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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Supporting Information

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 ± 1.2% and −6.5 ± 1.1%, P < 0.05) and whole body fat mass (−9.6 ± 2.4% and −12.4 ± 2.3%, P < 0.05) compared to leptin only group. Only treatment with LCE significantly reduced visceral fat mass (−11.0 ± 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.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Supporting Information

During weight loss, lean tissue is often lost in addition to fat tissue. This loss of lean tissue may have adverse consequences because of the important role skeletal muscle plays in the regulation of blood glucose and lipid levels [1]. Work by Allison et al. demonstrated that for every standard deviation of weight loss, mortality increased by 30%, but for every standard deviation of fat loss, mortality decreased by 15% [2]. This suggests that loss of fat mass has beneficial health effects, whereas loss of lean mass can be detrimental. Thus one of the main goals of any weight loss program is to maximize fat loss while minimizing lean tissue loss.

Ephedra-containing weight-loss supplements were widely used in the 1990s. Caffeine was combined with ephedrine, the most potent isomer of the four ephedra isomers, to stimulate weight loss pharmacologically, and it was an approved combination weight loss drug in Denmark for over a decade [3]. A meta-analysis of clinical trials concluded that ephedrine and ephedra enhanced weight loss 0.9 kg/month above the amount lost with placebo in trials lasting up to 6 months [4]. In a pilot study we performed at Pennington Biomedical Research Center, female subjects were treated with either caffeine and ephedrine (n = 6) or fenfluramine and mazindol or phentermine (n = 14) for 6-9 months. Both groups lost weight, but the caffeine/ephedrine group experienced no loss of lean tissue mass (unpublished data) suggesting that caffeine/ephedrine might preferentially preserve lean tissue mass during weight loss.

The discovery of leptin sparked great interest in its utility as a weight loss agent. Leptin plays a key role in energy homeostasis, and humans with congenital leptin deficiency exhibit severe hyperphagia and obesity [5]. The phenotype of these individuals can be completely reversed with leptin replacement therapy [6, 7]. However, in clinical trials with a normal obese population, high-dose leptin therapy failed to produce clinically meaningful weight loss [8]. Amgen developed a long-acting recombinant methionyl human Fc-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). Reducing the amount of visceral fat mass is especially desirable because central or visceral obesity is associated with the highest mortality risk and many co-morbidities of obesity [9-11].

Based on these initial pilot studies, we hypothesized that the combination of caffeine/ephedrine and leptin A-200 would produce selective loss of visceral fat mass, while simultaneously preserving lean body mass.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Supporting Information

Participants

Ninety men and women between 18 and 60 years of age were eligible for inclusion if they had a BMI of 30-40 kg/m2. Women of childbearing potential were required to use effective contraception and were excluded if they were pregnant or lactating. Participants were ineligible if they were using regular medication other than hormonal birth control pills or hormone replacement therapy; had gained or lost more than 4 kg in the past 6 months; had taken monoamine oxidase inhibitor medication in the past month; were sensitive to Escherichia coli or E. coli-derived products. Participants with hypertension (blood pressure >150/90), known heart disease, prostatism, or thyroid disease were also excluded from the study.

The study was undertaken at two sites: Pennington Biomedical Research Center and Scripps Clinic, from January 2001 until December 2001. The study was approved by the Institutional Review Boards of Pennington Biomedical Research Center and Scripps 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 reduce baseline group differences.

Study design

This study was a randomized, double-blind, 3-arm parallel group study comparing: 1) caffeine 200 mg orally three times a day (t.i.d.), ephedrine 20 mg orally t.i.d. and placebo subcutaneously (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 mg orally t.i.d., ephedrine 20 mg orally t.i.d. and leptin A-200 20 mg subQ q.d (LCE). The caffeine 200 mg and ephedrine 20 mg (25 mg ephedrine HCl) and matching placebos were obtained from Martek Pharmacal Company (Riverdale, NJ). Active and placebo tablets were identical in appearance. A forced dose titration schedule was used to allow subjects to acclimate to the caffeine dose. The caffeine and ephedrine were given once a day for the first week, twice a day for the second week, and t.i.d. for the rest of the study. Subjects who could not tolerate the titration schedule were dropped from the study. Leptin A-200 (recombinant methionyl human Fc-leptin), 40 mg/cc and placebo diluent were provided by Amgen Inc. (Thousand Oaks, CA) and were given as a 0.5 cc subcutaneous injection once a day throughout the study. Study site personnel, participants, and the study team were blinded to treatment assignment, and blinding was only broken in case of an emergency.

