CLINICAL THERAPEUTICSVVOL. 20, NO.

4, 1998

Efficacy and Safety of Azelaic Acid and Glycolic Acid

Combination Therapy Compared with Tretinoin Therapy
for Acne

Mary C. Spellman, MD,’ and Stephanie H. Pincus, AI@

‘University of California at San Diego and VA Medical Center; San Diego, California,
and 2State University of New York at BufSalo and Buffalo General Hospital, B@alo,
New York

ABSTRACT cantly less dryness, redness, and peeling

with azelaic/glycolic acid. Significantly
We conducted a 12-week, multicenter, more patients in the azelaic/glycolic acid
randomized, double-masked, parallel- group than the tretinoin group reported
group study of the efficacy, safety, and that they felt attractive. The combination
tolerability of azelaic acid 20% cream of azelaic acid and glycolic acid is a use-
and glycolic acid lotion compared with ful alternative to tretinoin, being at least
tretinoin 0.025% cream and a vehicle lo- as efficacious as the latter, while offering
tion to treat mild-to-moderate facial acne a superior tolerability and patient ap-
vulgaris. Patients treated with azelaic/gly- proval profile. Key words: azelaic acid,
colic acid experienced a significantly acne, glycolic acid, tretinoin.
greater reduction in the number of
papules, as well as a greater reduction in
INTRODUCTION
the number of inflammatory lesions, than
those treated with tretinoin. Overall Acne vulgaris, which is believed to result
global improvement was approximately from the interaction of four pathogenic
25% in both groups. In the physician eval- factors (hyperkeratinization, proliferation
uations, treatment with azelaic/glycolic of Propionibacterium acnes, inflamma-
acid was found to cause significantly less tion, and excessive sebum production),
dryness, scaling, and erythema than affects approximately 17 million Ameri-
tretinoin. Patients also reported signifi- cans.’ Historically, the majority of pa-

