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Long-term Pharmacotherapy of Obesity 2000
A Review of Efficacy and Safety
Gary Glazer, MD
Arch Intern Med. 2001;161:1814-1824.
ABSTRACT
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To clarify the efficacy of antiobesity drugs, this article reviews all
long-term ( 36 weeks), placebo-controlled trials of obesity pharmacotherapy
published since 1960. Since fears of anorexiant-induced heart valve damage
preclude many physicians and patients from even considering antiobesity drugs,
this area is also reviewed in-depth. Electronic database and manual bibliography
search was used to identify all relevant publications. While existing studies
are too few and heterogeneous to warrant meta-analysis, their review does
provide evidence highly relevant to the safety and efficacy of available anorexiants.
Weight loss attributable to obesity pharmacotherapy (ie, in excess of placebo)
in trials lasting 36 to 52 weeks was 8.1% or 7.9 kg for those receiving phentermine
resin, 5.0 % or 4.3 kg for those receiving sibutramine hydrochloride , 3.4%
or 3.4 kg for those receiving orlistat, and -1.5% or -1.5 kg for
those receiving diethylpropion hydrochloride. Physiologic, pathologic, and
epidemiological studies strongly support that anorexiant-induced valvulopathy
is attributable to specific serotonergic properties of the fenfluramines that
are not present with available weight loss drugs.
INTRODUCTION
Recent reports including the latest National Health and Nutrition Examination
Survey (NHANES III) have focused attention on an alarming recent increase
in the prevalence of obesity. The NHANES III1
(1988-1991) reported that obesity prevalence in the United States had risen
from 25% to 33%, a 31% increase since NHANES II (1976-1980). That report was
widely cited in a call to arms against obesity by the surgeon general and
others amidst predictions that 40% of the US population would be obese by
the year 2000 if present trends were unaltered. Although anorectic drugs have
been prescribed for more than 40 years, few patients were treated with diet
drugs prior to the mid 1990s. At that time an explosion in diet drug prescribing
was fueled by a variety of factors including the publication and publicizing
of "the phen-fen [phentermine resin–fenfluramine] study"2
and resultant aggressive direct-to-consumer promotion of diet drugs by for-profit
weight loss clinics. By 1997 well over 10 million prescriptions for the popular
phen-fen regimen had been written3 compared
with a mere 60 000 fenfluramine prescriptions in 1992.4
Our nation's acute interest in medications to treat obesity did not go unnoticed
by pharmaceutical manufacturers who broke a 23-year drought in the introduction
of new weight loss drugs by bringing 3 new drugs to market in a 2-year period
(dexfenfluramine hydrochloride in 1996, sibutramine hydrochloride in 1997,
and orlistat in 1998). This explosion in the drug treatment of obesity was
abruptly and dramatically curtailed with the September 1997 recall of dexfenfluramine
and fenfluramine from the market. That action immediately followed the reporting
of results of echocardiographic "surveys" of patients using fenfluramines
showing that up to one third of these patients had had echocardiographic abnormalities.
The above events have resulted in an atmosphere in which intense interest
in and fear of weight loss drugs coexist, a landscape of ambivalence toward
drug treatment of obesity perhaps unprecedented in medical therapeutics. Balanced
reviews of obesity pharmacotherapy are, therefore, needed to help reconcile
the justified interest in treating obesity with drugs with the fear of disastrous
adverse effects from such treatment. We need look no farther than our television
sets for a striking example of the degree to which conflicting messages about
diet drugs are now before us. Moments after one national television advertisement
promotes the new drugs (orlistat or sibutramine) a separate advertisement
invites past fenfluramine users to participate in a multibillion dollar class
action lawsuit.
RATIONALE FOR OBESITY PHARMACOTHERAPY
A growing body of evidence has eroded ingrained misconceptions about
obesity that have traditionally been obstacles to the appropriate use of medication
in obesity treatment. Of these paradigm shifts that have lead to the inclusion
of weight loss drugs in current guidelines for obesity treatment,5 3 are most compelling:
- Understanding that obesity is a true disease with
genetic determinants (not a "character flaw").
- Understanding that obesity is a major public health
threat (not merely a "cosmetic" issue).
- Understanding that weight regain after stopping
medications indicates that obesity is a typical chronic disease (not that
drug treatment is a failure).
