Hyperglycemia induced by pasireotide in patients with Cushing's disease or acromegaly

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hypoglycemia 1 endocrinologydiseases
metformin 11 endocrinologydiseasesdrugs
sitagliptin 1 endocrinologydiseasesdrugs
Insulin 1 endocrinologydiseasesdrugs
Pasireotide 13 endocrinologydiseasesdrugs
cortisol 7 endocrinologydiseasesdrugs
hyperglycemia 49 endocrinologydiseases
acromegaly 61 endocrinologydiseases
diabetes mellitus 2 endocrinologydiseases
glipizide 2 endocrinologydiseasesdrugs

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Insulin 13978 effects of pasireotide are primarily due to its tendency to reduce insulin and incretin secretion [[19]]. Insulin secretion is mediated in large part by sst2 and sst5 [[20], [21]], and glucagon secretion is mediated
Pasireotide 417 secretion resulting in comorbidities such as impaired glucose metabolism, diabetes and hypertension. Pasireotide is a new-generation, multireceptor-targeted somatostatin receptor ligand approved for CD (subcutaneous
Pasireotide 3947 full effect) is an option for patients with recurrent or persistent CD or acromegaly following surgery. Pasireotide is a new-generation, multireceptor-targeted somatostatin receptor ligand (SRL) approved for the treatment
Pasireotide 4306 patients who do not achieve control with surgery and/or for whom surgery is not an option [[5], [6]]. Pasireotide binds to several known somatostatin receptor (sst) subtypes that are expressed by corticotroph and somatotroph
Pasireotide 4762 to sst1 (30-fold), sst3 (5-fold), and sst5 (39-fold) and lower affinity to sst2 (3-fold) [[8], [9]]. Pasireotide also binds with higher affinity than lanreotide to sst1 (19-fold), sst3 (9-fold), and sst5 (106-fold)
Pasireotide 5619 pasireotide in patients with either acromegaly or CD.Clinical efficacy of pasireotide in CD and acromegaly Pasireotide SC in CDIn a phase 3 study of 162 patients with persistent or recurrent CD or newly diagnosed disease,
Pasireotide 6816 the study for 60 months achieved UFC levels at or below the upper limit of the normal range [[12]]. Pasireotide in acromegalyIn a phase 3 study of patients with acromegaly who were naive to medical therapy, significantly
Pasireotide 10507 AEsDiscontinuations due to hyperglycemia-related AEs (%)Colao et al. [[11]]Cushing’s diseasePhase 312 months Pasireotide SC (600, 900 µg b.i.d)73.0 %6.0Boscaro et al. [[16]]Cushing’s diseasePhase 2, extension6 monthsPasireotide
Pasireotide 10620 SC (600, 900 µg b.i.d)73.0 %6.0Boscaro et al. [[16]]Cushing’s diseasePhase 2, extension6 months Pasireotide SC (600 µg b.i.d; 900 µg with suboptimal control)68.4 %5.3Colao et al. [[13]]AcromegalyPhase 312 monthsPasireotide
Pasireotide 10741 (600 µg b.i.d; 900 µg with suboptimal control)68.4 %5.3Colao et al. [[13]]AcromegalyPhase 312 months Pasireotide LAR (40 mg; dose increase to 60 mg with suboptimal control)57.3 %3.4Gadelha et al. [[14]]AcromegalyPhase
Pasireotide 10881 to 60 mg with suboptimal control)57.3 %3.4Gadelha et al. [[14]]AcromegalyPhase 36 months or longer Pasireotide LAR (40, 60 mg)40 mg, 67.0 %60 mg, 61.0 %4.0Petersenn et al. [[15]]AcromegalyPhase 2, extension6 months
Pasireotide 11012 60 mg)40 mg, 67.0 %60 mg, 61.0 %4.0Petersenn et al. [[15]]AcromegalyPhase 2, extension6 months or longer Pasireotide SC (200, 400, 600 µg; 900 µg with suboptimal control)40.0 %10.0AE adverse event, b.i.d twice daily,
Pasireotide 14120 part by sst2 and sst5 [[20], [21]], and glucagon secretion is mediated primarily by sst2 [[21], [22]]. Pasireotide binds to sst2 and sst5 and binds with highest affinity to sst5, which is expressed not only by pituitary
Pasireotide 24773 is transient and not expected to cause long-term effects if pasireotide is discontinued.Conclusions Pasireotide is a viable medical therapy option for patients with CD or acromegaly but is associated with higher
cortisol 2640 adrenocorticotropic hormone (ACTH) in the former and growth hormone (GH) in the latter [[1]]. In CD, hyper cortisol emia is caused by the secretion of ACTH from a corticotroph pituitary tumor. In acromegaly, GH excess,