0149-2918/98/$19.00 711

tients seeking treatment for acne have
been adolescents; however, the number of
adult women seeking treatment has been
rising steadily. The latter population has
higher expectations for improvement and
is less tolerant of adverse effects associ-
ated with treatment. Cosmetic acceptabil-
ity appears to be especially important to
these patients.
Tretinoin is one of the most commonly
used antiacne agents because of its supe-
rior ability to eradicate existing come-
dones and prevent the formation of new
ones.’ Nevertheless, tretinoin is associ-
ated with certain adverse effects that many
patients cannot tolerate, including initial
exacerbation of existing lesions (flare-
up), local irritation, increased risk of pig-
mentary changes, and, in some patients,
photosensitivity.2.3
Azelaic acid, a newer agent, has a ther-
apeutic profile comparable to that of
tretinoin and is better tolerated by pa-
tients.4 Azelaic acid treatment normalizes
keratinization and reduces the number of
P acnes bacteria. 46 Unlike tretinoin, aze-
laic acid is typically associated with only
one adverse effect-a mild local irritation
that generally diminishes during the first
few weeks of treatment.5,6 Azelaic acid
has no recognized interactions with other
drugs; thus it is useful for both combina-
tion therapy and monotherapy.
Glycolic acid, a compound widely used
in cosmetic products, has been anecdo-
tally reported to be efficacious in the treat-
ment of acne; because glycolic acid re-
duced corneocyte cohesion in the stratum
corneum,7,8 its usefulness as a keratolytic
antiacne agent is currently being evalu-
ated in clinical trials.4,9 Glycolic acid may
be a useful adjunct to other antiacne treat-
ments, increasing their ability to penetrate
the skin. Many physicians select a combi-
712
CLINICAL THERAPEUTICS”
nation of antiacne agents to target a wider
range of pathogenic factors and increase
the likelihood of treatment success.2
This study compared the efficacy and
safety of combination azelaic acid 20%
cream and glycolic acid lotion with a stan-
dard antiacne treatment, tretinoin 0.025%
cream, combined with a vehicle lotion. A
preliminary report of our findings has
been presented in abstract form.1o
PATIENTS AND METHODS
Study Design
We conducted a multicenter, random-
ized, double-masked, parallel-group study
in which azelaic acid 20% cream com-
bined with glycolic acid lotion was com-
pared with tretinoin combined with a ve-
hicle lotion. We obtained written informed
consent from all patients before they en-
rolled, and most patients also signed a
photographic release.
Study Population
The group consisted of 70 adult patients
(17 males, 53 females) who had been
given a clinical diagnosis of mild-to-mod-
erate facial acne vulgaris. Patients were
excluded if they had an uncontrolled sys-
temic disease; had received topical anti-
acne therapy 14 days before or during the
study or any systemic therapy with an-
tibiotics 30 days before or during the
study; were known to be allergic or sen-
sitive to any of the study medications or
their components; had previously been
treated with systemic retinoids; had a skin
disease that might interfere with the diag-
nosis or evaluation of their hyperpigmen-
tation; or were pregnant, nursing, or plan-
ning to become pregnant.
MC. SPELLMAN AND S.H. PINCUS
Study Protocol
The study medications were azelaic
acid 20% cream,* glycolic acid 15% fa-
cial lotion,+ glycolic acid 20% facial lo-
tion,” tretinoin 0.025%,§ and the vehicle
lotion of glycolic acid.
At the first visit (baseline), facial pho-
tographs were taken of all patients, and a
urinary pregnancy test was performed in
women. Each patient’s medical history
was recorded. The baseline examination
included a lesion count, assessment of dis-
ease severity, and the recording of signs
(scaling, dryness, erythema, oiliness) and
symptoms (burning, itching).
Every morning and evening, patients
washed their face with a nonmedicated
soap, then thoroughly rinsed and dried it.
Over the 12-week course, patients in the
azelaic/glycolic acid group applied aze-
laic acid 20% cream in the morning and
evening and glycolic acid (15% lotion for
1 month, 20% lotion for the remainder of
the study) in the evening. Patients in the
tretinoin group applied vehicle lotion in
the morning and evening and tretinoin
0.025% cream in the evening. In both
treatment groups, the second evening
medication was applied approximately 10
to 15 minutes after the first medication.
Nonmedicated cosmetics were permitted
during the study provided the regimen
was consistently followed.
*Trademark: Azelex@ (Allergan Inc., Irvine, Califor-
nia).
+Trademark: M.D. Forte II@ (Allergan Inc., Irvine,
California).
‘Trademark: M.D. Forte I@ (Allergan Inc., Irvine,
California).
“Trademark: Retin-A@ (Ortho Pharmaceutical Cor-
poration, Raritan, New Jersey).
Outcome Measures
Evaluations of the primary efficacy
variables of disease severity, response to
treatment, lesion count, and signs and
symptoms were conducted by the same
study physician at weeks 4, 8, and 12. At
these time points, photographs of the pa-
tients who had signed a photographic re-
lease were also taken. At weeks 4 and 12,
patients were questioned about their im-
pressions of the efficacy and cosmetic
characteristics of the study medication. At
week 12, a urinary pregnancy test was
performed in all of the women, and all pa-
tients completed an exit form.
Counts of noninflammatory (open and
closed comedones) and inflammatory
(pustules, papules, nodules) lesions were
assessed according to the following
guidelines: only lesions on the face, from
the mandibular line to the hairline edge,
were included; prominent follicular
markings on the nose were not consid-
ered to be open comedones; lesions were
counted on one side of the face then the
other; and the total figures in each cate-
gory were recorded and inserted in the
appropriate boxes on the case report
form. Overall disease severity was rated
on a scale of 0 = none to 6 = severe.
Global evaluation of response to treat-
ment was rated on a scale of 0 = worse
to 8 = completely cleared.
The signs and symptoms evaluated
were scaling, dryness, erythema, oili-
ness, burning, and itching, and were
rated on a scale of 0 = none to 5 = se-
vere. Patient satisfaction variables were
dryness, redness, peeling, oiliness, burn-
ing, itching, pain, and dark spots or
blotches, rated on a scale of 0 = none to
4 = severe. Patients also rated the effect
of treatment on their perceived attrac-
713
 CLINICAL THERAPEUTICS”

