Original Article Obesity

CLINICAL TRIALS: BEHAVIOR, PHARMACOTHERAPY, DEVICES, SURGERY

The Effect of Leptin, Caffeine/Ephedrine and their Combination

Upon Visceral Fat Mass and Weight Loss
Ann G. Liu1, Steven R. Smith2, Ken Fujioka3 and Frank L. Greenway1

Objective: To evaluate the effects of combination caffeine/ephedrine and leptin A-200 on visceral fat
mass and weight loss over 24 weeks.
Design and Methods: In this randomized, double-blind, parallel-arm trial, 90 obese subjects received
one of the three treatments for 24 weeks: 200 mg caffeine/20 mg ephedrine t.i.d. (CE), leptin A-200
(recombinant methionyl human Fc-leptin, 20 mg q.d.) (L), or combination leptin A-200 and caffeine/
ephedrine (LCE). Outcomes included change in weight, visceral fat mass by computed tomography, lean
mass and fat mass by dual energy X-ray absorptiometry.
Results: Groups treated with CE and LCE lost significant amounts of weight (
5.9 6 1.2% and
6.5 6
1.1%, P < 0.05) and whole body fat mass (
9.6 6 2.4% and
12.4 6 2.3%, P < 0.05) compared to
leptin only group. Only treatment with LCE significantly reduced visceral fat mass (
11.0 6 3.3%, P <
0.05). There were no differences in lean mass between treatment groups.
Conclusions: Our study provides evidence that CE is a modestly effective weight loss agent and
produces significant reductions in fat mass. Leptin A-200 was not effective in producing weight loss and
did not have any significant additive or synergistic actions when combined with CE.

Obesity (2013) 21, 1991-1996. doi:10.1002/oby.20416

Introduction Denmark for over a decade (3). A meta-analysis of clinical trials

concluded that ephedrine and ephedra enhanced weight loss 0.9 kg/
During weight loss, lean tissue is often lost in addition to fat tissue. month above the amount lost with placebo in trials lasting up to 6
This loss of lean tissue may have adverse consequences because of
months (4). In a pilot study we performed at Pennington Biomedical
the important role skeletal muscle plays in the regulation of blood
glucose and lipid levels (1). Work by Allison et al. demonstrated Research Center, female subjects were treated with either caffeine
that for every standard deviation of weight loss, mortality increased and ephedrine (n ¼ 6) or fenfluramine and mazindol or phentermine
by 30%, but for every standard deviation of fat loss, mortality (n ¼ 14) for 6-9 months. Both groups lost weight, but the caffeine/
decreased by 15% (2). This suggests that loss of fat mass has benefi- ephedrine group experienced no loss of lean tissue mass (unpub-
cial health effects, whereas loss of lean mass can be detrimental. lished data) suggesting that caffeine/ephedrine might preferentially
Thus one of the main goals of any weight loss program is to maxi- preserve lean tissue mass during weight loss.
mize fat loss while minimizing lean tissue loss.
The discovery of leptin sparked great interest in its utility as a
Ephedra-containing weight-loss supplements were widely used in weight loss agent. Leptin plays a key role in energy homeostasis,
the 1990s. Caffeine was combined with ephedrine, the most potent and humans with congenital leptin deficiency exhibit severe hyper-
isomer of the four ephedra isomers, to stimulate weight loss pharma- phagia and obesity (5). The phenotype of these individuals can be
cologically, and it was an approved combination weight loss drug in completely reversed with leptin replacement therapy (6,7). However,

1
Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA, USA. Correspondence: Frank L. Greenway
([email protected]) 2 Translational Research Institute for Metabolism and Diabetes, Florida Hospital  Sanford | Burnham Medical Research Institute,
301 E. Princeton Ave., Orlando, FL, USA 3 Scripps Clinic, 11025 North Torrey Pines Road, Suite 200, La Jolla, CA, USA

