Tesamorelin

Tesamorelin.

In November 2010, tesamorelin (Egrifta; Theratechnologies/EMD Serono), a growth hormone-releasing factor analogue, was approved by the US Food and Drug Administration for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy.

Therapeutic Peptides in Orthopaedics: Applications, Challenges, and Future Directions.

Therapeutic peptides are emerging as promising adjuncts in the management of orthopaedic injuries, grounded in their ability to modulate molecular signaling networks central to cellular medicine. By acting on key pathways such as PI3K/Akt, mTOR, MAPK, TGF-β, and AMPK, peptides exert influence over tissue regeneration, inflammation resolution, and neuromuscular recovery. Wound-healing peptides such as BPC-157, TB-500, and GHK-Cu promote angiogenesis, integrin-mediated extracellular matrix remodeling, and fibroblast activation, whereas growth hormone secretagogues like ipamorelin, CJC-1295, tesamorelin, sermorelin, and AOD-9604 activate IGF-1 signaling and satellite cell repair. Recovery-enhancing agents such as epithalon, delta sleep-inducing peptide, and pinealon target circadian and mitochondrial regulators, and neuroactive peptides like selank, semax, and dihexa enhance brain-derived neurotrophic factor and HGF/c-Met pathways critical to neuroplasticity. Although preclinical studies are promising, there is a current lack of clinical trials. This review integrates current mechanistic insights with orthopaedic relevance, emphasizing safety, efficacy, and future directions for responsible integration into musculoskeletal care.

Safety and Efficacy of Approved and Unapproved Peptide Therapies for Musculoskeletal Injuries and Athletic Performance.

Peptides are short chains of amino acids with a unique pharmacological niche between small-molecule drugs and large proteins. Their use in sports medicine is rapidly expanding, driven by patient demand for accelerated injury recovery and performance enhancement. While numerous peptide drugs have undergone a rigorous approval process that evaluates both safety and efficacy, a parallel "gray market" of unapproved compounds has emerged, operating largely outside of regulatory oversight. Our objective is to present the pharmacological mechanisms, safety profiles, and regulatory status of prominent approved and unapproved peptides marketed direct to patients, including AOD-9604 (anti-obesity drug 9604), BPC-157 (body protection compound 157), CJC-1295, FS-344 (follistatin-344), GHK-Cu (glycyl-L-histidyl-L-lysine copper), ipamorelin, MOTS-C (mitochondrial ORF of the 12S rRNA type-c), sermorelin, SS-31 (elamipretide), tesamorelin (Egrifta), Tβ4 (thymosin beta-4), and TB-500 (thymosin beta-4 fragment). Many unapproved peptides demonstrate favorable tissue repair and metabolic outcomes in animal models, but rigorous human safety data are scarce, and there is potential for serious harm to patients. This narrative review focuses on the utilization of peptides in sports medicine, and alternative treatments that may be considered. We provide a framework to navigate patient discussions about peptides to better facilitate evidence-based practices for musculoskeletal healing and athletic performance. We also discuss the placebo effect as a mediator of peptide efficacy, and how social media amplifies this effect.

Injectable Peptide Therapy: A Primer for Orthopaedic and Sports Medicine Physicians.

Therapeutic peptides are short-chain amino acids that regulate cellular functions and facilitate biochemical processes. In recent years, there has been significant growth in the global market for therapeutic peptides and thus its popularity among patients. Given the increase in the development of peptides and increased marketing to patients for orthopaedic injuries, it is critical for orthopaedic surgeons to understand the current evidence behind these therapeutic peptides. To evaluate the current evidence and applications of injectable peptide therapy, focusing on its potential in regenerative medicine and sports performance, to help orthopaedic providers better understand the current state of different therapeutic peptide approaches. Narrative review. A comprehensive literature search was conducted using PubMed to identify biochemical and clinical studies on the most popular types of injectable peptide therapy. Key peptides evaluated included BPC-157, TB-4, TB-500, CJC-1295 + ipamorelin, tesamorelin, and GHK-Cu. BPC-157 demonstrated potential benefits in tendon and muscle repair, but these findings are largely unvalidated in human trials. A single human case series reported improvements in pain after intra-articular knee injections of BPC-157, although significant methodological flaws and a lack of controls limit its applicability and reliability. TB-4 and its derivative TB-500 promoted angiogenesis and tissue repair in preclinical models, but human orthopaedic data are lacking, and both remain banned substances in sports. CJC-1295 combined with ipamorelin showed significantly improved maximum tetanic tension in murine models with glucocorticoid-induced muscle loss, but these findings are limited to animal studies. Tesamorelin, approved for treating HIV-associated lipodystrophy, has no supporting orthopaedic evidence. GHK-Cu showed promise in wound healing and anti-inflammatory effects, but no clinical data support its use for musculoskeletal conditions. While peptide therapy may possess significant therapeutic and regenerative potential, it is critical that orthopaedic and sports medicine providers understand the current lack of evidence to support the clinical use of these peptides. Importantly, information regarding the indications, dosing, frequency, and duration of treatment remains unknown. Despite the popularity of these peptides in mainstream media and among patients, significant research regarding the safety and efficacy of these therapeutic methods is required before definitive recommendations can be made to patients.

Efficacy and safety of tesamorelin in people with HIV on integrase inhibitors.

Tesamorelin is the only FDA-approved therapy to treat abdominal fat accumulation in people with HIV (PWH). Phase III clinical trials were conducted prior to the introduction of integrase inhibitors (INSTIs), which are now a mainstay of HIV antiretroviral therapy. We leveraged a randomized double-blind trial of 61 PWH and metabolic dysfunction-associated steatotic liver disease to evaluate the efficacy and safety of tesamorelin 2 mg once daily vs. identical placebo among participants on INSTI-based regimens at baseline. In the parent clinical trial, visceral fat cross-sectional area, hepatic fat fraction, and trunk-to-appendicular fat ratio were quantified using magnetic resonance imaging, proton magnetic resonance spectroscopy, and dual-energy x-ray absorptiometry, respectively, at baseline and 12 months. Metabolic and safety outcomes were compared between treatment arms. Among 38 participants on INSTI-based regimens at baseline, 15 individuals on tesamorelin and 16 individuals on placebo completed the 12-month study. Tesamorelin led to significant declines in visceral fat (median [interquartile range]: -25 [-93, -2] vs. 14 [3, 41] cm 2 , P  = 0.001), hepatic fat (-4.2% [-12.3%, -2.7%] vs. -0.5% [-3.9%, 2.7%], P  = 0.01), and trunk-to-appendicular fat ratio (-0.1 [-0.3, 0.0] vs. 0.0 [-0.1, 0.1], P  = 0.03). Tesamorelin was well tolerated with a similar frequency of adverse events, including hyperglycemia, between groups. The current analysis provides the first dedicated data on the efficacy and safety of tesamorelin among PWH on INSTI-based regimens. Despite the association of INSTI use with weight gain and adipose tissue dysfunction, tesamorelin had beneficial effects on body composition with no exacerbation of glycemic control.

Tesamorelin update.

Tesamorelin: a growth hormone-releasing factor analogue for HIV-associated lipodystrophy.

