Novel approaches in the management of comorbidities and biochemical control in acromegaly

Acromegaly is a rare systemic endocrine disorder, caused in most cases by a growth hormone (GH)-secreting pituitary tumour, characterised by peculiar clinical manifestations and comorbidities due to chronic exposure to excessive amounts of GH and its peripheral mediator insulin-like growth factor-1 (IGF-1). Persistent hormonal excess results in a wide spectrum of cardiovascular, respiratory, metabolic, musculoskeletal, neurological and neoplastic pathologies that are not always reversible once disease control is achieved. Achieving biochemical control is the primary therapeutic goal; other treatment goals include volumetric reduction of the pituitary tumour, alleviation of symptoms, management of complications, reduction of morbidity and improvement of quality of life. Surgical therapy remains the first line of treatment for acromegaly, but recently much attention has been paid to identifying treatment algorithms that suggest the best strategies for patients requiring medical therapy. The need for a personalised approach in the management of patients with acromegaly is certainly a hot topic in pituitary disease research. In this scenario, real-life studies can play a key role in better understanding the correct positioning of the different therapeutic strategies currently available in the management of acromegaly, including medical therapy with pasireotide (PAS), a second-generation somatostatin receptor agonist. In cases of persistent disease, the use of PAS is currently suggested as a second or third line of medical therapy, especially in patients with normal glucose metabolism who show post-surgery residual tumour. From 2018 to date, several studies have evaluated the efficacy of PAS and its effects on glucose profile in populations with different characteristics, in real-life clinical settings. In our retrospective study, we analysed the biochemical outcome and the effects on the glycometabolic profile of PAS therapy in a peculiar cohort consisting of 21 acromegalic patients from two Pituitary Pathology Referral Centres. The study population included only patients previously treated with combination medical therapy or unconventional doses of first-generation somatostatin analogues, who were subsequently switched to PAS monotherapy due to incomplete response to previous therapy or difficult compliance, albeit in disease control. The switch to PAS monotherapy resulted in a significant reduction in IGF-1 levels, as well as in a higher percentage of patients achieving acceptable biochemical disease control (defined as IGF-1 <1.3 xULN, Upper Limit of Normality) and complete normalisation of age-adjusted IGF-1 values (IGF-1 ≤1 xULN), compared to baseline values. At the last follow-up, 90% of the patients (19/21) had IGF-1 values <1.3 xULN. None of the pre-PAS controlled patients lost biochemical control during the observation period and 7/9 (78%) of the non-pre-PAS controlled patients reached normal IGF-1 values at the last follow-up. The observed results showed a higher efficacy of PAS than reported in the literature, particularly compared to the data described in the first clinical trials. However, in line with other recent studies, we were unable to identify any clinical parameters that could strongly predict biochemical control after PAS treatment. With regard to hyperglycaemia-related adverse events during PAS treatment, our data are consistent with clinical trials and real-life studies. In our cohort, mean glycated haemoglobin values increased from 5.7% to 6.0% during PAS therapy. Metformin alone, combined with lifestyle interventions, proved effective in 7 of 9 subjects who needed to start hypoglycaemic treatment. Younger patients showed lower fasting plasma glucose levels than older patients. Furthermore, female patients had a higher statistical probability of developing diabetes mellitus than males, even after correction for age at the time of PAS initiation. Recent advances in acromegaly disease control and comorbidity management have led to a reduction in disease-related mortality, which now approaches (in controlled patients) that of the general population. Centres of excellence for pituitary pathology ensure multidisciplinary management of the biochemical dysfunction and mass effects of the pituitary lesion, as well as the availability of advanced procedures for the diagnosis, monitoring and treatment of disease-related comorbidities. The bone pathology associated with acromegaly is characterised by altered trabecular architecture and increased cortical bone, which predispose patients to vertebral fractures (VF). In addition, hypogonadism and diabetes mellitus may concomitant, contributing to the deterioration of bone structure. The higher prevalence of VF in patients with acromegaly compared to the general