A genetic contribution to obesity is supported by the
findings of greater similarity of body mass index (BMI) between
monozygotic vs dizygotic twins and correlation of BMI with biological
but not adoptive parents.6
In addition, low metabolic rates
have shown familial aggregation, greater similarity in monozygotic than
dizygotic twins, and correlation with weight gain and
BMI.7
Recent reviews of obesity's causes8-9 point out that
energy homeostasis is vigorously defended by multiple mechanisms whose
neuroendocrine and genetic basis are only beginning to be understood.
This redundancy in our energy stores' defense system probably explains
the refractoriness of obesity to
treatment and further justifies a
multifaceted attack on obesity including pharmacotherapy. Separate
studies suggest rising obesity in the United
States10 and
England11
is due to decreased activity and has occurred
despite less caloric intake. The genetically metabolically challenged
may, therefore, constitute a disproportionate percentage of the newly
obese. Ultimately, the recent rise in obesity must reflect nature and
nurture since the US genome could certainly not have changed to the
degree of our national girth in recent years.
The review by McGuiness and Foege12 defining
obesity and activity patterns as the second leading killer of Americans and
the report of Manson et al13 stating that 53%
of deaths in obese women (BMI >29 kg/m2) were attributable to their
obesity have drawn widespread attention to obesity's health risks. In men
similar increases in cardiovascular14 and cancer15 deaths have been attributed to obesity. While controversy
about a "J-shaped" bodyweight vs mortality curve has persisted, recent studies
controlling for smoking status and early death caused by preexisting disease
find this relationship to be linear.13-14
In addition to the well-known association of obesity with elevation of traditional
cardiac risk factors (blood pressure, cholesterol level), obesity also contributes
to emerging cardiac risk factors including endothelial dysfunction,16 hyperinsulinemia, and elevated C-reactive protein.17 The cost of treating the 50% to 80% of US cases of
diabetes mellitus attributable to obesity has been estimated at $10 billion
annually.18 Obesity-associated respiratory
illnesses include asthma, sleep apnea, pickwickian syndrome, and pulmonary
hypertension. Adenocarcinoma of the esophagus and gastric cardia,19 hepatic necrosis, and cirrhosis20
have recently shown strong correlations with obesity, joining increased rates
of cholecystitis, colon cancer, reflux esophagitis, and gastroesophageal reflux
disease on the traditional list of gastrointestinal tract complications of
obesity. Obesity may be the most potent risk factor for incident knee osteoarthritis21 and is a major cause of Social Security Insurance
disability claims.18 Obesity-associated pulmonary
embolism is likely an underreported source of obesity-related death since
obesity conferred a relative pulmonary embolism risk of 3.4 in the Nurses
Health Study22 and almost 120 000 deaths
per year are only attributed to pulmonary embolism after autopsy.23
The widely publicized failure of traditional diet and behavioral therapies
in sustaining weight loss continues to provide impetus for obesity pharmacotherapy.
In the 6 US studies providing at least 2.5-years' follow-up of traditional
(ie, dietary ± behavioral) obesity treatments, weight regain was 61%
to 86% at 2.5 to 3.5 years24-27
and 75% to 121% at 5 years.28-29
These low rates of maintained weight loss are certainly overestimates of the
response of the average patient since data are reported only for the fraction
of patients (54%-83%) available and willing to participate in follow-up surveys.
MECHANISM OF ACTION
With the exception of orlistat, which blocks absorption of ingested
fat by inhibiting pancreatic lipase, available weight loss drugs work by suppressing
appetite through central mechanisms and possess no significant thermogenic
abilities. Anorectics are classified as noradrenergic (ie, phentermine, mazindol,
or diethylpropion hydrochloride) or serotonergic (ie, fenflurmine, dexfenfluramine,
or fluoxetine hydrochloride) depending on which neurotransmitter they primarily
effect. Sibutramine hydrochloride is a serotonin norepinephrine reuptake inhibitor
effecting both serotonin and norepinephrine reuptake. Detailed reviews of
the mechanisms and sites of action of available and future anorectics are
presented elsewhere.30-31
STUDY SELECTION: STUDIES OF LONG-TERM OBESITY PHARMACOTHERAPY
Available long-term studies of obesity pharmacotherapy were identified
through MEDLINE and bibliographic review of published articles. For this discussion,
long-term studies are defined as including 9 months or more of treatment.
While selected shorter or open-label studies are cited, only long-term, double-blind,
placebo-controlled trials are considered in the comparative analysis. Since
results in subjects with diabetes mellitus may differ from the broader patient
base, trials limited to diabetic patients are reviewed but excluded from the
comparative analysis. With the exception of orlistat, which has data on 742
patients treated for at least 1 year, existing long-term studies on available
weight loss drugs contain data on fewer than 300 patients in aggregate.
