Category: weight loss

Metformin Extended Release Treatment of Adolescent Obesity

A 48-Week Randomized, Double-Blind, Placebo-Controlled Trial With 48-Week Follow-up

Glaser Pediatric Research Network Obesity Study Group

Arch Pediatr Adolesc Med. 2010;164(2):116-123.


Background  Metformin has been proffered as a therapy foradolescent obesity, although long-term controlled studies havenot been reported.

Objective  To test the hypothesis that 48 weeks of dailymetformin hydrochloride extended release (XR) therapy will reducebody mass index (BMI) in obese adolescents, as compared withplacebo.

Design  Multicenter, randomized, double-blind, placebo-controlledclinical trial.

Setting  The 6 centers of the Glaser Pediatric ResearchNetwork from October 2003 to August 2007.

Participants  Obese (BMI≥95th percentile) adolescents (aged13-18 years) were randomly assigned to the intervention (n = 39)or placebo groups.

Intervention  Following a 1-month run-in period, subjectsfollowing a lifestyle intervention program were randomized 1:1to 48 weeks’ treatment with metformin hydrochloride XR, 2000mg once daily, or an identical placebo. Subjects were monitoredfor an additional 48 weeks.

Main Outcome Measure  Change in BMI, adjusted for site,sex, race, ethnicity, and age and metformin vs placebo.

Results  After 48 weeks, mean (SE) adjusted BMI increased0.2 (0.5) in the placebo group and decreased 0.9 (0.5) in themetformin XR group (P = .03). This difference persistedfor 12 to 24 weeks after cessation of treatment. No significanteffects of metformin on body composition, abdominal fat, orinsulin indices were observed.

Conclusion  Metformin XR caused a small but statisticallysignificant decrease in BMI when added to a lifestyle interventionprogram.

Trial Registration Identifiers: NCT00209482and NCT00120146


 Jump to Section
 • Top
 • Introduction
 • Methods
 • Results
 • Comment
 • Author information
 • References

Childhood obesity rates in the United States have more thantripled over the past 50 years, with recent reports indicatingthat 31.9% of all children are overweight or obese.1 Obesityin childhood, particularly during adolescence, is associatedwith significant morbidity, including type 2 diabetes mellitusand hypertension, and a high risk for adult obesity and associatedrisks for diabetes mellitus and cardiovascular disease.2 Itis imperative that effective prevention and treatment modalitiesbe identified to address the epidemic of childhood and adolescentobesity.

Current standard treatment of childhood obesity is lifestylemodification, including diet and exercise.3 However, short-termprospective trials using various lifestyle modification programshave shown that effectiveness is often related to the intensityof the program, shows high intersubject variability, and haslimited longevity.4

Metformin hydrochloride is commonly used as a primary or adjunctivetreatment in obese, nondiabetic adolescents. However, thereare limited short-term data to support this therapy, and itis unclear whether any observed effects of metformin on bodymass index (BMI) are associated with changes in body compositionor insulin sensitivity. Therefore, we conducted a 48-week randomized,double-blind, placebo-controlled trial of extended-release (XR)metformin therapy in nondiabetic obese adolescents, followedby a 48-week monitoring period after completion of treatment.


 Jump to Section
 • Top
 • Introduction
 • Methods
 • Results
 • Comment
 • Author information
 • References


We hypothesized that treatment of obese adolescents with metforminXR coupled with a lifestyle intervention would decrease BMIas compared with treatment with placebo and the same lifestyleintervention.


The study was conducted from October 2003 to August 2007 atthe 5 clinical sites of the Glaser Pediatric Research Network,along with the Data Coordinating Center located at Children’sHospital Boston. The study was approved by the institutionalreview boards at each of the 6 centers; informed parental consentand subject assent were obtained. An external Data and SafetyMonitoring Board was involved throughout the study.


Adolescents aged 13.00 years to younger than 18 years were eligibleif they were obese (BMI≥95th percentile for age and sex5) butweighed less than 136 kg (the weight limit for the dual-emissionx-ray absorptiometry [DXA] table). Subjects were excluded ifthey had a previous diagnosis of diabetes mellitus, had everused a medication to treat diabetes mellitus or insulin resistance,had ever used a medication to aid in weight loss, were takingany medications known to increase metformin levels (eg, cimetidine),received recent glucocorticoid therapy, had any identified syndromeor medical disorder predisposing to obesity, had surgical therapyfor obesity, had attended a formal weight loss program withinthe previous 6 months, admitted to significant alcohol use inthe past 6 months, had elevated creatinine (>1.2 mg/dL [to convertto micromoles per liter, multiply by 88.4]) or liver enzymes(aspartate aminotransferase or alanine aminotransferase >80U/L [to convert to microkatals per liter, multiply by 0.0167])levels, had untreated disorders of thyroid function, had impairedambulation or mobility, or had ever been pregnant.


