Therapy of acromegalic patients exacerbated by concomitant type 2 diabetes requires higher pegvisomant doses to normalise IGF1 levels

Abstract

Objective: Acromegaly is associated with an increased prevalence of glucose metabolism disorders. Clinically confirmed diabetes mellitus is observed in approximately one quarter of all patients with acromegaly and is known to have a worse prognosis in these patients. Design: Of 514 acromegalic patients treated with pegvisomant and recorded in the German Cohort of ACROSTUDY, 147 had concomitant diabetes mellitus. We analysed these patients in an observational study and compared patients with and without concomitant diabetes. Results: Under treatment with pegvisomant, patients with diabetes mellitus rarely achieved normalisation (64% in the diabetic cohort vs 75% in the non-diabetic cohort, PZ0.04) for IGF1. Diabetic patients normalised for IGF1 required higher pegvisomant doses (18.9 vs 15.5 mg pegvisomant/day, P!0.01). Furthermore, those diabetic patients requiring insulin therapy showed a tendency towards requiring even higher pegvisomant doses to normalise IGF1 values than diabetic patients receiving only oral treatment (22.8 vs 17.2 mg pegvisomant/day, PZ0.11). Conclusions: Hence, notable interdependences between the acromegaly, the glucose metabolism of predisposed patients and their treatment with pegvisomant were observed. Our data support recent findings suggesting that intra-portal insulin levels determine the GH receptor expression in the liver underlined by the fact that patients with concomitant diabetes mellitus, in particular those receiving insulin therapy, require higher pegvisomant doses to normalise IGF1. It is therefore important to analyse various therapy modalities to find out whether they influence the associated diabetes mellitus and/or whether the presence of diabetes mellitus influences the treatment results of an acromegaly therapy.

Prediction of therapy response in acromegalic patients under pegvisomant therapy within the German ACROSTUDY cohort

“…And in a study by Parkinson et al [21] in 118 acromegalic patients, gender, body weight, previous radiotherapy, and baseline GH/IGF-1 influenced the pegvisomant dosage that was needed to reach biochemical control. Additionally, the role of the diabetes status in the pegvisomant therapy scheme has been emphasized as patients with acromegaly and type 2 diabetes mellitus require higher pegvisomant dosages to achieve IGF-1 normalisation than acromegalic patients without diabetes mellitus [22][23][24][25].…”

Profile of pegvisomant in the management of acromegaly: an evidence based review of its place in therapy

“…56,57 Diabetes mellitus is also associated with worse response to PEG therapy. 43,53 This has been observed in the German cohort of ACROSTUDY where IGF-I normalization rates were lower in diabetic patients (64%) than in non-diabetic ones (75%). Furthermore, the dose of PEG required for IGF-I normalization was higher in diabetic patients (18.9 mg/day) when compared to nondiabetic ones (15.5 mg/day).…”

“…Additionally diabetic patients treated with insulin required higher PEG doses (22.8 mg/day) than those treated with oral hypoglycemic agents (17.2 mg/ day). 43 A possible explanation for these findings is the role of insulin as one of the main regulators of GHR liver expression. 58 In this regard, hyperinsulinemic diabetic patients (especially insulin treated cases) exhibit an increased expression of hepatic GHR, 59-61 thus requiring higher concentrations of PEG for full receptor blockage.…”

“…43 PEG treatment improves blood pressure, especially diastolic pressure, reduces cardiac mass, and exerts beneficial effects on rhythm disorders. 44 The effect of PEG treatment on lipid profile is controversial: some studies did not find any change, 44 while others found an increase in total and low-density lipoprotein cholesterol without change in triglyceride levels and a reduction in lipoprotein (a) levels.…”

Pegvisomant Treatment in Acromegaly

“…Dose requirements to achieve control of IGF-I seem to be higher in diabetic versus non-diabetic subjects [25]. A Spanish study reported that PEG-V showed an efficacy of >90%, but patients needed a dose escalation to maintain this high efficacy [13].…”