Download The Effect of 7-Keto Naturalean TM on Weight

VOLUME 63, NO. 4, APRIL 2002
The Effect of 7-Keto Naturalean
on Weight Loss: A Randomized,
Double-Blind, Placebo-Controlled Trial
TM
John L. Zenk, MD, 1 Tami R. Helmer, MD, 1 Laurie J. Kassen, LD, RD, 1 and
Michael A. Kuskowski, PhD 2
1Minnesota Applied Research Center, Chanhassen, and 2Geriatric Research
Education and Clinical Center, Veterans Administration Medical
Center, Minneapolis, Minnesota
ABSTRACT
Background: A natural metabolite of d e h y d r o e p i a n d r o s t e r o n e (DHEA),
3-acetyl-7-oxo-dehydroepiandrosterone (7-oxo-DHEA), has been shown to be
effective in enhancing weight loss when combined with a diet and exercise
program.
Objective: This study assessed the effects of a formula containing 7-oxoDHEA, L-tyrosine, asparagus root extract, choline bitartrate, inositol, copper
gluconate, manganese, and potassium iodide (7-Keto Naturalean TM)on weight
loss, b o d y composition, and basal metabolic rate (BMR) in overweight patients
following a weight-reduction diet and exercise regimen.
Methods: In this prospective, randomized, double-blind, placebo-controlled
trial, healthy, overweight adults were given 7-Keto Naturalean (200 mg/d) or a
placebo of maltodextrin and followed a calorie-restricted diet (105 kJ/kg) and
an exercise program for 8 weeks. Body weight, body composition (by bioelectric impedance), and BMR (by indirect calorimetry) were measured at baseline,
week 4, and week 8. A thyroid panel was done at baseline and week 8.
Results: Of 35 healthy, overweight adults enrolled, 33 completed the study
(12 men, 21 women; age, 40-69 years; body mass index [BMI], 27.0-42.7 kg/m2).
Patients taking 7-Keto Naturalean lost significantly more weight after 8 weeks
than those taking placebo (mean + SD loss, 2.15 + 2.38 kg and 0.72 + 2.12 kg,
respectively) (P = 0.038). The change in BMI in the 7-Keto Naturalean-treated
group was significant c o m p a r e d with the change in the p l a c e b o group
(mean + SD decrease, 0.71 + 0.79 kg/m 2 and 0.01 + 1.05 kg/m 2, respectively)
(P = 0.036). There were no other statistically significant differences in any of the
other measured variables. 7-Keto Naturalean was well tolerated, and there were
no significant adverse events.
Accepted for publication February 8, 2002.
Printed in the USA. Reproduction in whole or part is not permitted.
0011-393X/02/$19.00
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CURRENT THERAPEUTICRESEARCH®
Conclusion: In this select population, 7-Keto Naturalean combined with a
reduced-calorie diet and an exercise program resulted in a significant weight
loss compared with diet and exercise alone.
Key words: weight loss, 7-oxo-DHEA, dehydroepiandrosterone, obesity.
(Curr Ther Res Clin Exp. 2002;63:263-272)
INTRODUCTION
Dehydroepiandrosterone (DHEA) has been shown in animal studies L2 to enhance thermogenesis and prevent obesity. Many mechanisms have been proposed for DHEA's action in this regard. The available literature supports
DHEA's ability to induce the formation of liver peroxisomes that oxidize fatty
acids, 3'4 foster futile cycling and the hydrolysis of fatty acyl coenzyme A (acylCoA), 5'6 increase the rate of mitochondrial oxidations, s-7 and enhance the liver
content of mitochondrial glycerol-3-phosphate dehydrogenase (G3PD) and cytosolic malic enzyme. ~-l° G3PD and malic enzyme are also induced by thyroid
hormone.11'12
3-Acetyl-7-oxo-dehydroepiandrosterone (7-oxo-DHEA) is a dietary supplement that is a naturally occurring metabolite of the adrenal steroid DHEA.
7-Oxo-DHEA is a more active inducer of G3PD and malic enzyme than its parent
steroid; it has the advantage of having no androgenic activity and is not converted to estrogens) 3
In 1993, Bobyleva et al 1 demonstrated in a rat model that 7-oxo-DHEA caused
an increase in liver catalase activity, rate of mitochondrial substrate oxidation, and fatty acyl-CoA oxidase activity. Hafner et a114 reported in 1988 that
in hyperthyroidism, an increase in proton conductance across the mitochondrial membrane may cause lower membrane potential, resulting in greater
thermogenesis.