After clinical eligibility was confirmed, diabetes mellituswas excluded at a baseline visit (study day 0) using an oralglucose tolerance test (OGTT). Other fasting laboratory studies,DXA, and abdominal computed tomography (CT) were also performedat baseline.

The study sample was enriched for subjects with a higher likelihoodof complying with the protocol using a 4-week placebo run-inphase, during which subjects were required to attend at least2 of 3 scheduled lifestyle modification sessions and demonstrate80% compliance with daily placebo treatment (pill count) forsubsequent randomization. Subjects were then randomized 1:1to treatment with either metformin XR (Glucophage XR) or identicalplacebo tablets and instructed to take 1 tablet/d (metforminhydrochloride XR 500 mg or placebo) orally before dinner for2 weeks, then 2 tablets/d for 2 weeks, then 4 tablets/d fromweek 8 to week 52. Investigators were permitted to adjust thedose of study drug as follows. If symptoms were mild and tolerable,study drug was continued. Persistent or severe gastrointestinalor other symptoms could lead to a reduction from 4 tablets/dto 1 tablet/d; the dose was then increased by 1 tablet/d inweekly intervals until the subject achieved a tolerable doselevel of up to 4 tablets/d. Compliance was assessed at eachstudy visit by asking the patient and parent(s) how many doseswere missed during the preceding 7 days. Adverse events wererecorded at each study visit, with investigator grading of relatednessand severity.

While healthy eating was a major component of the lifestylemodification program (described later), no specific caloriegoal was assigned to the subjects. To mitigate the possibleimpact of diet modification on vitamin and calcium intake, aswell as possible effects of metformin on vitamin B metabolismand excretion,6 subjects were also instructed to take a multivitamintablet and 1000 mg of calcium carbonate daily.7 After the baselinevisit (day 0) and randomization at week 4, subjects returnedat 16, 28, 40, 52, 64, 76, 88, and 100 weeks for a physicalexamination, anthropometry, and safety laboratory studies, includinga pregnancy test for girls. The OGTT, DXA, and abdominal CTwere performed at baseline, then at 52 weeks (last dose of studydrug) and 100 weeks (completion of study).

Subjects were asked to self-identify race from the followingcategories: American Indian or Alaska Native, Asian, NativeHawaiian or other Pacific Islander, black or African American,white, or other. Hispanic or Latino ethnicity was also voluntarilyself-identified.


All subjects were prescribed a lifestyle intervention programto increase physical activity level and optimize dietary intake.To decrease variability across sites, we selected the Weighof Life LITE8 program developed at Texas Children’s Hospital,Houston. Beginning with the run-in period, subjects were expectedto attend 10 individualized “intensive” sessions at weekly intervals,following a specific curriculum. Monthly follow-up sessionswere conducted for the remainder of the study. A trained healthspecialist led the sessions and parents/guardians were invitedto attend.


At each visit, height was measured twice using a calibrated,wall-mounted stadiometer and weight was measured twice usinga calibrated electronic scale. A third reading was taken ifthe difference between the first 2 readings was more than 0.5cm for height or more than 0.3 kg for weight. Body mass indexwas calculated as the mean weight in kilograms divided by themean height in meters squared2 and converted to a sex- and age-specificz score.5 Waist circumference was measured as the smallest circumferencebelow the rib cage and above the umbilicus.9 Tanner breast (female),genital (male), and pubic hair (both sexes) staging was assessedby an experienced clinician at each visit.


Abdominal CT scans were performed to evaluate abdominal fatcontent and distribution, using a modification of publishedmethods.10 The slice was aligned with the L4-L5 intervertebraldisc to the nearest millimeter using a low-dose abdominal scoutradiograph, and cross-sectional areas (in centimeters squared)for intraperitoneal and subcutaneous fat were determined usingsoftware available on the CT review console. Percentage of bodyfat and lean body mass were measured by whole-body DXA.11


A 3-hour OGTT (75-g glucose) was performed after 3 days of a150 g/d or more carbohydrate diet and a 10-hour overnight fast.Plasma insulin and glucose levels were measured at 0 (beforeglucose bolus), 15, 30, 60, 90, 120, and 180 minutes. Lipidprofiles and other laboratory test levels were measured in thefasting sample. Insulin was measured by 2-site immunochemiluminometricassays with sensitivities of 0.6 µU/mL. Safety laboratorytests included hematology and chemistry panels. All assays wereperformed at Esoterix Clinical Trials Services (Calabasas Hills,California).