NORADRENERGIC WEIGHT LOSS DRUGS
While older-generation noradrenergic appetite suppressants are approved
for obesity treatment in the United States, obesity experts agree that these
schedule II (eg, amphetamine-dextroamphetamine and methamphetamine) and schedule
III drugs (eg, benzphetamine hydrochloride and phendimetrazine tartrate) have
no current appropriate role in obesity treatment given the availability of
newer anorectics (schedule IV) with negligible addiction or abuse liabilities.
With the exception of 1 drug company's recent efforts to resurrect phendimetrazine
for obesity treatment, the older anorectics have appropriately received little
advertisement or use.
Diethylpropion
Introduced in 1960, diethylpropion is available as Tenuate, 25 mg (usually
taken 3 times daily) or Tenuate Dospan, 75 mg (extended release, once daily).
In the longest double-blind, placebo-controlled diethylpropion study,32 weight loss at both the 6- and 12-month follow-ups
was less in the drug-treated patients than in the placebo-treated patients
at 7.0 vs 8.7 kg and 8.9 vs 10.5 kg, respectively. In separate shorter placebo-controlled
trials, DeRamos33 and McKay34
reported weight loss after 6 months of diethylpropion treatment to be 7.8
and 11.7 kg, respectively, compared with 1.9 (P>.05)and
2.5 kg (P<.01) in placebo-treated patients. Overall,
data for long-term diethylpropion treatment are limited to 30 patients at
6 months and 5 patients at 12 months. Although it may have the least stimulant
adverse effects among the noradrenergic agents,31
a relatively rapid tolerance to its anorectic effects has been observed35 while weight loss beyond 6 months has not.
Mazindol
While mazindol's pharmacological and anorectic actions (ie, inhibition
of norepinephrine reuptake) resemble other noradrenergic anorectics, structurally
it is related to the tricyclic antidepressants and lacks the phenylethylamine
structure of the other noradrenergic anorectics and the fenfluramines. In
patients with stable cardiac disease, mazindol treatment has been associated
with untoward cardiac events (3 episodes of atrial fibrillation and 2 of syncope
in 15 patients receiving mazindol for 12 weeks)36
and significant withdrawls owing to adverse effects.37-38
The longest report of mazindol treatment was an open-label observation in
which 11 patients treated intermittently for 12.5 months with mazindol, 1
mg/d, lost 14 kg (P<.05) compared with a loss
of 10 kg in a historical control group treated with diet alone.37
Other long-term data on mazindol are limited to an uncontrolled observation
of 12-kg weight loss with 60 weeks' treatment and a higher rate of maintained
weight loss for 1 year following a very-low-calorie diet with (53%) than without
(20%) mazindol treatment.38 Overall, mazindol's
efficacy has not been assessed in a long-term, blinded, placebo-controlled
trial and its safety in cardiac patients is suspect.
Phentermine
Phentermine, the still available "phen" of the recent "phen-fen" phenomenon,
has been available since the 1960s with a worldwide exposure of more than
50 million prescriptions. It is available in a timed-release resin under the
brand name Ionamin (15 or 30 mg) or a more quickly released hydrochloride
form (15, 30, or 37.5 mg) in various brands and generic form. In the only
long-term, double-blind, placebo-controlled phentermine study, 108 obese women
were assigned to receive placebo, continuous phentermine (30 mg/d of phentermine
resin), or intermittent phentermine (4 weeks receiving phentermine therapy
and 4 weeks not receiving phentermine therapy) for 36 weeks.39
Nondrug treatment in this study was limited to a single dietary instruction
in a 1000-kcal diet at study initiation and monthly clinic visits for weigh-ins
and prescription renewals. Weight loss was significantly greater (P<.001) in patients treated with continuous (12.2 kg) or intermittent
phentermine (13.0 kg) than with placebo (4.8 kg). Adverse effects were minor
with only 8% of the drug-treated patients and 3% of placebo-treated patients
leaving because of perceived stimulant adverse effects such as agitation or
insomnia. As with virtually all other studies of obesity pharmacotherapy,
most weight loss occurred in the first 6 months. However, in contrast to the
weight regain that has been observed despite continued pharmacotherapy with
sibutramine40 and fluoxetine41
after 6 months, phentermine-treated patients in this study continued with
a slower rate of weight loss between months 6 and 9.
