Short- and long-term glycemic effects of pasireotide in patients with acromegaly: a comprehensive case study with review of literature

Abstract

Pasireotide (PAS), a multireceptor somatostatin analog, has been demonstrated to effectively control hormone levels, including those of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), in patients with acromegaly. However, it induces hyperglycemia by inhibiting insulin secretion via somatostatin receptor 5 (SSTR5). Despite the extensive literature on the occurrence of PAS-induced hyperglycemia, there is still no consensus on the optimal first-line treatment for this complication. Herein, we present two cases of acromegaly treated with PAS and highlight its short- and long-term effects on glucose metabolism. In the first case, postprandial hyperglycemia manifested rapidly following the commencement of PAS treatment and was effectively managed with dulaglutide under continuous glucose monitoring (CGM). In the second case, long-term PAS therapy resulted in a dose-dependent glycemic response that was controlled by different GLP-1 receptor agonists (GLP-1RAs), including semaglutide. CGM facilitated the early detection of significant glycemic fluctuations, underscoring the necessity for close monitoring in patients receiving PAS therapy. These cases demonstrate the efficacy of GLP-1RAs in managing PAS-induced hyperglycemia and highlights the value of CGM in early detection and intervention. Our findings suggest that GLP-1RAs, particularly semaglutide, are a valuable treatment option for this condition. Further research is needed to determine the optimal treatment strategy, particularly in East Asian populations, and to establish a clear consensus on the first-line therapy for PAS-induced hyperglycemia.

Introduction

Acromegaly is a rare endocrine disorder that is characterized by the excessive secretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) [1]. In most cases, this disorder is caused by the overproduction by GH-producing pituitary neuroendocrine tumors (PitNETs) [1]. When left untreated, acromegaly can result in a number of systemic symptoms, many of which are associated with significant complications and an increased risk of mortality. These include cardiovascular disease, hypertension, glucose intolerance, hypopituitarism, obstructive sleep apnea, dyslipidemia, musculoskeletal disorders, and cancer [1]. Transsphenoidal sinus surgery represents the initial treatment option, followed by somatostatin receptor ligand (SRL) and other pharmacological therapies when surgical intervention becomes contraindicated due to complications [1, 2]. Medical therapy is employed in patients whose disease is poorly controlled despite surgical resection or in whom complete tumor removal by surgery is not feasible [1, 2]. In recent years, SRLs have been administered preoperatively in some cases to reduce tumor size [3, 4].

Pasireotide (PAS) is a novel multireceptor-targeting SRL that differentiates itself from first-generation SRLs by its affinity for multiple subtypes, including SSTR1, 2, 3, and 5, with a particularly high affinity for SSTR5 [5]. This distinctive receptor affinity profile has been shown to enhance the efficacy of the drug against both GH-producing and ACTH-producing PitNETs [6]. Nevertheless, it should be noted that this medication may potentially induce an elevation in blood glucose levels in some patients [7]. Previous reports from overseas have indicated that the majority of cases of hyperglycemia are mild to moderate and do not necessitate treatment or can be controlled with biguanides, incretin-related agents, other oral hypoglycemic agents, or insulin [7-9]. Some experts recommend biguanides as the initial therapeutic option, while others advocate for incretin-related drugs. However, there is currently no consensus regarding the optimal first-line drug [7-9]. Furthermore, there is a paucity of evidence regarding the optimal pharmacotherapy for East Asians, who exhibit a diminished capacity to secrete insulin from pancreatic beta cells relative to Caucasians [10].

Here, we report two cases of acromegaly. The initial case study demonstrated the short-term impact of PAS administration on glucose tolerance, as monitored meticulously through continuous glucose monitoring (CGM). The second case study investigated the long-term impact of PAS administration on glucose tolerance during the first six years after initiation, as well as its tumor-shrinking and hormone-improving effects. In the latter case, the administration of different GLP-1RAs at different times was successful in controlling blood glucose levels. In this report, we provide detailed information on the effects of GLP-1RAs on PAS-induced hyperglycemia.

Case Presentations

Case 1

A 58-year-old woman presented with no relevant complaints. The patient had a history of hypertension and dyslipidemia at the age of 45 years and osteoarthritis of the hip at the age of 55 years. She had been taking amlodipine 5 mg/day, losartan potassium 50 mg/day, hydrochlorothiazide 12.5 mg/day, atorvastatin 5 mg/day, and fexofenadine 120 mg/day. At the age of 41 years, she noticed that her rings and shoes were no longer fit, leading her to seek medical consultation at the age of 58 years. The patient exhibited the hallmark symptoms of acromegaly and displayed elevated GH levels. A head computed tomography (CT) scan revealed the presence of pituitary tumor, resulting in the patient being referred to our department for further evaluation and management.

