Glucose metabolism outcomes in acromegaly patients on treatment with pasireotide-LAR or pasireotide-LAR plus Pegvisomant

Glucose homeostasis represents a relevant clinical problem in acromegaly, to which both GH and IGF-I hypersecrection and medical therapies can contribute, although their reciprocal role is not yet completely cLARified [2, 11‐15, 21, 22]. Concerning the latter aspect, an increased awareness was raised by the PAS- LAR use, which was associated with higher diabetes risk [13‐15].

In this study, we investigated the alterations of glucose metabolism in acromegaly patients before and during long-term treatment PAS- LAR alone and in combination with Peg-V.

Before starting treatment with PAS- LAR, 32.5% of patients had IGT/IFG and 22.5% had DM. These data are in line with previous epidemiological data and with the notion that conventional SRLs have only a marginal role in glucose homeostasis [23], as all the patients of this cohort were treated with conventional SRLs, before starting PAS- LAR. Instead, at the end of the study, the prevalence of IGT/IFG and DM increased, involving respectively the 50% and the 35% of cases. We found that the glucose status worsened in 25/34 on PAS-LAR (73.5%) and in a single patient treated with Pasi- LAR plus Peg-V. Our data are in line with previous authors that reported hyperglycemia and new onset DM in around 57% and 20% of patients on treatment with PAS- LAR [13‐15]. Interestingly, more than half of patients with worsened glusose metabolism had normal glycometabolic status before treatment although it was previously suggested a predictive role of pre-PAS LAR treament glucose parameters [24]. Conversely, we found that the higher PAS-LAR dose (60 mg/monthly) correlated significantly with glucose control worsening, in particular with the increase in HbA1c, both in active and controlled acromegaly, at the end of the study. Another original finding of our study is that the higher GH levels may predict the worsening of glucose metabolism during Pasi-LAR treatment. This finding was identified also in other co-morbidities of acromegaly as bone fragility [25‐28]. GH and IGF-I induce several metabolic changes that are actually not completely clarified [29, 30]. GH acts with a bimodal effect on glucose homeostasis, stimulating beta-cell proliferation, insulin synthesis and secretion, but also increasing lipolysis, gluconeogenesis [31, 32] and inducing systemic insulin resistance in active acromegaly [33, 34]. As a consequence, GH excess per se may induce IFG, IGT, and DMII [35, 36]. However, GH action is also mediated by IGF-I that is mostly synthesized in hepatocytes upon GH receptor binding [37]. Conversely, IGF-I has been shown to increase insulin sensitivity [29]. Deterioration of glucose metabolism in patients with higher GH and IG-I levels has also been observed in patients partially resistant to SRL treated with high octreotide dose [38].

Taken together, these findings suggest that the higher dose of PAS-LAR needed to control a more biochemically active disease may have contributed to a greater glucose metabolism alteration. In fact, it is already known that in the presence of a more active disease at baseline, it is more difficult to obtain biochemical control of acromegaly [39]. Moreover, PAS-LAR has been shown to decrease insulin secretion acting at pancreatic beta cell level and to also decrease GlP and GLP-1 secretion [24]. Therefore, based on our data it can be hypothesized that in our population a combined mechanism represented by negative direct pancreatic effect of PAS-LAR combined with detrimental effects of high GH on insulin resistance may occur [40] although our data did not allow to clarify which of the two mechanisms could be cliinically prevalent in determining the observed metaboslic worsening.

Finally, we found in the group of patients under Peg-V plus PAS- LAR the combination treatment may not only improve biochemical control but also mitigate the worsening of glucose metabolism caused by PAS- LAR alone. In fact, as shown in Fig. 4, all but one patients experienced a reduction of the HbA1c. Interestingly, the reduction of pre-treatment HbA1c was significantlly greater in patients treated with PAS-LAR in combination with Peg-V as compared to those of patients treated with PAS-LAR as monotherapy (Fig. 3). These results are different with those of Muhammad et al and could be explained by uptitrating doses of Peg-V in a clinical setting like ours vs a prospective design with fixed doses which aimed to spare Peg-V dose. Furthermore, PAS- LAR dose in that study was 60 mg monthly which we showed to have a worsening effect on glucose in our study.

This improvement of glucose metabolism can also be due to the biochemical efficacy of this combination therapy, that we recently described to be effective in a group of acromegaly patients affected by a disease resistant to multimodal treatments [41]. In fact, patients who required combination treatment PAS- LAR plus Peg-V had higher values of IGF-I at acromegaly diagnosis, if compared with cases treated with PAS- LAR alone. However, these IGF-I levels did not correlate with the glucose outcome (p = 0.943). Alternatively, though not confirmed in Muhammad et al. [42], it may be suggested that Peg-V per se may have a protective effect on the hyperglycemic effect of PAS- LAR possibly reducing insulin resistance in some patients [43].

The significant limitations of this study are its retrospective design and the absence of randomization for the acromegaly treatment. Likewise, the small size of the group of patients treated with PAS- LAR plus Peg-V reduced the power of comparative analysis. However, although the number of patients by us reported on treatment with PAS-LAR in combination with Peg-V is limited, experiences on glucose outcomes with this new form of therapy are scant and controversial [21, 38, 42, 44]. This combination is also currently included in consensus guidelines [21] for particularly resistant acromegaly, thus we think that this multicentric experience can be a useful addition to the available clinical evidence. In fact, based on our data it can be hypothesized that in patients in whom residual tumor and diabetes are both clinical concerns [45] and are not sufficiently controlled by first generation SRLs, a combination of PAS-LAR and Peg-V may be a viable option. In addition, the design of this study did not allow us to compare head to head Peg-V vs PAS-LAR in their effects on glucose metabolsim and did not provide any direct insights on the mechanisms underlying their effects.

In conclusion, we confirm previous data that glucose metabolism is often worsened during second line medical treatment with PAS-LAR in acromegaly. Our results suggest that this glucose worsening may be due to the use of PAS-LAR according to guidelines (45) in acromegaly patients with severe disease which in turn require high doses of the drug. In fact, both high GH levels per se as well as PAS-LAR may directly and potentially synergistically be detrimental for glucose metabolism. In this light, our data, although limited by small numbers, are among the first to suggest that the combination treatment PAS-LAR plus Peg-V can not only improve biochemical control but also glucose homeostasis in selected patients. If confirmed in larger studies, this combination could be suggested earlier in the treatment of patients with resistant acromegaly and concomitant abnormalities in glucose metabolism.