The homeostasis model assessment–insulin resistance (HOMA-IR)was calculated as [Fasting Glucose Level (in millimoles) x Fasting Insulin Level (in microunits per deciliter)]/22.5.12 The composite insulin sensitivity index13 was calculatedas


where FI is the fasting insulin level, FBG is the fasting glucoselevel, and MI and MG are the mean insulin and glucose levelsmeasured between 0 and 120 minutes during the OGTT.

Beta-cell activity was estimated using the corrected insulinrelease at the glucose peak14 calculated as


where Ggp is the peak glucose level (maximum of all 7 measures[0-180 minutes]) and Igp is the insulin concentration at thetime of the glucose peak.


Subjects who successfully completed the run-in period were randomizedto metformin XR or placebo treatment according to random sequencesconstructed at the Data Coordinating Center. To ensure balanceacross major factors, the randomization was stratified by siteand sex. Subjects and study personnel were blinded to assignmentthroughout the entire study. To ensure nonpredictability ofassignment, the randomization sequence was grouped in randomlypermuted blocks of 2 and 4, and assignments were randomly permutedwithin block. Study drugs were prepared so as to be indistinguishableand labeled with a unique but uninformative code. The Data CoordinatingCenter maintained the key to drug codes for use during unblindingas needed for safety concerns (eg, in 2 cases of pregnancy)and for the data analyses.


The intention-to-treat principle was used, analyzing each subjectas part of his or her assigned treatment group, regardless ofcompliance. All analyses used 2-tailed tests with P = .05as the critical value for statistical significance. SAS software(version 9.1; SAS Institute Inc, Cary, North Carolina) was usedfor all computations.

Between-group comparisons of baseline characteristics used the{chi}2 test for dichotomous and polytomous variables, corroboratedin cases of sparse data by the Fisher exact test, and the 2-samplet test for continuous measures, corroborated in cases of severelyskewed distribution or markedly unequal variance by the Wilcoxon2-sample test. The same methods were used to compare baselinecharacteristics between those who completed the 52-week primaryassessment and those who dropped out.

Repeated-measures analysis of variance was used to assess theeffect of treatment on the primary and secondary end point measures.For BMI, the analysis comprised 10 repeated measures over 100weeks and for the secondary end points, 3 measures, done atbaseline, 52 weeks, and 100 weeks. The independent variableswere treatment (1 df), time (9 df for BMI, 2 df for the otherend points), and time x treatment interaction, whichaddressed the question of treatment efficacy. The analysis wasadjusted for site, sex, race, ethnicity, and age and assumeda compound-symmetric covariance structure (equal correlationamong data from each subject, equivalent to a random-subjecteffect). Contrasts from parameters of the fitted model wereformed to estimate effects of particular interest, includingadjusted means, in each treatment arm at baseline, 52 weeks,and 100 weeks (eg, Y52; changes over those intervals in eachtreatment arm [eg, Y52-0 = Y52 – Y0];and differential change between the 2 treatment arms [eg, {Delta}52-0 = Y52-0,Metformin – Y52-0,Placebo ]). To test foreffect modification, we added preplanned interaction terms andformed corresponding contrasts (eg, change in {Delta}52-0 per unitHOMA-IR, tested by HOMA-IR x time x treatmentinteraction, or {Delta}52-0,Male – {Delta}52-0,Female, testedby sex x time x treatment interaction).

To test for biased dropout, we performed a logistic regressionanalysis to test whether BMI on a particular visit was associatedwith dropout before the following visit. In a second set ofanalyses, we tested for association between baseline variables(including BMI) and completion of the week 52 visit.

The repeated-measures analysis comprised all available measurementson all randomized subjects, including withdrawals and dropoutsas well as completers, through the last visit for those whowithdrew or were lost to follow-up. This analysis is unbiasedunder the assumption of missingness at random, ie, likelihoodof missing data related only to variables included in the model.15 For corroboration, we imputed the missing data in 2 ways,both conservatively biased toward the null hypothesis of nodrug effect: return to baseline BMI or last observation carriedforward. In both cases, intermittent missing values were imputedwith the last prior observation.