On physical examination, she had a height of 156.8 cm, a weight of 57.6 kg (BMI: 23.4 kg/m²), a blood pressure of 153/92 mmHg, and a pulse of 85 bpm. The patient displayed the clinical manifestations of acromegaly and exhibited a positive fist test result. The initial laboratory tests yielded the following results: a glucose level of 105 mg/dL, hemoglobin A1c (HbA1c) of 6.5%, GH of 13.6 ng/mL, and IGF-1 of 513 ng/mL (+5.4 SD) (Table 1). Magnetic resonance imaging (MRI) revealed a 27 mm heterogeneous tumor that extended laterally into the sphenoid sinus (Fig. 1A, B). In order to reduce the size of the tumor, preoperative therapy was initiated with a 40 mg/month intramuscular injection of PAS. Endocrine testing revealed no notable suppression of GH following a 75 g oral glucose tolerance test (OGTT), and a paradoxical elevation of GH was observed at 30 min during the thyrotropin-releasing hormone (TRH) test. The bromocriptine challenge test showed no notable suppression of GH. However, the octreotide challenge test indicated a reduction in GH to 73.3% of the baseline level at 4 hours (Table 2). Subsequently, a FreeStyle Libre^® was employed for CGM during the administration of PAS. Immediately following the initiation of PAS, a notable elevation in glucose levels was observed, particularly in the postprandial period (Fig. 2A). On the sixth day of PAS therapy, an increase in fasting glucose levels was observed in addition to postprandial hyperglycemia (Fig. 2B). Subcutaneous administration of 0.75 mg/week dulaglutide (Dula), a GLP-1RA, was initiated as a treatment. By the third day following the commencement of the Dula administration, a reduction in postprandial hyperglycemia with diminished fluctuations in glucose levels was observed (Fig. 2C). The administration of PAS resulted in a reduction in the size of the tumor. Subsequently, the patient underwent a transsphenoidal tumor resection and was discharged from the hospital (Fig. 1C, D).

Table 1 Laboratory data of Case 1

		Reference range
White blood cell (/μL)	7,300	3,300–8,600
Red blood cell (/μL)	382 × 104	386–492 × 104
Hemoglobin (g/dL)	11.0	11.6–14.8
Hematocrit (%)	34.0	35.1–44.4
Platelet (/μL)	32.8 × 104	15.8–34.8 × 104
Total protein (g/dL)	7.4	6.6–8.1
Albumin (g/dL)	4.3	4.1–5.1
Total bilirubin (mg/dL)	0.3	0.4–1.5
AST (U/L)	17	13–30
ALT (U/L)	12	7–23
LDH (U/L)	253	124–222
ALP (U/L)	459	106–322
γ–GTP (U/L)	14	9–32
BUN (mg/dL)	10	8–20
Creatinine (mg/dL)	0.43	0.46–0.79
Uric acid (mg/dL)	2.9	–7.0
Total cholesterol (mg/dL)	197	125–219
HDL cholesterol (mg/dL)	62	40–
Triglyceride (mg/dL)	96	35–149
Na (mEq/L)	141	138–145
K (mEq/L)	3.8	3.6–4.8
Cl (mEq/L)	103	101–108
Ca (mg/dL)	9.6	8.8–10.1
IP (mg/dL)	3.3	2.7–4.6
BNP (pg/mL)	18.9	–18.4
FPG (mg/dL)	105	70–109
CPR (ng/mL)	1.96	0.67–2.48
HbA1c (%)	6.5	4.9–6.0
GH (ng/mL)	13.60	0.13–9.88
IGF-1 (ng/mL)	513 (+5.4 SD)	81–218 (Female)
TSH (μIU/mL)	1.27	0.35–4.94
Free T4 (ng/dL)	1.05	0.70–1.48
Free T3 (pg/mL)	2.2	1.88–3.18
PRL (ng/mL)	43.86	5.18–26.53
ACTH (pg/mL)	27.5	–63.3
Cortisol (μg/dL)	12.1	7.1–19.6
LH (mIU/mL)	6.55
FSH (mIU/mL)	32.62
Testosterone (ng/mL)	0.13	0.30–1.28
Estradiol (pg/mL)	12
AVP (pg/mL)	0.8

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; γ-GTP, γ-glutamyl transpeptidase; BUN, blood urea nitrogen; HDL, high density lipoprotein; FPG, fasting plasma glucose; CPR, C-peptide immunoreactivity; HbA1c, hemoglobin A1c; BNP, brain natriuretic peptide; GH, growth hormone; IGF-1, insulin-like growth factor 1; TSH, thyroid stimulating hormone; T4, thyroxine; T3, triiodothyronine; PRL, prolactin; ACTH, adrenocorticotropic hormone; LH, luteinizing hormone;

FSH, follicle stimulating hormone; AVP, arginine vasopressin

Fig. 1  Pituitary contrast-enhanced MRI findings in Case 1 (arrows)

A, C. MRI image of Coronal section. B, D. MRI image of Sagittal section. A, B. Before transsphenoidal surgery. The tumor is heterogeneous internally, measuring 18.9 × 34.4 × 36.1 mm. It has destroyed the floor of the sella turcica and extended into the sphenoid sinus and has extended laterally. C, D. After transsphenoidal surgery. The tumor was totally removed.

