Acromegaly is a rare, chronic, debilitating, and insidious disease usually caused by a growth hormone (GH)-secreting pituitary tumor, which leads to GH and insulin‐like growth factor 1 (IGF1) excess (1, 2). Treatment goals include increasing life expectancy, reducing symptoms and signs of disease, and improving patients’ health-related quality-of-life (HRQoL) (2, 3). Biochemical treatment target includes normalization of age‐ and gender‐adjusted IGF1; however, IGF1 levels can be challenging to normalize, and even when normalized do not always correlate with improved HRQoL, symptoms and signs, or decreased burden of comorbidities (4, 5).

Treatment options for acromegaly include surgery, radiation, and medical therapy. In Canada, medical therapy with somatostatin analogs (SSAs) is recommended as first line agents (6–8). However, less than 50% of patients achieve IGF1 normalization with SSA monotherapy (7, 9). Moreover, HRQoL, symptoms and signs, as well as the burden associated with comorbid conditions often linger despite SSA monotherapy (9).

In comparison, pegvisomant (PEGV), a GH receptor antagonist, has been shown to normalize IGF1 levels in up to 90% of patients in whom SSA therapy was ineffective (10, 11). PEGV is also indicated if there is inadequate response to or inability to tolerate surgery, radiation therapy, and other medical therapies (10–12). In addition to normalizing IGF1 levels, PEGV has been demonstrated to have a positive impact on patients’ HRQoL, symptoms and signs of acromegaly and comorbidities (especially dysglycemia) (12–15). Two studies where PEGV was used in combination with SSAs also showed sustained improvement in HRQoL scores (5, 16). The very definition of patient control and IGF1 target varies from study to study, in which IGF1 levels of 1.0 to 1.3x upper limit of normal (ULN) can be found, with stricter control in more recent studies (16–20).

Together these studies suggest that normalization of IGF1 levels in patients insensitive to SSAs (i.e., IGF1 levels > 1.3x ULN) may benefit from symptomatic HRQoL improvements. Therefore, the objective of our pilot study was to determine if patients with acromegaly and modest IGF1 elevations (IGF1 levels 1 to 1.3x ULN) would benefit from stricter normalization of IGF1 with addition or dose escalation of PEGV therapy.

Normalization of IGF1 and reduction of GH levels (< 2.5 μg/L) reverses the excess mortality seen in untreated acromegaly to that of the general population (3, 4). Hence, conventional acromegaly treatment outcomes have focused on biochemical and radiological criteria, such as improvements in IGF1, GH, and pituitary tumor size (9). However, the current acromegaly treatment paradigm also considers additional patient-centred outcomes such as HRQoL to measure status of ongoing comorbidities and residual symptoms and signs (e.g. diaphoresis) (4, 5). Importantly, serum IGF1 and GH have been shown to be incomplete predictors of HRQoL in acromegaly. Indeed, surveys of acromegaly patients have highlighted the significance of symptomatic parameters in addition to conventional biochemical tools when assessing disease control of acromegaly (5, 19, 25, 26).

To further explore the relationship between IGF1 normalization and HRQoL improvement, in this study, we assess in a real-world setting whether normalization of modestly elevated serum IGF1 would significantly impact clinical parameters and HRQoL in patients with acromegaly. Our results shows that PEGV at a mean dose of 17 mg daily was effective in reducing IGF1 from 1.22 to 0.87x ULN, with normalization of IGF1 in nine of ten patients. This is similar to results in previous studies where PEGV was effective in normalizing IGF1 in up to 90% of patients (12–14).

In our small cohort of participants, although strict IGF1 control, i. e. normalization, compared with modestly elevated IGF1 (1.0 to 1.5x ULN), did not improve the AcroQoL score, the sum of PASQ1-6 score and the ACRODAT^® overall status showed measurable improvements. Previous studies have also shown poor correlation between IGF1 levels and the AcroQoL score. There has been speculations that AcroQoL may not be sensitive enough to detect small differences in HRQoL especially in patients with modest IGF1 elevation (4, 18). Other studies have shown that the addition of PEGV therapy alone results in improved AcroQoL scores, especially on the physical subscale (5, 17). In a recent study, based on real-world experience, IGF1 control with PEGV therapy had no effects on AcroQoL scores; however long term use resulted in small improvements in PASQ scores (27). In our study, the small sample size and short duration of follow-up may have been insufficient to detect a change in the AcroQoL score. Alternatively, given AcroQoL’s comparatively greater focus on psychosocial factors compared to PASQ/ACRODAT^®, a significant difference may not have been apparent (23).

