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Impact of Growth Hormone (GH) Treatment on Cardiovascular Risk Factors in GH-Deficient Adults: A Metaanalysis of Blinded, Randomized, Placebo-Controlled Trials

Clinical Pharmacology (P.M.), Clinical Research Unit, Assistance Pubique-Hôpitaux de Paris, Henri Mondor University Hospital, F-94010 Créteil, France; Institut National de la Santé et de la Recherche Médicale U258 (P.M., M.N.-B., N.H., B.B.), F-94807 Villejuif, France; Institute of Public Health (S.G.), CB2 2SR Cambridge, United Kingdom; and Endocrinology and Reproductive Diseases (P.C.), Assistance Publique-Hôpitaux de Paris, Bicêtre University Hospital, and University Paris XI, F-94275 Le Kremlin-Bicêtre, France

Address all correspondence and requests for reprints to: P. Chanson, M.D., Endocrinology, Bicêtre University Hospital, 78 rue du Général Leclerc, F-94275 Le Kremlin-Bicêtre, France. E-mail: philippe.chanson{at}bct.ap-hop-paris.fr.

	Abstract

Top Abstract Introduction Subjects and Methods Results Body mass Lipids Blood pressure Glucose/insulin Effects of the GH... Discussion References

 
Patients with hypopituitarism have an increased risk of cardiovascular mortality. GH treatment could modify the cardiovascular risk in adults with GH deficiency, but most published clinical trials involved few patients and the results are variable.

We conducted a systematic review of blinded, randomized, placebo-controlled trials of GH treatment in adult patients with GH deficiency published up to August 2003. Thirty-seven trials were identified. We combined the results for effects on lean and fat body mass; body mass index; triglyceride and cholesterol [high-density lipoprotein, low-density lipoprotein (LDL), and total] levels; blood pressure; glycemia; and insulinemia. Overall effect size was used to evaluate significance, and weighted differences between GH and placebo were used to appreciate the size of the effect.

GH treatment significantly reduced LDL cholesterol [–0.5 (SD 0.3) mmol/liter], total cholesterol [–0.3 (0.3) mmol/liter], fat mass [–3.1 (3.3) kg], and diastolic blood pressure [–1.8 (3.8) mm Hg] and significantly increased lean body mass [+2.7 (2.6) kg], fasting plasma glucose [+0.2 (0.1) mmol/liter], and insulin [+8.7 (7.0) pmol/liter]. All effect sizes remained significant in trials with low doses and long-duration GH treatment.

Thus, GH treatment has beneficial effects on lean and fat body mass, total and LDL cholesterol levels, and diastolic blood pressure but reduces insulin sensitivity. The global cardiovascular benefit remains to be determined in large trials with appropriate clinical endpoints.

	Introduction

Top Abstract Introduction Subjects and Methods Results Body mass Lipids Blood pressure Glucose/insulin Effects of the GH... Discussion References

 
SINCE THE ADVENT of recombinant GH in 1985, GH therapy has been extended to adults with pituitary deficiency, in whom GH deficiency (GHD) has been hypothesized to be a cardiovascular risk factor (1, 2, 3, 4). An adult GHD syndrome was recently described (5), in which patients exhibit cardiovascular risk factors such as abdominal obesity, hypercholesterolemia, and hypertriglyceridemia. GH replacement therapy may reduce some of these cardiovascular risk factors (reviewed in Ref.6). Adverse effects include insulin resistance and increased volemia (7). Because hypertension and diabetes are common in patients with acromegaly and are also well-known cardiovascular risk factors, these effects are of particular interest. Most clinical trials of GH therapy in GH-deficient adults have involved small numbers of patients. Reported effects on cardiovascular risk factors varied according to the dose and duration of GH therapy, age at onset of GHD, and gender.

To obtain a more reliable picture of the effects of GH treatment on the main cardiovascular risk factors in GH-deficient adults (body mass, lipids, blood pressure, plasma glucose, and insulin), we conducted a systematic review of all blinded, randomized, placebo-controlled trials of GH in adults with GHD published up to August 2003.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Body mass Lipids Blood pressure Glucose/insulin Effects of the GH... Discussion References

 
Identification of relevant trials

We searched the Medline (Ovid), Experta Medica (EMBASE), and Biosis electronic databases, from their year of inception to August 2003. The medical literature was searched for all reports containing the key words, growth hormone (or somatotropin), trial, and human. The search strategy was not limited by study design or language.

