A Randomized, Evaluator-Blinded, Controlled Study of the

Effectiveness and Safety of Small Gel Particle Hyaluronic

Acid for Lip Augmentation
RICHARD G. GLOGAU, MD,* DAVID BANK, MD,† FREDRIC BRANDT, MD,‡ SUE ELLEN COX, MD,§
LISA DONOFRIO, MD,¶ JEFFREY DOVER, MD,** STEVEN GREKIN, DO,†† IRA LAWRENCE, MD,‡‡
XIAOMING LIN, MS, RN,‡‡ MARK NESTOR, MD, PHD,§§¶¶ AVA SHAMBAN, MD,***
DANIEL STEWART, DO,††† ROBERT WEISS, MD,‡‡‡ ROBERT A. AXFORD-GATLEY, MD,§§§
MICHAEL J. THEISEN, PHD,§§§ AND STACY SMITH, MD¶¶¶

OBJECTIVES To assess the effectiveness and safety of small gel particle hyaluronic acid (SGP-HA) for lip
augmentation.
METHODS Adults (n = 180; aged 18–65) scoring 1 (very thin) to 2 (thin) on the 5-point validated Medicis Lip
Fullness Scale (MLFS) for the upper or lower lip were randomized (3:1) to SGP-HA (  1.5 mL/lip) or no
treatment. Co-primary effectiveness end points were blinded-evaluator MLFS score for upper or lower lip at
week 8. Secondary end points (MLFS score, independent photographic review, Global Aesthetic Improvement
Scale [GAIS], safety assessments) were measured throughout the study.
RESULTS Statistically significantly more MLFS responders (  1 grades of MLFS improvement at week 8)
received SGP-HA (93% combined upper and lower lip responders [95% upper lip; 94% lower lip]) than no
treatment (29% combined; p < .001). SGP-HA improved self-assessed combined lip GAIS (97% week 8; 74%
week 24) significantly more than no treatment (0% throughout; p < .001). The SGP-HA group reported
anticipated swelling (58%) and bruising (44%), 88% mild or 11% moderate severity, without unanticipated
device adverse events.
CONCLUSIONS SGP-HA is highly effective and well tolerated for lip augmentation. Statistically significant
improvement was evident based on the MLFS at 8 weeks, with visible results reported in the majority of
participants 6 months after treatment.
Medicis Aesthetics Inc. (Scottsdale, AZ) provided funding and materials for this study. Canfield loaned
photographic equipment. Complete Healthcare Communications, Inc. (Chadds Ford, PA) provided editorial
support. Dr. Glogau is a consultant to Medicis and Allergan. Dr. Nestor is a consultant to Medicis.
Dr. Shamban serves on the advisory board to Medicis.

D urable, nonpermanent dermal fillers, such as

hyaluronic acid (HA) products and formerly
collagen, are used in procedures for augmenting the
lips and perioral areas, including increasing the
overall volume of the lip or enhancing the vermilion
border, and sculpting and accentuating lip

*Richard G. Glogau, MD, Inc., San Francisco, California; †Center for Dermatology, Cosmetic and Laser Surgery,
Mount Kisco, New York; ‡Dermatology Research Institute LLC, Coral Gables, Florida; §Aesthetic Solutions, Chapel
Hill, North Carolina; ¶The Savin Center, New Haven, Connecticut; **SkinCare Physicians, Chestnut Hill,
Massachusetts; ††Grekin Skin Institute, Warren, Michigan; ‡‡Medicis Aesthetics, Scottsdale, Arizona; §§Center for
Clinical and Cosmetic Research, Aventura, Florida; ¶¶Department of Dermatology, University of Miami Miller School of
Medicine, Miami, Florida; ***Ava T Shamban, MD, Inc., Santa Monica, California; †††Michigan Center for Skin Care
Research, Clinton Township, Michigan; ‡‡‡Maryland Laser Skin and Vein Institute, Hunt Valley, Maryland; §§§Complete
Healthcare Communications, Inc., Chadds Ford, Pennsylvania; ¶¶¶Dermatology and Consulting, Cardiff, California

© 2012 by the American Society for Dermatologic Surgery, Inc.  Published by Wiley Periodicals, Inc. 
ISSN: 1076-0512  Dermatol Surg 2012;38:1180–1192  DOI: 10.1111/j.1524-4725.2012.02473.x