Table 2 Loading test results of Case 1

75 g OGTT
Time (min)	0	15	30	60	90	120
Glucose (mg/dL)	109	161	169	227	214	204
GH (ng/mL)	15.70	14.80	14.30	18.10	19.40	19.20
TRH test (0.5 mg)
Time (min)	0	30	60	90	120
GH (ng/mL)	16.20	25.40	18.60	15.80	16.40
PRL (ng/mL)	54.56	56.59	56.64	56.56	55.01
Bromocriptine challenge test (2.5 mg)
Time (hr)	0	2	3	6	9	12	24
GH (ng/mL)	14.70	12.70	11.60	13.90	16.60	20.60	10.00
Octreotide challenge test (50 μg)
Time (hr)	0	2	3	6	9	12	24
GH (ng/mL)	10.20	3.46	2.72	3.22	4.10	11.30	13.90

Abbreviations: OGTT, oral glucose tolerance test; TRH, thyrotropin-releasing hormone

Fig. 2  Glucose levels measured by CGM before and after the introduction of PAS and after the start of dulaglutide in Case 1

A. Glucose levels before PAS introduction (blue line) and on the day of PAS introduction (day 0; yellow line). An increase in postprandial glucose level was observed immediately after PAS introduction (magenta area). B. Glucose levels on day 6 of PAS introduction (day 6; magenta line). An increase in preprandial and postprandial glucose level was observed compared to before PAS introduction (magenta area). C. Glucose levels on day 3 after introduction of PAS and start of dulaglutide (orange line). There was a marked improvement in postprandial glucose level compared to day 6 after the introduction of PAS (blue area). Abbreviation: PAS, pasireotide

Case 2

A 38-year-old woman presented with menstrual irregularities and visual disturbances. She first experienced menstrual irregularities at 33 years of age and visual abnormalities at 37 years of age. At the age of 38 years, an ophthalmologist diagnosed bilateral hemianopia, prompting referral for further investigation and treatment.

Upon examination, the patient’s height was 164.1 cm, with a BMI of 24.7 kg/m², and she exhibited features consistent with acromegaly including macroglossia and thyroid enlargement. The initial laboratory test results were as follows: total cholesterol, 221 mg/dL; triglycerides, 292 mg/dL; fasting plasma glucose, 124 mg/dL; and HbA1c, 6.3%. Hormonal studies revealed the following results: thyroid stimulating hormone (TSH) 1.373 μIU/mL, luteinizing hormone (LH) <0.07 mIU/mL, follicle stimulating hormone (FSH) 0.70 mIU/mL, prolactin (PRL) 16.24 ng/mL, GH 33.8 ng/mL, and IGF-1 865.4 ng/mL (+9.1 SD) (Table 3).

Table 3 Laboratory data of Case 2

		Reference range
White blood cell (/μL)	7,200	3,300–8,600
Red blood cell (/μL)	421 × 104	386–492 × 104
Hemoglobin (g/dL)	12.9	11.6–14.8
Hematocrit (%)	39.2	35.1–44.4
Platelet (/μL)	22.5 × 104	15.8–34.8 × 104
Total protein (g/dL)	8.1	6.6–8.1
Albumin (g/dL)	4.8	4.1–5.1
Total bilirubin (mg/dL)	0.8	0.4–1.5
AST (U/L)	16	13–30
ALT (U/L)	13	7–23
LDH (U/L)	176	124–222
ALP (U/L)	240	106–322
γ-GTP (U/L)	12	9–32
BUN (mg/dL)	12	8–20
Creatinine (mg/dL)	0.66	0.46–0.79
Uric acid (mg/dL)	5.0	–7.0
Total cholesterol (mg/dL)	221	125–219
Triglyceride (mg/dL)	292	35–149
Na (mEq/L)	145	138–145
K (mEq/L)	3.9	3.6–4.8
Cl (mEq/L)	106	101–108
FPG (mg/dL)	124	70–109
HbA1c (%)	6.3	4.9–6.0
GH (ng/mL)	33.80	0.13–9.88
IGF-1 (ng/mL)	865.4 (+9.1 SD)	81–218 (Female)
TSH (μIU/mL)	1.37	0.35–4.94
Free T4 (ng/dL)	0.93	0.70–1.48
Free T3 (pg/mL)	2.34	1.88–3.18
PRL (ng/mL)	16.24	5.18–26.53
ACTH (pg/mL)	21.4	–63.3
Cortisol (μg/dL)	8.1	7.1–19.6
LH (mIU/mL)	<0.07
FSH (mIU/mL)	0.70
Testosterone (ng/mL)	0.70	0.30–1.28
Estradiol (pg/mL)	11

