Acromegaly and Cushing’s disease are rare, often debilitating endocrine conditions that, if left untreated, are associated with considerable comorbidities and increased mortality (1, 2). Both conditions are most commonly caused by a benign pituitary adenoma that secretes growth hormone (GH) in cases of acromegaly and adrenocorticotropic hormone (ACTH) in cases of Cushing’s disease (3). Increased GH (and, consequently, insulin-like growth factor 1 [IGF-1]) or increased ACTH (leading to elevated cortisol) are associated with multiple underlying conditions, including impaired glucose tolerance and diabetes (4–7). Pasireotide, a second-generation somatostatin receptor ligand, is an effective long-term, pituitary-targeted medical treatment approved for patients with acromegaly (for whom surgery is not an option or has not been curative and who are inadequately controlled on treatment with another somatostatin analogue) (8–10) or Cushing’s disease (for whom pituitary surgery is not an option or has failed) (10–12). Pasireotide works by targeting four of the five somatostatin receptor (SSTR) subtypes, predominantly SSTR5 and SSTR2, all of which can be expressed by pituitary tumors (13). However, SSTR5 and SSTR2 also play important roles in blood glucose regulation; pancreatic beta cells, which secrete insulin, predominantly express SSTR5, and pancreatic alpha cells, which secrete glucagon, predominantly express SSTR2 (14). As shown in healthy volunteers, as well as in those with active acromegaly, pasireotide suppresses insulin secretion, with smaller reductions in glucagon secretion, resulting in elevated blood glucose; this is, at least in part, mediated by dampening of the incretin response (glucagon-like peptide 1 [GLP-1] and gastric inhibitory polypeptide [GIP]) (15, 16). Development or worsening of existing hyperglycemia is therefore an expected side effect of treatment with pasireotide, although it is not experienced by all patients (17). Addition of metformin, alone or in combination with other oral antihyperglycemic medications, was shown to control glucose elevations in most patients with acromegaly (17). Incretin-based therapies (eg dipeptidyl peptidase 4 [DPP-4] inhibitors [eg vildagliptin] and GLP-1 receptor agonists [eg liraglutide]) have also been shown to be an effective treatment option in managing pasireotide-associated hyperglycemia (18, 19). As such, with appropriate management, treatment-emergent hyperglycemic events rarely lead to treatment discontinuation (19), allowing the clinical benefit of pasireotide treatment to be achieved (8, 9, 11, 12) and sustained for many years (20).

The Phase IV B2219 trial was the first prospective study specifically designed to assess the efficacy of incretin-based therapy versus insulin in the management of pasireotide-associated hyperglycemia that is not fully controlled despite treatment with metformin or other non-incretin-based oral antidiabetic drugs (OADs) in participants with acromegaly or Cushing’s disease (21). A large proportion (41%) of participants in the B2219 study did not require any antihyperglycemic medication during treatment with pasireotide (21). An additional 18% were managed solely with metformin/other oral non-incretin-based medications, and 8% received insulin from baseline (with or without additional metformin during the study). Overall, 33% received antihyperglycemic medication in addition to metformin to manage hyperglycemia (21). This post hoc analysis examines patient characteristics that might predict those more or less likely to require initiation of or additional antihyperglycemic medications during pasireotide treatment. Furthermore, we also sought to investigate how insulin requirements may change throughout treatment with pasireotide. Together, we hope that these analyses will advance our knowledge of the proactive management of pasireotide-associated hyperglycemia.

B2219 was the first trial to evaluate prospectively the management of pasireotide-associated hyperglycemia in a large number of patients with acromegaly or Cushing’s disease (21). Glucose metabolism disorders are common in patients with these endocrine disorders, with a high prevalence of complications such as impaired glucose tolerance and diabetes (4–7). As shown in other pivotal Phase III studies of pasireotide in patients with acromegaly or Cushing’s disease (9, 11), the majority of patients entering the B2219 study had diabetes or pre-diabetes (65.3% with acromegaly and 74.6% with Cushing’s disease). As hyperglycemia is a known side effect of treatment with pasireotide, patients can be appropriately monitored and managed (10). Previous data also highlight that if hyperglycemia does occur, it is most likely during the first 3 months of treatment with pasireotide (9, 22) and is reversible upon pasireotide discontinuation (17). However, it remains that some patients are more or less likely to require antihyperglycemic medications; therefore, understanding predictive patient characteristics is of interest.