tiveness, self-confidence, comfort in so- nificant differences between groups in

cial situations, satisfaction with their ap-
pearance, ease in a physical relationship,
embarrassment, and degree to which
acne negatively affected performance at
work or in school, on a scale of 0 = none
to 6 = very much.
Statistical Analysis
The level of statistical significance was
0.05 (two-tailed test) for all between-
group comparisons. Categorical variables,
such as symptoms, signs, and overall dis-
ease severity, were summarized using de-
scriptive statistics (ie, sample size and
mean) and were analyzed using Wilcoxon
rank sum tests. Continuous variables, such
as age, were summarized using descrip-
tive statistics and analyzed using analysis
of variance.
RESULTS
Patient demographic characteristics are
summarized in Table I. There were no sig-
terms of age or race. The female/male ra-
tio was significantly higher in the aze-
laic/glycolic acid group (P < 0.05). The
majority of patients in both groups were
white females. Twenty-eight of 35 (80%)
patients in the azelaic/glycolic acid group
and 3 1 of 35 (89%) patients in the tretinoin
group completed the study (Table II). The
primary reason for discontinuation of
treatment was loss to follow-up (6 [17%]
patients in the azelaic/glycolic acid group
and 1 [3%] patient in the tretinoin group).
One (3%) patient in the azelaic/glycolic
acid group and 2 (6%) patients in the
tretinoin group were terminated for lack
of efficacy. No patients were terminated
for adverse events.
Lacy
At baseline, no significant differences
were noted between groups in terms of
mean papule count (azelaic/glycolic acid =
11.1, tretinoin = 11.7). There were signif-
icantly fewer papules in the azelaic/gly-

Table I. Demographic characteristics of patients.

Azelaic/Glycolic Acid TretinoinNehicle

(n = 35) (n = 35)

Mean age (y)

Sex+
Male 4 13
Female 31 22
Race
Black 4 1
White 25 25
Hispanic 3 5
Oriental 2 2
Other 1 2

*Data unavailable in one patient.

+The female/male ratio was significantly higher in the azelaic/glycolic acid group (P < 0.05).

714
M.C. SPELLMAN AND S.H. PINCUS

Table II. Patient disposition.

Azelaic/Glycolic Acid (%) TretinoinNehicle (%)

(n = 35) (n = 35)

Completed 28 (80) 31 (89)

Discontinued 6 (17) 2 (6)
Missed visits 0 0
Personal reasons 0 0
Loss to follow-up 6 (17) 1 (3)
Other 0 1 (3)
Terminated 1 (3) 2 (6)
Adverse events 0 0
Lack of efficacy 1 (3) 2 (6)

