Please see sections 2. Adjustments in the dose of drugs known to slow the heart rate e. Use with caution in at-risk patients; evaluate ECG and electrolytes prior to dosing and periodically while on treatment Liver Test Elevations: Evaluate liver enzyme tests prior to and during treatment. Discontinue if complications of cholelithiasis are suspected. Please see section 5.
Cancel Submit. Are you a Healthcare Professional? Cancel Proceed. 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. In a phase 3 study of patients with persistent or recurrent CD or newly diagnosed disease, who were not eligible for surgery, twice-daily injections of pasireotide SC provided rapid reductions in mean levels of urinary-free cortisol UFC that were sustained during treatment [ 11 ].
Improvements in facial rubor and supraclavicular and dorsal fat pads were also reported. Improvements in symptom severity scores also occurred at higher degrees in patients in the pasireotide LAR 40 and mg groups than in those in the active control group. Symptoms included headache, fatigue, perspiration, paresthesia, and osteoarthralgia. The efficacy and safety of pasireotide SC in acromegaly have also been investigated. Additionally, the number of patients showing improvements in symptoms of disease i.
In clinical trials, the safety profile of pasireotide included AEs, mostly related to gastrointestinal symptoms and cholelithiasis, that were largely consistent with other SRLs [ 5 , 6 ].
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 and the percentage of 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 lower in patients with acromegaly who received pasireotide LAR Interestingly, fewer patients with acromegaly who received pasireotide LAR discontinued treatment because of hyperglycemia-related AEs, as reported in 2 separate trials 3.
In a clinical study that evaluated the efficacy and safety of pasireotide SC in acromegaly, hyperglycemia-related AEs occurred in AE adverse event, b. Several 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-related AEs were lower than those in CD Fig.
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 trials Fig. 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 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 has a predictable pattern, can be managed with antidiabetic medications ADM , and is reversible upon discontinuation of treatment with pasireotide. Factors 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.
Figure was created with Adobe Illustrator CC It 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 is associated with insulin resistance, 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 of insulin to peripheral tissues, resulting 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 insulin sensitivity by depleting storage of hepatic 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 are primarily due to its tendency to reduce insulin and incretin secretion [ 19 ].
Insulin secretion is mediated in large part by sst 2 and sst 5 [ 20 , 21 ], and glucagon secretion is mediated primarily by sst 2 [ 21 , 22 ]. Pasireotide binds to sst 2 and sst 5 and binds with highest affinity to sst 5 , which is expressed not only by pituitary cells but also by other cell types. For example, pasireotide binds to sst 5 in pancreatic islet cells, which leads to reduced insulin secretion that is not observed with SRLs that bind to sst 2 with greater affinity [ 19 , 23 ].
Reduced insulin levels associated 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, pasireotide has minimal effects on glucagon secretion and no effects on insulin sensitivity in healthy volunteers [ 19 ]. In contrast, octreotide and lanreotide suppress glucagon secretion, which could be due to increased binding of sst 2 [ 21 , 22 ], a key mediator of glucagon secretion to which octreotide and lanreotide bind with greater affinities than pasireotide [ 8 ].
By improving biochemical control, it is likely that insulin sensitivity will increase, which should improve glucose tolerance, even if insulin secretion remains reduced. Second, it was reported that levels of IGF-binding protein 2 increased after 24 weeks of pasireotide LAR [ 24 ], which could attenuate the long-term hyperglycemic effects of pasireotide LAR. Fasting plasma glucose FPG and glycated hemoglobin HbA 1c levels are parameters used to assess glycemic control [ 25 ].
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 decreased [ 11 , 12 , 14 , 26 — 28 ]. These observations suggest that pasireotide initially induces an increase in FPG and HbA 1c levels, which then stabilize during the course of treatment. 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 [ 30 ].
This suggests that baseline glycemic status before the initiation of pasireotide treatment could be predictive of the extent and severity of hyperglycemia associated with treatment.
Regarding 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 HbA 1c levels [ 33 ]; however, a similar association in patients treated with pasireotide has not yet been studied.
Because certain populations are at greater risk of hyperglycemia associated with pasireotide, proactive management and monitoring of these patients are critical for improving clinical outcomes. As 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 ].
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 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 for the reduction in GLP-1 associated with pasireotide [ 19 ]. 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 for some 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 [ 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 also be important for management of pasireotide-induced hyperglycemia [ 16 , 42 ].
Medical expert recommendations have been established for the management of pasireotide-induced hyperglycemia in patients with CD [ 17 , 43 ]. In cases in which patients fail to achieve glycemic control with metformin, it is suggested that a DPP-4 inhibitor be added.
If neither DPP-4 inhibitors nor GLP-1 receptor agonists 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 with acromegaly have been published, treatment with metformin plus a DPP-4 inhibitor, GLP-1 agonist, or insulin would most likely have similar efficacy.
Patients with CD or acromegaly who initiate, discontinue, or need dose adjustment of pasireotide should be proactively managed in accordance with current monitoring guidelines and recommendations. SST receptors are also expressed on pancreatic cells; their activation decreases insulin secretion This is a less stringent endpoint than the primary endpoint.
References: 1. Expert Opin Investig Drugs. Front Endocrinol. J Neurosurg. Expression analysis of dopamine receptor subtypes in normal human pituitaries, nonfunctioning pituitary adenomas and somatotropinomas, and the association between dopamine and somatostatin receptors with clinical response to octreotide-LAR in acromegaly. J Clin Endocrinol Metab.
Coexpression of dopamine and somatostatin receptor subtypes in corticotroph adenomas. Silverstein JM. Inhibition of human pancreatic islet insulin release by receptor-selective somatostatin analogs directed to somatostatin receptor subtype 5.
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