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Benefits of Lifestyle Modification in the Pharmacologic Treatment of Obesity
A Randomized Trial
Thomas A. Wadden, PhD;
Robert I. Berkowitz, MD;
David B. Sarwer, PhD;
Richard Prus-Wisniewski, MD;
Carrie Steinberg, MA
Arch Intern Med. 2001;161:218-227.
ABSTRACT
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Background Weight loss medications are recommended as an adjunct to diet and exercise
modification but seem to be prescribed as a monotherapy by many physicians.
This practice is likely to be associated with suboptimal weight loss.
Methods This 1-year, randomized trial compared the effects of sibutramine hydrochloride
used alone (ie, the drug-alone group) to sibutramine plus group lifestyle
modification, prescribed with either a 5021- to 6276-kJ/d diet (1200-1500-kcal/d
diet) (ie, the drug-plus-lifestyle group) or, for the first 4 months, a 4184-kJ/d
diet (1000-kcal/d diet (ie, drug-plus-lifestyle with a portion-controlled
diet [the combined treatment] group). Participants were 53 women with a mean
(±SD) age of 47.2 ± 9.8 years and weight of 101.3 ± 9.7
kg. At baseline, they reported the number of pounds they expected to lose
at the end of treatment.
Results At month 12, patients treated with the drug alone lost (mean ±
SD) 4.1% ± 6.3% of their initial body weight compared with significantly
(P<.05) larger losses in the drug-plus-lifestyle
group of 10.8% ± 10.3% and the combined treatment group of 16.5% ±
8.0%. Women in the 2 lifestyle groups achieved a significantly (P<.05) greater percentage of their expected weight loss than those
in the drug-alone group and were significantly more satisfied with the medication
and with changes in weight, health, appearance, and self-esteem (P<.05 for all). Significant reductions were observed at 12 months
in triglyceride and low-density lipoprotein cholesterol levels but systolic
and diastolic blood pressure both increased significantly (P<.05 for all).
Conclusion The addition of group lifestyle modification to the pharmacologic management
of obesity significantly improved weight loss and patients' satisfaction with
treatment outcome.
INTRODUCTION
SINCE NOVEMBER 1997, the Food and Drug Administration has approved 2
medications—sibutramine hydrochloride and orlistat—for the induction
and maintenance of weight loss.1 Sibutramine
is a combined norepinephrine-serotonin reuptake inhibitor that is associated
with increased satiation (ie, fullness) and a resulting reduction in food
intake.2, 3, 4, 5
Orlistat is a gastric and pancreatic lipase inhibitor that induces weight
loss by blocking the absorption of about one third of the fat contained in
a meal; the undigested fat (ie, oil) is excreted in stool.6, 7, 8, 9
In randomized trials, in which patients were prescribed a modest energy deficit
(ie, 2092-2929 kJ/d [500-700 kcal/d]) and encouraged to increase physical
activity, both medications were associated with a 7% to 10% reduction in initial
body weight during the first 6 months.2, 6, 7, 10
Continued use of sibutramine2, 11
and orlistat6, 7 therapy was associated
with generally favorable maintenance of weight loss at the end of 1 and 2
years, respectively.
In approving these medications, the Food and Drug Administration recommended
that they be limited to persons with a body mass index of 30 kg/m2or
more or 27 kg/m2 or more in the presence of obesity-related comorbid
conditions (eg, hypertension or diabetes mellitus).12, 13
In addition, these agents are recommended only as an adjunct to instruction
in diet and exercise modification14, 15;
the medications, by reducing appetite (or fat absorption), are thought to
facilitate patients' efforts to adhere to a reduced-energy diet.16, 17
In most primary care practices, however, weight loss medications seem to be
provided with little or no instruction in diet and exercise (ie, lifestyle)
modification. Previous studies18, 19
suggest that patients who are provided medication without adequate lifestyle
modification may lose less than half as much weight as those treated by the
combination of pharmacotherapy plus lifestyle modification.
Our study assessed the benefits of adding lifestyle modification to
the pharmacologic treatment of obesity. This is the obverse of the typical
design in which the benefits of pharmacotherapy are assessed by comparing
lifestyle modification plus placebo with lifestyle modification plus medication.3, 6, 20 In our study, results
of treating obese women with sibutramine alone (ie, the drug-alone group)
were compared with those for sibutramine combined with group lifestyle modification
(ie, the drug-plus-lifestyle group). (We selected sibutramine because it was
the only medication approved for long-term use when the study began in September
1998.) Patients in both groups were treated for 1 year and were asked to consume
a 5021- to 6276-kJ/d diet (1200-1500 kcal/d diet) and to increase their physical
activity. However, only those in the second group (the drug-plus-lifestyle)
were provided behavioral strategies for achieving these goals. Patients in
the third treatment group (the combined treatment group) also were prescribed
sibutramine and group lifestyle modification. During the first 4 months, however,
they were also provided a 4184-kJ/d (1000 kcal/d) portion-controlled diet.21 This diet was included to induce larger weight losses.22 A previous study23
suggested that obese women were dissatisfied with the 10% reduction in their
initial body weight produced by current behavioral and pharmacologic therapies.
