Download body weight and echocardiographic status

International Journal of Obesity (2007) 31, 850–857
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ORIGINAL ARTICLE
Comparison of combinations of drugs for treatment of
obesity: body weight and echocardiographic status
LD Whigham, NV Dhurandhar, PS Rahko and RL Atkinson
Departments of Medicine and Nutritional Sciences, University of Wisconsin, Madison, WI, USA
Background: Obesity treatment with single drugs produces weight losses of about 8–10% of initial body weight. Few studies of
combinations of drugs for treating obesity have been published. The combination of phentermine, an adrenergic agent, and
fenfluramine, a serotonergic agent, (phen–fen) produced weight losses of about 15% of initial body weight. Fenfluramine is no
longer available because it was associated with cardiac valve lesions. Phentermine–fluoxetine (phen–flu) has been proposed as
an alternative for phen–fen.
Objective: To compare the efficacy of treatment and prevalence of cardiac valve abnormalities on phen–flu vs phen–fen.
Design: Retrospective chart review of all patients treated for at least 3 months with phen–flu (N ¼ 97) to a random sample of
patients treated with phen–fen (N ¼ 98) in the Clinical Nutrition Clinic at the University of Wisconsin. Comparison of
echocardiograms in all patients treated solely with phen–flu (N ¼ 21) to a random sample of patients treated with phen–fen
(N ¼ 47), and to a group of subjects never treated with obesity drugs (N ¼ 26).
Results: With last observation carried forward analysis (LOCF), at 6 months of treatment the phen–fen patients lost 12.670.6%
of baseline weight and phen–flu patients lost 9.070.6% (Po0.001). With completers analysis, there were no significant
differences in weight loss as a percent of baseline weight at 6 months (14.470.6 vs 13.370.9%). LOCF decreases in body mass
index (BMI) at 6 months were 5.3 and 3.6 kg/m2 for phen–fen and phen–flu, respectively (Po0.001), and 6.270.3 vs
5.470.4 kg/m2, respectively, for the completers analysis (P – NS). Dropout rate at 6 months was higher in phen–flu subjects
(44 vs 28%). In subjects without atherosclerosis of valves (presumably pre-existing), cardiac valve lesions occurred in eight of
38 phen–fen subjects and in none of 15 phen–flu subjects or 25 control subjects who had not been treated with drugs.
Conclusions: The combination of phentermine and fluoxetine was not as effective as phen–fen, but was not associated with
cardiac valve lesions. Longer term, larger scale studies of phen–flu are warranted.
International Journal of Obesity (2007) 31, 850–857. doi:10.1038/sj.ijo.0803498; published online 5 December 2006
Keywords: fluoxetine; fenfluramine; phentermine; cardiac valves; weight loss; co-morbidities
Introduction
The use of drugs for the treatment of obesity was discouraged
by most physicians for several decades from the 1960s
into the early 1990s.1 Obesity drugs were thought to be
ineffective and dangerous. The US Food and Drug Administration (FDA) approved the use of obesity drugs for up to
about 12 weeks, and many states had laws prohibiting the
use of obesity drugs at all, or severely curtailing their use.1
The minority of physicians who prescribed obesity drugs
usually followed the recommendations for short-term use.
Only single drugs were prescribed and use of combinations
was virtually unknown.1,2 The seminal series of reports by
Correspondence: Dr RL Atkinson, Obetech Obesity Research Center, 800 E.
Leigh St., Suite 50, Richmond, VA 23219, USA.
