Weekly somapacitan had no adverse effects on glucose metabolism in adults with growth hormone deficiency

Abstract

Purpose: The long-term effects of long-acting growth hormone (LAGH) analogues on glucose metabolism in adult growth hormone deficiency (AGHD) are not known. We investigated the impact of LAGH somapacitan, administered once-weekly, on glucose metabolism in patients with AGHD.

Methods: In post hoc-defined analyses, we compared the effects of somapacitan with daily growth hormone (GH) and placebo on fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β) in patients with AGHD across a unique data set from three phase 3 randomized controlled trials (REAL 1, REAL 2 and REAL Japan).

Results: No new cases of diabetes mellitus were reported with somapacitan. Among GH-naïve patients (n = 120 somapacitan, n = 119 daily GH), higher changes from baseline in FPG, HOMA-IR and fasting insulin levels were observed with daily GH versus somapacitan at 34 weeks, but not at 86 weeks. HbA1c and HOMA-β did not differ between groups at either timepoint. Among treatment-naïve patients, sex, age, fasting insulin, glucose tolerance status and body mass index did not influence changes in glucose metabolism. In previously treated patients (REAL 1 extension: n = 51 somapacitan, n = 52 daily GH; REAL 2: n = 61 and n = 31, respectively; REAL Japan: n = 46 and n = 16, respectively), the difference in changes from baseline were not statistically significant between somapacitan and daily GH for any glucose metabolism parameters.

Conclusions: Somapacitan, compared with daily GH, did not adversely affect glucose metabolism up to 86 weeks in a large cohort of treatment-naïve or previously treated patients with AGHD. Trial registrations (date of registration): NCT02229851 (2 September 2014), NCT02382939 (3 March 2015), NCT03075644 (7 March 2017).

Keywords: Adult growth hormone deficiency; Glucose metabolism; Growth hormone; Growth hormone replacement therapy; Insulin sensitivity; Somapacitan.

Conflict of interest statement

YT has received honoraria from Novo Nordisk, Novartis, Eli Lilly, Recordati Rare Disease, Otsuka Pharma and Ascendis Pharma and has received grant support from Ono Pharma, Teijin Pharma, Novo Nordisk, Kowa Pharma, Taisho Pharma, Daiichi Sankyo Pharma and Tanabe Mitsubishi Pharma. BMKB has served as the PI of grants to Massachusetts General Hospital over the last 3 years from: Ascendis, Crinetics, Ionis, Millendo, Novartis and Strongbridge and has been an occasional consultant over the last 3 years to Aeterna Zentaris, Ascendis, Crinetics, HRA Pharma, Ipsen, EMD Serono, Novartis, Novo Nordisk, Recordati, Sparrow, Strongbridge and Xeris. HF declares no funding for this paper. KH serves as an advisor to Novo Nordisk and Ipsen. MHR is an employee of and stockholder in Novo Nordisk. NN is an employee of Novo Nordisk. CS is an employee of and stockholder in Novo Nordisk. KY has received research grants to Barrow Neurological Institute from Ascendis, Crinetics, Amryt and Corcept. Served as an occasional advisory board member for Novo Nordisk, Ascendis, Sandoz, Corcept, Ipsen, Amryt, Strongbridge, Crinetics, Xeris and Recordati. Served as occasional speaker for Novo Nordisk, Recordati and Corcept. GJ has received lecture fees from Merck Serono, Novartis, Novo Nordisk, Otsuka, Pfizer, and Sandoz, as well as consultancy fees from Astra Zeneca, Novo Nordisk and Shire.

© 2022. The Author(s).

Figures

Fig. 1

FPG over time in a treatment-naïve patients from REAL 1 study (main phase and main + extension phases) and in previously treated patients from b REAL 2, c REAL Japan and d REAL 1 extension phase following re-randomization. Data within tables and figures are mean (SD) (represented by points and error bars). Baseline and last visit values are observed values. Relative changes are shown as differences. Relative changes and ETDs were obtained using a mixed effects model. For patients in the REAL 1 study (a), there was a 1-week washout period between the main and extension phases; patients receiving daily GH in the main phase (red) were re-randomized at week 34 to receive either daily GH (pink) or somapacitan (dotted blue) in the extension phase. Δ baseline, change from baseline; CI confidence interval, ETD estimated treatment difference, Ext extension, FPG fasting plasma glucose, GH growth hormone, SD standard deviation

