr M, Tranchant C. Neuromuscular symptoms
and elevated creatine kinase after statin withdrawal. N Engl J Med
2010; 362: 564-5.
9. Cederberg H, Staniáková A, Yaluri N, Modi S, Kuusisto J, Laakso M.
Increased risk of diabetes with statin treatment is associated with
impaired insulin sensitivity and insulin secretion: a 6 year follow-
up study of the METSIM cohort. Diabetologia 2015; 58: 1109-17.
10. Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, et
al. Statin-associated muscle symptoms: impact on statin therapy-
European Atherosclerosis Society Consensus Panel Statement on
Assessment, Aetiology and Management. Eur Heart J 2015; 36:
1012-22.
11. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol
2006; 97: 52C-60C.
12. Murakami H, Sakaeda T, Kadoyama K, Okuno Y. Gender effects on
statin-associated muscular adverse events: an analysis of the FDA
AERS database. Pharmacol Pharm 2013; 4: 340-6.
13. Kennedy N, Keating P, O'Donnell J. HMGCR-associated myositis: a
New Zealand case series and estimate of incidence. Intern Med J
2016; 46: 622-5.
14. Bakri R, Wang J, Wierzbicki AS, Goldsmith D. Cerivastatin
monotherapy-induced muscle weakness, rhabdomyolysis and
acute renal failure. Int J Cardiol 2003; 91: 107-9.
15. FDA. Limit Use of 80 mg Simvastatin [online] 2011 [cited 2017 July
12]. Available from: URL: https://www.fda.gov/Drugs/
DrugSafety/ucm283137.htm
16. Pullatt RC, Gadarla MR, Karas RH, Alsheikh-Ali AA, Thompson PD.
Tendon rupture associated with simvastatin/ezetimibe therapy.
Am J Cardiol 2007; 100: 152-3.
17. Chazerain P, Hayem G, Hamza S, Best C, Ziza JM. Four cases of
tendinopathy in patients on statin therapy. Joint Bone Spine 2001;
68: 430-3.
18. de Oliveira LP, Vieira CP, Da Re Guerra F, de Almeida Mdos S, Pimentel
ER. Statins induce biochemical changes in the Achilles tendon after
chronic treatment. Toxicology 2013; 311: 162-8.
19. Movahed MR, Samsamsharaiat SA. Reproducible tendinitis-like
symptoms related to statin therapy. J Clin Rheumatol 2006; 12:
320-1.
20. eHealthMe. Lipitor and Enthesopathy - from FDA reports [Online]
2017 [Cited 2017 Nov 14]. Available from: URL:
http://www.ehealthme.com/ds/lipitor/enthesopathy/
21. Backes JM, Venero CV, Gibson CA, Ruisinger JF, Howard PA,
Thompson PD, et al. Effectiveness and tolerability of every-other-
day rosuvastatin dosing in patients with prior statin intolerance.
Ann Pharmacother 2008; 42: 341-6.
22. Pattanaik S, Malhotra S, Sharma YP, Pandhi P. Comparison of
Alternate-day Atorvastatin Treatment to Daily Treatment in
Maintaining LDL-cholesterol Targets in Patients with Variable
Coronary Risk Profile. J Cardiovasc Pharmacol 2012; 59: 479-84.
23. Rifaie O, Zahran A, Nammas W. Alternate-day versus daily
atorvastatin in coronary artery disease: a randomized study.
Anadolu Kardiyol Derg 2012; 12: 90-6.
24. Ghia CJ, Panda AS, Khobragade LR, Jha RK, Rambhad GS. Alternate
Day versus Once Daily Atorvastatin for Primary Prevention of (CHD)
in Naïve Patients of Dyslipidemia. J Clin Diagn Res 2014; 8: 27-31.
25. Keles T, Akar BN, Kayhan T, Canbay A, Sahin D, Durmaz T, et al. The
comparison of the effects of standard 20 mg atorvastatin daily and
20 mg atorvastatin every other day on serum LDL-cholesterol and
high sensitive C-reactive protein levels. Anadolu Kardiyol Derg
2008; 8: 407-12.
26. Matalka MS, Ravnan MC, Deedwania PC. Is alternate daily dose of
atorvastatin effective in treating patients with hyperlipidemia? The
Alternate Day versus Daily Dosing of Atorvastatin Study (ADDAS).
Am Heart J 2002; 144: 674-7.
27. Jafari M, Ebrahimi R, Ahmadi-Kashani M, Balian H, Bashir M. Efficacy
of alternate-day dosing versus daily dosing of atorvastatin. J
Cardiovasc Pharmacol Ther 2003; 8: 123-6.
28. Aghasadeghi K, Zare D. Efficacy of alternate day dosing of
atorvastatin. Cent Eur J Med 2008; 3: 163-6.
29. Piamsomboon C, Laothavorn P, Saguanwong S, Chatlaong B,
Nasawadi C, Tanprasert P, et al. Efficacy and safety of atorvastatin
10 mg every other day in hypercholesterolemia. J Med Assoc Thai
2002; 85: 297-300.
