Tesamorelin and the Fat Around Your Organs

Patients bring me their scans more often than they used to, usually a CT ordered for something else, and somewhere in the report sits a line about abdominal fat. The question that follows is always the same, whether anything can pull fat off the inside of the abdomen specifically, since that's the compartment they've read is dangerous. Tesamorelin is the one drug with real randomized evidence that it can, which makes it worth understanding carefully, including what happens when the injections stop.

Growth hormone is released in pulses from the pituitary under the direction of a hypothalamic peptide called growth hormone releasing hormone, and the liver answers those pulses by producing IGF-1. I laid out that whole axis, and why the output falls with age, in my post on sermorelin.

What tesamorelin is

Tesamorelin is the full 44-amino-acid growth hormone releasing hormone with one small chemical modification, a trans-3-hexenoyl group attached to the first tyrosine, which makes the peptide resistant to dipeptidyl aminopeptidase-IV, the enzyme that chews up the natural hormone within minutes. Ferdinandi and colleagues, characterizing the molecule in rats, dogs, and pigs, showed that the modification slowed degradation in plasma and raised growth hormone and IGF-1 after repeated injection, with reversible liver, kidney, and blood-count changes in dogs given prolonged high exposure [1]. The FDA approved it in 2010 as Egrifta for reducing excess abdominal fat in people with HIV-associated lipodystrophy, a redistribution of body fat that develops during antiretroviral therapy, and that remains its only approved indication [2]. Every other use, including the compounded 5 mg/mL product we prescribe, is off-label, and compounded tesamorelin isn't FDA-approved.

Why visceral fat is the target worth having

Visceral adipose tissue, the fat packed in and around the organs inside the abdominal wall, behaves differently from the subcutaneous fat you can pinch. Fox and colleagues measured both compartments by CT in 3,001 Framingham Heart Study participants and found that while both correlated with blood pressure, fasting glucose, triglycerides, and HDL cholesterol, the visceral compartment carried the stronger association with every one of them [3]. The odds of metabolic syndrome per standard deviation of visceral fat reached 4.7 in women against 3.0 for subcutaneous fat, and visceral fat still predicted risk after adjusting for body mass index and waist circumference [3]. This means two people with identical waistlines can carry meaningfully different metabolic risk depending on where the fat sits, which is exactly why a drug that shrinks one compartment and leaves the other alone attracted so much attention.

The phase 3 trials

Tesamorelin reduces visceral fat by roughly 15 percent over 26 weeks, and the trials that established this were large and well controlled. Falutz and colleagues randomized 412 people with HIV and abdominal fat accumulation to 2 mg of tesamorelin or placebo daily, and after 26 weeks visceral adipose tissue fell 15.2 percent in the treated group while rising 5.0 percent on placebo, with triglycerides down 50 mg per deciliter and IGF-1 up 81 percent [4]. A pooled analysis of both phase 3 trials, covering 806 patients, reproduced the result with a treatment effect of 15.4 percent on visceral fat, no meaningful change in abdominal subcutaneous fat, and sustained reductions through 52 weeks in people who stayed on the drug [5].

The reversal is the part that gets skipped in marketing. Reviewing the same program, Dhillon reported that discontinuing therapy led to reaccumulation of visceral fat, alongside a tolerability profile of injection-site reactions, joint pain, headache, and peripheral edema [2]. Tesamorelin holds the fat down while you take it, in the same way a GLP-1 holds appetite down while you take it.

Liver fat, and the trials I find most interesting

The liver work is newer and, to my mind, more clinically important than the waistline work. Stanley and colleagues randomized 50 people with HIV and abdominal fat accumulation to tesamorelin or placebo for 6 months and found reductions in both visceral fat and liver fat, with a net treatment effect of 2.9 percent in hepatic lipid-to-water percentage [6]. The same group then ran a 12-month randomized trial in 61 people with HIV and nonalcoholic fatty liver disease, where liver fat fell 37 percent relative to baseline against placebo, and 35 percent of treated participants finished with a hepatic fat fraction under 5 percent compared with 4 percent of controls [7]. Fasting glucose and HbA1c didn't differ between groups at 12 months, and the main complaint was local injection-site irritation [7]. If you're working on reversing fatty liver, that's an interesting signal from a molecule that works through your own pituitary.

