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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
J Falutz1, S Allas2, K Blot2, D Kotler3, M Somero4, D Berger5, S Brown6, G Richmond7, J Fessel8, and Steven Grinspoon*9
1Montreal Gen Hosp, McGill Univ Hlth Ctr, Canada; 2Theratechnologies, Inc, Montreal, Canada; 3St Lukes Roosevelt Hosp Ctr, Columbia Univ Coll of Physicians and Surgeons, New York, NY, US; 4Palm Springs, CA, US; 5Northstar Hlth Care, Chicago, IL, US; 6AIDS Res Alliance, West Hollywood, CA, US; 7Fort Lauderdale, FL, US; 8Kaiser Fndn Res Inst, San Francisco, CA, US; and 9Massachusetts Gen Hosp, Boston, US
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). 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).
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.
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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