Fig. 1

FPG over time in a treatment-naïve patients from REAL 1 study (main phase and main + extension phases) and in previously treated patients from b REAL 2, c REAL Japan and d REAL 1 extension phase following re-randomization. Data within tables and figures are mean (SD) (represented by points and error bars). Baseline and last visit values are observed values. Relative changes are shown as differences. Relative changes and ETDs were obtained using a mixed effects model. For patients in the REAL 1 study (a), there was a 1-week washout period between the main and extension phases; patients receiving daily GH in the main phase (red) were re-randomized at week 34 to receive either daily GH (pink) or somapacitan (dotted blue) in the extension phase. Δ baseline, change from baseline; CI confidence interval, ETD estimated treatment difference, Ext extension, FPG fasting plasma glucose, GH growth hormone, SD standard deviation

Fig. 2

HbA1c values vs time (mean ± SD) in a treatment-naïve patients from REAL 1 study (main phase and main + extension phase) and in previously treated patients from b REAL 2, c REAL Japan and d REAL 1 extension phase study following re-randomization of treatment. Data within tables and figures are mean (SD) (represented by points and error bars). Baseline and last visit values are observed values. Relative changes are shown as differences. Relative changes and ETDs were obtained using a mixed effects model. For patients in the REAL 1 study (a), there was a 1-week washout period between the main and extension phases; patients receiving daily GH in the main phase (red) were re-randomized at week 34 to receive either daily GH (pink) or somapacitan (dotted blue) in the extension phase. Δ baseline, change from baseline; CI confidence interval, ETD estimated treatment difference, Ext extension, GH growth hormone, HbA1c glycated hemoglobin, SD standard deviation

Fig. 2

HbA1c values vs time (mean ± SD) in a treatment-naïve patients from REAL 1 study (main phase and main + extension phase) and in previously treated patients from b REAL 2, c REAL Japan and d REAL 1 extension phase study following re-randomization of treatment. Data within tables and figures are mean (SD) (represented by points and error bars). Baseline and last visit values are observed values. Relative changes are shown as differences. Relative changes and ETDs were obtained using a mixed effects model. For patients in the REAL 1 study (a), there was a 1-week washout period between the main and extension phases; patients receiving daily GH in the main phase (red) were re-randomized at week 34 to receive either daily GH (pink) or somapacitan (dotted blue) in the extension phase. Δ baseline, change from baseline; CI confidence interval, ETD estimated treatment difference, Ext extension, GH growth hormone, HbA1c glycated hemoglobin, SD standard deviation

Fig. 3

HOMA-IR values over time (mean ± SD) in a treatment-naïve patients from REAL 1 study (main phase and main + extension phases) and in previously treated patients from b REAL 2, c REAL Japan and d REAL 1 extension phase study following re-randomization of treatment. Data within tables and figures are mean (SD) (represented by points and error bars). Baseline and last visit values are observed values. Relative changes are shown as ratios. Relative changes and ETRs were obtained using a mixed effects model. For patients in the REAL 1 study (a), There was a 1-week washout period between the main and extension phases; patients receiving daily GH in the main phase (red) were re-randomized at week 34 to receive either daily GH (pink) or somapacitan (dotted blue) in the extension phase. Δ baseline, change from baseline; CI confidence interval, ETR estimated treatment ratio, Ext extension, GH growth hormone, HOMA-IR homeostasis model assessment insulin resistance, SD standard deviation

Fig. 3

HOMA-IR values over time (mean ± SD) in a treatment-naïve patients from REAL 1 study (main phase and main + extension phases) and in previously treated patients from b REAL 2, c REAL Japan and d REAL 1 extension phase study following re-randomization of treatment. Data within tables and figures are mean (SD) (represented by points and error bars). Baseline and last visit values are observed values. Relative changes are shown as ratios. Relative changes and ETRs were obtained using a mixed effects model. For patients in the REAL 1 study (a), There was a 1-week washout period between the main and extension phases; patients receiving daily GH in the main phase (red) were re-randomized at week 34 to receive either daily GH (pink) or somapacitan (dotted blue) in the extension phase. Δ baseline, change from baseline; CI confidence interval, ETR estimated treatment ratio, Ext extension, GH growth hormone, HOMA-IR homeostasis model assessment insulin resistance, SD standard deviation