We wished to determine whether the inclusion of a portion-controlled diet
would increase initial weight losses and, thus, patients' satisfaction with
treatment outcome.
PARTICIPANTS AND METHODS
PARTICIPANTS
Participants were 53 women with the following mean (±SD) values:
age, 47.2 ± 9.8 years; weight, 101.3 ± 9.7 kg; height, 164.1
± 6.0 cm; and body mass index, 37.7 ± 3.6 kg/m2.
They were selected from more than 300 respondents to advertisements in local
newspapers. Participation was limited to women who had a body mass index of
30 to 45 kg/m2 and who were free of physical contraindications
including types 1 or 2 diabetes mellitus; uncontrolled hypertension (>140/90
mm Hg); a history of cerebrovascular, cardiovascular, kidney, or liver disease;
the use of medications known to affect body weight (eg, steroids); pregnancy
or lactation; a weight loss of 5 kg or more and/or the use of anorectic agents
in the previous 6 months; and the use of selective serotonin reuptake inhibitors,
monoamine oxidase inhibitors, or other medications contraindicated with the
use of sibutramine.13 Psychosocial contraindications
included the following: current psychotherapy; bulimia nervosa; major depression,
as suggested by a score higher than 25 on the Beck Depression Inventory24; or other psychiatric illness that significantly
disrupted daily functioning.25 Patients with
binge eating disorder26 were included.
Respondents were screened by telephone, and those who met the aforementioned
criteria were scheduled for a 1-hour meeting with a psychologist (T.A.W. or
D.B.S.) who described the nature and requirements of the study, obtained patients'
informed consent, and reviewed applicants' responses to the screening battery.
Women who were free of the psychosocial complications described earlier were
referred to their primary care physicians, who conducted a history intake
and physical examination to determine that applicants also were free of the
physical complications noted above. Physicians forwarded their findings to
the project physician (R.I.B.), who had final responsibility for accepting
patients into the trial. Participants deposited $600, which covered the costs
of medications and all professional fees. A total of $150 was returned for
completing study assessments at 6 and 12 months. This study was approved by
the University of Pennsylvania's Committee on Subjects Involving Human Beings,
Philadelphia.
PROCEDURES
Fifty-five women were randomly assigned to 1 of 3 treatment groups:
(1) drug-alone, (2) drug-plus-lifestyle modification (ie, drug-plus-lifestyle),
or (3) drug-plus-lifestyle with a portion-controlled diet (ie, combined treatment).
One woman in each of the first 2 groups withdrew prior to the start of the
trial, leaving a total of 53 patients. Baseline characteristics of the women
in the 3 groups are given in Table 1.
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Table 1. Participants' Baseline Characteristics*
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TREATMENT GROUPS
Drug-Alone Group
At week 0 (ie, baseline), these 19 patients met with a physician (R.I.B.
or R.P.-W.) who described the 1-year program, including the use of sibutramine
treatment and the importance of lifestyle modification. They were instructed
to consume a balanced diet of 5021 to 6276 kJ/d (1200-1500 kcal/d), with approximately
15% of the energy from protein, 30% from fat, and 55% from carbohydrates.
They were also encouraged to gradually increase their exercise (typically
by walking) to 4 to 5 sessions per week for 30 to 40 minutes per session.
To aid these efforts, they were given a copy of On Your
Way to Fitness,27 a 28-page guide that
describes the basics of healthy eating and activity habits. At week 0, patients
were prescribed 10 mg once daily of sibutramine hydrochloride that, if tolerated,
was increased to 15 mg once daily at week 8. Patients had a total of 10 brief
(5- to 10-minute) follow-up visits (at weeks 2, 4, 8, 12, 16, 20, 24, 32,
40, and 52) at which the physician measured their weight, blood pressure (BP),
and pulse rate and inquired about side effects. Patients were not asked to
keep records of their food intake or physical activity; physicians did not
provide lifestyle counseling.
Drug-Plus-Lifestyle Group
The 17 women in this group were prescribed sibutramine and had physician
visits on the same schedule as those in the drug-alone group. In addition,
during the first 20 weeks, they attended weekly group lifestyle modification
sessions, which were conducted by doctoral-level psychologists (T.A.W. or
D.B.S.), following the LEARN Program for Weight Control.28
These patients were prescribed the same diet and exercise goals as those in
the first group but were given behavioral strategies for achieving these objectives
and were asked to keep daily records of their food intake and physical activity
for at least the first 16 weeks. Records were reviewed at weekly sessions,
as were traditional behavioral topics including stimulus control, slowing
the rate of eating, social support, and cognitive restructuring.29
From weeks 24 to 52, participants attended monthly group sessions that focused
on the skills needed for the maintenance of weight loss.
