Long-Acting Growth Hormone for Replacement Therapy

GH replacement therapy has shown important beneficial effects on body composition, bone metabolism, lipid metabolism, and quality of life in adults with GH deficiency with a good safety profile (1, 2). Current management is based on daily sc injections before bedtime that are often experienced as cumbersome by the patient and may therefore affect adherence to treatment. Sustained-release GH formulations or long-acting GH for less frequent injections have therefore been developed. The paper by Biller et al. (3) published in this issue of the JCEM reports the results from a large 6-month study of adults with GH deficiency demonstrating efficacy and safety of a sustained-release formulation of GH with once weekly sc administration. The study concluded that the treatment was well tolerated and all clinical beneficial end-points were met, such as reduction in fat mass. GH is a powerful metabolic hormone with lipolytic actions, protein anabolic effects, and insulin antagonistic effects (4). The plasma pattern of GH, including pulse frequency, basal levels, and total integrated levels is influenced by several factors, including gender, age, and adiposity (5). Therefore, pattern of GH delivery and GH exposure may have an impact on the effects obtained by treatment. The importance of the mode of GH administration is supported by a number of animal studies demonstrating that a changed pattern of GH exposure has different effects on growth and metabolism (6). The GH secretion is suppressed by food and augmented by fasting. It is therefore a fasting hormone mobilizing energy from fat stores by lipolysis, inducing gluconeogenesis in the liver, and preserving protein mass during fasting through its protein anabolic action, i.e. in many aspects the reverse action to insulin in the postprandial state (7). Moreover, the gene expression and activity of some important regulatory enzymes in the liver are dependent on the pattern of GH exposure (8, 9). The clinical importance for safety and efficacy of not delivering GH in a physiological pulsatile manner is therefore something to consider in the pharmaceutical development of GH products for treatment. Current practice of GH treatment both in children and in adults is to administer GH as a bedtime sc injection. The basis for this practice comes from early observations that daily sc injections gave a better growth response in GH-deficient children than three injections per week (10). Moreover, the closest similarity to a normal diurnal metabolite pattern was achieved with evening sc injections of GH to GH-deficient adults (11). The diurnal plasma GH profile following daily sc evening injections is, however, an intermediate between a pulsatile and a continuous GH exposure time profile (12) and is therefore not physiological. The bedtime administration of GH means that most of the GH action occurs during the night in the fasting state. This is, however, the regime that has proved its safety and efficacy of modern GH therapy in children and in adults (1). Having a more continuous exposure, such as during treatment with long-acting GH, means that GH exerts its action both in fasting and in the fed state during the day, meaning that the normal interaction and balance with insulin is further set aside. The clinical importance of this is not clear. Whether the same efficacy and safety can be obtained by moving the GH exposure toward a more continuous pattern has been studied mainly in adults. In one small pediatric study, however, GH delivered either as daily sc injections or as a continuous GH administration using a sc pump demonstrated the same growth rate by the two treatment modes, but the serum IGF-I response was higher in the group receiving continuous GH (13). Studies in adults comparing the same dose of GH administered as a daily sc injection or as a continuous infusion have, in agreement with the pediatric experience, shown that the IGF-I and IGF binding protein-3 response is more marked with a continuous exposure of GH (14, 15). These data with a more marked serum IGF-I increase may suggest that a continuous GH exposure pattern could be more protein anabolic, but there are no clinical data to support that. Earlier data also raised some concern that a continuous pattern of GH is more likely than daily sc injections to increase lipoprotein(a) (16), an atherogenic lipoprotein. The importance of this lipoprotein fraction for overall cardiovascular risk has, however, been questioned. Also, a small study in adults has shown that a pulsatile pattern of delivery (iv) induces a more lipolytic action of GH than a continuous infusion (17). Taken together, these data have shown some minor differences between daily injection and continuous infusion of GH but have not raised any major concerns in terms of safety between the two modes of delivering GH to patients. Patients with acromegaly due to a GH-secreting pituitary adenoma have dysregulated GH secretion with elevated basal secretion that is distinct from the pulsatile nature of the normal GH secretion, with peaks and very low troughs in-between (18). Patients with active acromegaly have a poor outcome, with increased morbidity and mortality (19). Some patients with clinically active acromegaly with elevated serum IGF-I concentration can have apparent normal serum GH levels that show a continuous secretory pattern (20). Because acromegaly is associated with glucose intolerance, hypertension, and poor cardiovascular outcome, the concern is that by making GH exposure even more continuous, which occurs when using an extended-release GH product for long-term treatment in children and adults, the benefit-risk ratio may become less advantageous as compared with daily sc injections. The study by Biller et al. (3) demonstrates the expected effects of GH replacement in adults with reduction in fat mass (particularly abdominal), increase in lean mass, and an increase in serum IGF-I. No impairment in glucose or lipid metabolism was detected as compared with placebo during a 26-wk period of treatment, and no safety issues were raised (3). In a previous study using another sustained-release GH formulation, comparable efficacy and safety were demonstrated as with daily sc injections of GH (21). Current available data therefore suggest that a long-acting GH preparation with an even more continuous exposure than is obtained using daily sc injection, i.e. moving even further from the normal pulsatile secretory pattern, is efficacious and safe. Additional data of the metabolic action of the new long-acting GH formulations are needed before we can conclude that their metabolic benefits are at least similar to those obtained by current GH treatment. In this context, it is important to recognize that GH attenuates the action of insulin, meaning that insulin sensitivity is dependent on the actual GH levels at the time of measurement. This means that after a bedtime sc injection of GH, plasma glucose, free fatty acid, and serum triglyceride concentrations will be increased the morning after the injection compared with whether the same measurements were obtained 36 h after the last sc GH injection (22). The published studies on the efficacy and safety of long-acting GH products have measured fasting glucose and lipids during GH trough values (3, 21). The data shown have found no difference between long-acting GH and placebo or daily sc injections. What the levels of plasma glucose and lipids are between injections when GH levels are higher has not been shown, although one would expect those to be higher. Whether this has an impact on the long-term safety of the long-acting GH remains to be shown. The study data by Biller et al. (3) have demonstrated that the long-acting GH formulation for once-weekly injection is safe and efficient. Previous data using another formulation have also shown that the efficacy and safety over 32 wk are similar to what is obtained by daily sc injection in adults with GH deficiency (21). It is very likely that long-acting GH formulation will increase the convenience and compliance of treatment. They are, however, a further step away from normal physiology, which is something to consider when delivering replacement therapy for a hormonal deficiency. Future data on metabolism and safety will further support their place in the routine management of GH replacement and GH treatment in adults and growing children because the patient preference is high for these products. Disclosure Summary: The author has nothing to declare. For article see page 1718