colic acid group at weeks 4 (P = O.OOS),
8 (P = 0.16), and 12 (P = 0.12). At week
12, a significantly greater decrease in the
number of papules was found in the aze-
laic/glycolic acid group (mean decrease =
6.5, -56.8%) than in the tretinoin group
(mean decrease = 2.5, -22.2%; 0.030)
(Figure 1A). No
in the
of inflammatory at baseline
= 13.8, tretinoin 15.7).
Azelaic/glycolic acid treatment resulted
in
at weeks 4
(P = 0.002), 8 (P = 0.006), and 12 (P =
0.024). The greater decrease in numbers
of inflammatory lesions noted with aze-
laic/glycolic acid compared with tretinoin
at week 12 was not significant (aze-
laic/glycolic acid = -55.1%, tretinoin =
-28.7%; P = 0.088) (Figure 1B). Aze-
laic/glycolic acid was of equal efficacy to
tretinoin in decreasing the number of non-
inflammatory lesions at week 12 (Figure
1C). No significant between-group differ-
ences were found at any time point in
mean counts or decreases from baseline
of pustules or nodules.
Regarding overall disease severity, no
significant between-group differences
were seen in mean scores at baseline (aze-
laic/glycolic acid = 3.2, tretinoin = 3.4).
Overall disease severity was significantly
lower in the azelaic/glycolic acid group
than in the tretinoin group at week 8 (aze-
laic/glycolic acid = 2.5, tretinoin = 3.1; P
= 0.044). No significant between-group
differences in decreases from baseline
were reported at any time point.
At the end of the 12-week study, both
treatments resulted in global evaluations
of approximately 25% improvement.
Signs and Symptoms of Irritation
Study physicians reported that aze-
laic/glycolic acid caused significantly less
dryness than tretinoin at weeks 4 (P =
0.010) and 8 (P = 0.024); this difference
was not significant at week 12 (P = 0.074)
(Figure 2A). There was significantly less
scaling with azelaic/glycolic acid than

715
m
M.C. SPELLMAN AND S.H. PINCUS
with tretinoin at weeks 4 (P = 0.007), 8
(P = O.OOl), and 12 (P = 0.001) (Figure
2B). Azelaic/glycolic acid caused signifi-
cantly less erythema than tretinoin at
weeks 4 (P = 0.46), 8 (P = 0.019), and 12
(P = 0.026) (Figure 2C). No significant
between-group differences were noted in
oiliness, burning, and itching at any time
point. The mean severity scores for all
signs and symptoms were below 1 (trace)
throughout the study.
Patient Questionnaire
Patients reported that azelaic/glycolic
acid caused significantly less dryness
(weeks 4 and 12; P O.OOl),
DISCUSSION
To our knowledge, this was the first con-
trolled clinical trial evaluating the combi-
nation of azelaic acid and glycolic acid
for the treatment of acne. Azelaic/glycolic
acid was equivalent in efficacy to tretinoin
against comedones and significantly more
effective than tretinoin in decreasing the
number of inflammatory lesions and
papules. With azelaic/glycolic acid, physi-
cians noted significantly less dryness
(weeks 4 and 8), scaling (weeks 4, 8, and
12), and erythema (weeks 4, 8, and 12)
than with tretinoin; scores for all other
signs and symptoms were equivalent and
below trace levels. Additionally, patients
in the azelaic/glycolic acid group reported
significantly less dryness, redness, and
peeling and felt more attractive than did
those in the tretinoin group. No patients
in either treatment group were discontin-
ued because of adverse effects.
The profound comedolytic effects of
tretinoin have made it a popular treatment
for acne; however, it is associated with
adverse effects that many patients con-
sider objectionable. The most notable of
these is local irritation (eg, erythema, scal-
ing, dryness, burning); one study reported
an incidence rate of close to 90%.”
Tretinoin may induce sensitivity to sun-
light, necessitating repeated application
of sunscreen2 as well as an initial acne
flare-up due to the release of local follic-
ular inflammatory factors. Finally, treti-
noin can accentuate the postinflammatory
darkening related to the healing of acne
lesions in darker-skinned patients.3 The
end result may be diminished patient sat-
isfaction and treatment compliance.
Monotherapy studies have demon-
strated that azelaic acid 20% cream con-
sistently reduces the number of both non-
inflammatory and inflammatory lesions,
while typically producing only an occa-
sional, mild local irritation.t2 A 6-month
trial compared azelaic acid to tretinoin
0.05% cream and reported that the two
treatments were equivalent in the reduc-
tion of comedones and in overall thera-
peutic response; with azelaic acid, how-
ever, the incidence of burning, erythema,
and scaling was approximately 20% to
717
 CLINICAL THERAPEUTICS”