1180

contours.1–3 The clinical effectiveness of filler agents
is judged on aesthetic outcomes, including lip
fullness, smoothness, softness and flexibility, and
absence of nodules.4–7
Restylane (Medicis Aesthetics Inc., Scottsdale, AZ)
is a nonanimal-source small gel particle hyaluronic
acid (SGP-HA) that the U.S. Food and Drug
Administration (FDA) has approved for mid to deep
dermal implantation for the correction of moderate
to severe facial wrinkles and folds.8 It is supplied as
a clear gel formulation of small particles of HA in a
single-use syringe. The physical characteristics and
structure of an HA soft tissue filler and its rheolog-
ical properties are established during the manufac-
turing process. SGP-HA is formed by passing
stabilized gel through screens with a specific pore
size, producing well-defined gel particles that are
uniform in shape and diameter. This manufacturing
method coupled with other variables such as HA
concentration and percentage of cross-linking results
in a gel particle that is stiff but elastic, capable of
resisting deformation and maintaining its original
shape when subjected to external and skin tension
forces.9–11 Such characteristics may play an impor-
tant role in predicting how an HA filler may behave
in the skin and its ability to provide structural
support, definition, volume, and lift.
The effectiveness and safety of SGP-HA in the
treatment of facial wrinkles and folds was evaluated
in three prospective, randomized comparator trials
involving 430 treated patients.8 The injection of
SGP-HA was found to be as effective as the
correction of moderate to severe facial folds and
wrinkles as a bovine collagen product (previously in
common use, but no longer available in the United
States) and another HA dermal filler.
A retrospective review of 685 patients treated with
SGP-HA for lip augmentation in clinical practice
found that 61% were satisfied with their results after
9 months.12 Adverse effects, other than transient
injection site erythema and occasional bruising, were
rare and easily managed; induration and sterile
GLOGAU ET AL
suppuration at the injection site required drainage in
one patient and were self-limiting with warm com-
presses and topical corticosteroid cream in a second
patient. Many reports, including an open-label
study, in the literature describe the effectiveness of
HA in lip augmentation.6,12,13 In a small, open-label
pilot study, 89% (16/18) of patients treated with
SGP-HA had greater lip fullness, as measured by an
improvement of one grade or more on the validated
Medicis Lip Fullness Scale (MLFS) in both lips after
8 weeks.13 This prespecified improvement criterion
was met in 18 (100%) patients for the upper lip and
in 16 (89%) for the lower lip. The clinical relevance
of this MLFS improvement was consistent with
improved scores on the subjective Global Aesthetic
Improvement Scale (GAIS). No treatment-related
adverse events (AEs) were reported.
This article presents the results of a randomized, no
treatment–controlled, evaluator-blinded study that
assessed the safety and effectiveness of SGP-HA for
soft tissue lip augmentation.
Methods
Patients
Eligible patients were adult men and women no
older than 65 seeking lip augmentation at 12
investigational centers and scoring 1 or 2 on the 5-
point MLFS (1 = very thin, 5 = very full) for the
upper and lower lips in patients with Fitzpatrick skin
type I, II, or III or for one or both lips in patients
with skin type IV, V, or VI, as assessed at baseline by
the treating investigator. Participants were required
to abstain from any other facial plastic surgery or
cosmetic procedures during the 9-month study
period. Exclusion criteria included a history of
severe or multiple allergies, including allergy or
hypersensitivity to injectable HA gel or local anes-
thetics; history of any disease resulting in edema of
the face or changes in facial contour during the study
period; history of any tissue augmentation therapy
or aesthetic facial surgical therapy below the level of
the lower orbital rim; any contraindication to the
38:7 PART II:JULY 2012 1181
 LIP AUGMENTATION WITH SMALL GEL PARTICLE HYALURONIC ACID
implant procedures, including use of anticoagulants;
and significant abnormalities of the lips. A central
institutional review board (Quorum Review IRB,
Seattle, WA) approved the study protocol and
documents. Patients provided written informed
consent before being admitted to the study. The
study was conducted in accordance with the Decla-
ration of Helsinki and Good Clinical Practice.
Treatments
Patients were randomly assigned 3:1 to receive SGP-
HA or no treatment. A centralized randomization
system was used to ensure enrollment of a minimum
of 30 patients with darker skin types based on
classification of Fitzpatrick skin types IV, V, or VI.
Patients randomized to the no-treatment group were
untreated after screening and baseline assessments
(described below). Patients randomized to SGP-HA
were treated initially with SGP-HA for optimal lip
augmentation, which was defined as the best possi-
ble aesthetic result that could be obtained for an
individual patient, as agreed upon by the treating
investigator and patient. Patients could optionally
receive an additional touch-up treatment at 2 weeks.
All patients (treated and untreated groups) could
receive SGP-HA treatment after 6 months. SGP-HA
supplies were commercial Restylane, 1.0-mL syringe
of SGP-HA gel supplied with a 30-G, 0.5-inch
needle. The recommended dose of SGP-HA was up
to 1.5 mL per lip in any given injection session.
Recommended techniques were linear antegrade or
retrograde threading (most often used for enhance-
ment of the vermilion border) and serial puncture,
although injection techniques and anesthetic type
and use were at the discretion of the treating
investigator.
Assessments
The screening visit and initial treatment could be
performed on the same day for patient convenience.
Baseline assessments were obtained before treat-
ment, including pretreatment photographs, MLFS
score by the treating investigator, and safety
parameters (lip texture, firmness, symmetry, move-
1182 DERMATOLOGIC SURGERY
ment, function, sensation, and mass formation).
Diaries were dispensed to all patients with instruc-
tions to record daily the extent (none, tolerable,
affects activities, disabling) of bruising, redness,
swelling, pain, tenderness, itching, and other events
around or on the lips for the first 14 days after
treatment. Seventy-two hours after treatment, a
safety visit assessed safety parameters and inter-
viewed the patient regarding AEs. At weeks 2 and 4
after treatment, MLFS (treating investigator), GAIS
(treating investigator and patient), safety parame-
ters, and AEs were assessed; photographs obtained;
and diaries returned (week 2). At weeks 8, 12, 16,
20, and 24 after treatment, MLFS (live evaluations
of patients by treating and blinded investigators),
GAIS (treating investigator and patient), safety
parameters, and AEs were assessed, and photo-
graphs were obtained.
The MLFS is a validated, 5-point scale of lip fullness
(1 = very thin; 2 = thin; 3 = medium; 4 = full;
5 = very full), used in this study to assess effective-
ness in the upper and lower lips separately. The
MLFS has been validated in a separate study.14 Each
lip (upper and lower) receives a separate score at
each visit. The GAIS is a well-accepted categorical
scale used to evaluate aesthetic improvement
(Table 1). The treating investigator and patient
scored each lip separately on the GAIS at each time
point after treatment. As a final assessment, three
TABLE 1. Global Aesthetic Improvement Scale
Score Rating Definition
3 Very much Optimal cosmetic result
improved
2 Much Marked improvement,
improved but not completely optimal
1 Improved Obvious improvement
0 No change Appearance essentially
same as baseline
1 Worse Worse than original
appearance
2 Much Marked worsening in
worse appearance
3 Very much Obvious worsening in
worse appearance