Considering that 7-oxo-DHEA and thyroid hormone activate similar mitochondrial and cytosolic thermogenic enzymes, Bobyleva et al l~ then studied
7-oxo-DHEA using a similar rat system model. Sprague-Dawley rats were first
treated with respiratory inhibitors (succinate and G3PD); when they were further treated with 7-oxo-DHEA, there was a more rapid decline in membrane
potential, indicating enhanced thermogenesis. Realizing that the pharmacokinetic profile of 7-oxo-DHEA is similar to that of thyroid hormone, the investigators went on to test 7-oxo-DHEA in both the euthyroid and hypothyroid rat.
While 7-oxo-DHEA had no effect in the euthyroid rats, it restored mitochondrial
function in the hypothyroid rats. These investigators were not certain of the
mechanism by which 7-oxo-DHEA was able to exert these effects, but since
7-oxo-DHEA had no influence at all when added directly to the test systems,
they speculated that 7-oxo-DHEA is converted to a metabolite that is recognized
by a member of the steroid/thyroid hormone superfamily of receptors. Because
7-oxo-DHEA is known to convert to other in vivo metabolites, this concept
remains a viable explanation) 5
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J.L Zenk et aL
Results of the first human study to assess the thermogenic effect of 7oxo-DHEA were published in 2000 by Kalman et al. ~6 A randomized, doubleblind, placebo-controlled protocol was used to study a population of middleaged (mean age, 44.5 years), overweight (mean body mass index [BMI], 31.9
kg/m 2) subjects for 8 weeks. The subjects were required to exercise 3
times weekly for 60 minutes per session and were also required to follow a
calorie-restricted diet. During the study period, the 7-oxo-DHEA treatment
group (100 mg twice daily) lost significantly more weight and body fat than the
placebo group. There was also a statistically significant increase in serum triiodothyronine CI'3) levels in the 7-oxo-DHEA treatment group. However, the
T3 levels remained in the normal range. These researchers noted that the reduction in body fat observed in the group treated with 7-oxo-DHEA was consistent with the thermogenic profile of this agent and supported the previous
research done by Bobyleva et al 1'15 and Lardy et al. 13
The purpose of the present study was to assess the effects of a formula
containing 7-oxo-DHEA combined with 7 other ingredients thought to have a
synergistic effect on 7-oxo-DHEA in a similar population of middle-aged, overweight adults. The study was designed to compare this formula with 7-oxoDHEA alone with regard to weight and fat loss, as noted by Kalman et al, 1~ and
to further investigate the isolated increase in T3. Because T3 is known to have
a regulatory effect on basal metabolic rate (BMR), this study also investigated
changes in metabolic rate attributable to this formula.
PATIENTS AND METHODS
Patients
Healthy adults aged 40 to 70 years with a BMI >27 kg/m 2 were eligible for the
study. Individuals with hepatic or renal disease, diabetes, cardiovascular disease, uncontrolled hypertension, cancer, human immunodeficiency virus infection, AIDS, Cushing's disease, Addison's disease, thyroid disease, or seizure
disorder were excluded from the study. Patients were also excluded if they
were using medications for weight loss or were pregnant or lactating.
This study was approved by the Western Institutional Review Board, Olympia, Washington. All participants gave their written informed consent.
Study Design
Participants were r a n d o m i z e d to receive 1 capsule (200 mg) of 7-Keto
Naturalean TM* twice per day (n = 18) or placebo (maltodextrin) twice per day
(n = 17) for 8 weeks.
7-Keto-Naturalean contains 7-oxo-DHEA 100 mg, c-tyrosine 100 mg, asparagus
root extract 100 rag, choline bitartrate 50 mg, inositol 50 mg, copper gluconate
*Trademark: Enzymatic Therapy, Green Bay, Wisconsin.
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CURRENTTHERAPEUTICRESEARCH®
500 lag, manganese (Krebs cycle chelate) 500 lag, and potassium iodide 100 lag.
Because the purpose of this study was to assess all of the ingredients in 7-Keto
Naturalean, not just 7-oxo-DHEA, a placebo of maltodextrin was chosen. Indistinguishable capsules for the treatment and placebo groups were precoded by
the manufacturer according to a randomization table and were assigned sequentially as patients enrolled. Investigators remained blinded to the randomization code.
All patients were interviewed by a registered dietitian and prescribed a
reduced-calorie diet consisting of 105 kJ per kilogram of desirable b o d y
weight (DBW) per day. DBW was calculated using a standard formula: DBW for
men = 48.2 kg for height of 150 cm + 2.7 kg for every additional 2.5 cm of height,
±10%; DBW for women = 45.5 kg for height of 150 cm + 2.3 kg for every additional 2.5 cm of height, +10%. Patients were instructed to follow a specific
program of aerobic exercise and strength training for 45 minutes 3 times a week
for 8 weeks.
