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Gadde KM, Franciscy DM, Wagner II HR, Krishnan KRR. Zonisamide for Weight Loss in Obese AdultsA Randomized Controlled Trial. JAMA. 2003;289(14):1820–1825. doi:10.1001/jama.289.14.1820
Context Zonisamide is a marketed antiepileptic drug that has serotonergic and
dopaminergic activity in addition to blockade of sodium and calcium channels.
Weight loss was an adverse effect associated with zonisamide treatment in
epilepsy clinical trials.
Objective To evaluate the efficacy of zonisamide for weight loss in obese adults.
Design and Setting Sixteen-week randomized, double-blind, placebo-controlled trial with
an optional single-blind extension of the same treatment for another 16 weeks,
conducted at Duke University Medical Center from March 2001 to March 2002.
Participants Fifty-five (92%) women and 5 (8%) men (mean [SE] body mass index, 36.3
[0.5]; mean age, 37.0 (1.0) years).
Interventions Patients were randomly assigned to receive zonisamide (n = 30) or placebo
(n = 30). All participants were prescribed a balanced hypocaloric diet (500
kcal/d deficit) and compliance was monitored with self-rated food diaries.
Zonisamide therapy was started at 100 mg/d orally, with gradual increase to
400 mg/d and further increase to 600 mg/d for patients losing less than 5%
of body weight at the end of 12 weeks. Placebo dosing was identical.
Main Outcome Measure Change in body weight.
Results Of the 60 randomized patients, 51 completed the 16-week acute phase.
In an intent-to-treat analysis using the available data for all randomized
participants with the last observation carried forward, the zonisamide group
lost more body weight than the placebo group (mean [SE], 5.9 [0.8] kg [6.0%
loss] vs 0.9 [0.4] kg [1.0% loss]; t = 5.5; P<.001) during the 16-week period. A longitudinal mixed-model
regression for weight change controlling for age, race, sex, body mass index,
and percent body fat estimated that zonisamide treatment over the 16-week
study duration was associated with significantly greater weight loss than
was placebo (t = 6.4; P<.001).
Seventeen (57%) of 30 in the zonisamide group and 3 (10%) of 30 in the placebo
group lost at least 5% of body weight (P<.001)
by week 16. Of the 37 participants who entered the extension phase, 36 completed
week 32. The zonisamide group (n = 19) had a mean weight loss of 9.2 kg (1.7
kg) (9.4% loss) at week 32 compared with 1.5 kg (0.7 kg) (1.8% loss) for the
placebo group (n = 17) (t = 4.0; P<.001). Zonisamide was tolerated well, with few adverse effects.
Conclusion In this short-term, preliminary trial, zonisamide and hypocaloric diet
resulted in more weight loss than placebo and hypocaloric diet in the treatment
The prevalence of obesity has increased dramatically in the past decade
in the United States and many other developed countries.1,2 Because
obesity is associated with a significantly increased risk for type 2 diabetes,
coronary heart disease, hypertension, numerous other major illnesses, and
overall mortality from all causes,3,4 weight
reduction is critical for the obese patient.5,6 There
is good evidence that pharmacotherapy can enhance weight loss when combined
with interventions aimed at changing lifestyle,7 although
pharmacological therapies currently approved by the US Food and Drug Administration
fail to provide adequate benefit for many obese patients because of adverse
effects, contraindications, or lack of positive response.7 Hence,
there is impetus for developing new treatments for the management of obesity.
Zonisamide is a marketed antiepileptic drug. In short-term clinical
trials of zonisamide in epileptic patients concomitantly receiving other antiepileptic
agents, weight loss was an adverse effect.8 Whereas
the anticonvulsant activity of zonisamide is believed to be related to its
sodium and calcium channel (T-type) blocking activity,8 this
drug is also known to exert dose-dependent biphasic dopaminergic9 and
serotonergic10 activity. With this background,
we hypothesized that zonisamide would be therapeutic for obese patients seeking
to lose weight.
This study was conducted at Duke University Medical Center, Durham,
NC, from March 2001 to March 2002. The protocol was approved by the medical
center's institutional review board before the trial began.
Study participants were selected from the clinic patient population
and those responding to advertisement fliers posted in the local area, and
were enrolled between March 2001 and July 2001. Sixty-eight individuals were
screened for participation and 60 were randomized. All participants provided
written informed consent.
