Metabolic effects of a growth hormone-releasing factor in obese subjects with reduced growth hormone secretion: a randomized controlled trial.

CONTEXT Obesity is associated with reduced GH secretion and increased cardiovascular disease risk. OBJECTIVE We performed this study to determine the effects of augmenting endogenous GH secretion on body composition and cardiovascular disease risk indices in obese subjects with reduced GH secretion. DESIGN, PATIENTS AND METHODS A randomized, double-blind, placebo-controlled study was performed involving 60 abdominally obese subjects with reduced GH secretion. Subjects received tesamorelin, a GHRH(1-44) analog, 2 mg once daily, or placebo for 12 months. Abdominal visceral adipose tissue (VAT) was assessed by abdominal computed tomography scan, and carotid intima-media thickness (cIMT) was assessed by ultrasound. Treatment effect was determined by longitudinal linear mixed-effects modeling. RESULTS VAT [-16 ± 9 vs.19 ± 9 cm(2), tesamorelin vs. placebo; treatment effect (95% confidence interval): -35 (-58, -12) cm(2); P = 0.003], cIMT (-0.03 ± 0.01 vs. 0.01 ± 0.01 mm; -0.04 (-0.07, -0.01) mm; P = 0.02), log C-reactive protein (-0.17 ± 0.04 vs. -0.03 ± 0.05 mg/liter; -0.15 (-0.30, -0.01) mg/liter, P = 0.04), and triglycerides (-26 ± 16 vs. 12 ± 8 mg/dl; -37 (-67, -7) mg/dl; P = 0.02) improved significantly in the tesamorelin group vs. placebo. No significant effects on abdominal sc adipose tissue (-6 ± 6 vs. 3 ± 11 cm(2); -10 (-32, +13) cm(2); P = 0.40) were seen. IGF-I increased (86 ± 21 vs. -6 ± 8 μg/liter; 92 (+52, +132) μg/liter; P < 0.0001). No changes in fasting, 2-h glucose, or glycated hemoglobin were seen. There were no serious adverse events or differences in adverse events between the groups. CONCLUSION Among obese subjects with relative reductions in GH, tesamorelin selectively reduces VAT without significant effects on sc adipose tissue and improves triglycerides, C-reactive protein, and cIMT, without aggravating glucose.

[1]  T. McLaughlin,et al.  Preferential fat deposition in subcutaneous versus visceral depots is associated with insulin sensitivity. , 2011, The Journal of clinical endocrinology and metabolism.

[2]  J. Després,et al.  Effect of rimonabant on carotid intima–media thickness (CIMT) progression in patients with abdominal obesity and metabolic syndrome: the AUDITOR Trial , 2011, Heart.

[3]  S. Grinspoon,et al.  Effects of a growth hormone-releasing hormone analog on endogenous GH pulsatility and insulin sensitivity in healthy men. , 2011, The Journal of clinical endocrinology and metabolism.

[4]  L. Hemphill,et al.  Reduced growth hormone secretion is associated with increased carotid intima-media thickness in obesity. , 2009, The Journal of clinical endocrinology and metabolism.

[5]  N. Møller,et al.  Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. , 2009, Endocrine reviews.

[6]  K. Ho,et al.  Faculty Opinions recommendation of Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. , 2009 .

[7]  M. C. Savanelli,et al.  Growth hormone treatment on atherosclerosis: results of a 5-year open, prospective, controlled study in male patients with severe growth hormone deficiency. , 2009, The Journal of clinical endocrinology and metabolism.

[8]  S. M. You,et al.  The effects of central adiposity on growth hormone (GH) response to GH-releasing hormone-arginine stimulation testing in men. , 2008, The Journal of clinical endocrinology and metabolism.

[9]  L. Hemphill,et al.  Growth hormone deficiency by growth hormone releasing hormone-arginine testing criteria predicts increased cardiovascular risk markers in normal young overweight and obese women. , 2008, The Journal of clinical endocrinology and metabolism.

[10]  S. Heymsfield,et al.  Femoral-gluteal subcutaneous and intermuscular adipose tissues have independent and opposing relationships with CVD risk. , 2008, Journal of applied physiology.

[11]  D. Potvin,et al.  Metabolic effects of a growth hormone-releasing factor in patients with HIV. , 2007, The New England journal of medicine.

[12]  G. Mancini,et al.  Visceral Adipose Tissue, a Potential Risk Factor for Carotid Atherosclerosis: Results of the Multicultural Community Health Assessment Trial (M-CHAT) , 2007, Stroke.

