Clinical Trial Experience with Fat-Restricted
vs. Carbohydrate-Restricted Weight-Loss Diets
Samuel Klein
Abstract
KLEIN, SAMUEL. Clinical trial experience with fat-
restricted vs. carbohydrate-restricted weight-loss diets.
Obes Res. 2004;12:141S–144S.
It is unlikely that one diet is optimal for all overweight or
obese persons. Both low-fat and low-carbohydrate diets
have been shown to induce weight loss and reduce obesity-
related comorbidities. Low-carbohydrate diets cause greater
short-term (up to 6 months) weight loss than low-fat diets,
but the long-term clinical safety and efficacy of these diets
has not been studied.
Key words: clinical trial, macronutrient composition,
energy density, weight loss
Introduction
Very small but chronic differences in daily energy bal-
ance can cause dramatic changes in body composition over
a long period of time. In the United States, people gain an
average of 13 to 14 kg of body weight between 25 and 55
years of age, or ⬃1 lb of fat per year (1). This amount of
weight gain represents a very small imbalance between the
number of calories ingested and the number expended;
consuming one Lifesaver (⬃10 kcal) a day more than the
calories expended every day will result in a gain of about 1
lb/yr. The reverse is also true; therefore, a small but daily
negative energy imbalance can lead to a significant amount
of weight loss. Moreover, modest weight loss has been
associated with considerable medical benefits (2,3). For
example, a 2% to 5% weight loss in patients who have type
2 diabetes can improve insulin sensitivity (3).
Altering dietary habits is the cornerstone of weight-loss
therapy for obese patients. Although many different diets
have been shown to induce short-term weight loss, poor
Center for Human Nutrition, Washington University School of Medicine, St. Louis, Mis-
souri.
Address correspondence to Samuel Klein, Washington University School of Medicine, 660
S. Euclid Avenue, Box 8031, St. Louis, MO 63110-1093.
E-mail: sklein@imgate.wustl.edu
Copyright © 2004 NAASO
OBESITY RESEARCH Vol. 12 Supplement November 2004
long-term compliance and weight regain are common. The
optimum diet for effective, safe, and lasting weight loss is
unknown. Several intrinsic factors within food may be in-
volved in regulating energy intake. These factors include
macronutrient composition, energy density, fiber content,
fat and sugar substitutes, portion size, food variety, and the
physical properties of food (e.g., taste and feel). In addition,
extrinsic factors related to societal, social, and economic
influences, including food cost, availability, variety, and
marketing also affect food intake. Therefore, effective diet
therapy may need to consider both intrinsic and extrinsic
food factors to achieve successful long-term weight loss in
obese patients.
Macronutrient Composition of Diets
The macronutrient composition of a diet can have signif-
icant clinical effects, independent of any changes in body
weight. For example, switching from a weight-maintaining
high-carbohydrate diet to a high-monounsaturated-fat diet
has decreased serum triglyceride and increases serum
high-density lipoprotein-cholesterol concentrations (4 –7),
whereas a weight-maintaining diet that is high in saturated
fat has often increased low-density lipoprotein-cholesterol
concentrations. In addition, it is possible that a diet that has
adverse metabolic effects in patients who are maintaining
their body weight can result in metabolic benefits if it
induces significant weight loss.
Traditionally, a low-fat, high-carbohydrate diet has been
recommended to help obese patients lose weight (8). This
approach makes sense because fat contains more than twice
as many calories per gram than protein or carbohydrate, and
fat tends to make food more palatable, which may increase
intake. Data from epidemiological studies (9), meta-analysis
of clinical trials that evaluated the effect of reduced fat
intake on serum lipids (10), and randomized controlled
trials on the effect of a low-fat diets on body weight in obese
subjects (11) have supported the notion that limiting dietary
fat intake causes weight loss. However, limiting fat intake
may not be more effective than focusing on restricting total
calorie intake. Data from a recent meta-analysis that eval-
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Weight-Loss Diets, Klein

Table 1. Atkins diet approach

Phase
Phase 1: induction diet
Phase 2: on-going weight loss Critical carbohydrate level
Phase 3: premaintenance
Phase 4: maintenance
Criteria
20 grams of carbohydrates
daily (14 days)
for losing
Increase carbohydrate
intake until losing ⬍1
lb/wk
Goal weight achieved;
consume level of
carbohydrate most
comfortable without
weight regain

No limit on fat, protein, or calories.