Procedures

Participants were seen at weeks 0, 1, 2, 3, 4, 8, 12, 16, 20, and 24 at which time weight, vital signs, adverse events (including injection site inspection), and medication dispensing was done. At baseline, subjects were instructed in lifestyle modification principles, a walking program with a goal of 30 min five times per week and a balanced calorie-restricted diet, 1200 kcal/day for women and 1500 kcal/day for men. Data for compliance with diet and exercise instruction were not obtained.

Efficacy measures included weight and BMI at each visit. At baseline, 12 and 24 week, whole body fat mass and lean mass were assessed by dual energy X-ray absorptiometry (DXA), and visceral adipose tissue mass was obtained using abdominal multislice CT scan as previously described [12]. A lipid panel, glucose, and insulin were obtained at baseline and 24 week.

Screening measures included a medical history, TSH and T3 by RIA, at baseline. A physical examination, CBC, urinalysis, chemistry panel, and EKG were done at baseline and 24 week. A pregnancy test was done on females with childbearing potential at baseline, 12 and 24 week. During the forced dose titration of caffeine and ephedrine, subjects remained in the clinic for three hours after taking the first dose of caffeine and ephedrine, and blood pressure and pulse rate were taken every hour during that period. If blood pressure exceeded 180/110 or pulse rate exceeded 110/min during that period, the subject would have been withdrawn from the study. If the blood pressure was between 180/110 and 160/100 or the pulse rate was between 100 and 110 the 3-h period of observation was repeated on the next visit when the dose of caffeine and ephedrine was increased.

Statistical analysis

The study was powered to detect a 10% difference in visceral adipose tissue mass based on previous pilot data. A sample size of 25 subjects gives 80% power to detect a 10% difference between treatments with a significance level of α = 0.05. We enrolled 30 participants per arm to allow for an expected drop rate of 15-20%. Only data from subjects completing the trial were included in the final analyses.

All data were analyzed using the Mixed Models procedure of SAS Statistical Software (version 9.2; SAS Institute, Cary, NC). Weight was analyzed using a repeated measures analysis of variance (ANOVA). This model included percent change as the dependent variable and fixed effects for the three treatments, with the random effect of subject within treatment as an independent variable. Percent change in body fat mass, lean mass, visceral adipose tissue mass, and blood metabolites from baseline were analyzed using ANOVA. Assumptions of normality and homogeneity of variance were satisfied for all data analyzed. All hypotheses were tested against two-directional alternatives. Statistical significance was defined as P < 0.05, and pair-wise comparisons of the three treatments were performed using a Tukey-Kramer adjustment.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Supporting Information

Participants

Baseline characteristics of all subjects enrolled in the study are provided in Table 1. In total, 61 of 90 subjects completed the study (Figure 1). A total of 17 of 30 subjects completed the study in the caffeine and ephedrine group (57%). A total of 18 of 30 subjects completed the study in the leptin plus caffeine and ephedrine group (60%). A total of 26 of 30 subjects completed the study in the leptin only group (87%). The differential dropout suggests that approximately 25-30% of subjects dropped due to intolerance of the caffeine and ephedrine forced dose titration schedule used in this trial. Subjects experiencing caffeine/ephedrine-related adverse events, such as insomnia or anxiety, dropped out between weeks 2 and 4. Injection site-related adverse events such as erythema were most common in the leptin groups, and subjects who were unable to tolerate these symptoms dropped out between weeks 5 and 8. The demographics of subjects completing the trial are shown in Supporting Information Table 1.

image

Figure 1. Trial profile.

