Taking simvastatin in the morning compared with in the evening: randomised controlled trial
BMJ 2003; 327 doi: https://doi.org/10.1136/bmj.327.7418.788 (Published 02 October 2003) Cite this as: BMJ 2003;327:788All rapid responses
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Dr. Wallace et al. conclude that evening dosing of
simvastatin is superior because it lowers total and LDL
cholesterol levels more than morning dosing.
In their study, they measured cholesterol levels in the
morning. Is it possible that the effects of evening
simvastatin are greater on morning cholesterol levels
(but not on average cholesterol levels) than morning
simvastatin?
If simvastatin has an effect on lowering cholesterol
levels that is maximal several hours after a dose, rather
than just an effect that occurs over weeks, if cholesterol
levels had been measured in the evening the opposite
results might have been found.
Competing interests:
None declared
Competing interests: No competing interests
Editor – Wallace et al found an increase in fasting total cholesterol
and LDL concentrations after the application of simvastatin had been
switched from evening to morning 1. Sixty patients who already took
simvastatin were randomised to take simvastatin in the morning or the
evening. Compliance was checked by tablet count and did not differ between
the groups.
These results are interesting but how sure can the authors be that
compliance behaviour actually did not differ between the groups? We would
like to mention results from previous studies which used electronic
monitoring for compliance measurement. There is good evidence that
compliance is overestimated by tablet count 2,3, and actual timing of drug
use as measured by continuous electronic monitoring often differed
extremely from what had been prescribed 4,5,6.
Compliance with another statin, lovastatin prescribed to be taken
once daily in the morning or in the evening and lipid-lowering effects
were studied in patients with familial hypercholesterolaemia 7. The mean
decrease in total and LDL-cholesterol concentrations was not significantly
different between the morning and the evening schedule, i.e. 1.97 mmol/l
(95% CI 1.55, 2.39), 1.59 mmol/l (95% CI 1.39, 2.50), and 2.38 mmol/l (95%
CI 1.68, 3.07), 2.10 mmol/l (95% CI 1,45, 2.75), respectively. Pill counts
significantly overestimated compliance as was revealed by electronic
monitoring. Furthermore, time compliance (percentage of dosing events
recorded within defined time intervall) was 66.8% (95% CI 50.1, 83.4) with
the morning schedule and 62.2% (95% CI 46.1, 78.2) with the evening
schedule. In patients on the evening schedule, about a quarter of total
dosing events (23.1%; 95% CI 7.53, 38.75) were recorded between 6.00 to
17.00 h. In patients on the morning schedule, significantly fewer dosing
events were recorded between 12.00 to 24.00 h, i.e. 10.8% (95% CI 2.96,
24.50) (p<_0.002. in="in" some="some" patients="patients" on="on" the="the" evening="evening" schedule="schedule" days="days" without="without" dosing="dosing" events="events" were="were" immediately="immediately" followed="followed" by="by" with="with" _2="_2" recorded="recorded" medication="medication" instead="instead" of="of" one.="one." catch="catch" up="up" later="later" after="after" remembering="remembering" omission="omission" a="a" dose.="dose." this="this" may="may" have="have" explained="explained" during="during" morning="morning" hours="hours" schedule.="schedule." authors="authors" concluded="concluded" that="that" peference="peference" ensuring="ensuring" optimal="optimal" compliance="compliance" an="an" adequate="adequate" guide="guide" for="for" choosing="choosing" dosage="dosage" regime.="regime." once-daily="once-daily" however="however" not="not" necessarily="necessarily" be="be" best="best" option="option" as="as" had="had" been="been" shown="shown" excel="excel" study="study" results="results" _8.="_8." p="p"/> 1 Wallace A, Chinn D, Rubin G. Taking simvastatin in the morning
compared with in the evening: randomised controllled trial. Br Med J 2003;
327:788
2 Pullar T, Kumar S, Tindall H, Feely M. Time to stop counting the
tablets? Clin Pharmacol Ther 1989; 46:163-8
3 Rudd P, Byyny RL, Zachary V, LoVerde ME, Titus C, Mitchell WD. The
natural history of medication compliance in a drug trial: Limitations of
pill counts. Clin Pharmacol Ther 1989; 46:169-76
4 Rudd P, Ahmed S, Zachary V, Barton C, Bonduelle D. Improved compliance
measures: applications in an ambulatory hypertensive drug trial. Clin
Pharmacol Ther 1990; 48:676-85
5 Mallion J-M, Dutrey-Dupagne C, Vaur L et al. Benefits of electronic
pillboxes in evaluating treatment compliance of patients with mild to
moderate hypertension. J Hypertens 1996; 14:137-44
6 Vander Stichele RH, Thomson M, Verkoelen K, Droussin AM. Measuring
patient compliance with electronic monitoring: lisinopril versus atenolol
in essential hypertension. Post Market Surv 1992; 6:77-90
7 Kruse W, Nikolaus T, Rampmaier J, Weber E, Schlierf G. Actual
versus prescribed timing of lovastatin doses assessed by electronic
compliance monitoring. Eur J Clin Pharmacol 1993; 45:211-15
8 Bradford RH, Shear CL, Hesney M et al. Expanded clinical evaluation of
lovastatin (EXCEL) study results. Arch Intern Med 1991; 151:43-9
Wolfgang von Renteln-Kruse professor, geriatrics and gerontology
Jennifer Anders MD
Medizinisch-Geriatrische Klinik,
Albertinen-Haus, Zentrum für Geriatrie und Gerontologie,
Wiss. Einrichtung an der Universität Hamburg,
Sellhopsweg 18-22, D-22459 Hamburg
w.renteln-kruse@albertinen.de
Competing interests:
None declared
Competing interests: No competing interests
It was interesting to read that Simvastatin is best taken at night.