Combined Treatment Group
The 17 women in this group received, with one exception, the same treatment
as those in the drug-plus-lifestyle group. For the first 16 weeks, they were
prescribed a 4184-kJ/d (1000 kcal/d) portion-controlled diet that consisted
of 4 servings a day of a nutritional supplement combined with an evening meal
of a frozen food entree, a serving of fruit, and a green salad. Each serving
of the liquid supplement provided 669 kJ (160 kcal) with 14 g of protein,
20 g of carbohydrates, and 3 g of fat (OPTIFAST 800; Novartis Nutrition Co,
Minneapolis, Minn). Beginning at week 17, participants gradually decreased
their consumption of the liquid supplement, so that by week 20 they were prescribed
a 5021- to 6276-kJ/d diet (1200-1500-kcal/d diet) of conventional foods, similar
to the patients in the other 2 conditions.
DEPENDENT MEASURES
Weight
Weight was measured at each treatment visit, on the schedule of patients
in the drug-alone group (ie, weeks 0, 2, 4, 8, 12, 16). Patients were weighed
in light clothing without shoes.
Behavioral Adherence
Adherence to the behavioral program was assessed in the second and third
groups by the number of food records patients completed the first 16 weeks.
For each week, participants were given a score of 0 to 7, reflecting the number
of days that they recorded their food intake. At each meeting, women who reported
forgetting to bring their records were asked to do so the next week. If they
did not, they were given a score of 0 for the week in question.
Weight Loss Expectations and Satisfaction
Before treatment, but after having been informed of their treatment
assignment, patients completed a questionnaire that asked how much weight
they expected to lose after 1, 3, 6, and 12 months of treatment. For each
month, they recorded the cumulative number of pounds they expected to lose
by that time. They also noted the weight loss goal they ultimately hoped to
achieve, even if not in this program. At months 3, 6, and 12, participants
rated their satisfaction with their weight loss, as well as with changes in
their health and energy level, appearance, and self-esteem. Ratings were made
on a 1- to 10-point scale in which 1 indicated very dissatisfied and 10 indicated
very satisfied. Using the same scale, they also reported their satisfaction
with the medication (ie, sibutramine), as well as with the medical care they
received from the study physicians.
BP and Lipids
Blood pressure and pulse rate were measured on the same schedule as
weight using a Dinamap monitor (XL Model 9300; Johnson & Johnson, New
Brunswick, NJ), an automated instrument that eliminates potential observer
bias in the detection of Korotkoff sounds. On each occasion, 2 readings were
taken at 1-minute intervals after the patient had been seated for at least
5 minutes. The levels of triglycerides, total cholesterol (TC), and high-density
lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)
were measured at baseline and weeks 8, 26, and 52 following an overnight fast;
methods used have been described elsewhere.30
ATTRITION AND STATISTICAL ANALYSES
Attrition
All 17 patients in the combined treatment group completed the study
(ie, 0% attrition). By contrast, 6 (31.6%) of 19 patients in the drug-alone
group discontinued treatment prematurely, as did 4 (23.5%) of 17 patients
in the drug-plus-lifestyle group.  2 Analyses revealed a significantly
(P<.05) greater rate of attrition in the drug-alone
group than in the combined treatment group, with no other significant differences
among conditions. Table 2 lists
the time of attrition for each patient, weight loss at the time, and factors
associated with discontinuation. Six patients withdrew because of apparent
scheduling conflicts and/or dissatisfaction with treatment; the other 4 discontinued
participation because of concomitant medical conditions (ie, migraine headache,
surgery for a fibroid tumor), increased BP, and reports of heartburn and insomnia.
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Table 2. Summary of Attrition for 10 Participants
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Statistical Analyses
Differences between conditions in changes in weight (and other measures)
were compared using analysis of variance with repeated measures. In cases
in which a significant treatment effect was observed, the Tukey honestly significant
difference test31 was used to identify differences
among the 3 groups. This method, similar to the Bonferroni adjustment,31 sets the experimentwise error rate at P<.05, thus, controlling for the effect of multiple comparisons.
Weight data were analyzed in 2 ways. A last-observation-carried-forward (LOCF)
analysis was used in which the patient's body weight at the time of attrition
was included at the 6- and 12-month assessments. A more conservative intention-to-treat
analysis was also conducted in which participants who discontinued treatment
were assumed to gain 0.3 kg/mo after leaving the study. This value was selected
based on the 1-year weight regain of approximately 3.0 kg observed in trials
of behavior modification.29, 32
This calculation may be preferable to the LOCF analysis, which does not account
for the weight regain that occurs during long-term obesity trials. For example,
a patient who loses 10% of his or her initial body weight during the first
3 months of treatment and then drops out is unlikely to maintain a loss of
this size at a 1-year assessment, although a 10% loss would be credited if
the LOCF analysis were used.11 All values are
expressed as means (±SDs).
