Introduction
Growth hormone (GH) plays a role in the regulation of protein, lipid, and carbohydrate metabolism during adult life. About three-quarters of adult growth hormone deficiency (GHD) cases are associated with pituitary tumours and subsequent surgery and radiotherapy. Clinical manifestations of GHD in adults include decreased lean body and muscle mass, increased fat mass, reduced bone mineral density, lipid profile changes, and psychiatric symptoms. Diagnosis of adult GHD is usually based on a medical history (childhood-onset GHD, hypothalamic–pituitary disease or surgery, cranial irradiation or traumatic brain injury) and biochemical tests (GH stimulation tests). In a European study, the prevalence of hypopituitarism was estimated to be 29 to 45 per 100,000, and the incidence 4.2 cases per 100,000. There are no data on prevalence or incidence of GHD in Canada.
Once diagnosed, patients with GHD may receive replacement therapy with somatropin, which is identical in amino acid sequence to endogenous GH and synthesized through recombinant DNA technology. The goals of replacement therapy are to correct the metabolic, functional, and psychological abnormalities associated with adult GHD. A number of somatropin products are available in Canada for replacement of endogenous growth hormone in adults with GHD, including Genotropin. The approved dose of Genotropin in this population is 0.15 mg to 0.3 mg per day, administered subcutaneously.
Results and Interpretation
No randomized controlled trials (RCTs) comparing Genotropin with other somatropin drugs available in Canada in adults with GHD were identified. Common Drug Review (CDR), in consultation with the clinical expert contracted for the review, identified three key clinical issues of relevance to consideration of Genotropin treatment in adults with GHD: a summary of systematic reviews of somatropin in adult GHD; comparison of the pharmaceutical, pharmacokinetic, and pharmacodynamic characteristics of somatropin products available in Canada; and a summary of manufacturer-submitted placebo-controlled RCTs of Genotropin.
Summary of Systematic Reviews of Somatropin
Eight systematic reviews comparing somatropin with placebo or no treatment were included, and data on key efficacy and safety parameters (as identified a priori in the protocol for the CDR review) were summarized. The number of included individual studies ranged from 8 to 54. The included studies in these reviews varied with respect to study design (RCT, non-randomized comparative studies, and observational studies, etc.), quality of evidence, patient characteristics, and outcome measures of interest. Meta-analysis was performed in six reviews. Data on survival were assessed in only one systematic review; however, no data on cardiovascular morbidity were reported. Most of the reviews did not differentiate between various somatropin products. In one systematic review that specifically indicated that Genotropin was one of the study drugs, the dose used in the included studies (ranging from 0.4 mg to 1.8 mg per day) was generally higher than the dose approved in Canada.
Efficacy
Two systematic reviews of RCTs and non-RCTs reported findings on health-related quality of life (HRQoL) in adults with GHD. Inconsistent results were presented. Some studies indicated that long-term or short-term somatropin therapy was associated with improvement in HRQoL, mainly energy levels, while other studies reported no difference between somatropin and placebo. Numerical results were not provided in these two reviews, and minimal clinically important differences are not available; hence, the clinical significance of the observed differences (where they existed) could not be determined.
Two meta-analyses of RCTs reported findings on exercise capacity. Both suggested statistically significant improvements for patients who received 3 to 18 months of somatropin therapy, compared with placebo. The expert consulted by CDR considered the improvements in exercise capacity to be of moderate clinical significance.
Pooled data in two meta-analyses of RCTs showed no significant difference in muscle strength between 3 to 12 months of somatropin and placebo; in addition, long-term (5 to 10 years) results from non-RCTs and observational studies suggested that somatropin improved muscle strength during the first five years of treatment, but the effect was not sustained after five years.
Three reviews reporting lipid profiles from RCTs and non-RCTs indicated that, in some of the included trials, somatropin therapy was associated with lower levels of total cholesterol and low-density lipoprotein compared with no treatment or placebo, while other trials did not detect a significant between-group difference in these parameters.