Included were men or women aged 21 to 50 years, with mean (SE) body
mass index (BMI) of 36.3 (0.5). The minimum BMI range for inclusion, as specified
in the protocol, was 30 to 44. Exclusion criteria were obesity of a known
endocrine origin, such as hypothyroidism or Cushing syndrome; serious/unstable
medical or psychiatric illness; current major psychiatric disorder; current
drug or alcohol abuse; history of or current kidney disease or renal calculi;
significant liver disease; uncontrolled hypertension; current diabetes mellitus;
untreated or uncontrolled thyroid disease; weight loss or gain greater than
4 kg in past 3 months; history of obesity surgery; current or recent use of
weight loss medications, herbs, or supplements; current or recent use of drugs,
herbs, or dietary supplements known to significantly affect body weight; concomitant
medications that significantly affect cytochrome P450 3A4 hepatic
microsomal enzymes; hypersensitivity to sulfonamides; women of childbearing
age not adhering to an acceptable form of contraception; pregnant or breastfeeding
women; and individuals judged to be unable to follow instructions and study
The study had 2 phases. The first was a 16-week, randomized, double-blind,
parallel-group comparison of zonisamide and placebo. At the end of this phase,
participants wishing to continue received the same treatment in a single-blinded
fashion for an additional 16-week extension phase.
Study participants were randomized in a 1:1 ratio to receive zonisamide
(Elan Biopharmaceuticals, Dublin, Ireland) or placebo capsules. The research
pharmacy dispensed the study medication under blinded conditions through computer-based
randomization. The randomization was generated using a random-number table
with a block size of 10. There was no stratification by sex or other demographic
variables. The study investigators were blinded to the "blocking" method used
by the pharmacy. Treatment assignment codes were not available to the investigators
until all patients completed the acute phase, the data had been entered, and
the database for this phase was locked, precluding any subsequent changes
to the data.
The study medication was dispensed in identically designed capsules—each
capsule containing either 100 mg of zonisamide or placebo. The dose escalation
was as follows: 1 capsule (zonisamide, 100 mg or placebo) daily for the first
2 weeks; 2 capsules (zonisamide, 200 mg or placebo) daily during weeks 3 and
4; 3 capsules (zonisamide, 300 mg or placebo) daily during weeks 5 and 6;
and 4 capsules (zonisamide, 400 mg or placebo) daily from week 7 onward. At
week 12, the dose could be increased further to 6 capsules (zonisamide 600
mg or placebo) daily for participants who had not lost at least 5% of their
initial body weight. The entire daily dose was administered in the evening.
If a patient preferred not to take all 6 capsules at one time, taking half
of the daily dose in the morning was an option. Based on tolerability, dose
escalation could be withheld or decreased. Medication compliance was overseen
by recording the number of tablets returned and comparing this number with
the number of capsules dispensed at each visit.
Patients in both groups were instructed to follow an individual diet
that was calculated to reduce their daily energy intake by 500 kcal/d from
the amount needed to maintain weight using the World Health Organization recommendations.
The prescribed diet, based on eating a variety of foods from the US Department
of Agriculture Food Guide Pyramid, emphasized decreasing portions, eating
more fruits and vegetables, and drinking eight 8-oz glasses of water each
day. Increased physical activity was also encouraged for participants in both
groups. All study participants were asked to record their dietary intake and
portion sizes in provided food diaries. A registered dietitian reviewed food
diaries and provided counseling to all participants, who were encouraged to
make healthy changes in their diets and physical activity.
Patients were examined at weeks 0, 2, 4, 8, 12, and 16 in the acute
phase, and every 4 weeks in the extension phase. During each visit, the following
assessments were performed: blood pressure, heart rate, weight, dietary compliance,
medication accountability and tolerability, and adverse effects. Body weight
was measured on a calibrated electronic scale to the nearest 0.1 kg. The participants
were always weighed in a hospital gown and weighed twice for accuracy. A registered
dietitian reviewed food diaries and assessed dietary compliance. Adverse effects
were gathered via spontaneous reporting by patients as well as open-ended
inquiries by the clinicians. Reportable adverse effects were new symptoms
or illnesses that emerged during treatment or those that had an increase in
severity compared with baseline.