(Reference 1).
I had always wondered whether we give a diuretic for congestive
cardiac failure at the right time of day. Most patients are instructed to
take their diuretic in the morning. We all know when we take a history
from these patients that their ankle oedema progresses during the day and
then they admit to nocturia as this fluid passes back into their
circulation in a recumbent position and is promptly excreted. They then
arise the following morning to take their diuretic when their fluid
overload is at the lowest. Surely, it would be sensible to instruct these
patients to take their diuretic at 4 or 5 o'clock in the afternoon.
Reference 1: Wallace A, Chinn D and Rubin G. Taking Simvastatin in
the morning compared with in the evening. Randomised controlled trial. BMJ
2003;327:788
Competing interests:
None declared
Competing interests: No competing interests
Dear Editor,
Wallace et al’s paper on the timing of simvastatin administration raises
some interesting questions but has a fundamental flaw, critically the
assessment of cholesterol levels at one particular time point and the
relation of that time point to both time of drug dosing and diurnal
variations in cholesterol (1,2). A more appropriate trial design would
have assessed non-inferiority of morning compared with evening dosing
based on cholesterol measurements at several time points.
Furthermore the
reporting of the trial does not follow the CONSORT guidelines as suggested
by the BMJ’s own advice for contributors (3). Whilst recognising the
difficulties of reporting a randomised trial in 600 words, would it not be
possible for short reports of RCT’s to publish electronically any
additional details required to fulfil the CONSORT criteria?
Whatever problems this study might have, it has important
implications for Primary Care finances. From April of next year, the
salaries of many of BMJ readers will depend in part on serum cholesterol
levels as documented in the new GMS contract (4). Attaining a total
cholesterol level of <_5 xmlns:are="urn:x-prefix:are" mmol="mmol" l="l" in="in" up="up" to="to" _60="_60" of="of" patients="patients" with="with" coronary="coronary" heart="heart" disease="disease" diabetes="diabetes" and="and" stroke="stroke" accounts="accounts" for="for" _27="_27" quality="quality" points.="points." the="the" population="population" described="described" by="by" wallace="wallace" et="et" al="al" _77="_77" would="would" achieve="achieve" this="this" target="target" when="when" taking="taking" simvastatin="simvastatin" evening="evening" compared="compared" _61="_61" it="it" morning.="morning." these="these" results="results" reflect="reflect" mean="mean" cholesterol="cholesterol" _4.4="_4.4" at="at" baseline="baseline" whereas="whereas" practice="practice" those="those" groups="groups" whom="whom" points="points" are="are" available="available" may="may" be="be" nearer="nearer" _5mmol="_5mmol" rms="rms" concentrations="concentrations" are:_="are:_" chd="chd" _4.6mmol="_4.6mmol" _5.4mmol="_5.4mmol" _4.9="_4.9" l.="l." small="small" variations="variations" serum="serum" a="a" therefore="therefore" have="have" big="big" impact="impact" on="on" income="income" since="since" achieving="achieving" targets="targets" _2004="_2004" _5="_5" equates="equates" total="total" just="just" over="over" _2000="_2000" per="per" average="average" practice.="practice." we="we" suggest="suggest" that="that" prudent="prudent" practitioners="practitioners" will="will" ask="ask" their="their" take="take" statin="statin" night="night" base="base" annual="annual" check="check" morning="morning" blood="blood" sample.="sample." or="or" not="not" lead="lead" improvements="improvements" cardiovascular="cardiovascular" health="health" but="but" should="should" predictably="predictably" doctors="doctors" bank="bank" balance="balance" p="p"/> References:
1. Wallace A, Chinn D, Rubin G. Taking simvastatin in the morning compared
with in the evening: randomised controlled trial. BMJ 2003;327:788.