To evaluate the efficacy and safety of tesamorelin, a growth hormone releasing factor analogue approved by the Food and Drug Administration in November 2010 for the treatment of lipodystrophy associated with HIV infection. Literature was obtained through MEDLINE (1948-November 2011) and International Pharmaceutical Abstracts (1970-October 2011) using the search terms tesamorelin, TH9507, growth hormone releasing factor, and HIV-associated lipodystrophy syndrome. Additional publications were obtained through review of references within primary literature publications as well as pertinent Web sites. All articles published in English identified from the data sources were evaluated and all pertinent information was included. All studies relevant to the evaluation of efficacy and safety of tesamorelin in the management of HIV-associated lipodystrophy were included, with a focus on trials completed in humans. In 2 Phase 3 clinical trials and their pooled analyses, tesamorelin was proven to significantly decrease waist circumference and visceral adipose tissue (VAT) following 26 weeks of treatment. Both trials also demonstrated significant improvements in some subjective body image parameters. Both studies had 26-week extension phases that confirmed maintenance of VAT improvements on treatment without adverse impact on blood glucose and lipid parameters. Limited data support off-label uses of tesamorelin at this time. Tesamorelin is effective in improving visceral adiposity and body image in patients with HIV-associated lipodystrophy over 26-52 weeks of treatment. Potential limitations for its use include high cost and lack of long-term safety and adherence data. Tesamorelin provides a useful treatment option for management of patients with significant lipodystrophy related to HIV infection.

Effects of Tesamorelin on Neurocognitive Impairment in Persons With HIV and Abdominal Obesity.

In people with HIV who are virally suppressed with antiretroviral therapy, abdominal obesity (AO) is linked to neurocognitive impairment (NCI), potentially due to visceral adiposity, inflammation, and reduced insulin-like growth factor 1 (IGF-1). Tesamorelin, a growth hormone-releasing hormone, reduces AO and increases IGF-1, suggesting that it might mitigate NCI in people with HIV and viral suppression. This 6-month phase 2 randomized open-label clinical trial compared tesamorelin vs standard of care (SOC) for NCI in people with HIV who were virally suppressed and abdominally obese (elevated waist circumference [WC]). Exclusions included conditions other than HIV causing NCI, active substance use disorder, and malignancy. Seventy-three participants were randomized 3:2 to tesamorelin or SOC (2 mg subcutaneously daily). The primary outcome was the change in neurocognitive performance at 6 months, with secondary outcomes including WC, mood, and daily functioning. The groups were well matched at baseline. The tesamorelin group showed a trend toward improved neurocognitive performance after 6 months (mean change, 0.146; 95% CI, -.002 to .294; P = .060) while the SOC group did not (0.103; 95% CI, -.095 to .301; P = .295), but the between-group difference was not significant (P = .673). IGF-1 levels increased, but changes did not correlate with summary regression change score or WC. The tesamorelin group had a greater reduction in WC than the SOC group (median difference, -2.7 cm; P = .015). While tesamorelin reduced WC, the cognitive benefits did not significantly differ between groups. Recognizing the limitations of insufficient power and no placebo arm, this study suggests no clear benefit of short-term AO reduction with tesamorelin on NCI.

Tesamorelin: a review of its use in the management of HIV-associated lipodystrophy.

Tesamorelin (Egrifta&#x2122;) is a synthetic analogue of human growth hormone-releasing hormone (also known as growth hormone-releasing factor) that stimulates the synthesis and release of endogenous growth hormone. It is the first and, so far, only treatment indicated for the reduction of excess abdominal fat in patients with HIV-associated lipodystrophy. This article reviews the pharmacological properties, clinical efficacy and tolerability of tesamorelin in patients with HIV-associated central fat accumulation. Subcutaneous tesamorelin was effective in reducing visceral adipose tissue (VAT), but did not affect subcutaneous adipose tissue to a clinically significant extent in two 26-week, well designed, clinical trials in patients with HIV-associated central fat accumulation. This reduction in VAT was maintained in the longer term in patients who continued to receive tesamorelin until week 52 in the extension phases of the two trials. However, discontinuation of therapy during this period resulted in the reaccumulation of VAT. Tesamorelin therapy was also associated with significant improvements in other body composition measures (e.g. trunk fat and waist circumference) and improvements were generally seen in some body image parameters (e.g. belly image distress). Tesamorelin was generally well tolerated, with treatment-emergent serious adverse events occurring in <4% of patients during 26 weeks of therapy. Most of these events were injection-site reactions or events known to be associated with growth hormone therapy (e.g. arthralgia, headache and peripheral oedema). Although long-term clinical experience is needed to further assess the benefits and risks of therapy, current evidence suggests that tesamorelin may be useful for reducing visceral adiposity in patients with HIV-associated lipodystrophy, thereby potentially improving self image.

Advances in the detection of growth hormone releasing hormone synthetic analogs.

The administration of growth hormone releasing hormone (GHRH) and its synthetic analogs is prohibited by the World Anti-Doping Agency (WADA). Although there is evidence of their use, based on admissions and intelligence, they do not appear to have been found in anti-doping samples by WADA accredited laboratories. This might be due to their small concentration in urine and limited knowledge about their metabolism, especially for unapproved synthetic analogs. This study investigates the in vitro metabolism and detection of four of the larger GHRH synthetic analogs (sermorelin, tesamorelin, CJC-1295, and CJC-1295 with drug affinity complex) in fortified urine. Nineteen major in vitro metabolites were identified, selected for synthesis, purified, and characterized in house. These were used as reference materials to spike into urine together with commercially available parent peptides and a metabolite of sermorelin (sermorelin(3-29)-NH2 ) to develop a sensitive liquid chromatography-tandem mass spectrometry method for their detection to help prove GHRH administration. Limits of detection of the target peptides were generally 1&#xa0;ng/ml (WADA required performance limit) or less.

Spotlight on tesamorelin in HIV-associated lipodystrophy.

Tesamorelin (Egrifta&#x2122;) is a synthetic analog of human growth hormone-releasing hormone (also known as growth hormone-releasing factor) that stimulates the synthesis and release of endogenous growth hormone. It is the first and, so far, only treatment indicated for the reduction of excess abdominal fat in patients with HIV-associated lipodystrophy. This article reviews the pharmacological properties, clinical efficacy and tolerability of tesamorelin in patients with HIV-associated central fat accumulation. Subcutaneous tesamorelin was effective in reducing visceral adipose tissue (VAT), but did not affect subcutaneous adipose tissue to a clinically significant extent in two 26-week, well designed, clinical trials in patients with HIV-associated central fat accumulation. This reduction in VAT was maintained in the longer term in patients who continued to receive tesamorelin until week 52 in the extension phases of the two trials. However, discontinuation of therapy during this period resulted in the reaccumulation of VAT. Tesamorelin therapy was also associated with significant improvements in other body composition measures (e.g. trunk fat and waist circumference) and improvements were generally seen in some body image parameters (e.g. belly image distress). Tesamorelin was generally well tolerated, with treatment-emergent serious adverse events occurring in <4% of patients during 26 weeks of therapy. Most of these events were injection-site reactions or events known to be associated with growth hormone therapy (e.g. arthralgia, headache and peripheral edema). Although long-term clinical experience is needed to further assess the benefits and risks of therapy, current evidence suggests that tesamorelin may be useful for reducing visceral adiposity in patients with HIV-associated lipodystrophy, thereby potentially improving self image.

