Treatment of Obesity International Textbook of Diabetes Mellitus, Third Edition Arne Astrup in

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Treatment of Obesity
Arne Astrup
in
International Textbook of Diabetes Mellitus, Third Edition
Editors-in-Chief
R A DeFronzo, E Ferrannini, H Keen and P Zimmet
c
John Wiley & Sons, Ltd., Chichester, 2004
36
Arne Astrup
The Royal Veterinary and Agricultural University, Frederiksberg, Denmark
INTRODUCTION AND OVERVIEW
The epidemic of type 2 diabetes is due to environmental
factors, but the individuals developing the disease have
a strong genetic predisposition. A number of recent observational surveys and intervention studies have shown
that excess body fatness is the major environmental cause
of type 2 diabetes, and that even a minor weight loss can
prevent its development in high-risk subjects. Randomized trials using diet, weight loss agents, or surgical treatment of obesity have all clearly demonstrated that fat loss
per se is crucial, whereas diet composition and physical
activity play a minor role in improving insulin resistance
and reducing the risk of overt diabetes. Weight loss improves glycemic control in type 2 diabetic patients and has
a clinically relevant beneficial effect on all cardiovascular
risk factors. Weight management programs are therefore a
cornerstone in both the prevention and treatment of type 2
diabetes. A weight loss of 5–10% can be induced in almost
all simple and diabetic obese patients, provided treatment
is offered by a professional team consisting of a physician
and dieticians or nurses trained to focus on weight loss and
maintenance. Although increasing daily physical activity
and regular exercise does not significantly affect the rate
of weight loss in the induction phase, it plays an important
role in the weight maintenance phase due to an important
impact on daily energy expenditure and also to a direct enhancement of insulin sensitivity. Weight loss drugs have a
role in patients in whom the lifestyle treatment is insufficient to produce the required weight control, and in obese
subjects drugs like orlistat and sibutramine may both produce weight loss and reduce the risk of complications of
obesity, such as type 2 diabetes. In obese individuals with
impaired glucose tolerance (IGT), metformin and orlistat
reduce the risk of developing type 2 diabetes, and in type 2
diabetic patients the drugs produce weight loss, improved
glycemic control, and beneficial effects on cardiovascular
risk factors. Bariatric surgery is a very effective means to
produce a longer lasting weight loss, and may be an option in the severely obese patients who are difficult to treat
with the other weight management tools.
PRINCIPLES TO ACHIEVE DIET-INDUCED
WEIGHT LOSS
In almost every overweight and obese patient the diet must
be adjusted to reduce energy intake. Dietary therapy consists of instructing patients on how to modify their dietary intake to achieve a decrease in energy intake while
maintaining a nutritionally adequate diet. Obese patients
have, because of their enlarged body size, higher energy
requirements for a given level of physical activity than
their normal-weight counterparts (Figure 1). Obese diabetic patients have slightly higher energy requirements
than simple obese patients for a given body size and composition. Reducing the obese patient’s total energy intake
compared to that of a normal-weight individual will inevitably cause weight loss, consisting of about 75% fat
and 25% lean tissue, until weight normalization occurs at
a new energy equilibrium [1, 2]. For patients with class I
obesity this requires an energy deficit of 300–500 kcal/day,
and for patients with class III obesity, 500–1000 kcal/day.
There is no evidence to support that differences in diet
composition exert clinically important effects on energy
absorption and energy expenditure, and so the main mechanism of weight-reduction diets is to reduce total energy
intake. This can be achieved by setting an upper limit
for energy intake. The larger the daily deficit in energy
balance, the more rapid the weight loss. A deficit of
International Textbook of Diabetes Mellitus, Third Edition. Edited by R. A. DeFronzo, E. Ferrannini, H. Keen, and P. Zimmet.
c 2004 John Wiley & Sons, Ltd. ISBN: 0-471-48655-8.
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Obesity
Figure 1 Energy expenditure (energy requirements) of normal
weight, overweight, and obese subjects. Relationship between
body weight and energy requirements assessed by measurement
of energy expenditure or by apparent energy intake during weight
stability. The growing underreporting with increasing body fatness makes the self-reported energy intake invalid for estimation
of energy requirements in obese patients
300–500 kcal/day will produce a weight loss of 300–
500 g/week, and a deficit of 500–1000 kcal/day will produce a weight loss of 500–1000 g/week [1]. Greater initial
energy deficits may produce even larger weight loss rates.
Total energy expenditure declines and normalizes along
with weight loss, and total energy intake should therefore gradually be further reduced to maintain the energy
deficit. An alternative approach is to take advantage of the
differences in the satiating power of the various dietary
components in order to cause a spontaneous reduction in
energy intake. This is the principle of the ad libitum lowfat diet.
Choosing the Dietary Deficit
Initially, the target of a weight loss program should be to
decrease body weight by 10% [1–4]. Once this is achieved
a new target can be set. Patients will generally want to
lose more weight, but it should be remembered that even a
5% weight reduction improves risk factors and risk of comorbidities. However, several factors should be taken into
consideration, e.g. the patient’s degree of obesity, previous weight loss attempts, risk factors, comorbidities, and
personal and social capacity to undertake the necessary
lifestyle changes. To prescribe a diet with a defined energy deficit, it is necessary to estimate the patient’s actual
energy requirements. It would seem natural to estimate
the patient’s habitual energy intake from self-reported diet
registration over 3–7 days of weight stability, calculating
the energy content of the diet by use of food table programs. However, these estimates are invalid because of
systematic underreporting by obese individuals of energy
intake amounting to 30–40%. Energy requirements should
therefore be assessed indirectly by estimation of total energy expenditure. Resting metabolic rate (RMR) can be
measured by indirect calorimetry, or be estimated with
great accuracy using equations based on body weight,
gender, and age [5] (Table 1) or, even better, estimated
from information on the size of fat-free mass and fat mass
[6]. Total energy expenditure (=energy requirement) is
estimated by multiplication of RMR (kcal/day) by an activity factor (PAL, physical activity level) [5] (Table 1).
The energy level of the prescribed diet is defined as the
patient’s energy requirement minus the prescribed daily
energy deficit.
Theoretical Versus Clinical Outcome
Translating the physiologically based considerations regarding energy balance and weight loss into clinical practice requires a high degree of compliance, which can be
difficult to obtain. Weight loss results tend to be much better in clinical trials conducted in specialized clinics than
in trials conducted by nonspecialists without sufficient resources and access to auxiliary therapists (dieticians, psychologists, etc.). Compliance and adherence to the diet
are the cornerstones of successful weight loss, and are the
most complicated part of the dietary treatment of obesity.
To improve adherence, consideration should be given to
Table 1 Estimating energy needs∗
Revised WHO equations for estimating basal metabolic rate (BMR)
Men
18–30 years
=(0.0630 × actual weight in kg + 2.8957) × 240 kcal/day
31–60 years
Women
18–30 years
31–60 years
Estimated total energy expenditure = BMR × activity factor
Activity level
Low (sedentary)
Intermediate (some regular exercise)
High (regular activity or demanding job)
∗
Reproduced by permission of Handbooks in Health Care Co. [5].
Activity factor
1.3
1.5
1.7
the patient’s food preferences, as well as to personal, educational, and social factors. Great efforts should be made
to see the patient frequently and regularly.
Furthermore, long-term weight reduction is unlikely to
succeed unless the patient acquires new eating and physical activity habits. These behavioral changes should be an
integral part of the treatment program.