Study participants also completed the Impact of Weight on Quality of
Life (IWQOL) questionnaire11 at baseline, week
8, and week 16. The IWQOL is a self-report measure with 74 items that assess
the perceived effect of weight on quality of life in the following domains
(subscales): health, social/interpersonal life, work, mobility, self-esteem,
sexual life, activities of daily living, and eating (comfort with food). Improvement
with treatment is reflected by decreasing scores on all the subscales with
the exception of the eating (comfort with food) subscale, which tends to move
in the opposite direction. Body composition (fat and lean masses) and bone
mineral density (BMD) were determined at baseline and week 32 by dual-energy
x-ray absorptiometry (DXA). All DXA measurements were obtained using the same
equipment and techniques. Participants were instructed to fast for 8 hours
and not to drink water or other beverages for at least 4 hours prior to DXA
The primary study end point was change in absolute body weight in kilograms
from baseline to final assessment. In addition, we examined percent change
in weight and the number of participants in each group who achieved weight
losses of 5% or greater and 10% or greater. Secondary outcome measures included
heart rate, blood pressure, frequency of adverse effects, fasting electrolytes
and lipids, waist measurement, IWQOL score, body composition, and BMD.
All randomized patients were included in the primary analysis. Weight
change during the study was assessed in terms of actual weight change over
the 6 study intervals using multivariable regression methods, and as a dichotomous
outcome of response, ie, 5% and 10% weight loss at week 16, and 10% weight
loss at week 32. The proxy variables denoting response status were tested
across treatment conditions using the Fisher exact test. Three multivariable
regression analyses were conducted. In the first, body weights were regressed
as above with missing observations carried forward from the last recorded
weight, based on an intent-to-treat (ITT) approach. For the second set of
analyses, body weight at each time point was modeled using a random-effects
growth-curve model. Heuristically, the model fits a regression line for each
patient using available data points, thus maximizing use of actual data. The
final model was restricted to the subset of respondents with no missing data
(completers). All models included covariates for age, sex, race, and baseline
measures of percent body fat and BMI as well as proxy variables denoting treatment
condition, time, and a term for the interaction of treatment × time.
In some instances, differences between the baseline and final measures were
tested with the t test.
Secondary analyses were conducted for various clinical and laboratory
measures (see "End Points and Measures of Outcome" section). When appropriate,
analyses were based on 2-way repeated-measures analysis of variance that included
time, treatment, and their interaction (time × treatment). In each case,
the interest was to determine if patients in the zonisamide group were differentially
affected relative to controls as operationally determined by testing the significance
of the estimated interaction term. For analysis of the IWQOL subscales, repeated
measurements were taken at baseline, week 8, and week 16. In some instances,
differences between the baseline and final measures were tested with the t test.
Bivariate change in body mass from baseline to week 32 by treatment
condition was tested using the t test. As a null
hypothesis postulating equality of variances between the 2 conditions was
rejected, differences were tested using the Satterwaite method for unequal
variances. Data also are presented as percent change although statistical
testing was conducted using actual units. The association between change in
body weight and change in fat mass was tested using ordinary least-squares
regression. Change in body weight from baseline to week 32 was regressed on
change in fat mass, treatment condition, and an interaction term crossing
the 2 main effect variables.
The frequencies of occurrence of individual adverse effects were tested
across drug conditions using the Fisher exact test. All analyses were carried
out using SAS v8.0 (SAS Institute Inc, Cary, NC); P =
.05 was used to determine statistical significance.
Of the 68 individuals screened for participation, 8 were ineligible
(Figure 1). The 60 remaining patients
were randomized,with 30 receiving zonisamide and 30 receiving placebo; all
patients also adhered to a hypocaloric diet. Nine patients—3 in the
zonisamide group and 6 in the placebo group—dropped out prematurely;
thus, 51 of 60 completed the first 16 weeks.
The baseline characteristics of participants were similar between the
treatment groups, except that all 5 men in the study were randomized to zonisamide
(P = .08) and baseline BMI was slightly lower (P = .07) in the zonisamide group (Table 1).
The prescribed mean (SE) highest daily dose of zonisamide was 427 (29)
mg, corresponding to 4.27 capsules, whereas the placebo group received 500
mg, corresponding to 5.00 capsules.