A manual search of the Journal of Clinical Endocrinology and Metabolism since 1985 was used to assess the sensitivity of our electronic search. Additional information was requested from GH manufacturers, references cited in published articles, and clinical trials investigators.

Inclusion criteria

We included all randomized, blinded, placebo-controlled trials involving patients aged over 17 yr with GHD corresponding to less than 5 µg/liter after stimulation, as recommended by the consensus guidelines for the diagnosis and treatment of adults with GHD (8).

Included trials had at least one of the following outcome measures: diastolic blood pressure, systolic blood pressure, fasting blood glucose, fasting insulinemia, triglyceridemia, cholesterolemia [high-density lipoprotein, low-density lipoprotein (LDL), or total], lean body mass, fat mass (when expressed in absolute terms), and body mass index (BMI). These outcomes are the main cardiovascular risk factors in this setting and are the most frequently reported in clinical trials. Lean body mass is not, strictly speaking, a direct cardiovascular risk factor, but, because of the relationship between BMI, fat mass, and lean body mass, the effects of GH on these three parameters are of interest. From more than 3000 published reports, one of the authors (P.M.) selected the abstracts of trials that potentially met the inclusion criteria. The corresponding articles were then checked for the inclusion criteria, independently by three authors (N.H., M.N.-B., and P.M.). Discrepancies were resolved through discussion with all the authors. To detect a possible publication bias, we asked GH manufacturers what proportion of randomized, placebo-controlled trials were finally published.

Data extraction and outcomes

Three metaanalysts (N.H., M.N.-B., and P.M.) extracted data from published reports to a standard form. Authors were contacted to verify the extracted data where necessary. Discrepancies were resolved by discussion among all the authors of the present paper. The following data were extracted: population characteristics (setting, age, sex, number, weight, BMI, and disease onset), treatment (dose, duration, and frequency), study quality (design, randomization method, blinding, placebo vials, and statistical methods), losses to follow-up (for each outcome measure), baseline and follow-up values and changes (means and SD or SEM), and methods used to measure outcomes. All data extracted were summary data.

Statistical methods

For primary analyses of continuous outcome measures, we first calculated standardized effect sizes for each trial and then the global effect size for each outcome (9). The effect size is a measure of the overlap in the distribution of outcome scores between two treatment groups. The effect size was calculated differently for parallel-group and cross-over studies, to reflect intergroup and intragroup comparisons (9). For parallel groups, the effect size was computed as the mean difference (GH minus placebo) in the changes (follow-up minus baseline) for each outcome divided by the estimated variance of changes in the two groups. For cross-over trials, the effect size was calculated as the mean difference in values at the end of each period divided by the variance in the placebo group at follow-up. In some instances, these values had to be estimated from graphs in the articles [four for lean body mass (10, 11, 12, 13, 14), two for insulin (10, 11), one for glucose (10), and three for blood pressure (15, 16, 17). To calculate the overall effect size, the effect size in each study was weighted by the reciprocal of the variance. We present these scores with their 95% confidence intervals. A positive effect size implies an increase in the frequency of the outcome with GH treatment, and a negative effect size implies a decrease.

Because the variances for changes were not directly reported in all articles, they were calculated from t statistics, probability values, or confidence intervals (variances) for the GH and placebo groups (parallel design) or the study period (cross-over design) (9). We used a Q test to explore heterogeneity between studies. The analyses were repeated using a random-effects model when the effect size was significant in a fixed model (18). Because the random-effects model incorporates statistical heterogeneity (results, methodology, and publication bias) and provides a more conservative estimate of the pooled effect size than a fixed model, we present all the results of effect-size according to a random model. Funnel plots were drawn and their asymmetry was assessed to determine the possible influence of publication and location biases (19). The intercept of the weighted and unweighted linear regression lines, when the effect size divided by the SE is regressed against the reciprocal of the SE, provides a measure of asymmetry. Because the effect size may be significant because of a single trial (e.g. large trials or trials with large effects), we also conducted a sensitivity analysis. When the effect was carried by one or two trials, these studies were dropped from the analysis to verify whether the same trend was observed with the remaining trials. To quantify the size of the effect, we present the weighted (by the variance) mean difference (and SD) between the GH and placebo groups for each outcome measure.