An interim analysis was performed and presented to the Dataand Safety Monitoring Board after 50% of subjects had reachedthe 52-week primary evaluation point, for purposes of assessingsafety and progress. Unblinded data were seen only by the Dataand Safety Monitoring Board and study statistician. There wereno plans to stop the study for early success or lack of powerbased on the interim results, as it was expected that all subjectswould be enrolled by that time. Consequently, no adjustmentwas made to the critical P value for final analysis of the primaryend point.


To estimate power, we analyzed a simulated sample with 15% AfricanAmerican and 15% Hispanic subjects, balanced by sex, with 20%attrition and a bias induced by selective dropout.16 Assumingan SD of 1.9 for BMI change,17 an enrolled sample of 72 provided80% power to detect a differential of 1.46 between treatmentarms or between sexes and 1.75 between white subjects and others.The final randomized sample was 77, owing to simultaneous successfulrun-ins at different sites in the final weeks of recruitment.


 Jump to Section
 • Top
 • Introduction
 • Methods
 • Results
 • Comment
 • Author information
 • References


Ninety-two subjects were screened and 77 were randomized, 39to metformin XR, 38 to placebo; 27 and 19 in each group weremeasured at weeks 52 and 100, respectively (Figure 1). For therandomized participants, there were no between-group differencesin baseline characteristics (Table 1). During the treatmentperiod, the odds of dropping out after any particular visitincreased by a factor of 1.15 per unit BMI at that visit, butthat rate did not differ between metformin and placebo subjects.The 23 subjects not measured at week 52 had a higher mean (SE)baseline BMI compared with the remaining 54 subjects (37.8 [1.1]vs 35.1 [0.7]; P = .04); however, the influence ofBMI on dropout did not differ between the 2 treatment arms (P = .63)for treatment x completion interaction and no otherbaseline characteristic had an influence on the likelihood ofdropout. One subject withdrew from the study after week 16 butreturned for measurement at week 100. There were 2 pregnancies(1 each, metformin and placebo groups) resulting in discontinuationfrom study.

Figure 1
View larger version (20K):
[in this window]
[in a new window]
[as a PowerPoint slide]
Figure 1. Disposition of subjects. “Withdrew” refers to withdrawal of consent. One subject in the metformin hydrochloride extended release group withdrew consent at week 16 but returned for a measurement at week 100 (end of study). See text for further details. 

View this table:
[in this window]
[in a new window]
[as a PowerPoint slide]
Table 1. Subject Characteristics at Baselinea 



Metformin XR had a small but statistically significant impacton BMI over the initial 52 weeks of the study (Table 2) (Figure 2). The mean (SE) BMI (adjusted for site, sex, race, ethnicity,and age) increased 0.2 (0.5) in the control group and decreased0.9 (0.5) in the metformin XR group. Repeated-measures analysisshowed significant time x treatment interaction (P < .05)and treatment contrast between baseline and 52 weeks (P = .03).The mean (SE) BMI difference of –1.1 (0.5) representsan approximately 3-kg weight difference at a height of 165 cm.The difference in mean adjusted BMI was fully established byweek 28 (32 weeks of study drug treatment) (Figure 2A). Imputationof missing data by last observation carried forward left theweek 52 results unchanged in each arm (–0.9 for metformin,+0.5 for placebo) and the treatment contrast slightly enhanced(–0.09) and significant at P = .02. Imputationby return to baseline slightly attenuated the treatment contrast(–0.07; P = .05).

View this table:
[in this window]
[in a new window]
[as a PowerPoint slide]
Table 2. Primary and Secondary Outcomesa 

Figure 2
View larger version (17K):
[in this window]
[in a new window]
[as a PowerPoint slide]
Figure 2. Body mass index (BMI) (calculated as mean weight in kilograms divided by mean height in meters squared) (A) and adjusted change in BMI from baseline (B) (see text for further details). Data are plotted as the mean and 1 SE. Vertical dotted lines separate the study drug treatment (4-52 weeks) and post–study drug treatment (52-100 weeks) monitoring periods. Part A includes data for the run-in period (0-4 weeks). Metformin was given as metformin hydrochloride extended release. 



Neither sex, race, nor ethnicity significantly modified themetformin effect on BMI found in the entire group (P > .20for interaction in repeated-measures analysis). The treatmenteffect did not vary by study center, parental education, orfamily history of type 1 or type 2 diabetes (P > .10).Likewise, baseline fasting insulin level, OGTT insulin response,composite insulin sensitivity index, and HOMA-IR did not modifythe effect in the full sample or when restricted to white race.