Tesamorelin improves fat quality independent of changes in fat quantity.

Fat quality and quantity may affect health similarly or differently. Fat quality can be assessed by measuring fat density on CT scan (greater density&#x200a;=&#x200a;smaller, higher quality adipocytes). We assessed the effects of tesamorelin, a growth hormone-releasing hormone analogue that reduces visceral fat (VAT) quantity in some people living with HIV (PWH), on fat density. Participants from two completed, placebo-controlled, randomized trials of tesamorelin for central adiposity treatment in PWH were included if they had either a clinical response to tesamorelin (VAT decrease &#x2265;8%, &#x2248;70% of participants) or were placebo-treated. CT VAT and subcutaneous fat (SAT) density (Hounsfield Units, HU) were measured by a central blinded reader. Participants (193 responders, 148 placebo) were 87% male and 83% white. Baseline characteristics were similar across arms, including VAT (-91 HU both arms, P&#x200a;=&#x200a;0.80) and SAT density (-94 HU tesamorelin, -95 HU placebo, P&#x200a;=&#x200a;0.29). Over 26 weeks, mean (SD) VAT and SAT density increased in tesamorelin-treated participants only [VAT: +6.2 (8.7) HU tesamorelin, +0.3 (4.2) HU placebo, P&#x200a;<&#x200a;0.0001; SAT: +4.0 (8.7) HU tesamorelin, +0.3 (4.8) HU placebo, P&#x200a;<&#x200a;0.0001]. The tesamorelin effects persisted after controlling for baseline VAT or SAT HU and area, and VAT [+2.3 HU, 95% confidence interval (4.5-7.3), P&#x200a;=&#x200a;0.001) or SAT (+3.5 HU, 95% confidence interval (2.3-4.7), P&#x200a;<&#x200a;0.001] area change. In PWH with central adiposity who experienced VAT quantity reductions on tesamorelin, VAT and SAT density increased independent of changes in fat quantity, suggesting that tesamorelin also improves VAT and SAT quality in this group.

Approach to the Patient With Lipodystrophy.

Lipodystrophy constitutes a spectrum of diseases characterized by a generalized or partial absence of adipose tissue. Underscoring the role of healthy fat in maintenance of metabolic homeostasis, fat deficiency in lipodystrophy typically leads to profound metabolic disturbances including insulin resistance, hypertriglyceridemia, and ectopic fat accumulation. While rare, recent genetic studies indicate that lipodystrophy is more prevalent than has been previously thought, suggesting considerable underdiagnosis in clinical practice. In this article, we provide an overview of the etiology and management of generalized and partial lipodystrophy disorders. We bring together the latest scientific evidence and clinical guidelines and expose key gaps in knowledge. Through improved recognition of the lipodystrophy disorders, patients (and their affected family members) can be appropriately screened for cardiometabolic, noncardiometabolic, and syndromic abnormalities and undergo treatment with targeted interventions. Notably, insights gained through the study of this rare and extreme phenotype can inform our knowledge of more common disorders of adipose tissue overload, including generalized obesity.

Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity among people living with HIV that has a more aggressive course than NAFLD among the general population. In a recent randomized placebo-controlled trial, we demonstrated that the growth hormone-releasing hormone analog tesamorelin reduced liver fat and prevented fibrosis progression in HIV-associated NAFLD over 1 year. As such, tesamorelin is the first strategy that has shown to be effective against NAFLD among the population with HIV. The current study leveraged paired liver biopsy specimens from this trial to identify hepatic gene pathways that are differentially modulated by tesamorelin versus placebo. Using gene set enrichment analysis, we found that tesamorelin increased hepatic expression of hallmark gene sets involved in oxidative phosphorylation and decreased hepatic expression of gene sets contributing to inflammation, tissue repair, and cell division. Tesamorelin also reciprocally up- and downregulated curated gene sets associated with favorable and poor hepatocellular carcinoma prognosis, respectively. Notably, among tesamorelin-treated participants, these changes in hepatic expression correlated with improved fibrosis-related gene score. Our findings inform our knowledge of the biology of pulsatile growth hormone action and provide a mechanistic basis for the observed clinical effects of tesamorelin on the liver.

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.

HIV patients treated with antiretroviral therapy (ART) often develop increased visceral adipose tissue (VAT). Our objective was to perform a pooled analysis of two phase-3 studies of tesamorelin in ART-treated HIV patients with excess abdominal fat. Two multicenter, international studies were conducted; a 26-wk randomized, placebo-controlled primary intervention phase was followed by a 26-wk safety extension. A total of 806 ART-treated HIV patients with excess abdominal fat were randomized in a 2:1 fashion to receive tesamorelin 2 mg (n = 543) or placebo (n = 263) sc daily. At wk 26, patients initially on tesamorelin were rerandomized to 2 mg tesamorelin (T-T group, n = 246) or placebo (T-P, n = 135) for an additional 26 wk, whereas patients on placebo were switched to tesamorelin (P-T, n = 197). Tesamorelin (GHRH(1-44)) at a dose of 2 mg or identical placebo, sc, was given daily. We evaluated percent change in VAT by computed tomography scan at wk 26. At wk 26, VAT decreased significantly in tesamorelin-treated patients (-24 +/- 41 vs. 2 +/- 35 cm(2), tesamorelin vs. placebo, P < 0.001; treatment effect, -15.4%). No significant changes were observed in abdominal sc adipose tissue (-2 +/- 32 vs. 2 +/- 29 cm(2), P = 0.08; treatment effect, -0.6%). Treatment with tesamorelin resulted in significant decreases in triglycerides (-37 +/- 139 vs. 6 +/- 112 mg/dl, P < 0.001; treatment effect, -12.3%) and cholesterol to high-density lipoprotein ratio (-0.18 +/- 1.00 vs. 0.18 +/- 0.94, P < 0.001; treatment effect, -7.2%) vs. placebo. Tesamorelin improved body image [belly appearance distress (P = 0.002)], patient rating of belly profile (P = 0.003), and physician rating of belly profile (P < 0.001). Mean IGF-I increased 108 +/- 112 vs.-7 +/- 64 ng/ml (P < 0.001 vs. placebo). At wk 52, decreases in VAT [-35 +/- 50 cm(2) (-17.5 +/- 23.3%)], waist circumference (-3.4 +/- 6.0 cm), triglycerides (-48 +/- 182 mg/dl), cholesterol (-8 +/- 38 mg/dl), and non-high-density lipoprotein (-7 +/- 38 mg/dl) were maintained (all P < 0.001 vs. original baseline) in the T-T group. Treatment with tesamorelin was generally well tolerated. No clinically meaningful differences were observed between groups in glucose parameters at wk 26 and 52. Treatment with tesamorelin reduces VAT and maintains the reduction for up to 52 wk, preserves abdominal sc adipose tissue, improves body image and lipids, and is overall well tolerated without clinically meaningful changes in glucose parameters.

The Growth Hormone Releasing Hormone Analogue, Tesamorelin, Decreases Muscle Fat and Increases Muscle Area in Adults with HIV.