cortisol 2896 tumor, causes downstream hypersecretion of insulin-like growth factor 1 (IGF-1). Chronic elevation of cortisol (CD) and GH and IGF-1 (acromegaly) levels is associated with increased mortality risk and worsening
cortisol 3353 macroadenomas [[1], [3]].Surgery is considered first-line treatment and provides adequate control of cortisol levels in many patients with CD (65–90 %) [[4]] and GH and IGF-1 levels in patients with acromegaly
cortisol 5867 surgery, twice-daily injections of pasireotide SC provided rapid reductions in mean levels of urinary-free cortisol (UFC) that were sustained during treatment [[11]]. After 12 months of pasireotide 600 and 900 µg
cortisol 11681 could be uniquely linked to downstream effects associated with chronic exposure to elevated levels of cortisol or GH/IGF-1, respectively [[17], [18]]. Also, because studies of pasireotide in CD occurred before those
cortisol 13327 cells in patients with acromegaly with normal glucose tolerance [[18]]. Similarly, in CD, chronic hyper cortisol ism blocks the binding of insulin to peripheral tissues, resulting in insulin resistance, and inhibits
cortisol 13501 in insulin resistance, and inhibits the release of insulin by pancreatic beta cells [[17]]. Excess cortisol can also affect glucose metabolism in hepatic tissue by stimulating gluconeogenesis or indirectly inhibiting
glipizide 19801 with CD exemplified that control of hyperglycemia could be achieved with metformin in combination with glipizide and sitagliptin [[38]]. These results suggest that metformin is useful for some patients in treating
glipizide 20169 with pasireotide-induced hyperglycemia [[39]–[41]]. In these cases, treatment with insulin alone or glipizide with or without insulin was able to quickly reduce FPG levels. Dietary control or modification could
metformin 19114 glucose metabolism after only 6 days, which may have been too brief to observe long-term effects of metformin . For instance, metformin has been shown to increase glucagon-like peptide 1 (GLP-1) [[36]], which may
metformin 19139 only 6 days, which may have been too brief to observe long-term effects of metformin. For instance, metformin has been shown to increase glucagon-like peptide 1 (GLP-1) [[36]], which may at least partially compensate
metformin 19354 compensate for the reduction in GLP-1 associated with pasireotide [[19]]. Antidiabetic medication, primarily metformin , was administered in 38–48 % of patients in acromegaly trials [[13], [14], [26]]. Mean HbA1c levels
metformin 19614 therapy who developed pasireotide-induced hyperglycemia were <7 % after 12 months when treated with metformin alone or in combination with other ADMs [[37]]. A case study of a patient with CD exemplified that control
metformin 19771 A case study of a patient with CD exemplified that control of hyperglycemia could be achieved with metformin in combination with glipizide and sitagliptin [[38]]. These results suggest that metformin is useful
metformin 19862 achieved with metformin in combination with glipizide and sitagliptin [[38]]. These results suggest that metformin is useful for some patients in treating pasireotide-associated hyperglycemia.In some case study reports,
metformin 19992 patients in treating pasireotide-associated hyperglycemia.In some case study reports, treatment with metformin alone was insufficient in providing glycemic control to patients with pasireotide-induced hyperglycemia
metformin 21300 currently treated with insulin, and particularly for those with insulin resistance, it is recommended that metformin be initiated or continued if FPG > 126 g/dL or HbA1c is >6.5 % [[43]]. In cases in which patients
metformin 21450 FPG > 126 g/dL or HbA1c is >6.5 % [[43]]. In cases in which patients fail to achieve glycemic control with metformin , it is suggested that a DPP-4 inhibitor be added. A GLP-1 receptor agonist should replace the DPP-4