2. Rapid responses at http://bmj.bmjjournals.com/cgi/eletters/327/7418/788
accessed 21st October 2003.
3. Advice to contributors.
http://bmj.bmjjournals.com/advice/special_methods.shtml#consort accessed
21st October 2003.
4.The New GMS
contract.http://www.bma.org.uk/ap.nsf/Content/__Hub+gmscontract accessed
21st October 2003.
Competing interests: Nick Freemantle has received funding for research from several
manufacturers of cholesterol lowering drugs.
Competing interests: No competing interests
The study by Wallace, Chinn and Rubin(1) highlights some important
issues with regard to national policy on managing what is misleadingly called
‘hyperlipidaemia’ with statins. The timing of the dose is largely irrelevant
faced with current policy and practice which is not designed to deliver the
important clinical outcomes seen in the large statin trials. Wallace et al studied patients on 10 or 20 mg of simvastatin which can now be
regarded as sub-optimal doses. This appears common: prescribing data in the
West Midlands suggests that 36% of patients are prescribed simvastatin 10mg or
pravastatin 10mg, lower doses than used in the large drug trials, and it is on
the evidence from such trials(2) that current practice should be based.
Table: Strength of pravastatin and simvastatin issued on
GP prescriptions in the West Midlands in the year between July 2002 and June
2003.
Strength |
Pravastatin (6,697,175 items) |
Simvastatin (33,656,378 items) |
10mg |
28% |
38% |
20mg |
35% |
37% |
40mg |
37% |
24% |
80mg |
- |
1% |
The Prescription Pricing Authority
kindly gave permission to analyse and show this data.
The National Service Framework for Coronary Heart Disease
from 2000 set a target: "Statin therapy should aim to lower cholesterol
below 5.0 mmol/l or to reduce total serum cholesterol by 20-25%, whichever
would result in the lowest level(3)."
This is only partly reflected in the Quality and Outcome Framework of
the New General Medical Services
General Practitioner contract(4), which will reward practices with extra
payments according to the proportion of patients with coronary heart disease,
or stroke/TIA, or with diabetes, with total cholesterol levels less than
5mmol/l.
The evidence has moved on and this policy and the quality
framework are clearly not now evidence-based. The key statin trials, most
notable the UK Heart Protection Study (HPS)(5), show that anybody either with
atheromatous vascular disease, or at high risk, will derive benefit from use of
statin drugs, irrespective of their starting cholesterol level. (Incidentally evening dosing was used in
HPS, but with 40 mg of simvastatin). Our fear is that, on one hand, people are
either not treated or are inadequately treated because their total cholesterol
is less than 5mmol/l. On the other hand,
some people are aggressively treated, with drugs such as rosuvastatin or
ezitimibe, where there is no clinical outcome data, believing a total
cholesterol less than 5mmol/l to be the ‘holy grail’. This latter approach clearly suits the drug industry.
Do we need to rethink national policy? To truly reflect
current evidence a better proposal is that everyone with atheromatous
cardiovascular disease, or significant risk, including those with Type 2
diabetes, should receive the same dose of statin used in the big drug trials
(for example, simvastatin 40mg daily, or pravastatin 40mg daily). None of the
large, recent studies involved cholesterol ‘target-chasing’. If you like,
giving treatment in the evening can be recommended, but more importantly a
proper dose should be used. The general
practitioner quality payment could then be for the proportion of appropriate
people receiving these adequate, evidence-based doses.
1.
Wallace A, Chinn D and Rubin G. Taking simvastatin in the
morning compared with in the evening: randomised controlled trial. BMJ 2003;327:788.
2.
Durrington P. Dyslipidaemia. Lancet 2003;362:717-31.
3.
Boyle R. Letter: DoH explains thinking behind national service
framework for coronary heart disease. BMJ 2000;321:1083.
4.
New GMS Contract. Investing in General Practice. British Medical
Association, 2003.
5.
Heart Protection Study Collaborative Group. MRC/BHF Heart
Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk
individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7-22.