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; γ-GTP, γ-glutamyl transpeptidase; BUN, blood urea nitrogen; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; GH, growth hormone; IGF-1, insulin-like growth factor 1; TSH, thyroid stimulating hormone; T4, thyroxine; T3, triiodothyronine; PRL, prolactin; ACTH, adrenocorticotropic hormone; LH, luteinizing hormone; FSH, follicle stimulating hormone

Endocrine testing revealed no notable suppression of GH following a 75 g OGTT, with paradoxical GH elevation observed at 30 min during the TRH test. The bromocriptine challenge test demonstrated a 46.3% reduction in GH levels compared to the baseline at 6 h, whereas the octreotide challenge test resulted in a 79.0% reduction in GH levels at 4 h (Table 4).

Table 4 Loading test results of Case 2

75 g OGTT
Time (min)	0	30	60	90	120
Glucose (mg/dL)	99	179	218	226	212
GH (ng/mL)	27.20	30.30	25.60	20.40	17.50
TRH test (0.5 mg)
Time (min)	0	30	60	90	120
GH (ng/mL)	29.40	246.00	113.00	70.20	58.10
PRL (ng/mL)	18.72	48.64	32.48	26.86	22.48
Bromocriptine challenge test (2.5 mg)
Time (hr)	0	2	4	6	8	12	24
GH (ng/mL)	48.20	29.50	28.40	25.90	30.20	34.00	36.20
Octreotide challenge test (50 μg)
Time (hr)	0	2	4	6	8	12	24
GH (ng/mL)	33.60	7.54	7.03	7.86	8.55	12.80	39.20

Abbreviations: OGTT, oral glucose tolerance test; TRH, thyrotropin-releasing hormone

A transsphenoidal resection of the tumor was performed. Postoperative MRI revealed tumor shrinkage with the persistence of some residual tumors, and GH and IGF-1 levels remained elevated (Fig. 3A, B, Table 5). Immunohistochemistry of the resected tumor revealed positive staining for GH, with weakly positive for PRL, and negative staining for TSH, adrenocorticotropic hormone (ACTH), FSH, and LH (Fig. 4A–F).

Fig. 3  Postoperative MRI findings of Case 2 pituitary gland (arrows)

A, C, E. MRI image of Coronal section. B, D, F. MRI image of Sagittal section. A, B. After transsphenoidal surgery. Although the tumor was reduced by transsphenoidal surgery, residual tumor (24.9 × 27.5 × 26.2 mm) was observed. C, D. Before PAS treatment (at the age of 46). Cystic degeneration within the tumor compressing the third ventricle. E, F. Six years after the initiation of PAS treatment (at the age of 52). The cystic degeneration of the tumor was absorbed, and a reduction in tumor size was observed.

Table 5 Laboratory data of Case 2 after surgery

		Reference range
White blood cell (/μL)	5,500	3,300–8,600
Red blood cell (/μL)	399 × 104	386–492 × 104
Hemoglobin (g/dL)	12.1	11.6–14.8
Hematocrit (%)	37.3	35.1–44.4
Platelet (/μL)	32.1 × 104	15.8–34.8 × 104
Total protein (g/dL)	8.5	6.6–8.1
Albumin (g/dL)	5.2	4.1–5.1
Total bilirubin (mg/dL)	1.0	0.4–1.5
AST (U/L)	15	13–30
ALT (U/L)	11	7–23
LDH (U/L)	150	124–222
ALP (U/L)	242	106–322
γ-GTP (U/L)	17	9–32
BUN (mg/dL)	10	8–20
Creatinine (mg/dL)	0.59	0.46–0.79
Na (mEq/L)	144	138–145
K (mEq/L)	4.0	3.6–4.8
Cl (mEq/L)	103	101–108
FPG (mg/dL)	106	70–109
GH (ng/mL)	33.50	0.13–9.88
IGF-1 (ng/mL)	528 (+6.1 SD)	81–218 (Female)
TSH (μIU/mL)	1.05	0.35–4.94
Free T4 (ng/dL)	0.77	0.70–1.48
Free T3 (pg/mL)	1.96	1.88–3.18
PRL (ng/mL)	3.85	5.18–26.53
ACTH (pg/mL)	12.9	–63.3
Cortisol (μg/dL)	6.3	7.1–19.6
LH (mIU/mL)	0.08
FSH (mIU/mL)	1.97