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Table 2 Adverse effects and complications of VLEDs
Adverse effect
Cold intolerence
Dry skin
Fatigue, dizzines, muscle cramps, headache,
gastrointestinal distress
Hair loss
Gallstones
Bad breath
Occurrence
∼50%
∼50%
10–20%
10%
10–30%
20–30%
OPTIONS FOR WEIGHT LOSS DIETS
Therapeutic obesity diets distinguish between several recognized weight reduction regimens. Low-energy diets
(LEDs) usually provide 800–1500 kcal/day and use fatreduced foods, though weight loss occurs independent of
the diet composition. Diets providing 1200 kcal/day or
more can be classified as balanced-deficits diets [4, 6],
but this definition will not be used in this chapter. Very
low energy diets (VLEDs) are “modified fasts”, providing
200–800 kcal/day that replace normal foods. Examples
of weight loss on such diets are shown in Figure 2 Ad
libitum low-fat diets do not restrict energy intake directly,
but target a restriction of ad libitum fat intake to 20–30%
of total energy intake. Energy intake is spontaneously reduced because of the higher satiating effect of this diet and
a modest weight loss occurs.
Very Low Energy Diets
Starvation (diet providing less than 200 kcal/day) is the ultimate dietary treatment of obesity, but it is no longer used
because of the numerous and serious medical complications associated with prolonged starvation [8]. Starvation
has been replaced by VLEDs (200–800 kcal/day), which
aims to supply very little energy but all essential nutrients.
Reducing the energy content of a diet requires an increased
nutrient density. This can be difficult to obtain with natural foods if the diet is to be acceptable once the energy
content of the diet becomes lower than 800 kcal/day. This
has led to the commercial production of VLEDs, supplemented with all nutrients in RDA (recommended dietary
allowance) amounts. For decades, 250–400 kcal/day formula diets were extremely popular. The first VLEDs were
clearly nutritionally insufficient, but reports of adverse effects and results from research have brought about a gradual increase in energy level. Today the 800 kcal/day VLED
is the only version recognized as being both effective and
safe [8]. A number of studies have shown that VLEDs
with energy levels of less than 800 kcal/day do not produce a greater weight loss and are less well accepted than
those comprising 800 kcal/day [9]. VLEDs usually provide a ketogenic diet with an energy content of around
800 kcal/day in the form of nutrition powders, or in the
form of protein-, mineral-, trace-element-, and vitaminenriched meals or drinks. VLEDs can induce very rapid
weight loss over a 2–3-month period (Figure 2), but do
not seem to facilitate weight maintenance [9]. This is not
because a rapid initial weight loss causes poorer long-term
weight maintenance per se [10], as initial weight losses
are positively, not negatively, associated with long-term
weight loss [11]. However, VLEDs are not educational
and do not facilitate the gradual modification of the patient’s eating behavior, nutritional knowledge, and skills,
which seems to be required for long-term weight maintenance. Some concern has been raised about the cardiac
safety of the use of VLEDs with less than 800 kcal/day
[3], and patients using VLEDs have an increased risk of
developing gallstones (Table 2). Their use without medical supervision has generally been abandoned and should
not be recommended [1, 3, 4, 8].
Low-Energy Diets
Figure 2 Weight loss in obese patients randomized to either an
LED or a VLED. Initial mean body weight was nearly 100 kg
and mean weight loss 12.6 kg in both groups. (Reproduced by
permission of the British Medical Journal [7])
LEDs usually provide 800–1500 kcal/day and normally
consist of natural normal foods. LEDs are also called traditional diets and calorie-counting diets, because previously
more emphasis was put on restricting the total energy level
of the diet and less on the macronutrient composition. Although macronutrient composition of the diet is of less
importance for short-term weight loss, it is now usually
modified in order to maximize the beneficial effect on cardiovascular risk factors and insulin resistance, and to prevent cancers, perhaps also promoting long-term weight
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Obesity
Table 3 Example of the composition of an LED
Nutrient
Calories
Total fat
Saturated fatty acids
Monunsaturated fatty acids
Polyunsaturated fatty acids
Protein
Carbohydrate
Fiber
Calcium
Other vitamins, minerals, and trace elements
maintenance. For practical reasons, LEDs are low-fat,
carbohydrate-rich diets with a fixed energetic allowance.
An example of an appropriate nutrient composition for an
LED is given in Table 3. It should be supplemented with
a daily vitamin and mineral tablet. A patient may choose
an energy level of 1000–1200 kcal/day for women and
1200–1500 kcal/day for men. LEDs produce a lower rate
of weight loss than VLEDs (Figure 2), but randomized
clinical trials demonstrate that the long-term (>1 year)
weight loss is not different from that of the LEDs [1].
Furthermore, using LEDs for weight loss induction introduces healthy eating habits early in the weight reduction
program, giving a longer period in which to familiarize the
patient with the dietary changes that are a central element
in a weight maintenance program.
Based on 34 randomized clinical trials examining the
impact of LED in obese subjects, it was concluded that
LED produces weight loss regardless of duration of treatment, and body weight was reduced by an average of 8%
over 3–12 months [1]. In trials lasting 3–6 months, and
6–12 months, LED produced mean weight losses of approximately 8% compared to controls [1]. Although they
targeted the same energy deficit there was a large variation
in mean weight loss between the studies. The variation is
less owing to differences in patient selection than to the
differences in efforts to promote a low-fat intake as a practical way to reduce energy intake, and owing to differences
in the skills and efforts of the therapeutic teams. The same
large variation exists within each cohort of patients, and
the mean weight loss of 8% corresponds to approximately
80% of the patients losing >5% and 15% losing >10%.
It is difficult to separate the impact of the dietary therapy because all trials included some elements of behavior
modification, which clearly contributed to the results.
Prognostic Markers of Weight Loss Success and
Reasons for Failure
There is considerable variation in the weight loss and
weight maintenance achieved by patients enrolled in dietary treatment programs. Some variation can be attributed
Recommended intake
500–1000 kcal/day below energy requirements
20–30% of total calories
<10% of total calories
15–20% of total calories
>55% of total calories
20–30 g/day
1000–1500 mg/day
RDA. Full coverage should be ensured by a
vitamin/mineral supplement daily
to physiological differences (RMR, age, gender, sympathetic activity) and some to differences in adherence (behavior), though combinations of and interactions between
physiology and behavior may be the major factor. This
variation is not seen from the mean weight loss of a group,
which is difficult to translate into a clinically relevant
success rate based on the intention-to-treat principle, i.e.
how large a proportion of the patients entering a treatment achieve a certain weight loss, typically >5% and
>10% of pretreatment body weight. It is difficult to identify clinically the patients who will benefit most before
treatment is initiated. Positive predictors of weight loss are
(1) high initial body weight, (2) high RMR and/or 24-h
energy expenditure, (3) high fat oxidation rate, (4) high
sympathetic activity, (5) high plasma dihydrotestosterone
concentration, and (6) high perceived self-efficacy [4, 12].
However, these factors, separately or in combination, do
not seem to explain enough of the variation to have a measurable clinical relevance.
Ad Libitum Low-Fat Diets (<30% Energy from
Fat)
Efficacy
Data from animal and experimental research, observational studies, and numerous randomized clinical trials
have shown that a high dietary fat content plays an important role in the development of obesity [13–15]. A high-fat
diet promotes weight gain and obesity in sedentary individuals with little self-restraint, who have a genetic predisposition to obesity in particular. The main mechanisms
are the passive overconsumption of energy promoted by
the high energy density of fatty foods and a reduced fat oxidation capacity in susceptible individuals. Low-fat diets
are more satiating because of the high content of complex
carbohydrates and protein. Restricting intake of dietary
fat should be seen as a means to reducing the diet’s energy density and hence restricting the patient’s total energy
intake. Unfortunately, while the effect of fat-rich foods
on weight gain and obesity is substantial, the ability of
the ad libitum low-fat, carbohydrate-rich diet to induce
weight loss is less pronounced. A systematic review of 28
ad libitum low-fat diet randomized clinical trials showed
that a weight loss of 1.6 g/day was achieved per each
percentage point reduction in energy from fat [14]. A
realistic reduction in dietary fat can result in a weight
loss of 20–100 g/week, which becomes clinically significant when the total exceeds 5% of body weight [14].