reviewers blinded to treatment randomization per-
formed an independent photographic review (IPR) at
the end of the study using the MLFS.
Statistical Methods
Effectiveness and safety were analyzed based on the
intention-to-treat (ITT) population, including all
treated patients and those randomized to no treat-
ment. The co-primary effectiveness end points were
the blinded evaluator MLFS scores for upper and
lower lips at week 8. A responder was defined as a
patient with an at least 1-grade improvement on the
MLFS for upper and lower lips assessed by the
blinded evaluator at week 8 over the treating
investigator’s baseline MLFS assessment. This pro-
cedure ensured that the blinded evaluator had no
knowledge of the patient’s lip fullness at baseline.
The proportion of responders was calculated for
each group at week 8 and the statistical difference
analyzed using the Fisher exact test; p < .05 for the
treatment difference on both lips was considered
effective. Enrollment of at least 160 patients (120
with SGP-HA treatment and 40 with no treatment)
was targeted to have an estimated 99% power to
detect a difference in response at week 8 for the
primary effectiveness end point of 70% in the
treated patients compared with 25% in the patients
who received no treatment. Separate from analysis
of the overall study population, a prespecified
analysis was performed to compare treatment
response to SGP-HA with no treatment at week 8 only
in patients with Fitzpatrick skin types IV, V, and VI.
The secondary effectiveness analyses included the
treating investigator and blinded evaluator MLFS
assessments at other study visits, IPR evaluation (the
median score of the three reviewers’ MLFS assess-
ments was used), and the proportion of responders
on the GAIS calculated for each treatment group as
rated by the treating investigator and the patient.
Differences in the proportion of responders (based
on the MLFS or the GAIS) between the SGP-HA and
no treatment groups was evaluated using the Fisher
exact test. Correlations between GAIS ratings by the
GLOGAU ET AL
treating investigator and patient were assessed sep-
arately at each time point for the upper and lower
lips using Spearman rank correlation coefficients;
agreement between the MLFS ratings by the treating
investigator and blinded evaluator and from IPR
assessments was assessed based on weighted kappa
statistics. Safety was assessed based on the occur-
rence of all reported and observed treatment-emer-
gent AEs (TEAEs) in patients throughout the
6-month study period.
Results
Of 180 patients randomized, 135 received SGP-HA,
and 45 received no treatment and were included in
the ITT population. Eighty patients in the SGP-HA
group received a touch-up 2 weeks after the first
treatment session. One hundred sixteen (86%) in the
SGP-HA group and 39 (87%) in the no-treatment
group completed the study. The majority of enrolled
patients were women (99%) and white (94%), with
a mean age of 47.6; 139 (77%) patients had
Fitzpatrick skin type I, II, or III, and 41 (23%) had
Fitzpatrick skin type IV, V, or VI. The demographic
characteristics of the SGP-HA and no treatment
groups were similar (Table 2).
Effectiveness
At week 8, 134 patients who received SGP-HA were
evaluated in person for upper lip treatment response,
and 127 (95%) were responders, having at least a
1-grade improvement on the MLFS; lower lip
treatment response was evaluated in 122 patients, of
whom 115 (94%) were MLFS responders. In com-
parison, the prevalence of MLFS responders at week
8 in the untreated group was 36% for the upper lip
(16/44) and 38% for the lower lip (15/39). The
prevalence of combined upper and lower lip MLFS
responders at week 8 differed significantly
(p < .001) between the SGP-HA treated group
(93%, 125/135) and the untreated group (29%,
13/45). A prespecified analysis of patients with
Fitzpatrick skin types IV, V, and VI found a similar
pattern of response (Table 3). Significant differences
38:7 PART II:JULY 2012 1183
 LIP AUGMENTATION WITH SMALL GEL PARTICLE HYALURONIC ACID