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; γ-GTP, γ-glutamyl transpeptidase; BUN, blood urea nitrogen; FPG, fasting plasma glucose; GH, growth hormone; IGF-1, insulin-like growth factor 1; TSH, thyroid stimulating hormone; T4, thyroxine; T3, triiodothyronine; PRL, prolactin; ACTH, adrenocorticotropic hormone; LH, luteinizing hormone; FSH, follicle stimulating hormone

Fig. 4  Tumor immunohistochemical staining images of Case 2 (original magnification × 100)

A. GH staining. B. PRL staining. C. TSH staining. D. ACTH staining. E. FSH staining. F. LH staining. GH was positive, PRL was weakly positive, and TSH, ACTH, FSH, and LH were negative.

Abbreviations: GH, growth hormone; PRL, prolactin; TSH, thyroid stimulating hormone; ACTH, adrenocorticotropic hormone; FSH, follicle stimulating hormone; LH, luteinizing hormone

Postoperatively, the patient was treated with octreotide long-acting release 40 mg/month intramuscular injection, a first-generation SRL, pegvisomant 10 mg/day subcutaneous injection, and cabergoline 0.25 mg/week orally for the residual tumor. Insulin therapy was initiated three years post-surgery when the patient joined a SOM230 trial (age 42–44) and exhibited hyperglycemia. MRI revealed the presence of cystic degeneration within the tumor, which was compressing the third ventricle (Fig. 3C, D). Prior to the initiation of PAS treatment, pegvisomant was discontinued due to side effects, including weight gain, and cabergoline was discontinued due to its limited efficacy in lowering IGF-1 levels. At 46 years of age, PAS treatment was initiated to control the residual tumor and IGF-1 levels.

Following PAS initiation at 20 mg/month, the HbA1c levels increased from 6.6% to 7.8% (Fig. 5A). Consequently, the insulin dosage was increased, and Dula 0.75 mg weekly was initiated, gradually improving the HbA1c to 7.2%. Subsequently, the dosage of PAS was increased to 40 mg/month.

Fig. 5  Short-term and long-term blood glucose control after the introduction of PAS in Case 2

A. Short-term blood glucose control after introduction of PAS. After introduction of PAS 20 mg, the C-peptide index decreased, and after the dose was increased to 40 mg, it decreased further. After introduction of PAS 20 mg, HbA1c increased to 7.8%, and when dulaglutide was started, a trend of improvement in HbA1c was observed. B. Long-term blood glucose control 6 years after introduction of PAS. In pituitary MRI tumor images, tumor size was reduced after 6 years compared to immediately after starting treatment. There was a significant decrease in CPI in a dose-dependent manner with PAS. There was no significant difference in CPI between the different types of GLP-1RA. However, we occasionally observed an increase in CPI when administering semaglutide 1 mg (dotted red circle). C. A dose-dependent decrease in IGF-1 was observed with PAS administration. IGF-1 SD scores significantly decreased at PAS doses of 40 mg and 60 mg compared to baseline (p = 0.0073 and p < 0.0001, respectively).

Data are shown as median (interquartile range). The difference between the groups was evaluated using the student’s t-test. Abbreviations: PAS, pasireotide; HbA1c, hemoglobin A1c; GLP-1RA, glucagon-like peptide-1 receptor agonist; MRI, magnetic resonance imaging; IGF-1, insulin-like growth factor 1; IRMA, immunoradiometric assay; ECLIA, electro chemiluminescence immunoassay; Dula, dulaglutide; Lira, liraglutide; Sema, semaglutide

Following the administration of PAS, a decrease in the C-peptide index (CPI), an indicator of endogenous insulin secretion, was observed. Pre- and post-PAS 75 g OGTT results showed a decrease in CPI from 1.1 to 0.47 and in the Insulinogenic Index from 0.82 to 0.46, suggesting a reduction in both basal and postprandial endogenous insulin secretion following PAS administration (Table 6).

Table 6 75 g OGTT results of Case 2 before and after PAS introduction

Before PAS introduction: C-peptide Index = 1.1, Insulinogenic Index = 0.82
Time (min)	0	15	30	60	120
Glucose (mg/dL)	151	174	220	308	296
IRI (μU/mL)	8.90	11.30	15.60	47.20	57.90
CPR (ng/mL)	1.73	2.00	2.30	4.36	7.60
After PAS introduction: C-peptide Index = 0.47, Insulinogenic Index = 0.46
Time (min)	0	15	30	60	120
Glucose (mg/dL)	191	215	269	320	261
IRI (μU/mL)	2.90	3.40	8.70	16.10	36.80
CPR (ng/mL)	0.89	0.99	1.25	2.30	4.78

Abbreviations: OGTT, oral glucose tolerance test; PAS, pasireotide; IRI, immunoreactive insulin; CPR, C-peptide immunoreactivity.

