Predictive factors and the management of hyperglycemia in patients with acromegaly and Cushing's disease receiving pasireotide treatment: post hoc analyses from the SOM230B2219 study

Abstract

Introduction: Pasireotide, a somatostatin receptor ligand, is approved for treating acromegaly and Cushing's disease (CD). Hyperglycemia during treatment can occur because of the drug's mechanism of action, although treatment discontinuation is rarely required. The prospective, randomized, Phase IV SOM230B2219 (NCT02060383) trial was designed to assess optimal management of pasireotide-associated hyperglycemia. Here, we investigated predictive factors for requiring antihyperglycemic medication during pasireotide treatment.

Methods: Participants with acromegaly or CD initiated long-acting pasireotide 40 mg/28 days intramuscularly (acromegaly) or pasireotide 600 μg subcutaneously twice daily during pre-randomization (≤16 weeks). Those who did not need antihyperglycemic medication, were managed with metformin, or received insulin from baseline entered an observational arm ending at 16 weeks. Those who required additional/alternative antihyperglycemic medication to metformin were randomized to incretin-based therapy or insulin for an additional 16 weeks. Logistic-regression analyses evaluated quantitative and qualitative factors for requiring antihyperglycemic medication during pre-randomization.

Results: Of 190 participants with acromegaly and 59 with CD, 88 and 15, respectively, did not need antihyperglycemic medication; most were aged <40 years (acromegaly 62.5%, CD 86.7%), with baseline glycated hemoglobin (HbA_1c) <6.5% (<48 mmol/mol; acromegaly 98.9%, CD 100%) and fasting plasma glucose (FPG) <100 mg/dL (<5.6 mmol/L; acromegaly 76.1%, CD 100%). By logistic regression, increasing baseline HbA_1c (odds ratio [OR] 3.6; P=0.0162) and FPG (OR 1.0; P=0.0472) and history of diabetes/pre-diabetes (OR 3.0; P=0.0221) predicted receipt of antihyperglycemic medication in acromegaly participants; increasing baseline HbA_1c (OR 12.6; P=0.0276) was also predictive in CD participants. Investigator-reported hyperglycemia-related adverse events were recorded in 47.9% and 54.2% of acromegaly and CD participants, respectively, mainly those with diabetes/pre-diabetes.

Conclusion: Increasing age, HbA_1c, and FPG and pre-diabetes/diabetes were associated with increased likelihood of requiring antihyperglycemic medication during pasireotide treatment. These risk factors may be used to identify those who need more vigilant monitoring to optimize outcomes during pasireotide treatment.

Keywords: Cushing’s disease; acromegaly; diabetes mellitus; glucose intolerance; hyperglycemia; pasireotide; pituitary adenoma.

Figure 1

Participant disposition during the core phase of the study according to whether antihyperglycemic medication was received. *Includes unacceptable test procedure results, laboratory values, past medical history or concomitant medications.

Figure 2

Forest plots summarizing predictive factors for the requirement of antihyperglycemic medication after initiation of pasireotide treatment in participants with (A) acromegaly and (B) Cushing’s disease. A backward method for selecting the predictors was applied, with a threshold of P ≤ 0.2 for remaining in the reduced (final) model. The criterion of –2 log likelihood was also applied to identify the reduced model that best fits the data.

Figure 3

Mean HbA_1c and FPG levels over the first 16 weeks (pre-randomization period) in participants with (A) acromegaly and (B) Cushing’s disease. Numbers below the horizontal axes refer to numbers of participants with diabetes/pre-diabetes/NGT. Dashed lines are at 6.5% (48 mmol/mol) for HbA_1c and 126 mg/dL (7.0 mmol/L) for FPG. NGT, normal glucose tolerance.

Figure 4

Shift from baseline to last post-baseline HbA_1c and FPG during the 16­week pre-randomization period in participants with (A) acromegaly and (B) Cushing’s disease.