Weight Loss. The curves for weight loss in
kilograms over the 16-week duration for the zonisamide and placebo groups
are shown in Figure 2. In the last
observation carried forward (LOCF) analyses for the ITT population, the mean
(SE) absolute weight for the zonisamide group changed from 98.2 (2.5) kg at
baseline to 92.3 (2.5) kg at week 16, whereas for the placebo group, the corresponding
change was 97.8 (2.6) kg to 96.9 (2.8) kg; ie, the zonisamide group lost 5.9
(0.8) kg (6.0%) during the initial 16-week period vs 0.9 (0.4) kg (1.0%) for
placebo patients (t = 5.5; P<.001).
For the subset of patients completing the initial 16-week phase as randomized,
the mean (SE) absolute weight for the zonisamide group changed from 97.2 (2.4)
kg at baseline to 90.8 (2.3) kg at week 16; for the placebo group, the corresponding
change was 97.6 (2.7) kg to 96.5 (2.9) kg. Thus, the difference between treatment
groups in the achieved weight loss over time remained significant (6.4 [0.8]
kg [6.6%] vs 1.1 [0.4] kg [1.3%]; t = 5.4; P<.001).
Results from the longitudinal regression analyses supported differential
weight loss for zonisamide-treated patients. Regardless of imputation procedure,
the time × treatment interaction differed significantly from zero in
all models. For the LOCF–imputed ITT model, the estimated regression
coefficient associated with the interaction term predicted weight loss in
excess of 0.29 kg/wk over the 16-week study period (t =
6.4; P<.001); complementary values for the other
2 models were 0.33 kg/wk using the growth-curve model (t = 10.5; P<.001), and 0.31 kg/wk as estimated
from the model only on data for patients completing the protocol as randomized
(t = 6.1; P<.001).
In the LOCF population, 17 of 30 patients (57%) in the zonisamide group
and 3 of 30 patients (10%) in the placebo group achieved a weight loss of
5% or greater at week 16 (P<.001). Of the 17 responders
in the zonisamide group, 7 attained a weight loss of 10% or more; none of
the patients in the placebo group achieved 10% weight loss (P = .005).
Other Efficacy Measures. The following subscales
of the IWQOL scale improved more significantly in the zonisamide group over
the placebo group at week 16: health (F2,98 = 4.6; P<.01), work (F2,98 = 4.5; P<.01),
mobility (F2,98 = 3.9; P<.02), and
activities of daily living (F2,98 = 4.9; P<.01).
Mean (SE) waist circumference decreased more with zonisamide therapy over
the 16 weeks (103.5 [1.6] cm to 97.2 [1.8] cm vs 103.2 [1.9] cm to 100.5 [2.0]
cm; interaction of treatment × time: F2,98 = 7.8; P<.001). Heart rate decreased by an average of approximately 2/min
in the overall sample (P<.001), although there
was no difference between the groups. Systolic and diastolic blood pressure
readings did not change over time. There were no clinically significant changes
in levels of lipids or fasting blood glucose with either treatment.
Safety Measures. Patients assigned to zonisamide
reported, on average, 2.1 adverse effects over the study period compared with
1.6 for those assigned to placebo (t = 1.6; P = .12). Of the individual adverse effects, 10 patients
in the zonisamide group and 1 in the placebo group reported fatigue (P<.006 by Fisher exact test); no other adverse effects
were reported differentially between the groups. Mean (SE) serum creatinine
concentration increased from 0.79 (0.03) mg/dL (69.8 [2.6] µmol/L) at
baseline to 0.92 (0.03) mg/dL (81.3 [2.6] µmol/L) with zonisamide treatment
while the change for placebo was 0.76 (0.02) mg/dL (67.2 [1.8] µmol/L)
to 0.79 (0.02) mg/dL (69.8 [1.8] µmol/L) (t =
There were no significant group differences with regard to baseline
characteristics of the extension phase participants with the exception of
a slightly lower mean BMI in the zonisamide group (34.9 vs 37.3; P<.05). Moreover, the characteristics of those who participated
in the extension phase were essentially the same as those of the 60 participants
who originally entered the study. Of the 37 patients (20 zonisamide, 17 placebo)
who entered the extension phase, 36 completed week 32. One patient in the
zonisamide group withdrew prematurely, citing time constraints. Ten of 19
zonisamide patients and none of the placebo patients lost at least 10% weight
at week 32 (P<.001). Mean (SE) weight changed
over the 32 weeks for patients in the zonisamide group from 96.9 (3.0) kg
to 87.6 (3.0) kg, whereas the change for the patients in the placebo group
was from 96.4 (3.0) kg to 94.9 (3.4) kg; ie, zonisamide therapy led to a weight
loss of 9.2 (1.7) kg (9.4%) at week 32 compared with 1.5 (0.7) kg (1.8%) with
placebo therapy (t = 4.0; P<.001).
