In Patients With Controlled Acromegaly, Indices of Glucose Homeostasis Correlate With IGF-1 Levels Rather Than With Type of Treatment

Amelie Decock; Charlotte Verroken; Frederique Van de Velde; Tina Vilsbøll; Jens Juul Holst; Guy T'Sjoen; Bruno Lapauw

Disclosures

Clin Endocrinol. 2021;95(1):65-73. 

In This Article

Discussion

In this cross-sectional study, we explored glucose homeostasis and postprandial substrate metabolism in patients with controlled acromegaly under different treatment modalities (remission after surgery, LA-SSA or LA-SSA + PEG).[4] No differences in glucose tolerance, insulin sensitivity or postprandial triglyceride and incretin responses between the different treatment modalities were found. These results on glucose tolerance and insulin sensitivity are in line with previous studies: after changing LA-SSA to LA-SSA + pegvisomant combination therapy in a priori controlled patients, no substantial differences in substrate metabolism or glucose homeostasis were observed.[27] Two other studies showed that there was no or only minimal difference in glucose metabolism in patients cured after surgery or under LA-SSA treatment.[16,28] Upon pegvisomant treatment, several studies did show an improvement in glucose tolerance.[29–31] Most of these studies were performed in patients with active disease, making it difficult to distinguish between the results of a better disease control versus the effects of therapy alone. A recent meta-analysis suggests a drug-related effect seen the improvement in glucose metabolism in the pegvisomant monotherapy group was independent of disease control and treatment duration and a meta-regression analysis showed no correlation with changes in IGF-1 levels.

To our best knowledge, our study is the first to evaluate the impact of different treatment modalities on the incretin system, which has been suggested to be altered in acromegaly.[32] LA-SSA is known to inhibit the incretin response,[33–35] but we did not find differences in fasting nor in postprandial incretin response according to treatment modality. Although surprising, this might be explained by the fact that GLP-1 secretion can partially escape from suppression during ongoing lanreotide administration.[35]

This study found an inverse correlation between serum IGF1 levels and indices of insulin sensitivity. These results suggest that, even among patients with controlled disease, patients with a lower IGF1 level have a better metabolic profile. This relationship between insulin sensitivity and IGF1 in patients with acromegaly was observed by others,[36–38] and Puder et al also found a negative correlation between IGF1 levels and insulin sensitivity across the spectrum of normal IGF1 levels in patients with acromegaly.[36] Considering these results and the persistence of metabolic abnormalities in a lot of patients with acromegaly,[39] one could suggest to target IGF1 levels towards the lower or middle reference range as suggested earlier.[36] Of course, this needs further investigation and confirmation in prospective trials. On the other hand, adult-onset and long-standing growth hormone deficiency (GHD) is associated with lower insulin sensitivity and impaired glucose tolerance as well, probably due to visceral adiposity with increased free fatty acid flux, reduced LBM and impaired physical fitness. So theoretically lowering the IGF-level to subphysiological levels should be avoided as well.[3] However, it is still largely unknown if GHD in patients post-acromegaly (eg after surgery or radiotherapy) benefit from GH replacement and if substituted, towards which IGF-1 level the treatment should be targeted.[40] Even more, it is difficult to diagnose GHD in treated acromegalic patients by classic provocative tests with arginine or insulin and patients may have GHD with normal IGF-1 levels.[41] In conclusion, more investigation about the optimal IGF-1 level to balance between disease activity and overtreatment in acromegaly is necessary.

Our study has several strengths. We used a well-described homogeneous study population, with controlled disease under the three most important treatment modalities. Furthermore, we performed an extensive investigation with a hyperinsulinaemic-euglycaemic clamp and mixed meal tolerance test with evaluation of incretin responses besides common parameters of postprandial substrate metabolism. Important limitations of this study are the small sample size, the cross-sectional design and the lack of a pegvisomant monotherapy group.

In conclusion, in this cross-sectional study we observed no differences in glucose homeostasis or postprandial substrate metabolism between patients with controlled acromegaly after surgery, with LA-SSA monotherapy or with LA-SSA + pegvisomant combination therapy. However, although all patients had IGF1 levels within the normal range, IGF1 levels correlated inversely with parameters of insulin sensitivity. This may suggest that, even in controlled disease, lower IGF1 levels are associated with a better metabolic profile.

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