Body Composition Changes With Long-Term Pegvisomant Therapy of Acromegaly

Adriana P. Kuker; Wei Shen; Zhezhen Jin; Simran Singh; Jun Chen; Jeffrey N. Bruce; Pamela U. Freda

Disclosures

J Endo Soc. 2021;5(3) 

In This Article

Discussion

A main finding of this study is that increases in AT mass, especially that of VAT, occur with pegvisomant therapy and are maintained, but do not escalate, during long-term therapy. In accord with this, we found persistent increases in DXA measured total and percent body and trunk fat with pegvisomant treatment. The effects of pegvisomant on body composition have been examined previously in a few small, short-term studies. In one, 7 patients treated with 4 weeks of pegvisomant had a moderate increase in percent body fat assessed by bioimpedance analysis (BIA)[31] and, in another, 5 patients treated for 6 months with pegvisomant, computed tomography–measured intra-abdominal fat mass increased, but SAT did not.[18] Our larger and longer study, by contrast, showed a significant rise in VAT and SAT that persisted over years of pegvisomant therapy. Waist circumference increased, in accord with the increases in central adiposity seen by MRI and DXA. Although our patients' prior acromegaly therapy might be considered a limitation of our study, they had been unsuccessfully treated for years prior to starting pegvisomant (Table 2) and had biochemical changes with it similar to those that occur with successful surgery.[32] This likely explains why their prepegvisomant body composition pattern was similar to that of newly diagnosed acromegaly[8] and their VAT and SAT changes with pegvisomant were similar or just somewhat less than those observed in a surgical cohort.[9] We also found that VAT and SAT did not differ from predicted with long-term therapy. Use of a predictive model is advantageous to matching acromegaly patients to controls because abnormalities of body composition, including the skeleton, make matching on typical parameters, such as BMI, unreliable.[33] The fact that VAT did not rise above predicted is reassuring that long-term GHR antagonism does not produce a growth hormone deficiency (GHD) like pattern of central adiposity and elevated VAT mass, which might increase cardiovascular risk as in other populations.[34,35] Long-term outcome studies are needed to investigate this further.

The changes in AT mass we observed with GHR antagonist therapy are consistent with reversal of the mechanisms by which GH reduces AT, in particular VAT, mass.[36–41] The effects of pegvisomant on fat metabolism have been studied in a few prior, short-term studies in acromegaly and healthy subjects and showed no changes[31,42,43] or suppression of lipid mobilization and oxidation.[44] Interestingly, cases of localized SAT hypertrophy have been reported with pegvisomant use.[45–48] Biopsied SAT in one such patient showed normal AT.[48] Antagonism of the effects of GH on local adipocyte lipid metabolism and unopposed insulin effects resulting in lipogenesis were suggested to be responsible for this lipohypertrophy.[45] We did not observe localized lipohypertrophy in our patients, but similar generalized effects on AT metabolism could have contributed to produce the increased AT mass we observed.

Our study also importantly shows that pegvisomant monotherapy leads to a rise in IHL. IHL was lower than in controls in active disease and similar to controls on pegvisomant, suggesting that it returns to expected levels on therapy. The magnitude of change of IHL was less than VAT, suggesting a possible predominance of the mechanisms by which GH exerts its lipid reducing effects in VAT compared with liver as has been shown for VAT compared with SAT,[38–40] but the small number of subjects studied is a limitation of this analysis. In a 24-week study of patients well controlled on long-acting somatostatin analog therapy, pegvisomant added to this increased IHL in 9 patients compared with that in 9 who continued somatostatin analog alone.[19] We and others previously showed that IHL increases with surgical treatment of acromegaly and is higher than in controls years after surgery.[9,10,49,50] Other data in rodents and patients with GHD support a role for GH in regulating IHL accumulation.[51–53] Taken together, these results suggest that in active acromegaly IHL is low and rises to normal with therapy.