Tesamorelin, a growth hormone-releasing hormone analogue, decreases visceral adipose tissue in people living with HIV, however, the effects on skeletal muscle fat and area are unknown. The goals of this exploratory secondary analysis were to determine the effects of tesamorelin on muscle quality (density) and quantity (area). Secondary, exploratory analysis of two previously completed randomized (2:1), clinical trials. U.S. and Canadian sites. People living with HIV and with abdominal obesity. Tesamorelin participants were restricted to responders (visceral adipose tissue decrease &#x2265;8%). Tesamorelin or placebo. Computed tomography scans (at L4-L5) were used to quantify total and lean density (Hounsfield Units, HU) and area (centimeters2) of four trunk muscle groups using a semi-automatic segmentation image analysis program. Differences between muscle area and density before and after 26 weeks of tesamorelin or placebo treatment were compared and linear regression models were adjusted for baseline and treatment arm. Tesamorelin responders (n=193) and placebo (n=148) participants with available images were similar at baseline; most were Caucasian (83%) and male (87%). In models adjusted for baseline differences and treatment arm, tesamorelin was associated with significantly greater increases in density of four truncal muscle groups (coefficient 1.56-4.86 Hounsfield units; all p<0.005), and the lean anterolateral/abdominal and rectus muscles (1.39 and 1.78 Hounsfield units; both p<0.005) compared to placebo. Significant increases were also seen in total area of the rectus and psoas muscles (0.44 and 0.46 centimeters2; p<0.005), and in the lean muscle area of all four truncal muscle groups (0.64-1.08 centimeters2; p<0.005). Among those with clinically significant decrease in visceral adipose tissue on treatment, tesamorelin was effective in increasing skeletal muscle area and density. Long term effectiveness of tesamorelin among people with and without HIV, and the impact of these changes in daily life should be further studied.

How to diagnose a lipodystrophy syndrome.

The spectrum of adipose tissue diseases ranges from obesity to lipodystrophy, and is accompanied by insulin resistance syndrome, which promotes the occurrence of type 2 diabetes, dyslipidemia and cardiovascular complications. Lipodystrophy refers to a group of rare diseases characterized by the generalized or partial absence of adipose tissue, and occurs with or without hypertrophy of adipose tissue in other sites. They are classified as being familial or acquired, and generalized or partial. The genetically determined partial forms usually occur as Dunnigan syndrome, which is a type of laminopathy that can also manifest as muscle, cardiac, neuropathic or progeroid involvement. Gene mutations encoding for PPAR-gamma, Akt2, CIDEC, perilipin and the ZMPSTE 24 enzyme are much more rare. The genetically determined generalized forms are also very rare and are linked to mutations of seipin AGPAT2, FBN1, which is accompanied by Marfan syndrome, or of BANF1, which is characterized by a progeroid syndrome without insulin resistance and with early bone complications. Glycosylation disorders are sometimes involved. Some genetically determined forms have recently been found to be due to autoinflammatory syndromes linked to a proteasome anomaly (PSMB8). They result in a lipodystrophy syndrome that occurs secondarily with fever, dermatosis and panniculitis. Then there are forms that are considered to be acquired. They may be iatrogenic (protease inhibitors in HIV patients, glucocorticosteroids, insulin, graft-versus-host disease, etc.), related to an immune system disease (sequelae of dermatopolymyositis, autoimmune polyendocrine syndromes, particularly associated with type 1 diabetes, Barraquer-Simons and Lawrence syndromes), which are promoted by anomalies of the complement system. Finally, lipomatosis is currently classified as a painful form (adiposis dolorosa or Dercum's disease) or benign symmetric multiple form, also known as Launois-Bensaude syndrome or Madelung's disease, which are sometimes related to mitochondrial DNA mutations, but are usually promoted by alcohol. In addition to the medical management of metabolic syndrome and the sometimes surgical treatment of lipodystrophy, recombinant leptin provides hope for genetically determined lipodystrophy syndromes, whereas modifications in antiretroviral treatment and tesamorelin, a GHRH analog, is effective in the metabolic syndrome of HIV patients. Other therapeutic options will undoubtedly be developed, dependent on pathophysiological advances, which today tend to classify genetically determined lipodystrophy as being related to laminopathy or to lipid droplet disorders.

Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach.

NAFLD is a leading comorbidity in HIV with an exaggerated course compared to the general population. Tesamorelin has been demonstrated to reduce liver fat and prevent fibrosis progression in HIV-associated NAFLD. We further showed that tesamorelin downregulated hepatic gene sets involved in inflammation, tissue repair, and cell division. Nonetheless, effects of tesamorelin on individual plasma proteins pertaining to these pathways are not known. Leveraging our prior randomized-controlled trial and transcriptomic approach, we performed a focused assessment of 9 plasma proteins corresponding to top leading edge genes within differentially modulated gene sets. Tesamorelin led to significant reductions in vascular endothelial growth factor A (VEGFA, log2-fold change -&#x2009;0.20&#x2009;&#xb1;&#x2009;0.35 vs. 0.05&#x2009;&#xb1;&#x2009;0.34, P&#x2009;=&#x2009;0.02), transforming growth factor beta 1 (TGFB1, -&#x2009;0.35&#x2009;&#xb1;&#x2009;0.56 vs. -&#x2009;0.05&#x2009;&#xb1;&#x2009;0.43, P&#x2009;=&#x2009;0.05), and macrophage colony stimulating factor 1 (CSF1, -&#x2009;0.17&#x2009;&#xb1;&#x2009;0.21 vs. 0.02&#x2009;&#xb1;&#x2009;0.20, P&#x2009;=&#x2009;0.004) versus placebo. Among tesamorelin-treated participants, reductions in plasma VEGFA (r&#x2009;=&#x2009;0.62, P&#x2009;=&#x2009;0.006) and CSF1 (r&#x2009;=&#x2009;0.50, P&#x2009;=&#x2009;0.04) correlated with a decline in NAFLD activity score. Decreases in TGFB1 (r&#x2009;=&#x2009;0.61, P&#x2009;=&#x2009;0.009) and CSF1 (r&#x2009;=&#x2009;0.64, P&#x2009;=&#x2009;0.006) were associated with reduced gene-level fibrosis score. Tesamorelin suppressed key angiogenic, fibrogenic, and pro-inflammatory mediators. CSF1, a regulator of monocyte recruitment and activation, may serve as an innovative therapeutic target for NAFLD in HIV. Clinical Trials Registry Number: NCT02196831.

Body composition, hepatic fat, metabolic, and safety outcomes of Tesamorelin, a GHRH analogue, in HIV-associated lipodystrophy: A meta-analysis of randomized controlled trials.

