To the best of our knowledge, this is the first study to investigate the metabolic effects of CAB in the acromegaly population. Specifically, our results confirm that CAB is a good therapeutic option for achieving good disease control but with modest metabolic impact.

In our study, following the initiation of CAB, a significant decrease in median IGF-I values was observed at 6 and 12 months compared to baseline, despite no significant differences in median GH levels. The discrepancy observed between IGF-I and GH is not surprising: indeed, IGF-I better reflects the daily overall exposure to GH and therefore is a better predictor of the overall disease activity [18].

This finding is also in line with what previously reported in patients undergone neurosurgery [19] and in patients treated with SSAs [20], and it could be attributable to biological factors such as sex, glucose metabolism, and GH receptor polymorphisms as well as the consequence of using different measurement techniques [21, 22].

The incidence of glycemic alterations in patients with acromegaly is higher compared to that of the general population, with over 50% of patients developing either DM or IGM [23].

In choosing the appropriate treatment for patients, it is thus important to consider the effects that therapy may have on glycemic control and weight, as these are significant determinants of the quality and life expectancy of acromegaly individuals [24, 25].

In this regard, DAs have shown to significantly reduce FBG levels, regardless of the presence of hyperPRL.

In several studies, a favorable effect of CAB on the glycemic profile of patients with prolactinoma has also been observed, particularly an improvement in surrogate indices of insulin resistance, insulin sensitivity, and pancreatic β-cell function after only 6 months of therapy, regardless of PRL values [10, 12, 14, 26].

In our study, the metabolic impact of CAB was less evident than hypothesized and considering the entire cohort, no significant variations were observed in terms of FBG levels and HbA1c at 6 or 12 months.

Compared to subjects with prolactinomas, it can be speculated that in acromegaly patients, the action of CAB may require a longer treatment period in order to appreciate its positive impact on glucose metabolism. Indeed, it is well known that GH is a key hormone in glycemic counter-regulation and the primary culprit for alterations in glycemic homeostasis in these patients [27]. CAB in monotherapy, in acromegaly, is significantly less effective in normalizing GH/IGF-I levels, and this certainly affects its metabolic action. Only 40% of patients are actually able to normalize GH secretion; in 60% of cases, patients still have pathological levels of GH, negatively impacting the glycemic profile [28].

In our study, a notable difference in FBG levels at T12 compared to T0 was observed in non-diabetic patients, contrasting with previous findings in subjects with prolactinomas. In the latter group, the impact on glycemic control was shown to be more prominent among patients with IGM or DM, occasionally leading to the normalization of glycemic tolerance or a dosage reduction in antidiabetic therapy [12].

Then, in acromegaly patients, it is possible that CAB might modulate glycemic parameters more effectively in subjects who likely retain a better-preserved β-cell pancreatic function.

Although CAB has shown suboptimal performance in improving the glycemic profile, our results demonstrate a significant weight and BMI reduction at 6 months, sustained at 12 months, more noticeable in the subgroup of overweight patients. However, there were no significant differences in the percentage of weight loss based on the initial BMI class. Therefore, it is likely that most patients, regardless of being obese or overweight, can benefit from CAB therapy. An important aspect to note is that no patient with DM was on therapy with drugs like GLP1-RA or SGLT2-i, antidiabetic medications known for their weight loss effects [29]. This exclusion ensures the elimination of significant pharmacological confounders.

Similarly, patients with untreated concurrent hormonal deficiencies, particularly those with secondary hypogonadism, were excluded from the analysis, thereby also reducing the impact of restoring eugonadism on the evaluation of glycemic and weight variations.

The effect on weight has also been documented in patients with prolactinomas. Specifically, in some studies, a significant weight loss was observed as early as 3–6 months [13, 30], while in others, it took more than 60 months of treatment to detect it [12].

The weight loss observed in prolactinomas correlates with elevated baseline PRL levels and male gender [30], but it is independent of the improvement in other metabolic parameters [12, 26].

In our study, no association was demonstrated between PRL levels at T0 and weight changes. However, it is worth noting that most of our patients had either normal or suppressed PRL values already at baseline.