E-mail: [email protected]
Received 30 August 2005; revised 17 July 2006; accepted 13 September 2006;
published online 5 December 2006
Weintraub et al.2 in 1992, demonstrating that the combination of phentermine and fenfluramine (phen–fen) could
produce clinically significant weight loss for periods of up
to 3.5 years, ignited the ‘phen–fen revolution’ that saw
thousands of physicians prescribing this combination to
millions of patients. Subsequent studies confirmed longterm weight losses that were superior to diet and exercise
alone and to treatment with single drugs.3–9 Weight losses at
1 year were approximately 15–17% of initial body weight
with phen–fen3–9 compared to losses of 6–10% of initial
body weight with single-drug treatment using fenfluramine.10–19
When fenfluramine and dexfenfluramine were removed
from the market in September 1997 because of concerns
about cardiac valve lesions,4,6,20–33 some physicians turned
to combinations of phentermine and other serotonin-active
drugs such as fluoxetine and sertraline in an attempt to
reproduce the phen–fen effect. However, there are very few
Combinations of obesity drugs
LD Whigham et al
851
studies published on the efficacy of these combinations
for obesity, and none have compared results with phen–fen.
Also, there are minimal data about the safety of selective
serotonin reuptake inhibitors (SSRI) when used in combination with phentermine.
Rowland et al.34 reported in animals that the combination
of phentermine and fluoxetine (phen–flu) had additive
effects on weight loss. Anchors35 published a book for the
lay press proposing the use of phen–flu, but did not perform
controlled studies. Devlin et al.36 treated overweight binge
eaters with phen–flu for 20 weeks and found a reduction
of 9% of initial body weight and a reduction in binge eating.
These effects did not persist when the medications were
stopped. Reeve et al.37 demonstrated that phentermine and
fluoxetine did not appear to increase the risk of pulmonary
hypertension. Bostwick and Brown38 reported a single case
of toxicity with the use of phen–flu. In an uncontrolled
case series, Griffen and Anchors39 reported in a letter that
phen–flu was not associated with cardiac lesions on
echocardiography.
The objectives of this study were to evaluate the efficacy
and safety of treatment with the combination of phen–flu,
and to compare to treatment with the combination of
phen–fen. We evaluated changes in body weight, blood
pressure and selected laboratory tests, and the occurrence of
cardiac valve lesions on echocardiography with the two
combinations.
with cardiac valve lesions, we were concerned that the
combination of phen–flu might have a similar association.
We contacted all the subjects who had taken or were taking
phen–flu and invited them to undergo an echocardiogram.
Of the subjects who agreed to have an echocardiogram, 21
had never taken fenfluramine or dexfenfluramine, and had
been treated with phen–flu for at least 3 months. The average
time of treatment with phen–flu was 5137310 days (7s.d.).
As a comparison group, randomly selected subjects from
the University of Wisconsin CNC population who had been
treated with phen–fen for at least 3 months and had not ever
taken fluoxetine were invited to obtain an echocardiogram.
A total of 47 subjects underwent an echocardiogram, so all
were included. The average time of treatment with phen–fen
was 4457216 days (7s.d.).
Finally, an additional comparison group of 26 subjects
from the University of Wisconsin CNC research population
who had never taken fenfluramine or any selective serotonin
reuptake inhibitor medication was invited to have an
echocardiogram and acted as a negative control group.
Treatment protocol, efficacy evaluation
An initial history was taken and physical examination was
carried out on all subjects and an electrocardiogram and
Table 1
Materials and methods
Subjects, efficacy evaluation
In a retrospective chart review, all patients who had received
phentermine and fluoxetine in the Obesity Treatment
Program of the Clinical Nutrition Clinic (CNC) of the
University of Wisconsin between 1994 and 1998 were
identified. A second inclusion criterion was that none of
these subjects had ever taken fenfluramine or dexfenfluramine before the study period. In some instances, subjects
who took phen–flu had been precluded from taking phen–
fen because of a history of depression, which was an
exclusion criterion for phen–fen in our clinic. A total of
97 phen–flu subjects were identified. A comparison group of
98 patients was selected randomly from over 700 patients
in the CNC program who had undergone treatment with
the combination of phen–fen, but who had never taken
fluoxetine or other selective serotonin reuptake inhibitors.