HIV-associated lipodystrophy leads to visceral fat accumulation, metabolic complications, body image concerns, medication non-adherence, and increased cardiovascular risks. We thought to assess the effects of Tesamorelin, a synthetic growth hormone-releasing hormone analogue, that has been proposed as a targeted therapy. We systematically searched PubMed, Embase, Scopus, Web of Science, and CENTRAL through July 2025 for randomized controlled trials (RCTs) evaluating Tesamorelin versus placebo in adults with HIV. Random-effects meta-analysis was applied. Outcomes included changes in body composition, hepatic and metabolic parameters, hormonal markers, and adverse events. Risk of bias was assessed with RoB 2.0, and certainty of evidence with GRADE. Five RCTs evaluating Tesamorelin were included in the analysis. Tesamorelin was associated with significant reduction in visceral adipose tissue (MD=-27.71&#x202f;cm&#xb2;, 95&#x202f;% CI [-38.37, -17.06]; P&#x202f;<&#x202f;0.001), trunk fat (MD=-1.18&#x202f;kg, 95&#x202f;% CI [-1.40, -0.96]; P&#x202f;<&#x202f;0.001), limb fat (MD=-0.22&#x202f;kg, 95&#x202f;% CI [-0.35, -0.08]; P&#x202f;=&#x202f;0.001), hepatic fat percentage (MD=-4.28&#x202f;%, 95&#x202f;% CI [-6.31, -2.24]; P&#x202f;<&#x202f;0.001), and waist circumference (MD=-1.61&#x202f;cm, 95&#x202f;% CI [-2.28, -0.95]; P&#x202f;<&#x202f;0.001). A significant increase in lean body mass was observed (MD=1.42&#x202f;kg, 95&#x202f;% CI [1.13, 1.71]; P&#x202f;<&#x202f;0.001). However, no significant reductions in subcutaneous adipose tissue or BMI were observed. Tesamorelin showed no significant change in CD4&#x202f;+&#x202f;T-cell counts. Tesamorelin was associated with adverse events, including arthralgia, myalgia, paresthesia, and injection-site reactions like erythema. Tesamorelin improves body composition, hepatic fat, lean body mass, and IGF-1 levels in HIV-associated lipodystrophy, without serious side effects or perturbation of glucose.

Population pharmacokinetic analysis of tesamorelin in HIV-infected patients and healthy subjects.

Tesamorelin is a synthetic analogue of growth hormone-releasing factor (GRF), which increases basal and pulsatile growth hormone (GH) secretion and subsequently increases insulin-like growth factor (IGF)-1. Limited information is available about the pharmacokinetics of this compound. Consequently, the aim of this study was to characterize the population pharmacokinetics of tesamorelin in HIV-infected patients and healthy subjects. A total of 38 HIV-infected patients and healthy subjects receiving subcutaneous tesamorelin doses of 1 or 2&#xa0;mg administered daily during 14 consecutive days were included in the analysis. An open one-compartment model with first- and zero-order absorption and first-order elimination was developed to best describe the data using NONMEM(&#xae;) VII. The effect of different covariates on tesamorelin pharmacokinetics was investigated. Model evaluation was performed using predictive checks and non-parametric bootstrap. Plasma clearance and its interindividual variability [% coefficient of variation (CV)] was estimated to be 1,060&#xa0;L/h (33.6&#xa0;%). Volume of distribution was calculated to be 200&#xa0;L (17.7&#xa0;%). Age, body size measures, race and health status were not related to tesamorelin pharmacokinetic parameters within the range of covariates studied. The fraction of tesamorelin absorbed by a first-order process is 13.1&#xa0;% higher on day 14 compared with day 1. Predictive checks and non-parametric bootstrap demonstrated that the model is appropriate in describing the time course of tesamorelin plasma concentrations in both HIV-infected patients and healthy subjects. An open one-compartment model with first and zero order absorption processes and linear elimination is suitable to characterize the pharmacokinetics of tesamorelin. The fraction of tesamorelin absorbed by a first-order process evolves with time. No clinically relevant covariates were identified as predictors of tesamorelin pharmacokinetics.

Growth hormone in the aging male.

Secretion of growth hormone (GH) and IGF-1 levels decline during advancing years-of-life. These changes (somatopause) are associated with loss of vitality, muscle mass, physical function, together with the occurrence of frailty, central adiposity, cardiovascular complications, and deterioration of mental function. For GH treatment to be considered for anti-aging, improved longevity, organ-specific function, or quality of life should be demonstrable. A limited number of controlled studies suggest that GH supplementation in older men increases lean mass by &#x223c;2&#xa0;kg with similar reductions in fat mass. There is little evidence that GH treatment improves muscle strength and performance (e.g. walking speed or ability to climb stairs) or quality of life. The GHRH agonist (tesamorelin) restores normal GH pulsatility and amplitude, selectively reduces visceral fat, intima media thickness and triglycerides, and improves cognitive function in older persons. This report critically reviews the potential for GH augmentation during aging with emphasis on men since women appear more resistant to treatment.

Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial.

Non-alcoholic fatty liver disease (NAFLD) is a substantial cause of comorbidity in people with HIV and there are no proven pharmacological treatments for the disease in this population. We assessed the effects of tesamorelin on liver fat and histology in people with HIV and NAFLD. This randomised, double-blind, multicentre study with identical placebo as a comparator was done in a hospital and a medical research centre in the USA. People with HIV infection and a hepatic fat fraction (HFF) of 5% or more by proton magnetic resonance spectroscopy were eligible. Participants were randomly assigned (1:1) to receive either tesamorelin 2 mg once daily or placebo once daily for 12 months, followed by a 6-month open-label phase during which all participants received tesamorelin 2 mg daily. The randomisation list was prepared by the study statistician using a permuted block algorithm within each stratum with randomly varying block sizes. The primary endpoint was change in HFF between baseline and 12 months. The primary safety endpoint was glucose. Analysis was by intention to treat using all available data. This trial is registered with ClinicalTrials.gov, number NCT02196831. 61 patients were enrolled between Aug 20, 2015, and Jan 16, 2019, of whom 30 received tesamorelin and 30 received placebo. Patients receiving tesamorelin had a greater reduction of HFF than did patients receiving placebo, with an absolute effect size of -4&#xb7;1% (95% CI -7&#xb7;6 to -0&#xb7;7, p=0&#xb7;018), corresponding to a -37% (95% CI -67 to -7, p=0&#xb7;016) relative reduction from baseline. After 12 months, 35% of individuals receiving tesamorelin and 4% receiving placebo had a HFF of less than 5% (p=0&#xb7;0069). Changes in fasting glucose and glycated haemoglobin were not different between groups at 12 months. Individuals in the tesamorelin group experienced more localised injection site complaints than those in the placebo group, though none were judged to be serious. Tesamorelin might be beneficial in people with HIV and NAFLD. Further studies are needed to determine the long-term effects of tesamorelin on liver histology. National Institutes of Health and National Institute of Allergy and Infectious Diseases.

Therapeutic Peptides in Aesthetic, Metabolic and Endocrine Conditions: Effects, Safety, Clinical Applications, and Future Perspectives.

Therapeutic peptides are short chains of amino acids used to treat metabolic and endocrine conditions such as obesity and type 2 diabetes. While several peptide drugs have undergone rigorous approval processes that evaluate both safety and efficacy, novel, unapproved compounds have emerged and are rapidly expanding into preventive medicine and performance enhancement. Our objective is to present the effects, clinical applications, safety profiles, and regulatory status of prominent peptides used to treat several conditions. We reviewed 106 articles, prioritizing systematic reviews, meta-analyses, and randomized controlled trials in the PubMed, ScienceDirect, and SciELO databases. Our results suggest that therapeutic peptides are a promising tool for treating type 2 diabetes and obesity, for skin rejuvenation, and as hormone analogs for specific diseases and conditions. Although these are strategic and innovative options that can improve health, performance, and longevity, further studies are needed before most new peptides can be used safely in humans.