RESULTS
WEIGHT LOSS
Women in all 3 treatment groups achieved their maximum weight loss (as
assessed by the LOCF analysis) at month 6, when the patients in the drug-alone
group had lost 5.8% ± 5.0% of their initial body weight, compared with
substantially larger losses of 11.0% ± 6.7% in the drug-plus-lifestyle
group and 17.7% ± 5.9% in the combined treatment group (Table 3 and Figure 1).
(The losses were 5.6 ± 5.0 kg, 11.4 ± 7.1 kg, and 17.9 ±
5.8 kg for the 3 groups, respectively.) Pairwise comparisons (ie, Tukey honestly
significant difference test) showed that all 3 groups differed significantly
from each other. Thus, patients in the drug-plus-lifestyle group lost significantly
(P<.05) more weight than those treated with sibutramine
alone. Similarly, women who received combined treatment, which included a
4184-kJ/d (1000-kcal/d) portion-controlled diet, lost significantly (P<.05) more than those in the drug-plus-lifestyle group,
who were prescribed a 5021- to 6276-kJ/d (1200-1500 kcal/d) diet (Table 3 and
Figure 1).
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Table 3. Percent Reduction in Initial Weight for Participants in the
3 Groups*
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Figure 1. Percentage reduction in initial
body weight for women treated with sibutramine hydrochloride alone (drug-alone),
sibutramine plus group lifestyle modification (drug-plus-lifestyle), and sibutramine
and lifestyle modification group (combined treatment), as assessed by a last-observation-carried
forward analysis. All 3 groups differed significantly (P<.05
for all) from each other at month 6. At month 12, the 19 women in the drug-alone
group lost significantly (P<.05) less weight than women in
the other 2 groups (which did not differ significantly from each other). Drug-alone
group indicates the participants who received sibutramine treatment alone;
drug-plus-lifestyle group, participants who received sibutramine treatment
and attended weekly group lifestyle modification sessions for the first 20
weeks; and the combined treatment group, participants who received sibutramine
treatment, attended weekly group lifestyle modification sessions for the first
20 weeks, and ate a 4184-kJ/d (1000-kcal/d) diet for the first 16 weeks. For
more detailed information see the "Treatment Groups" subsection of the "Participants
and Methods" section.
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The benefits of group lifestyle modification persisted at month 12.
Patients in the drug-alone group maintained a loss of 4.1% ± 6.3% of
their initial body weight, compared with significantly (P<.05) greater reductions in the drug-plus-lifestyle group of 10.8%
± 10.3% and in the combined treatment group of 16.5% ± 8.0%.
(The losses were 3.8 ± 6.1 kg, 11.1 ± 10.5 kg, and 16.6 ±
7.5 kg for the 3 groups, respectively.) Differences between the latter 2 treatment
groups approached statistical significance (P<.12).
(The LOCF and intention-to-treat analyses yielded the same results in all
cases, thus only the LOCF results are reported here.)
At month 12, significantly more patients in the drug-plus-lifestyle
group, as well as in the combined treatment group, had lost 5% or more or
10% or more of their initial body weight than had those in the drug-alone
group (P<.05 for both) (Table 4). In addition, significantly more patients in the combined
treatment group than in the drug-plus-lifestyle group achieved losses of 10%
or more or 15% or more of their initial body weight (P<.05
for both). Thus, at the end of 1 year, the 4184-kJ/d (1000-kcal/d) portion-controlled
diet was superior to the conventional 5021- to 6276-kJ/d (1200-1500 kcal/d)
diet in promoting weight losses of 10% or more or 15% of initial body weight.
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Table 4. Percentage of the 53 Participants Meeting Different Weight
Loss Criteria at Month 12*
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BEHAVIORAL ADHERENCE AND WEIGHT LOSS
During the first month, women in the lifestyle groups completed more
than 85% of their daily food records. For the total 4-month period, patients
in the combined treatment group completed 78.% ± 19.6% of the possible
records, which was significantly (P<.05) greater
than the 60.1% ± 26.1% completed by women in the drug-plus-lifestyle
group. Partial correlation analyses, which controlled for the effect of treatment
condition, revealed a strong positive relationship between weight loss and
the completion of food records. For example, the greater the total number
of records women completed in the first 2 months, the greater their weight
loss at month 2 (r = 0.56, P<.001).
Similarly, the greater the total number of records completed in the first
4 months, the greater the weight loss at month 4 (r
= 0.57, P<.001), month 6 (r = 0.55, P<.002), and month 12 (r = 0.41, P<.03).
