Once Weekly Growth Hormone in Patients With GH Deficiency
Once Weekly Growth Hormone in Patients With GH Deficiency
The main results of our study show that treatment with the new sustained-release GH formulation LB03002 for 6 or 12 months does not worsen glucose metabolism and insulin sensitivity, but lacks to improve lipid metabolism, while it significantly reduces FM and leptin levels and increases ghrelin levels in adult patients with GHD.
It is still a matter of debate whether GH substitution improves, worsens or does not affect glucose homoeostasis and insulin sensitivity. The duration of GH substitution seems to play an important role. As glucose and insulin levels increase, an impairment of insulin sensitivity occurs at the beginning of GH substitution. This is thought to be caused by a reduction in peripheral glucose utilization, impaired β-cell function and an increase in lipid oxidation. Ongoing GH treatment decreases glucose and insulin levels and improves glucose tolerance, may be due to a substantial reduction in adipose tissue. Interestingly, substitution with LB03002 does not worsen glucose metabolism, insulin sensitivity and β-cell function after 1 year of therapy, especially as it has been described once that depot GH may worsen glucose metabolism. Two of our patients developed an impaired glucose tolerance after GH treatment, although glucose levels were only just above the limit of 140 mg/dl (154 and 156 mg/dl, respectively). Interestingly, these two patients had a weight gain of 6 and 4 kg during the year, but without big changes in the percentage of FM (49·2–48·5% and 36·6–36·5%, respectively). One of the two patients was treated with GH for 6 months and the other patient for 12 months.
The lack of significant deterioration of glucose homoeostasis during GH treatment is considered beneficial and may be due to the increase in ghrelin levels and the decrease in FM and leptin levels. Visceral FM has been shown to be an independent predictor of endogenous insulin sensitivity and glucose tolerance. Ghrelin could have an important function in glucose metabolism and insulin secretion as low ghrelin levels are associated with elevated insulin levels and IR. A reduction in abnormal high FM in patients with GHD during GH substitution is well known. Leptin is secreted in fat cells, and leptin levels are positively correlated with the amount of FM. This could be confirmed in our study. A decline in leptin levels in parallel to the decline in FM in our patients during GH substitution was expected and is in accordance with other published studies. In contrast, some investigations did not find a significant reduction in leptin levels in patients with GHD after GH substitution.
Whether ghrelin levels are changed in patients with GHD is still not clear. Some authors reported that lower ghrelin levels in patients with GHD increase after GH substitution, and others did not find a significant increase in ghrelin levels after GH substitution. Our patients showed significantly higher ghrelin levels after treatment with LB03002. This may reflect the beneficial effects of GH substitution on metabolism as ghrelin levels are high in lean subjects and low in obese patientsand patients with hyperinsulinaemia.
An increase in WHR after GH substitution with LB03002 was not expected and cannot be explained. But WHR has been shown to be a poor method of assessing visceral FM, cardiovascular risk and mortality. The best predictor of cardiovascular risk and mortality seems to be the WHtR, which was not significantly different before and after GH substitution in our patients. We would have expected a lower WHtR after GH substitution especially as FM was significantly reduced. Maybe study population was too small or treatment with GH was too short to get statistically significant results.
It was unexpected not to find an improvement in lipid variables after GH substitution in our patients. Generally, lipid variables improve after daily GH treatment. In line with our results, no change in lipid variables after GH therapy has also been described, particularly when using the Nutropin depot. But from the KIMS database (Pfizer International Metabolic Database), we know that favourable effects of GH on lipid metabolism occur and can be maintained. Reasons for the missing statistical improvement in our patients could again be the small study population or treatment with GH was too short to obtain statistically significant results. But looking at the data, all lipid variables show a tendency of improvement.
Bone mineral density and T-score measured by DXA were not significantly different before and after GH therapy with LB03002. It has been reported that patients with adult-onset GHD have similar BMD compared with controls. Furthermore, remodelling of the bone takes place during the first 12–18 months of GH treatment and BMD may increase thereafter. Still, most of the published data showed an increase in BMD after GH substitution. Low leptin levels may have caused the lack of increment in BMD of our cohort as leptin has been shown to stimulate bone growth and increase BMD.
The small study population and a selection bias, caused by some patients being put on GH replacement while others did not agree to participate in the study, may have had an impact on the outcome of our study.
Further studies on a larger population and on GH in combination with other metabolic hormones should be performed, on the one hand, to confirm our results and, on the other hand, to gain more knowledge about the influence of combined hormone substitution on the metabolism. Giannoulis et al. could show that the combined treatment of GH and testosterone even at low dose can achieve much benefit without significant side effects.
In conclusion, once-a-week GH, LB03002, is an effective GH formulation for improving metabolic variables such as FM, leptin and ghrelin levels without affecting glucose homoeostasis.