We also found that IR improved with pegvisomant therapy in parallel with the rise in adiposity and IHL. The patterns of greater IR with lower adiposity/IHL in active and less IR yet higher adiposity/IHL in treated acromegaly contrasts with other populations where these correlate positively.[54] Pegvisomant treatment of acromegaly improves hepatic and peripheral insulin sensitivity[42,55] and glycemic control.[13,55–58] In our study, HOMA, QUICKI, and HbA1C improved during pegvisomant therapy and no patients had a worsening of these parameters of glucose metabolism despite increases in VAT and IHL. Since liver and muscle IR developed in a model of pegvisomant-induced GHD in healthy adults[59] and pegvisomant-induced GHD may manifest as a combination of increased adiposity and glucose intolerance,[18] our data are not consistent with GHD during pegvisomant therapy. We also found that plasma leptin levels rise with pegvisomant therapy, in accord with another prospective study.[60] As expected, since leptin correlates positively with fat mass,[61,62] we found that percent change in leptin correlated with that of SAT and IMAT masses and % body fat by DXA. Interestingly, however, leptin changes did not correlate inversely with measures of IR as in other populations, likely because mechanisms for IR other than fat mass are most important to IR in acromegaly. The small number of subjects with diabetes in our study precluded a separate analysis of them, but they showed trends for all body composition changes in accord with those of the subjects without DM.

We also studied, for the first time, the effect of pegvisomant on IMAT.[8] We found, unexpectedly, that despite improved insulin sensitivity, IMAT was not lowered and remained above predicted during long-term pegvisomant therapy. Increased IMAT in active acromegaly suggests that GH-induced AT lipolysis leads to lipid movement out of VAT and SAT and into IMAT, thus ectopic lipid deposition in muscle. In our study, IMCL also did not change. In another study, IMCL did not differ in 7 pegvisomant treated acromegaly patients and controls,[50] but in another IMCL decreased with the addition of pegvisomant to somatostatin analog therapy.[19] Other data suggest that GH excess produces muscle lipid accumulation. In acromegaly and GH use, free fatty acids (FFA) flux and muscle uptake are increased[63–68] and in supraphysiologic GH increased IMCL on SM biopsy.[69] Ectopic lipid deposition in and around SM may contribute to IR in acromegaly. In other settings, higher IMCL[67] and IMAT mass correlate with IR[70–74] and in a combined acromegaly and control cohort IMCL correlated inversely with insulin sensitivity.[50] We did not directly test IR in SM in our study and the reason why IMCL and IMAT did not change with pegvisomant while IR improved is unknown.

Another important finding in our study is that SM mass did not change with long-term pegvisomant therapy. No prior study has reported on the effects of pegvisomant on SM mass. Stability of SMDXA, which correlates highly with SM measured by MRI in acromegaly,[20] further supports our MRI findings. The small number of subjects at some time points and variations in their duration of follow-up and magnitude of body composition changes should be considered in the interpretation of this analysis and others and are limitations of our study. Although lean tissue decreased, this could be accounted for by that of its non-SM component, which includes soft tissues and organs, and not SMDXA. Reports of the effects of acromegaly and its treatment on muscle mass, strength, and performance vary.[6,7,61,75–80] Pegvisomant increased protein oxidation in acromegaly patients,[31] but did not change this over 36 hours in healthy subjects[81] and attenuated exercise performance in healthy males.[43] Adult GHD is associated with reduced muscle strength, at least partly due to reduced muscle mass.[16,82,83] Since pegvisomant therapy, in sufficient doses, could potentially cause a functional GHD in tissues, and serum IGF-1 level is not a reliable indicator of GHD in adults,[84] investigation of potential SM changes was warranted. While muscle mass does not necessarily predict its quality or performance, lack of reduction and stability at predicted levels seem reassuring that GHD in SM does not occur with long-term pegvisomant use. Weight and BMI did not change with pegvisomant therapy, as has been reported by others,[15] likely reflecting that gains in AT were matched by losses in lean tissue other than SM, but some component of loss of bone mass is also possible. As after surgery, lean tissue losses likely represent those of extracellular water,[4] other soft tissue, or vital organ mass.[7] Further study is needed to discern components of lean tissue change with pegvisomant therapy. Although IGF-1 values were expressed relative to assay-specific normal ranges, our use of 3 different IGF-1 assays is a limitation of our study.

In conclusion, this study provides novel evidence of a sustained increase in adiposity, but no change in SM mass with long-term pegvisomant therapy. The stability of SM mass and the facts that AT mass does not rise above predicted or escalate over time and IR improves, suggest that years of GHR antagonism does not result in a GHD pattern of body composition. Pegvisomant therapy leads to a seemingly less favorable body composition profile and rise in cardiovascular risk markers[85] that parallel normalization of IGF-1 levels and improvement in glucose metabolism. Long-term outcome data are needed to confirm that normalization of IGF-1 level on pegvisomant returns excess mortality to normal despite these other effects.

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