Because of the exclusion criteria, none of these subjects had
a history of depression. Table 1 describes the inclusion
and exclusion criteria and Table 2 describes the baseline
characteristics of the subjects in the two groups.
Subjects, echocardiogram evaluation
When fenfluramine and dexfenfluramine were taken off
the market in September, 1997, because of an association
Inclusion and exclusion criteria for drug treatment
Inclusion criteria
1
Body mass index (kg/m2) greater than 27.
2
Committed to area for at least 2 years.
Exclusion criteria
1
Age greater than 65 years or less than 18 years.
2
Pregnancy or lactation
3
Malignant arrhythmia, CHF, or unstable cardiac disease.
4
Uncontrolled hypertension – diastolic 4110, systolic 4195 mm Hg.
5
Presence of any severe systemic illness.
6
At risk of increased protein catabolism (disease or drugs).
7
Other drug therapy if there is interaction with study drugs.
8
History of psychosis, bipolar disorder, or anorexia nervosa.
9
Presence of major active depression.
Abbreviation: CHF, chronic heart failure.
Table 2
Baseline characteristics of subjects in the efficacy evaluation
Phen–fen s.e.m. Phen–flu s.e.m. P-value
Age (year)
Weight (kg)
BMI (kg/m2)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Glucose (mg/dl)
Total cholesterol (mg/dl)
Triglycerides (mg/dl)
HDL (mg/dl)
44.0
120.7
42.3
133.5
85.4
103.6
213.7
167.1
43.8
71.04
73.6
71.03
71.91
71.16
73.30
73.75
711.63
71.22
44.8 70.93 0.6
107.1 72.6 0.002
38.7 70.80 0.005
128.6 71.78 0.06
82.6 70.89 0.056
100.1 72.73 0.4
210.9 73.95 0.6
153.4 710.76 0.4
47.9 71.30 0.02
Abbreviations: BMI, body mass index; HDL, high-density lipoprotein.
International Journal of Obesity
Combinations of obesity drugs
LD Whigham et al
852
standard laboratory tests were performed. The laboratory
tests included a complete blood count, chemistry-20 panel,
lipid panel, magnesium, thyroid function tests, urinalysis
and pregnancy test in fertile females. Then, all subjects were
prescribed a diet designed to provide about 500–1000 kcal/
day lesser than their usual intakes, calculated from 7-day
food diaries. The calorie deficit was determined by initial
size, personal preference and desired rate of weight loss. An
exercise/activity program consisting of walking or comparable activity for 30 min or more, three or more times weekly,
was prescribed. At each visit, subjects filled out a follow-up
questionnaire listing symptoms, complaints and compliance
to the diet and exercise program. Subjects who did not
adhere to the diet and/or exercise program were encouraged
to do so at each visit, but no penalties were incurred for
failure to adhere.
Subjects were prescribed medications starting with low
doses and increasing if weight loss was unsatisfactory.
Phentermine was started at half of a 37.5-mg tablet, or
18.75 mg per day. Fenfluramine and fluoxetine were started
at 20 mg per day. A weight loss of less than one pound per
week, averaged over 4 weeks was used as the criteria to go to
the next highest dose. The usual pattern of stepwise increase
was to raise fenfluramine to 40 mg per day, then to 60 mg per
day, followed by increasing phentermine to 37.5 mg per day.
On rare occasions, phentermine would be increased to
1.5 tablets per day (56.25 mg) if the patient had responded
to the initial increase in phentermine. Except in very rare
instances, the maximum doses of fenfluramine and
fluoxetine were 60 mg per day.