While no other long-term, placebo-controlled data are available for
phentermine, several shorter double-blind placebo-controlled studies corroborate
the efficacy of phentermine observed in the study by Munro et al.39 In what could be termed the "other" phen-fen study,
Weintraub et al42 compared weight loss in patients
treated with placebo, phentermine, fenfluramine, or the phen-fen combination
for 5 months. Weight loss with phentermine in this study was 11.3 kg (P<.01 vs placebo) nearly identical to the 11.2-kg loss
seen with phentermine at 5 months in the study by Munro et al. In this only
published comparison of phen-fen with any other regimen, patients receiving
phentermine monotherapy actually lost more weight than those receiving the
phen-fen combination (11.3 vs 9.3 kg, P>.05). In
a shorter 4-month trial,43 weight loss in phentermine-treated
patients (8.8 kg, P<.01 vs placebo) was consistent
with weight loss at the 4-month mark in phentermine-treated patients in the
studies by Munro et al39 (10.4 kg) and Weintraub
et al42 (9.2 kg). In a double-blind comparison
of 5 different regimens of phentermine and/or fenfluramine, Steel and Munro44 reported 9-month weight loss in phentermine-treated
patients to be essentially the same (eg, 12.0 kg) as that seen in the Munro
et al39 prior 9-month study. While no placebo
group was used in the Steel and Munro44 study,
the placebo group from the Munro et al study could reasonably serve as historical
controls since both studies originated from the same research department and
seem to have used the same nondrug treatments. Phentermine adverse effects
in the comparative trial were low, with only 1 patient (3%) withdrawing because
of phentermine adverse effects compared with 11 withdrawals (8%) because of
perceived fenfluramine adverse effects.
Overall, available data suggest that phentermine is well tolerated and
efficacious. Comparative studies suggest that its efficacy exceeds monotherapy
with the fenfluramines42, 44 and
is comparable to combination therapy with phen-fen.42
Sibutramine
Sibutramine is a serotonin norepinephrine reuptake inhibitor, blocking
the reuptake of norepinephrine and serotonin. Since its appetite suppression
is completely reversed by adrenergic blockade45
and pure selective serotonin reuptake inhibitors (SSRIs) have been shown not
to produce long-term weight loss,41 sibutramine's
weight loss effects are primarily mediated by its noradrenergic action. Sibutramine
is dispensed as Meridia and given at 10 or 15 mg/d, doses shown in a large
dose ranging study to optimize weight loss vs adverse effects.46
Long-term data on sibutramine for initial weight loss are from a 1-year
trial comparing sibutramine at 10 or 15 mg/d to placebo in 485 patients.40 The published results gave few details of any supportive
treatments. Weight loss at 1 year was 1.8 kg in the placebo-treated group
and 4.8 kg and 6.1 kg in the 10- and 15-mg sibutramine-treated groups, respectively
(P<.001). Sibutramine was well tolerated with
57% of the 173 patients initially assigned to sibutramine therapy completing
the study and an overall withdrawl rate of 13% because of adverse effects.
In the other long-term sibutramine study, 160 patients who had been
successful in losing at least 13 lb (5.85 kg) on a 4-week very-low-calorie
diet were given placebo or 10 mg/d of sibutramine for 1 year.47
While providing valuable long-term data, this study is not comparable with
others cited thus far because of 2 opposing selection biases. First, the study
enrolled only patients who were already successful in losing weight on a low-calorie
diet and may, therefore, have been more motivated and success prone than patients
enrolled in other drug studies. Second, the usual tendency of patients to
rapidly regain weight after rapid weight loss may have made it tougher for
patients to lose more weight with or without medications. With these factors
in mind, a significant positive effect of sibutramine therapy was noted at
1 year. After 1 year, the 81 sibutramine-treated patients had lost an average
of 5.2 kg (in addition to the weight they had lost during the 4-week prestudy
diet) compared with an average gain of 0.5 kg in placebo-treated patients
(P = .004). Sibutramine was well tolerated with 73%
of the sibutramine-treated patients completing the full year of treatment
compared with 62% of the placebo-treated patients. The number and type of
adverse events were similar in both patient groups with only 2 sibutramine-treated
and 5 placebo-treated patients actually withdrawing from the study owing to
perceived adverse effects.