metformin 21752 provide glucose control, it is suggested that treatment with insulin be initiated while maintaining metformin treatment. Although no specific recommendations regarding pasireotide-induced hyperglycemia in patients
metformin 21918 regarding pasireotide-induced hyperglycemia in patients with acromegaly have been published, treatment with metformin plus a DPP-4 inhibitor, GLP-1 agonist, or insulin would most likely have similar efficacy.Monitoring
sitagliptin 19815 exemplified that control of hyperglycemia could be achieved with metformin in combination with glipizide and sitagliptin [[38]]. These results suggest that metformin is useful for some patients in treating pasireotide-associated
Select Disease Character Offset Disease Term Instance
acromegaly 93 Title: PituitaryHyperglycemia induced by pasireotide in patients with Cushing’s disease or acromegaly Julie M. SilversteinPublication date (epub): 7/2016Publication date (pmc-release): 7/2016Publication
acromegaly 266 date (pmc-release): 7/2016Publication date (ppub): /2016AbstractPurposeCushing’s disease (CD) and acromegaly are characterized by excessive hormone secretion resulting in comorbidities such as impaired glucose
acromegaly 564 multireceptor-targeted somatostatin receptor ligand approved for CD (subcutaneous [SC] injection formulation) and acromegaly (long-acting release [LAR] formulation). In clinical studies of pasireotide, hyperglycemia-related adverse
acromegaly 968 pasireotide-associated hyperglycemia.MethodsClinical trials evaluating pasireotide in patients with CD or acromegaly were reviewed.ResultsThe frequency of hyperglycemia-related AEs was lower in patients with acromegaly
acromegaly 1070 acromegaly were reviewed.ResultsThe frequency of hyperglycemia-related AEs was lower in patients with acromegaly treated with pasireotide LAR (57.3–67.0 %) than in patients with CD treated with pasireotide SC (68.4–73.0 %).
acromegaly 1218 (57.3–67.0 %) than in patients with CD treated with pasireotide SC (68.4–73.0 %). Fewer patients with acromegaly treated with pasireotide LAR discontinued therapy because of hyperglycemia-related AEs (Colao et al.
acromegaly 1704 Med 366(10):914–924, [11], 6.0 %). Hyperglycemia-related AEs occurred in 40.0 % of patients with acromegaly treated with pasireotide SC, and 10.0 % discontinued treatment because of hyperglycemia. Ongoing studies
acromegaly 1943 LAR in patients with CD and management of pasireotide-induced hyperglycemia in patients with CD or acromegaly (ClinicalTrials.gov identifiers NCT01374906 and NCT02060383, respectively) will address these key safety
acromegaly 2248 potentially influence the differences in reported rates of pasireotide-induced hyperglycemia in CD and acromegaly . Hyperglycemic effects associated with pasireotide have a predictable pattern, can be managed with antidiabetic
acromegaly 2460 antidiabetic agents, and are reversible upon discontinuation.IntroductionCushing’s disease (CD) and acromegaly are rare diseases characterized by the increased production of adrenocorticotropic hormone (ACTH) in
acromegaly 2728 In CD, hypercortisolemia is caused by the secretion of ACTH from a corticotroph pituitary tumor. In acromegaly , GH excess, most commonly from a somatotroph pituitary tumor, causes downstream hypersecretion of insulin-like
acromegaly 2928 hypersecretion of insulin-like growth factor 1 (IGF-1). Chronic elevation of cortisol (CD) and GH and IGF-1 ( acromegaly ) levels is associated with increased mortality risk and worsening comorbidities in both conditions [[1],
acromegaly 3454 cortisol levels in many patients with CD (65–90 %) [[4]] and GH and IGF-1 levels in patients with acromegaly (microadenomas, >85 %; macroadenomas, 40–50 %) [[3]]. Despite the success rates associated with
acromegaly 3640 success rates associated with surgery, 5–10 % of patients with CD [[4]] and 2–8 % of patients with acromegaly [[3]] will experience disease recurrence within 5 years after achieving postoperative hormone remission.