What happens outside HIV

Two randomized trials have tested this molecule in people without HIV, and both are small. Makimura and colleagues randomized 60 abdominally obese adults with reduced growth hormone secretion to tesamorelin 2 mg daily or placebo for 12 months and found a treatment effect of 35 square centimeters on visceral fat, with improvements in triglycerides, C-reactive protein, and carotid intima-media thickness, no change in subcutaneous fat, and no worsening of glucose or HbA1c [8]. Baker and colleagues took a different angle, randomizing 152 older adults, 66 of them with mild cognitive impairment, to 1 mg of tesamorelin nightly or placebo for 20 weeks, and found a favorable overall effect on cognition driven mainly by executive function, with IGF-1 up 117 percent and body fat down 7.4 percent [9]. Fasting insulin rose 35 percent in the participants with mild cognitive impairment, and adverse events were reported by 68 percent of treated participants against 36 percent on placebo [9].

I read that cognition trial as a real finding in need of replication rather than a reason to prescribe, since one 20-week study measuring test scores doesn't tell us whether anyone's dementia course changed.

Safety, and who shouldn't use it

Across the program the consistent adverse effects are injection-site reactions, joint pain, and fluid retention, all of which follow from raising growth hormone [2]. Glucose deserves specific attention, and a post-hoc analysis of the phase 3 data gives the clearest look at it. Stanley and colleagues compared participants whose visceral fat fell at least 8 percent with those who didn't respond, and the nonresponders drifted upward in fasting glucose and HbA1c over 52 weeks while responders held steady [10]. This means the metabolic benefit tracks the fat loss rather than the drug itself, so continuing to inject someone who isn't responding buys glucose risk with no return.

Tesamorelin raises IGF-1 substantially, which is why we don't use it in anyone with an active malignancy, and it has no place in pregnancy. The reasoning behind the cancer caution, and the observational data underneath it, sits in my sermorelin post. Anyone whose abdominal fat is being driven by fat behaving as an endocrine organ deserves that conversation before starting.

How we use it

Tesamorelin is a tool for a specific compartment, not a weight-loss drug and not a substitute for fixing insulin resistance. Since the visceral fat returns when the injections stop, the months on it are borrowed time that only pay off if you use them to change what put the fat there, meaning protein-forward eating, resistance training, less alcohol, and better sleep. We check IGF-1, fasting glucose, and HbA1c before starting and during treatment, we measure whether the abdominal fat is moving rather than assuming it, and we stop in anyone who isn't responding. Tracking body fat percentage over time tells you more about where you're headed than any single scan does.

Ask a provider about tesamorelin

References

1. Ferdinandi ES, Brazeau P, High K, et al. Non-clinical pharmacology and safety evaluation of TH9507, a human growth hormone-releasing factor analogue. Basic Clin Pharmacol Toxicol. 2007. PMID: 17214611
2. Dhillon S. Tesamorelin: a review of its use in the management of HIV-associated lipodystrophy. Drugs. 2011. PMID: 21668043
3. Fox CS, Massaro JM, Hoffmann U, et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation. 2007. PMID: 17576866
4. Falutz J, Allas S, Blot K, et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. 2007. PMID: 18057338
5. Falutz J, Mamputu JC, Potvin D, et al. Effects of tesamorelin (TH9507), a growth hormone-releasing factor analog, in human immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind placebo-controlled phase 3 trials with safety extension data. J Clin Endocrinol Metab. 2010. PMID: 20554713
6. Stanley TL, Feldpausch MN, Oh J, et al. Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: a randomized clinical trial. JAMA. 2014. PMID: 25038357
7. Stanley TL, Fourman LT, Feldpausch MN, et al. Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial. Lancet HIV. 2019. PMID: 31611038
8. Makimura H, Feldpausch MN, Rope AM, et al. Metabolic effects of a growth hormone-releasing factor in obese subjects with reduced growth hormone secretion: a randomized controlled trial. J Clin Endocrinol Metab. 2012. PMID: 23015655
9. Baker LD, Barsness SM, Borson S, et al. Effects of growth hormone-releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial. Arch Neurol. 2012. PMID: 22869065
10. Stanley TL, Falutz J, Marsolais C, et al. Reduction in visceral adiposity is associated with an improved metabolic profile in HIV-infected patients receiving tesamorelin. Clin Infect Dis. 2012. PMID: 22495074