Competing interests:
None declared
Competing interests: The study by Wallace, Chinn and Rubin(1) highlights some importantissues with regard to national policy on managing what is misleadingly called‘hyperlipidaemia’ with statins. The timing of the dose is largely irrelevantfaced with current policy and practice which is not designed to deliver theimportant clinical outcomes seen in the large statin trials.
Congratulations to the authors for conducting what initially looks like
a neat little GP based piece of research into a small but common day to
day issue. However I do not believe it amounts to significant evidence to
change practice.
The cholesterol measurements were taken 12 hours closer to the dose
in the night dosing group, this may explain the result. Having the
medication onboard in higher concentrations during the day when most of
the eating is done may have an important interaction effect on clinical
outcomes.
The real question to answer from the patients point of view is the
net benefit to well being from different dosing regimens. This includes
convenience factors and impact on compliance with other medications etc.
This study does not take this into account. Simvastatin is usually one of
several medications these patients are asked to take.
Dan Ewald
Competing interests:
None declared
Competing interests: No competing interests
Whether
statins should be given in the evening or in the morning,1 if at all,
depends on whether it is advisable to lower cholesterol as much or as little as
possible. There is much evidence for the latter, because in all clinical2,3
and angiographic4 trials, where dose-response was calculated, the
outcome was independent on the degree of cholesterol lowering, indicating that
the effect of the statins is due to other mechanisms. In favour of the latter
view is also that in almost all cohort studies of old people high cholesterol
was not a risk factor for coronary5-10 or total5,7,11-13
mortality and has even been associated with longevity,10,14-17 and,
in Russia, with cardiovascular health.18 These findings have been
ignored or belittled as minor aberrations from the LDL receptor hypothesis, but
considering that more than 90 per cent of all cardiovascular disease occur in
people above age 60, it is in fact one of the most serious blows against it. Why
should we lower cholesterol if a high cholesterol is unimportant or beneficial?
It may be fruitful to search for a drug with the same effects on the
cardiovascular system as the statins but without influencing cholesterol
synthesis. In the meantime it seems worth while to test the lowest, effective
statin dose instead of trying to lower cholesterol as much as possible.
- Wallace
A, Chinn D, Rubin G. Taking simvastatin in the morning compared with in the
evening: randomised controlled trial. BMJ 2003; 327: 788 [Full
text] - Sacks
FM, Moye LA, Davis BR, Cole TG, Rouleau JL, Nash DT, Pfeffer MA, Braunwald
E. Relationship between plasma LDL concentrations during treatment with
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Text] - Schwartz
GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman
BR, Leslie S, Stern T; Myocardial Ischemia Reduction with Aggressive
Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin
on early recurrent ischemic events in acute coronary syndromes: the MIRACL
study: a randomized controlled trial. JAMA
2001; 285:1711-8. [Pub
Med] - Ravnskov
U. Is atherosclerosis caused by high cholesterol? QJM2002; 95:
397-403. [Full
text] - Siegel
D, Kuller L, Lazarus NB, Black D, Feigal D, Hughes G, Schoenberger JA,
Hulley SB. Predictors of cardiovascular events and mortality in the Systolic
Hypertension in the Elderly Program pilot project. Am
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A, Pekkanen J, Porath A, Punsar S, Karvonen MJ. Risk factors for
cardiovascular disease among 55 to 74 year-old Finnish men: a 10-year
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[PubMed] - Krumholz
HM, Seeman TE, Merrill SS, Mendes de Leon CF, Vaccarino V, Silverman DI,
Tsukahara R, Ostfeld AM, Berkman LF.Lack
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MP, Feskens EJ, Bowles CH, Kromhout D.Serum total cholesterol and systolic blood
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I, Marniemi J, Puukka P, Toikka T, Ehnholm C, Sourander L. Effect of serum
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Biol1997; 17:1224-32. [Full
Text] - Zimetbaum
P, Frishman WH, Ooi WL, Derman MP, Aronson M, Gidez LI, Eder HA. Plasma
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LP, Kronmal RA, Newman AB, Bild DE, Mittelmark MB, Polak JF, Robbins JA,
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[PubMed] - Chyou
PH, Eaker ED.Serum cholesterol concentrations and
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B, Tortrat D, Wolmark Y. Cholesterol as risk factor for mortality in elderly
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A, Sigvaldason H, Sigfusson N. Total cholesterol and mortality after age 80
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Competing interests:
None declared
Competing interests: No competing interests
Wallace at al (1) reported a higher lipid lowering effect of
sinvastatin after evening compared with morning assumption. This is a
further confirmation of available data. The rate of cholesterol synthesis
in the liver shows a well known diurnal periodicity, with production
peaking at nighttime (2), and dietary cholesterol, which increases the
intracellular pool of cholesterol and plasma cholesterol levels, can only
blunt the nocturnal increase in cholesterol biosynthesis.