acromegaly 3918 radiation therapy has taken full effect) is an option for patients with recurrent or persistent CD or acromegaly following surgery.Pasireotide is a new-generation, multireceptor-targeted somatostatin receptor ligand
acromegaly 4126 ligand (SRL) approved for the treatment of patients with CD (subcutaneous [SC] formulation) [[5]] or acromegaly (long-acting release [LAR] formulation) [[6]]. It is indicated for patients who do not achieve control
acromegaly 5092 preferential binding to sst5 provides therapeutic rationale for its use in the treatment of CD and acromegaly . Although its efficacy in clinical studies has warranted consideration of pasireotide as the first treatment
acromegaly 5549 document hyperglycemia-related adverse events (AEs) associated with pasireotide in patients with either acromegaly or CD.Clinical efficacy of pasireotide in CD and acromegalyPasireotide SC in CDIn a phase 3 study of
acromegaly 5609 with pasireotide in patients with either acromegaly or CD.Clinical efficacy of pasireotide in CD and acromegaly Pasireotide SC in CDIn a phase 3 study of 162 patients with persistent or recurrent CD or newly diagnosed
acromegaly 6831 60 months achieved UFC levels at or below the upper limit of the normal range [[12]].Pasireotide in acromegaly In a phase 3 study of patients with acromegaly who were naive to medical therapy, significantly more
acromegaly 6877 upper limit of the normal range [[12]].Pasireotide in acromegalyIn a phase 3 study of patients with acromegaly who were naive to medical therapy, significantly more patients achieved biochemical control (GH < 2.5 ng/mL
acromegaly 7494 osteoarthralgia, paresthesia, headache) and quality of life.In another phase 3 study that enrolled patients with acromegaly who were inadequately controlled by other SRLs, monthly injections of pasireotide LAR 40 mg (15 %)
acromegaly 8260 fatigue, perspiration, paresthesia, and osteoarthralgia.The efficacy and safety of pasireotide SC in acromegaly have also been investigated. In a phase 2 extension study, 33 % of patients (3 of 9) achieved biochemical
acromegaly 8768 approximately doubled during the course of the study.Hyperglycemia associated with pasireotide in CD and acromegaly Clinical trials experienceIn clinical trials, the safety profile of pasireotide included AEs, mostly
acromegaly 9133 treatment with pasireotide is associated with a higher frequency of hyperglycemia in patients with CD or acromegaly [[11], [13], [14]]. The reported rates of hyperglycemia-related AEs and the percentage of patients who
acromegaly 9341 patients who discontinued therapy from such events differ across clinical studies of pasireotide in CD and acromegaly (Table 1). Further comparison of the rates shows that the frequency of hyperglycemia-related AEs was
acromegaly 9477 comparison of the rates shows that the frequency of hyperglycemia-related AEs was lower in patients with acromegaly who received pasireotide LAR (57.3–67.0 %) [[13], [14]] than in patients with CD who received pasireotide
acromegaly 9666 with CD who received pasireotide SC (68.4–73.0 %) [[11], [16]]. Interestingly, fewer patients with acromegaly who received pasireotide LAR discontinued treatment because of hyperglycemia-related AEs, as reported
acromegaly 10040 5.3 %) [[11], [16]]. In a clinical study that evaluated the efficacy and safety of pasireotide SC in acromegaly , hyperglycemia-related AEs occurred in 40.0 % of patients, and 10.0 % of patients discontinued treatment
acromegaly 10296 [[15]].Table 1Hyperglycemia-related AEs associated with pasireotide in clinical studies of Cushing’s disease or acromegaly StudyDiseaseStudy descriptionStudy durationDrug formulation (dosing)Hyperglycemia-related AEsDiscontinuations
acromegaly 11317 differences in the reported frequency of pasireotide-induced hyperglycemia among patients with CD or acromegaly . In clinical studies of acromegaly, the rates of pasireotide-induced hyperglycemia-related AEs were
acromegaly 11352 frequency of pasireotide-induced hyperglycemia among patients with CD or acromegaly. In clinical studies of acromegaly , the rates of pasireotide-induced hyperglycemia-related AEs were lower than those in CD (Fig. 1a).