In the present study, not all participants required antihyperglycemic medication. In total, 53.7% of participants with acromegaly and 74.6% of participants with Cushing’s disease received antihyperglycemic medication during the pre-randomization phase, mostly metformin, either alone or in addition to insulin received from baseline. Of these participants, approximately half (if eligible) were then randomized to receive additional/alternative antihyperglycemic medication in the form of incretin-based therapy or insulin. The participants who received antihyperglycemic medication in the 16 weeks following initiation of pasireotide were generally older (mean age >40 years), had higher baseline HbA_1c (>6.5% [>48 mmol/mol]) and FPG levels (>100 mg/dL [>5.6 mmol/L]), and were diagnosed with diabetes or pre-diabetes. The logistic-regression analysis also identified increasing baseline HbA_1c and FPG, as well as a history of diabetes/pre-diabetes, as risk factors for requiring antihyperglycemic medication in participants with acromegaly; notably, elevated baseline HbA_1c and a history of diabetes/pre-diabetes were associated with a threefold increase in risk. In participants with Cushing’s disease, increasing HbA_1c was also identified as a risk factor along with receipt of previous treatment, although the majority of participants with Cushing’s disease had received prior treatments (80%). Both mean HbA_1c and FPG levels increased steadily during the first 8–12 weeks of the study in participants who received antihyperglycemic medication, notably those with diabetes/pre-diabetes. Post hoc and exploratory analyses from other clinical trials of pasireotide in patients with acromegaly (C2305 and C2402 [PAOLA]) have also suggested that hyperglycemia during pasireotide treatment was less frequent in patients with lower age (<40 years, C2402; <30 years, C2305) and normal glucose tolerance (17, 23). As such, pre-treatment glucose status may be a particularly useful predictor of the development of pasireotide-associated hyperglycemia. History of hypertension or dyslipidemia at baseline has also been identified as a predictive factor (17); however, data were not available in the present study.

Interestingly, in the participants randomized to receive insulin in addition to or instead of metformin in the present study, dose requirements increased considerably in a relatively short period of time.

Hyperglycemia-related AEs were more frequently reported in participants with diabetes or pre-diabetes at baseline, and serious AEs related to hyperglycemia were infrequent. Our results highlight and support previous findings that hyperglycemia-related AEs rarely require treatment interruption or discontinuation (19), emphasizing that when hyperglycemia does occur, it is manageable. Several treatment guidelines and expert recommendations also exist on the management of hyperglycemia, which, although focused on patients with Cushing’s disease, can be extrapolated to those with acromegaly (24, 25). Together with the findings from the B2219 study and the results presented herein, patients can be appropriately managed on an individual basis to ensure continued treatment with pasireotide, which can provide prolonged maintenance of biochemical control and improve clinical symptoms (20). For most patients who develop hyperglycemia, initiation of medical therapy with metformin alone is sufficient, followed by staged treatment with incretin-based therapies and insulin, as required, to achieve and maintain glycemic control (21, 24). Furthermore, hyperglycemia may also be managed with dietary modification, exercise and education (24). As clinical experience with pasireotide is increasing, including long-term follow-up studies and real-world experience (26–28), management of hyperglycemia is also improving.

There is increasing evidence that a personalized medical treatment approach based on patient-specific clinical and tumor characteristics can improve outcomes in patients with acromegaly (29–31). As well as identifying which patients are more likely to respond to different medical therapies, our findings contribute to optimizing patient management during medical treatment, which will be useful in clinical practice to tailor therapeutic approaches.

We acknowledge the limitations of these post hoc analyses as they are descriptive in nature. Findings in participants with Cushing’s disease may be limited by the relatively small number of participants in this group compared with those with acromegaly. Levels of GH/IGF-1 and urinary free cortisol were measured but were used only to guide therapeutic decisions locally; they were not recorded as part of the study design, so no comment can be made on the impact of disease control on the need for antihyperglycemic medication. Furthermore, these analyses did not consider the occurrence/recurrence of hyperglycemia that may arise with long-term pasireotide treatment; to this end, further investigation is still warranted.

Individual patient characteristics are useful indicators of whether patients are more or less likely to develop hyperglycemia during treatment with pasireotide. Notably, increased age, HbA_1c and FPG levels, as well as a previous diagnosis of diabetes or pre-diabetes, should be considered as potential predictive factors. These factors may be used to identify patients who require more vigilant, proactive monitoring and early intervention to ensure continued treatment with pasireotide and optimal outcomes.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by an independent ethics committee/institutional review board at each site. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

All academic investigators enrolled patients in the study. Data were collected by investigators using the funder’s data management systems and analyzed by the funder’s statistical team. All authors contributed to the article and approved the submitted version.