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Effect of Tesamorelin on Visceral Fat and Liver Fat in HIV-Infected Patients With Abdominal Fat Accumulation
A Randomized Clinical Trial
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JAMA. 2014
"In this preliminary study, our data demonstrate a modest but statistically significant decrease in liver fat with tesamorelin in HIV-infected individuals selected for abdominal fat accumulation, although the clinical importance of this finding is uncertain. Liver fat and visceral fat were closely associated at baseline, and the reduction in liver fat during the study was significantly associated with the reduction in visceral adipose tissue."
Abstract
Importance Among patients infected with human immunodeficiency virus (HIV), visceral adiposity is associated with metabolic dysregulation and ectopic fat accumulation. Tesamorelin, a growth hormone-releasing hormone analog, specifically targets visceral fat reduction but its effects on liver fat are unknown.
Objective To investigate the effect of tesamorelin on visceral and liver fat.
Design, Setting, and Patients Double-blind, randomized, placebo-controlled trial conducted among 50 antiretroviral-treated HIV-infected men and women with abdominal fat accumulation at Massachusetts General Hospital in Boston. The first patient was enrolled on January 10, 2011; for the final patient, the 6-month study visit was completed on September 6, 2013.
Interventions Participants were randomized to receive tesamorelin, 2 mg (n=28), or placebo (n=22), subcutaneously daily for 6 months.
Main Outcomes and Measures Primary end points were changes in visceral adipose tissue and liver fat. Secondary end points included glucose levels and other metabolic end points.
Results
Forty-eight patients received treatment with study drug.
Tesamorelin significantly reduced visceral adipose tissue (mean change, -34 cm2 [95% CI, -53 to -15 cm2] with tesamorelin vs 8 cm2 [95% CI, -14 to 30 cm2] with placebo; treatment effect, -42 cm2 [95% CI, -71 to -14 cm2]; P = .005) and liver fat (median change in lipid to water percentage, -2.0% [interquartile range {IQR}, -6.4% to 0.1%] with tesamorelin vs 0.9% [IQR, -0.6% to 3.7%] with placebo; P = .003) over 6 months, for a net treatment effect of -2.9% in lipid to water percentage.
Fasting glucose increased in the tesamorelin group at 2 weeks (mean change, 9 mg/dL [95% CI, 5-13 mg/dL] vs 2 mg/dL [95% CI, -3 to 8 mg/dL] in the placebo group; treatment effect, 7 mg/dL [95% CI, 1-14 mg/dL]; P = .03), but changes at 6 months in fasting glucose (mean change, 4 mg/dL [95% CI, -2 to 10 mg/dL] with tesamorelin vs 2 mg/dL [95% CI, -4 to 7 mg/dL] with placebo; treatment effect, 2 mg/dL [95% CI, -6 to 10 mg/dL]; P = .72 overall across time points) and 2-hour glucose (mean change, -1 mg/dL [95% CI, -18 to 15 mg/dL] vs -8 mg/dL [95% CI, -24 to 8 mg/dL], respectively; treatment effect, 7 mg/dL [95% CI, -16 to 29 mg/dL]; P = .53 overall across time points) were not significant.
Conclusions and Relevance In this preliminary study of HIV-infected patients with abdominal fat accumulation, tesamorelin administered for 6 months was associated with reductions in visceral fat and additionally with modest reductions in liver fat. Further studies are needed to determine the clinical importance and long-term consequences of these findings.
Baseline measures of visceral fat and liver fat were positively associated (ρ = 0.42; P = .003)
Changes in Body Composition and Ectopic Fat
The tesamorelin group experienced a significant decrease in mean abdominal visceral adipose tissue area (-34 cm2; 95% CI, -53 to -15 cm2 vs placebo, 8 cm2; 95% CI, -14 to 30 cm2; treatment effect, -42 cm2; 95% CI, -71 to -14 cm2; P = .005) without effects on mean subcutaneous adipose tissue area (tesamorelin, 2 cm2; 95% CI, -5 to 10 cm2 vs placebo, 8 cm2; 95% CI, -3 to 20 cm2; treatment effect, -6 cm2; 95% CI, -19 to 7 cm2; P = .29) (Table 2. Mean change in visceral adipose tissue was -9.9% (95% CI, -19.7% to -0.2%) with tesamorelin vs 6.6% (95% CI, -4.1% to 17.3%] with placebo, for a net treatment effect of -16.6% (95% CI, -30.6% to -2.6%), similar to that seen in previous studies.7,8
Hepatic lipid to water percentage decreased significantly in the tesamorelin group (median, -2.0%; IQR, -6.4% to 0.1%) compared with placebo (median, 0.9%; IQR, -0.6% to 3.7%; P = .003), for a net effect between groups of -2.9% in lipid to water percentage (Table 2. This effect of tesamorelin on liver fat remained statistically significant (P = .005) controlling for age, duration of HIV, and lipid-lowering therapy. In a sensitivity analysis excluding 2 patients who were not fasting for 1H magnetic resonance spectroscopy, both in the placebo group, the change in liver fat remained significant (P<.001). For the 3 patients with poor adherence, change in hepatic fat was within the IQR for the respective treatment groups. Both total fat and trunk fat as measured by dual-energy x-ray absorptiometry decreased significantly compared with placebo (Table 2). Intramyocellular lipid did not change (Table 2).
