ASSOCIATION OF STATIN USE AND RISK

FOR
SEVERE HEADACHE OR MIGRAINE BY
SERUM
VITAMIN D STATUS: A CROSS-SECTIONAL
POPULATION-BASED STUDY
Disusun Oleh :

INTRODUCTIO
N

Use of statin medications has been associated with both increased and
decreased risk for migraine and headache.

Statins may have variable effect on headache related to an interaction

between statin and vitamin D status.
Use of statin

Low vitamin D
status

Higher prevalence
of experiencing
severe headache
or migraine

Higher vitamin D
status

Lower prevalence
of experiencing
severe headache
or migraine

METHODS

A cross-sectional study using data from the National Health and

Nutrition Examination Survey (NHANES), a stratified multistage
probability survey of the civilian, non-institutionalized United States
population
We analyzed data from the 20012004 NHANES, as those were the
only years for which information on primary exposures of interest,
serum 25-hydroxy vitamin D (25(OH)D) and statin use, as well as the
outcome, severe headache or migraine, was available using inhome interview
Measurements of serum 25(OH)D were performed at the Centers for
Disease Control in Atlanta, GA, using the DiaSorin RIA kit (Stillwater,
MN)

OTHER COVARIATES
Principal
confounders
previously known or
suspected
to
be
associated with statin use
or
to
affect
the
relationship
between
statin use and vitamin D

Use of
specif
c pain
relief

Age

Sex

Number of
concurren
t
medicatio
n use

Ethnici
ty/race

Numbe
r of
times
seen
by
doctor

Educati
onal
attain
ment
Confou
nders

Selfreporte
d
health
status

History
of
stroke

Corona
ry
heart
diseas
e

Physic
al
activity
Body
mass
index
(BMI)

Alcohol
intake

Smokin
g

SENSITIVITY AND POST HOC ANALYSES

We performed sensitivity analyses to explore if use of other

medications or conditions influenced our results

Self
Self report
report
depression/anxi
depression/anxi
ety/emotional
ety/emotional
problem
problem

Diabetes
Diabetes

Systolic
Systolic blood
blood
pressure
pressure

Do
Do they
they
influenced
influenced
our
our
result??
result??

Use
Use of
of
preventive
preventive
migraine
migraine
therapy
therapy

Post
Post
menopausal
menopausal
status/
status/
exogenous
exogenous
hormone
hormone

Cardiovascular
medications
(except for statin and aspirin)
were removed from the main
model to avoid redundancy

Performed
analyses
restricting models (1) to
age greater than 55 years,
and (2) to women 40
years, while adding a
variable
for
use
of
estrogen-containing
contraceptives or HCT

RESULTS

THE CHARACTERISTICS OF THESTUDY

PARTICIPANTS ACCORDING TO STATIN USE
(NHANES 20012004, 40 YEARS)

CHARACTERISTICS OF THE PARTICIPANTS

ACCORDING TO SERUM 25(OH)D (NHANES 2001
2004, 40 YEARS)

PREVALENCE OF SEVERE HEADACHE OR

MIGRAINE

ADJUSTED ODDS RATIOS (OR) AND 95% CONFIDENCE INTERVALS

(CI) OF THE EFFECT OF STATIN AND OTHER CARDIOVASCULAR
MEDICATIONS ON SEVERE HEADACHE OR MIGRAINE IN THE
OVERALL SAMPLE AND STRATIFIED BY VITAMIN D STATUS
(NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY,
20012004, 40 YEARS).