A meta-analysis of 34 ad libitum low-fat diet interventions lasting >2 months and 35 control groups found a
statistically highly significant weight loss difference of
3.3 kg [16]. The size of the weight loss was mainly determined by the reduction in dietary fat energy, but pretreatment body weight was also positively associated with the
weight loss. The analysis indicates that obese patients with
a body weight of 95 kg who reduce dietary fat from 45 to
25 energy% under ad libitum conditions will reduce energy intake and will, on average, achieve a weight loss of
7.1 kg before a new equilibrium is reached. On the other
hand, a normal-weight subject (60 kg) will loose only
0.5 kg with the same fat reduction. These weight loss predictions are probably underestimated because the analysis
relies on the reductions in dietary fat as reported by the
patients, which tend to be exaggerated. Moreover, patients
with better adherence also achieved better weight loss than
those with poorer adherence [17] (Figure 3). The systematic review [14] and the meta-analysis [16, 18] show that
ad libitum low-fat, high-carbohydrate diet have a modest
but predictable effect on weight loss. This is clinically relevant for obese patients habitually consuming a high-fat
677
diet, where an ad libitum low-fat, high-carbohydrate diet
would be 15–20 percentage points lower in energy from
fat than the habitual diet.
Safety
Under certain experimental conditions the change from
a normal-fat to a low-fat, high-carbohydrate diet has
been shown to induce hyperinsulinemia, hypertriglyceridemia, and low high-density lipoprotein (HDL) cholesterol concentrations [19, 20]. Such observations have
prompted some researchers to advocate the implementation of healthier high-fat diets, i.e. emphasizing the replacement of saturated and trans-fats with unsaturated
oils instead of with carbohydrates [20]. However, these
studies replaced fat for carbohydrate under strictly isoenergetic conditions, not allowing the spontaneous weight
loss with the accompanying beneficial changes in these
risk factors to occur as in other studies [21–23]. This was
stressed by Schaefer et al., who reduced dietary fat isoenergetically from 35 to 15% of total energy in hypercholesterolemic patients and found plasma reductions of 13%
in total cholesterol and 17% in low-density lipoprotein
(LDL) cholesterol, but a 23% decrease in HDL cholesterol. A rise of 47% in plasma triglycerides after 6 weeks
was also seen [21]. The same diet was subsequently continued for 10–12 weeks under ad libitum conditions and it
produced a mean weight loss of 3.6 kg, a further reduction
in LDL cholesterol and a normalization of HDL cholesterol to total cholesterol ratio. Improvements in other risk
factors, e.g. blood pressure [24], blood coagulation, and
fibrinolysis, occurred independent of weight loss [18, 25].
Blood lipids should be monitored in obese patients with
type 2 diabetes resistant to weight loss. This is the only
precaution currently recommended. The use of ad libitum
low-fat, high-carbohydrate diets in which carbohydrates
are mainly of the complex and fiber-rich types have not
given rise to safety concerns.
LED Versus Ad Libitum Low-Fat Diets?
Figure 3 A 5-year follow-up of a 1-year randomized controlled
trial of a reduced-fat ad libitum diet versus a usual diet. Obese
patients with IGT were randomized to a reduced-fat diet or control, and participated in monthly small-group education sessions
on reduced-fat eating for 1 year. Weight decreased significantly
in the reduced-fat-diet group; the greatest difference was noted
at 1 year (−3.3 kg), best in the most compliant group, but diminished at subsequent follow-up (∗∗ denotes differences between
low-fat and normal-fat diets). Glucose tolerance also improved
in patients on the reduced-fat diet; a lower proportion had type
2 diabetes or IGT at 1 year (47% vs. 67%). This difference disappeared in subsequent years, but the more compliant 50% of
the intervention group maintained lower fasting and 2-h glucose
c 2001
at 5 years compared to control subjects. (Copyright American Diabetes Association. From Diabetes Care, Vol 24,
2001; 619–624. Reprinted with permission from The American
Diabetes Association [17])
Ad libitum low-fat diets produce a rate of weight loss of
100–200 g/week in unselected obese patients, whereas
LEDs induce weight losses of 300–700 g/week. Four randomized clinical trials have compared LEDs (using lowfat diets) with ad libitum low-fat diets. Taken together,
these studies show that the impact of the ad libitum lowfat diets on weight loss is increased if total energy intake
is restricted to some extent [26–29].
LEDs using low-fat diets are more effective in inducing
weight loss than ad libitum low-fat diets, and they allow a
better adjustment of the reduction in energy intake. LEDs
are therefore the preferred dietary treatment for obesity.
However, in an individually tailored treatment the first
step could be to prescribe an ad libitum low-fat diet to
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Obesity
patients habitually consuming a high-fat diet, subsequently limiting energy intake if weight loss proves unsatisfactory.
Ad Libitum Low-Carbohydrate Diets (<25 g/day
Carbohydrate)
Diets that promote very low-carbohydrate intakes have
become very popular as part of a popular physiological
concept that links surges in blood glucose and insulin to
weight gain and obesity [30–32]. The Atkins’ New Diet
Revolution is the most popular and recommends a daily
intake of <25 g carbohydrates [33]. It is likely that such
a “ketogenic” diet possesses anorectic properties and produces weight loss in the short term, but it may be very
problematic in the weight maintenance phase because of
side effects, adverse effects on risk factor profile, and
an increased risk of developing type 2 diabetes in overweight and obese subjects. Very few controlled studies
testing the low-carbohydrate diet have been published.
Westman et al. found, in an uncontrolled study, that an
ad libitum low-carbohydrate diet (<25 g/day) produced a
weight loss of 10.3% over 6 months in 51 obese subjects
[34]. They also found positive changes in blood lipids and
blood pressure, but 68% of the participants experienced
constipation, probably because of the low fiber intake.
Other studies have shown that a fat-rich diet impairs the
beneficial effects of training on insulin resistance [35].
When the weight loss has subsided it is likely that the
low-carbohydrate (high-fat) diet will have very negative
effects on most cardiovascular risk factors, and despite
the weight loss, may increase insulin resistance and risk
of type 2 diabetes. Low-carbohydrate diets cannot therefore be recommended.
DIETARY WEIGHT MAINTENANCE
PROGRAMS
In professional weight loss programs LEDs induce a 5%
weight loss in almost all patients, and frequent clinical
encounters during the initial 6 months of weight reduction appear to facilitate achievement of the therapy goals.
Larger success criteria (>10% weight loss) can be met by
the majority of patients if the treatment program also includes group therapy and behavior modification. The real
challenge is to maintain the reduced body weight and prevent subsequent relapse (Figure 4). In a systematic review
of long-term (>3-year follow-up) efficacy of dietary treatment of obesity, success was defined as maintenance of all
weight initially lost or maintenance of at least 9 kg of initial
weight loss [36]. Initial weight loss was 4–28 kg, and 15%
of the followed-up patients fulfilled one of the criteria for
success, and the success rate was stable for up to 14 years
of observation. Diet combined with group therapy led to
better long-term success rates (27%) than did diet alone
Figure 4 Weight loss outcomes for obese patients treated in
weight management programs compared to predicted outcome of
continued habitual lifestyle. It is noted that even weight stability
may be a partial success and a goal in certain patients
(15%), or diet combined with behavior modification and
active follow-up, though active follow-up produced better weight maintenance than passive follow-up (19% vs.
10%).
Although the principle of energy restriction (LED) is
successful for weight loss induction independent of dietary composition, the low-fat, high-protein/carbohydrate
diet seems to be more effective for long-term weight maintenance and preventing weight regain. In a study by Toubro
and Astrup, patients were randomly assigned to two different weight maintenance groups, receiving either a low-fat
diet ad libitum or a fixed-energy diet (LED) for 1 year
after having lost a mean of 13.6 kg on energy restricted
diets [7]. There was only a small weight regain during
the weight maintenance program. However, 2 years after the weight loss the LED group had regained 11.3 kg
whereas the low-fat group had regained only 5.4 kg. Forty
percent of the patients in the LED group and 65% of the patients in the low-fat group had maintained a weight loss of
>5 kg [7].