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Table 1. Demographics and baseline characteristics of study participants
 Caffeine/ Ephedrine (n = 30)Leptin (n = 30)Caffeine/ Ephedrine plus Leptin (n = 30)
  1. Data are mean (SD) or number of participants (%).

Age (years)35.5 (19.0)40.0 (10.1)41.5 (13.9)
Women27 (90%)22 (73%)25 (83%)
Ethnic origin   
White21 (70%)19 (63%)21 (70%)
Black7 (23%)9 (30%)5 (17%)
Other2 (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)
Systolic blood pressure (mm Hg)116 (12)120 (11)117 (11)
Diastolic blood pressure (mm Hg)74 (8)76 (7)75 (7)

Body weight and body composition

Both CE and LCE treatments led to significant reductions in body weight compared to the leptin only group (Figure 2). All fixed effects were significant: treatment (P = 0.006), time (P < 0.0001), and the treatment × time interaction (P = 0.026). The percent of body weight lost reached statistical significance (P < 0.05) at week 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 ± 0.9%, 5.9 ± 1.2%, and 6.5 ± 1.1% of their original body weight, respectively.

image

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

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These changes in body weight were mainly due to a decrease in fat mass. While the leptin only group lost an average of 0.6 ± 0.8 kg of total fat mass, the CE lost 4.3 ± 0.9 kg, and the LCE group lost 4.9 ± 0.9 kg of total fat mass after 24 weeks of treatment. The percent change in total fat mass from baseline is shown in Figure 3A. The CE group lost 9.6 ± 2.4% of total fat mass (P = 0.037) and the LCE group lost 12.4 ± 2.3% of total fat mass (P = 0.003) after 24 weeks of treatment. In contrast, treatment with leptin only resulted in only a 1.8 ± 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% reduction in their lean mass over the entire course of the study (L: −1.78 ± 0.73%, CE: −1.02 ±0.90%, LCE: −2.18 ± 0.87%).

image

Figure 3. Change in body composition. (A) Percent change in total body fat mass 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 mass from baseline as measured by abdominal multi-slice CT scan. leptin, ○ caffeine/ephedrine, Δ leptin/caffeine/ephedrine. Data are means ± SE. *P<0.05 compared with leptin only.

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Percent changes in visceral adipose tissue mass from baseline are shown in Figure 3C. Treatment with LCE resulted in an 11.0 ± 3.3% reduction in visceral adipose tissue (P = 0.049) after 24 weeks. The group treated with CE had a mean reduction in visceral adipose tissue of 10.3 ± 3.4% that did not reach statistical significance (P = 0.08). The group treated with leptin only lost 0.6 ± 2.8% of visceral adipose tissue mass.

Metabolic Parameters

No significant changes were observed in blood glucose, insulin, triglycerides, 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 = 0.03). There were no significant differences in pulse rate or systolic blood pressure between groups. Diastolic blood pressure was increased by 4.4 mm Hg in the CE group and reduced by 2.5 mm Hg in the LCE group (Table 2). While these groups were significantly different from each other (P = 0.03), they were not different when compared to the leptin only group.

Table 2. Secondary endpoints at 24 weeks
 Caffeine/Ephedrine (n = 17)Leptin (n = 26)Caffeine/Ephedrine plus Leptin (n = 18)
  1. Data are mean (SD). Different letter superscripts indicate significant differences (P < 0.05).

Fasting blood glucose (mmol/l)   
Baseline5.34 (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)   
Baseline72.9 (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   
Baseline2.49 (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)   
Baseline1.35 (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)   
Baseline1.39 (0.33)1.39 (0.33)1.37 (0.37)
Percent change2.3% (12.6)ab−4.6% (11.0)a5.0% (12.8)b
LDL cholesterol (mmol/l)   
Baseline2.83 (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)   
Baseline112.8(9.3)119.5 (11.5)116.2 (11.0)
Change1.1 (11.4)−3.3 (10.0)−4.2 (9.9)
Diastolic blood pressure (mm Hg)   
Baseline71.6 (9.7)75.4 (9.4)74.9 (6.6)
Change4.4 (7.8)b1.1 (9.0)ab−2.5 (5.8)a
Pulse rate (beats/min)   
Baseline72.6 (7.0)70.9 (9.5)69.6 (7.4)
Change−1.4 (10.2)−1.5 (11.0)−4.5 (11.5)