Jurevics et al
(3) measured the extent of this diurnal variation in rats. They found
that, in liver, there was a peak of cholesterol synthesis from 8 pm to
midnight, with a 4-fold increase over synthesis rates from 8 am to noon,
and this diurnal variation of hepatic cholesterol synthesis was driven
primarily by varying the steady-state mRNA levels for the rate limiting
enzyme, hydroxymethylglutaryl (HMG)-CoA reductase, regardless of diet.
Recently, a study has been carried out on subjects with heterozygous
familial hypercholesterolemia (FH) (4), to determine whether a diurnal
variation in cholesterol synthesis existed as well, and to test the
effects of HMG-CoA reductase inhibitors on this diurnal cycle. Treatment
with both lovastatin or simvastatin (at the dosage of 40 mg b.i.d.)
obtained a significant reduction of 24-mean plasma mevalonate levels from
baseline values, but the evening administration of lovastatin reduced the
nocturnal increase in mevalonate levels, and that of simvastatin
completely abolished it. Again, Lund et al (5) performed a randomized,
crossover trial on 25 patients with coronary artery disease, in which each
patient received simvastatin in the morning or in the evening and then
crossed over to the alternate regimen. The dosage was 10 mg in two
patients, 20 mg in eighteen, and 40 mg in another five. They found a
significant increase in total and LDL cholesterol when simvastatin was
taken in the morning instead of in the evening (186 ± 40 vs 170 ± 34,
p=0.002, and 108 ± 37 vs 97 ± 28, p<_0.001 respectively.="respectively." p="p"/>Thus, we believe that, taken together, these available data are
convincing enough, and, in the absence of reports of side effects, evening
dosing of simvastatin should be not only suggested but strongly
recommended by practitioners. Especially in these times of paucity of
economic resources, the potential of expensive drugs should be fully
overworked, also before a potential risk of reduced compliance on
evening dosing. This probably deserves a further effort in health
education and patients counselling.
1) Wallace A, Chinn D, Rubin G. Taking sinvastatin in the morning
compared with in the evening: randomised controlled trial. Br Med J
2003:327:788.
2) Jones PJH, Schoeller DA. Evidence of diurnal periodicity in human
cholesterol synthesis. J Lipid Res 1990;31:667-73.
3) Jurevics H, Hostettler J, Barrett C, Morell P, Toews AD. Diurnal
and dietary-induced changes in cholesterol synthesis correlate with levels
of mRNA for HMG-CoA reductase. J Lipid Res 2000;41:1048-54.
4) Pappu AS, Illingworth DR. The effects of lovastatin and
simvastatin on the diurnal periodicity of plasma mevalonate concentrations
in patients with heterozygous familial hypercholesterolemia.
Atherosclerosis 2002;165:137-44.
5) Lund TM, Torsvik H, Falch D, Christophersen B, Skardal R,
Gullestad L. Effect of morning versus evening intake of simvastatin on the
serum cholesterol level in patients with coronary artery disease. Am J
Cardiol 2002;90:784-5.
Competing interests:
None declared
Competing interests: No competing interests
Taking Simvastatin at night may better control the lipid profile, but
I wonder if the author also studied the side effects.Apparently, taken at
night the drug has a greater side effect of loss of libido and
impotency.Not so when it is taken during the daytime
Competing interests:
None declared
Competing interests: No competing interests
Re: Serum cholesterol - a surrogate outcome
I have tried to talk to my colleagues regarding the
statins/cholesterol issue. The response I have received is the inference
that I must be stupid. How can someone call him/herself a scientist if it
is unable to listen to a different opinion,
History has shown us some stories to the above attitude:
For instance the wise men of the time laughed at Dr. Finlay the
eminent Cuban physician ( It was not Walter Reed ) who discovered the mode
of transmission of yellow fever. They called him the "Mosquitoe Dr.". What
about Dr. Semmelweis the pioneer of antisepsis in obstetrics. All this men
suffered the obstracisim of the medical stablishment of the time.
Keep up the good work. congratulations.
Francisco A. Campos, M.D.
6820 Sw 94 ave.
Miami, fl. 33173
USA
Competing interests:
None declared
Competing interests: No competing interests