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Effects of TH9507, a Growth Hormone Releasing Factor Analog, on HIV-associated Abdominal Fat Accumulation: A Multicenter, Double-blind Placebo-controlled Trial with 412 Randomized Patients
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Reported by Jules Levin
CROI, LA, Feb 26, 2007
Steven Grinspoon from Mass Gen Hosp, Boston, US reported the study results.
Grinspoon concluded:
"TH9507 may be useful to prefertially decrease VAT and improve lipid parameters in HIV+ patients with abdominal fat accumulation, thereby improving cardiovascular risk. TH9507 appears generally well tolerated and does not significantly effect insulin resistance or glucose levels over 26 weeks, even among HIV patients with IGT or diabetes"
In addition limb fat did not appear to decrease.
Background: A significant proportion of HIV patients treated with ART develop increased visceral adipose tissue (VAT), a known cardiovascular risk factor. No medical treatment is approved to reduce VAT. Prior preliminary studies suggest that treatment with GRF (GHRH) decreased visceral fat while preserving subcutaneous fat.
Method: HIV patients (86% male) with evidence of abdominal fat accumulation in the context of treatment for HIV disease (waist circumference [WC] ≥95 cm and waist-to-hip ratio [WHR] ≥0.94 for male, WC≥94 cm and WHR≥0.88 for female), on stable ART, were randomized to TH9507 2 mg (n = 275) or placebo (n = 137) subcutaneously daily for 26 weeks. The primary endpoint was the percentage of change in VAT by abdominal CT. Secondary endpoints included triglyceride level, cholesterol-to-HDL ratio, and IGF-I. Safety endpoints included glucose and insulin. The study was analyzed by intent-to-treat analysis, and ANCOVA and had 90% power to detect an 8% reduction in VAT between TH9507 and placebo. Final data are presented.
Results: Baseline age was 48±7 years, WHR 1.1±0.1, and WC 104±10 cm (mean±SD). Study population included 19% with T2DM or glucose intolerance. Study parameters were similar at baseline between groups. In all, 80% of subjects completed 26 weeks. At week 26, VAT decreased significantly (-15.2±20.8 vs +5.0±23.4%, p <0.001, TH9507 vs placebo. Trunk fat by DEXA also decreased (-1.0±1.9 vs +0.4±1.6 kg, p <0.001), whereas lesser changes were observed in abdominal SAT (+0.4±15.8 vs +1.8±14.5%, TH9507 vs placebo, p = 0.05) and limb fat (-0.0±0.8 vs +0.2±1.0 kg, TH9507 vs placebo, p = 0.01). Absolute changes for VAT are -27.8 cm2 for TH9507 and 4.9 cm2 for placebo.
The lipid profile improved with significant reduction in triglycerides (-0.6±1.7 vs +0.1±1.3 mmol/L, p <0.001, TH9507 vs placebo) and in cholesterol to HDL ratio (-0.3±1.0 vs +0.2±1.0, p <0.001, TH9507 vs placebo). Mean IGF-I increased within the physiological range (+80% vs -5%, TH9507 vs placebo, p <0.001).
Changes in delta glucose (mmol/L0: 0.17 for TH9507; 0.03 for placebo (p 0.28); delta 2 hr glucose (mmol/L): 0.06 for TH9507, 0.45 for placebo, (p, 0.17); delta insulin (pmol/L: 11.9 for TH9507, 17.4 for placebo, (p 0.93).
Overall, treatment was well tolerated. The number of patients with adverse events was not different between the groups (p = 0.12). Adverse events in >10% of subjects were headache (16 vs 18%, p = 0.78) and arthralgia (13 vs 10%, p = 0.43). No significant changes were seen in fasting and 2-hour glucose and insulin at week 26. 53% taking TH9507 had related AEs compared to 34% taking placebo (p<0.001); 12% discontinued due to AE on TH9505 compared to 3% on placebo (p<0.01). 6 patients (2%) experienced urticaria and/or rash on TH9507. Most of them after 4+ months of treatment, often accompanied by flare-ups at previous sites of injection, and moderate eosinophilia. One of them had more systemic reactions: sweating, tachycardia, shortness of breath. There were no SAEs related to these reactions, subjects were discontinued out of precaution.
Conclusions: These data indicate that daily administration of 2 mg TH9507 for 26 weeks preferentially decreased VAT and improved lipid profile. TH9507 was well tolerated and may represent a novel treatment strategy for HIV patients with central fat accumulation, including those with impaired glucose homeostasis.
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