TABLE 2. Patient Characteristics

Small Gel Particle
No Treatment Hyaluronic Acid
Characteristic (n = 45) (n = 135) Total (n = 180)
Age, mean ± standard deviation, 47.2 ± 10.9, 47.8 ± 10.5, 47.6 ± 10.6,
median (range) 47.0 (25.0–65.0) 51.0 (18.0–65.0) 50.0 (18.0–65.0)
Female, n (%) 45 (100) 134 (99) 179 (99)
Race, n (%)
White 41 (91) 128 (95) 169 (94)
American Indian or Alaskan native 1 (2) 1 (<1) 2 (1)
Black 0 2 (1) 2 (1)
Native Hawaiian or other 0 1 (<1) 1 (<1)
Pacific Islander
Asian 0 0 0
Other 3 (7) 3 (2) 6 (3)
Ethnicity, n (%)
Not Hispanic or Latino 39 (87) 122 (90) 161 (89)
Hispanic or Latino 6 (13) 13 (10) 19 (11)
Fitzpatrick skin type, n (%)
I, II, or III 35 (77) 104 (78) 139 (77)
IV, V, or VI 10 (22) 31 (23) 41 (23)
Baseline Medicis Lip Fullness
Scale score, n (%)
Upper lip
1 (very thin) 26 (58) 82 (61) 108 (60)
2 (thin) 18 (40) 52 (39) 70 (39)
3 (medium) 1 (2) 1 (<1) 2 (1)
4 (full) 0 0 0
5 (very full) 0 0 0
Lower lip
1 (very thin) 20 (44) 44 (33) 64 (36)
2 (thin) 19 (42) 78 (58) 97 (54)
3 (medium) 4 (9) 9 (7) 13 (7)
4 (full) 2 (4) 3 (2) 5 (3)
5 (very full) 0 1 (<1) 1 (<1)

Data represent the intention-to-treat patient population.

between the SGP-HA and no-treatment groups were
observed at all time points after week 8, up to and
including week 24, at which point, 70% of the
SGP-HA group were MLFS responders, compared
with 37% of the control patients (p < .001;
Figure 1). Representative baseline and posttreat-
ment results are shown in Figure 2.
The percentages of responders as assessed by the
treating investigator also showed statistically signif-
icant between-treatment differences and were in
close agreement with the findings of the blinded
evaluators at all time points. Furthermore, the
blinded IPR analysis demonstrated statistically sig-
nificant differences in proportions of MLFS
responders at each time point through 24 weeks
(p < .05). Although the proportion of responders
according to IPR was notably lower in each group
than according to live evaluation, this finding is
expected based on prior studies and because photo-
graphs rarely provide the same level of information
or detail as seen with live grading.15
The findings for GAIS scoring according to patients
and unblinded treating investigators are shown in
Figure 3. Significant differences between the SGP-
HA and no-treatment groups were seen at all visits
(p < .001). No untreated patients rated themselves

1184 DERMATOLOGIC SURGERY

 GLOGAU ET AL

TABLE 3. Proportion of Responders to Small Gel Particle Hyaluronic Acid (SGP-HA) Compared With No
Treatment at Week 8*
No Treatment SGP-HA
Overall ITT population
Upper lip
n/N 16/44 127/134
Proportion of responders (95% CI) 0.364 (0.224–0.522) 0.948 (0.895–0.979)‡
Lower lip
n/N 15/39 115/122
Proportion of responders (95% CI) 0.385 (0.234–0.554) 0.943 (0.885–0.997)‡
Upper and lower lips combined†
n/N 13/45 125/135
Proportion of responders (95% CI) 0.289 (0.164–0.443) 0.926 (0.868–0.964)‡
Fitzpatrick IV, V, VI subpopulation
Upper lip
n/N 5/9 28/30
Proportion of responders (95% CI) 0.556 (0.212–0.863) 0.933 (0.779–0.992)‡
Lower lip
n/N 0/4 17/18
Proportion of responders (95% CI) 0.000 (0.000–0.602) 0.944 (0.727–0.999)‡
Upper and lower lips combined†
n/N 3/10 29/31
Proportion of responders (95% CI) 0.300 (0.067–0.652) 0.935 (0.786–0.992)‡

CI, confidence interval.

*Response is defined as an improvement of  1 points in Medicis Lip Fullness Scale score in the intention-to-treat (ITT) population from
that assessed by the treating investigator at baseline to that assessed by the blinded evaluator at week 8.
†
Includes the entire ITT population (patients with both lips eligible for efficacy evaluation plus those with Fitzpatrick IV, V, VI with only one
lip eligible for efficacy evaluation).
‡
p < .02 for SGP-HA versus no treatment based on Fisher exact test.

Figure 1. Percentage of responders (  1 grade improvement from baseline based on the Medicis Lip Fullness Scale) after
treatment with small gel particle hyaluronic acid (SGP-HA) or no treatment, according to live assessments by blinded
evaluators. The first assessment occurred at 8 weeks. Statistical significance of difference was p < .001 for SGP-HA versus
no treatment at all time points.

as improved at any time point; treating investigators The volume of SGP-HA injected was left to the
rated 0% to 8.8% of patients in this group as discretion of the treating investigators to achieve the
improved at any time point. optimal aesthetic result for individual patients, with

38:7 PART II:JULY 2012 1185

 LIP AUGMENTATION WITH SMALL GEL PARTICLE HYALURONIC ACID

(A) (D)

(B) (E)

(C) (F)

Figure 2. Representative photographs of patients’ lips (A,D) before treatment, (B,E) 8 weeks after treatment, and (C,F)
24 weeks after treatment. The patient on the left received 1.2 mL in her lower lip followed by 0.2 mL touch-up and 1.5 mL in
her upper lip followed by 0.5 mL touch-up. The patient on the right received 0.9 mL in her lower lip followed by 0.3 mL
touch-up and 0.9 mL in her upper lip followed by 0.5 mL touch-up.

