Is pasireotide-induced diabetes mellitus predictable? A pilot study on the effect of a single dose of pasireotide on glucose homeostasis

Barbot, Mattia; Regazzo, Daniela; Mondin, Alessandro; Zilio, Marialuisa; Lizzul, Laura; Zaninotto, Martina; Plebani, Mario; Arnaldi, Giorgio; Ceccato, Filippo; Scaroni, Carla

doi:10.1007/s11102-020-01055-x

Cited by 8 publications

(6 citation statements)

References 39 publications

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“…Our findings in patients with acromegaly are in line with previous mechanistic studies in healthy volunteers ( 17 ) and in patients with Cushing’s syndrome ( 27 ). The development of diabetes and the impact on insulin secretion during pasireotide therapy can be explained by its binding affinity.…”

Section: Discussionsupporting

confidence: 92%

Impairment in insulin secretion without changes in insulin resistance explains hyperglycemia in patients with acromegaly treated with pasireotide LAR

Wolf

Dormoy

Maione

et al. 2022

Endocrine Connections

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Objective: Pasireotide is a second-generation somatostatin receptor ligand (SRL) used for treating acromegaly. Its clinical use is limited by adverse effects on glucose homeostasis. The aim of this study was to evaluate longitudinal changes in beta-cell function and insulin sensitivity associated with pasireotide in patients not controlled by first-generation SRLs. Design: We performed a retrospective study. Methods: Efficacy (GH/IGF-I concentrations; tumor size) and effects on glucose homeostasis were analyzed in 33 patients. Longitudinal data on oral glucose tolerance tests were available before, shortly (mean±SD, 6.1±3.8 months) and on long term (24.4±11.1 months) after initiation of pasireotide in 14 patients. Insulin secretion (Insulinogenic index; Disposition index) and insulin sensitivity were calculated by validated indices. Results: Pasireotide-induced diabetes occurred in 12 patients (36%). It was mediated by impaired insulin secretion, which occurred shortly after initiation of treatment and then remained stable on long term [Insulinogenic index, median (min; max), 80 (12; 542) vs 16 (6.4; 101) vs 25 (3.7; 396) pmol/mmol, respectively; p=0.028; Disposition index, 1.45 (0.42; 4.88) vs 0.53 (0.17; 2.63) vs 0.60 (0.22; 1.71), respectively; p=0.024]. No significant changes in insulin sensitivity were observed, despite a marked reduction of GH/IGF-I concentrations. Older age and a worse glycemic control at baseline were the strongest predictors for hyperglycemia and the need for antidiabetic treatment. Conclusion: Worsening of glycemic control during pasireotide therapy is caused by an impaired insulin secretion, whereas insulin sensitivity is not affected. These findings might be important for the choice of anti-diabetic treatment for pasireotide induced hyperglycemia.

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Section: Discussionsupporting

confidence: 92%

Impairment in insulin secretion without changes in insulin resistance explains hyperglycemia in patients with acromegaly treated with pasireotide LAR

Wolf

Dormoy

Maione

et al. 2022

Endocrine Connections

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“…It has also been reported that a single PAS injection also inhibits α-cell activity, causing a decrease in glucagon secretion [15]. Vice versa, in the present report glucagon levels were not reduced by two-months of PAS therapy, thus leading to an imbalance of the insulin:glucagon ratio due to the marked reduction of insulin secretion.…”

Section: Discussionsupporting

confidence: 44%

“…PAS administration produces a rapid decrease in insulin secretion with a consequent increase in glucose levels, as we previously reported. The incretin system was also partially affected but to a less extent compared to that observed in healthy subjects [14,15].…”

Section: Introductionmentioning

confidence: 69%

“…However, a direct effect of ACTH on glucose homeostasis cannot be excluded, especially considering that ACTH has been proved to induce insulin resistance in vitro [23]. High ACTH level was already reported in our previous study as a potential contributor to DM development during PAS therapy [15]. Further studies are required to obtain a deeper understanding of these mechanisms.…”

Section: Discussionmentioning

confidence: 91%

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Incretin Response to Mixed Meal Challenge in Active Cushing’s Disease and after Pasireotide Therapy