Among the secondary measures of obesity, BMI z score and DXAfat mass revealed similar changes to BMI, although the meanadjusted difference between the 2 groups did not reach statisticalsignificance. Only BMI z score showed a P value less than .10.Metformin XR treatment had no significant impact on DXA fatmass, DXA lean mass, CT intraperitoneal fat area, CT subcutaneousfat area, CT intraperitoneal fat, abdominal fat by CT, or CTintraperitoneal fat to subcutaneous fat ratio (Table 2). Likewise,metformin XR had no significant impact on HOMA-IR; the areaunder the insulin curve; the area under the glucose curve; compositeinsulin sensitivity index; corrected insulin release at theglucose peak; levels of low-density lipoprotein cholesterol,triglycerides, or high-density lipoprotein cholesterol; or thetriglycerides to high-density lipoprotein cholesterol ratio.


The BMI difference between the groups persisted for 12 to 24weeks after cessation of study drug (Figure 2) (Table 2). Thereafter,the mean BMI in the metformin group increased toward that inthe control group.


Compliance with medications was good and similar in both groups(mean [SD] number of missed doses per week, 1.2 [1.7] metforminvs 1.3 [3.5] control; P = .29). Likewise, the mean[SD] number of the lifestyle modification sessions attendedwas similar in both groups (6.3 [3.1] metformin vs 6.7 [3.3]control; P = .38). Neither the estimate of the numberof missed doses nor the number of lifestyle sessions attendedwere associated with the change in BMI in the metformin group.


During weeks 4 to 52, the safety population consisted of allsubjects who received at least 1 dose of study drug. Duringweeks 52 to 100, the safety population included all subjectswho had at least 1 visit during this period.

During weeks 4 to 52, the following adverse events occurredat least once in 5% or more of subjects in either group and5 or more percentage points greater in 1 group relative to theother (metformin vs placebo): headache (n = 12 [31%]vs 8 [21%]), nausea (n = 9 [23%] vs 3 [8%]), vomiting(n = 6 [15%] vs 1 [3%]), upper respiratory tract infection(n = 18 [46%] vs 23 [61%]), and musculoskeletal complaints(n = 5 [3%] vs 7 [18%]). There was no statisticallysignificant difference between the metformin and placebo groupsin the incidence of any particular class of adverse events.Two events of nausea in 2 metformin-treated subjects were consideredprobably related; 1 subject discontinued taking the study drug.Two subjects in the metformin group and 1 in the placebo grouphad elevated alanine aminotransferase levels before week 52and discontinued taking the study drug. There was 1 severe adverseevent (appendectomy, metformin group) considered unrelated tothe study drug; all other adverse events were mild or moderate.In total, the dose of study drug was decreased during weeks4 to 52 for 6 subjects in the metformin group and 3 in the placebogroup.

During weeks 52 to 100, headache was more frequent in the grouppreviously treated with metformin XR (n = 6 [30%]vs 5 [24%]; P = .73), and there was 1 severe adverseevent (leg vein thrombosis) considered unrelated to previousstudy drug (metformin) treatment.


Telmisartan shows antihypertensive and several pleiotropic effects that interact with metabolic pathways. In the present study we tested the hypothesis that telmisartan prevents adipogenesis in vitro and weight gain in vivo through activation of peroxisome proliferator-activated receptor (PPAR)-delta-dependent pathways in several tissues. In vitro, telmisartan significantly upregulated PPAR-delta expression in 3T3-L1 preadipocytes in a time- and dose-dependent manner. Other than enhancing PPAR-delta expression by 68.2+/-17.3% and PPAR-delta activity by 102.0+/-9.0%, telmisartan also upregulated PPAR-gamma expression, whereas neither candesartan nor losartan affected PPAR-delta expression. In vivo, long-term administration of telmisartan significantly reduced visceral fat and prevented high-fat diet-induced obesity in wild-type mice and hypertensive rats but not in PPAR-delta knockout mice. Administration of telmisartan did not influence food intake in mice. Telmisartan influenced several lipolytic and energy uncoupling related proteins (UCPs) and enhanced phosphorylated protein kinase A and hormone sensitive lipase but reduced perilipin expression and finally inhibited adipogenesis in 3T3-L1 preadipocytes. Telmisartan-associated reduction of adipogenesis in preadipocytes was significantly blocked after PPAR-delta gene knockout. Chronic telmisartan treatment upregulated the expressions of protein kinase A, hormone-sensitive lipase, and uncoupling protein 1 but reduced perilipin expression in adipose tissue and increased uncoupling protein 2 and 3 expression in skeletal muscle in wild-type mice but not in PPAR-delta knockout mice. We conclude that telmisartan prevents adipogenesis and weight gain through activation of PPAR-delta-dependent lipolytic pathways and energy uncoupling in several tissues.