100 PaƟent InvesƟgator

RaƟngs RaƟngs
SGP-HA
80 Upper Lip
Lower Lip
GAIS Responders, %

Both Lips
60 No treatment
Upper Lip
Lower Lip
40 Both Lips

20

0
0 4 8 12 16 20 24
Weeks

Figure 3. Percentage of responders (  1 grade improvement from baseline based on the Global Aesthetic Improvement
Scale) after treatment with small gel particle hyaluronic acid (SGP-HA) or no treatment according to patients (triangular
symbols; percentage of responders in the no-treatment group was zero at all time points) and according to live assessments
by unblinded treating investigators (circular symbols; there is complete overlap between the values for both lips and upper
lip). Statistical significance of difference was p < .001 for SGP-HA versus no treatment at all time points, for patient
assessments and treating investigator assessments.

1186 DERMATOLOGIC SURGERY


a recommended maximum volume of 1.5 mL per lip
at each treatment session. The mean volume injected
at the initial visit was 1.3 mL (range 0.3–2.5 mL)
for upper lips and 1.1 mL (range 0.1–2.0 mL) for
lower lips. For patients who required touch-up
injections 2 weeks after the initial treatment, the
mean volumes were 0.5 mL (range 0.08–1.8 mL) for
upper lips and 0.4 mL (range 0.05–1.0 mL) for
lower lips. The mean total volume injected at the
initial session plus 2-week touch-up was 1.6 mL
(range 0.4–3.6 mL) for upper lips and 1.3 mL
(range 0.1–2.6 mL) for lower lips. Patients ran-
domized to receive SGP-HA who subsequently
underwent repeat treatment at month 6 required
mean volumes of 1.0 and 0.9 mL for upper and
lower-lip correction, respectively, including any
touch-ups. Post hoc subgroup analyses found no
predictive correlation between volume, age, race,
injection technique, or need for touch-up and
effectiveness according to MLFS scores at week 8.
Safety
Safety assessments included review of safety
parameters (lip texture, firmness, symmetry, move-
ment, function, sensation, mass formation, and
device palpability) and patient-reported AEs at each
visit.
The specific lip safety assessments showed no
significant effect on lip sensation or function. Rare
findings of changes in texture or asymmetry were
short lived and well tolerated. No persistent lumps
or nodules were noted.
There were 1,062 TEAEs reported in patients who
received SGP-HA (Table 4); the majority of these
were classified as mild (88%; 936/1,062) or mod-
erate (11%; 116/1,062) in intensity, whereas only 10
(1%; 10/1,062) were classified as severe. Only three
patients had severe treatment-related AEs (pain,
swelling), all of which resolved within 5 days
without the need for prescription medications or
medical intervention.16 The most commonly
reported TEAEs were pain, swelling, tenderness,
GLOGAU ET AL
contusion (bruising or ecchymosis), and erythema,
which were most often considered mild or moderate
in severity and generally lasted 5 to 10 days after the
procedure. The occurrence of any TEAEs was lower
in patients who received injections of SGP-HA by
serial puncture than in those treated with a linear
injection technique (Table 4). This difference corre-
sponded primarily to a lower occurrence of pain,
swelling, and contusion in patients receiving serial
puncture injections. TEAEs were generally less
frequent and less severe with repeat treatment. The
volume of SGP-HA injected had little effect on the
frequency of TEAEs. The respective incidences of the
five most common TEAEs (swelling, contusion,
tenderness, pain, and erythema) according to injec-
tion volume were, for the upper lip and more than
1.5 mL (n = 83), 51%, 42%, 17%, 16%, and 12%;
for the upper lip and 1.5 mL or less (n = 89); 57%,
27%, 27%, 25%, and 21%; for the lower lip and
more than 1.5 mL, 57%, 43%, 20%, 20%, and
13%; and for the lower lip and 1.5 mL or less, 51%,
28%, 18%, 19%, and 16%. Using more than 3 mL
of SGP-HA per treatment session compared with
3 mL or less may increase the incidence of moderate
to severe AEs in the lip area (43%, 33/76 vs 21%,
20/96; p = .001).
The most common AEs reported in patients’ diaries
were redness, bruising, tenderness, pain, and swell-
ing; a majority of patients (56–95%) considered
them tolerable. The percentage of patients reporting
symptoms and the severity of the symptoms gener-
ally fell with subsequent treatments.
Five serious AEs (SAEs) were reported; four were
judged to be unrelated to treatment, and one (transient
ischemic attack) was considered probably not related to
the device and not related to the procedure. The SAE of
transient ischemic attack resolved 1 day after onset,
three of the other SAEs resolved within 3 to 7 days after
onset, and resolution of the fifth SAE was unknown
(patient was found to be pregnant, did not receive SGP-
HA, and was withdrawn from the study and then lost to
follow-up). No deaths were reported during the study,
and no patients discontinued because of an AE.
38:7 PART II:JULY 2012 1187
1188
TABLE 4. Summary of Treatment-Emergent Adverse Events (TEAEs)
Linear Retrograde and Serial Linear Antegrade, Retrograde,
Linear Retrograde Linear Antegrade and Retrograde Puncture and Serial Puncture

