Effective Combination Treatment with Cabergoline and Low-Dose Pegvisomant in Active Acromegaly: A Prospective Clinical Trial

Previous studies have demonstrated that pegvisomant, a growth hormone receptor antagonist, is effective in patients with treatment-resistant acromegaly. With dose titration up to 40 mg/d, pegvisomant normalizes insulin-like growth factor I (IGF-I) in up to 97% of patients. Its high cost, especially in high doses, has limited its optimal use. In an attempt to reduce cost and maintain efficacy, pegvisomant has been combined with somatostatin analogs. Although the combination has been shown to reduce IGF-I levels, a prospective, controlled trial found no cost savings at the doses required compared with pegvisomant monotherapy. Moreover, use of this combination has been associated with deterioration in glucose tolerance, increased risk of diabetes mellitus, and abnormal liver function tests. Cabergoline is a well-tolerated inexpensive oral dopamine agonist that as monotherapy has been reported to normalize IGF-I in up to 30% of patients with acromegaly. Although cabergoline may provide additional benefit in IGF-I reduction when used in combination with pegvisomant, no clinical studies have investigated this combination. This multicenter, open-label, prospective study investigated the efficacy of combined low-dose pegvisomant and cabergoline and of cabergoline monotherapy to reduce serum IGF-I in patients with active acromegaly. Participants were 24 patients enrolled at 5 centers in the United Kingdom. Patients received cabergoline monotherapy for 18 weeks to a maximum dose of 0.5 mg once daily followed by addition of pegvisomant. The primary study outcome measure was the change in serum IGF-I levels over time. Dose titration with cabergoline monotherapy did not significantly reduce IGF-I levels [454 (219) ng/mL at baseline vs 389 (192) ng/mL for cabergoline at 18 weeks]; 2 patients (11%), however, did achieve a normal IGF-I. Addition of low-dose pegvisomant (10 mg/d) for 12 weeks significantly reduced IGF-I [389 (192) ng/mL for cabergoline at 18 weeks vs 229 (101) ng/mL for the combination at 30 weeks]; 13 patients (68%) achieved a normal IGF-I. After withdrawal of cabergoline at 30 weeks, 12 weeks of pegvisomant monotherapy resulted in increased IGF-I levels [305 (177) ng/mL for pegvisomant at 42 weeks vs 229 (101) ng/mL for the combination at 30 weeks], with only 5 patients (26%) maintaining a normal IGF-I. No serious adverse events occurred that were related to the study medications. There were no significant changes in liver function or glucose metabolism during the study. These findings show that use of cabergoline in combination with pegvisomant is more effective at reducing IGF-I levels in patients with acromegaly than either drug alone.