Author contribution: AGL analyzed the data, interpreted the data, searched the literature, generated the figures and wrote the manuscript. SRS and FLG designed the
study and were awarded an investigator-initiated grant to support the study, collected the data, analyzed the data, interpreted the data, reviewed the literature, and edited
the manuscript. KF collected the data, interpreted the data, reviewed the literature and edited the manuscript.
Funding agencies: This study was funded through an investigator-initiated grant from Amgen Pharmaceuticals to SRS and FLG.
Disclosure: AGL, FLG, and KF have no conflicts of interest to declare. SRS is a consultant to Amylin Pharmaceuticals, Arena Pharmaceuticals, Inc., AstraZeneca,
BristolMeyersSquibb, Elcelyx, Five Prime Therapeutics, Inc., Eli Lilly and Company, NGM Pharma, Novo Nordisk A/S, Orexigen Therapeutics, Inc., Piramal Life Sciences,
Takeda Pharaceuticals, and Zafgen. Amgen pharmaceuticals provided the leptin and an unrestricted grant to conduct the study.
CLINICAL TRIAL REGISTRY: This trial is registered at ClinicalTrials.gov NCT01710722
Additional Supporting Information may be found in the online version of this article.
Received: 11 December 2012 Accepted: 30 January 2013 Published online 19 May 2013. doi:10.1002/oby.20416

www.obesityjournal.org Obesity | VOLUME 21 | NUMBER 10 | OCTOBER 2013 1991

Obesity Leptin and Caffeine/Ephedrine for Weight Loss Liu et al.

in clinical trials with a normal obese population, high-dose leptin injection once a day throughout the study. Study site personnel, par-
therapy failed to produce clinically meaningful weight loss (8). ticipants, and the study team were blinded to treatment assignment,
Amgen developed a long-acting recombinant methionyl human Fc- and blinding was only broken in case of an emergency.
leptin molecule (leptin A-200), which was tested in a pilot study at
Pennington Biomedical Research Center. Obese subjects receiving
leptin A-200 experienced a 23.5% reduction in visceral fat mass
compared to only 1% in the placebo group (unpublished data).
Procedures
Participants were seen at weeks 0, 1, 2, 3, 4, 8, 12, 16, 20, and 24
Reducing the amount of visceral fat mass is especially desirable
at which time weight, vital signs, adverse events (including injection
because central or visceral obesity is associated with the highest
site inspection), and medication dispensing was done. At baseline,
mortality risk and many co-morbidities of obesity (9,10,11).
subjects were instructed in lifestyle modification principles, a walk-
ing program with a goal of 30 min five times per week and a bal-
Based on these initial pilot studies, we hypothesized that the combi-
anced calorie-restricted diet, 1200 kcal/day for women and 1500
nation of caffeine/ephedrine and leptin A-200 would produce selec-
kcal/day for men. Data for compliance with diet and exercise
tive loss of visceral fat mass, while simultaneously preserving lean
instruction were not obtained.
body mass.
Efficacy measures included weight and BMI at each visit. At base-
line, 12 and 24 week, whole body fat mass and lean mass were
Methods assessed by dual energy X-ray absorptiometry (DXA), and visceral
adipose tissue mass was obtained using abdominal multislice CT
Participants scan as previously described (12). A lipid panel, glucose, and insulin
Ninety men and women between 18 and 60 years of age were eligi- were obtained at baseline and 24 week.
ble for inclusion if they had a BMI of 30-40 kg/m2. Women of
childbearing potential were required to use effective contraception Screening measures included a medical history, TSH and T3 by
and were excluded if they were pregnant or lactating. Participants RIA, at baseline. A physical examination, CBC, urinalysis, chemis-
were ineligible if they were using regular medication other than hor- try panel, and EKG were done at baseline and 24 week. A preg-
monal birth control pills or hormone replacement therapy; had nancy test was done on females with childbearing potential at base-
gained or lost more than 4 kg in the past 6 months; had taken mono- line, 12 and 24 week. During the forced dose titration of caffeine
amine oxidase inhibitor medication in the past month; were sensitive and ephedrine, subjects remained in the clinic for three hours after
to Escherichia coli or E. coli-derived products. Participants with taking the first dose of caffeine and ephedrine, and blood pressure
hypertension (blood pressure >150/90), known heart disease, prosta- and pulse rate were taken every hour during that period. If blood
tism, or thyroid disease were also excluded from the study. pressure exceeded 180/110 or pulse rate exceeded 110/min during
that period, the subject would have been withdrawn from the study.
The study was undertaken at two sites: Pennington Biomedical If the blood pressure was between 180/110 and 160/100 or the pulse
Research Center and Scripps Clinic, from January 2001 until De- rate was between 100 and 110 the 3-h period of observation was
cember 2001. The study was approved by the Institutional Review repeated on the next visit when the dose of caffeine and ephedrine
Boards of Pennington Biomedical Research Center and Scripps was increased.
Clinic and was conducted in accordance with the Declaration of
Helsinki. All subjects provided written informed consent before
study initiation. Ninety participants were enrolled in total, 45 from
each site. Randomization was stratified by gender and BMI to Statistical analysis
reduce baseline group differences. The study was powered to detect a 10% difference in visceral adi-
pose tissue mass based on previous pilot data. A sample size of 25
subjects gives 80% power to detect a 10% difference between treat-
Study design ments with a significance level of a ¼ 0.05. We enrolled 30 partici-
This study was a randomized, double-blind, 3-arm parallel group pants per arm to allow for an expected drop rate of 15-20%. Only
study comparing: 1) caffeine 200 mg orally three times a day data from subjects completing the trial were included in the final
(t.i.d.), ephedrine 20 mg orally t.i.d. and placebo subcutaneously analyses.
(subQ) daily (q.d.) (CE); 2) leptin A-200 20 mg subQ q.d. and two
placebo pills t.i.d. (L) to; 3) the combination of caffeine 200 All data were analyzed using the Mixed Models procedure of SAS
mg orally t.i.d., ephedrine 20 mg orally t.i.d. and leptin A-200 20 Statistical Software (version 9.2; SAS Institute, Cary, NC). Weight
mg subQ q.d (LCE). The caffeine 200 mg and ephedrine 20 mg (25 was analyzed using a repeated measures analysis of variance
mg ephedrine HCl) and matching placebos were obtained from Mar- (ANOVA). This model included percent change as the dependent
tek Pharmacal Company (Riverdale, NJ). Active and placebo tablets variable and fixed effects for the three treatments, with the random
were identical in appearance. A forced dose titration schedule was effect of subject within treatment as an independent variable. Per-
used to allow subjects to acclimate to the caffeine dose. The caf- cent change in body fat mass, lean mass, visceral adipose tissue
feine and ephedrine were given once a day for the first week, twice mass, and blood metabolites from baseline were analyzed using
a day for the second week, and t.i.d. for the rest of the study. Sub- ANOVA. Assumptions of normality and homogeneity of variance
jects who could not tolerate the titration schedule were dropped were satisfied for all data analyzed. All hypotheses were tested
from the study. Leptin A-200 (recombinant methionyl human Fc- against two-directional alternatives. Statistical significance was
leptin), 40 mg/cc and placebo diluent were provided by Amgen Inc. defined as P < 0.05, and pair-wise comparisons of the three treat-
(Thousand Oaks, CA) and were given as a 0.5 cc subcutaneous ments were performed using a Tukey-Kramer adjustment.

