Objectives:

This is an evidence report prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center (EPC) examining the benefits and harms associated with using recombinant human growth hormone (rhGH) in patients with cystic fibrosis (CF).

Data Sources:

MEDLINE (starting from 1950), Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews from the earliest possible date through April 2010.

Review Methods:

The methods used to answer questions of rhGH usage in CF patients specifically are given. Randomized controlled trials, observational studies, systematic reviews/meta-analyses, or case reports were included if they: administered rhGH therapy to patients with CF and reported data on pre-specified harms, intermediate outcomes or final health outcomes. Using a standardized protocol with predefined criteria, data on study design, interventions, quality criteria, study population, baseline characteristics, and outcomes was extracted. Some of the data allowed for statistical pooling. When pooling continuous endpoints, weighted mean differences (WMD) with 95 percent confidence intervals (CIs) were calculated using a DerSimonian and Laird random effects model. I² was used to detect statistical heterogeneity. Visual inspection of funnel plots and Egger’s weighted regression statistics were used to assess for publication bias. The overall body of evidence was graded for each outcome as insufficient, low, moderate, or high.

Results:

Ten articles based on unique trials, eight articles based on trials reported in previous articles, and eight articles based on observational studies met our inclusion criteria. Controlled trials were limited to patients with CF and impaired baseline growth indices. Upon quantitative synthesis of controlled trials, several markers of pulmonary function [forced vital capacity (FVC) (WMD 0.67 L, 95 percent CI 0.24 to 1.09 L), percent predicted FVC (WMD 9.34 percent, 95 percent CI 3.41 to 15.27 percent), and forced expiratory volume in one second (FEV₁) (WMD 0.23 L, 95 percent CI 0.01 to 0.46 L)], anthrometrics [change in height (WMD 3.13 cm, 95 percent CI 0.88 to 5.38 cm), height velocity (WMD 3.27 cm/year, 95 percent CI 2.33 to 4.21 cm/year), and height Z-score (WMD 0.51, 95 percent CI 0.35 to 0.66), weight (WMD 1.48 kg, 95 percent CI 0.62 to 2.33 kg), weight velocity (WMD 2.15 kg/year, 95 percent CI 1.52 to 2.78 kg/year), body mass index (BMI) (WMD 2.08 kg/m², 95 percent CI 1.20 to 2.96 kg/m²), percent ideal body weight (IBW) (WMD 12.57, 95 percent CI 7.01 to 18.12), lean body mass (LBM) (WMD 1.92 kg, 95 percent CI 1.47 to 2.37 kg)] and bone strength (bone mineral content (WMD 192 g, 95 percent CI 110 to 273 g)] were significantly improved versus control. A moderate to high degree of statistical heterogeneity was seen for many of these intermediate outcomes, but the directions of effect for individual studies were almost always consistent. Single-arm observational studies for the aforementioned outcomes were generally supportive of findings in clinical trials. Patients receiving rhGH therapy in controlled trials had no significant changes in percent predicted FEV₁ (WMD 2.43 percent, 95 percent CI −3.99 to 8.85 percent ), weight Z-score (WMD 0.49, 95 percent CI −0.02 to 1.00), exercise work rate (WMD 11.80 W, 95 percent CI −0.44 to 24.04 W), FEV₁ Z-score (WMD −0.005, 95 percent CI −0.22 to 0.21) or BMI Z-score (WMD −0.05, 95 percent CI −0.30 to 0.20) versus control therapy.

Despite promising findings on intermediate outcomes, there is insufficient evidence to determine the effect of rhGH on IV antibiotic use during therapy, pulmonary exacerbations, health-related quality-of-life (HRQoL), bone consequences, or total mortality. There is moderate evidence to suggest that rhGH therapy reduces the rate of hospitalization (WMD −1.62 hospitalizations per year, 95 percent CI −1.98 to −1.26 hospitalizations per year) versus control although one trial not amenable for quantitative synthesis reported that there were no statistically significant differences in hospitalization days between groups. In qualitative assessment, rhGH therapy does not seem to improve sexual maturation in males and the impact in females cannot be determined at this time.

In quantitative synthesis of controlled trials, rhGH therapy significantly increases fasting blood glucose (WMD 5.68 mg/dl, 95 percent CI 0.43 to 10.93 mg/dl) and nonsignificantly increases stimulated glucose concentrations (WMD 4.93 mg/dl (95, percent CI −15.13 to 24.98 mg/dl) but long term glucose control, as assessed by hemoglobin A1c, is not impacted (WMD −0.10 percent, 95 percent CI −0.40 to 0.20 percent) versus control. In qualitative analysis, insulin-like growth factor-I (IGF-I) concentrations in rhGH treated patients are more than 100 ng/mL higher than control. While IGF-I is a marker for malignancy, insufficient evidence exists to determine the impact of rhGH on cancer incidence.

In patients with CF not receiving rhGH, the associations between the aforementioned intermediate outcomes and final health outcomes were generally weak.

Conclusions:

rhGH improved almost all intermediate measures of pulmonary function, height, and weight in patients with CF. Improvements in bone mineral content are also promising. However, with the exception of hospitalizations, the benefits on final health outcomes cannot be directly determined at this time. In the relatively low doses used in CF patients for a time period of 6 to 12 months, rhGH therapy may worsen short term markers of glucose control but may not impact long terms glucose control. The increase in IGF-I with rhGH therapy is above a threshold thought to increase the risk of malignancy but the strength of this marker in determining malignancy is not firmly established.