The following subscales of the IWQOL scale improved more significantly
in the zonisamide group vs the placebo group at week 32: health (F3,102 = 5.0; P<.003), work (F3,102 =
4.5; P<.005), mobility (F3,102 = 5.3; P<.002), and activities of daily living (F3,102 = 6.4; P<.001).
Mean (SE) waist circumference decreased more in the zonisamide group
over the 32 weeks (103.5 [2.0] cm to 93.6 [2.2] cm vs 103.8 [2.4] cm to 100.5
[2.5] cm in the placebo group; ie, a reduction of 9.8 (1.7) cm for patients
treated with zonisamide vs 3.3 (0.6) cm for patients receiving placebo (F3,102 = 8.4; P<.001).
Mean (SE) systolic blood pressure decreased in both treatment groups
although the decrease was significantly greater in the zonisamide group (129.1
[2.5] mm Hg to 122.3 [1.8] mm Hg vs 128.2 [1.8] mm Hg to 126.8 [1.8] mm Hg;
interaction of treatment × time: F9,306 = 2.7; P<.005). Diastolic blood pressure decreased with zonisamide treatment,
but not with placebo (82.5 [1.8] mm Hg to 79.7 [1.2] mm Hg vs 82.5 [1.8] mm
Hg to 82.2 [1.1] mm Hg; interaction of treatment with time: F9,306 =
2.0; P<.04). Neither treatment was associated
with a significant change in heart rate. There were no clinically significant
changes in lipid levels with either treatment.
Mean (SE) fat mass for patients receiving placebo increased by 0.5%
(1.5%) over the course of 32 weeks. In contrast, patients treated with zonisamide
had a decrease in fat mass of 11.7% (3.2%). Satterwaite t test of this difference was significant (t =
3.7; P<.001). A multivariable analysis regressing
weight change on fat mass change, treatment, and an interaction term crossing
the latter 2 variables yielded a significant interaction term indicating that
weight loss for patients treated with zonisamide was significantly associated
with a decrease in fat mass (t = 2.2; P<.04). Lumbar spine BMD did not change over time in either group.
Total BMD showed a small but statistically significant (P<.02) increase in the overall sample although there was no difference
between the groups. As in the acute phase, fatigue was the only adverse event
that was reported more frequently by patients treated with zonisamide than
by controls (7 vs 0; P<.009). Mean (SE) serum
creatinine concentration increased from 0.78 (0.03) mg/dL (69.0 [2.6] µmol/L)
at baseline to 0.92 (0.03) mg/dL (81.3 [2.6] µmol/L) with zonisamide
treatment while the change for placebo was 0.75 (0.02) mg/dL (66.3 [1.8] µmol/L)
to 0.77 (0.02) mg/dL (68.1 [1.8] µmol/L) (F2,68 = 11.0; P<.001).
This randomized study demonstrated that zonisamide therapy combined
with a hypocaloric diet produced significantly greater weight loss than dietary
intervention alone in a population of obese. During the first 16 weeks, when
the treatment was administered in a double-blind fashion, the superior weight
loss efficacy of zonisamide over placebo was demonstrated in all the various
analyses undertaken. The difference in the weight loss efficacy between the
active treatment and placebo was evident by 4 weeks and increased as the study
The extension phase (second 16 weeks) of the trial demonstrated that
patients receiving zonisamide therapy continued to lose weight, whereas the
group that received dietary intervention and placebo lost less weight. Given
the low-key adjunctive dietary and lifestyle intervention provided in this
study, a mean weight loss of 9.2 kg (9.4%) at 32 weeks may be regarded as
a clinically meaningful finding.