acromegaly 11568 could be related to disease pathophysiology since the dysregulation of glucose metabolism in CD and acromegaly could be uniquely linked to downstream effects associated with chronic exposure to elevated levels of
acromegaly 11798 GH/IGF-1, respectively [[17], [18]]. Also, because studies of pasireotide in CD occurred before those in acromegaly , the benefit of physician experience could have led to lower rates of study discontinuation in the acromegaly
acromegaly 11908 acromegaly, the benefit of physician experience could have led to lower rates of study discontinuation in the acromegaly trials (Fig. 1b). This could be attributed to a better understanding of the mechanisms underlying pasireotide-induced
acromegaly 12096 mechanisms underlying pasireotide-induced hyperglycemia and its optimal management in patients with acromegaly or CD. Despite the higher frequency of hyperglycemia-related AEs associated with pasireotide than with
acromegaly 12238 frequency of hyperglycemia-related AEs associated with pasireotide than with other medical therapies for acromegaly or CD, results from other clinical studies suggest that the hyperglycemic effect associated with treatment
acromegaly 12715 hyperglycemia and b the frequency of discontinuations associated with hyperglycemia among patients with CD or acromegaly . AE adverse event, CD Cushing’s disease, LAR long-acting release, SC subcutaneous. Figure was created
acromegaly 12993 hyperglycemiaIt has been reported that impaired glucose metabolism observed in patients with CD or acromegaly is uniquely associated with disease pathophysiology. Chronic exposure to elevated GH and IGF-1 levels
acromegaly 13247 which may be counteracted by the compensatory hyperfunction of pancreatic beta cells in patients with acromegaly with normal glucose tolerance [[18]]. Similarly, in CD, chronic hypercortisolism blocks the binding
acromegaly 13811 greater understanding of the mechanisms that underlie the development of hyperglycemia in patients with acromegaly or CD treated with pasireotide. The hyperglycemic effects of pasireotide are primarily due to its tendency
acromegaly 14600 with pasireotide are unable to counterbalance the reduced insulin sensitivity caused by uncontrolled acromegaly or CD [[18]]. However, two mechanisms could explain why the hyperglycemic effect is transient. First,
acromegaly 15691 levels are parameters used to assess glycemic control [[25]]. In a clinical study of patients with acromegaly , it was reported that up to 45 % of patients with baseline FPG between 100 and 126 mg/dL had FPG levels
acromegaly 16087 patients who had normal HbA1c levels at baseline [[27]]. During the course of treatment in patients with acromegaly or CD, mean FPG levels peaked after 1 month of pasireotide and thereafter remained stable or slightly
acromegaly 16832 [[29]]. Similarly, the prevalence of impaired fasting glucose and diabetes are higher in patients with acromegaly compared with the general population, predisposing patients to a greater risk of developing hyperglycemia
acromegaly 17175 extent and severity of hyperglycemia associated with treatment. In a phase 3 study of patients with acromegaly , baseline FPG > 100 mg/dL correlated with the development of higher FPG and HbA1c levels and a higher
acromegaly 17644 disease control as a predictive factor, reductions in GH and IGF-1 in patients with newly diagnosed acromegaly who were treated with octreotide for 6 months without ADM were shown to correlate with change in HbA1c
acromegaly 17956 been studied. Other predictive risk factors associated with developing hyperglycemia in patients with acromegaly treated with pasireotide LAR include body mass index ≥25 kg/m2, diabetes at baseline, and history
acromegaly 18450 with ADMsAs previously discussed, in phase 3 studies of pasireotide SC in CD and pasireotide LAR in acromegaly , the majority of hyperglycemia-related AEs were mild to moderate in severity [[11], [13], [14]]. Even
acromegaly 18580 hyperglycemia-related AEs were mild to moderate in severity [[11], [13], [14]]. Even in patients with acromegaly with FPG > 250 mg/dL at baseline, ADM initiated within 2 weeks of the first dose of pasireotide
acromegaly 19411 [[19]]. Antidiabetic medication, primarily metformin, was administered in 38–48 % of patients in acromegaly trials [[13], [14], [26]]. Mean HbA1c levels in patients with acromegaly naive to medical therapy who
acromegaly 19484 38–48 % of patients in acromegaly trials [[13], [14], [26]]. Mean HbA1c levels in patients with acromegaly naive to medical therapy who developed pasireotide-induced hyperglycemia were <7 % after 12 months
acromegaly 21871 treatment. Although no specific recommendations regarding pasireotide-induced hyperglycemia in patients with acromegaly have been published, treatment with metformin plus a DPP-4 inhibitor, GLP-1 agonist, or insulin would
acromegaly 22064 agonist, or insulin would most likely have similar efficacy.Monitoring recommendationsPatients with CD or acromegaly who initiate, discontinue, or need dose adjustment of pasireotide should be proactively managed in accordance
acromegaly 23455 discontinuation of pasireotideClinical studies of pasireotide in healthy volunteers and in patients with CD or acromegaly suggest that the hyperglycemic effects associated with pasireotide have a predictable pattern and could
acromegaly 24335 pasireotide SC because of lack of response to treatment [[44]]. In a phase 3 clinical trial of patients with acromegaly who were treated with pasireotide, mean FPG and mean HbA1c levels were reduced to 104 mg/dL (mean value
acromegaly 24844 pasireotide is discontinued.ConclusionsPasireotide is a viable medical therapy option for patients with CD or acromegaly but is associated with higher rates of hyperglycemia and diabetes mellitus than other medical therapies.