1992 Obesity | VOLUME 21 | NUMBER 10 | OCTOBER 2013 www.obesityjournal.org

Original Article Obesity
CLINICAL TRIALS: BEHAVIOR, PHARMACOTHERAPY, DEVICES, SURGERY

(Figure 1). A total of 17 of 30 subjects completed the study in the

TABLE 1 Demographics and baseline characteristics of study
caffeine and ephedrine group (57%). A total of 18 of 30 subjects
participants completed the study in the leptin plus caffeine and ephedrine group
Caffeine/ (60%). A total of 26 of 30 subjects completed the study in the leptin
only group (87%). The differential dropout suggests that approxi-
Caffeine/ Ephedrine
mately 25-30% of subjects dropped due to intolerance of the caf-
Ephedrine Leptin plus Leptin
feine and ephedrine forced dose titration schedule used in this trial.
(n ¼ 30) (n ¼ 30) (n ¼ 30) Subjects experiencing caffeine/ephedrine-related adverse events,
Age (years) 35.5 (19.0) 40.0 (10.1) 41.5 (13.9) such as insomnia or anxiety, dropped out between weeks 2 and 4.
Women 27 (90%) 22 (73%) 25 (83%) Injection site-related adverse events such as erythema were most
Ethnic origin common in the leptin groups, and subjects who were unable to toler-
White 21 (70%) 19 (63%) 21 (70%) ate these symptoms dropped out between weeks 5 and 8. The demo-
graphics of subjects completing the trial are shown in Supporting
Black 7 (23%) 9 (30%) 5 (17%)
Information Table 1.
Other 2 (7%) 2 (7%) 4 (13%)
Weight (kg) 97.5 (12.9) 98.1 (13.6) 95.8 (10.3)
Body-mass index (kg/m2) 35.1 (3.1) 34.6 (3.4) 34.5 (2.7) Body weight and body composition
Systolic blood 116 (12) 120 (11) 117 (11) Both CE and LCE treatments led to significant reductions in body
pressure (mm Hg) weight compared to the leptin only group (Figure 2). All fixed
Diastolic blood 74 (8) 76 (7) 75 (7) effects were significant: treatment (P ¼ 0.006), time (P < 0.0001),
pressure (mm Hg) and the treatment  time interaction (P ¼ 0.026). The percent of
body weight lost reached statistical significance (P < 0.05) at week
Data are mean (SD) or number of participants (%). 8 for the LCE group and by week 12 for the CE group compared to
the leptin only group. Over the entire course of the 24 week study,
the leptin only, CE, and LCE groups lost 1.8 6 0.9%, 5.9 6 1.2%,
Results and 6.5 6 1.1% of their original body weight, respectively.