Diet and exercise compliance was monitored by a dietitian every 2 weeks,
either by telephone or during clinic visits. Participants completed a 24-hour
diet recall, which was analyzed by a dietitian and reviewed with participants.
Medication compliance was reviewed at clinic visits and assessed with a pill
count at the final clinic visit.
Measurements
All measurements were performed at baseline, week 4, and week 8. Patients
were weighed using a Tanita TBF-300 digital scale (Tanita Corp, Arlington
Heights, Illinois). Body composition was assessed using a Quantum II Bioelectric Impedance Analysis instrument (RJL Systems, Clinton Township, Michigan). BMR was determined by indirect calorimetry using a Deltatrac II Metabolic Monitor (Sensor Medics Corp, Yorba Linda, California). Vital signs (blood
pressure, pulse rate, and temperature) were measured using digital assessment
equipment. A thyroid panel (thyroxine IT4], total T3, and thyroid-stimulating
hormone) was obtained at baseline and week 8.
Statistical Analysis
Baseline characteristics, which were normally distributed in both the placebo
and 7-Keto Naturalean groups, were compared between groups using MannWhitney tests (except for sex, where the chi-square test was used). Testing
for normality of variable distributions (Lilliefors test) revealed that variables
(body weight and BMI) in both the treatment and placebo groups were not
normally distributed. Therefore, nonparametric comparison methods were
used to compare the groups (Mann-Whitney Test). The computed change
from baseline was compared for all measured variables and expressed as the
mean, with variability expressed as the SD. There were no missing data for
patients completing the study. Two patients (1 in the 7-Keto Naturalean group
and 1 in the placebo group) dropped out of the study after 5 weeks, without
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J.L. Zenk et aL
completing the week-4 assessment, and were excluded from the statistical
analysis.
RESULTS
Study Population
Thirty-five patients (23 women, 12 men) enrolled in the study. The mean age of
the participants was 48.7 years (range, 40-69 years), mean b o d y weight was
96.5 kg, and mean BMI was 33.1 kg/m 2 (range, 27.0-42.7 kg/m 2) (Table I). There
were no significant differences in baseline characteristics between the 2 treatment groups. Of the 35 patients randomized, 33 completed the study--17 in the
7-Keto Naturalean treatment group (7 men and 10 women) and 16 in the placebo
group (5 men and 11 women). One patient in the placebo group was withdrawn
due to acute gouty arthritis and inability to continue the exercise program. One
patient in the 7-Keto Naturalean treatment group withdrew due to personal
reasons unrelated to study participation. Throughout the study, there were no
significant differences in dietary compliance (the amount of carbohydrate, protein, fat, and total kilocalories consumed), exercise compliance, or medication
compliance between the 2 groups.
Weight Loss
Table II lists BMI and body weight for each patient at baseline and at weeks 4
and 8. Weight loss in the 7-Keto Naturalean group differed significantly from the
Table I. Baseline characteristics.
7-Keto Naturalean TM*
(n=18)
Sex, no.
Male
Female
Age, yt
BMI, kg/m 2t
BMR, k~/d t
Body weight, kg t
Body fat, % t
SBP, m m Hg t
DBP, m m Hg t
Triiodothyronine, nmol/L t
Thyroxine, nmol/L t
Thyroid-stimulating hormone, mU/L t
49.0
33.1
7032.5
97.0
38.8
134.9
78.1
2.0
89.0
2.3
7
11
+ 7.3
+ 4.1
_+ 1075.8
_ 16.3
_+ 11.6
+ 11.3
__+8.2
+ 0.3
+ 15.5
_+ 1.8
Placebo
(n=17)
48.5
33.0
7137.1
95.9
39.8
135.5
82.4
2.1
91.6
2.8
5
12
+ 5.3
+ 3.8
_ 1172.1
+ 19.4
__+ 10.3
+ 17.8
+ 8.0
_+ 0.4
_+ 14.2
_+ 1.8
BMI = body mass index; BMR = basal metabolic rate; SBP = systolic blood pressure; DBP = diastolic
blood pressure.
*Trademark: Enzymatic Therapy, Green Bay, Wisconsin.
tMean _+ SD.
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Table II. Body weight and body mass index (BMI) for each patient at baseline, week 4, and
week 8.
7-Keto NaturaleanTM* (n = 18)
Body Weight (kg)
BMI (kg/m 2)
Patient
No.