Sibutramine boosts metabolism and therefore also calorie burning, and suppresses appetite. It used to go by the trade name Meridia. Sibutramine was fairly effective, but was banned after studies indicated that its use led to cardiovascular disease. When the Italians did their experiment, in which they gave 254 men and women with diabetes-2 a daily 10 mg sibutramine for a year, sibutramine was still a legal substance.

Because L-carnitine has theoretically purely beneficial effects for diabetes sufferers, the researchers wanted to learn about the effects of a combination of sibutramine and carnitine. So they gave half of their subjects sibutramine only, and the other half 2 g L-carnitine a day in addition.

In the course of the year the sibutramine group lost 9.1 kg; the carnitine-sibutramine group lost 10.9 kg. The combined group not only lost more weight, they also appeared to become more sensitive to insulin.

 HbA1c = glycated haemoglobin, a marker for diabetes; FPG = fasting plasma glucose; PPG = postprandial plasma glucose; HOMA-IR = homeostasis model assessment of insulin resistance index fasting plasma insulin.



L-carnitine supplementation resulted in an increased production of the ‘good’ fat cell hormone adiponectin, and reduced the production of the inflammatory factor TNF-alpha. This would suggest that L-carnitine reduced the inflammatory reactions that diabetes-2 causes.

 And there were no side effects among the group that were given L-carnitine. For the record: the research was not funded by an L-carnitine manufacturer, but by the university that employs the researchers.

Effects of combination of sibutramine and L-carnitine compared with sibutramine monotherapy on inflammatory parameters in diabetic patients


The aim of the study was to evaluate the effects of 12-month treatment with sibutramine plus l-carnitine compared with sibutramine alone on body weight, glycemic control, insulin resistance, and inflammatory state in type 2 diabetes mellitus patients. Two hundred fifty-four patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA1c] >8.0%) in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomized to take sibutramine 10 mg plus l-carnitine 2 g or sibutramine 10 mg in monotherapy. We evaluated at baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index, HbA1c, fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, tumor necrosis factor–α, adiponectin, vaspin, and high-sensitivity C-reactive protein. Sibutramine plus l-carnitine gave a faster improvement of fasting plasma glucose, postprandial plasma glucose, lipid profile, leptin, tumor necrosis factor–α, and high-sensitivity C-reactive protein compared with sibutramine alone. Furthermore, there was a better improvement of body weight, HbA1c, fasting plasma insulin, homeostasis model assessment of insulin resistance index, vaspin, and adiponectin with sibutramine plus l-carnitine compared with sibutramine alone. Sibutramine plus l-carnitine gave a better and faster improvement of all the analyzed parameters compared with sibutramine alone without giving any severe adverse effect.

BUY hCG 5000 units from us $45

A controversial usage of hCG is as an adjunct to the British endocrinologist Dr. A.T.W. Simeons’ ultra-low-calorie weight-loss diet. Simeons, while studying pregnant women in India on a calorie-deficient diet, and fat boys with pituitary problems treated with low-dose hCG, discovered that both lost fat rather than lean (muscle) tissue. He reasoned that hCG must be programming the hypothalamus to do this in the former cases in order to protect the developing fitus, and proceeded to use low-dose daily hCG injections (125 mg) in combination with a customized ultra-low-calorie (500 cal/day, high-protein, low-carbohydrate/fat) diet to help obese adults lose dramatic amounts of adipose tissue without loss of lean, at a Salvator Mundi International Hospital in Rome, Italy, clinic mainly for celebrities. After Simeons death, the diet started to spread to specialized centers and via popularization by such as the controversial popular author Kevin Trudeau (search for hCG in that article for more details).