This and other studies show that the success rate may be
improved by using the ad libitum low-fat diet for prevention of relapse, although it is not effective in all patients
[1]. Whether long-term weight maintenance failure is due
to lack of treatment efficacy or lack of compliance is unknown. Notably, the amount of time spent with the patient
and frequent contact between the professional counselors
and patients favorably affect weight maintenance.
DOES DIET COMPOSITION MATTER?
Numerous popular diet books promote changing diet compositions in accordance with principles that are claimed
to have a particularly favorable impact on weight loss and
maintenance. Generally these claims are unsubstantiated
and scientifically improbable, and some may even promote
nutritionally insufficient diets (for review see references
4 and 37). For LEDs there is little evidence to support
that weight loss may be improved by diets different from
that given in Table 2. For ad libitum diets, and for weight
maintenance diets particularly, differences in the satiating
effects of different macronutrients may have some importance.
Carbohydrate Types
The high carbohydrate content of low-fat diets stems
mainly from the complex carbohydrates of different vegetables, fruits, and whole grains, which are more satiating
for fewer calories than fatty foods and are a good source
of vitamins, minerals, trace elements, and fiber. A high
fiber content may further improve the satiating effect of
the diet and a diet rich in soluble fiber, including oat bran,
legumes, barley, and most fruits and vegetables, may be
effective in reducing blood cholesterol and blood pressure
levels. The recommended intake is 20–30 g of fiber daily.
The role of simple carbohydrates in low-fat diets remains
controversial, mainly because of the lack of proper randomized clinical trials. One large European multicenter
trial has compared two different ad libitum low-fat diets,
high in either complex or simple carbohydrates, with a
normal-fat diet. The two low-fat diets induced similar fat
loss in overweight and obese subjects over 6 months, and
the diet high in simple carbohydrates had no detrimental
effects on blood lipids [38]. However, more recent studies
suggest that a high intake of sugar from soft drinks may
have a special fattening property [39, 40].
Glycemic Index
Some scientists have warned against the fattening properties of high-GI (glycemic index) foods such as potatoes,
white bread, bagels, and rice—foods that people are otherwise advised to eat more of as part of the currently recommended low-fat diet. Instead, the public is advised to eat
more whole grain products, and types of rice and potatoes
characterized by a low GI. Although low-GI foods are
beneficial for glycemic control in diabetic patients [41]
and have a modest beneficial effect on cardiovascular risk
factors, its effect on body weight regulation is controversial [42]. The proponents of the GI hypothesis suggest that
high-GI foods produce rapid and transient surges in blood
glucose and insulin, which are in turn followed by rapidly
returning hunger sensations and excessive caloric intake
[31]. However, a recent systematic review of the different
types of studies found that of the 31 studies that measured
appetite sensations following low-GI vs. high-GI meals,
low-GI meals produced greater satiety and reduced hunger
in 15 studies, no difference was found in 14 studies, and
in 2 studies the high-GI meals produced greatest satiety.
Similarly, among the 20 longer term intervention studies
identified, 4 studies found larger weight loss and 2 studies
less weight loss on the low-GI diets, and 14 studies found
no difference [32]. It was concluded that most of the stud-
679
ies were statistically underpowered to pick up clinically
relevant differences in weight loss.
The lack of robust evidence prohibits issuing general
dietary advice that low-GI foods are preferable to highGI foods in preventing weight gain, although it appears
likely that this dietary change will have beneficial effects
on risk factors of cardiovascular disease and diabetes, and
unlikely that it will exert any adverse effects. However,
the GI concept is complicated for the patients and comprehensive tables are required in order to calculate the diet
[43]. Newer research shows that GI of meals cannot accurately be calculated by the carbohydrate source alone, but
requires information about the energy, fat, and protein contents as well [44]. There is a need for well-powered, randomized, long-term trials to show the potential for low-GI
vs. high-GI diets to produce weight loss or maintenance,
and for a more patient-friendly classification of carbohydrate foods (Figure 5).
Protein Content
A large body of experimental human data suggests that
protein possesses a higher satiating power per calorie than
do carbohydrate and fat [45]. The impact on weight loss of
replacing carbohydrate with protein in ad libitum low-fat
diets has been addressed in only one randomized clinical
trials. Two fat-reduced diets (30% of energy) with either
normal protein (12% of energy) or high protein content
(25%) were compared with a normal fat diet in 65 obese
patients. Weight loss after 6 months was 5.1 kg in the
low-protein group and 8.9 kg in the high-protein group,
and more subjects lost >10 kg in the high-protein group
(35%) than in the low-protein group (9%). The proteinrich diet had no adverse effect on blood lipids, renal function, or bone mineral density, and seems to have a positive
influence on the atherogenic risk factor profile in abdominally obese men [46]. Replacement of some dietary
carbohydrate by protein in ad libitum low-fat diets may
improve weight loss. More freedom to choose between protein-rich and complex-carbohydrate-rich foods
may encourage obese subjects to choose more lean meat
and dairy products and hence improve adherence to lowfat diets in weight reduction programs. Increased protein
allowances in weight reduction diets should await confirmation of these results by other studies. The study results do not endorse the dietary principles promoted in
recent popular diet books advocating high-protein, lowcarbohydrate diets [47].
Fat Quality and High-Monounsaturated-Fat Diets
Although similar amounts of different fats contain nearly
the same amount of energy, differences may exist in their
satiating effects, which could influence total energy intake
of ad libitum low-fat diets and weight maintenance diets.
680
From a biochemical and physiological view saturated fatty
acids behave very differently from monounsaturated fats
(MUFA), which seem to be more neutral than other fats in
relation to cardiovascular disease, insulin resistance, and
cancer. However, animal studies suggest that MUFA increase body weight more than polyunsaturated fatty acids
(PUFA) do [48]. In a cross-sectional, observational study
in 128 males the highest positive correlation was found
between the intake of MUFA and body fat mass, whereas
no significant association was found between PUFA and
body fat, and only a weak association to saturated fat was
seen [49]. Two experimental appetite studies have concordantly shown that meals/infusions with MUFA produce
lower satiety, and that they suppress energy intake for the
remainder of the day less than PUFA [50, 51]. These preliminary reports suggest that a high MUFA content in the
diet may promote passive overconsumption and obesity.
Two randomized trials have compared diets moderate in
fat, high MUFA, with low-fat diet. The first trial failed to
find any difference in weight loss after 18 months [52].
However, in this study, both groups were on energy restriction, the study was small, and it had a large dropout
rate in the low-fat group. The other study randomized 257
obese subjects with IGT to ad libitum diets of reducedfat, high-carbohydrate with either high- or low-GI, or a
third normal-fat (35% energy from fat), high-MUFA, lowcarbohydrate diet for 16 weeks [53] (Figure 5). The highMUFA group gained more weight, increased insulin resistance and HbA1c , and the high-carbohydrate, low-GI diet
had the most positive effect on -cell function and body
weight.
The ad libitum normal-fat, high-MUFA diets might
therefore have adverse effects on body weight, insulin sensitivity, and other risk factors as compared to fat-reduced,
high-carbohydrate diets with low GI [53, 54]. Some caution should be exercised before recommending replacement of low-fat diets with higher-fat, MUFA-based diets
for both simple obese and diabetic obese patients until
Figure 5 The only randomized trial compared ad libitum
diets with either a low-carbohydrate, high-MUFA diet; highcarbohydrate, high-GI diet; or high-carbohydrate, low-GI diet.
There was a statistically significant difference in weight loss between all three diets. Low-carbohydrate, high-MUFA diet also
adversely influenced glucose homoestasis. (Reproduced by permission of The Nutrition Society [53])
Obesity
more and better randomized clinical trials have been conducted.