The long-term treatment with PAS (Fig. 5B) resulted in a dose-dependent reduction in IGF-1 SD scores at PAS doses of 40 and 60 mg in comparison to the baseline (Fig. 5C). At the PAS dose of 40 mg, the median IGF-1 SD score was +4.0 (interquartile range: 3.5–4.1), and at 60 mg, it was +2.9 (interquartile range: 2.6–3.3). Both values were significantly lower than the baseline score of +4.9 (interquartile range: 4.8–5.0) (p = 0.0073 and p < 0.0001, respectively). In addition, the evaluation of CPI at various PAS concentrations revealed a significant dose-dependent decrease in endogenous insulin secretion (Fig. 5B, see C-peptide index).

MRI findings indicated notable tumor shrinkage at six years post-treatment compared to the initial pre-treatment scan (Fig. 3E, F). Over the course of the long-term PAS treatment, the cystic changes were likely absorbed and mostly disappeared over the 6-year period, and the tumor regressed, particularly in the longitudinal direction (Fig. 3E, F and Fig. 5B, see Pituitary MRI image).

Given the observed increase in HbA1c, the total insulin dose was adjusted and glucose control was maintained using GLP-1RAs. During the course of treatment period, the patients were switched to treatment with 0.75 mg/week of dulaglutide subcutaneous injection, 0.6 mg/day of liraglutide subcutaneous injection, and 0.5 mg–1 mg/week of semaglutide subcutaneous injection. Although no obvious significant differences in CPI were observed among the drug types, there was an increase in CPI with 1 mg semaglutide (Fig. 5B). Overall, the combination of PAS and semaglutide has demonstrated efficacy in reducing tumor size and improving IGF-1 levels. Moreover, the patient’s glycemic control has been maintained, thus allowing for the continuation of PAS treatment.

Discussion

These two case studies demonstrate the complexity of managing acromegaly with PAS, particularly in terms of the adverse effects of hyperglycemia. The early hyperglycemia observed in the first case, particularly postprandial hyperglycemia, indicates the importance of CGM for effective glucose level control during PAS treatment. In the second case, a dose-dependent reduction in endogenous insulin secretion was observed following prolonged treatment with PAS. The short- and long-term effects of PAS on blood glucose levels indicate that GLP-1RAs may be an effective means of improving hyperglycemia caused by PAS (Graphical Abstract).

Graphical Abstract

In clinical trials comparing PAS LAR with first-generation SRLs (octreotide LAR and lanreotide), PAS LAR demonstrated higher rates of biochemical control in acromegaly, though with comparable tumor-shrinking effects [8, 11]. Notably, approximately 20% of patients who exhibited an inadequate response to octreotide LAR or lanreotide experienced additional tumor shrinkage after switching to PAS [9]. While both PAS and first-generation SRLs show comparable overall efficacy in tumor reduction, PAS offers distinct advantages for specific patient subgroups. For these patients, the benefits of PAS as a treatment option are likely to be of considerable significance. Furthermore, in certain cases, such as young patients with few metabolic complications or those with large tumors, PAS may be the preferred initial treatment option [1]. The two cases presented in this study both involved large, invasive tumors, which supports the selection of PAS as a treatment option. In light of the genomic and clinical heterogeneity of GH-producing pitNETs [12], future research should focus on the identification of predictors of PAS response, with the aim of optimizing patient selection.

A detailed analysis of glucose levels was conducted using CGM in the first case, revealing a rapid elevation in blood glucose levels following the administration of PAS, particularly after meals. Glucagon-producing alpha cells of the pancreas predominantly express SSTR2, whereas insulin-producing beta cells predominantly express SSTR1 and SSTR5 [13]. PAS, owing to its high affinity for SSTR5, markedly suppresses insulin secretion from beta cells; however, it is thought to have only a minimal impact on glucagon secretion from alpha cells. In addition, the administration of PAS has been reported to lower blood concentrations of GLP-1 and GIP, suggesting the presence of SSTRs in K and L cells of the small intestine [14]. Based on these findings, it is hypothesized that PAS induces hyperglycemia by influencing the secretion of incretins and insulin secretion. Indeed, in clinical studies of pasireotide in patients with acromegaly, although the results varied from report to report, hyperglycemia was observed in 40–90% of cases, diabetes in 30–70% of cases, and HbA1c increased compared to baseline (Table 7). In regard to the correlation between PAS concentration and glucose metabolism, Henry et al. observed no significant differences in glucose, insulin, glucagon, GLP-1, or GIP levels between patients receiving varying doses of PAS (600 μg vs. 900 μg twice daily) [14]. This indicates that there may not be a simple, dose-dependent correlation between blood PAS concentration and postprandial blood glucose levels. The precise mechanism underlying the acute postprandial hyperglycemia observed on day 0 in Case 1 remains unclear. However, it is plausible that a compensatory mechanism was triggered in response to the initial PAS exposure. Further research is required to elucidate the precise mechanism underlying this early blood glucose response.