Patients returned to the CNC every 2 weeks for 24 weeks,
then were scheduled to be seen every 4 weeks. At each visit,
patients were seen by the dietitian and the physician
or nurse practitioner for individual evaluation, examination
of follow-up questionnaire and food diaries, and refilling
of prescriptions when necessary. For most of the sessions,
a group lesson was also given. Group lessons lasted about
30 min and dealt with some aspects of obesity or its
treatment, as previously reported by our group.40
Research design, efficacy evaluation
Measures of efficacy included percent change from initial
body weight and changes in body mass index (BMI), blood
pressure, serum glucose, serum cholesterol, triglycerides and
high-density lipoprotein (HDL). Last observation carried
forward (LOCF) analyses were performed on the variables
of change in BMI and percent change in body weight. Also,
analyses were performed on subjects who completed
6 months of treatment.
Research design, echocardiogram evaluation
Echocardiograms were performed in the Cardiology Laboratory of the University of Wisconsin Hospital using an Agilent
Technologies, model 5500 Andover (MA, USA) apparatus.
International Journal of Obesity
The co-author, Dr Peter Rahko, read the echocardiograms
blinded to the subject group. Subjects who had calcifications
in the aortic valve or in the aortic root were discarded from
analysis from all groups because atherosclerosis is not a
feature of phen–fen-associated valvulopathy, but may produce valvular insufficiency. Valvulopathy was rated in two
ways. First, numerical scores were assigned to the severity
of valvular insufficiency: 0 – none, 1 – trace, 2 – mild,
3 – moderate, 4 – severe. Second, ‘significant’ valvulopathy
as defined by the US FDA was identified.21,41 The FDA
designated mild or greater aortic insufficiency, and moderate
or greater mitral insufficiency, as serious valvular insufficiency. The number of subjects in each group who had
serious valvulopathy by these criteria was recorded.
Statistical analyses
The obesity treatment data were analyzed using both an
LOCF analysis and a completers analysis (completing 6
months of treatment). The two drug groups were compared
by the non-paired Student’s t-test. The echocardiographic
data were compared by analysis of variance (ANOVA),
followed by Fisher’s least significant difference (LSD) (protected t-tests) for the numerical scoring of valvular disease,
and by non-parametric analysis, Kruskal–Wallis one-way
ANOVA, for ‘significant’ valve disease. Software used
for the statistical analyses were Excel (Microsoft, 1997) and
GB Stat, Version 6.5 (Dynamic Microsystems, Silver Springs,
MD, USA).
The protocols and informed consent forms were approved
by the Human Subjects Committee of the University of
Wisconsin, Madison, Medical School.
Results
Changes in body weight and BMI
The data were analyzed using both an LOCF analysis and a
completers analysis (completing 6 months of treatment)
(Figure 1). Regardless of the method of analysis, differences
from baseline to 6 months were highly significantly different
in both groups (Po0.01). In the LOCF analyses, body weight
decreased in the phen–fen group from 120.573.6 to 105.47
3.2 kg and BMI decreased from 42.371.0 to 37.070.9 kg/m2.
In the phen–flu group, body weight decreased from 107.27
2.6 to 97.372.3 kg and BMI decreased from 38.870.8 to
35.270.7 kg/m2. The phen–fen group weight loss of
15.170.9 kg was significantly greater than the weight loss
of 9.970.8 kg in the phen–flu group (Po0.0001). When
expressed as percent change from baseline, phen–fen lost
12.6% and phen–flu lost 9.0% (Table 3).
A completers analysis was performed on the 71 phen–fen
subjects (72%) and the 44 phen–flu subjects (45%) who
completed 6 months of treatment. Body weight decreased
in the phen–fen group from 126.074.3 to 108.373.9 kg and
BMI decreased from 44.171.3 to 37.971.2 kg/m2. In the
Combinations of obesity drugs
LD Whigham et al
853
phen–flu group, body weight decreased from 112.074.4 to
97.274.1 kg and BMI decreased from 40.071.3 to 34.77
1.2 kg/m2. When expressed as percent change from baseline,
phen–fen lost 14.4% and phen–flu lost 13.3% (Table 3).