Alcohol
Alcohol provides energy that displaces more nutritious
foods. Alcohol suppresses fat oxidation, thereby allowing
more dietary fat to be stored. The satiating effect of alcohol energy may be low and alcohol consumption has
been shown to promote passive overconsumption of fat
[55]. Alcohol has also been associated with obesity in
epidemiological studies [56]. High alcohol consumption
also increases the risk of losing control over otherwise
restrained behavior. Consequently, energy from alcohol
should be limited and needs to be assessed and appropriately controlled.
WEIGHT MANAGEMENT PROGRAMS FOR
THE PREVENTION OF TYPE 2 DIABETES
The potential of intensive lifestyle treatment to induce and
maintain weight loss has been evaluated in two recent major studies on the prevention of type 2 diabetes in obese
subjects with IGT [57, 58]. In the Finnish Diabetes Prevention study, 522 overweight individuals with IGT were
randomized to an intensive lifestyle intervention or to a
control group [58]. The intervention aimed at a weight loss
of >5% achieved by reduction of total fat to <30% of calories from fat (<10% from saturated fat), >15 g/1000 kcal
fiber, and >30 min of exercise per day (walking, jogging,
etc.). The subjects were instructed to have a frequent intake
of whole grain products, vegetables, fruits, low-fat milk
and meat products, and soft margarines, and vegetables
oils rich in monounsaturated fatty acids. Subjects attended
seven counseling sessions with nutritionists during the first
year of the intervention, and one session every 3 months in
the subsequent years. The weight loss after 1 year was 5%,
and after 5 years the weight loss maintained was still 3 kg.
This intervention produced a 58% reduction in the incidence of type 2 diabetes. In a subsequent analysis weight
loss was the strongest predictor of the diabetes preventive
effect, and a weight reduction of 5% was associated with
a reduction in relative risk of 61%. Every 3 kg of additional weight loss doubled this effect. In the much larger,
but very similar, American Diabetes Prevention Program,
3234 obese individuals (mean BMI, 34 kg/m2 ) with IGT
were randomized to intensive lifestyle, metformin, or a
control group [57]. The goals of the lifestyle intervention
were >7% weight loss, achieved by a diet providing <25%
energy from fat and restricted to 1200–1800 kcal/day, and
>150-min brisk walking per week [57]. The participants
in the intervention group had 16 sessions with a nutritionist over the first 6 months, and subsequently one session
per month for the remaining 2.5 years. After 1 year the
weight loss was 7%, and 5% was maintained throughout
the trial as compared to the placebo group. The relative
risk reduction of diabetes was the same as in the Finnish
study, 58% [57, 58]. These studies strengthen the evidence
to support the low-fat diet in combination with physical
activity as the superior strategy for diabetes prevention.
Achieving and maintaining a desirable body weight is
a major goal in management of type 2 diabetes. Weight
loss dramatically improves glycemic control, lipid profile, and blood pressure in obese individuals with type 2
diabetes (ADA recommendations). Although it is more
difficult to produce and maintain weight loss in type 2
diabetic patients than in simple obese patients, it is possible, and the health benefits are more substantial [59]. In
overweight and obese type 2 diabetic patients who have
difficulty in losing weight on a conventional diet, a liquidformula 800 kcal/day diet may be a safe alternative. Irrespective of whether an intensive 800 kcal/day diet consists
of normal foods or of a liquid-formula diet, weight loss
after 3 months is 14–15% of initial body weight. This also
produces substantial improvements in glycemic control,
blood lipids, and blood pressure [60]. Most of the weight
loss is maintained after 1 year. These studies show that it
is possible to obtain substantial benefits in the treatment of
type 2 diabetic patients through intensive diet therapy and
lifestyle modification. The major problem in the execution
of this treatment is that most diabetologists do not give it
the priority it deserves, and resources are not allocated to
staff with the necessary skills.
Physical Activity in Type 2 Diabetes
Physical activity alone may have a modest, but nevertheless important, effect on glycemic control. Favorable
changes in glucose tolerance and insulin sensitivity usually deteriorate within 72 h of the last exercise session.
Consequently, regular physical activity is imperative to
sustain glucose-lowering effects and improved insulin
sensitivity [61].
According to a meta-analysis of intervention studies
(>8 weeks) addressing the effect of exercise on glycemic
control and body weight in type 2 diabetic patients, aerobic and resistance training produced a beneficial effect
on HbA1c of −0.66%, whereas they failed to find any effect on body weight [62]. However, training may reduce
body fat and increase lean tissue mass, so that body mass
index (BMI) is unchanged. In addition, physical activity
has other important beneficial effects in type 2 diabetes,
such as those on cardiovascular risk factors and general
well-being.
CURRENT DRUGS FOR TREATMENT OF
OBESITY
This section focuses solely on drugs currently available
for the treatment of obesity, or drugs with weight-reducing
681
properties used for the treatment of type 2 diabetes or for
smoking cessation. These will be grouped within each
of the following three categories: those that shift nutrient
metabolism; those that reduce food intake; and those that
increase energy expenditure. For more recent reviews covering most of the current drugs, including new potential
compounds, the reader is referred to references 63 and 64.
Amylase Inhibitors (Acarbose)
Inhibition of digestion of starch and disaccharides reduces
absorption of di- and monosaccharides and may produce
a negative energy balance, providing that energy intake is
not increased because of counterregulatory mechanisms.
Theoretically, the efficacy with respect to body weight regulation is modest, as starch that is not digested in the small
intestine is fermented in the colon and finally absorbed as
short-chain fatty acids. It is estimated that fermentation
of carbohydrates in the colon is associated with a 50%
reduction of energy content available for the body, thus
reducing the energetic value of carbohydrates from 4 to
2 kcal/g.
Acarbose is an antidiabetic drug that lowers blood glucose by inhibition of -glucosidase in the gastrointestinal
tract, thereby delaying the hydrolysis of ingested disaccharides and complex carbohydrates. However, the effect
of acarbose on glycemic control in diabetic patients is
modest, and the effect on body weight is negligible in
simple obese [65], obese with IGT [66], and in type 2
diabetic [67] patients. In a weight maintenance study in
obese subjects, Hauner et al. failed to find any effect of
6-month acarbose treatment on body weight after an initial
diet-induced weight loss of 10 kg [65]. About 50% more
patients reported side effects on treatment with acarbose
than with placebo, these being mainly flatulence, abdominal pain, and diarrhea. In the STOP-NIDDM trial, 1429
overweight and obese patients with IGT were randomized
to a 3-year treatment with acarbose or placebo [66]. After
3 years acarbose produced a weight loss of 0.8 kg compared to placebo, and the risk of progression to diabetes
over 3.3 years was reduced by 25%. The risk reduction
was partially attributable to the weight loss [66]. However, 31% of the patients in the acarbose group, compared
to 19% in placebo group, discontinued treatment early,
mainly owing to gastrointestinal side effects [66]. The effects of acarbose in type 2 diabetes are equally unpromising. In the UK Prospective Diabetes Study (UKPDS),
1946 type 2 diabetic patients randomized to acarbose or
placebo were followed for 3 years [67]. Fifty-eight percent of the included patients discontinued acarbose versus 39% dropouts in the placebo group. In an intentionto-treat analysis acarbose produced only a 0.2% lower
HbA1c than did placebo, while in those who remained
on the allocated therapy HbA1c was 0.5% lower. Mean
body weight was lower by 0.4 kg in the acarbose group
682
after 1 year, but no difference was seen after 2 or 3 years
[66].
In conclusion, acarbose produces only a very modest
weight loss (<1 kg), if any, and taken together with its low
tolerability due to prevalent gastrointestinal side effects,
has no place in the treatment of obesity. Acarbose may,
however, have some role in type 2 diabetic patients with a
capacity to tolerate the compound [63].
Lipase Inhibitors (Orlistat)
Mechanism of Action and Use
Malabsorption of dietary fat is an obvious drug target as
high dietary fat intake plays a special role in promoting
weight gain and obesity. A number of compounds that
act as intestinal lipase inhibitors are currently being investigated for use in the treatment of obesity and related
disorders, but only orlistat is currently approved and freely
available.
