In the current analysis, we show that, in contrast to nonresponders, individuals who responded to tesamorelin, defined as an ≥8% reduction in VAT, experienced significantly greater improvements in levels of triglycerides and adiponectin and preservation of long-term glucose homeostasis over 52 weeks, suggesting metabolic benefits associated with reducing VAT in this population.
Baseline IGF-I levels were not related to tesamorelin response, but the 26-week data suggest that the magnitude of the change in IGF-I levels during tesamorelin therapy was significantly associated with the percentage decreases in VAT, with responders having greater increases in IGF-I levels than nonresponders at 26 weeks. Changes in IGF-I levels were not significantly different between responders and nonresponders at 52 weeks.
Tesamorelin significantly reduced triglyceride levels by approximately 0.5 mmol/L (40 mg/dL) in pooled analysis of the ITT population [11
]. This reduction in triglyceride levels is likely mediated at least in part by the direct effect of tesamorelin in augmenting growth hormone levels, which, in turn, increases lipolysis, increases lipid β-oxidation, and reduces de novo lipogenesis [18
]. The current data, demonstrating that reductions in triglyceride levels were strongly associated with reductions in VAT, also suggest a possible role of VAT reduction itself in decreasing triglyceride levels. Mechanistically, VAT is highly lipolytic and contributes free fatty acids to the portal circulation, [23
], potentially leading to increased hepatic production of very-low-density lipoprotein cholesterol. The improvement in triglyceride levels seen among the small number of placebo-treated patients with VAT loss further suggests the importance of VAT loss in this group to the improvement of metabolic parameters.
The novel associations between percentage reductions in VAT and changes in glucose parameters in the current data, whereby the more that VAT is reduced, the more that glucose control improves, lend strong support to a potential relationship between VAT and glucose homeostasis. Exogenous administration of recombinant human growth hormone is well-known to exacerbate insulin resistance in both the HIV-infected population [24
] and in non-HIV infected cohorts [27
]. However, longer-term studies of recombinant human growth hormone in obese adults have shown that initial exacerbations in insulin resistance may be reversed with longer-term treatment in association with improvements in VAT [29
]. The current results suggest, similarly, that any adverse effects that augmentation of growth hormone levels might have on glucose metabolism may be counterbalanced by the beneficial effects that reductions in VAT have on glucose homeostasis. VAT may affect glucose homeostasis through multiple mechanisms, including its contribution to increased systemic inflammation [31
] and increased hepatic delivery of free fatty acids, resulting in increased hepatic gluconeogenesis [32
]. Indeed, individuals who did not experience VAT reduction with tesamorelin had significant increases in fasting glucose levels, fasting insulin levels, and HOMA-IR score, as well as increased HbA1c levels, whereas changes in glucose homeostasis were significantly attenuated in responders, who experienced only a slight increase in HbA1c levels in 26-week analysis and no significant changes in the 52-week analysis in association with a highly significant reduction in VAT. One potential mechanism for the preservation of glucose homeostasis in responders is the increase in adiponectin levels seen among responders compared with nonresponders.
The current analysis has some limitations. The analysis was designed to explore the differences between responders and nonresponders who were taking the drug as prescribed (ie, individuals in the per-protocol population). However, nearly identical data were seen in sensitivity analyses among the larger population finishing the study, demonstrating that responders had significantly less deterioration of glucose levels among all patients finishing the study, regardless of compliance. A direct measure of insulin sensitivity was not used, but all the measures of glucose homeostasis that were evaluated, including glucose level, insulin level, HOMA-IR score, 2-hour glucose level, and HbA1c level, were consistent, suggesting a true effect related to responder status.
The current study suggests that achieving an 8% or greater reduction in visceral adiposity as a result of tesamorelin is associated with metabolic benefits. In the clinical setting, however, it is often not possible to determine the precise degree of VAT loss. Clinicians can measure waist circumference response [33
] in subjects receiving tesamorelin, as the change in waist circumference is highly correlated with the reduction in VAT. Moreover, the majority of fat loss represented by the decrease in waist circumference is loss of VAT, as the VAT decrease is approximately five to six times the SAT decrease in responders. In this regard, even a 1 cm reduction in waist circumference corresponded to a significant reduction in VAT greater than 8% in response to tesamorelin and might be useful as an initial minimal acceptable reduction for continuation of tesamorelin. Additional considerations as to whether to continue patients should also include assessment of overall clinical status, with consideration to safety, tolerability and mood. Of note, the change in trunk fat by DXA was even more highly associated with VAT reduction than waist circumference, but performance of DXA is not routinely available to clinicians or standardized, as in this study, for the assessment of changes in regional body composition. In contrast, there was no change in BMI between tesamorelin vs placebo, and thus change in BMI is not useful as a predictor for change in VAT.
Although IGF-I levels were somewhat higher in responders vs nonresponders over the initial 26 weeks of treatment, no differences in safety (ie, frequency of serious adverse events) were seen in responders versus nonresponders over 26 and 52 weeks, including malignancy rates. Nonetheless, clinicians should consider monitoring IGF-I level, not as a means to predict response but rather to ensure that it remains within an acceptable range if a patient is a responder and going on to longer-term use of tesamorelin. As the safety of longer-term tesamorelin use beyond 52 weeks is not known, it is prudent to keep IGF-I levels within the assay’s normal range or within 2–3 SD to minimize any potential long-term effects associated with tesamorelin use.
In addition to metabolic benefits, greater responses to tesamorelin in terms of VAT reduction are also associated with less distress regarding abdominal adiposity, and this may be an important benefit of therapy in patients among whom baseline body dysmorphia and related distress have been shown [34
Overall, the current report demonstrates that reductions in VAT during tesamorelin therapy are associated with improvements in triglyceride levels, adiponectin levels, and long-term preservation of glucose homeostasis. In contrast, these benefits are not seen in individuals who do not respond to tesamorelin with a reduction in VAT.