1
3
6
7
9
11
13
15
18
20
21 t
23
25
28
30
31
33
35
Baseline
Week 4
Week 8
Baseline
Week 4
Week 8
78.82
94.09
63.36
106.64
87.64
80.82
78.73
100.36
101.27
122.18
99.64
103.55
93.36
114.82
105.55
105.45
83.64
127.09
77.91
87.91
61.55
104.27
86.73
81.27
76.55
98.73
102.18
119.45
-103.09
91.45
113.18
101.73
107.27
80.00
129.00
79.00
84.18
62.27
104.09
85.91
80.00
77.18
99.09
101.36
118.45
-100.00
90.91
111.36
103.36
104.55
81.1 8
127.82
30.72
31.02
29.05
30.12
32.08
27.03
29.73
36.74
39.47
42.74
32.37
31.33
32.1 7
34.26
31.49
35.28
31.10
39.00
30.36
28.98
28.30
29.40
31.75
27.19
28.91
36.14
39.82
41.78
-31.19
31.51
33.77
30.35
35.88
29.74
39.58
30.79
27.75
28.63
29.40
31.45
26.76
29.15
36.28
39.61
41.43
-30.26
31.32
33.23
30.84
34.97
30.18
39.22
Placebo (n = 1 7)
Patient
No.
2
4
5
8
10
12 t
14
16
17
19
22
24
26
27
29
32
34
Body Weight (kg)
BMI (kg/m 2)
Baseline
Week 4
Week 8
Baseline
Week 4
Week 8
86.00
69.09
92.82
105.09
91.73
69.55
111.09
105.27
109.27
122.73
119.55
1 34.00
76.45
84.09
97.45
75.82
79.55
84.64
70.09
92.82
102.36
90.45
-111.36
101.27
109.64
123.91
118.82
1 33.45
74.73
85.64
96.18
76.91
79.27
84.45
69.27
92.73
101.45
91.00
-111.73
99.18
108.82
124.09
119.09
1 32.45
74.82
84.36
96.27
79.45
79.36
30.54
27.80
31.05
29.68
35.75
29.88
37.71
36.82
35.50
36.62
38.84
37.85
28.87
30.79
32.60
27.76
34.18
30.05
28.20
31.05
28.91
35.25
-37.81
35.42
36.97
36.97
38.60
37.70
28.22
31.35
32.1 7
28.16
34.06
29.99
27.87
31.02
28.60
35.46
-37.93
34.69
35.35
39.46
38.69
37.41
28.25
30.89
32.20
29.09
34.10
*Trademark: EnzymaticTherapy, Green Bay, Wisconsin.
tpatient terminated or dropped out.
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J.L. Zenk et aL
placebo group from baseline to 8 weeks (P = 0.038). In the 7-Keto Naturalean
group, mean weight loss was 2.15 + 2.38 kg, and in the placebo group mean
weight loss was 0.72 + 2.12 kg. BMI decreased significantly in the 7-Keto Naturalean group compared with the placebo group from baseline to week 8
(P= 0.036). In the 7-Keto Naturalean group and the placebo group, the decrease
in BMI was 0.71 + 0.79 kg/m 2 and 0.01 + 1.05 kg/m 2, respectively.
Body Composition and Basal Metabolic Rate
There were no significant between-group differences in changes in body fat,
BMR, or fat-free mass (Table III). Intracellular water and extracellular water, as
measured by bioelectric impedance analysis, were also not significantly different between the 2 groups.
Safety and Tolerability
There were no significant between-group differences in vital signs (blood pressure, pulse rate, and temperature). With regard to adverse events, the 7-Keto
Naturalean group reported 2 adverse events (metallic taste and heartburn) that
were considered possibly related to treatment. No serious adverse events were
reported. The incidence of all adverse events, regardless of whether they were
thought to be related to the study drug, is listed in Table IV. Laboratory assessment of thyroid function revealed no differences between treatment
groups.
DISCUSSION
For individuals who are overweight or obese, the goal of an ideal weight or fat
percentage may be practically unachievable. Fortunately, even small reductions in weight (5%-10%) can substantially improve blood pressure, serum lipid
levels, and glucose tolerance, IT and can diminish the incidence of diabetes and
hypertensionJ s']9 In this study, 7-Keto Naturalean combined with a reducedcalorie diet and moderate exercise resulted in a significant change in body
weight and BMI. The treatment group taking 7-Keto Naturalean experienced a
significantly greater decrease in body weight and BMI than did the group taking
Table III. Changes in body composition and basal metabolic rate (BMR).