Orlistat is a specific inhibitor of intestinal lipase, the enzyme secreted from the exocrine pancreas and responsible
for enzymatic fat digestion [68, 69]. Within the small intestine, lipase and colipase hydrolyze ingested triglyceride,
and produce fatty acids and mono- and diglycerides that
interact with bile to form micelles, enabling absorption of
ingested fat. Orlistat inhibits lipase activity through formation of a covalent bond with serine within the catalytic
site of gastric and pancreatic lipase. At the recommended
therapeutic dose (120 mg) taken immediately prior to or
within 1 h of each of the three daily main meals, the absorption of dietary fat is reduced by ∼30%. Fecal energy
loss is not fully compensated by an increased total caloric
intake, and so orlistat produces a negative energy balance
resulting in weight loss. Moreover, the reduced absorption
of saturated fatty acids and trans-fatty acids has, independent of weight loss, a beneficial effect on plasma total and
LDL cholesterol and triglycerides. Furthermore, there is
some evidence to support that the reduction in total fat uptake exerts a similar positive effect on thrombotic factors.
Orlistat is recommended for use as the pharmacological support for a nutritional strategy of a modest caloric
restriction and a diet providing less than 30% of energy
from fat. An obese patient with a typical energy requirement of 2600 kcal/day will, on a 600 kcal deficit diet
with 30% of calories from fat, experience an extra loss
of 220 kcal fat in fecal energy. Systemic absorption of
orlistat and its metabolites is negligible, and so adverse
effects of orlistat are a consequence of the partial reduction of fat absorption, leading to an increased proportion
of undigested fat in the bowel. The most frequent adverse
effects of orlistat are flatulence, flatulence with discharge,
oily spotting, fecal urgency and incontinence, oily stools,
and steatorrhea. In the majority of patients these adverse
effects are self-limiting and mostly transient, generally
Obesity
occurring within the first months of treatment and often
triggered by the ingestion of high-fat meals. The unabsorbed fat binds some fat-soluble vitamins (A, D, and E)
and secondary nutrients (-carotene, lycopene, flavanoids,
etc.). A simple vitamin supplement and increased intake
of fruit and vegetables counteracts this effect. Pharmacodynamic studies suggest that orlistat does not affect the
pharmacokinetic properties of lipid-soluble drugs such as
digoxin, phenytoin, warfarin, glyburide, furosemide, captopril, nifedipine, atenolol, or oral contraceptives [64].
Efficacy and safety in adolescents have so far only been
examined in an open-labeled pilot study [70], and remain
to be demonstrated in pregnant women.
Treatment in Simple Obese Subjects
The efficacy and safety of orlistat have been documented
in several short- and long-term double-blind trials lasting
for up to 4 years, involving a total of more than 30 000
patients, making orlistat the most well-investigated drug
for the treatment of obesity. In most trials, orlistat induces
a dose-dependent reduction in body weight, and the recommended dose induces a mean weight loss that typically
exceeds that of the placebo group by 3–5 kg, to some
extent independent of the degree of dietary energy restriction or other ancillary treatment (Figure 6). The weight
loss typically continues for the first 3–6 months of treatment and then plateaus, and the patients may subsequently
remain weight stable or regain some weight, depending
on the intensity of the dietary treatment. However, the
weight difference between the orlistat and placebo groups
is sustained over 1–4 years, which indicates that efficacy
is maintained. The weight loss may not seem large viewed
in relation to the patients’ excessive body fat, but it has
important clinical implications. Typically, orlistat doubles the proportion of patients achieving >5% and >10%
weight loss, and it also doubles the proportion maintaining
this goal after 1 and 2 years. The immediate weight regain
Figure 6 Weight loss and maintenance of simple obese patients
treated with energy-restricted diet and randomized to orlistat or
placebo. ∗ P < 0001; least-squares mean difference from placebo.
(Reproduced by permission of Elsevier [71])
683
Table 4 Changes in body weight and HbA1C in overweight type 2 diabetes during long-term orlistat treatment∗
Medication
Sulfonylurea
Insulin
Metformin
Baseline HbA1C (%)
7.5
9.0
8.9
Change in HbA1C † (%)
−0.46
−0.35
−0.29
Change in Body weight† (%)
−1.9
−2.6
−2.9
∗
c 2001 American Diabetes Association. From Diabetes Care, Vol 25, 2002; 1033–1041. Reprinted with permission from The
Copyright American Diabetes Association [74].
†
Placebo subtracted.
is greater in orlistat-treated patients after discontinuation
of treatment than in placebo-treated patients which indicates that orlistat maintains its pharmacological efficacy.
However, the total weight loss and maintenance is greater
after orlistat than after placebo.
In obese subjects with metabolic syndrome (insulinresistance syndrome) orlistat produces weight loss of the
same magnitude as in simple obese subjects, and the
weight loss is associated with significant decreases in fasting insulin, triglycerides, and the LDL/HDL cholesterol
ratio and increase in HDL cholesterol [72].
Treatment in Obese Subjects with IGT
Treatment of obese subjects with IGT by orlistat as an adjuvant to diet and lifestyle modification has been shown to
decrease the incidence of conversion to type 2 diabetes. In
a retrospective analysis of obese adults with IGT treated
with orlistat, the additional weight loss produced by orlistat reduced the 1-year incidence of type 2 diabetes from
7.6% in the placebo group to 3.0% [73]. Moreover, while
49% converted from IGT to normal glucose tolerance in
the lifestyle (plus placebo) group, 72% did so in the orlistat
group [73]. In a recent multicenter trial, 3304 nondiabetic
obese subjects underwent intensive lifestyle modification
with a dietary energy deficit of 800 kcal/day, and were
randomized to either orlistat or placebo for 4 years [71].
They attended reinforcement sessions every fortnight for
the first 6 months, and subsequently every month for the
following 3.5 years. More orlistat-treated than placebotreated patients completed the trial (52% vs. 34%). The
mean weight loss was greater by 4 kg in the orlistat group
after 1 year, and most of this weight loss was maintained
throughout the rest of the study period. The weight loss
was 6.9 kg in the orlistat group and 4.1 kg in the placebo
group after 4 years. About 50% more patients treated with
orlistat achieved and maintained >5% and >10% weight
loss after 1 and 4 years. Nine percent in the placebo group
and only 6.2% in the orlistat group had developed type 2
diabetes after 4 years (relative risk reduction = 37%,
P = 0.003). In addition, orlistat patients obtained greater
reductions in waist circumference, LDL cholesterol, and
systolic and diastolic blood pressures than did placebo patients. The study clearly shows that the additional weight
loss achieved by orlistat is sufficient to reduce the incidence of diabetes, even among more nonselected obese
subjects where 80% had normal glucose tolerance. In the
20% of patients with IGT, at enrollment the intensive
lifestyle change alone resulted in a similar absolute diabetes incidence as the lifestyle treatment in the Diabetes
Prevention Program [57]. The addition of orlistat further
improved the preventive effect.
Treatment in Obese Diabetic Patients
One-year multicenter trials have been conducted with the
use of orlistat in addition to each of the treatments of
type 2 diabetic patients: sulfonylurea, insulin, and metformin. Whatever medication the diabetic patients received at baseline, orlistat produced weight loss above
that produced by diet and placebo (of 2–5 kg) [68], and
reductions in HbA1c of 0.46% (sulfonylurea), 0.35% (insulin) [63, 74], and 0.29% (metformin) (Table 4). Greater
reductions were also seen in LDL cholesterol and blood
pressure in the orlistat groups. Consequently, orlistat can
be used as first drug of choice in type 2 diabetic patients
when diet and lifestyle is not sufficient to achieve glycemic
control, and it can be used safely in combination with the
second drug of choice, metformin.