None of the differences between groups were significant
for the completers analyses. Evaluation of individuals who
remained in treatment for 1 year showed that phen–fen
patients lost 18.571.2% of initial body weight and phen–flu
patients lost 15.471.8% of initial weight. The difference in
weight loss between groups was not significant, but dropout
rate was 45% with phen–fen and 82% with phen–flu.
a 130
Kilograms (kg)
125
120
Responses of blood pressure and laboratory assays
Systolic blood pressure decreased significantly from baseline
to 6 months in both phen–fen and phen–flu groups (Tables 4
and 5), but there was no significant difference between
groups. Diastolic blood pressure dropped significantly in the
phen–fen, but not in the phen–flu group, and the difference
between groups was not significant (Tables 4 and 5). Serum
glucose, cholesterol and triglycerides all decreased significantly from baseline to 6 months in both groups (Tables 4
and 5). Serum cholesterol decreased by 32.973.1 mg/dl in
the phen–fen group, vs a decrease of only 9.274.1 mg/dl in
the phen–flu group (Po0.0001). However, HDL decreased by
3.071.12 mg/dl (Po0.001) in the phen–fen group compared
to a non significant increase of 1.171.4 mg/dl for the phen–
flu group. The difference in change in HDL was significant
between groups (Po0.01).
115
Subject dropouts
The average time in treatment for phen–fen subjects was 393
days, and was 226 days for phen–flu subjects (Po0.0001).
110
105
100
95
Table 4
90
Baseline
Month 3
b 50
Phen–fen patients
Glucose (mg/dl)
Total Cholesterol
(mg/dl)
Triglycerides (mg/dl)
HDL (mg/dl)
Systolic blood pressure
(mmHg)
Diastolic blood pressure
(mmHg)
45
BMI (kg/m2)
Laboratory and blood pressure values from baseline to month 6
Month 6
40
35
30
Baseline
Month 3
Month 6
Figure 1 Changes in body weight (a) and BMI (b) during 6 months of
treatment, last observation carried forward. Circle ¼ phen–fen; trianglephen–flu.
Table 3 Change in body weight and BMI for last visit carried forward (LOCF)
analysis and completers analysis
Phen–Fen
s.e.m.
LOCF
Change in Weight (kg)
15.1
70.9
Percent Change in Weight 12.6% 70.6%
Change in BMI
5.3
70.3
Phen–Flu
s.e.m.
s.e.m.
105.27
213.27
73.63 95.11
74.36 180.36
72.32 o0.0001
73.67 o0.000001
154.07
45.56
136.48
79.35 101.01
71.56 42.49
72.33 129.34
75.64 o0.000001
71.54 o0.001
72.35 o0.0001
71.45
71.24 o0.001
86.56
101.15
205.20
Month 6
82.34
73.62 95.05
76.90 196.03
s.e.m.
P-value
72.67 o0.05
77.10 o0.05
151.12 715.41 110.10 710.84 o0.0001
47.02 72.10 48.15 72.07
NS
131.21 72.77 124.70 72.02 o0.05
82.64
71.31
81.30
71.40
NS
Abbreviations: HDL, high-density lipoprotein; NS, not statistically significant.
P-value
9.9
70.8
o0.001
9.0% 70.6% o0.001
3.6
70.3
o0.001
Completers
Change in Weight (kg)
17.7
71.0
14.8
71.2
Percent Change in Weight 14.4% 70.6% 13.3% 70.9%
Change in BMI
6.2
70.3
5.4
70.4
Phen–flu patients
Glucose (mg/dl)
Total Cholesterol
(mg/dl)
Triglycerides (mg/dl)
HDL (mg/dl)
Systolic blood pressure
(mmHg)
Diastolic blood pressure
(mmHg)
Baseline
NS
NS
NS
Abbreviations: BMI, body mass index; LOCF, last visit carried forward; NS, not
statistically significant.
Table 5 Changes in laboratory and blood pressure values after 6 months of
treatment
Phen–fen s.e.m. Phen–flu s.e.m.