Participants These changes in body weight were mainly due to a decrease in fat
Baseline characteristics of all subjects enrolled in the study are pro- mass. While the leptin only group lost an average of 0.6 6 0.8 kg
vided in Table 1. In total, 61 of 90 subjects completed the study of total fat mass, the CE lost 4.3 6 0.9 kg, and the LCE group lost

FIGURE 1 Trial profile.

www.obesityjournal.org Obesity | VOLUME 21 | NUMBER 10 | OCTOBER 2013 1993

Obesity Leptin and Caffeine/Ephedrine for Weight Loss Liu et al.

FIGURE 2 Change in body weight. Data are means 6 SE. *P<0.05 compared with
leptin only.

4.9 6 0.9 kg of total fat mass after 24 weeks of treatment. The per-
cent change in total fat mass from baseline is shown in Figure 3A.
The CE group lost 9.6 6 2.4% of total fat mass (P ¼ 0.037) and
the LCE group lost 12.4 6 2.3% of total fat mass (P ¼ 0.003) after
24 weeks of treatment. In contrast, treatment with leptin only
resulted in only a 1.8 6 1.9% reduction in total fat mass. There
were no significant differences between groups in percent change in
total lean mass (Figure 3B). All groups experienced a 1-2% reduc-
tion in their lean mass over the entire course of the study (L:
1.78
6 0.73%, CE:
1.02 60.90%, LCE:
2.18 6 0.87%).

Percent changes in visceral adipose tissue mass from baseline are

shown in Figure 3C. Treatment with LCE resulted in an 11.0 6
3.3% reduction in visceral adipose tissue (P ¼ 0.049) after 24
weeks. The group treated with CE had a mean reduction in visceral
adipose tissue of 10.3 6 3.4% that did not reach statistical signifi-
cance (P ¼ 0.08). The group treated with leptin only lost 0.6 6
2.8% of visceral adipose tissue mass.

Metabolic Parameters
No significant changes were observed in blood glucose, insulin, tri-
glycerides, and LDL-cholesterol. Interestingly, the group treated with
leptin only experienced a 4.6% reduction in HDL-cholesterol levels
while the group treated with LCE experienced a 5.0% increase in
HDL levels (Table 2). These groups were significantly different from
each other (P ¼ 0.03). There were no significant differences in pulse FIGURE 3 Change in body composition. (A) Percent change in total body fat mass
rate or systolic blood pressure between groups. Diastolic blood pres- from baseline as measured by DXA. (B) Percent change in total body lean mass
from baseline as measured by DXA. (C) Percent change in visceral adipose tissue
sure was increased by 4.4 mm Hg in the CE group and reduced by 2.5 mass from baseline as measured by abdominal multi-slice CT scan.  leptin, *
mm Hg in the LCE group (Table 2). While these groups were signifi- caffeine/ephedrine, D leptin/caffeine/ephedrine. Data are means 6 SE. *P<0.05
cantly different from each other (P ¼ 0.03), they were not different compared with leptin only.
when compared to the leptin only group.

contrast, the CE and LCE treatments produced weight loss >5% and
Discussion significant reductions in total fat mass. Our primary outcome of vis-
In summary, treatment with leptin A-200 did not produce clinically ceral fat mass was also significantly decreased by the LCE treat-
relevant weight loss or changes in body composition. While our ment. However, there were no significant additive or synergistic
study was limited in that we did not have a true placebo group to actions between CE and leptin. This is perhaps not surprising in
compare to, the alterations in the leptin group were minimal (
1.8% light of the ineffectiveness of leptin in altering body weight or body
body weight,
1.8% total fat mass, and
1.8% total lean mass). In composition.