A positive impact of somatropin therapy on bone mineral density in different sites was demonstrated in one meta-analysis of RCTs and non-RCTs; however, its long-term (ranging from 5 to 15 years) effect on bone mineral density varied from trial to trial in another systematic review. Fractures were infrequently reported, and the clinical significance of the observed bone mineral density improvements is uncertain.
Statistically significantly increased lean body mass and decreased fat mass related to the use of somatropin were reported in two meta-analyses of RCTs; however, inconsistent results were reported in two systematic reviews of RCTs and non-RCTs without data pooling. The impacts of the observed changes in body composition on clinical end points such as cardiovascular disease or mortality are uncertain.
Harms
The effect of somatropin therapy on mortality from systematic reviews was inconclusive as a result of scarce data. Results for glucose levels and blood pressure were inconsistent across two reviews of RCTs and non-RCTs.
Comparison of Somatropin Products Available in Canada
Somatropin products available in Canada for replacement of endogenous growth hormone in adults with GHD include Humatrope, Nutropin, Omnitrope, Saizen, and Genotropin. While there are differences in the manufacturing process, formulation components, administration methods, and recommended doses of these products, their pharmacokinetic profiles are only slightly different from each other. According to the clinical expert, these differences are unlikely to result in clinically important consequences. However, the differences in dosing and administration formats may add complexity when a patient is switched from one somatropin product to another.
Summary of Manufacturer-Submitted Placebo-Controlled Trials
The manufacturer’s submission detailed six placebo-controlled RCTs of Genotropin, all of which were six months in duration. The only consistent benefit observed in these trials was improved body composition (i.e., increased lean body mass and reduced body fat). The clinical significance of the observed changes was uncertain. Positive effects on HRQoL, lipid profile, and bone mineral density were not consistently observed. The risks of adverse events were numerically higher in the Genotropin group compared with placebo. Common adverse events observed in the somatropin group included general disorders, peripheral swelling, and musculoskeletal disorders. All of the trials were small (N ranged from 20 to 52); hence, statistical power was likely limited for many outcomes. As well, all six trials excluded patients older than 60 years; hence, efficacy and safety data were not available for elderly patients.
Pharmacoeconomic Summary
Somatropin (Genotropin) is available as an injection with multiple strengths (0.6 mg, 0.8 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, and 2.0 mg syringes, and 5.3 mg and 12 mg pens). The manufacturer used a cost-minimization analysis to support its request for reimbursement of Genotropin for use in adults with GHD. Similar clinical effectiveness for Genotropin versus comparators was assumed based on the results of one trial comparing Genotropin to Omnitrope in children with GHD. There were no published indirect comparisons of these agents. Based on CDR calculations using a confidential price of $▬ per milligram, the daily cost of the maximum dose of Genotropin ($▬; 0.15 mg to 1.33 mg per day) is less than that of Humatrope ($49; 0.006 mg/kg to 0.0125 mg/kg per day), Nutropin ($82; 0.042 mg/kg to 0.175 mg/kg per week), and Omnitrope ($41; 0.15 mg to 1.33 mg per day), but higher than that of Saizen ($38; 0.005 mg/kg to 0.01 mg/kg per day).
Conclusions
There was no evidence to assess the relative efficacy and safety of Genotropin versus other somatropin products available in Canada for the treatment of adults with GHD. While all somatropin products have the same amino acid sequence as endogenous human GH and similar pharmacokinetic profiles, they differ somewhat with respect to manufacturing processes, dosage forms, excipients, dosing recommendations, and approved indications. Systematic reviews of somatropin products for the treatment of adult GHD indicate possible improvements in some dimensions of quality of life, exercise performance, lipid profile, and body composition compared with placebo or no treatment, although results were inconsistent across studies for some outcomes, and the clinical importance of the observed changes is uncertain. The only consistent benefit of Genotropin in the manufacturer-submitted placebo-controlled RCTs was improved body composition, but, once again, the effects were of uncertain clinical significance.