Glucose (mg/dl)
Total Cholesterol (mg/dl)
Triglycerides (mg/dl)
HDL (mg/dl)
Systolic blood pressure (mm Hg)
Diastolic blood pressure (mm Hg)
10.2
32.9
53.1
3.0
7.1
4.2
P-value
72.5
6.1 72.7
NS
73.1
9.2 74.1 o0.0001
77.7 41.0 79.8
NS
70.9
1.1 71.4 o0.01
71.8
6.5 72.8
NS
71.3
1.4 71.3
NS
Abbreviations: HDL, high-density lipoprotein; NS, not statistically significant.
International Journal of Obesity
Combinations of obesity drugs
LD Whigham et al
854
Dropout rate in the phen–fen group was 9% at 3 months,
28% at 6 months and 44% at 1 year, whereas it was 29, 56,
and 82%, respectively in the phen–flu group. The most
common reasons for dropouts in the phen–fen group were
discontinuation of program (42%) and removal of the drug
from the market (27%). The most common reason for
dropout from the phen–flu group was a desire to switch
medications (44%), virtually always to phen–fen. Dropouts
due to side effects were 13% in each group. Eight percent
of subjects dropped out of the phen–flu group for slow
or insufficient weight loss. Only 1% dropped out of the
phen–fen group for insufficient weight loss.
Echocardiogram evaluation
Subjects in each of the three groups who had calcifications in
the aortic or mitral valves or in the aortic root were discarded
from the analysis (phen–flu: six of 21; phen–fen: nine of 47
and control: one of 26). Remaining subjects were compared
by ANOVA using scores for severity of valvular disease and
by nonparametric analysis for presence or absence of FDA
classification of valvular disease, as described above. Fisher’s
LSD (protected t-tests) after ANOVA revealed that subjects on
phen–fen had significantly higher severity of aortic insufficiency valvular disease (0.4770.14) than did phen–flu
(0.0070.00) or control (0.1270.07) (Po0.05). There were
no significant differences in severity score for mitral
insufficiency valvular disease among the three groups
(Table 6).
Using FDA criteria for significant valve disease, eight of
the 38 subjects (21%) on phen–fen had ‘significant’ aortic
disease and one had significant mitral disease. None of the
phen–flu or control subjects had significant valve disease.
However, Kruskal–Wallis one-way ANOVA revealed no
significant differences among the three groups for either
aortic or mitral valve disease.
Discussion
Obesity is a chronic disease that requires continuous,
probably lifelong treatment.42 Like other chronic diseases,
if treatment stops, the results of treatment are lost, and
weight is regained in the vast majority of patients. Virtually
all other chronic diseases are treated with pharmacologic
agents, and it seems likely that the standard treatment of
obesity eventually will include drugs. Unfortunately, few
chronic diseases can be treated with single drugs, and
combinations of drugs are required for most. However,
current FDA recommendations and manufacturers’ recommendations generally discourage the use of combinations of
obesity drugs. The major contribution of Weintraub’s studies
with phentermine and fenfluramine were to demonstrate
that a combination of two obesity drugs was more effective
than either drug alone, and that long-term treatment
produced continued weight loss.2
International Journal of Obesity
Table 6 Severity scores for valvular disease on echocardiograms (7s.e.m.)
Groups
Control
Phen–fen
Phen–flu
Aortic insufficiency
Mitral insufficiency
0.1270.07
0.4770.14a
0.0070.00
0.8070.16
0.8470.15
0.6770.16
a
Po0.05 compared to control and phen–flu groups.