Changes in Glucose Homeostasis
Fasting glucose increased in the tesamorelin group compared with the placebo group between baseline and 2 weeks (mean change: tesamorelin, 9 mg/dL; 95% CI, 5-13 mg/dL vs placebo, 2 mg/dL; 95% CI, -3 to 8 mg/dL; treatment effect, 7 mg/dL; 95% CI, 1-14 mg/dL; P = .03 at 2 weeks) ( but was not different from baseline at subsequent assessments (mean change at 3 months: tesamorelin, 6 mg/dL; 95% CI, 2-10 mg/dL vs placebo, 2 mg/dL; 95% CI, -4 to 7 mg/dL; treatment effect, 4 mg/dL; 95% CI, -2 to 11 mg/dL; P = .20 at 3 months; mean change at 6 months: tesamorelin, 4 mg/dL; 95% CI, -2 to 10 mg/dL vs placebo, 2 mg/dL; 95% CI, -4 to 7 mg/dL; treatment effect, 2 mg/dL; 95% CI, -6 to 10 mg/dL; P = .56 at 6 months) (Table 3). Mixed-effects modeling showed no significant effects of tesamorelin on fasting glucose (P = .72 overall across time points), fasting insulin (P = .68), or HOMA-IR (P = .45) (Table 3) over the 6-month period. There was a slight but statistically significant increase in hemoglobin A1c from baseline to 6 months (mean change: tesamorelin, 0.20%; 95% CI, 0.04%-0.36% vs placebo, 0.02%; 95% CI, -0.07% to 0.10%; treatment effect, 0.19%; 95% CI, 0.01%-0.36%; P = .03). One patient in each treatment group progressed from impaired fasting glucose to diabetes by fasting glucose measurement, whereas 1 additional patient in each group progressed from impaired glucose tolerance to diabetes by 2-hour oral glucose tolerance test (see eTable 5 in Supplement 2 for distribution of glucose values). During the 6-month treatment period, no patient in either group experienced fasting blood glucose levels greater than 150 mg/dL, which was the predetermined cutoff for study discontinuation.
In the euglycemic hyperinsulinemic clamp subgroup, there was a significant difference in the change from baseline to 3 months in insulin-stimulated glucose uptake, whereby insulin sensitivity decreased in the tesamorelin group and increased in the placebo group (mean change: tesamorelin, -0.5 mg/kg/min; 95% CI -1.7 to 0.7 mg/kg/min vs placebo, 1.3 mg/kg/min; 95% CI, 0.6-2.1 mg/kg/min; treatment effect, -1.8 mg/kg/min; 95% CI, -3.3 to -0.4 mg/kg/min; P = .02). In contrast, the change from baseline was not significant at 6 months (mean change: tesamorelin, 0.4 mg/kg/min; 95% CI, -1.2 to 1.9 mg/kg/min vs placebo, 0.7 mg/kg/min; 95% CI, -0.6 to 2.1 mg/kg/min; treatment effect, -0.4 mg/kg/min; 95% CI, -2.3 to 1.5; P = .68). Results were similar when insulin-stimulated glucose uptake was corrected for steady-state insulin level and, at 6 months, for lean body mass.
Changes in Transaminases
There were no significant overall changes in alanine aminotransferase, whereas aspartate aminotransferase decreased with
tesamorelin (median change, -4 U/L; IQR, -12 to 2 U/L) compared with placebo (median change, 0 U/L; IQR, -6 to 5 U/L; P = .046) (eTable 2 in Supplement 2).
Changes in Cardiovascular Risk Measures
Intima-media thickness of the left carotid artery decreased in the tesamorelin group (mean change, -0.03 mm; 95% CI, -0.07 to -0.00 mm; P = .04) but did not change in the placebo group (mean change, -0.00 mm; 95% CI, -0.03 to 0.03 mm; P = .89), though the primary comparison between groups was not significant (treatment effect, -0.03 mm; 95% CI, -0.08 to 0.01 mm; P = .14) (Table 2). Blood pressure and lipids did not significantly change (eTable 2 in Supplement 2). C-reactive protein did not significantly change, whereas tesamorelin tended to increase adiponectin (P = .07) (eTable 2 in Supplement 2).
Safety and Adverse Events
Adverse events that occurred in greater than 5% of patients are reported in Table 4. There were 3 serious adverse events in both the treatment and placebo groups. Serious adverse events in the tesamorelin group consisted of 1 hospitalization due to exacerbation of existing congestive heart failure, 1 hospitalization for pneumonia, and 1 diagnosis of basal cell carcinoma in a patient with a history of the same. Serious adverse events in the placebo group consisted of 1 hospitalization for acute stroke, 1 hospitalization for Heller myotomy, and 1 diagnosis of basal cell carcinoma in a patient with a history of the same. Two patients underwent blinded dose reductions (eAppendix and eTable 6 in Supplement 2). For further information on adverse events, see Table 4 and the eAppendix in Supplement 2.