1994 Obesity | VOLUME 21 | NUMBER 10 | OCTOBER 2013 www.obesityjournal.org

Original Article Obesity
CLINICAL TRIALS: BEHAVIOR, PHARMACOTHERAPY, DEVICES, SURGERY

TABLE 2 Secondary endpoints at 24 weeks

Caffeine/Ephedrine Leptin Caffeine/Ephedrine

(n ¼ 17) (n ¼ 26) plus Leptin (n ¼ 18)
Fasting blood glucose (mmol/l)
Baseline 5.34 (0.44) 5.46 (0.46) 5.55 (0.57)
Percent change
2.6% (9.9) 0.7% (8.3)
1.9% (9.5)
Fasting insulin (pmol/l)
Baseline 72.9 (26.4) 79.9 (32.6) 103.5 (100.7)
Percent change
1.5% (31.4)
8.2% (28.1)
13.9% (34.9)
HOMA-IR
Baseline 2.49 (0.94) 2.84 (1.37) 2.96 (1.83)
Change
0.27 (0.82)
0.25 (1.14)
0.42 (1.83)
Triglycerides (mmol/l)
Baseline 1.35 (0.78) 1.40 (0.86) 1.71 (1.09)
Percent change
8.1% (55.7)
1.1% (46.3)
14.4% (42.1)
HDL cholesterol (mmol/l)
Baseline 1.39 (0.33) 1.39 (0.33) 1.37 (0.37)
Percent change 2.3% (12.6)ab
4.6% (11.0)a 5.0% (12.8)b
LDL cholesterol (mmol/l)
Baseline 2.83 (0.88) 3.01 (0.66) 3.12 (0.96)
Percent change
5.4% (16.3) 3.2% (20.0) 7.4% (23.2)
Systolic blood pressure (mm Hg)
Baseline 112.8(9.3) 119.5 (11.5) 116.2 (11.0)
Change 1.1 (11.4)
3.3 (10.0)
4.2 (9.9)
Diastolic blood pressure (mm Hg)
Baseline 71.6 (9.7) 75.4 (9.4) 74.9 (6.6)
Change 4.4 (7.8)b 1.1 (9.0)ab
2.5 (5.8)a
Pulse rate (beats/min)
Baseline 72.6 (7.0) 70.9 (9.5) 69.6 (7.4)
Change
1.4 (10.2)
1.5 (11.0)
4.5 (11.5)

Data are mean (SD). Different letter superscripts indicate significant differences (P < 0.05).

Our results are contrary to our previously observed results in two trial results (8). Leptin is still used to treat individuals with congeni-
pilot studies. Leptin did not produce enhanced visceral fat loss, and tal leptin deficiency (6,7). A few studies have investigated leptin’s
it even failed to produce significant weight loss. This discrepancy potential for improving insulin sensitivity, but results thus far have
may have been influenced by the small sample size in the pilot stud- been null or marginal (15,16). There has also been interest in com-
ies. However, this is in agreement with other clinical trials demon- bining leptin with other therapeutic drugs to induce weight loss.
strating that leptin is not an effective weight loss agent for obese Amylin and Takeda were pursuing the combination of pramlintide
individuals without congenital leptin deficiency (8,13). Studies and metreleptin as an anti-obesity therapy, and the combination
reported thus far have seen little change in total fat mass with leptin showed promising results in early clinical trials (17). However, in
treatment, which is in agreement with our results (8,14). To our 2011, phase II clinical trials were halted and the program was dis-
knowledge this is the first trial to examine effects of leptin adminis- continued after patients reportedly developed antibodies to metrelep-
tration specifically on visceral fat mass. Additionally, CE did not tin. A separate trial investigating the effects of metreleptin in obese
preferentially preserve lean tissue mass. The 1.02 6 0.9% reduction patients with type 2 diabetes reported significant increases in leptin-
in lean mass with CE treatment was not statistically different from binding protein and antileptin antibodies in the majority of subjects
the percentage of lean mass lost by the leptin only group (1.8 6 treated with metreleptin (16). At this time, there are no ongoing
0.7%). Our data demonstrate that leptin A-200 is not an effective combination leptin therapies for weight loss reported in the public
weight loss agent, whereas CE is effective in producing modest domain.
weight loss.
In 2004, the United States Food and Drug Administration banned the
The status of both leptin and caffeine/ephedrine as weight loss use of ephedra in supplements due to concerns over adverse psychiat-
agents have changed substantially since 2001, when this trial was ric, autonomic, or gastrointestinal symptoms or heart palpitations
completed. The idea of leptin as a weight loss drug for the general (18). In particular, the FDA cited concerns that increases in blood
population has largely been abandoned due to disappointing clinical pressure and heart palpitations could lead to increased risk of

www.obesityjournal.org Obesity | VOLUME 21 | NUMBER 10 | OCTOBER 2013 1995

Obesity Leptin and Caffeine/Ephedrine for Weight Loss Liu et al.