Overall, sibutramine has demonstrated effectiveness in producing weight
loss in its 1-year studies. While it is generally well tolerated, its effects
on heart rate (average increase of 3-4 beats/min) and blood pressure (average
increase of 2 mm Hg) may be more than other noradrenergic anorectics.48
Orlistat
Orlistat received Food and Drug Administration (FDA) approval for obesity
treatment April 23, 1999, making it the newest of the available weight loss
drugs. While it also inhibits gastric and carboxylester lipases, its inhibition
of pancreatic lipase is responsible for its therapeutic action of blocking
the absorption of approximately 30% of ingested fat calories.49
Orlistat is available only as Xenical (Hoffmann-LaRoche Inc, Nutley, NJ) and
is given at 120 mg 3 times daily, the dose determined to maximize the benefit-adverse
effects ratio in separate dose ranging studies.49-50
In patients having type 2 diabetes mellitus, 1 year of orlistat treatment
produced a 1.9% greater weight loss (eg, 6.2% vs 4.3%, P<.001) than placebo.51 Long-term
data for weight loss with orlistat in nondiabetic subjects is from 2 multicenter,
randomized, double-blind, placebo-controlled, 2-year trials.52-53
The first (European) study of these compared weight loss in 340 placebo-treated
patients with 343 patients receiving orlistat, 120 mg 3 times daily.52 Supportive treatment of both groups was dietary instruction
(600 kcal/d–deficit for year 1 with eucaloric maintenance in year 2)
and monthly clinic visits. One-year weight loss for orlistat-treated patients
was 10.3 kg compared with 6.1 kg (P<.001) in placebo-treated
patients. At the conclusion of year 1, patients were randomly reassigned to
medication or placebo for year 2. During year 2, patients switched from placebo
to orlistat lost an additional 0.9 kg while patients continuing to take orlistat
regained aproximately 25% of the weight lost during year 1. Six gastrointestinal
tract adverse effects occurred in at least 10% of the orlistat-treated patients
and more frequently than with placebo; oily stool, 31% vs 5%; increased defecation,
20% vs 7%; oily spotting, 18% vs 1%; soft stool, 15% vs 9%; liquid stools,
13%vs 10%; and fecal urgency, 10% vs 3%. Completion rates were high with 83%
of the orlistat-treated group and 76% of the placebo-treated group finishing
1 year of treatment.
The similar US multicenter orlistat trial yielded nearly identical results
with a 1-year weight loss of 8.8 kg in 657 orlistat-treated patients compared
with 5.8 kg in 223 placebo-treated patients (P<.001,
intent-to-treat analysis).53 At the end of
year 1, orlistat-treated patients were randomly reassigned to placebo or orlistat
at 60 or 120 mg, 3 times daily, while placebo-treated patients continued receiving
placebo. During year 2, weight regain occurred in all 3 patients groups receiving
orlistat for year 1 but was less (P<.001) for
those receiving 120 mg of orlistat ( 3.2 kg, 35%), than for those receiving
either 60 mg of orlistat (4.3 kg, 51%) or placebo (5.6 kg, 63%).
The concern about a possible association of orlistat with breast cancer
that postponed FDA approval of orlistat was addressed in the US study during
which 3 orlistat-treated patients (0.54%) and 1 placebo-treated patient (0.51%)
developed breast cancer. In contrast to the evidence implicating adiposity
in breast cancer risk,54 a mechanism for an
orlistat–breast cancer association is difficult to propose in light
of its negligible systemic absorption55 and
lack of demonstrated carcinogenic or estrogen-stimulating effects.56 Because of its inhibition of fat absorption, concerns
about deficiencies in fat-soluble vitamins during orlistat treatment were
addressed by both multicenter studies. Small decreases in vitamins D and E
reached statistical significance in the US trial only while mean levels of
these vitamins remained in the reference range in both studies. Vitamin supplements
were required in 14.1% of the orlistat-treated and 6.5% of placebo-treated
patients in the US study with restoration of normal levels in every case.
The manufacturer recommends that patients taking orlistat use a multivitamin
containing the fat-soluble vitamins once daily at least 2 hours prior to an
orlistat dose.
Overall, in 2 of the largest and most well-designed trials of obesity
pharmacotherapy to date, orlistat has been shown to induce 1-year weight loss
of 3 to 4 kg in excess of placebo. Adverse effects are virtually limited to
the gastrointestinal tract because of its low absorption with adverse gastrointestinal
events leading to the withdrawal of 9.0% and 3.5% of patients from the European
and US studies, respectively.