The unexpected finding of cardiac valve lesions associated
with fenfluramine and dexfenfluramine resulted in the
removal of these drugs from the market.4,6,20–33 This left
the field of obesity with only three classes of FDA-approved
obesity drugs: adrenergic agents (e.g. phentermine, diethylpropion, phendimetrazine), a combined adrenergic–serotonergic agent (sibutramine), and a malabsorptive agent
(orlistat). There are very limited data on the subject, but
combinations of either sibutramine and orlistat43 or phentermine and orlistat44 do not appear to increase weight loss
over the use of single drugs. Thus, there are no accepted or
commonly used combinations of obesity drugs at this time.
Fluoxetine has been studied extensively as a potential
weight reduction agent, and has been shown to cause
significant weight loss after 6 months of treatment.45,46
However, unlike other drugs approved for the treatment
of obesity, weight losses did not persist, and after 1 year of
treatment body weight was back to baseline.45,46 Longer
term studies suggest that fluoxetine, when used alone, may
cause significant weight gain over time.47
Data on phen–flu treatment are minimal. An uncontrolled
case series reported in the lay press that the combination of
phen–flu had a greater effect on weight loss than did the use
of single drugs alone.35 In an open, uncontrolled case series
Devlin et al.36 noted that phen–flu reduced body weight and
incidence of binge eating at 20 weeks, but these benefits were
lost when the medications were stopped. As both obesity and
binge eating disorder are chronic diseases, it is not surprising
that the response stopped when treatment was stopped. In
virtually all other chronic diseases, when effective treatment
is stopped, the disease returns. This has been amply
demonstrated for obesity as well,42 so the conclusions
of these authors that, ‘this study does not support the
long-term clinical utility of adding phentermine/fluoxetine
to cognitive-behavioral therapy for binge eating disorder’,
does not appear justified.
The current study extends the preliminary, uncontrolled
observations of Anchors35 and Devlin et al.36 and demonstrated that the combination of phen–flu produced a weight
loss of 13.3% of initial weight at 6 months of treatment in
subjects remaining on treatment. This loss was not different
from the 14.4% weight loss achieved with phen–fen in
completers at 6 months. The LOCF analyses present a
different picture of the effectiveness of phen–flu. Weight
loss at 6 months was 9.0% compared to 12.6% for phen–fen,
a highly significant difference (Po0.001). It is likely that
phen–fen is more effective than phen–flu owing to the
Combinations of obesity drugs
LD Whigham et al
855
nature of the drugs, but subjects on phen–flu also had other
variables that may have affected the difference in weight
loss. The phen–flu subjects were 13.3 kg lighter. Weight loss
tends to be greater in heavier individuals. Also, some of
the phen–flu subjects had a history of depression or had
been treated with antidepressants in the past, and this
precluded treatment with phen–fen in our clinic. Therefore,
the populations may have been somewhat different at the
baseline. The dropout rate was greater in the phen–flu
subjects. For example, at 1 year, only 18% of the subjects
remained on phen–flu, compared to 56% on phen–fen. The
differential in the dropout rate may be partially explained by
the fact that these studies were conducted at the height of
the interest in phen–fen, and many of our patients asked to
be switched from phen–flu to phen–fen, despite significant
weight loss. As subjects who had lost less weight were more
likely to drop out, this makes the phen–flu weight loss for
completers look better.
A limitation of this study is that neither of the combinations was compared to single-drug treatment. There have
been numerous studies conducted with all of the obesity
drugs on the market, and the weight losses average about
5–10% of initial body weight at 6 months to 1 year. An
exception was the Sibutramine Trial of Obesity Reduction
and Maintenance (STORM) trial with sibutramine,48 carried
on in multiple sites in Europe, which achieved a loss of about
13% of initial body weight, and a study by Wadden et al.49
that demonstrated a weight loss of 16.5% at 1 year with
sibutramine, rigid diet and lifestyle modification. However,
the study by Wadden et al.49 and most of the sites in the
STORM trial used very low-calorie diets to achieve a large
initial weight loss, so the data are not comparable to those of
other trials. Our data, and the data of Anchors,35 suggest that
the weight losses achieved with phen–flu may be higher than
those usually achieved with single obesity drugs currently
on the market, and that this combination therapy may be
justified.
