Tesamorelin

Overview

Tesamorelin (trade names Egrifta and Egrifta SV) is a synthetic analog of human growth hormone-releasing hormone (GHRH) consisting of all 44 amino acids of endogenous GHRH with a trans-3-hexenoic acid modification at the N-terminus. This modification confers resistance to dipeptidyl peptidase-IV (DPP-IV) degradation, extending the peptide's biological activity compared to native GHRH. Developed by Theratechnologies Inc. and approved by the FDA in November 2010, tesamorelin is the only GHRH analog approved for clinical use in the United States.

The FDA-approved indication is the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy, a common metabolic complication of antiretroviral therapy. This approval was based on two pivotal Phase III randomized controlled trials (ADORE and MEASURE) involving over 800 patients, which demonstrated significant reductions in visceral adipose tissue (VAT) of 15-18% compared to placebo. Unlike exogenous growth hormone, tesamorelin preserves the body's natural pulsatile GH secretory pattern and physiological feedback mechanisms, resulting in a more favorable safety profile.

Beyond its approved indication, tesamorelin has garnered significant interest for off-label applications including body composition optimization, cognitive enhancement in aging populations, and treatment of non-alcoholic fatty liver disease (NAFLD). These applications are supported by randomized controlled trial data, positioning tesamorelin as one of the most evidence-supported peptides available to prescribers.

Mechanism of Action

Tesamorelin functions as a full agonist at the GHRH receptor (GHRHR), a class B G-protein-coupled receptor expressed primarily on anterior pituitary somatotroph cells. Upon binding, it activates the Gs/cAMP/PKA signaling cascade, which triggers both immediate exocytosis of stored GH vesicles and longer-term transcriptional upregulation of GH gene expression via CREB and Pit-1 transcription factors.

The resulting elevation in circulating GH stimulates hepatic production of insulin-like growth factor-1 (IGF-1), which mediates many of tesamorelin's metabolic effects. Key downstream pathways include:

• Lipolysis: GH directly activates hormone-sensitive lipase in adipocytes, with preferential effects on visceral adipose tissue due to its higher density of GH receptors
• Protein synthesis: IGF-1 promotes lean body mass accrual through enhanced protein synthesis in skeletal muscle
• Hepatic effects: Reduction in hepatic lipogenesis and improvement in hepatic steatosis through modulation of lipid metabolism
• Neuroprotection: IGF-1 crosses the blood-brain barrier and activates PI3K/Akt and MAPK neuroprotective cascades, supporting neuronal survival and synaptic plasticity

A critical distinction from exogenous GH administration is that tesamorelin maintains the hypothalamic-pituitary feedback loop. Somatostatin and IGF-1 negative feedback remain intact, preventing supraphysiological GH exposure and reducing the risk of GH-related adverse effects.

Clinical Applications

Primary Indication: HIV-Associated Lipodystrophy

Tesamorelin is FDA-approved for reducing excess abdominal fat in HIV-infected patients with lipodystrophy. Visceral adipose tissue accumulation is a common complication of antiretroviral therapy, associated with cardiovascular risk, insulin resistance, and significant psychological distress. In pooled Phase III data (n=816), tesamorelin achieved:

• 15-18% reduction in visceral adipose tissue vs placebo (p<0.001)
• Significant improvement in triglyceride levels
• Improved patient-reported body image and quality of life
• Effects sustained at 52 weeks in extension studies
• Effects are reversible upon discontinuation

Secondary / Off-Label Uses

Tesamorelin's evidence base extends well beyond its approved indication, with RCT-level data supporting several off-label applications:

• Cognitive enhancement: A 20-week RCT (Baker et al., n=152) demonstrated improved executive function, verbal memory, and favorable changes in biomarkers of Alzheimer's disease in healthy older adults and those with mild cognitive impairment
• Non-alcoholic fatty liver disease: A randomized trial (Stanley et al., n=61) showed 37% resolution of hepatic steatosis vs 0% in the placebo group in HIV patients with NAFLD
• Body composition optimization: Off-label use in non-HIV populations for visceral fat reduction, supported by the same physiological mechanisms but with less formal trial data
• Cardiovascular risk reduction: The TEBEAT trial demonstrated stabilization of carotid intima-media thickness, suggesting cardiovascular protective effects

Dosing & Administration

Administration Tips

Reconstitute lyophilized tesamorelin with the provided diluent (sterile water). Egrifta SV comes as a single-vial formulation simplifying preparation. Inject subcutaneously into the abdomen with a 29-31 gauge insulin syringe. Rotate injection sites within the abdominal area to minimize lipodystrophy at the injection site. Reconstituted solution should be refrigerated and used within 14 days. Administer at the same time each day, preferably in the morning to align with the natural circadian GH surge.

Safety Considerations

Common Side Effects

The most frequently reported adverse effects from pooled Phase III data include arthralgia (13.3% vs 8.5% placebo), injection site reactions including erythema (7.9%) and pruritus (5.1%), peripheral edema (6.1%), extremity pain (6.1%), myalgia (5.5%), and paresthesia (4.9%). These GH-related effects are generally mild, dose-dependent, and self-limiting. Injection site reactions typically diminish over the first 2-4 weeks of therapy.

• Arthralgia and myalgia are the most common GH-related effects and often resolve within 2-4 weeks
• Peripheral edema and paresthesia (including carpal tunnel symptoms) indicate GH/IGF-1 elevation and may warrant dose reassessment
• Injection site reactions are minimized by proper rotation technique and room-temperature injection

Drug Interactions

Tesamorelin's primary drug interactions relate to the GH/IGF-1 axis:

• Glucocorticoids: May inhibit the GH response, potentially reducing tesamorelin efficacy. Consider timing separation
• Insulin and oral hypoglycemics: Tesamorelin may increase insulin resistance, necessitating dose adjustments of diabetes medications
• Somatostatin analogs (octreotide, lanreotide): Directly antagonize GHRH signaling; avoid concurrent use
• Thyroid hormones: GH affects peripheral T4-to-T3 conversion; monitor thyroid function tests
• Other GH secretagogues: Additive effects on GH/IGF-1 elevation; avoid stacking without careful monitoring

Evidence Summary

Tesamorelin has one of the strongest evidence bases of any peptide used in clinical practice. The FDA approval was supported by two large, well-designed Phase III randomized controlled trials (ADORE, n=412; MEASURE, n=404) with consistent results. Pooled safety data encompasses over 800 patients with systematic adverse event collection, providing robust safety characterization.

Beyond the pivotal trials, tesamorelin has RCT-level data for cognitive enhancement (Baker et al., 2012, n=152), NAFLD treatment (Stanley et al., 2014 and 2019, n=61), and cardiovascular biomarkers. Long-term extension studies at 52 weeks confirm sustained efficacy and safety. The total published evidence base includes over 20 peer-reviewed clinical studies.

Regulatory Status

Tesamorelin is FDA-approved under the brand names Egrifta (original two-vial formulation) and Egrifta SV (single-vial formulation) for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. It is a Schedule II controlled substance in some jurisdictions due to its GH-releasing properties. For off-label use, prescribers may use the FDA-approved product or compounded formulations through 503A pharmacies. When using compounded tesamorelin, verify the pharmacy's accreditation, request certificates of analysis, and ensure patients understand the compounded product is not FDA-approved. The patent for the branded product has limited remaining exclusivity, which may affect availability and pricing dynamics.