°7o Body fat change
BMR change (kl/d)
% Fat-free mass change
7-Keto Naturalean TM*t
(n = 18)
Placebo t
(n = 17)
,~
- 0 . 5 8 ± 1.49
14.78 ± 662.35
0.52 ± 1.49
-0.01 ± 1.54
- 7 . 8 2 ± 775.96
0.10 ± 1.54
0.41
0.86
0.39
*Trademark: Enzymatic Therapy, Green Bay, Wisconsin.
tMean _+ SD change from baseline to week 8.
*P value (Mann-Whitney test).
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CURRENTTHERAPEUTICRESEARCH
®
Table IV. Number of patients reporting each adverse event.
Adverse Event
7-Keto-Naturalean TM*
(n = 18)
Placebo
(n = 17)
2
1
1
1
0
0
0
0
0
0
0
0
0
0
0
0
2
1
1
1
1
1
1
1
Heartburn
Hypothyroidism
Metallic taste
Upper respiratory tract infection
Insomnia
Acute gout
Edema
Cough
Headache
Hyperthyroidism
Temporal mandibular joint symptoms
Urinary tract infection
*Trademark: Enzymatic Therapy, Green Bay, Wisconsin.
placebo over an 8-week period. The mean difference in body weight change
between the 2 groups was 1.43 kg, with the 7-Keto Naturalean treatment group
losing 2.15 kg and the placebo group losing 0.72 kg in 8 weeks. There were no
statistically significant differences in the amount of carbohydrate, protein, or
fat, or in total kilocalories consumed between the 2 groups, nor was there a
significant difference in the intra- or extracellular water or exercise regimens
between the 2 groups. Therefore, the differences in body weight and BMI
changes are attributable to 7-Keto Naturalean and not a lack of compliance in
the placebo group. The purpose of the study was to investigate differences
between the groups with regard to the use of 7-Keto Naturalean compared with
placebo, not to maximize weight loss in these individuals.
The present study and the study by Kalman et al ~6 both reveal a statistically
significant reduction in body weight in the groups taking either 7-oxo-DHEA
alone or 7-Keto Naturalean when compared with groups taking a placebo.
The present study revealed no significant changes in the thyroid profile
between the 2 groups. This differs from the data reported by Kalman et al, z6
who found an isolated increase in T3 in the patients taking 7-oxo-DHEA alone
compared with placebo.
The results of our study are promising, as they reveal a mean weight loss of
2.15 kg or 2.2% from baseline in the 7-Keto Naturalean group. In a study by
Dhurandhar et al, 2° weight loss was measured after 1 month and 6 months of
treatment in patients receiving obesity drugs. Initial weight loss with obesity
drugs was found to be highly correlated with weight loss response after 6
months. The results showed that individuals who lose >-1.81 kg in the first
month had a 98% chance of achieving at least a 5% weight loss after 6 months
270
J.L. Zenk et aL
of treatment, and those who lost <1.81 kg in the first month had a 77% chance
of achieving at least a 5% weight loss after 6 months. The investigators went on
to study the population of patients who lost only 0.45 kg in the first month and
found that 69% of this group achieved at least a 5% weight loss after 6 months
of treatment. 2° The North American Association for the Study of Obesity guidelines 2~ for drug treatment of obesity state that a 5% weight loss over a period
of 6 to 12 months is an indicator of success, as this is associated with significant
health benefits.
Based on these observations and given the results of the present study
(mean weight loss in the 7-Keto Naturalean group of 1.47 kg in the first 4 weeks),
we could reasonably expect to see at least 69% of the 7-Keto Naturalean group
achieving a meaningful ->5% weight loss at 6 months. Further long-term weight
loss studies are, therefore, warranted to validate this conclusion.
CONCLUSIONS
The results of this study in a select population reveal that, when combined with
a reduced-calorie diet and an exercise program, 7-Keto Naturalean was more
effective at reducing b o d y weight over an 8-week period than exercise and diet
alone.
ACKNOWLEDGMENTS
The authors wish to acknowledge the contribution of Eva Shronts, MMSc, RD,
CNSD, LD, in helping to develop and implement the study protocol.
This trial was s p o n s o r e d by Enzymatic Therapy, Green Bay, Wisconsin, and
Humanetics Corporation, Chanhassen, Minnesota.
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Address correspondence to:
J o h n L. Zenk, MD
M i n n e s o t a Applied R e s e a r c h Center
18894 Lake Drive East
C h a n h a s s e n , MN 55317
E-marl: j o h n @ o n t h e m a r c r e s e a r c h . c o m
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