Whereas the PASQ score focuses on symptoms and signs related to acromegaly, the ACRODAT^® overall status emphasizes a combination of paraclinical (IGF1 levels, tumor size) and clinical factors (comorbidities, symptoms, and HRQoL) (5, 24). Improvement in the sum of PASQ1-6 score and the ACRODAT^® overall status in our study ( Table 3 ) suggest that the main effect of strict IGF1 control is related to improved symptom control. In the case of the ACRODAT^® overall status, even after exclusion of IGF1, the summation of the scores for symptoms and HRQoL impairment remained significant. Taken together, given the lack of significant improvement in AcroQoL, in addition to lowering of IGF1, another driver of improvement in ACRODAT^® is improvement in symptom control.

A possible basis for PEGV-induced improvement of QoL symptoms may be related to its mechanism of action (28). The “extra-hepatic” acromegaly hypothesis, which has been put forth by Neggers and colleagues, proposes that SSA effect reduces proportionally more hepatic IGF1 production compared with GH production, leading to disproportionately elevated peripheral GH responsible for perpetuating some acromegaly symptoms (29). The addition of PEGV antagonizes peripheral GH receptors, thereby diminishing GH activity throughout the body (15). Indeed, even when circulating IGF1 is within age-adjusted normal range with SSA monotherapy, addition of PEGV has been shown to improve PASQ (5). In contrast, although HRQoL improved with SSA monotherapy, changes in PASQ scores were independent of biochemical control (30).

In regard to important cardiovascular risk factors associated with acromegaly, in our small series, there were no differences in hemoglobin A1c, lipid panel, and blood pressure after six months of treatment. This in part reflected reasonable control of these parameters at baseline (hemoglobin A1c 6.6%, low-density lipoprotein 2.26 mmol/L, and blood pressure 131/82 mmHg) and management options (lifestyle or pharmacotherapy) employed to treat these comorbidities. Among the three patients with diabetes, one with uncontrolled diabetes had improved hemoglobin A1c with intensification of insulin therapy. Previous studies have demonstrated improved glycemic control (12, 13) with PEGV treatment; however glycemic control may not necessarily improve with combination therapy (31, 32). In our study, eight of ten patients were on combination therapy.

Eight patients reported 14 AEs, none were severe and all were transient with eight possibly related to the use of PEGV. Previous studies have demonstrated transient elevation in liver enzymes with PEGV, which usually resolved after therapy cessation and seemed to occur more frequently in patients with diabetes mellitus and when used in combination with SSA (14, 17). Even though eight of ten patients were on combination therapy, elevated liver enzymes were not seen in our study; however, the duration of the study was only six months.

Limitations of our study include relatively small sample size, largely due to difficulty obtaining medication coverage for patients with mild elevations of IGF1 in some Canadian provinces, and the study being conducted during the COVID-19 pandemic. Other limitations include short duration of study, lack of a control group due to an open-label design, and heterogeneity of patient population. Also, seven patients had hypopituitarism and one patient had prior radiation therapy, which may be confounding factors as they are known to contribute to impaired HRQoL. Moreover, given the well recognized variabilities of the IGF1 measurements, in particular in patients who are on SSA (33, 34), optimal PEGV dosing was not possible in a subset of our patients. There also was a gender imbalance in our study with two female and eight male participants, whereas in an epidemiological review of population studies, there is usually an equal distribution of acromegaly prevalence between males and females (35, 36). However, two previous studies have indicated higher prevalence rates in men than in women, including a male-to-female ratio of 1:1.8 in an older study (37, 38). The applicability of our study to the general population in countries where the public payer does not cover PEGV may also be difficult due to its expensive cost. Other options to normalize IGF1 such as the addition of cabergoline to SSA was only used in four of ten patients prior to the study (39).

In spite of the small number of patients participating in this trial, strict control in acromegaly patients with modest IGF1 elevations by PEGV initiation or dose escalation was accompanied by clinical improvements detected by the PASQ score. Whereas patients with worse initial PASQ scores showed improvement with IGF-1 normalization, those with relatively preserved baseline PASQ scores showed minimal change. This observation implies that our findings may not be applicable to all acromegaly patients. Instead, the results suggest that stringent IGF-1 control might be particularly beneficial for patient subgroups with more impaired HRQoL and a larger scale clinical trial will need to be completed to confirm this finding.