SEROTONERGIC WEIGHT LOSS DRUGS
Selective Serotonin Reuptake Inhibitors
Fluoxetine and sertaline hydrochloride have both been studied for long-term
weight loss with neither drug receiving FDA approval for obesity treatment.
A 655-patient, 8-week dose ranging study showed that the 60-mg/d dose of fluoxetine
hydrochloride was optimal for weight loss, producing a 4.0-kg loss vs 0.6
kg (P<.001) in placebo-treated patients.57 The long-term data of fluoxetine for weight loss
in nondiabetic patients consist of a multicenter US trial by Goldstein et
al58 in which drug treatment produced no weight
loss at 1 year. Maximal weight loss in both groups occurred at 20 weeks and
was modestly greater in the fluoxetine-treated group (5.1 vs 2.4 kg, P<.05). However, weight regain from that point forward
was significantly faster in the fluoxetine-treated group with 52-week weight
loss in the fluoxetine-treated and placebo-treated groups being 1.7 kg and
2.1 kg, respectively. Separate analysis of data from the participating centers
showed a significant weight loss with fluoxetine treatment at only 1 of the
10 sites, possibly because of greater emphasis on a walking regimen.59 It is difficult to attribute lack of fluoxetine effect
at the other 9 sites to factors other than fluoxetine itself since the patients
enrolled and the supportive treatments used in this study were similar to
studies in which other anorectic agents did produce significant weight loss
at 1 year. Other long-term data on fluoxetine for weight loss is limited to
2 studies in subjects with diabetes mellitus showing a small advantage in
weight loss of 2 to 3 kg (P<.05) at 9 to 12 months
of fluoxetine treatment.60-61
The remaining data on SSRIs for long-term weight loss consist of a study of
sertaline hydrochloride, 200 mg/d, given to patients for 1 year to maintain
weight loss after an initial very-low-calorie diet.62
Sertaline-treated patients regained 70.9% of their lost weight vs a 46.5%
regain in the placebo-treated group (P<.05). Overall,
the modest anorectic effects of SSRIs seem to wear off after about 5 months
with no weight loss remaining at 1 year.
Nonselective Serotonin Reuptake Inhibitors
In addition to blocking synaptic reuptake of serotonin, the nonselective
serotonergic weight loss drugs fenfluramine and dexfenfluramine stimulate
serotonin release both in the central nervous system and from its major peripheral
storage pool in platelets and can directly stimulate serotonin receptors.63-65 Although they are
no longer available, a brief look at the long-term studies with fenfluramines
is necessary to dispel the common misconceptions and lamentations that fenfluramines,
particularly their combination with phentermine (ie, phen-fen), were so uniquely
effective that obesity pharmacotherapy ceased to be worthwhile after their
removal from the market. Long-term data on fenfluramine is limited to an open-label,
1-year observation in which 176 fenfluramine-treated patients lost 8.2 kg
vs 4.5 kg (P value not reported) in patients treated
with diet alone.66 Long-term data on dexfenfluramine
come mainly from the INDEX study, a double-blind, placebo-controlled trial
in which 256 patients completing 1 year of dexfenfluramine treatment lost
9.8 kg vs 7.2 kg (P<.001) in the placebo-treated
group.67 A smaller placebo-controlled trial
of dexfenfluramine showed a similarly small (eg, 2.7 kg) and nonsignificant
increment in weight loss from 1 year of dexfenfluramine treatment.68
Combination Therapy
Long-term, double-blind, placebo-controlled data on the initial treatment
of obesity with phen-fen is limited to weeks 0 to 34 of the multiphase 190-week
long-term weight control study.2 Weight loss
was 14.2 kg in the 58 phen-fen–treated patients vs 4.6 kg (P<.001) in the placebo-treated group.
Efficacy of Obesity Pharmacotherapy
Figure 1 shows the weight
loss attributable to diet drugs in all long-term, double-blind, placebo-controlled
trials to date. In general, the lower the study completion rate, the more
reported weight loss may overestimate results for the average patient since
study completers are generally those who have lost the most weight. To highlight
weight loss attributable to the drugs themselves, weight loss is reported
as weight lost in excess of placebo. Percentage weight loss may be a better
estimate of comparative efficacy than absolute weight loss as it controls
for the tendency of heavier patients to lose more weight than lighter patients.
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Graphs show weight loss using diet drugs (A) and the percentage of
weight loss using diet drugs (B). N indicates the total number of patients
completing drug treatment for the referenced trials; percentage, the completion
rate for patients assigned to drug treatment in the referenced trials; and
the asterisk, P<.001 vs placebo. See "References"
section for research study source.