Barbot

Mondin

Regazzo

et al. 2022

IJMS

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Cushing’s disease (CD) causes diabetes mellitus (DM) through different mechanisms in a significant proportion of patients. Glucose metabolism has rarely been assessed with appropriate testing in CD; we aimed to evaluate hormonal response to a mixed meal tolerance test (MMTT) in CD patients and analyzed the effect of pasireotide (PAS) on glucose homeostasis. To assess gastro-entero-pancreatic hormones response in diabetic (DM+) and non-diabetic (DM–) patients, 26 patients with CD underwent an MMTT. Ten patients were submitted to a second MMTT after two months of PAS 600 µg twice daily. The DM+ group had significantly higher BMI, waist circumference, glycemia, HbA1c, ACTH levels and insulin resistance indexes than DM− (p < 0.05). Moreover, DM+ patients exhibited increased C-peptide (p = 0.004) and glucose area under the curve (AUC) (p = 0.021) during MMTT, with a blunted insulinotropic peptide (GIP) response (p = 0.035). Glucagon levels were similar in both groups, showing a quick rise after meals. No difference in estimated insulin secretion and insulin:glucagon ratio was found. After two months, PAS induced an increase in both fasting glycemia and HbA1c compared to baseline (p < 0.05). However, this glucose trend after meal did not worsen despite the blunted insulin and C-peptide response to MMTT. After PAS treatment, patients exhibited reduced insulin secretion (p = 0.005) and resistance (p = 0.007) indexes. Conversely, glucagon did not change with a consequent impairment of insulin:glucagon ratio (p = 0.009). No significant differences were observed in incretins basal and meal-induced levels. Insulin resistance confirmed its pivotal role in glucocorticoid-induced DM. A blunted GIP response to MMTT in the DM+ group might suggest a potential inhibitory role of hypercortisolism on enteropancreatic axis. As expected, PAS reduced insulin secretion but also induced an improvement in insulin sensitivity as a result of cortisol reduction. No differences in incretin response to MMTT were recorded during PAS therapy. The discrepancy between insulin and glucagon trends while on PAS may be an important pathophysiological mechanism in this iatrogenic DM; hence restoring insulin:glucagon ratio by either enhancing insulin secretion or reducing glucagon tone can be a potential therapeutic target.

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“…Real-world evidence and clinical trial extension studies have demonstrated that glucose metabolism alterations tend to occur primarily within the first weeks of therapy with pasireotide and stabilize over time (68)(69)(70)(71). The risk of developing pasireotideinduced hyperglycemia is the highest in patients with high glucagon levels, HbA1c > 34.5 mmol/L (5.3%), and glucose peak > 9 mmol/L after pasireotide administration (72). However, careful monitoring for glucose metabolism abnormalities is required for all patients undergoing therapy.…”

Section: Pasireotidementioning

confidence: 99%

Medical treatment of Cushing’s disease with concurrent diabetes mellitus

et al. 2023

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Cushing’s disease (CD) is a severe endocrine disorder characterized by chronic hypercortisolaemia secondary to an overproduction of adrenocorticotropic hormone (ACTH) by a pituitary adenoma. Cortisol excess impairs normal glucose homeostasis through many pathophysiological mechanisms. The varying degrees of glucose intolerance, including impaired fasting glucose, impaired glucose tolerance, and Diabetes Mellitus (DM) are commonly observed in patients with CD and contribute to significant morbidity and mortality. Although definitive surgical treatment of ACTH-secreting tumors remains the most effective therapy to control both cortisol levels and glucose metabolism, nearly one-third of patients present with persistent or recurrent disease and require additional treatments. In recent years, several medical therapies demonstrated prominent clinical efficacy in the management of patients with CD for whom surgery was non-curative or for those who are ineligible to undergo surgical treatment. Cortisol-lowering medications may have different effects on glucose metabolism, partially independent of their role in normalizing hypercortisolaemia. The expanding therapeutic landscape offers new opportunities for the tailored therapy of patients with CD who present with glucose intolerance or DM, however, additional clinical studies are needed to determine the optimal management strategies. In this article, we discuss the pathophysiology of impaired glucose metabolism caused by cortisol excess and review the clinical efficacy of medical therapies of CD, with particular emphasis on their effects on glucose homeostasis.

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Is pasireotide-induced diabetes mellitus predictable? A pilot study on the effect of a single dose of pasireotide on glucose homeostasis

Cited by 8 publications

References 39 publications

Impairment in insulin secretion without changes in insulin resistance explains hyperglycemia in patients with acromegaly treated with pasireotide LAR

Impairment in insulin secretion without changes in insulin resistance explains hyperglycemia in patients with acromegaly treated with pasireotide LAR

Incretin Response to Mixed Meal Challenge in Active Cushing’s Disease and after Pasireotide Therapy

Medical treatment of Cushing’s disease with concurrent diabetes mellitus

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