acromegaly 25256 could be performed of baseline FPG and HbA1c levels across clinical studies of pasireotide in CD or acromegaly to further assess the predictability and manageability of pasireotide-induced hyperglycemia. A phase
acromegaly 25532 incretin-based therapy compared with insulin on glycemic control at 16 weeks in patients with CD or acromegaly (ClinicalTrials.gov identifier NCT02060383) [[46]]. Significant progress has been made over the years
acromegaly 25790 impaired glucose metabolism in patients is uniquely linked to the disease pathophysiology of CD and acromegaly and how pasireotide modulates insulin secretion and sensitivity. There is growing evidence to demonstrate
acromegaly 26070 hyperglycemia-related AEs associated with pasireotide during the course of treating patients with CD or acromegaly
diabetes mellitus 16655 factors of pasireotide-induced hyperglycemiaIn CD, the prevalence of impaired glucose tolerance or diabetes mellitus at diagnosis is 21–64 % and 20–47 %, respectively [[29]]. Similarly, the prevalence of impaired
diabetes mellitus 24912 option for patients with CD or acromegaly but is associated with higher rates of hyperglycemia and diabetes mellitus than other medical therapies. Further research is needed to determine optimal treatment strategies with
hyperglycemia 652 formulation) and acromegaly (long-acting release [LAR] formulation). In clinical studies of pasireotide, hyperglycemia -related adverse events (AEs) were frequently observed. This review highlights differences in reported
hyperglycemia 777 adverse events (AEs) were frequently observed. This review highlights differences in reported rates of hyperglycemia in pasireotide trials and discusses risk factors for and management of pasireotide-associated hyperglycemia.MethodsClinical
hyperglycemia 885 hyperglycemia in pasireotide trials and discusses risk factors for and management of pasireotide-associated hyperglycemia .MethodsClinical trials evaluating pasireotide in patients with CD or acromegaly were reviewed.ResultsThe
hyperglycemia 1017 trials evaluating pasireotide in patients with CD or acromegaly were reviewed.ResultsThe frequency of hyperglycemia -related AEs was lower in patients with acromegaly treated with pasireotide LAR (57.3–67.0 %) than
hyperglycemia 1290 (68.4–73.0 %). Fewer patients with acromegaly treated with pasireotide LAR discontinued therapy because of hyperglycemia -related AEs (Colao et al. in J Clin Endocrinol Metab 99(3):791–799, [13], 3.4 %; Gadelha et al. in
hyperglycemia 1790 patients with acromegaly treated with pasireotide SC, and 10.0 % discontinued treatment because of hyperglycemia . Ongoing studies evaluating pasireotide LAR in patients with CD and management of pasireotide-induced
hyperglycemia 1906 Ongoing studies evaluating pasireotide LAR in patients with CD and management of pasireotide-induced hyperglycemia in patients with CD or acromegaly (ClinicalTrials.gov identifiers NCT01374906 and NCT02060383, respectively)
hyperglycemia 2224 physician experience potentially influence the differences in reported rates of pasireotide-induced hyperglycemia in CD and acromegaly. Hyperglycemic effects associated with pasireotide have a predictable pattern,
hyperglycemia 5454 [[10]]. This review provides a summary of data from clinical studies and case reports that document hyperglycemia -related adverse events (AEs) associated with pasireotide in patients with either acromegaly or CD.Clinical
hyperglycemia 9096 However, compared with other SRLs, treatment with pasireotide is associated with a higher frequency of hyperglycemia in patients with CD or acromegaly [[11], [13], [14]]. The reported rates of hyperglycemia-related AEs
hyperglycemia 9186 frequency of hyperglycemia in patients with CD or acromegaly [[11], [13], [14]]. The reported rates of hyperglycemia -related AEs and the percentage of patients who discontinued therapy from such events differ across clinical
hyperglycemia 9424 pasireotide in CD and acromegaly (Table 1). Further comparison of the rates shows that the frequency of hyperglycemia -related AEs was lower in patients with acromegaly who received pasireotide LAR (57.3–67.0 %) [[13],
hyperglycemia 9740 Interestingly, fewer patients with acromegaly who received pasireotide LAR discontinued treatment because of hyperglycemia -related AEs, as reported in 2 separate trials (3.4 and 4.0 %), [[13], [14]] compared with patients
hyperglycemia 10052 [16]]. In a clinical study that evaluated the efficacy and safety of pasireotide SC in acromegaly, hyperglycemia -related AEs occurred in 40.0 % of patients, and 10.0 % of patients discontinued treatment because
hyperglycemia 10423 descriptionStudy durationDrug formulation (dosing)Hyperglycemia-related AEsDiscontinuations due to hyperglycemia -related AEs (%)Colao et al. [[11]]Cushing’s diseasePhase 312 monthsPasireotide SC (600, 900 µg