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While available data do not permit definitive comparisons, phentermine
resin seems to be the most effective available agent. The apparent weight
loss advantage of phen-fen over phentermine in Figure 1 is mitigated by the slightly greater weight loss with phentermine
monotherapy in the only head-to-head comparison of the 2 regimens.42 Sibutramine may have a small efficacy edge over orlistat
with both of these agents being comparable to, or slightly more effective
than, the discontinued dexfenfluramine.
Comparative Cost-effectiveness
Currently phentermine resin, sibutramine, and orlistat are the only
drugs approved for obesity treatment in the United States that have demonstrated
efficacy in long-term, double-blind, placebo-controlled studies. Their comparative
cost efficacy is summarized in Table 1.
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Comparative Cost Efficacy of Available* Weight Loss Drugs
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SAFETY OF OBESITY PHARMACOTHERAPY
Valvular Heart Disease
On September 15, 1997, the fenfluramines were voluntarily withdrawn
from the market. That action resulted from an FDA survey of reports from several
independent sites showing asymptomatic valve abnormalities in 32% of 271 phen-fen
users and the report by Connolly et al69 of
24 cases of symptomatic valvular heart disease associated with phen-fen use.
Subsequent reports have clarified the prevalence, incidence, mechanism, and
natural history of the effects of these medications on heart valves.
Prevalence of Valvular Regurgitation in Uncontrolled Surveys
In the original FDA survey a case of valvular regurgitation attributable
to anorectic use was defined as at least mild aortic regurgitation (FDA AR)
and/or at least moderate mitral regurgitation (FDA MR) since these levels
of regurgitation were present in only 1% of the healthy adults aged between
23 and 35 years in the large CARDIA study.70
In uncontrolled surveys, this FDA case definition may overestimate the risk
of valvular regurgitation attributable to anorectic use since patients in
these surveys had a mean age of 48 years where the background prevalence of
valvular regurgitation is likely severalfold higher than the CARDIA study's
younger reference population.
Since the original FDA survey, 4 additional uncontrolled surveys provide
data on the prevalence of echocardiographic findings associated with anorectics.
Burger and Sherman71 noted that the finding
of FDA AR in 6.6% of 226 phen-fen– treated patients in their survey
was similar to the prevalence in like-aged normal offspring of the Framingham
study. Kancherla et al72 reported an FDA AR
prevalence of 12% in 200 consecutive patients referred after having used phen-fen
or dexfenfluramine for an average of 8 months. Teramae et al73
reported FDA valvulopathy in 60 (31%) of 191 patients referred to Mayo Clinic
because of anorectic use. A much smaller survey found FDA AR in 10 of 22 phen-fen
users.74
Prevalence of Valvular Regurgitation in Case-Controlled Studies
Six case-control studies compared the prevalence of FDA AR and FDA MR
in a total of 3505 patients receiving a fenfluramine with (n = 1557) or without
(n = 1672) phentermine to that in 2017 generally well-matched control patients.75-80
In the 5 of these studies containing separate data on FDA AR and FDA MR,75-79
4 reported FDA AR to be significantly more prevalent in patients (6.3%-25.0%;
weighted average, 8.8%) than in controls (1.6%-4.1%; weighted average, 3.5%).75-78 In
contrast, FDA MR was not significantly more common in patients than in controls
in any of those reports. Much of the variability in FDA AR prevalence between
studies75-76 and between treatment
groups within studies80 can be attributed to
differences in duration of drug exposure. In the most vigorous analysis to
date of the effect of exposure duration on FDA AR, Jollis et al76
reported the prevalence of FDA AR as 4.4% for 0- to 6-months' exposure(relative
risk, 1.5; P>.05; n = 314), 7.0% for 6 to 12 months'
(relative risk, 2.4; P = .002; n = 420), 13.7% for
12 to 24 months' (relative risk, 4.6; P<.001;
n = 317) and 17.4% for longer than 24 months' (relative risk, 6.2; P<.001; n = 86).76
Incidence of Valvular Regurgitation
Two reports provide information on the incidence of FDA AR or FDA MR
in patients with echocardiograms before and after diet drug use. Wee et al81 described 46 patients who had echocardiograms done
before (average, 1.9 years) and after (average, 6 months) using a fenfluramine
for a mean of 160 days. The lone case of new FDA AR or FDA MR was a 66-year-old
man who developed moderate FDA AR (not seen on a prior study 9 years earlier)
after 402 days of phen-fen use. While the prevalence of FDA valvulopathy was
8.3% among phen-fen users, use of the methodologic advantage of the cohort
design to exclude patients with FDA AR or FDA MR on pretreatment echocardiograms
gave a rate of 2.6% for incident FDA valvulopathy. Ryan et al82
reported new FDA AR in 13 (12 patients with mild FDA AR and 1 with moderate
FDA MR and FDA AR) of 86 patients with a longer fenfluramine exposure averaging
13.8 months.
