How to Position Pasireotide LAR Treatment in Acromegaly

Eva C. Coopmans; Ammar Muhammad; Aart J. van der Lely; Joseph A. M. J. L. Janssen; Sebastian J. C. M. M. Neggers


J Clin Endocrinol Metab. 2019;104(6):1978-1988. 

In This Article

Management of Pasireotide-induced Hyperglycemia

Good and early management of hyperglycemia during pasireotide LAR therapy is important because hyperglycemia and diabetes are long-term risk factors for cardiovascular disease and because proactive management of hyperglycemia after pasireotide LAR initiation is likely to improve long-term compliance with pasireotide LAR. A wider use of pasireotide LAR in the medical management of acromegaly depends on the endocrinologist's willingness to try pasireotide LAR and to recommend it to the appropriate patients. The challenge in daily practice for every endocrinologist is to decide for each individual patient with acromegaly whether the potential advantages of pasireotide LAR treatment outweigh the potential disadvantages of such treatment. We provide recommendations to achieve optimal management of pasireotide-induced hyperglycemia in Figure 2. In contrast to previous published recommendations for management of pasireotide-induced hyperglycemia,[34,65–67] we use a less stringent and more liberal strategy in the frequency of patient monitoring.

Figure 2.

Proposed algorithm for management of pasireotide-induced hyperglycemia.

Baseline HbA1c is the most important predictor for development of diabetes after pasireotide LAR administration.[11,12,32,40] We recommend that baseline FPG and HbA1c levels should be assessed before pasireotide LAR therapy is initiated, and in case of impaired FPG or diabetes at baseline, lifestyle management or antidiabetic treatment should be started or optimized before pasireotide LAR is initiated (Figure 2). Clinical studies consistently show that after pasireotide LAR is started, FPG andHbA1c levels rise for the first 3 months and remain stable without further antidiabetic therapy.[8,21,23,32,40] Therefore, blood glucose monitoring is especially important in the first 3 months after initiation of pasireotide LAR treatment, and the EMA and FDA recommend that self-monitoring of blood glucose or FPG assessments should be done weekly for the first 3 months for all patients.[8,9] After these 3 months, the intensity of blood glucose monitoring can be reduced. In contrast to the EMA and FDA recommendations, and in contrast to Wildemberg and Gadelha[67] and Samson,[66] who propose home blood glucose monitoring twice a week for 3 months for patients with normoglycemia, we recommend monitoring at the outpatient clinic with monthly FPG and HbA1c the first 3 months (Figure 2). Because of the low likelihood of deterioration of glucose tolerance in young patients (aged <40 years) with normal glucose tolerance at baseline, this latter group can be monitored less intensively and with a lower frequency (Figure 2). In our experience, however, for patients already known to have impaired glucose tolerance and or diabetes at baseline, who make up the majority of patients with acromegaly, more extensive monitoring is indicated. These latter patients should receive home blood glucose monitoring the first 3 months, by measuring daily fasting and 2-hour postprandial glucose levels, and monthly HbA1c monitoring at the outpatient clinic (Figure 2). For patients with diabetes on insulin treatment at baseline, we advise continued home blood glucose monitoring with additional HbA1c monitoring, especially at the start of pasireotide LAR therapy, and thereafter every 3 months in accordance with the current American Diabetes Association (ADA) guidelines (Figure 2).[68]

Both the EMA and the FDA recommend that for patients who develop hyperglycemia, the initiation or adjustment of antidiabetic treatment is recommended, according to the established treatment guidelines for the management of hyperglycemia.[8,9] However, Breitschaft et al.[34] have shown in healthy volunteers that dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists are more effective than metformin or sulfonylureas to treat pasireotide-induced hyperglycemia. In our experience, switching patients with acromegaly from metformin to DPP-4 inhibitors resulted in less pasireotide-induced hyperglycemia. If monitoring reveals glucose in the diabetic range per ADA criteria, we recommend, in contrast to the EMA and FDA recommendations, that first-line treatment with DPP-4 inhibitors is more suitable and that metformin be considered for patients with mild diabetes or if DPP-4 inhibitors are not available (Figure 2). If patients do not achieve their ADA criteria–based FPG and HbA1c goal with these interventions, we recommend discontinuing the DPP-4 inhibitor and starting a GLP-1 receptor agonist once daily (Figure 2). If a GLP-1 receptor agonist is not available, we recommend sulfonylureas as an alternative treatment (Figure 2). Treatment with insulin is indicated for patients who cannot tolerate GLP-1 analogs or when GLP-1 analogs do not provide glycemic control (Figure 2). In case of clinically relevant severe hyperglycemias (i.e., FPG >10 mmol/L or postprandial glucose levels >15 mmol/L), which may occur even after the first injection, it is important to promptly initiate insulin treatment (Figure 2). In our experience, patients with diabetes using insulin treatment or high dosages of oral antidiabetic agents have a high risk of clinically relevant hyperglycemias after the first injection of pasireotide LAR. On the other hand, in patients without diabetes the onset of hyperglycemia occurs later, after the start of the treatment, and it is often less severe.

Pasireotide-induced hyperglycemia is reversible after discontinuation of pasireotide LAR.[67] Our data indicate that within 8 weeks after discontinuation of pasireotide LAR and reinitiation of first-generation SRL or PEGV therapy, FPG and HbA1c levels return to baseline.[11] To prevent hypoglycemia for patients using insulin or sulfonylureas and discontinuing pasireotide LAR, it is recommended to gradually taper down these antidiabetic agents while more frequently monitoring blood glucose levels. After discontinuation of pasireotide LAR, sulfonylureas should be rapidly tapered down within the first 2 weeks to avoid hypoglycemia, whereas GLP-1 receptor analogs can be safely continued with a lower dosage for a longer period.