The Effects of Weekly Administration of 40 mg Pegvisomant or Placebo on Quality of Life and Insulin Sensitivity in Acromegalic Patients With Normal IGF-I Concentrations During Long-Term Treatment With Long-Acting Somatostatin Analogs

Introduction Both lanreotide (Somatulin Autosolution ™ (SL)) and octreotide (Sandostatin LAR ™ (LAR)) are equally effective in controlling disease activity in acromegalic subjects with a normalization of serum insulin-like growth factor-I (IGF-I) levels in roughly 65%. However, SL is injected as a deep intramuscular injection, while LA is injected as a deep subcutaneous injection. Physicians, involved in the treatment of acromegalic patients know that biochemical control of the disease in their patients not necessarily means that all those patients stop complaining. To address these issues, Sonino and co-workers studied with several symptom questionnaires the effects on quality of life (QoL) of SL. Together with a significant decrease in growth hormone (GH) and IGF-I, treatment with SL significantly improved psychological distress, well-being and social fears (1). In another study on the efficacy of the novel GH receptor antagonist pegvisomant to lower serum IGF-I concentrations a questionnaire evaluating five clinical signs and symptoms of acromegaly showed dose dependent significant differences from placebo (2). Recently, Webb and co-workers reported the successful development of a disease-specific questionnaire suitable to measure health-related quality of life in acromegaly (ACROQOL) (3).

No clear biochemical parameter appears to be available that correlates well with disease activity related quality of life (4). At the same time, serum GH concentrations and serum total IGF-I levels, but not QoL, are used as parameters to determine dosing of Sandostatin LAR, or any of the available medical therapies for acromegaly (5-8).

The growth hormone receptor antagonist pegvisomant as monotherapy once daily normalizes IGF-I in virtually all acromegalics (9;10), but pegvisomant monotherapy is also very costly. Recently, we reported the results of a 42-week dose-finding study on the efficacy of the combination of long-acting somatostatin analogues once monthly and pegvisomant once weekly in 26 patients with active acromegaly. Pegvisomant dose was increased until IGF-I levels normalized or until a weekly dose of 80 mg was reached. IGF-I levels normalized in 25 (95 %) with a median weekly dose of 60 mg pegvisomant. There were no signs of pituitary tumor growth but mild elevations in liver enzymes were observed in 10 patients (38%) (11). One of the potential advantages of combining pegvisomant with somatostatin analogues is that pegvisomant monotherapy improves insulin sensitivity compared to somatostatin analogues (12;13), although it is unclear yet whether or not long-term pegvisomant administration would improve insulin sensitivity in normal subjects (13;14). Therefore, one might expect that pegvisomant monotherapy has beneficial effects on insulin sensitivity, compared to the combination of both pegvisomant and somatostatin analogues, as the latter ones decrease insulin sensitivity by several mechanisms (13;15).

Conclusion:

• So-called biochemically well controlled acromegalic subjects with normal serum IGF-I concentrations frequently still have an impaired QoL.
• These subjects, when controlled by long-acting somatostatin analogs have impaired insulin sensitivity because of the pharmacological properties of these somatostatin analogs.
• We postulate that co-administration of the growth hormone receptor antagonist pegvisomant will improve QoL and insulin sensitivity