population, already at the time of diagnosis, suggests that VF could be an early manifestation of acromegaly, directly related to elevated circulating GH concentrations. Bone mineral density (BMD) in these patients is often within normal ranges. The study of trabecular bone using Trabecular Bone Score (TBS) could therefore be a more reliable tool to assess fracture risk. The aim of our study was to investigate the superiority of TBS over BMD in identifying patients with compromised trabecular microarchitecture of the lumbar spine. Thus, disease control, metabolic and gonadal status, bone metabolism parameters and the presence of VF were assessed in 44 patients with acromegaly, who underwent bone densitometry (DEXA) for BMD and TBS evaluation, compared with a group of healthy volunteers. The mean TBS values were lower in patients than in controls (p<0.001), but with no significant differences in mean lumbar and femoral BMD. TBS values were also significantly higher in patients with controlled disease than in uncontrolled subjects (p=0.012). No significant difference was found in biochemical markers of bone metabolism activity compared to disease control. Mean TBS or lumbar BMD did not differ significantly in patients with or without VF (VF prevalence: 11.4%). As expected, TBS and BMD levels were lower in hypogonadal than in eugonadal patients (p=0.030 and p<0.001, respectively). In conclusion, TBS values were significantly reduced in patients compared to controls, confirming the presence of lumbar trabecular bone impairment in acromegaly. Another emerging aspect is the effect of acromegaly on skeletal muscle tissue, one of the main targets of GH and IGF-1. Given the known anabolic functions of GH and the inhibition of IGF-1-mediated proteolysis, an increase in skeletal muscle mass should be assumed in patients with active disease. With regard to muscle quality and performance, it has largely been shown that, despite an increase in muscle mass, patients with acromegaly experience myopathy with weakness and pain, along with a reduction in muscle endurance. We conducted a systematic review of the literature that included 15 studies. In our analysis we included 360 acromegalic patients assessed for skeletal muscle mass, 122 for muscle atrophy and 192 for muscle performance. There was no clear evidence of increased skeletal muscle mass in patients with active acromegalic disease compared to control subjects or healthy controls. Regarding muscle quality, we observed a trend towards greater adipose infiltration among patients with acromegaly compared to healthy subjects. Similarly, patients with active disease showed consistently worse physical performance than control or healthy subjects. In conclusion, skeletal muscle in acromegaly showed inferior quality and performance compared to healthy subjects. The limited number of published studies and the presence of multiple confounding factors (e.g., the heterogeneity of the radiological techniques used in the different studies, but also the different medical therapies, the presence of comorbidities that may impact the muscle, or the different degree of physical activity of the patients) contributed to the conflicting results, especially with regard to skeletal muscle mass. A gold standard for assessing muscle characteristics in patients with acromegaly has yet to be identified. The aim of another study was to investigate whether the measure of temporal (TMT) and masseter muscle thickness (MMT) (easily visible at the brain/sella turcica MRIs routinely performed by acromegalic patients), was consistent and whether it correlated with demographic characteristics associated with skeletal muscle mass. We also investigated the potential correlations between disease activity, time from diagnosis, and muscle thickness. We included sixty-nine patients and analyzed 182 MRIs. At baseline, both TMT and MMT were higher in males than females (p=0.001 and p=0.016, respectively). TMT and MMT were directly associated (β 0.508, p<0.001). TMT was directly correlated with IGF-1 xULN (p=0.047); MMT was directly correlated with IGF-1 xULN (p=0.001), patient weight (p=0.015) and height (p=0.006). No correlation was found between TMT, MMT and the presence of hypogonadism. Considering all available MRIs, sex and IGF-1 xULN were significant determinants of TMT and MMT at multivariable analysis (female sex: β -0.345/-0.426, p<0.001; IGF-1 xULN: β 0.257/0.328, p<0.001). At longitudinal evaluation, uncontrolled patients at baseline showed a significant reduction of MMT over time (p=0.044). Remarkable fatty infiltration was observed in 34-37% of MRIs; age was the main determinant (temporal muscle: OR 1.665; p=0.013; masseter: OR 1.793; p=0.009). In conclusion, male patients with higher IGF-1 values have thicker temporal and masseter muscles, indicating greater muscle mass compared to the other subjects.