A 0.6

g! 0.6
8
(I)
I
0.4

0
Baseline Week4 Week 0 Week 12

0.6
6

p! 0.6
8
(I)
r-l

Baseline Week 4 Week 6 Week 12

C 1.6

/ r

Baseline Week 4 Week 6 Week 12

Figure 2. Physician-evaluated signs of irritation (scale: 0 = none to 5 = severe). (A) Mean

dryness score at 4,8, and 12 weeks; (B) Mean scaling score at 4,8, and 12 weeks;
(C) Mean erythema score at 4,8, and 12 weeks. *P= 0.010 versus tretinoin; +P=
0.024 versus tretinoin; $P= 0.007 versus tretinoin; @P= 0.001 versus tretinoin;
"P= 0.046 versus tretinoin; qP= 0.019 versus tretinoin; #P= 0.026 versus tretinoin.

718
M.C. SPELLMAN AND S.H. PINCUS

50
n Azelaiclglywlii acid
qTretlnoin

40
rn
E
a”
d 30 -

L
6 -
E8 20

b
CL
10

*
0 -r- -
Dryness Redness reeling Attractiveness

Figure 3. Patient survey variables that were significantly different between groups.
*P< 0.001 versus tretinoin at weeks 4 and 12; +P= 0.037 versus tretinoin at
week 12; $P= 0.033 versus tretinoin at week 12.

30% lower than with tretinoin.13 Similar
efficacy and safety results were found in
a 6-month trial comparing azelaic acid
with benzoyl peroxide 5% ge1.i4 Investi-
gators treating other skin disorders found
that azelaic acid was associated with only
minor, transient local irritation during a 9-
week period of treatment for rosaceai5
and a 24-week period of treatment for hy-
perpigmentation. I6 Neither phototoxicity
nor other more serious adverse events
have been reported in association with
azelaic acid treatment.
Glycolic acid has also been demon-
strated to be effective and safe. It is widely
used in home skin-care products and has
been studied clinically in such dermato-
logic conditions as acne, melasma, and
photoaging.4T’7 Wang et al9 demonstrated
that glycolic acid (35% to 50% peels in
the treatment of acne in addition to 15%
home-care products) caused only minimal
adverse effects; they suggested that gly-
colic acid “may be an ideal adjunctive
treatment of acne.“9 Erythema is the most
commonly reported adverse effect related
to glycolic acid treatment. I7 Our study ex-
tends these earlier findings by supporting
the efficacy and safety of glycolic acid in
combination therapy.
The efficacy seen of the combination
of azelaic acid and glycolic acid may re-
sult from synergistic effects on kera-
tinization or from the enhanced penetra-
tion of azelaic acid due to glycolic acid’s
thinning of the stratum comeum.7T8 This
thinning may also hasten azelaic acid’s
beneficial effects. The minimal irritation
seen with this combination is notewor-
thy, because both azelaic acid and gly-
colic acid separately cause minor irrita-
tion; the absence of significant irritation

719

is a further benefit. Moreover, the favor-
able results of evaluations by both physi-
cians and patients may appeal particu-
larly to patients who are less tolerant of
adverse effects.
CONCLUSIONS
It has been suggested that any new acne
treatment should be at least as effective as
those currently available, with equal or
fewer adverse effects.18 These criteria are
met by azelaic acid, both used alone and
combined with glycolic acid, as in the pres-
ent study. Patient satisfaction was higher
with azelaic/glycolic acid than with
tretinoin, which suggests that compliance
may improve. Azelaic/glycolic acid may
be especially appropriate in adult women,
to whom cosmetic considerations may be
highly important.
ACKNOWLEDGMENT
This research was supported by a grant
from Allergan, Inc., Irvine, California.
Address correspondence to: Mary C.
Spellman, MD, 5000 Executive Parkway,
Suite 575, San Ramon, CA 94583.
10. Spellman MC, Pincus SH. Combined aze-
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