Metformin
Metformin is a biguanide that is approved for the treatment
of type 2 diabetes. It lowers plasma glucose by reducing
the intestinal absorption of glucose, suppressing hepatic
glucose production and increasing peripheral insulin sensitivity. It has long been known to induce a slight weight
loss not only in diabetic patients but also in obese subjects
with metabolic syndrome or IGT. The size of the placebosubtracted weight loss induced by metformin in diabetic
patients varies from 0.5 to 8 kg, probably depending on
BMI, age, and glycemic control [63]. In the Diabetes Prevention Program of obese subjects with IGT, metformin
produced a 2 kg weight loss and reduced the incidence of
diabetes by 31% above placebo after 3 years [57]. A subgroup analysis revealed no difference in efficacy across
gender and ethnicity, but the effect was mainly seen in
subjects aged 25–59 years with a BMI above 30 kg/m2 ,
whereas it was largely ineffective in nonobese (BMI <
30 kg/m2 ) and those above 60 years [57]. In this trial,
more than 1000 patients entered each treatment arm and
the resulting high statistical power gives more credit to the
outcome than to that of smaller trials.
684
Obesity
It is not known how metformin produces weight loss,
but it is possible that the improvement in insulin sensitivity
increases the central effect of insulin where it acts as a
satiety hormone [75]. Another possibility is that reduced
food intake is caused by nausea and other gastrointestinal
effects. There are no indications of any thermogenic effect
of metformin.
Sibutramine
Sibutramine is a serotonin and norepinephrine reuptake inhibitor with only a weak inhibitory action on dopamine reuptake. Unlike amphetamine, sibutramine does not stimulate locomotor activity, and unlike dexfenfluramine and
fenfluramine, it does not induce serotonin release, and has
not been implicated in the development of valvular disease
[76].
Sibutramine decreases food intake in humans by increasing meal-induced satiety [77, 78]. It also exerts a
weak thermogenic effect both acutely and during longterm use [78, 79].
Controlled trials in simple obesity have consistently
shown dose-related weight loss, and optimal weight loss
with a dose of 10–15 mg sibutramine once daily. Typically, weight loss was 3–5 kg greater than with placebo at
24 weeks, and weight loss was sustained for 2 years. The
proportion of patients losing at least 5% of body weight
over 12 months was 29% with placebo, 56% with sibutramine 10 mg, and 65% with sibutramine 15 mg/day [80].
Intermittent and continuous sibutramine therapies are
similar in regard to effectiveness and safety [81]. Wadden
et al. found that patients treated with sibutramine alone
achieved a weight loss of 4% after 12 months, but the drug
plus lifestyle intervention produced a weight loss of 11%
and better outcomes in terms of risk factor reductions
[82].
In the STORM trial, sibutramine was assessed for the
potential to both induce and maintain weight loss [83].
Six-hundred five obese individuals were treated with a
600 kcal/day deficit diet and sibutramine 10 mg daily for
6 months (Figure 7). The 467 participants who lost more
than 5% were randomly assigned to continue to receive
sibutramine or placebo for 18 months. The mean weight
loss after 6 months was 12 kg, and whereas weight was
gradually regained in the placebo group during the second year of follow-up, the sibutramine group essentially
maintained the weight lost during the initial 6 months [83].
Although sibutramine had positive effects on blood lipids
as expected from the weight loss, it seems to have an HDLcholesterol increasing effect that is independent of weight
loss [83], and it has been shown to be appropriate for
correction of lipid abnormalities in obese patients having
high-serum triglyceride levels and low HDL-cholesterol
levels [84]. Sibutramine also increases weight loss and improves maintenance of reduced weight in obese patients
Figure 7 The STORM trial. Mean body weight changes during weigh-loss and weight-maintenance phases. During the first 6
months all patients received −600 kcal/day diet and sibutramine.
Those who lost >5% were randomized to continue on sibutramine or placebo. (Reprinted with permission from Elsevier
Science (The Lancet, 2000, 356; 2119–2125) [83])
who have previously lost weight on a very low calorie diet
[85].
Sibutramine is generally well tolerated and has few side
effects. These include dry mouth, headache, insomnia,
and constipation. The adverse effects of sibutramine include increase in blood pressure and heart rate. Although
these increases are generally mild and without clinical relevance, blood pressure should be monitored on a regular
basis. Increases in blood pressure may lead to discontinuation of treatment in about 5% of patients.
Obese patients with well-controlled hypertension (calcium-channel blockers, -blocking agents,
angiotensin-converting enzyme inhibitors, thiazide
diuretics) do not experience any rise in blood pressure
with sibutramine therapy, and their overall risk factor
profile will benefit from the induced weight loss [86–88].
Sibutramine has been shown to produce a substantial
weight loss above that of placebo (∼9 kg) and a 2% decrease in HbA1c over 6 months in type 2 diabetic patients
with poor glycemic control despite maximum doses of
sulfonylureas and metformin [89]. In a 12-month study
Rissanan et al. found sibutramine to produce a weight
loss of 7.1 kg in diet-treated type 2 diabetic patients vs.
2.6 kg in the placebo group. Overall, there was no benefit
of sibutramine therapy on glycemic control (−0.3% vs.
−0.2%), but in a subgroup with HbA1c >8% the improvement was superior in the sibutramine group (−1.4% vs.
−0.6%). Longer term studies and studies in other groups
of diabetic patients have not been published.
Bupropion
Bupropion has dual neurotransmitter properties working as norepinephrine and dopamine reuptake inhibitors,
which may both have relevance for body weight regulation. Sustained-release bupropion is approved for the
treatment of smoking cessation and for major depression. In depressed patients with normal weight, bupropion
seems to have a weight neutral profile, whereas there are
suggestions of weight-reducing properties in overweight
and obese depressed patients [90, 91]. Moreover, weight
gain after smoking cessation is less in bupropion-treated
subjects than in placebo-treated subjects [92, 93]. Two randomized, placebo-controlled trials have been conducted
in nondiabetic obese subjects. Both found that bupropion
was superior to placebo in reducing body weight when
given together with an energy-restricted diet [94, 95]. In
the largest trial, 327 simple obese patients were treated
with diet and lifestyle modification and randomized to
bupropion SR 300 mg/day, SR 400 mg/day, or placebo
for 24 weeks. In completers, weight loss was greater than
with placebo by 2.2 kg in the SR 300 mg/day group, and
by 5.1 kg in the SR 400 mg/day group [95]. In a 24-week
extension of the study, weight loss was essentially maintained. Bupropion has little, if any, effect on heart rate and
blood pressure, but should be used with caution in patients
with a history of seizures.
These studies suggest that bupropion may be of particular relevance for smoking cessation in obese and diabetic
patients, and perhaps even for weight reduction in nonsmoking obese individuals.
Nicotine
Cigarette smoking is recognized as one of the most important preventable causes of premature death, but still
20–35% of the population in the affluent world continue
to smoke. One of the most important barriers to quit smoking is the subsequent weight gain, and the weight control
properties of smoking reinforce the decision to continue
smoking.
Anorectic and thermogenic properties produced by
nicotine are considered to be factors responsible for the
lower body weight of smokers compared with nonsmokers. Nicotine gum has been shown to relieve withdrawal
symptoms and to double the success rates over placebo
in trials of smoking cessation, and has been shown to diminish weight gain after smoking cessation. The use of
nicotine gum is therefore an accepted tool to treat withdrawal symptoms and prevent weight gain in a vulnerable
phase after smoking cessation. Dale et al. [96] demonstrated that 100% replacement does not completely prevent weight gain. To determine whether attempts to prevent weight gain will increase success rates for stopping
smoking, 287 female weight-concerned smokers were enrolled into a combination of a standard smoking cessation
program with nicotine gum and a behavioral weight control program including a low-energy diet [97]. A control
group was treated with the identical program but without
the diet. After 16 weeks, 50% of the women had stopped
smoking in the diet group versus 35% in the control group.