Table 7 Previous reports of glycemic effect and medication in clinical studies of pasireotide in patients with acromegaly

Clinical study	N	Incidence of hyperglycemia (IFG, IGT, diabetes)		Incidence of diabetes		Changes in HbA1c levels		Medication at the end of study
		Baseline	At the end of study	Baseline	At the end of study	Baseline	At the end of study	Percentage	Most used medication
Colao et al. (2014) [8]	178	not reported	57.3%	not reported	44.4%	not reported	not reported	44.4%	metformin and SU
Gadelha et al. (2014) [9]	125	83.8%	64.0%	66.2%	not reported	not reported	not reported	38.4%	metformin, insulin and glimepiride
Sheppard et al. (2015) [15]	178	32.6%	62.9%	3.9%	47.8%	not reported	not reported	not reported	not reported
Tahara et al. (2017) [10]	33	not reported	42.4%	not reported	24.2%	6.1%	7.0%	not reported	DPP-4 inhibitor and insulin
Muhammad et al. (2018) [16]	61	not reported	98.4%	68.9%	77.0%	6.0 (5.8–6.1)%	7.0 (6.6–7.4)%	73.8%	metformin and DPP-4 inhibitor
Shimon et al. (2018) [17]	35	not reported	62.9%	31.4%	48.6%	6.1 ± 1.1%	6.7 ± 1.3%	48.6%	not reported
Gadelha et al. (2020) [18]	123	48.8%	76.4%	42.3%	62.6%	not reported	not reported	not reported	not reported
Colao et al. (2020) [19]	173	48.0%	69.0%	32.3%	64.3%	not reported	Diabetic: 7.0 ± 1.1% (40 mg), 7.9 ± 1.9% (60 mg) Pre-diabetic: 6.1 ± 0.6% (40 mg), 6.7 ± 2.1% (60 mg) Normal glucose tolerance: 5.9 ± 0.1% (40 mg), 6.8 ± 1.0% (60 mg)	not reported	metformin, DPP-4 inhibitor, SU and insulin
Witek et al. (2021) [20]	39	61.6%	92.4%	10.3%	46.2%	5.6 (5.0–7.5)%	6.2 (5.0–9.8)%	66.7%	metformin, GLP-1 RA, DPP-4 inhibitor and basal insulin
Chiloiro et al. (2021) [21]	40	50.0%	85.3%	14.7%	32.4%	not reported	not reported	not reported	not reported
Akirov et al. (2021) [22]	19	70.6%	84.2%	29.4%	64.7%	6.0 ± 0.8%	6.5 ± 1.0%	86.7%	metformin, DPP-4 inhibitor, and SU
Stelmachowska-Banas et al. (2022) [23]	26	88.5%	96.2%	15.4%	42.3%	5.9 ± 0.4%	6.5 ± 0.6%	not reported	metformin, DPP-4 inhibitor, and SU
Wolf et al. (2022) [24]	33	45.5%	90.9%	6.1%	36.4%	5.8 ± 0.4%	6.8 ± 1.7%	42.4%	metformin, GLP-1 RA, DPP-4 inhibitor, SU and insulin
Gadelha et al. (2023) [25]	50	64.0%	72.0%	44.0%	72.0%	5.9%	7.2%	72.0%	metformin, DPP-4 inhibitor, SU, insulin and liraglutide
Corica et al. (2024) [26]	21	33.3%	90.5%	14.3%	66.7%	5.7 (5.5–5.9)%	6.0 (5.7–7.0)%	42.9%	metformin, glinide, and DPP-4 inhibitor

Data were shown as mean or mean ± SD or median (25th–75th percentile). Abbreviations: IFG, impaired fasting glucose; IGT, impaired glucose tolerance; HbA1c, hemoglobin A1c; SU, sulfonylurea; DPP-4, dipeptidyl peptidase-4; GLP-1 RA, glucagon-like peptide-1 receptor agonist