cardiovascular events such as heart attack or stroke. The report on 3. Greenway FL. The safety and efficacy of pharmaceutical and herbal caffeine and
ephedrine use as a weight loss agent. Obes Rev 2001;2:199-211.
which the decision was based relied primarily on adverse event
4. Shekelle PG, Hardy ML, Morton SC, et al. Efficacy and safety of ephedra and
reporting in randomized controlled trials and spontaneous case reports ephedrine for weight loss and athletic performance: a meta-analysis. JAMA 2003;
(4). However, the long-term (> 6 months) cardiotoxicity of ephedrine 289:1537-1545.
has never been assessed in a clinical trial. A six-month randomized 5. Montague CT, Farooqi IS, Whitehead JP, et al. Congenital leptin deficiency is asso-
clinical trial of caffeine, ephedrine, and their combination for weight ciated with severe early-onset obesity in humans. Nature 1997;387:903-908.
6. Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a
loss found the metabolic side effects to be transient and by week 8 child with congenital leptin deficiency. N Engl J Med 1999;341:879-884.
were comparable to the placebo group (19). An observational case- 7. Farooqi IS, Matarese G, Lord GM, et al. Beneficial effects of leptin on obesity, T
crossover study from Denmark found no association between pre- cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human con-
scribed caffeine/ephedrine use and adverse cardiovascular outcomes genital leptin deficiency. J Clin Invest 2002;110:1093-1103.
(20). Although not approved for use in the treatment of obesity in 8. Heymsfield SB, Greenberg AS, Fujioka K, et al. Recombinant leptin for weight loss
in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA
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available without a prescription, whereas ephedrine requires a pre- 9. Lapidus L, Bengtsson C, Larsson B, Pennert K, Rybo E, Sjostrom L. Distribution
scription. As ephedrine has been used as a starting product to make of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up
of participants in the population study of women in Gothenburg, Sweden. Br Med J
illegal methamphetamine, the sale of ephedrine is now more tightly (Clin Res Ed) 1984;289:1257-1261.
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from the supplement market because most companies sought to avoid 11. Fox CS, Massaro JM, Hoffmann U, et al. Abdominal visceral and subcutaneous adi-
liability and costly litigation associated with its use. pose tissue compartments: association with metabolic risk factors in the Framing-
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12. Smith SR, Lovejoy JC, Greenway F, et al. Contributions of total body fat, abdomi-
Our study provides evidence that caffeine/ephedrine is a modestly nal subcutaneous adipose tissue compartments, and visceral adipose tissue to the
effective weight loss agent and produces significant reductions in fat metabolic complications of obesity. Metabolism 2001;50:425-435.
mass. While we did not observe increases in pulse rate or blood 13. Zelissen PM, Stenlof K, Lean ME, et al. Effect of three treatment schedules of
recombinant methionyl human leptin on body weight in obese adults: a randomized,
pressure, these signs have been reported in previous trials and case placebo-controlled trial. Diabetes Obes Metab 2005;7:755-761.
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15. Mittendorfer B, Horowitz JF, DePaoli AM, McCamish MA, Patterson BW, Klein S.
added to CE.O Recombinant human leptin treatment does not improve insulin action in obese sub-
jects with type 2 diabetes. Diabetes 2011;60:1474-1477.
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Acknowledgments Diabetes 2011;60:1647-1656.
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Amgen provided the leptin A-200. The sponsor did not participate metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy.
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18. Food and Drug Administration. Final rule declaring dietary supplements containing
C 2013 The Obesity Society
V ephedrine alkaloids adulterated because they present an unreasonable risk. Final
rule. Fed Regist 2004;69:6787-6854.
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1996 Obesity | VOLUME 21 | NUMBER 10 | OCTOBER 2013 www.obesityjournal.org