The controversy proceeds from warnings by the Journal of the American Medical Association[ and the American Journal of Clinical Nutrition that hCG is not safe, indeed ineffective, as a weight-loss aid on its own; yet its usage as cited above to increase testosterone production contradicts this assertion, since much late-life male obesity is associated with estrogen dominance and deficient testosterone in the mis-named, so-called andropause. Furthermore, in the Simeons protocol, it is, as in any diet, the ultra-low-calorie component (caloric deficit) that results in weight loss, if the protocol is followed strictly. hCGs role is supposedly to trigger the hypothalamic lean-protection mechanisms Simeons thought he saw, thus promoting mobilization and consumption of abnormal, excessive adipose deposits, while protecting normal adipose and lean tissue from being consumed, with the assumption that these protective hypothalamic mechanisms exist in males as well as females, to be acted upon by hCG.

hCG for bodybuilding

hCG is provided as a glycoprotein powder to be diluted with water, and acts in the body like luteinizing hormone (LH), stimulating the testes to produce testosterone even when natural LH is not present or is deficient. It therefore is useful for maintaining testosterone production and/or testicle size during a steroid cycle. Use of this drug in the taper is rather counterproductive, since the resulting increased testosterone production is itself inhibitory to the hypothalamus and pituitary, delaying recovery. Thus, if this drug is used, it is preferably used during the cycle itself. A daily amount of 500 IU is generally sufficient, and in my opinion usage should not exceed 1000 IU per day.

Daily administration is superior to less frequent administration.

Doses over 1000 IU are noted for their tendency to cause or aggravate gynecomastia, and also act to desensitize the testicles to LH.

hCG may be injected intramuscularly, subcutaneously, or in a shallow injection about 1/4″ deep with the needle going straight in. A 29 gauge insulin needle is recommended. Injection speed should be slow.

Some hCG products are diluted 5000 or even 10,000 IU per mL, while others are diluted 1000 IU per mL. So far as I know there is no need to make the preparation so dilute. Once mixed, the preparation should be refrigerated and used within a few weeks. The substance is also somewhat temperature sensitive before mixing and should not be exposed to excessive heat.

hCG does not correct the problem of  progressively-decreasing ejaculatory volume that is typical during a steroid cycle. So far as I know the only cure is to go off-cycle and use Clomid, but it is possible that human menopausal gonadotropin (hMG), a related drug which works analogously to follicle stimulating hormone (FSH) might be useful during a cycle to treat this problem. HMG supports spermatogenesis and is commonly used in conjunction with hCG to treat male fertility problems. (Consider use of HMG to maintain ejaculatory volume to be a strictly past-the-cutting-edge hypothesis: I have not yet had the opportunity to test the matter.)

The athlete who would otherwise fail a urinary ratio test because of low epitestosterone may find hCG useful in increasing epitestosterone and therefore improving this ratio. A 500 IU dose is sufficient, but on the other hand, hCG itself is also banned by the IOC and is readily detected in urine.

hCG can also useful for returning testosterone to normal levels should levels be low post-cycle, or, with care, to increase levels from normal to high normal. Titration of the dose, by measuring T levels and then adjusting the hCG dose accordingly, is recommended for long term use.

COMPRA CJC-1295 con DAC (drug affintiy complex) 2 mg de nosotros $49

CJC-1295 es un peptídico análogo del GHRH (growth hormone releasing hormone) o hormona liberadora de hormona de crecimiento. Por la forma en que CJC-1295 es manipulada su vida media, o periodo de semidesintegracion, fue extendida de 7 minutos a mas de 8 días!

Debido a la extremadamente larga vida media del CJC-1295 es plausible usar este peptídico unas ves a la semana y adquirir resultados extraordinarios. Es recomendado usar media dosis dos veces por semana para mantener los niveles de suero estables en su clímax y obtener resultados óptimos.

Varios experimentos han sido conducidos para comprobar la efectividad del CJC-1295 en vivo y el Journal of Clinical Endocrinology & Metabolism (Dario de Endocrinología Clínica & Metabolismo), informo dosis–dependiente incrementos del promedio de concentración de plasma GH (growth hormone) o hormona de crecimiento, multiplicados por 2 a 10 por mas de 6 días e incremento de concentración de IGF-1 (insulin like growth factor 1) o factor de crecimiento similar a insulina 1, multiplicados por 1.5 a 3 por 9 a 11 días después de solo una inyección.

Tambien han comprobado el promedio de vida media siendo 5.8 a 8.1 días y después de dosis múltiples demostró el promedio de los niveles de IGF-1 se mantuvo sobre la línea de fondo por asta 28 días después! En ningún grupo fueron reportadas serias reacciones adversas.

GH (hormona de crecimiento) es compuesta de una secuencia de 191 amino ácidos y es producida en el cuerpo humano por la glándula pituitaria. Existen niveles altos de esta hormona especialmente durante la adolescencia donde estimula el crecimiento de tejidos, deposición de proteínas, y la descomposición de almacenes de grasa subcutánea.