Additional analyses, which included patients in all 3 treatment groups,
revealed the importance of early weight loss. Partial correlation analyses,
controlling for treatment condition, showed that the greater the weight loss
the first month, the greater the loss at month 2 (r
= 0.81, P<.001), month 4 (r = 0.61, P<.001), month 6 (r = 0.53, P<.001), and month 12 (r = 0.33, P<.02). Women who
discontinued treatment prematurely tended (P<.07)
to lose less weight the first month than did those who completed the full
program (3.0% ± 1.9% vs 4.3% ± 1.8%, respectively).
WEIGHT LOSS EXPECTATIONS AND SATISFACTION
Patients in all 3 treatment groups expected to lose large amounts of
weight, as shown in Figure 2. By
month 6, eg, they expected to reduce their initial body weight by an average
of 16.3% ± 4.7%, increasing by month 12 to 25.2% ± 7.7%. Their
ultimate goal was to lose 34.4% ± 11.3% of their initial body weight.
There were no significant differences among the 3 groups in the size of expected
weight losses for any period.
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Figure 2. Expected percentage reduction
in initial body weight for women in the 3 groups. Respondents reported the
cumulative number of pounds they expected to lose by each period. These values
were converted to the percent reduction in initial body weight. Drug-alone
group indicates the participants who received sibutramine hydrochloride treatment
alone; drug-plus-lifestyle group, participants who received sibutramine treatment
and attended weekly group lifestyle modification sessions for the first 20
weeks; and the combined treatment group, participants who received sibutramine
treatment, attended weekly group lifestyle modification sessions for the first
20 weeks, and ate a 4184-kJ/d (1000-kcal/d) diet for the first 16 weeks. For
more detailed information see the "Treatment Groups" subsection of the "Participants
and Methods" section.
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There were, however, marked differences among groups in patients' achievement
of their expected weight losses. At month 12, for example, women in the drug-alone
group achieved only 21.9% ± 22.5% of their expected end-of-treatment
weight loss, as compared with a significantly (P<.05)
greater 60.7% ± 59.1% for the women in the drug-plus-lifestyle group
and 66.2% ± 34.8% for the women in the combined treatment group (with
no differences between the latter 2 groups). Partial correlation analyses
(controlling for treatment condition) showed that the greater the percentage
of their expected end-of-treatment weight loss patients achieved, the greater
their reported satisfaction at month 12 with changes in their weight (r = 0.72, P<.001), health and
energy (r = 0.67, P<.001),
appearance (r = 0.71, P<.001),
and self-esteem (r = 0.62, P<.001). Figure 3A-D
shows that at the 3-, 6-, and 12-month assessments, women in the combined
treatment group were significantly more satisfied with changes in their weight,
health and energy level, appearance, and self-esteem than were those in the
drug-alone group (P .05 for all). Women in the
drug-plus-lifestyle group were similarly more satisfied at 3 and 6 months
with their changes in weight and appearance and at 12 months were significantly
more satisfied than women in the drug-alone group on all 4 measures (P<.05 for all). No significant differences in satisfaction
were observed between the 2 lifestyle conditions.
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Figure 3. A, Satisfaction with weight loss
at months 3, 6, and 12, as reported by women in the 3 groups. B, Satisfaction
with changes in physical health and energy levels at months 3, 6, and 12,
as reported by women in the 3 groups. C, Satisfaction with changes in appearance
at months 3, 6, and 12, as reported by women in the 3 groups. D, Satisfaction
with changes in self-esteem at months 3, 6, and 12, as reported by women in
the 3 groups. Bars with different lowercased alphabet letters differ significantly
(P<.05), as determined by the Tukey honestly significant difference
test. Drug-alone group indicates the participants who received sibutramine
hydrochloride treatment alone; drug-plus-lifestyle group, participants who
received sibutramine treatment and attended weekly group lifestyle modification
sessions for the first 20 weeks; and the combined treatment group, participants
who received sibutramine treatment, attended weekly group lifestyle modification
sessions for the first 20 weeks, and ate a 4184-kJ/d (1000-kcal/d) diet for
the first 16 weeks. For more detailed information see the "Treatment Groups"
subsection of the "Participants and Methods" section. The extremes of the
10-point scale were as follows: 1, very dissatisfied; 10, very satisfied.
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At no time during the study were there any significant differences among
the 3 groups in reported satisfaction with the medical care provided by the
study physicians; ratings were uniformly high throughout treatment (8.7 ±
1.4 at month 12 for the 3 groups combined). By contrast, there were marked
differences in satisfaction with sibutramine therapy. As shown in Figure 4, women in the 2 lifestyle groups
were significantly (P<.05) more satisfied with
sibutramine at months 6 and 12 than were patients treated with sibutamine
alone. In the drug-alone group, satisfaction with the medication declined
significantly (P<.05) from month 3 to month 12,
while ratings remained generally positive (and statistically unchanged) in
the 2 other groups.