Reduction in visceral adiposity is associated with an improved metabolic profile in HIV-infected patients receiving tesamorelin.

Tesamorelin, a growth hormone-releasing hormone analogue, decreases visceral adipose tissue (VAT) by 15%-20% over 6-12 months in individuals with human immunodeficiency virus (HIV)-associated abdominal adiposity, but it is unknown whether VAT reduction is directly associated with endocrine and metabolic changes. In 2 phase III, randomized, double-blind studies, men and women with HIV-associated abdominal fat accumulation were randomly assigned (ratio, 2:1) to receive tesamorelin or placebo for 26 weeks. At week 26, patients initially receiving tesamorelin were randomly assigned to continue receiving tesamorelin or to receive placebo for an additional 26 weeks. In per-protocol analysis of 402 subjects initially randomly assigned to receive tesamorelin, those with &#x2265;8% reduction in VAT were defined a priori as responders per the statistical analysis plan. Post hoc analyses were performed to assess differences between responders and nonresponders. Compared with tesamorelin nonresponders, responders experienced greater mean (&#xb1;SD) reduction in triglyceride levels (26 weeks: -0.6 &#xb1; 1.7 mmol/L vs -0.1 &#xb1; 1.2 mmol/L [P = .005]; 52 weeks: -0.8 &#xb1; 1.8 mmol/L vs 0.0 &#xb1; 1.1 mmol/L [P = .003]) and attenuated changes in fasting glucose levels (26 weeks: 1 &#xb1; 16 mg/dL vs 5 &#xb1; 14 mg/dL [P = .01]; 52 weeks: -1 &#xb1; 14 mg/dL vs 8 &#xb1; 17 mg/dL [P < .001]), hemoglobin A1c levels (26 weeks: 0.1 &#xb1; 0.3% vs 0.3 &#xb1; 0.4% [P < .001]; 52 weeks: 0.0 &#xb1; 0.3% vs 0.2 &#xb1; 0.5% [P = .003]), and other parameters of glucose homeostasis. Similar patterns were seen for adiponectin levels, with significant improvement in responders vs nonresponders. Changes in lipid levels and glucose homeostasis were significantly associated with percentage change in VAT. In contrast to nonresponders, HIV-infected patients receiving tesamorelin with &#x2265;8% reduction in VAT have significantly improved triglyceride levels, adiponectin levels, and preservation of glucose homeostasis over 52 weeks of treatment. CLINICALTRIALS.GOV REGISTRATION: NCT00123253, NCT00435136, NCT00608023.

Visceral fat reduction with tesamorelin is associated with improved liver enzymes in HIV.

Tesamorelin reduces visceral adipose tissue (VAT) in HIV. We investigated whether reductions in VAT with tesamorelin are associated with changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). We utilized data from two multicenter Phase III trials of tesamorelin among 806 HIV-infected patients with abdominal obesity. These studies showed that the majority of patients treated with tesamorelin are 'responders', defined a priori by the Food and Drug Administration as achieving at least 8% reduction in VAT. In the current analysis, we sought to examine the impact of VAT reduction on ALT and AST among patients participating in the Phase III trials with baseline elevated ALT or AST. Within this group, we compared changes in ALT and AST in VAT responders vs. nonresponders after 26 weeks of treatment, and then assessed the effects of drug discontinuation on these endpoints over a subsequent 26-week period. At baseline, VAT was positively associated with ALT (P&#x200a;=&#x200a;0.01). In study participants assigned to tesamorelin with baseline ALT or AST more than 30&#x200a;U/l, VAT responders experienced greater reductions in ALT (-8.9&#x200a;&#xb1;&#x200a;22.6 vs. 1.4&#x200a;&#xb1;&#x200a;34.7&#x200a;U/l, P&#x200a;=&#x200a;0.004) and AST (-3.8&#x200a;&#xb1;&#x200a;12.9 vs. 0.4&#x200a;&#xb1;&#x200a;22.4&#x200a;U/l, P&#x200a;=&#x200a;0.04) compared with nonresponders over 26 weeks. This improvement among VAT responders persisted over 52 weeks even in those switched to placebo despite a partial reaccumulation of VAT. A clinically significant VAT reduction with tesamorelin was associated with improved liver enzymes among HIV-infected patients with abdominal obesity and elevated baseline transaminases.

Tesamorelin, a human growth hormone releasing factor analogue.

The combination of clinical effectiveness with a variety of adverse side effects from the use of recombinant human growth hormone (rhGH) in therapy for growth hormone (GH)-deficient disorders has led to the development of human growth hormone releasing factor (GFR) analogues, which may be better tolerated. Tesamorelin, a synthetic GFR, has been developed as a potential treatment for a variety of conditions that may be associated with a relative deficiency of GH including HIV-related lipodystrophy. This article reviews the development of tesamorelin and its purported role in HIV-related lipodystrophy and other potential indications. Relevant articles and abstracts were obtained from searches of the medical and chemical literature databases and the references from published articles. A multicenter, randomized, placebo-controlled, Phase III clinical trial suggested that tesamorelin might be a beneficial treatment strategy for HIV-related lipodystrophy with a good safety profile and a positive effect on reducing visceral fat. Other potential indications for tesamorelin appear less promising from the current data.

A placebo-controlled, dose-ranging study of a growth hormone releasing factor in HIV-infected patients with abdominal fat accumulation.

To investigate the effects of TH9507, a novel growth hormone releasing factor, on abdominal fat accumulation, metabolic and safety parameters in HIV-infected patients with central fat accumulation. Randomized, double-blind, placebo-controlled trial enrolling 61 HIV-infected patients with increased waist circumference and waist-to-hip ratio. Participants were randomized to placebo or 1 or 2 mg TH9507 subcutaneously, once daily for 12 weeks. The primary outcome was change in abdominal fat, assessed by dual energy X-ray absorptiometry and cross-sectional computerized tomography scan. Secondary endpoints included change in insulin-like growth factor-I (IGF-I), metabolic, quality of life, and safety parameters. TH9507 resulted in dose-related physiological increases in IGF-I (P < 0.01 for 1 mg (+48%) and 2 mg (+65%) versus placebo). Trunk fat decreased in the 2 mg group versus placebo (0.8, -4.6 and -9.2%; placebo, 1 and 2 mg, respectively, P = 0.014 for 2 mg versus placebo), without significant change in limb fat. Visceral fat (VAT) decreased most in the 2 mg group (-5.4, -3.6 and -15.7%; placebo, 1 and 2 mg, respectively) but this change was not significant versus placebo. Subcutaneous fat (SAT) was preserved and did not change between or within groups. Lean body mass and the ratio of VAT to SAT improved significantly in both treatment groups versus placebo. Triglyceride and the cholesterol to high-density lipoprotein ratio decreased significantly in the 2 mg group versus placebo. Treatment was generally well tolerated without changes in glucose. TH9507 reduced truncal fat, improved the lipid profile and did not increase glucose levels in HIV-infected patients with central fat accumulation. TH9507 may be a beneficial treatment strategy in this population, but longer-term studies with more patients are needed to determine effects on VAT, treatment durability, and safety.