It is therefore likely that the mechanisms behind the weight loss observed in acromegaly individuals are somewhat different from those in patients with isolated hyperPRL. Furthermore, weight loss does not seem to correlate with the state of active or controlled disease.

In more recent studies, it has been shown that even reduced levels of PRL compared to the normal range can have a negative impact on weight, glycemic profile and lipid levels, promoting an increased risk of metabolic syndrome, similarly to an excess of PRL [31].

In our investigation, this data did not find confirmation; indeed, analyzing subjects with inhibited PRL levels, our results showed significant reductions in FBG levels at T12. Similarly, patients with suppressed PRL levels showed significant weight loss at both T6 and T12. As previously observed at baseline, however, the majority of patients in our cohort exhibited suppressed PRL levels following initiation of CAB therapy, with only three patients showing normal levels. The small sample size could be responsible for the obtained results, but the suppression of PRL values, anyway, did not appear to be detrimental to metabolic status. In any case, it is worth noting that the definition of hypoprolactinemia (hypoPRL) is a relatively new nosological entity [32] and has not yet been fully codified as of today, since different studies have proposed values lower than 7 or 5 µg/L, or even undetectable levels for the cutoff [31, 33, 34]. Therefore, the adverse effects of low PRL levels on cardiovascular and metabolic risk are likely dependent on the specific definition of hypoPRL being used.

Stratifying subjects based on hormone secretion, no significant variations were observed in metabolic parameters or disease hormone compensation. This data confirms that CAB is effective regardless of PRL co-secretion [3]. Moreover, in the subgroup with GH-secreting adenoma, a significant reduction in weight was observed at 6 and confirmed at 12 months. The metabolic effect of CAB, when present, appears to primarily affect anthropometric parameters but does not seem to be progressive, at least in the short-term period.

Our results confirm the efficacy of CAB in hormonal control, administered alone or in combination with SSAs or PEG. SSAs are known to inhibit pancreatic secretion of insulin and glucagon, promoting the development of metabolic alterations in euglycemic patients, and aggravating the already partially impaired pancreatic function in patients with IGM or DM.

In recent studies, the impact on metabolism of SSAs, at least first-generation ones, has been reassessed.

It appears that their effect is actually marginal, as their use is associated with a transient reduction in insulin levels, without, however, significant effects on glycemic homeostasis [35]. On the other hand, pasireotide is a second-generation SSA known to significantly worsen glucose metabolism, with an average increase of about 0.4–0.5% in HbA1c levels [36, 37]; anyway, no patients in our cohort were on treatment with such a drug.

Finally, it is well known that PEG primarily presents favorable effects on glycemic homeostasis, reducing FBG levels even after achieving good disease control [38].

In our study, the type of treatment being administered did not show advantages in terms of either FBG or HbA1c levels, but it is worth noting that only 3 people were on PEG treatment.

In the subgroup receiving combination therapy with SSAs, a positive effect on weight was observed, with a significant weight loss at 6 and 12 months compared to baseline, suggesting an influence of other acromegaly therapies, particularly SSAs, on weight [39].

Although this is the first study to evaluate the metabolic impact of CAB in patients with acromegaly, it has some limitations. Firstly, the sample size was rather small. Moreover, its retrospective nature did not allow the assessment of parameters such as the lipid profile, insulin, HOMA-IR, as well as other anthropometric measures such as waist circumference, hips, waist-to-hip ratio or body composition. Similarly, data on blood pressure, as well as information about potential significant changes in dietary habits were not available for most patients. Finally, there was no control group, and the follow-up was limited to a period of 12 months.

In conclusion, our results confirm the efficacy of CAB in providing a significant improvement in the biochemical disease control but do not demonstrate a marked benefit on glucose metabolism of acromegaly patients. Anyway, in such patients, CAB appears to have a rapid effect on weight and BMI, with significant changes noticeable as early as 6 months and persisting for at least 12 months.

Considering the importance of preventing and managing complications related to the excess of GH and/or IGF-I and considering the established efficacy of CAB in other clinical settings, further prospective studies involving larger cohort and longer observation periods are necessary to evaluate more deeply the potential clinical and metabolic benefits of CAB in acromegaly disease.