SGP-HA SGP-HA SGP-HA SGP-HA

No First Second No First Second No First Second No First Second

Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment
(n = 12) (n = 43) (n = 21) (n = 8) (n = 68) (n = 47) (n = 6) (n = 25) (n = 11) (n = 8) (n = 31) (n = 14)

DERMATOLOGIC SURGERY
TEAE n (%)

Any TEAE 4 (33) 42 (98) 21 (100) 3 (38) 59 (87) 35 (74) 3 (50) 23 (92) 2 (18) 4 (50) 20 (65) 2 (14)
TEAEs in  5% of patients
Swelling* 0 42 (98) 21 (100) 0 37 (54) 30 (64) 0 15 (60) 0 0 1 (3) 0
Contusion 0 15 (35) 5 (24) 0 41 (60) 20 (43) 0 12 (48) 0 0 4 (13) 0
Pain 0 15 (35) 8 (38) 1 (13) 17 (25) 11 (23) 0 2 (8) 0 0 0 0
Tenderness 0 4 (9) 0 0 19 (28) 15 (32) 0 11 (44) 1 (9) 0 0 0
Erythema 0 3 (7) 0 0 18 (26) 10 (21) 0 2 (8) 0 0 2 (6) 0
Headache 0 2 (5) 0 0 7 (10) 3 (6) 0 1 (4) 0 2 (25) 1 (3) 0
Skin exfoliation† 0 1 (2) 0 0 10 (15) 2 (4) 0 0 0 0 3 (10) 0
Nasopharyngitis 0 3 (7) 0 0 5 (7) 2 (4) 0 1 (4) 0 1 (13) 0 0
Oral herpes 1 (8) 1 (2) 0 0 2 (3) 2 (4) 0 2 (8) 0 0 1 (3) 0
Sinusitis 1 (8) 1 (2) 0 0 3 (4) 1 (2) 1 (17) 0 0 0 2 (6) 0
Mass 0 5 (12) 2 (10) 0 0 0 0 0 0 0 0 1 (7)
Upper respiratory 0 1 (2) 0 1 (13) 1 (1) 0 1 (17) 2 (8) 0 0 2 (6) 0
tract infection
LIP AUGMENTATION WITH SMALL GEL PARTICLE HYALURONIC ACID

Edema 0 1 (2) 0 0 0 0 0 5 (20) 1 (9) 0 0 0

Lip swelling 0 0 0 0 5 (7) 0 0 2 (8) 0 0 0 0
Ecchymosis 0 0 0 0 2 (3) 0 0 4 (16) 0 0 0 0
Acne 0 0 0 0 2 (3) 1 (2) 0 2 (8) 0 0 0 0
Herpes simplex 2 (17) 2 (5) 0 0 0 0 0 0 0 0 0 0
Influenza 0 1 (2) 0 0 1 (1) 0 0 0 0 0 2 (6) 0
Urinary tract 0 2 (5) 0 0 1 (1) 0 0 1 (4) 0 0 0 0
infection
Lip exfoliation 0 0 0 0 0 0 0 0 0 0 3 (10) 0
Arthropod bite 0 2 (5) 0 0 0 0 0 0 0 0 0 0
Influenza-like 0 0 0 0 1 (1) 0 0 0 0 1 (13) 0 0
illness
Insomnia 0 2 (5) 0 0 0 0 0 0 0 0 0 0
Rhinitis 0 0 0 0 0 0 0 0 0 1 (13) 1 (3) 0
 TABLE 4. Continued

Linear Retrograde and Serial Linear Antegrade, Retrograde,

Linear Retrograde Linear Antegrade and Retrograde Puncture and Serial Puncture

SGP-HA SGP-HA SGP-HA SGP-HA

No First Second No First Second No First Second No First Second

Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment
(n = 12) (n = 43) (n = 21) (n = 8) (n = 68) (n = 47) (n = 6) (n = 25) (n = 11) (n = 8) (n = 31) (n = 14)

TEAE n (%)

Rhinorrhea 0 0 0 0 0 0 0 0 0 0 2 (6) 0
Bronchitis 0 0 0 1 (13) 0 0 0 0 0 0 0 0
Contact dermatitis 1 (8) 0 0 0 0 0 0 0 0 0 0 0
Depression 0 0 0 0 0 0 0 0 1 (9) 0 0 0
Dysplastic nevus 0 0 1 (5) 0 0 0 0 0 0 0 0 0
syndrome
Joint sprain 0 0 0 0 0 0 1 (17) 0 0 0 0 0
Lip discoloration‡ 0 0 1 (5) 0 0 0 0 0 0 0 0 0
Muscle spasms 1 (8) 0 0 0 0 0 0 0 0 0 0 0
Oral dysesthesia 0 0 0 0 0 0 0 0 0 0 0 1 (7)
Oral hypoesthesia 0 0 0 0 0 0 0 0 0 0 0 1 (7)
Sinus headache 0 0 0 0 0 0 1 (17) 0 0 0 0 0

TEAEs occurring in  5% of the safety populations of the SGP-HA or no-treatment groups are listed for each injection type.
*Swelling of facial areas from any cause, including local anesthetic or bruising.
†
Includes sloughing of the skin, peeling, desquamation, and superficial desquamation.
‡
Tyndall effect22 or other discoloration not caused by bruising.