hyperglycemia 11277 underlying factors could contribute to differences in the reported frequency of pasireotide-induced hyperglycemia among patients with CD or acromegaly. In clinical studies of acromegaly, the rates of pasireotide-induced
hyperglycemia 11397 patients with CD or acromegaly. In clinical studies of acromegaly, the rates of pasireotide-induced hyperglycemia -related AEs were lower than those in CD (Fig. 1a). This could be related to disease pathophysiology
hyperglycemia 12038 This could be attributed to a better understanding of the mechanisms underlying pasireotide-induced hyperglycemia and its optimal management in patients with acromegaly or CD. Despite the higher frequency of hyperglycemia-related
hyperglycemia 12146 hyperglycemia and its optimal management in patients with acromegaly or CD. Despite the higher frequency of hyperglycemia -related AEs associated with pasireotide than with other medical therapies for acromegaly or CD, results
hyperglycemia 12605 pasireotide.Fig. 1Factors potentially affecting reported differences in a the frequency of pasireotide-induced hyperglycemia and b the frequency of discontinuations associated with hyperglycemia among patients with CD or acromegaly.
hyperglycemia 12675 frequency of pasireotide-induced hyperglycemia and b the frequency of discontinuations associated with hyperglycemia among patients with CD or acromegaly. AE adverse event, CD Cushing’s disease, LAR long-acting release,
hyperglycemia 12894 SC subcutaneous. Figure was created with Adobe Illustrator CC 2015Mechanisms of pasireotide-induced hyperglycemia It has been reported that impaired glucose metabolism observed in patients with CD or acromegaly is uniquely
hyperglycemia 13780 glycogen.Recently, there has been a greater understanding of the mechanisms that underlie the development of hyperglycemia in patients with acromegaly or CD treated with pasireotide. The hyperglycemic effects of pasireotide
hyperglycemia 16587 which then stabilize during the course of treatment.Predictive risk factors of pasireotide-induced hyperglycemia In CD, the prevalence of impaired glucose tolerance or diabetes mellitus at diagnosis is 21–64 % and
hyperglycemia 16935 acromegaly compared with the general population, predisposing patients to a greater risk of developing hyperglycemia [[30]]. This suggests that baseline glycemic status before the initiation of pasireotide treatment could
hyperglycemia 17098 status before the initiation of pasireotide treatment could be predictive of the extent and severity of hyperglycemia associated with treatment. In a phase 3 study of patients with acromegaly, baseline FPG > 100 mg/dL
hyperglycemia 17301 FPG > 100 mg/dL correlated with the development of higher FPG and HbA1c levels and a higher degree of hyperglycemia during pasireotide LAR treatment [[24]]. Moreover, it was reported that increasing the dose of pasireotide
hyperglycemia 17506 of pasireotide LAR from 40 to 60 mg was associated with a 21–36 % increased risk of developing hyperglycemia [[31], [32]]. Regarding disease control as a predictive factor, reductions in GH and IGF-1 in patients
hyperglycemia 17925 with pasireotide has not yet been studied. Other predictive risk factors associated with developing hyperglycemia in patients with acromegaly treated with pasireotide LAR include body mass index ≥25 kg/m2, diabetes
hyperglycemia 18143 at baseline, and history of dyslipidemia [[34]]. Because certain populations are at greater risk of hyperglycemia associated with pasireotide, proactive management and monitoring of these patients are critical for
hyperglycemia 18319 monitoring of these patients are critical for improving clinical outcomes.Management of pasireotide-induced hyperglycemia Optimal treatment with ADMsAs previously discussed, in phase 3 studies of pasireotide SC in CD and pasireotide
hyperglycemia 18478 discussed, in phase 3 studies of pasireotide SC in CD and pasireotide LAR in acromegaly, the majority of hyperglycemia -related AEs were mild to moderate in severity [[11], [13], [14]]. Even in patients with acromegaly with
hyperglycemia 18824 FPG, suggesting that early treatment intervention with ADMs could optimally manage pasireotide-induced hyperglycemia [[34]]. Metformin has been shown to be minimally effective in reducing pasireotide-induced hyperglycemia
hyperglycemia 18929 hyperglycemia [[34]]. Metformin has been shown to be minimally effective in reducing pasireotide-induced hyperglycemia in healthy volunteers [[35]]; however, this study measured effects on glucose metabolism after only
hyperglycemia 19554 HbA1c levels in patients with acromegaly naive to medical therapy who developed pasireotide-induced hyperglycemia were <7 % after 12 months when treated with metformin alone or in combination with other ADMs [[37]].
