1.4. Summary of Available Evidence

No RCTs comparing Genotropin with other somatropin products in adults with GHD were identified in this review, nor were there indirect comparisons of these products. The following information was reviewed in order to provide context for the use of Genotropin in adults with GHD: a summary of systematic reviews of treatments for adult GHD; a summary of all somatropin products available in Canada; and a summary of placebo-controlled studies of Genotropin in adult patients with GHD.

1.5. Interpretation of Results

Some of the potential benefits of somatropin in adults with GHD include improved HRQoL, improved exercise capacity, increased BMD, enhanced body composition, and slightly decreased blood pressure.⁵ Patient group input received by CDR also suggested that treatment with somatropin was felt to improve mental health, social relationships, and energy level. Two systematic reviews reviewed by CDR found benefits on some dimensions of HRQoL with somatropin; however, results were inconsistent across studies. As well, the clinical relevance of any observed benefits was uncertain since numerical results were not presented and MCIDs were not available. Two meta-analyses of RCTs on exercise capacity suggested statistically significant improvements in exercise capacity for patients receiving somatropin therapy compared with placebo. The effect sizes were moderate, according to the clinical expert consulted on this review. In clinical practice, exercise capacity is usually assessed by exercise tests such as stair climbing or distance walked. The clinical relevance of the exercise outcome measures reported in the included systematic reviews are therefore uncertain. Results from two meta-analyses showed no significant difference in muscle strength between somatropin and placebo. Observational data from another review suggested that somatropin improved muscle strength during the first five years of treatment, but the effect was not sustained thereafter.

The effect of somatropin on lipid profile remains uncertain given conflicting results for TC, LDL, and HDL. One systematic review reported small reductions in total cholesterol and low-density lipoprotein with the use of somatropin in patients older than 60 years: 4% to 8% reductions in TC and 11% to 16% reductions in LDL. According to the clinical expert, these reductions in cholesterol may be meaningful, since even small changes in cholesterol are associated with a reduced risk of cardiovascular events. The positive impact of somatropin therapy on BMD on different body sites was demonstrated in one meta-analysis; however, its long-term effect on BMD varied from trial to trial in another systematic review. Inconsistent results for body composition were observed in the four systematic reviews that reported this outcome, although statistically significant increases in lean body mass and decreased fat mass related to the use of somatropin were reported in two meta-analyses. The clinical expert indicated that even small increases in lean body mass and reductions in body fat could be beneficial and clinically meaningful, although no evidence was found in the literature to suggest minimally important differences for these outcomes. There was no compelling evidence available for the effect of somatropin on mortality, since data were scarce.

Most of the included systematic reviews and meta-analyses did not specify the type of somatropin products being evaluated, except the Hazem et al. review. The dose of Genotropin in this review ranged from 0.4 mg to 1.8 mg per day (assuming 80 kg of body weight). The recommended dosing for Genotropin in adults with GHD is 0.15 to 0.3 mg per day (maximum of 1.33 mg per day) in the product monograph. Therefore, the dose adopted in the clinical trials was higher than that approved by Health Canada, and this may impact the generalizability of the findings to Canadian clinical practice. Evidence from the placebo-controlled RCTs of Genotropin, which were restricted to six months of treatment, suggested favourable effects on body composition, but other benefits such as improvements in HRQoL were inconsistently observed. Other purported benefits of Genotropin such as on lipid profile and BMD were also not consistently observed. The clinical significance of the body composition effects is uncertain for a number of reasons. First, the trials were small in terms of sample size and of short duration; hence, long-term effects in the general adult GHD population are uncertain. Second, it is unknown whether the observed changes predict clinical end points such as cardiovascular events or mortality. It is also noteworthy that the included trials did not enrol patients older than 60 years of age; therefore, evidence for Genotropin in the elderly is scant. The risks of adverse events during the six-month treatment were numerically higher in the Genotropin group compared with placebo.

All somatropin products have some similarities in manufacturing processes in that all products use recombinant DNA technology in E. coli host cells, except for Saizen. The excipients used as preservatives or stabilizers vary greatly between formulations (lyophilized powder and solution) as well as among products. Pharmacokinetic profiles of various somatropin products are slightly different from each other; however, these differences do not appear to be significant and are not expected to result in important clinical consequences. In addition, the clinical expert indicated that there was no apparent difference in efficacy and safety between different somatropin drugs in clinical practice, although differences in dosing and administration formats may add complexity when a patient is switched from one product to another.