We found:
o

A significant association between statin use and a lower prevalence of

severe headache or migraine, adjusted odds ratio (OR): 0.67 (95%
confidence interval (CI): 0.46, 0.98)

A statistically significant interaction between these factors, with a lower

prevalence of severe headache or migraine for statin use and
25(OH)D>57 nmol/l (p for interaction=0.005)

To account for the possibility that endogenous or exogenous estrogen

influenced

1)Restricting age to 55 years in men and women

In overall model OR of 0.62 (95% CI: 0.41, 0.95)
Those with 25(OH)D57 nmol/l OR of 0.82 (95%CI: 0.50, 1.37)
Those with 25(OH)D>57 nmol/l OR of 0.33 (95% CI:0.17, 0.66)

2) Restricting the sample to women only, for ages 40 years, and

including use of exogenous estrogen
In overall model OR of 0.71 (95%CI: 0.43, 1.16)
Those with 25(OH)D 57 nmol/l OR of 0.91 (95% CI: 0.52, 1.57)
Those with 25(OH)D>57 nmol/l OR of 0.43 (95% CI: 0.20, 0.91)

DISCUSSION

This study is based on the association between migraine with aura and the
risk for developing vascular disease, most notably stroke and suggested
associations between vascular diseases and any migraine, although the latter
remains controversial

Hypothetical mechanism, endothelial dysfunction precursor to vascular

disease, may be both a consequence of migraine and a possible
cause/contributor of migraine pathogenesis

Evidence for endothelial dysfunction in migraine:

Increased
Increased tumor
tumor
necrosis
factor
necrosis factor
(TNF)alpha
(TNF)alpha

Increased
Increased
interleukin
interleukin
(IL)-1)
(IL)-1)

Increased
Increased
plasminogen
plasminogen
activator
activator antigen
antigen

Increased
Increased
thrombosis
thrombosis (von
(von
Willebrand
factor
Willebrand factor
(vWF)
(vWF) activity
activity

Alterations
Alterations in
in the
the
nitric
nitric oxide
oxide
pathway
pathway

Several studies have shown an association of migraine with increased

augmentation index (AIx),

Statin may reduce attack frequency of migraine by :

1. Improving endothelial function
2. Improving arterial stiffness
3. Improving muscular tone
4. Reduce inflammatory response
5. Decreased platelet aggregation and thrombosis

it seems unlikely that statins might decrease migraine via a direct action
on cholesterol reduction, suggesting further investigations on lipid
independent actions would be of most interest

It is speculated that the effects of statin are facilitated by vitamin D,

which has overall anti-inflammatory effects on cytokines

Another speculation on how vitamin D might interact with statin to

reduce migraine involves muscle pain, a suspected trigger of migraine
when occurring in the neck

Included
40
Included only
only people
people 40
years
years in
in order
order to
to evaluate
evaluate
statin
statin use
use
may
may not
not be
be
generalizable
to
younger
generalizable to younger
individuals
individuals
This
This study
study cannot
cannot address
address
causality
or
causality or the
the direction
direction of
of
the
the association
association we
we
observed
observed between
between statin
statin
use
and
vitamin
use and vitamin D
D with
with
lower
lower prevalence
prevalence of
of severe
severe
headache
headache or
or migraine.
migraine.

Although
Although we
we adjusted
adjusted
for
several
for several
confounders,
confounders, residual
residual
confounding
confounding may
may
exist
exist

Our
Our findings
findings of
of dichotomized
dichotomized
versus
versus linear
linear models
models of
of
25(OH)D
are
consistent
25(OH)D are consistent with
with
the
the notion
notion that
that the
the effect
effect of
of
25(OH)D
25(OH)D on
on statin
statin use
use is
is
nonlinear
nonlinear

Outcome
Outcome
based
based on
on selfselfreport
report
Although
Although 25(OH)D
25(OH)D
showed
showed a
a normal
normal
distribution,
distribution, the
the range
range
was
was relatively
relatively narrow,
narrow,
which
which prevented
prevented us
us from
from
examining
higher
examining higher levels
levels

STUDY LIMITATION

CONCLUSION

Our preliminary findings indicate that people who haveserum

25(OH)D>57 nmol/l and use a statin have alower prevalence
of severe headache or migraine. Itremains to be seen
whether combined treatment withstatin and vitamin D
supplementation might serve as atherapy to prevent
headache or migraine

Clinical implications
. Statins have a variable effect on the prevalence of
severe headache or migraine that depends on vitamin D
status.
. Statin use in those with higher serum vitamin D levels
is significantly associated with a lower prevalence of
having severe headache or migraine.

THANK YOU