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Figure 4. Satisfaction with weight loss
medication (ie, sibutramine hydrochloride) at months 3, 6, and 12, as reported
by women in the 3 groups. Women treated with sibutramine alone were significantly
(P<.05) less satisfied with the medication at months 6 and
12 than were the participants in the drug-plus-lifestyle group and combined
treatment group (which did not differ significantly). (Data were analyzed
using the Tukey honestly significant difference test.) Drug-alone group indicates
the participants who received sibutramine treatment alone; drug-plus-lifestyle
group, participants who received sibutramine treatment and attended weekly
group lifestyle modification sessions for the first 20 weeks; and the combined
treatment group, participants who received sibutramine treatment, attended
weekly group lifestyle modification sessions for the first 20 weeks, and ate
a 4184-kJ/d (1000-kcal/d) diet for the first 16 weeks. For more detailed information
see the "Treatment Groups" subsection of the "Participants and Methods" section.
The extremes of the 10-point scale were as follows: 1, very dissatisfied;
10, very satisfied.
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BP, LIPIDS, AND MEDICATION DOSE
Blood Pressure
Table 5 gives the changes
in BP, pulse rate, and lipid and lipoprotein levels for the 43 women who completed
the full 1-year study. Data were collapsed across the 3 groups after analyses
revealed no significant differences among groups, at the end of treatment,
in changes on any of these variables. As listed in Table 5, small, but statistically nonsignificant increases, were
observed in systolic BP (SBP) and diastolic BP (DBP) during the first few
months. By month 12, however, both values had increased significantly (P<.05 for both) above baseline, SBP by 5.0 ±
13.3 mm Hg and DBP by 6.1 ± 8.1 mm Hg. These mean increases may well
have been higher if the medication dose had not been tapered from 15 mg/d
to 10 mg/d in 4 patients and discontinued altogether in a fifth patient (in
the drug-plus-lifestyle group), all of whom had increases in SBP or DBP of
15% or more of baseline values in response to the 15-mg/d dose. (No patient
was allowed to remain on this dosage for >1 week with a BP  150/95 mm Hg.)
Increases in BP in the 13 (30%) of 43 patients who had baseline BPs of 130
mm Hg or more and/or 85 mm Hg or more were of the same magnitude as those
in the normotensive patients. Blood pressure increases could not be explained
by reductions in the use of antihypertensive medications. Only 4 patients
(spread evenly across the 3 groups) took medication at the study's outset,
and the drug dose was not changed in any of these inividuals over the 1-year
study. Medication was started in a fifth patient, who had borderline hypertension
at baseline, after the third month of the study.
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Table 5. Mean Changes in Blood Pressure and Triglyceride and Lipid
Levels in 43 Participants Who Completed the 52-Week Study*
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Mean pulse rate was essentially unchanged during the study, with the
exception of month 2, when it increased significantly (P<.05) by 4.2 ± 12.4 beats per minute. Once again, however,
the mean changes may have been greater if the medication dose had not been
reduced to 10 mg/d in 3 patients in whom the pulse rate increased 15% or more
above baseline while receiving the 15-mg/d dose. (No patient was allowed to
remain on this dosage for >1 week with a pulse rate >100 beats per minute.)
No significant correlations were found, at any assessment period, among changes
in weight, BP, or pulse rate. In addition, there were no significant differences
among treatment conditions, at any time, in the changes in BP or pulse rate.
Lipids and Lipoproteins
Collapsing across the 3 groups, significant reductions were observed
in the levels of triglycerides, LDL-C, and TC beginning at month 2 (P<.05 for all). These reductions, combined with significant
increases in the level of HDL-C at months 6 and 12, resulted in significant
reductions in the TC/HDL-C ratio, indicative of a reduced risk of cardiovascular
disease (P<.05 for all). At the 1-year assessment,
a positive relation (r = 0.40, P<.02) was found between weight loss and the reduction in the TC/HDL
ratio. Thus, patients who lost more weight tended to have greater reductions
in the risk of cardiovascular disease. The correlations between 1-year weight
loss and changes in the levels of triglycerides (r
= 0.25) and LDL-C (r = 0.27) were in the expected
direction but did not reach statistical significance.
At month 2, women in the combined treatment group had significantly
greater reductions in TC, LDL-C, and HDL-C levels than did those treated with
subutramine alone. There were no other statistically significant differences
among the 3 groups at this time or at the 6- and 12-month assessments.
Medication Dose and Weight Loss
In addition to the 8 women noted above who took reduced doses of sibutramine
hydrochloride (ie, 10 mg/d) because of increased BP or pulse rate, doses were
reduced in 2 additional women because of reports of disturbed sleep and in
a third woman because of reports of severe heartburn. These 11 women were
evenly distributed across the 3 groups. Analysis of covariance, controlling
for the effect of treatment group, showed that mean weight loss of these 11
patients did not differ significantly at month 12 from that of patients who
received full doses of sibutramine hydrochloride (ie, 15 mg/d) (mean losses,
10.4% ± 9.5% vs 12.5% ± 9.8%, respectively).