There were no significant changes in immunologic measures in the tesamorelin group (Table 2.
Discussion
In this preliminary study, our data demonstrate a modest but statistically significant decrease in liver fat with tesamorelin in HIV-infected individuals selected for abdominal fat accumulation, although the clinical importance of this finding is uncertain. Liver fat and visceral fat were closely associated at baseline, and the reduction in liver fat during the study was significantly associated with the reduction in visceral adipose tissue.
To our knowledge, the data from this study are the first to demonstrate in a clinical trial that an agent selectively reducing visceral fat simultaneously reduced liver fat independent of changes in weight. Thus, our data support the hypothesis that visceral fat accumulation is linked to liver fat accumulation and suggest that selective targeting of visceral adipose tissue reduction can lead to reductions in liver fat. The mechanisms by which growth hormone augmentation reduced liver fat are unknown. Growth hormone augmentation by tesamorelin may increase oxidation of visceral fat. In addition, growth hormone may reduce liver fat through inhibition of hepatic de novo lipogenesis21,22 or other mechanisms. Two prior articles investigated growth hormone replacement in non-HIV hypopituitary models and showed mixed results on hepatic fat.23,24 In contrast, the current study used growth hormone-releasing hormone to augment endogenous growth hormone secretion as a strategy to reduce visceral fat in an HIV model selected for excess visceral adipose tissue.
The decrease in liver fat in this study suggests that strategies to reduce visceral adiposity merit further investigation in HIV-infected patients with NAFLD, a condition for which there are no approved treatments. Importantly, NAFLD is associated with visceral adiposity and other metabolic abnormalities in HIV.1,25
Although the causal pathways underlying these interrelationships are not yet clear, visceral adiposity results in increased inflammatory cytokine production and increased portal free fatty acid flux, either or both of which may contribute to steatohepatosis and hepatic insulin resistance.26-28
In this study, tesamorelin resulted in reductions in visceral adipose tissue without reductions in subcutaneous adipose tissue. Subcutaneous fat is thought to represent a beneficial depot that may serve as a buffer to protect against ectopic fat distribution into other organs.26,29-31 Strategies such as tesamorelin, which are selective to visceral adipose tissue and do not simultaneously reduce subcutaneous adipose tissue, may be optimal to reduce ectopic fat. Further studies of the effects of tesamorelin on other depots linked to visceral adipose tissue, including epicardial fat, should be performed in HIV-infected patients.
Our data also further elucidate effects of tesamorelin on glucose homeostasis. Administration of growth hormone increases glucose.13,32 In contrast, studies to date have suggested that tesamorelin has limited adverse effect on glucose homeostasis.7,8,33 Our data demonstrate that tesamorelin initially perturbed glucose as well as insulin sensitivity as assessed by clamp. However, these initial changes were reversed and glucose returned to baseline over longer durations of treatment. We showed a modest increase in hemoglobin A1c, consistent with data from larger studies of tesamorelin,7,8 which may reflect initial increases in glucose.
Our study has limitations. First, the purpose of this study was to determine detailed metabolic end points, including those involving 1H magnetic resonance spectroscopy and euglycemic hyperinsulinemic clamp measurements, limiting sample size. Thus, the study may have been underpowered to detect changes in secondary end points. Nonetheless, nonsignificant improvement in adiponectin and significant improvements in aspartate aminotransferase suggest additional metabolic effects of visceral adipose tissue reduction in the HIV-infected population. In this study, we chose to enroll patients based on the Food and Drug Administration-approved indication for tesamorelin to reduce abdominal fat, and we determined benefits to liver fat and metabolic indexes. Because the cohort was not specifically chosen for increased liver fat and the absolute change in lipid to water percentage was modest, the clinical significance of our data are not known. Changes in liver fat may have been more pronounced in a cohort specifically selected for NAFLD. Nonalcoholic fatty liver disease may have a benign clinical course and may not progress to liver disease. Liver biopsies, which are the gold standard for assessing features of steatohepatitis and advanced liver disease, were not performed in this study. Our population was primarily male and had been living with HIV and receiving ART for a long period, consistent with many patients exhibiting lipodystrophic changes in fat. Although abdominal hypertrophy may be less common with newer ART, there exists a substantial group of patients with abdominal fat accumulation in the context of long-term prior ART. Furthermore, we did not collect data following discontinuation of tesamorelin. Previous studies have shown that visceral fat may reaccumulate after discontinuation of tesamorelin,34 and future studies will be necessary to determine if reductions in liver fat with tesamorelin are maintained following treatment discontinuation. Moreover, tesamorelin is expensive, which is a barrier to its use.
Conclusions
In this preliminary study of HIV-infected patients with abdominal fat accumulation, tesamorelin administered for 6 months was associated with reductions in visceral fat and additionally with modest reductions in liver fat. Further studies are needed to determine the clinical importance and long-term consequences of these findings.
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