In Japan, the “Side Effect Countermeasures Guide for the Proper Use of Signifor LAR” recommends that, in cases where the patient with acromegaly has a different doctor for diabetes, the doctor for diabetes should be consulted prior to initiating treatment with PAS [27]. Additionally, it is advised that patients without diabetes and with insulin- naïve diabetes measure their fasting blood glucose levels on a weekly basis for the initial month after the initial dose, and that insulin-treated patients monitor their blood glucose levels through self-monitoring of blood glucose (SMBG) [27]. For patients without diabetes and without insulin treatment, it is recommended that fasting blood glucose levels be measured once or twice a week for a period of 2–3 months following the initial dose. For patients undergoing insulin therapy, it is recommended that blood glucose levels be monitored through self-monitoring of blood glucose (SMBG) [27].

Our case report and the results of existing research on PAS administration have demonstrated that the commencement of PAS administration results in a reduction in basal insulin secretion. Accordingly, there is a potential for the occurrence of both fasting and postprandial hyperglycemia [14]. Therefore, monitoring fasting blood glucose alone, as indicated in the current guidelines, is inadequate, and CGM is highly beneficial for promptly detecting fasting and postprandial hyperglycemia following PAS administration. In our study, a dose-dependent decrease in endogenous insulin secretion was observed after PAS administration, which is consistent with the known pharmacodynamic properties of PAS. This is due to the fact that PAS inhibits insulin secretion by binding to SSTR5 in pancreatic beta cells [14].

Given the potential for high doses of PAS to exacerbate glucose intolerance, it is imperative that clinicians carefully monitor blood glucose levels as well as markers of insulin secretion, such as the CPI and insulin secretion index, especially when escalating the dose. If a decline in insulin secretion is identified early, timely interventions to optimize blood glucose control may be implemented, including the introduction of GLP-1RAs, the initiation or adjustment of diabetes medications, and a reduction in the dose of PAS. These findings are of particular significance for the management of acromegaly in East Asians, who are known to have relatively lower pancreatic beta-cell function than Caucasians [10]. This highlights the importance of blood glucose control in PAS treatment, the necessity for improved monitoring methods, and a personalized treatment approach.

The administration of GLP-1RA has been demonstrated to be an effective method for the management of hyperglycemia caused by PAS. These drugs have been shown to directly target the reduction in incretin (GIP and GLP-1) secretion caused by PAS [7, 14, 28]. A review of the literature revealed no case reports of semaglutide in GLP-1RA for PAS-induced hyperglycemia, and this is the first such report. The administration of a high dose (1 mg) of semaglutide resulted in the observation of CPI recovery, which suggests that differences in efficacy may be dependent on the specific GLP-1RA type. A recent consensus statement by European endocrinologists recommends the use of incretin-related drugs such as dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1RAs in combination with metformin as a first-line treatment for hyperglycemia induced by PAS. In particular, the statement highlights the efficacy of GLP-1RAs, which have been proven to be effective in managing hyperglycemia caused by PAS [29]. It is therefore recommended that further large-scale studies should be conducted to investigate the efficacy of GLP-1RAs in the management of PAS-induced hyperglycemia in Asian patients, including Japanese patients. This may facilitate the optimization of blood glucose control in patients receiving PAS treatment. It should be noted that this study has certain limitations. First, while CGM was used to monitor glucose trends, it does not directly measure blood glucose levels. Therefore, invasive methods such as SMBG remain essential for accurate blood glucose assessment. Secondly, although the study primarily focused on the efficacy of GLP-1RAs, the concomitant use of other oral hypoglycemic agents and insulin underwent fluctuations throughout the course of treatment. Consequently, the effects of these additional therapies were not fully taken into account, which may have affected the outcomes attributed to GLP-1RA. In addition, the limited availability of preserved tumor tissue precluded further immunohistochemical analysis of SSTRs. Lastly, in patients with acromegaly and hyperglycemia, both PAS-induced hyperglycemia and insulin resistance associated with GH excess must be considered as contributing factors.

Our findings contribute to the growing body of evidence supporting the critical role of CGM and GLP-1RAs in the management of PAS-induced hyperglycemia. It would be beneficial for future studies to focus on long-term outcomes in Asian populations to assess the sustained efficacy of this combination therapy and its impact on the overall management of acromegaly.

Acknowledgements

We thank Wiley Editing Services (https://wileyeditingservices.com) for editing a draft of this manuscript.

Informed Consent

Consent was obtained from the patient for publication of this case report.

Funding Source

None of the authors received any specific grants related to this report from funding agencies in the public, commercial, or not-for-profit sectors.

Disclosure

None of authors have conflicts of interest to declare. Tomoaki Tanaka is a member of Endocrine Journal’s Editorial Board.

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