Non-clinical pharmacology and safety evaluation of TH9507, a human growth hormone-releasing factor analogue.

TH9507, an analogue of human growth hormone-releasing factor (hGRF1-44NH2) minimally modified by addition of a trans-3-hexenoyl moiety to Tyr1 of the amino acid sequence, was found to be resistant to dipeptidyl aminopeptidase-IV deactivation. Compared to natural hGRF1-44NH2, the modification slowed the in vitro degradation of the peptide in rat, dog and human plasma and prolonged the in vivo plasma elimination kinetics of immunoreactive TH9507. Plasma growth hormone and insulin-like growth factor-1 (IGF-1) markedly increased in pigs, rats and dogs after daily repeat intravenous or subcutaneous injections of TH9507 at doses up to 600 microg/kg. Subchronic toxicity studies in rats and dogs with TH9507 treatment for up to 4 months showed a significant, but not dose-related, increase in body weight gain associated with increased biomarker response. Although TH9507 was well tolerated by both rats and dogs, a more pronounced anabolic effect and more evident (reversible) adverse effects (liver and kidney findings, anaemia, clinical chemistry changes, organ weight effects) were observed in dogs after repeat daily subcutaneous injections, which were attributed to prolonged exposure to supraphysiological levels of growth hormone and/or IGF-1. In both rats and dogs, toxicokinetic evaluations indicated that exposure to immunoreactive TH9507 was dose related after both routes of administration. The apparent elimination t1/2 in dogs ranged from 21 to 45 min. In conclusion, TH9507 is a modified hGRF peptide having enhanced potency and duration of action. The adverse treatment-related effects in dogs appear to be associated with sustained exposure to supraphysiological levels of growth hormone and IGF-1 induced by prolonged TH9507 treatment.

Effect of tesamorelin in people with HIV with and without dorsocervical fat: Post hoc analysis of phase III double-blind placebo-controlled trial.

Tesamorelin, a synthetic growth hormone-releasing hormone, is indicated for the reduction of visceral adipose tissue (VAT) in people with HIV. Here, we performed a post hoc analysis of participants receiving tesamorelin for 26 weeks in a phase III clinical trial. Efficacy data were compared between individuals with and without dorsocervical fat, stratified by tesamorelin response. Among tesamorelin responders, VAT and waist circumference (WC) decreased in both dorsocervical fat groups and did not statistically differ (VAT P = 0.657, WC P = 0.093). These data demonstrate that tesamorelin is equally effective and should be considered in the treatment of excess VAT regardless of the presence of dorsocervical fat.

The effects of tesamorelin on phosphocreatine recovery in obese subjects with reduced GH.

Few studies have assessed the relationship between GH and mitochondrial function. The objective of this study was to determine the effects of improving IGF-I using a GHRH analog, tesamorelin, on mitochondrial function assessed by phosphocreatine (PCr) recovery using (31)P magnetic resonance spectroscopy in obese adults with reduced GH. A total of 39 obese men and women with reduced GH secretion as determined by GHRH-arginine stimulation tests underwent magnetic resonance spectroscopy as part of a 12-month, double-blind, randomized, placebo-controlled trial comparing tesamorelin vs placebo. PCr recovery after submaximal exercise was assessed at baseline and at 12 months. At baseline, there were no differences in age, sex, race/ethnicity, and GH or PCr parameters between tesamorelin and placebo. After 12 months, tesamorelin treatment led to a significantly greater increase in IGF-I than did placebo treatment (change, 102.9&#xb1;31.8 &#x3bc;g/L vs 22.8&#xb1;8.9 &#x3bc;g/L, tesamorelin vs placebo; P=.02). We demonstrated a significant positive relationship between increases in IGF-I and improvements in PCr recovery represented as ViPCr (R=0.56; P=.01). The association between IGF-I and PCr recovery was even stronger among subjects treated with tesamorelin only (ViPCr: R=0.71; P=.03). This association remained significant after controlling for age, sex, race, ethnicity, and parameters of body composition and insulin sensitivity (all P<.05). Increases in IGF-I from 12 months of treatment with tesamorelin were significantly associated with improvements in PCr recovery parameters in obese men and women with reduced GH secretion, suggestive of improvements in mitochondrial function.

Fibroblast growth factor 21 decreases after liver fat reduction via growth hormone augmentation.

Fibroblast growth factor 21 (FGF21) ameliorates steatohepatitis but is increased in humans with fatty liver, potentially due to compensatory mechanisms and/or FGF21 resistance. Further, animal models suggest that GH increases serum FGF21. Tesamorelin, a growth hormone releasing hormone agonist, reduces liver fat in HIV-infected individuals. The objectives of this study were to investigate changes in FGF21 during tesamorelin treatment, to elucide the interplay between FGF21, GH augmentation, and liver fat reduction in humans. 50 HIV-infected men and women with increased abdominal adiposity participated in this randomized, placebo-controlled trial of tesamorelin, 2mg vs. identical placebo daily for six months. Fasting laboratory measures, liver fat by 1H-magnetic resonance spectroscopy, and visceral adipose tissue (VAT) by computed tomography were obtained. Euglycemic hyperinsulinemic clamp was performed in a randomly selected subset. At baseline, serum log10 FGF21 was significantly associated with log10 liver fat (r=0.32, p=0.03). Log10 FGF21 tended to decrease in the tesamorelin group compared to placebo (p=0.06). Among the entire cohort, reductions in FGF21 were significantly associated with reductions in liver fat (&#x3c1;=0.41, p=0.01), log10 gamma glutamyl tran speptidase (GGT, r=0.40, p=0.009), and FIB4 index (r=0.37, p=0.02). In HIV-infected individuals, FGF21 is significantly positively associated with liver fat. FGF21 decreases in association with reductions in liver fat, GGT, and FIB4, suggesting that FGF21 is upregulated in the context of steatosis and steatohepatitis and is reduced when these conditions improve. Moreover, these data suggest that tesamorelin improves liver fat via pathways other than increasing serum FGF21. clinicaltrials.govNCT01263717.

Population pharmacokinetic and pharmacodynamic analysis of tesamorelin in HIV-infected patients and healthy subjects.

The objective of this analysis was to characterize the time course of selected pharmacodynamic (PD) markers of tesamorelin: growth hormone (GH) and insulin-like growth factor (IGF-1) concentrations in HIV-infected patients and healthy volunteers. A total of 41 subjects in Phase I trials receiving subcutaneous daily doses of 1 or 2&#xa0;mg of tesamorelin during 14 consecutive days were included in this analysis. A previous pharmacokinetic (PK) model of tesamorelin was used as the input function for the PD model of GH. Tesamorelin was hypothesized to stimulate the secretion of GH in an "episodic" manner, i.e., for a finite duration of time. The resulting PK/PD model of GH was used to describe the time course of IGF-1. The effect of age, body weight, body mass index, sex, race, and health status on the model parameters was evaluated. The model was qualified using predictive checks and non-parametric bootstrap. Within the range of the values evaluated no covariates were significantly associated with GH or IGF-1 model parameters. Model evaluation procedures indicated accurate prediction of the selected pharmacodynamic markers. The time course of GH and IGF-1 concentrations following multiple doses of tesamorelin were well predicted by the sequential PK/PD model developed using Phase I data.