[13]  A. Munafo,et al.  Polyethylene glycol-conjugated growth hormone-releasing hormone is long acting and stimulates GH in healthy young and elderly subjects. , 2005, European journal of endocrinology.

[14]  S. Grottoli,et al.  The cut-off limits of the GH response to GH-releasing hormone-arginine test related to body mass index. , 2005, European journal of endocrinology.

[15]  A. Rissanen,et al.  Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study , 2005, The Lancet.

[16]  J. Elashoff,et al.  Body mass index determines evoked growth hormone (GH) responsiveness in normal healthy male subjects: diagnostic caveat for adult GH deficiency. , 2004, The Journal of clinical endocrinology and metabolism.

[17]  Andrew R. Coggan,et al.  Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. , 2004, The New England journal of medicine.

[18]  R. Ross,et al.  Visceral fat and liver fat are independent predictors of metabolic risk factors in men. , 2003, American journal of physiology. Endocrinology and metabolism.

[19]  M. Espeland,et al.  Associations of Extracranial Carotid Atherosclerosis Progression With Coronary Status and Risk Factors in Patients With and Without Coronary Artery Disease , 2002, Circulation.

[20]  D. Cook,et al.  Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency. , 2002, The Journal of clinical endocrinology and metabolism.

[21]  F. Lönnqvist,et al.  A pilot study of long-term effects of a novel obesity treatment: omentectomy in connection with adjustable gastric banding , 2002, International Journal of Obesity.

[22]  M. Schambelan,et al.  Effects of recombinant human growth hormone on hepatic lipid and carbohydrate metabolism in HIV-infected patients with fat accumulation. , 2002, The Journal of clinical endocrinology and metabolism.

[23]  H. Pijl,et al.  Altered neuroregulation of GH secretion in viscerally obese premenopausal women. , 2001, The Journal of clinical endocrinology and metabolism.

[24]  E. Arvat,et al.  Growth hormone-releasing hormone combined with arginine or growth hormone secretagogues for the diagnosis of growth hormone deficiency in adults , 2001, Endocrine.

[25]  J. Després,et al.  Elevated C-Reactive Protein: Another Component of the Atherothrombotic Profile of Abdominal Obesity , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[26]  Raymond Chan,et al.  Anisotropic edge-preserving smoothing in carotid B-mode ultrasound for improved segmentation and intima-media thickness (IMT) measurement , 2000, Computers in Cardiology 2000. Vol.27 (Cat. 00CH37163).

[27]  P. Wahl,et al.  Visceral adiposity and incident coronary heart disease in Japanese-American men. The 10-year follow-up results of the Seattle Japanese-American Community Diabetes Study. , 1999, Diabetes care.

[28]  B. Bengtsson,et al.  Effect of growth-hormone therapy on early atherosclerotic changes in GH-deficient adults , 1999, The Lancet.

[29]  H. Orskov,et al.  Abdominal adiposity rather than age and sex predicts mass and regularity of GH secretion in healthy adults. , 1997, The American journal of physiology.

[30]  J D Veldhuis,et al.  Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men. , 1991, The Journal of clinical endocrinology and metabolism.

[31]  A Tremblay,et al.  Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. , 1990, Arteriosclerosis.

[32]  D L Kaiser,et al.  Pulsatile growth hormone secretion in normal man during a continuous 24-hour infusion of human growth hormone releasing factor (1-40). Evidence for intermittent somatostatin secretion. , 1985, The Journal of clinical investigation.

[33]  W. Vale,et al.  Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour , 1982, Nature.

[34]  N. Ling,et al.  Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. , 1982, Science.

[35]  K. Kovacs,et al.  Somatotroph hyperplasia. Successful treatment of acromegaly by removal of a pancreatic islet tumor secreting a growth hormone-releasing factor. , 1982, The Journal of clinical investigation.

[36]  G. Borkan,et al.  Assessment of abdominal fat content by computed tomography. , 1982, The American journal of clinical nutrition.

[37]  V. Dávila-Román,et al.  Effect of Moderate Diet-Induced Weight Loss and Weight Regain on Cardiovascular Structure and Function , 2010 .

[38]  N. Tritos,et al.  Effects of recombinant human growth hormone therapy in obesity in adults: a meta analysis. , 2009, The Journal of clinical endocrinology and metabolism.

[39]  B. Cha,et al.  Visceral fat amount is associated with carotid atherosclerosis even in type 2 diabetic men with a normal waist circumference , 2009, International Journal of Obesity.

[40]  Moyses Szklo,et al.  Risk factors for progression of common carotid atherosclerosis: the Atherosclerosis Risk in Communities Study, 1987-1998. , 2002, American journal of epidemiology.