As would be expected, both phen–flu and phen–fen
reduced the complications of obesity, including blood
pressure, serum cholesterol and triglycerides. Phen–fen had
a much greater effect on lowering serum cholesterol than did
phen–flu (Po0.001). In contrast, phen–flu produced a slight
increase in serum HDL that was significantly different
(Po0.01) from the reduction in HDL seen with phen–fen.
Thus, the improvements in cardiovascular risk with weight
loss from both of the combinations appear approximately
comparable. These improvements in cardiovascular risk
profile may justify treatment with obesity drugs, even if
total weight loss falls far short of what patients desire.50
The numbers of subjects who underwent echocardiography are relatively small, and our data may be subject to
a type 2 error. Nevertheless, there was a difference between
the groups in one of the methods used to assess cardiac
valve lesions. Using a scoring system for the degree of valve
damage, phen–fen had a significantly greater aortic valve
damage score than did either of the other groups. However,
when using the FDA scoring system of ‘significant’ aortic or
mitral valve lesions, there were no significant differences,
probably owing to inadequate power. Neither phen–flu nor
control subjects had any FDA ‘significant’ lesions, whereas
eight of 38 phen–fen subjects had such lesions. Despite the
extensive use of fluoxetine for long-term treatment of
depression, there have been no reports of cardiac valve
lesions similar to those seen with fenfluramine and dexfenfluramine.4,6,20–33 Rothman et al.51 suggested that serotonergic drugs that bind to 5-HT (2B) receptors were associated
with cardiac valve lesions. Fenfluramine and dexfenfluramine were among those that bound to 5-HT (2B) receptors,
but fluoxetine did not.51 Reeve et al.37 evaluated the effects
of phentermine and fluoxetine on pulmonary arterial
pressure and electrophysiology, as the fenfluramines had
been demonstrated to be associated with primary pulmonary
hypertension.52,53 In contrast to dexfenfluramine, fluoxetine
and phentermine had minimal effects on the cell resting
membrane potential, and Reeve et al.37 concluded that they
were unlikely to be associated with pulmonary hypertension.
During the initial stages of the alert regarding cardiac valve
lesions associated with obesity drugs, several authors
speculated that the addition of phentermine might have
exacerbated the association of fenfluramine and dexfenfluramine with valve lesions.20,21,25,54 However, there is no
credible evidence that this is so, and the FDA has not limited
the use of phentermine. Phentermine was not associated
with primary pulmonary hypertension, in contrast with the
fenfluramines.53
Our data do not provide assurance that phen–flu will not
be associated with cardiac valve lesions, but they do suggest
that any effects would be much smaller than those associated
with fenfluramine, dexfenfluramine, or phen–fen. However,
any practitioner who chooses to use the combination of
phen–flu would be wise to provide extensive information
and obtain informed consent, preferably written.
In summary, the combination of phen–flu produced
weight losses that were not as great as those achieved
with phen–fen when LOCF analysis was used. There were no
differences in weight loss between the two combinations in
patients who completed 6 months of treatment, but there
was a much higher dropout rate in the phen–flu group.
Blood pressure and serum lipids demonstrated significant
improvements with both combinations. The weight losses
and improvements in cardiovascular risk achieved in our
trial give encouragement that additional, larger trials with
phen–flu combination would be useful. Future trials should
compare the combination of phen–flu with the results of
phentermine and other obesity drugs used alone.
Acknowledgements
We thank Dr E Shrago, H Walaski, E Freitick, and A
Rettammel for clinical assistance; and J Hansen and V
International Journal of Obesity
Combinations of obesity drugs
LD Whigham et al
856
Schmidt for administrative assistance. Supported by grants
from the Eli Lilly Company and funds from the Beers–
Murphy Clinical Nutrition Center, University of Wisconsin,
Madison.
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