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Supporting Information

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

Our results are contrary to our previously observed results in two pilot studies. Leptin did not produce enhanced visceral fat loss, and it even failed to produce significant weight loss. This discrepancy may have been influenced by the small sample size in the pilot studies. However, this is in agreement with other clinical trials demonstrating that leptin is not an effective weight loss agent for obese individuals without congenital leptin deficiency [8, 13]. Studies reported thus far have seen little change in total fat mass with leptin treatment, which is in agreement with our results [8, 14]. To our knowledge this is the first trial to examine effects of leptin administration specifically on visceral fat mass. Additionally, CE did not preferentially preserve lean tissue mass. The 1.02 ± 0.9% reduction in lean mass with CE treatment was not statistically different from the percentage of lean mass lost by the leptin only group (1.8 ± 0.7%). Our data demonstrate that leptin A-200 is not an effective weight loss agent, whereas CE is effective in producing modest weight loss.

The status of both leptin and caffeine/ephedrine as weight loss agents have changed substantially since 2001, when this trial was completed. The idea of leptin as a weight loss drug for the general population has largely been abandoned due to disappointing clinical trial results [8]. Leptin is still used to treat individuals with congenital leptin deficiency [6, 7]. A few studies have investigated leptin's potential for improving insulin sensitivity, but results thus far have been null or marginal [15, 16]. There has also been interest in combining leptin with other therapeutic drugs to induce weight loss. Amylin and Takeda were pursuing the combination of pramlintide and metreleptin as an anti-obesity therapy, and the combination showed promising results in early clinical trials [17]. However, in 2011, phase II clinical trials were halted and the program was discontinued after patients reportedly developed antibodies to metreleptin. A separate trial investigating the effects of metreleptin in obese patients with type 2 diabetes reported significant increases in leptin-binding protein and antileptin antibodies in the majority of subjects treated with metreleptin [16]. At this time, there are no ongoing combination leptin therapies for weight loss reported in the public domain.

In 2004, the United States Food and Drug Administration banned the use of ephedra in supplements due to concerns over adverse psychiatric, autonomic, or gastrointestinal symptoms or heart palpitations [18]. In particular, the FDA cited concerns that increases in blood pressure and heart palpitations could lead to increased risk of cardiovascular events such as heart attack or stroke. The report on which the decision was based relied primarily on adverse event reporting in randomized controlled trials and spontaneous case reports [4]. However, the long-term (> 6 months) cardiotoxicity of ephedrine has never been assessed in a clinical trial. A six-month randomized clinical trial of caffeine, ephedrine, and their combination for weight loss found the metabolic side effects to be transient and by week 8 were comparable to the placebo group [19]. An observational case-crossover study from Denmark found no association between prescribed caffeine/ephedrine use and adverse cardiovascular outcomes [20]. Although not approved for use in the treatment of obesity in USA, both caffeine and ephedrine are approved drugs; caffeine is available without a prescription, whereas ephedrine requires a prescription. As ephedrine has been used as a starting product to make illegal methamphetamine, the sale of ephedrine is now more tightly controlled than it was in 2001. While the legality of the FDA ruling has been challenged in court, ephedra has essentially disappeared from the supplement market because most companies sought to avoid liability and costly litigation associated with its use.

Our study provides evidence that caffeine/ephedrine is a modestly effective weight loss agent and produces significant reductions in fat mass. While we did not observe increases in pulse rate or blood pressure, these signs have been reported in previous trials and case reports that led to the FDA ban on ephedra use in dietary supplements. Leptin A-200 was not effective in producing weight loss and did not have any significant additive or synergistic actions when added to CE.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Supporting Information

Amgen provided the leptin A-200. The sponsor did not participate in the analysis or interpretation of the data.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Supporting Information

Additional Supporting Information may be found in the online version of this article.

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