GH estimula el crecimiento de la mayoría de los tejidos, ante todo debido al incremento en número de células en vez del incremento en tamaño de estas. La transportación de amino ácido también incrementa al igual que la síntesis de proteína. Todos estos efectos son causados mediante el IGF-1, una hormona altamente anabólica producida en el hígado y otros tejidos en respuesta al GH.

GH también estimula hidrólisis de triglicéridos en tejido adiposo, usualmente produciendo una notable desminuida en cantidad de grasa corporal durante tratamiento. También incrementa el rendimiento de la glucosa en el hígado y provoca resistencia a la insulina bloqueando la actividad de esta hormona en ciertas células causando un cambio en la cual grasas se favorecen mas como recursos primarios de combustible, aumentando aun mas la perdida de grasa corporal.

Sus efectos estimuladores de crecimiento también fortalecen tejidos conectivos, cartílago, y tendones. Este efecto debería desminuir la susceptibilidad a lesión dado al entrenamiento pesado de pesas.

IGF-1 (factor de crecimiento similar a insulina 1) es una hormona peptídico compuesta de 70 amino ácidos y es encontrado naturalmente en el cuerpo humano. IGF-1 a demostrado incrementar la velocidad y el alcance de la reparación muscular después de lesión e incrementa la velocidad hipertrófica o crecimiento muscular del entrenamiento físico. No solo las existentes fibras musculares son reparadas más rápido, IGF-1 es responsable por la hiperplasia, o incremento en la cantidad de fibras musculares.

Hiperplasia es el santo gremial de los beneficios de la mejor acción del rendimiento, y ocurre cuando fibras musculares se dividen, creando más fibras musculares. Hipertrofia es simplemente el incremento del tamaño de las existentes células musculares y ocurre através del entrenamiento con resistencia, o pesas y uso de esteroides anabólicos. Hiperplasia mas hipertrofia es equivalente a una increíble nueva raza de atleta.

Otro beneficio bastante positivo del CJC-1295 es su habilidad de estimular SWS (slow wave sleep) o sueño de ondas lentas. Sueño de ondas lentas es conocido como sueño profundo y es la parte del sueño responsable por los más alto niveles de hipertrofia y retención de memoria muscular. Este tipo se sueño es significantemente desminuido en personas de tercera edad y en gente con tendencia a ejercitar en la tarde. Este peptídico tiene una proporción de benéfico a efecto segundario que supera a cualquier otro actualmente siendo vendido y seria una gran adición al régimen de entrenamiento o terapia post -ciclo de cualquiera.

>Branded Ovutrig 5000 IU from VHB Lifesciences $30.

In the 1950s a quiet revolution in dieting began when Dr. A.T.W. Simeons published the results of a study the tracked the progress of participants who combined an extremely low calorie diet with a naturally occurring supplement called HCG. HCG injections for weight loss produced weight loss in the form of body fat reduction rather than lean tissue. With the results of his study, it became clear with HCG injections weight loss was achievable in a healthy way.

That was the ‘50s and clinics popped up to serve clients willing to pay for the shots and the medical staff to administer the injections, but this was a small percentage of dieters. Now HCG is widely administered through oral supplements and began to replace the HCG injections weight loss program

quite rapidly. What used to require a much larger investment of time and money has become available to the general public through the advances in the process by which the low dose of HCG is introduced to the body. The diet is still harsh; 500 calories a day for a brief period of time isn’t something that everyone will be able to achieve.

Unfortunately, the number of people going on crash diets is only increasing in this age of body image obsession and without a supplement like HCG to compel the body to let go of stubborn fat stores people are throwing their systems into a starvation mode that is ending up costing muscle, bone density, and even teeth in some cases, but rarely flab. After the dieter stops, they tend to gain much more weight than they lost because their metabolism is still reeling from the trauma and the fat stores are easier to maintain than muscle.

With the Simeons diet and HCG injections weight loss is possible. But now that oral supplements are available, shots are no longer the preferred method of administration.

HCG is naturally occurring in both women and men, and FDA approved for both. The hormone spikes during pregnancy in women, but what Dr. Simeons found was that even the slightest rise in level was enough to promote healthy fat loss.

With HCG, some people with more than 40 pounds or so to lose will repeat the diet after waiting for the body levels to get back to normal. But due to the fact that this particular diet leaves you with a better chemistry for future weight loss and maintenance, people often find that even if they still have more weight to lose it requires less effort and the desperation aspect has dissolved.