Effects of tesamorelin on inflammatory markers in HIV patients with excess abdominal fat: relationship with visceral adipose reduction.

To report the effects of tesamorelin, a growth hormone-releasing hormone analogue, on inflammatory and fibrinolytic markers and to relate these effects to changes in visceral adipose tissue (VAT). Four hundred and ten HIV-infected patients with abdominal adiposity were randomized to 2 mg tesamorelin (n = 273) or placebo (n = 137) subcutaneously daily for 26 weeks. Circulating plasminogen activator inhibitor-1 (PAI-1) antigen, tissue plasminogen activator (tPA) antigen, C-reactive protein (CRP), and adiponectin were assessed. At baseline, VAT was significantly associated with PAI-1 antigen (&#x3c1; = 0.36, P < 0.001), tPA antigen (&#x3c1; = 0.29, P < 0.001), CRP (&#x3c1; = 0.18, P < 0.001), and adiponectin (&#x3c1; = -0.22, P < 0.001). Treatment with tesamorelin resulted in a significant decrease from baseline in tPA antigen (-2.2 &#xb1; 2.5 vs. -1.6 &#xb1; 2.9 ng/ml, tesamorelin vs. placebo, P < 0.05). Changes in PAI-1 antigen were not significant in the tesamorelin group compared to placebo. Among patients receiving tesamorelin, changes in inflammatory markers were associated with change in VAT (PAI-1 antigen: &#x3c1; = 0.16, P = 0.02; tPA antigen: &#x3c1; = 0.16, P = 0.02; adiponectin: &#x3c1; = -0.27, P < 0.001), and these associations remained significant when controlling for changes in insulin-like growth factor-1. In HIV patients with abdominal adiposity, tesamorelin may have a modest beneficial effect on adiponectin and fibrinolytic markers in association with changes in VAT. Further studies are needed to determine the clinical significance of these changes. These data further highlight the deleterious role of excessive VAT and the utility of strategies to improve VAT in this population.

Metabolic dysfunction-associated steatotic liver disease in people with HIV.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent among people with HIV (PWH) and increasingly recognized as a major contributor to morbidity and mortality. The field of MASLD is rapidly evolving with adoption of a new nomenclature and approval of the first FDA-approved therapy within the past year. These developments underscore the need to consider the current state of the science specifically in the context of HIV. MASLD in PWH (MASLD-HIV) follows a more aggressive clinical course compared to HIV-negative individuals. While MASLD-HIV shares common pathogenic mechanisms with MASLD in the general population, HIV-specific factors - including altered body composition, chronic immune activation, enhanced gut permeability, and antiretroviral therapy - exacerbate disease progression. Despite an expanding pipeline of MASLD therapies, a critical gap remains in evaluating these interventions specifically among PWH. Nonetheless, dedicated studies of glucagon-like peptide-1 receptor agonists and the growth hormone-releasing hormone analog tesamorelin have shown promise in MASLD-HIV. MASLD is a key contributor to liver-related and cardiovascular-morbidity in PWH. While there have been exciting advances to improve diagnosis and management of MASLD in the general population, differences in MASLD pathophysiology demonstrate the need to tailor our approach specifically for PWH.

Long-term safety and effects of tesamorelin, a growth hormone-releasing factor analogue, in HIV patients with abdominal fat accumulation.

Treatment of HIV patients with daily tesamorelin, a growth hormone-releasing factor analogue, for 26 weeks resulted in a significant decrease in visceral adipose tissue (VAT) and improvement in lipids. The objective of the 26-week extension phase was to evaluate long-term safety and effects of tesamorelin. HIV patients with central fat accumulation in the context of antiretroviral therapy were randomized to tesamorelin 2 mg (n = 273) or placebo (n = 137) s.c. daily for 26 weeks. At week 26, patients originally on tesamorelin were rerandomized to 2 mg tesamorelin (T-T group, n = 154) or placebo (T-P group, n = 50), whereas patients originally on placebo were switched to tesamorelin (P-T group, n = 111). Safety included adverse events and glucose parameters. Tesamorelin was generally well tolerated. The prevalence of adverse events and serious adverse events during the extension phase was comparable with the initial phase. Changes in glucose parameters over 52 weeks were not clinically significant and similar to those after 26 weeks. The change in VAT was sustained at -18% over 52 weeks of treatment (P < 0.001 versus baseline) as was the change in triglycerides (-51 mg/dl, P < 0.001 versus baseline). Similar sustained beneficial effects were seen for total cholesterol, but high-density lipoprotein decreased minimally over 52 weeks. Upon discontinuation of tesamorelin, VAT reaccumulated. Treatment with tesamorelin was generally well tolerated and resulted in sustained decreases in VAT and triglycerides over 52 weeks without aggravating glucose. Though effects on VAT are sustained during treatment for 52 weeks, these effects do not last beyond the duration of treatment.

Predictors of Treatment Response to Tesamorelin, a Growth Hormone-Releasing Factor Analog, in HIV-Infected Patients with Excess Abdominal Fat.

Tesamorelin, a synthetic analog of human growth hormone-releasing factor, decreases visceral adipose tissue (VAT) in human immunodeficiency virus (HIV)-infected patients with lipodystrophy. 1) To evaluate the utility of patient characteristics and validated disease-risk scores, namely indicator variables for the metabolic syndrome defined by the International Diabetes Federation (MetS-IDF) or the National Cholesterol Education Program (MetS-NCEP) and the Framingham Risk Score (FRS), as predictors of VAT reduction during tesamorelin therapy at 3 and 6 months, and 2) To explore the characteristics of patients who reached a threshold of VAT <140 cm2, a level associated with lower risk of adverse health outcomes, after 6 months of treatment with tesamorelin. Data were analyzed from two Phase 3 studies in which HIV-infected patients with excess abdominal fat were randomized in a 2:1 ratio to receive tesamorelin 2 mg (n = 543) or placebo (n = 263) subcutaneously daily for 6 months, using ANOVA and ANCOVA models. Metabolic syndrome (MetS-IDF or MetS-NCEP) and FRS were significantly associated with VAT at baseline. Presence of metabolic syndrome ([MetS-NCEP), triglyceride levels >1.7 mmol/L, and white race had a significant impact on likelihood of response to tesamorelin after 6 months of therapy (interaction p-values 0.054, 0.063, and 0.025, respectively). No predictive factors were identified at 3 months. The odds of a VAT reduction to <140 cm2 for subjects treated with tesamorelin was 3.9 times greater than that of subjects randomized to placebo after controlling for study, gender, baseline body mass index (BMI) and baseline VAT (95% confidence interval [CI] 2.03; 7.44). Individuals with baseline MetS-NCEP, elevated triglyceride levels, or white race were most likely to experience reductions in VAT after 6 months of tesamorelin treatment. The odds of response of VAT <140 cm2 was 3.9 times greater for tesamorelin-treated patients than that of patients receiving placebo.