The growth hormone releasing factor analogue tesamorelin (TH9507) reduces visceral fat, but what else does it do?

This GHRF analogue has already been reported to significantly improve visceral fat accumulation by an average of 20% as compared to placebo in HIV-positive subjects with increased waist circumference and waist-to-hip ratio (CROI 2007).

Importantly, this occurs without a significant decrease in subcutaneous fat. Steve Grinspoon from Harvard expanded on his CROI report on this growth hormone releasing factor (GHRF) analog, which recently received the name tesamorelin, from the Canadian biotech company Theratec.

GHRF is made by the hypothalamus gland and stimulates the pituitary gland to produce growth hormone. But growth hormone therapy is associated with many side effects, including diabetes/impaired glucose tolerance/insulin resistance as well as various aches and pains like carpal tunnel syndrome and joint aches. None of these problems have been a major issue with tesamorelin, which is actually safe to give to patients with mild, diet-controlled diabetes.

Because of a feedback mechanism, when a GHRF-like substance is administered, growth hormone levels from the pituitary increase but presumably do not reach excessive, or supraphysiologic, levels (as may happen when growth hormone itself is given) due to this feedback loop. Insulin-like growth factor-1 (IGF-1) increases when you give either GHRF or growth hormone, and it is the IGF-1 that appears to mediate the improvement in muscle mass and the reduction in belly fat seen with either tesamorelin or growth hormone.

Levels of IGF-1 increased with tesamorelin by about 80% over placebo and the greater the increase in IGF-1, the greater the reduction in belly fat. The people who benefited the most from tesamorelin were those that had the most visceral fat to begin with. In a related poster presentation, there appeared to be some subjective and quality-of-life benefit to tesamorelin over placebo. Unfortunately this agent is occasionally associated with hypersensitivity reactions (~ 2%), which while none have been life-threatening, these may limit its long-term use.

So, it appears that tesamorelin is effective at reducing belly fat (particularly in those with a lot of it by CT) and this is associated with a variety of improvements in markers of cardiovascular risk, without the adverse glucose effects and with few of the adverse musculoskeletal effects of growth hormone. Its place in therapy remains to be clarified, and a lot will depend on how costly it will be. Alternatives for abdominal obesity in HIV-positive patients include metformin for those with impaired glucose tolerance, growth hormone for those without IGT, and of course diet and exercise should have a primary role here.

If reduction of CV risk is the primary goal, interventions for smoking cessation and dyslipidemia may be more cost-effective than tesamorelin.

Of course, there remains the consideration that increased belly fat, whilst it does occur in patients with HIV, appears to be less prevalent in men with HIV than in the general population. Even if increased belly fat is more common among HIV-positive women, it is likely that the effect of GH and GHRF analogues is somewhat attenuated in women. Further, we currently lack any long-term data with tesamorelin, so the durability of the response to it and the need for maintenance therapy, for how long, with what dose, also remain open questions.

Finally, if this agent will be costly, more data will be needed to be able to target those individuals most likely to benefit from its use.

Grinspoon S et al. Further data on the effects of tesamorelin (TH9507), a growth hormone-releasing factor analogue, on body composition and metabolic parameters in HIV-infected patients with abdominal fat accumulation.