Clinical Cases
Available data strongly suggest that clinically important valvular disease
caused by the use of anorectics is rare. The above prevalence studies in more
than 3500 patients consistently report a rare prevalence of FDA AR greater
than mild, and rare or 0 prevalence of FDA AR greater than moderate. Three
of the case-control prevalence studies contained specific comments on clinical
valve disease in their patients (N>2800) and noted no clinically significant
valvulopathy.75-76,79
In the most rigorous published search to date for anorectic-associated clinical
valvulopathy, Jick et al83 used a national
UK database identifying almost 10 000 anorectic-exposed patients. New
cases of symptomatic valvulopathy were identified in 8 of 8903 patients exposed
to dexfenfluramine or fenfluramine and 0 of 862 phentermine users. Reported
symptoms were chest pain or angina in 3 patients, and fatigue, dyspnea, syncope,
and palpitations in 1 patient each. Surgical cases and congestive heart failure
were absent and the degree of valvular regurgitation was not specified.
Apart from isolated case reports, published data on symptomatic or surgical
cases of anorectic-associated valvulopathy are preponderantly from the Mayo
Clinic. In May 2000, Mayo Clinic researchers reported an update72
of the August 1997 findings by Connolly et al69
that reported 24 symptomatic (5 surgical) cases of anorectic-associated valvulopathy.
That update included patients referred between June 1997 and December 1997,
and identified a total of 92 symptomatic and 5 surgical patients. Twenty of
the 24 patients (not specified as surgical or symptomatic) from the original
report were included in the update. Given the relatively short 12-month interval
from anorectic initiation to symptomatic valvulopathy in the initial report
by Connolly et al, the scarcity of reported symptomatic or surgical cases
now 2 years after the fenfluramines recall is reassuring. In addition, case
reports84-85 and the lower prevalence
of FDA AR or FDA MR in prevalence studies with a longer elapsed time between
anorectic cessation and echocardiography77
suggest that the natural history of anorectic valvulopathy is regression.
The relatively few clinical cases to date are, therefore, more likely to be
the majority that will be detected rather than the tip of the iceberg.
Mechanism
A serotonergic mechanism for anorectic valvulopathy was strongly suggested
as early as the initial report by Connolly et al.69
Specifically, endocardial fibroplasia seen in heart valves removed from anorectic-exposed
patients was described as indistinguishable from the pathologic changes unique
to carcinoid syndrome (serotonin excess) and ergotamine toxic reactions (serotonin-agonist
effect86). Unlike other anorectics, the fenfluramines
have shown serotonin agonist effects.63-65
These agonist properties, rather than their serotonin (5-hydroxytryptamine)-releasing
or reuptake inhibition effects, are likely primarily responsible for their
demonstrated effects on the aortic valve since circulating serotonin is rapidly
metabolized in the lungs. Recently, the fenfluramine metabolite norfenfluramine
showed a high affinity for serotonin receptors (5-HT2) that are highly expressed
in heart valves and whose stimulation is known to cause fibroblast hyperplasia.87 The serotonin-agonist hypothesis of anorectic-induced
valvulopathy would also explain the lack of valve abnormalities in patients
treated with SSRIs,88 serotonin norepinephrine
reuptake inhibitors (sibutramine),89 and phentermine
monotherapy.73, 83 In terms of
causality, anorectic valvulopathy is, therefore, reminiscent of primary pulmonary
hypertension where physiologic,90-91
pathologic,92-93 and epidemiological94 studies support a serotonergic mechanism and causal
role for fenfluramines but not phentermine.
COMMENT
Pharmacotherapy Fundamentals
Available data can support the practitioner in an evidence-based approach
to long-term obesity pharmacotherapy. While weight loss attributable to medications
is modest (Figure 1), this degree
of weight loss is associated with important health and psychological benefits.95-98 In
consideration of recent studies relating BMI to morbidity and mortality, there
is general agreement that patients with a BMI exceeding 27 kg/m2
with complications or a BMI exce |