38:7 PART II:JULY 2012

GLOGAU ET AL

1189
 LIP AUGMENTATION WITH SMALL GEL PARTICLE HYALURONIC ACID
Discussion
Multiple assessment methods were used to confirm
the benefit of SGP-HA for lip augmentation.
Whether live grading by blinded evaluators, live
grading by unblinded treating investigators, or
independent review by blinded evaluators of
photographs taken during the study, all assessment
methods showed significant differences in lip fullness
between patients treated with SGP-HA and the no-
treatment group. The results from the unblinded
physicians demonstrated the best response, but
results from the live evaluations by blinded physi-
cians closely matched those results. That the
response measured from the IPR was the lowest is
not surprising because in-person examination of
patients allows three-dimensional assessment, inter-
active repositioning of the lips, and assessment with
movement—views that are not possible with
photographs.
The results of the current study clearly demonstrated
the durability of the augmentation provided by
SGP-HA. All of the pivotal assessments (live blinded
evaluations, unblinded evaluator scoring, and IPR)
showed statistically significant differences in MLFS
response between the treatment group and the
control group through 6 months (week 24). The
data from the GAIS scoring, on which patients and
physicians noted significant differences at all time
points, further corroborated the persistence of effect.
This durability compares favorably with collagen
products (animal and human, no longer available in
the United States), which produce results that last an
average of approximately 3 months.6
SGP-HA treatment for lip augmentation was well
tolerated. The majority of reported AEs were mild to
moderate in severity, anticipated in their nature
(swelling, contusion, pain), and generally resolved
promptly. No persistent nodules, masses, or signif-
icant asymmetry were noted during the study.
A number of injection techniques are used for SGP-
HA treatment, and the choice of injection techniques
1190 DERMATOLOGIC SURGERY
used in this study was left to the discretion of the
treating investigators to reflect clinical practice.
Different injection techniques may influence the final
treatment outcome.8,17 The recommended tech-
niques in this study were serial puncture or linear
antegrade threading for the body of the lips and
linear retrograde threading for enhancement of the
vermilion border. Instructions included taking care
to avoid intramuscular injection or excess deposition
of material into individual areas, gentle palpation
for uniform deposition, and topical cooling if
excessive swelling occurred after the injection. A
somewhat surprising finding was fewer AEs with the
serial puncture technique. It is generally thought that
reducing the number of needle punctures and
threading the needle along a plane of tissue before or
during implantation will lead to less bleeding or
bruising when performing facial wrinkle correction.
These unexpected findings from this study may
warrant further investigation to confirm whether
injectors should adjust their technique when per-
forming lip augmentation.
A number of dermal fillers (carboxymethylcellulose
gel with calcium hydroxyapatite microspheres,
collagen with polymethylmethacrylate microspheres,
silicone polymethylsiloxane, and HA formulations
other than SGP-HA) have been studied for lip
augmentation but do not have FDA approval for this
indication, and large randomized controlled trials are
lacking.7 Soft tissue fillers differ in effectiveness,
safety, and tolerability.6,18 Fillers derived from non-
animal sources pose less risk of allergic reactions;
animal-source collagen fillers, although no longer
available in the United States, are associated with
allergic reactions and short persistence, whereas
nonanimal-source HA has little antigenic specificity,
conferring a low risk for an allergic response.4,19 In
contrast to collagen, superficial injection of HA fillers
may produce nodules and the Tyndall effect. No such
effects were observed in the present study with SGP-
HA. A clinical advantage with HA fillers is the
reversibility of the effect; HA can be hydrolyzed with
hyaluronidase, resulting in the dispersion of the filler
and reversal of lip augmentation within hours. The