Discussion
The main results of our study show that treatment with the new sustained-release GH formulation LB03002 for 6 or 12 months does not worsen glucose metabolism and insulin sensitivity, but lacks to improve lipid metabolism, while it significantly reduces FM and leptin levels and increases ghrelin levels in adult patients with GHD.
It is still a matter of debate whether GH substitution improves, worsens or does not affect glucose homoeostasis and insulin sensitivity. The duration of GH substitution seems to play an important role. As glucose and insulin levels increase, an impairment of insulin sensitivity occurs at the beginning of GH substitution. This is thought to be caused by a reduction in peripheral glucose utilization, impaired β-cell function and an increase in lipid oxidation. Ongoing GH treatment decreases glucose and insulin levels and improves glucose tolerance, may be due to a substantial reduction in adipose tissue. Interestingly, substitution with LB03002 does not worsen glucose metabolism, insulin sensitivity and β-cell function after 1 year of therapy, especially as it has been described once that depot GH may worsen glucose metabolism. Two of our patients developed an impaired glucose tolerance after GH treatment, although glucose levels were only just above the limit of 140 mg/dl (154 and 156 mg/dl, respectively). Interestingly, these two patients had a weight gain of 6 and 4 kg during the year, but without big changes in the percentage of FM (49·2–48·5% and 36·6–36·5%, respectively). One of the two patients was treated with GH for 6 months and the other patient for 12 months.
The lack of significant deterioration of glucose homoeostasis during GH treatment is considered beneficial and may be due to the increase in ghrelin levels and the decrease in FM and leptin levels. Visceral FM has been shown to be an independent predictor of endogenous insulin sensitivity and glucose tolerance. Ghrelin could have an important function in glucose metabolism and insulin secretion as low ghrelin levels are associated with elevated insulin levels and IR. A reduction in abnormal high FM in patients with GHD during GH substitution is well known. Leptin is secreted in fat cells, and leptin levels are positively correlated with the amount of FM. This could be confirmed in our study. A decline in leptin levels in parallel to the decline in FM in our patients during GH substitution was expected and is in accordance with other published studies. In contrast, some investigations did not find a significant reduction in leptin levels in patients with GHD after GH substitution.
Whether ghrelin levels are changed in patients with GHD is still not clear. Some authors reported that lower ghrelin levels in patients with GHD increase after GH substitution, and others did not find a significant increase in ghrelin levels after GH substitution. Our patients showed significantly higher ghrelin levels after treatment with LB03002. This may reflect the beneficial effects of GH substitution on metabolism as ghrelin levels are high in lean subjects and low in obese patientsand patients with hyperinsulinaemia.
An increase in WHR after GH substitution with LB03002 was not expected and cannot be explained. But WHR has been shown to be a poor method of assessing visceral FM, cardiovascular risk and mortality. The best predictor of cardiovascular risk and mortality seems to be the WHtR, which was not significantly different before and after GH substitution in our patients. We would have expected a lower WHtR after GH substitution especially as FM was significantly reduced. Maybe study population was too small or treatment with GH was too short to get statistically significant results.
It was unexpected not to find an improvement in lipid variables after GH substitution in our patients. Generally, lipid variables improve after daily GH treatment. In line with our results, no change in lipid variables after GH therapy has also been described, particularly when using the Nutropin depot. But from the KIMS database (Pfizer International Metabolic Database), we know that favourable effects of GH on lipid metabolism occur and can be maintained. Reasons for the missing statistical improvement in our patients could again be the small study population or treatment with GH was too short to obtain statistically significant results. But looking at the data, all lipid variables show a tendency of improvement.
Bone mineral density and T-score measured by DXA were not significantly different before and after GH therapy with LB03002. It has been reported that patients with adult-onset GHD have similar BMD compared with controls. Furthermore, remodelling of the bone takes place during the first 12–18 months of GH treatment and BMD may increase thereafter. Still, most of the published data showed an increase in BMD after GH substitution. Low leptin levels may have caused the lack of increment in BMD of our cohort as leptin has been shown to stimulate bone growth and increase BMD.
The small study population and a selection bias, caused by some patients being put on GH replacement while others did not agree to participate in the study, may have had an impact on the outcome of our study.
Further studies on a larger population and on GH in combination with other metabolic hormones should be performed, on the one hand, to confirm our results and, on the other hand, to gain more knowledge about the influence of combined hormone substitution on the metabolism. Giannoulis et al. could show that the combined treatment of GH and testosterone even at low dose can achieve much benefit without significant side effects.
In conclusion, once-a-week GH, LB03002, is an effective GH formulation for improving metabolic variables such as FM, leptin and ghrelin levels without affecting glucose homoeostasis.