30. Ferrer-García JC, Pérez-Silvestre J, Martínez-Mir I, Herrera-Ballester
A. Alternate-day dosing of atorvastatin: effects in treating type 2
diabetic patients with dyslipidaemia. Acta diabetol 2006; 43: 75-
8.
31. Rindone JP, Hiller D, Arriola G. A comparison of fluvastatin 40 mg
every other day versus 20 mg every day in patients with
hypercholesterolemia. Pharmacotherapy 1998; 18: 836-9.
Z.A. Muhammad, T. Ahmad, N. Baloch
32. Rindone JP, Achacoso R, Bledsoe R. Effect of Lovastatin administered
every other day on serum low-density lipoprotein cholesterol >
160 mg/dl. Am J Cardiol 1995; 76: 312-3.
33. Dennis VC, Britton ML, Sirmans SM, Letassy NA, Freeman DA. The
use of alternate-day lovastatin in hypercholesterolemic men. Ann
Pharmacother 1997; 31: 708-12.
34. Graham MR, Lindsey CC, Kennedy JA. Maintenance of Low-Density
Lipoprotein Goal with Step-Down Pravastatin Therapy.
Pharmacotherapy 2002; 22: 21-6.
35. Wongwiwatthananukit S, Sansanayudh N, Dhummauppakorn R,
Kitiyadisai C. Efficacy and safety of rosuvastatin every other day
compared with once daily in patients with hypercholesterolemia.
Ann Pharmacother 2006; 40: 1917-23.
36. Li JJ, Yang P, Liu J, Jia YJ, Li ZC, Guo YL, et al. Impact of 10mg
rosuvastatin daily or alternate-day on lipid profile and inflammatory
markers. Clin Chim Acta 2012; 413: 139-42.
37. Dulay D, LaHaye SA, Lahey KA, Day AG. Efficacy of alternate day
versus daily dosing of rosuvastatin. Can J Cardiol 2009; 25: e28-31.
38. Kayikçioglu M, Ozerkan F, Soydan I. Effectiveness and safety of
alternate-day simvastatin and fenofibrate on mixed hyperlipidemia.
Am J Cardiol 1999; 83: 1135-7.
39. Copher HR, Stewart RD. Daily Dosing versus Alternate-Day Dosing
of Simvastatin in Patients with Hypercholesterolemia.
Pharmacotherapy 2002; 22: 1110-6.
40. Hrab RV, Hartman HA, Cox RH, Jr. Prevention of fluvastatin-induced
toxicity, mortality, and cardiac myopathy in pregnant rats by
mevalonic acid supplementation. Teratology 1994; 50: 19-26.
41. Flint OP, Masters BA, Gregg RE, Durham SK. HMG CoA reductase
inhibitor-induced myotoxicity: pravastatin and lovastatin inhibit
the geranylgeranylation of low-molecular-weight proteins in
neonatal rat muscle cell culture. Toxicol Appl Pharmacol 1997; 145:
99-110.
42. Rundek T, Naini A, Sacco R, Coates K, DiMauro S. Atorvastatin
decreases the coenzyme Q10 level in the blood of patients at risk
for cardiovascular disease and stroke. Arch Neurol 2004; 61: 889-
92.
43. Bouitbir J, Singh F, Charles AL, Schlagowski AI, Bonifacio A, Echaniz-
Laguna A, et al. Statins Trigger Mitochondrial Reactive Oxygen
Species-Induced Apoptosis in Glycolytic Skeletal Muscle. Antioxid
Redox Signal 2016; 24: 84-98.
44. Itagaki M, Takaguri A, Kano S, Kaneta S, Ichihara K, Satoh K. Possible
mechanisms underlying statin-induced skeletal muscle toxicity in
L6 fibroblasts and in rats. J Pharmacol Sci 2009; 109: 94-101.
45. Mombelli G, Pavanello C. Statin Muscle Toxicity and Genetic Risk
Factors. Int J Genomic Med 2013; 1: 111.
46. Needham M, Fabian V, Knezevic W, Panegyres P, Zilko P, Mastaglia
FL. Progressive myopathy with up-regulation of MHC-I associated
with statin therapy. Neuromuscul Disord 2007; 17: 194-200.
47. de Oliveira LP, Vieira CP, Guerra FD, Almeida MS, Pimentel ER.
Structural and biomechanical changes in the Achilles tendon after
chronic treatment with statins. Food Chem Toxicol 2015; 77: 50-7.
48. Riaz R, Merchant AZ, Ul Haq MS, Nasir SAR, Rizvi Y, Khan JA, et al.
Statins Everyday Versus Alternate days: Is There a Difference in
Myalgia rates? Indian Heart J 2018; 70: 492-6.
Can alternate-day Statin regimen minimize its adverse effects on muscle......
1013
Vol. 69, No. 07, July 2019