FDA has recently approved SGP-HA for lip augmen-
tation, based largely on results of the pivotal study
presented in this report.8
The results of this study should be interpreted in the
context of its limitations. Blinded evaluators per-
formed the baseline primary efficacy end point
assessments, whereas unblinded treating investiga-
tors performed the week 8 assessments. This
approach ensured that knowledge of treatment
assignment did not bias the baseline MLFS scores.
It could be argued that scoring by the blinded
evaluators and treating investigators might have
been inconsistent, reducing the accuracy of assess-
ments of postbaseline changes in lip fullness, but the
MLFS has high interobserver reliability, with
weighted kappa values (range 0.60–0.83) that indi-
cate substantial to almost perfect agreement.14,20
Therefore, it is likely that any between-observer
effects on baseline scoring were minimal. The
protocol specified that investigators could use their
discretion regarding the injection techniques and
comfort measures used, which may have introduced
technique-related variability of results, but permit-
ting investigator discretion enabled this study to
more authentically reflect clinical practice than a
protocol that dictated details of technique. Evidence
that discretionary choice of technique influenced
outcomes was seen in a higher rate of AEs with
linear threading than with serial puncture.
Lip augmentation is associated with procedural dis-
comfort that is frequently managed using topical or
infiltrative anesthetics or regional blocks. Nearly all
(96%) patients enrolled in the present study received
an anesthetic during the first SGP-HA treatment,
including topical, regional, or a combination of both
types of anesthesia. Injecting local anesthetic for an
infraorbital or submental nerve block can distort
anatomic features and complicate the augmentation
procedure. A recently available FDA-approved for-
mulation of SGP-HA is premixed with lidocaine to
circumvent this effect.21 This formulation was not
included in the present study because it was not yet
approved when the study took place.
GLOGAU ET AL
Conclusions
SGP-HA is highly effective and well tolerated for lip
augmentation. Statistically significant improvement
was evident based on the MLFS at 8 weeks, with
visible results reported in the majority of patients
6 months after treatment.
Acknowledgments The independent photographic
reviewers were Michael A.C. Kane, MD (New York,
NY), Z. Paul Lorenc, MD (New York, NY), and
Mark Rubin, MD (Beverly Hills, CA).
References
1. Beer KR. Rejuvenation of the lip with injectables. Skin Therapy
Lett 2007;12:5–7.
2. Glavas IP. Filling agents. Ophthalmol Clin North Am
2005;18:249–57, v–vi.
3. Buck DW II, Alam M, Kim JY. Injectable fillers for facial
rejuvenation: a review. J Plast Reconstr Aesthet Surg 2009;62:
11–8.
4. Ali MJ, Ende K, Maas CS. Perioral rejuvenation and lip
augmentation. Facial Plast Surg Clin North Am 2007;15:491–
500, vii.
5. Clymer MA. Evolution in techniques: lip augmentation. Facial
Plast Surg 2007;23:21–6.
6. Sarnoff DS, Saini R, Gotkin RH. Comparison of filling agents for
lip augmentation. Aesthet Surg J 2008;28:556–63.
7. Smith KC. Reversible vs. nonreversible fillers in facial aesthetics:
concerns and considerations. Dermatol Online J 2008;14:3.
8. Medicis Aesthetics Inc. Restylane® (hyaluronic acid). Instructions
for use. Scottsdale, AZ: Medicis Aesthetics Inc; 2011.
9. Kablik J, Monheit GD, Yu L, Chang G, et al. Comparative
physical properties of hyaluronic acid dermal fillers. Dermatol
Surg 2009;35:302–12.
10. Sundaram H, Voigts B, Beer K, Meland M. Comparison of the
rheological properties of viscosity and elasticity in two categories
of soft tissue fillers: calcium hydroxylapatite and hyaluronic acid.
Dermatol Surg 2010;36:1859–65.
11. Stocks D, Sundaram H, Michaels J, Durrani MJ, et al.
Rheological evaluation of the physical properties of hyaluronic
acid dermal fillers. J Drugs Dermatol 2011;10:444–9.
12. Bosniak S, Cantisano-Zilkha M, Glavas IP. Nonanimal stabilized
hyaluronic acid for lip augmentation and facial rhytid ablation.
Arch Facial Plast Surg 2004;6:379–83.
13. Solish N, Swift A. An open-label, pilot study to assess the
effectiveness and safety of hyaluronic acid gel in the restoration
of soft tissue fullness of the lips. J Drugs Dermatol 2011;10:
145–9.
38:7 PART II:JULY 2012 1191
 LIP AUGMENTATION WITH SMALL GEL PARTICLE HYALURONIC ACID

14. Kane MAC, Lorenc ZP, Lin X, Smith SR. Validation of a lip
fullness scale for assessment of lip augmentation. Plast Reconstr
Surg 2012;129:822e–8e.
15. Cohen SR, Holmes RE. Artecoll: a long-lasting injectable wrinkle
filler material: report of a controlled, randomized, multicenter
clinical trial of 251 subjects. Plast Reconstr Surg 2004;114:964–
76; discussion 977–9.
countries: a retrospective study from 1997 to 2001. J Eur Acad
Dermatol Venereol 2004;18:422–5.
20. Landis JR, Koch GG. The measurement of observer agreement for
categorical data. Biometrics 1977;33:159–74.
21. Medicis Aesthetics Inc. Restylane-L. Instructions for use.
Scottsdale, AZ: Medicis Aesthetics Inc; 2010.

16. Medicis Aesthetics Inc. Restylane injectable gel lip augmentation 22. Hirsch RJ, Narurkar V, Carruthers J. Management of injected
indication: general and plastic surgery devices panel meeting hyaluronic acid induced Tyndall effects. Lasers Surg Med
(Data on File). Scottsdale, AZ: Medicis Aesthetics; 2011. 2006;38:202–4.

17. Glogau RG, Kane MA. Effect of injection techniques on the rate
of local adverse events in patients implanted with nonanimal
hyaluronic acid gel dermal fillers. Dermatol Surg 2008;34: Address correspondence and reprint requests to:
S105–9.
Richard G. Glogau, MD, San Francisco Dermatology, 350
18. Niamtu J 3rd. Complications in fillers and Botox. Oral Parnassus Ave, Suite 400, San Francisco, CA 94117, or
Maxillofac Surg Clin North Am 2009;21:13–21, v. e-mail: rglogau@aol.com
19. Andre P. Evaluation of the safety of a non-animal stabilized
hyaluronic acid (NASHA – Q-Medical, Sweden) in European

1192 DERMATOLOGIC SURGERY