COMMENT
This study's principal finding was that lifestyle modification significantly
improved the pharmacologic treatment of obesity. After 1 year, women treated
with sibutramine plus lifestyle modification lost 10.8% of their initial body
weight, more than twice as much as those treated with sibutramine alone. The
addition to the group lifestyle intervention of a 4184-kJ/d (1000-kcal/d)
portion-controlled diet increased weight loss even further to 16.5%. To our
knowledge, this is one of the largest mean weight losses reported in a randomized
trial of weight loss medications.
A second major finding was that the obese women in our study had very
unrealistic weight loss expectations. Before treatment, participants in all
3 groups expected to lose the equivalent of 25% of their initial body weight
by the end of the year. They anticipated this despite having been informed
verbally, in the initial interview, that participants in all 3 groups should
expect to lose approximately 5% to 15% of their initial body weight. Moreover,
they maintained these expectations even after having been informed of their
treatment assignment and after having signed a consent form that stated, in
2 separate places, that they could expect to lose 5% to 15% of their initial
body weight. Participants hoped ultimately to lose the equivalent of 34% of
their initial body weight, a figure strikingly similar to that reported by
women in a diet and exercise clinical trial who were asked to identify their
"dream" weight.23
Data on weight loss expectations have 3 important implications for practice.
First, more effort must be devoted to informing obese persons of the health
benefits of a 5% to 15% reduction in their initial body weight. These benefits
have been summarized by several investigators33, 34, 35
and scientific panels.15, 36, 37
Second, physicians who prescribe anorectic agents must try throughout treatment
to correct the patient's unrealistic weight goals. This is particularly true
after the first 4 to 6 months of treatment when weight loss, in most patients,
slows and then stops. Women in our study clearly did not anticipate the weight
loss plateau that occurred at this time; this plateau is a hallmark of all
behavioral and pharmacologic therapies for obesity.1, 2, 6, 29, 32
Third, the findings clearly revealed the adverse effects of unmet expectations.
Participants in the drug-alone group, who were less successful in meeting
their weight loss goals, were less satisfied with the medication and with
the changes in their health and energy level, appearance, and self-esteem.
By contrast the greater the percentage of expected weight loss participants
achieved, the greater their satisfaction with changes in their weight and
the other outcomes.
Our findings clearly showed that group lifestyle modification improved
the pharmacologic treatment of obesity. We, like others,16
believe that lifestyle modification provides obese persons strategies to manage
the external food environment. These strategies include shopping from a list,
storing foods out of sight, controlling portion sizes, avoiding fast food
restaurants, and keeping food records.28, 29
By contrast, centrally acting weight loss medications, including sibutramine,
seem to modify the internal environment by increasing satiation or by decreasing
hunger or preoccupation with food.1, 4, 5
Such medications may reduce the obese person's responsiveness (or vulnerability)
to the pervasive food triggers encountered throughout the day. Our findings,
however, suggest that anorectic agents are likely to be most effective when
combined with the individual's efforts to manage the external environment.
Persons who are prescribed medication alone, without behavioral counseling,
seem to be at greater risk of discontinuing treatment prematurely, as they
did in our study, because of disappointment with their results. Although participating
in a structured program of lifestyle modification required more time and effort
from participants in our study, these costs seemed to yield substantial benefits,
in terms of patients' increased satisfaction with changes in their weight,
health and energy levels, and psychosocial outcomes.
Two additional points should be noted. First, we are unable to identify
which components of the lifestyle modification program contributed to our
participants' improved results. It is possible, eg, that the greater frequency
of clinic visits alone increased weight loss in the participants in the drug-plus-lifestyle
group compared with those in the drug-alone group. One behavioral component,
however, that seemed to be particularly important was keeping food records,
as shown in other studies.29, 38
The more food records women in the 2 lifestyle modification groups kept during
the first 4 months, the greater their weight loss both short- and long-term.
The second point is that many physicians may believe that they are unprepared
to help patients modify their eating and activity habits. We have previously
shown, in patients treated by weight loss medications, that 10 brief physician
counseling visits (of 15 minutes each) were as effective as 32 group behavior
modification sessions (of 75 minutes each) in inducing weight losses of approximately
15% of initial body weight.39 This study also
found a strong correlation between weight loss and completion of food records.