In addition to weight loss, zonisamide therapy led to improvement of
some risk factors associated with obesity. Waist circumference decreased more
significantly with zonisamide therapy compared with placebo, which was likely
related to a greater degree of weight loss rather than being an independent
effect. In addition, a reduction in systolic blood pressure was noted with
zonisamide therapy although the study participants were not hypertensive at
baseline. Zonisamide therapy was associated with a significant improvement
of quality of life as noted by decreased scores on the following IWQOL measures:
mobility, general health, occupational functioning, and activities of daily
living. Because there is some evidence12 that
weight loss leads to reduction of BMD, we examined this before and after 32
weeks of treatment. No significant loss of BMD was observed for participants
in our study.
Zonisamide was tolerated well in this study. Premature withdrawals were
much less frequent than expected in obesity trials of similar duration. Only
1 patient withdrew from the zonisamide group citing an adverse effect. Overall,
fatigue was the only adverse effect that occurred at a significantly higher
frequency for zonisamide treatment than for placebo. Our data collection relied
on spontaneous reporting and open-ended inquiries that may have yielded a
lower frequency of adverse effects than could be elicited with structured
questionnaires. Although not observed frequently in this study, the following
adverse effects occurred frequently with zonisamide therapy in epilepsy trials:
dizziness, cognitive impairment, and somnolence.8,13 Because
zonisamide is a sulfonamide, there is a potential for hypersensitivity reactions.
Although rare, kidney stones and serious hematologic events have been reported
with zonisamide therapy in patients with epilepsy. Consistent with data from
epilepsy trials, we noted an increase in serum creatinine concentration with
zonisamide therapy, but not with placebo. Whereas the increase in the first
16 weeks (approximately 16%) was significant, there was no further increase
in the extension phase; no value exceeded the upper limit of normal range,
and there were no clinical events associated with the increase.
To our knowledge, the present study is the first clinical trial to specifically
assess the therapeutic potential of zonisamide as a weight loss tool in the
management of clinically defined obesity. Whereas zonisamide was associated
with a small degree of weight loss as an adverse effect in the treatment of
patients with epilepsy, this was investigated as the desired effect in this
study, and the observed weight loss was significant and clinically meaningful.
The pharmacological properties of zonisamide that contributed to its
anorectic effect have not been precisely delineated. Whereas the antiepileptic
properties of zonisamide are believed to be related to its blocking effects
on sodium and T-type calcium channels,8 its
effects on brain serotonin (5-HT)10 and dopamine9 systems may explain, at least partly, its weight loss
efficacy in the present study. Serotonin has been implicated in modulation
of satiety; nevertheless, some, but not all, drugs that enhance serotonergic
tone via different mechanisms have been found to be valuable tools in the
management of obesity.14 There is evidence
that zonisamide stimulates serotonin turnover in the striatum and hippocampus
in therapeutic doses, whereas very high doses have the opposite effect.10
Although the precise mechanisms involving a zonisamide-induced increase
in extracellular serotonin levels are not known, 2 mechanisms have been suggested:
an increase in ion-dependent serotonin release,15,16 and
increased synthesis of serotonin.17 Dopamine
is thought to mediate many pleasurable behaviors including food intake.18 Dopamine D2-receptor agonists inhibit
feeding,19 and obese individuals have reduced
density of striatal D2 receptors.20 Zonisamide,
in therapeutic doses, enhances dopamine synthesis with a resultant increase
in levels of intracellular dopamine and metabolites; although some degree
of monoamine oxidase type B enzyme inhibition may be caused by zonisamide,
this is not a major finding during chronic administration of this drug. It
has also been suggested that zonisamide stimulates D2 receptors.9
Nevertheless, other drugs (eg, carbamazepine) having a few similar effects
on monoamine systems have not been known to be associated with significant
weight loss. A relatively weak property of zonisamide is inhibition of carbonic
anhydrase activity.13 In this context, it may
be of interest that carbonic anhydrase inhibitors have been reported to alter
taste, thereby causing an anorexic effect.21-23 Numerous
peptides acting in the brain as well as in the periphery have been strongly
implicated in modulating appetite and feeding signals,24 and
the effects, if any, of zonisamide on these substrates are not known. Although
we have speculated about the possible mechanisms for zonisamide-induced weight
loss, the precise mechanism is not known.
In conclusion, the results of this short-term study provide preliminary
evidence that zonisamide, in conjunction with diet, can be more effective
than diet alone for obese patients seeking to lose weight.