Adapted from Atkins RC (15).
uated randomized clinical trials that compared fat-restricted
and calorie-restricted diets has found no difference in
weight loss between diet groups (12).
Recently, low-carbohydrate diets have become increas-
ingly popular. The first documentation of successful weight
loss using a low-carbohydrate diet dates back to 1863, when
William Banting published a Letter on Corpulence, which
details his own loss of 50 lb and a decrease in BMI from
33.7 to 25.3 kg/m2 by consuming a low-carbohydrate diet
(13). Dr. Robert Atkins is probably the single person most
responsible for the recent increase in low-carbohydrate di-
eting, and his diet books have been exceptionally popular
(14,15). The Atkins’ low-carbohydrate diet approach is out-
lined in Table 1.
The results from four randomized controlled trials that
compared the effect of a low-carbohydrate diet with a
low-fat diet on body weight in adult obese subjects have
recently been published (16 –20). A consistent difference in
weight loss at 6 months has been observed between groups
across studies; subjects randomized to the low-carbohydrate
diet lost 4 to 5 kg more weight than those randomized to the
low-fat diet. However, weight loss was no different between
groups at 1 year (18,20). In addition, in subjects who had
type 2 diabetes, there were greater improvements in fasting
blood glucose concentrations and insulin sensitivity with a
low-carbohydrate than with a low-fat diet (17,20). The data
from these studies has also found greater improvements in
serum triglyceride and high-density lipoprotein-cholesterol
concentrations, but not in serum low-density lipoprotein-
cholesterol concentrations, in the low-carbohydrate than the
low-fat group (Figure 1).
Surreptitious reduction in carbohydrate intake by switch-
ing foods containing sucrose with foods containing an in-
Figure 1: Effect of low-carbohydrate and low-fat diets on serum
lipids. Reproduced with permission from Foster et al. A random-
ized trial of low-carbohydrate diet for obesity. N Engl J Med.
2003;348:2082–90 (18).
tense sweetener can also result in weight loss (21). In one
short-term (10-week) study, energy intake and body weight
was lower in subjects who were given foods that contained
an intense sweetener than those given foods that contained
sucrose.
Energy Density
Energy density is defined as the energy (kilocalories)
present in a certain weight (grams) of food. The energy
density of foods can affect the total number of calories
consumed during a meal, because the volume or weight of
food may be involved in the regulation of food intake (22).
Energy-dense foods are usually high in fat (e.g., butter)
and/or are dry (e.g., pretzels). Therefore, the fat and water
content of a food determines its energy density. In general,
most energy-dense foods are high-fat foods, and most foods
that contain a lot of water (e.g., fruits, vegetables, soups)
have a low-energy density (Figure 2).
Data from a series of studies has suggested that food
intake is regulated, in part, by food weight, so energy intake
is inversely correlated with food energy density (22–24).
Moreover, the results of short-term studies have suggested
that manipulating energy density might be a useful approach
to noncognitively regulate total ad libitum energy intake. In
fact, in a 6-month randomized controlled trial, obese sub-
jects randomized to a low-energy-density diet (containing
25% calories as fat and 55% as carbohydrate) have lost

142S OBESITY RESEARCH Vol. 12 Supplement November 2004

Weight-Loss Diets, Klein
Figure 2: Effects of fat and water content on energy density. Reproduced with permission from Rolls and Bell: Dietary approaches to the
treatment of obesity. Med Clin North Am 2000;84:401– 418 (22).
more weight (⬃1% to 2% weight loss) than those random-
ized to a medium-energy-density diet (containing 35% cal-
ories as fat and 45% as carbohydrate; no weight loss) (11).
Conclusions
A modern industrialized society has unhealthy effects on
eating behavior. Many environmental factors, such as food
marketing, convenient food acquisition and preparation,
food variety, and supersizing, encourage overconsumption
of calories. In addition, most people are genetically pro-
grammed to eat food and store excess ingested calories as
fat. The combination of these genetic and environmental
influences makes it difficult for obese persons to lose
weight and maintain long-term weight loss by dieting. Suc-
cessful dieters must be exceptionally vigilant or they will
rapidly regain their lost weight. Therefore, additional re-
search is needed to identify the factors in food, such as
macronutrient composition and energy density, that may be
involved in regulating food intake. Taking advantage of
these noncognitive factors in food may provide a useful
strategy to reduce energy intake without the need for con-
stant cognitive monitoring that is difficult to maintain.
At present, it is unlikely that one diet is optimal for all
overweight or obese persons, and dietary guidance should
be individualized to allow for specific food preferences and
individual approaches to reducing energy intake. Low-car-
bohydrate diets cause greater short-term (up to 6 months)
weight loss than low-fat diets, but the long-term clinical
safety and efficacy of these diets are not known and require
additional investigation.
Question and Answer Period
Dr. Roth.What we all notice is that when people start
on a diet, they do well, and then their weight loss eases
OBESITY RESEARCH Vol. 12 Supplement November 2004
off. How about serial diets, by that I mean, you try a
given diet for 3 months, and it has its novelty and then
you switch the diet. Can you keep the freshness of the
early weight loss?
Dr. Klein.You present an interesting concept, but I am
not aware of any studies that have directly addressed this
issue. In general, many people do follow serial diets over
long periods of time. They try one diet for a few months
or 1 year and another diet the next year. It is possible that
a structured serial diet approach could be successful, but
we need data from randomized controlled trials to answer
this question.
Dr. Roth.That’s what I’m suggesting, with cheerleading
by the health professionals. Because what happens is that
when people fail on a diet, they get discouraged, and there’s
depression associated with it. However, if it’s done as a
thoughtful upbeat set of serial diets, would that work?
Dr. Klein.I agree that most diets cause short-term weight
loss, but the lack of long-term dietary adherence results in
weight regain. It is possible that the novelty of interval diets
will improve adherence.
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