The largest mean weight losses were obtained by women in our combined
treatment group who consumed a 4184-kJ/d (1000-kcal/d) portion-controlled
diet for the first 4 months. At 1 year, they maintained a loss of 16.5% of
their initial body weight—a reduction similar to that recently reported
by Apfelbaum et al.11 Patients in that study
were treated for a first month by a very low-calorie diet, providing 837 to
3347 kJ/d (200-800 kcal/d), on which they lost approximately 7.5 kg. Participants
who were subsequently assigned to sibutramine treatment lost an additional
5.2 kg during the ensuing year, whereas those who received placebo gained
0.5 kg. These findings, with those from other recent trials,6, 7, 8
suggest that sibutramine and orlistat treatment may significantly improve
the long-term maintenance of weight loss. Additional studies are needed to
determine whether medication will facilitate the maintenance of the larger
losses of 15% to 25% of initial body weight that are typically produced by
the 12- to 16-week consumption of a very low-calorie diet.40
This would be a very important finding, given that patients typically regain
35% to 50% of their weight loss in the year following treatment by a very
low-calorie diet.29, 32, 40
Our study was designed explicitly to determine whether lifestyle modification
would improve the results of pharmacotherapy. The investigation did not examine
whether medication would improve the results of group lifestyle modification,
on either a short- or long-term basis. Thus, for example, it is possible that
women in our combined treatment group would have lost 16.5% of their initial
body weight at the end of 1 year without taking sibutramine. Future studies
should compare the effects of medication alone with lifestyle modification
alone with the combination of the 2 therapies. The results of a study by Craighead
et al18 suggested that medication and lifestyle
modification had additive effects. Patients treated for 6 months with fenfluramine
alone lost approximately 7% of their initial body weight, while those treated
with lifestyle modification alone lost approximately 11%. Patients who received
the 2 therapies together lost a significantly greater 16% of their initial
body weight. Clearly, these results are of limited clinical value, in view
of the withdrawal from the market of fenfluramine and dexfenfluramine.41, 42 However, the study provides a model
for assessing the combined effects of lifestyle modification and weight loss
medication. Investigations are needed to determine if the promising effects
of such combined therapy are maintained for 2 years or longer, a question
not answered by the study by Craighead et al or by our investigation.
Weight losses in our study were associated with significant long-term
(ie, 1-year) improvements in the levels of triglycerides, TC, and LDL-C, and
the TC/HDL-C ratio. These findings confirm the health benefits of modest weight
losses.15, 33, 34, 35, 36, 37
By contrast, SBP and DBP increased by 5 and 6 mm Hg, respectively, at the
end of the year, despite participants having lost more than 10% of their initial
body weight. These changes are greater than the increases of 2 to 3 mm Hg
noted in previous studies10, 11, 13
and cannot be definitively interpreted in the absence of a placebo-control
condition. We note, however, that Hansen et al5
recently reported, in participants treated for 8 weeks with 15 mg/d of sibutramine
hydrochloride, that DBP increased by 7.1 mm Hg, which was significantly greater
than the 0.8–mm Hg increase observed in placebo-treated control subjects.
(No significant increases were observed in SBP.) These findings, with ours,
underscore the importance of ensuring that sibutramine treatment is used only
with appropriate subjects and that BP and pulse rate are monitored regularly.
CONCLUSIONS
Results of our study indicate that primary care physicians who prescribe
weight loss medications will need to help their obese patients set more realistic
weight reduction goals, particularly after the first 4 to 6 months of treatment.
In addition, patients will achieve the best outcome by combining weight loss
medication with efforts to modify their eating and activity habits. For many
patients, keeping a daily food record and increasing daily physical activity
would seem to be excellent first steps.
AUTHOR INFORMATION
Accepted for publication July 11, 2000.
This study was supported, in part, by grants DK56124-01 (Dr Wadden)
and DK547130-01 (Dr Berkowitz) from the National Institutes of Health, Bethesda,
Md, and by grants from the Novartis Nutrition Co, Minneapolis, Minn (Dr Wadden);
Knoll Pharmaceutical Co, Mount Olive, NJ (Dr Wadden); and the American Health
Publishing Co, Dallas, Tex (Dr Wadden).
We thank the Novartis Nutrition Co for providing the OPTIFAST used in
this study; Knoll Pharmaceutical Co for providing the sibutramine; and the
American Health Publishing Co for providing copies of the LEARN Program for
Weight Control: Special Medication Edition.
From the Department of Psychiatry, University of Pennsylvania School
of Medicine, Philadelphia. Drs Wadden, Berkowitz, and Sarwer have all received
speaking honoraria from Knoll Pharmaceutical Company and Hoffman-La Roche
Laboratories, which manufacture sibutramine and orlistat, respectively. Drs
Wadden and Berkowitz have also served as consultants to both companies, as
well as to the Novartis Nutrition Company.
Corresponding author and reprints: Thomas A. Wadden, PhD, Department
of Psychiatry, University of Pennsylvania School of Medicine, 3600 Market
St, Suite 738, Philadelphia, PA 19104 (e-mail: Wadden{at}mail.med.upenn.edu).
REFERENCES
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