hyperglycemia 19734 in combination with other ADMs [[37]]. A case study of a patient with CD exemplified that control of hyperglycemia could be achieved with metformin in combination with glipizide and sitagliptin [[38]]. These results
hyperglycemia 19935 These results suggest that metformin is useful for some patients in treating pasireotide-associated hyperglycemia .In some case study reports, treatment with metformin alone was insufficient in providing glycemic control
hyperglycemia 20092 metformin alone was insufficient in providing glycemic control to patients with pasireotide-induced hyperglycemia [[39]–[41]]. In these cases, treatment with insulin alone or glipizide with or without insulin was
hyperglycemia 20336 levels. Dietary control or modification could also be important for management of pasireotide-induced hyperglycemia [[16], [42]]. In healthy volunteers who were administered pasireotide SC, coadministration with liraglutide,
hyperglycemia 20968 adapting treatment with ADMs on the basis of each patient’s glycemic status, pasireotide-induced hyperglycemia can be effectively managed.Treatment recommendationsMedical expert recommendations have been established
hyperglycemia 21129 recommendationsMedical expert recommendations have been established for the management of pasireotide-induced hyperglycemia in patients with CD [[17], [43]]. In patients not currently treated with insulin, and particularly for
hyperglycemia 21840 maintaining metformin treatment. Although no specific recommendations regarding pasireotide-induced hyperglycemia in patients with acromegaly have been published, treatment with metformin plus a DPP-4 inhibitor, GLP-1
hyperglycemia 23072 [17], [43]]. If warranted, dose reduction or discontinuation of pasireotide should be implemented if hyperglycemia is not controllable despite medical management [[5], [6]]. It is suggested that FPG and HbA1c levels
hyperglycemia 23325 pasireotide may need to be assessed frequently to reduce the risk of developing hypoglycemia.Reversibility of hyperglycemia upon discontinuation of pasireotideClinical studies of pasireotide in healthy volunteers and in patients
hyperglycemia 24632 respectively, within 3 months of switching from pasireotide LAR to octreotide LAR [[28]]. In conclusion, hyperglycemia associated with pasireotide is transient and not expected to cause long-term effects if pasireotide
hyperglycemia 24894 viable medical therapy option for patients with CD or acromegaly but is associated with higher rates of hyperglycemia and diabetes mellitus than other medical therapies. Further research is needed to determine optimal
hyperglycemia 25104 optimal treatment strategies with ADMs to achieve glycemic control in patients with pasireotide-induced hyperglycemia . For example, a multivariate analysis could be performed of baseline FPG and HbA1c levels across clinical
hyperglycemia 25345 pasireotide in CD or acromegaly to further assess the predictability and manageability of pasireotide-induced hyperglycemia . A phase 4 study is currently ongoing that will evaluate the effects of incretin-based therapy compared
hyperglycemia 25966 There is growing evidence to demonstrate that proactive management with ADMs can effectively manage hyperglycemia -related AEs associated with pasireotide during the course of treating patients with CD or acromegaly
hypoglycemia 23295 patients who discontinue pasireotide may need to be assessed frequently to reduce the risk of developing hypoglycemia .Reversibility of hyperglycemia upon discontinuation of pasireotideClinical studies of pasireotide in

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