685
Among these women, weight fell by mean 2.1 kg in the
diet group but increased by 1.6 kg in the control group
(P < 0.001). After 1 year the success rates in the diet and
control groups were 28 and 16% respectively (P < 0.05),
but there was no statistical difference in weight gain. Combining the smoking cessation program with an intervention
to control body weight helped women to stop smoking and
control weight; nicotine replacement alone is insufficient
to prevent weight gain when quitting smoking. No weight
loss trials have been conducted with the use of nicotine.
Ephedrine/Caffeine
Ephedrine is both an indirect sympathomimetic, causing
release of norepinephrine from the sympathetic nerve endings, and a direct agonist on -receptors. Numerous studies have shown that ephedrine (E) as monotheraphy decreases body fat in obese subjects by a combined action of
suppression of appetite and stimulation of energy expenditure. Adenosine antagonists such as caffeine (C) potentiate the thermogenic and clinical effects. Combinations
of E+C have been shown to be effective for treatment of
obesity for up to 50 weeks. In a study including 180 obese
patients it was found that E+C (20 mg/200 mg t.i.d.) produced a larger weight loss than did placebo, C, or E, in
combination with a hypoenergetic diet over 24 weeks [98].
After 24 weeks the placebo group had lost 13.2 kg, and
E+C further increased the weight loss by 3.4 kg to a total
of 16.6 kg. Also, more patients in the E+C group than in
the placebo group lost more than 5% and 10% of initial
body weight. Breum et al. tested E+C against dexfenfluramine in a double-blind, placebo-controlled trial, and
found that E+C produced a greater weight loss than did
dexfenfluramine in subjects with a BMI of more than
30 kg/m2 [99]. The reductions in pulse rate and blood
pressure were similar with the two treatments. E+C has
also been evaluated for prevention of weight gain after
smoking cessation. The double-blind, placebo-controlled
trial included 225 subjects and after 12 weeks weight gain
was less in the E+C group than in placebo group [100].
However, after 1 year there was no difference in the proportion of subjects not smoking.
Molnar reported a 20-week, randomized double-blind,
placebo-controlled trial of E+C in adolescents aged
16 years and in Tanner stage III–V, and found that E+C
produced more substantial weight loss than did placebo
(14.4 vs. 2.2%) [101]. Subjects dropped out only in the
placebo group, and adverse effects were mild and not different from those in the placebo group after 4 weeks.
Notably, E+C increases blood pressure and heart rate
slightly with the first exposure [102]. However, during
chronic treatment tachyphylaxis develops to the cardiovascular effects of the compound, but not to the anorectic
and thermogenic [98]. In the largest trial of E+C, only a
slight increase in blood pressure and heart rate could be
686
detected when the treatment was initiated, but after
12 weeks of dietary treatment, the reductions in blood
pressure were similar in the E+C group to those in
the placebo group [98]. A hypothetical cardiovascular safety concern could be raised by the combination
of E+C and exercise. With more extensive measurement of cardiovascular function by thoracic impedance,
automatic sphygmomanometry, and continuous electrocardiographic recording, Waluga et al. concluded that
E+C had no undesirable effects on cardiovascular function in obese subjects [103]. E+C has also been tested
in overweight subjects with controlled hypertension
[104]. Treatment with E+C produced a larger weight
loss and a greater reduction in systolic blood pressure
(5.5 mmHg) than did treatment with placebo; moreover the antihypertensive effect of -blockers was not
reduced by E+C [104]. E+C does not seem to have any
long-term effect on glucose and lipid metabolism apart
from the beneficial changes in risk factors secondary to
weight loss. Buemann et al. reported that E+C prevented
the decline in HDL cholesterol associated with weight
loss, and it increased the ratio of HDL cholesterol to
total cholesterol, whereas no effect on fasting glucose
metabolism was observed [105].
The clinical studies of E+C clearly show that the compound is effective in the treatment of obesity for up to
1 year [10]. However, because of the limited number of
patients treated in the trials, the total evidence does not
meet the efficacy and safety requirements of the American FDA or the European CPMP for licensing E+C as a
prescription compound.
Various herbal combinations of E+C based on Ma
Huang, guarana, and aspirin are sold over the counter
in the United States and the total sales reached about
950 million dollars in 1999. The pharmacokinetics of these
herbal preparations may vary, and they contain many other
ingredients such as minerals and herbs that might alter or
interact with E or C [106].
As concluded by Greenway [106],
These herbal products containing ephedrine and caffeine
should be tested in controlled clinical trials to confirm their
presumed efficacy and safety which cannot truly be extrapolated from the peer-reviewed scientific literature using
pharmaceutical grade caffeine and ephedrine in isolation.
No studies exist in obese subjects with IGT or type 2
diabetes, and the use of E/C compounds in these conditions
is not substantiated.
SURGICAL TREATMENT OF OBESITY
Weight management programs fail in a substantial proportion of the severely obese patients, and to ensure a better long-term outcome, bariatric surgery is the treatment
of choice for well-informed and well-motivated obese
Obesity
patients with acceptable operative risks [107]. Patients
should be obese for at least 5 years and have a strong
desire for a substantial weight loss, or have severe impairments because of their obesity. Surgery is indicated for
patients with a BMI greater than 40 kg/m2 , or for those
with serious medical comorbidities and a BMI greater than
35 kg/m2 . A number of different procedures are available:
(1) adjustable silicone gastric banding, (2) vertical gastric
banding, and (3) gastric bypass, which should be reserved
for the heavier patients. The malabsorptive intestinal bypass ( jejuno-ileal) has a high rate of complications and
cannot be recommended.
Effect in Simple Obesity
In a series of 100 obese patients gastric bypass was shown
to prevent the progression of IGT to frank type 2 diabetes
[108]. In the Swedish Obese Subjects (SOS) study, 2000
matched morbidly, but simple obese patient pairs will be
followed for 10 years each, one pair member is surgically
treated, while the other serves as a control group [109].
The 2-year mean weight reduction was 28 kg in the operated patients and 0.5 kg in the controls. After 8 years
the weight loss was 20 kg in the surgical group, while the
controls had gained 0.7 kg. The average weight loss for
gastric bypass and vertical banded gastroplasty was 16%
after 10 years. These weight reductions were sufficient to
reduce the 2-year incidence of type 2 diabetes 32 times
as compared to the controls. After 5 years the relative
risk reduction was 80%, and after 10 years, 67%. However, while the incidence of hypertension was markedly
reduced the first years, after 8 years the incidence of hypertension was almost equal in the two study groups. The
weight loss achieved by surgery has pronounced effects
on cardiac structure and function, quality of life, rates of
employment, and health care costs.
Gastric Surgery in Type 2 Diabetes
The weight loss achieved by surgical procedures in obese
type 2 diabetic patients has marked effects on glycemic
control, cardiovascular risk factors, progression of the disease, and mortality [110, 111]. In a study of 154 type 2 diabetic patients followed for up to 10 years, the proportion
of control subjects being treated with oral hypoglycemics
or insulin increased from 56.4% at initial contact to 87.5%
at last contact, whereas the percentage of surgical patients
requiring medical management fell from 31.8% preoperatively to 8.6% at last contact. The mortality rate in the
control group was 28% compared to 9% in the surgical
group. The improvement in the mortality rate in the surgical group was primarily due to a decrease in the number
of cardiovascular deaths.
Laparoscopic adjustable gastric banding is a minimally
invasive and reversible surgical procedure that yields a
significant reduction in gastric volume and hunger sensation. This procedure has been shown to be a very effective treatment of grade 3 obesity, inducing long-lasting
reduction of body weight and arterial blood pressure,
modifying body fat distribution, and improving glucose
and lipid metabolism, especially in type 2 diabetic patients
[112, 113].
These data show that surgical treatment of obesity has
a place in the prevention and treatment of severely obese
patients with type 2 diabetes, and with the less invasive
techniques this treatment should be used in more obese
type 2 diabetic patients resistant to other treatment programs [114].
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