Prior studies have shown that QoL in patients with acromegaly improves after treatment of GH excess, whether by surgical or pharmacological means, but it does not normalize.[19–22] Many factors may contribute to impaired QoL, including persistent symptoms and treatment side effects. To our knowledge, this is the first study to compare QoL in patients with acromegaly who achieved biochemical control by a GH receptor antagonist vs somatostatin analogs, the majority of whom failed transsphenoidal surgery. We hypothesized that QoL would be better in patients on pegvisomant than somatostatin analogs given its favourable side effect profile. Contrary to our hypothesis, we found that QoL measures did not differ significantly between patients controlled by GH receptor antagonism vs somatostatin receptor monotherapy. We also found that higher HbA1c, BMI and IGF-1 levels were all associated with poorer QoL.
It should be noted that the majority (83%) of the PEG group had previously received somatostatin analogs, which had been discontinued due to lack of efficacy (52%) or side effects (41%), and that there was a higher proportion of men with hypogonadism in the PEG vs SSA groups. Additionally, a larger proportion of patients in the PEG group underwent radiation than in the SSA group (41% and 26%, respectively, P = NS). While this finding was not statistically significant, it does suggest that the PEG group may have included patients with treatment-resistant pituitary tumours. In addition, although radiation therapy was not associated with worse QoL measures in our cohort, it has been in other studies,[23,24] and therefore we cannot rule out an effect. It is notable that the PEG group did not have worse QoL despite the number of subjects with SSA-resistant disease, prior SSA intolerance and requirement for radiation therapy, factors which may suggest the possibility of more aggressive underlying disease or that directly impact QoL. Thus, it is encouraging that patients who do not respond to or are not able to tolerate somatostatin analogs achieve a comparable QoL on average when switched to pegvisomant as those who do well on somatostatin analogs.
Our data are consistent with some published studies that have demonstrated that pharmacologic therapy may improve QoL in patients with acromegaly, though our results did not show as large differences as some other reports, especially after correcting for multiple comparisons. Several studies have demonstrated an improvement in QoL following biochemical control of acromegaly by somatostatin analogs.[25,26] Additional small studies suggest that subjects requiring somatostatin analog therapy have poorer QoL measures than those cured by surgery alone. However, none of these studies can account for the inherent differences in disease severity of patients controlled by surgery alone vs those who require additional treatment.[27–29]
There are currently no other studies that directly compare QoL in subjects treated with pegvisomant vs somatostatin analogs. The few studies of pegvisomant, both as monotherapy and in combination with somatostatin analog treatment, have showed positive effects on QoL compared to active acromegaly. In a long-term safety and efficacy analysis of 110 naïve/semi-naïve patients with acromegaly treated with pegvisomant (an extension of ACROSTUDY), patients who were biochemically controlled after 2 years of daily pegvisomant experienced improvement in all four domains of AcroQoL (Physical Domain, Appearance Domain, Personal Relationships Domain and Global Score). Patients in the ACROSTUDY extension who were not biochemically controlled on pegvisomant still showed improvement in the AcroQoL Global Score, although they had worsening in the other three domains. Similarly, in a randomized placebo-controlled trial of patients biochemically controlled on an somatostatin analogs, the addition of pegvisomant 40 mg weekly resulted in significant improvement in the AcroQoL Psychological Domain and Global Score, despite no change in mean IGF-1 level.
Several QoL domains in this study were negatively associated with HbA1c. Somatostatin analog treatment can suppress insulin secretion, and a meta-analysis of somatostatin analog treatment in patients with acromegaly showed a decrease in fasting insulin levels following somatostatin analog initiation without any significant change in fasting glucose or HbA1c. In contrast, pegvisomant has been shown to decrease fasting glucose in both patients with and without diabetes.[33,34]
Within the subset of participants without diabetes mellitus of the current cross-sectional study, HbA1c and fasting glucose were not significantly different across groups. Fasting insulin and HOMA-IR were lower in the SSA vs PEG groups. However, we cannot rule out selection bias that may have been introduced by the fact that pegvisomant may have been chosen for some patients due to concerns about insulin resistance or hyperglycaemia. These data underscore the importance of achieving good glycemic control in patients with acromegaly; however, further studies are needed to clarify whether HbA1c is simply a biomarker of disease severity or independently affects QoL in patients with acromegaly.
The cross-sectional design of this study prevents conclusions about causality. An additional limitation is the nonrandomized study design and greater disease severity of the pegvisomant group, given that nearly half of subjects treated with pegvisomant had somatostatin analog-resistant disease. We recognize that we may have detected differences in QoL if we had studied a larger group of patients. In the future, a randomized comparison of QoL in medication-naïve subjects subsequently treated with somatostatin analogs or pegvisomant may be informative.
In conclusion, our data do not suggest that QoL differs significantly between patients who are biochemically controlled on somatostatin analogs vs pegvisomant, despite the fact that many patients receiving pegvisomant had failed somatostatin analog therapy, some of them due to side effects.
This study was funded through an investigator-initiated grant from Pfizer (PI: Miller). This work was additionally conducted with support from the following National Institutes of Health grants: K24 HL092902 (Miller), T32 DK007028 (Kimball, Haines, Dichtel), K23 DK113220 (Dichtel), K23 DK115903 (Haines) and the Harvard Catalyst|The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centres. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centres, or the National Institutes of Health. Additional support was provided by the Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts (Woodmansee).
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Clin Endocrinol. 2021;94(1):58-65. © 2021 Blackwell Publishing