The effects of the GH dose, GH treatment duration, percentage of patients with adult onset, and study design on overall estimates were assessed by stratification or metaregression. Weighted least-squares regression analysis was used for metaregression, individual study effects being weighted by the reciprocal of the estimated variance. The ß-coefficient and its significance are presented, along with the adjusted R² value, to show the overall variability explained by the model. Analyses were conducted using the SPSS (SPSS Inc., Chicago, IL) for Windows package.

	Results

Top Abstract Introduction Subjects and Methods Results Body mass Lipids Blood pressure Glucose/insulin Effects of the GH... Discussion References

 
The combined search strategy identified 37 blinded, randomized, placebo-controlled trials of GH in GH-deficient adults that included at least one of the necessary outcome measures (Tables 1 and 2) (7, 10, 11, 12, 13, 14, 15, 16, 17, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54). Different publications describing the same trial may refer to different outcomes. Eight trials could not be included because the required summary data could not be obtained. One trial was single blinded (13, 14). The trials were generally of good quality. Median losses to follow-up were 10% of patients [95% confidence interval = (0, 57)], and data were rarely analyzed on an intention-to-treat basis: their low number did not allow pertinent specific analysis of this subgroup of trials. Most reported comparisons were pretreatment vs. posttreatment rather than GH vs. placebo. Whatever the outcome measure, no significant heterogeneity was observed (Table 3). However, to obtain more conservative estimates, we present effect sizes with random-effects models. Funnel plotting and linear regression suggested a selection bias for insulin only (intercept, 9.4; P = 0.03 with weighted regression, and intercept, 7.3; P = 0.02 with unweighted regression), but publication bias was unlikely when this outcome was reported because it rarely reached statistical significance in individual trials. Three of the five GH manufacturers informed us that all the randomized, placebo-controlled trials they sponsored were finally published; the other two manufacturers did not answer or were unable to provide us with this information.

	Body mass

Top Abstract Introduction Subjects and Methods Results Body mass Lipids Blood pressure Glucose/insulin Effects of the GH... Discussion References

The overall effect size was significantly negative for fat mass [–0.62 (–0.78; –0.48)], with a weighted mean dif-ference of –3.05 kg (3.29). No effect was found on BMI (Table 3).

	Lipids

Top Abstract Introduction Subjects and Methods Results Body mass Lipids Blood pressure Glucose/insulin Effects of the GH... Discussion References

 
Significant beneficial effects were observed only for LDL and total cholesterol (Table 3). Weighted mean differences were –0.53 (0.29) mmol/liter and –0.34 (0.31) mmol/liter, respectively. Effect sizes were –0.35 (–0.52; –0.17) and –0.24 (–0.39; –0.08), respectively. In the analysis of sensitivity for LDL cholesterol, excluding the two trials (27, 48) with the most marked effects on this outcome measure, the overall effect size was still significant [–0.26 (–0.47; –0.05)].

	Blood pressure

Top Abstract Introduction Subjects and Methods Results Body mass Lipids Blood pressure Glucose/insulin Effects of the GH... Discussion References

 
Ten trials involving a total of 401 patients were included in the metaanalysis (Table 3). Ambulatory blood pressure was measured in two trials (15, 41). In the other eight trials, blood pressure was measured manually, usually after the participants had been lying or sitting for at least five min. The effect size was not significant for systolic blood pressure. In contrast, the overall effect size was significantly negative for diastolic blood pressure [–0.25 (–0.43; –0.07)]. The weighted mean difference in diastolic blood pressure was –1.80 (3.77) mm Hg. The effect size was still significant after exclusion of one large trial (27).

	Glucose/insulin

Top Abstract Introduction Subjects and Methods Results Body mass Lipids Blood pressure Glucose/insulin Effects of the GH... Discussion References

 
With 13 trials involving 511 patients, a significant overall effect of GH treatment on fasting glucose was observed [+0.43 (0.26; 0.60)] (Table 3). The mean weighted difference in blood glucose between the groups was +0.22 (0.14) mmol/liter, but weighted mean fasting glucose values were within the normal range on both GH treatment [5.1 mmol/liter (0.5)] and placebo [4.8 mmol/liter (0.4)]. In the analysis of sensitivity, the effect size was still significant after excluding three large trials (7, 14).

With 11 trials involving 378 patients, a significant overall effect of GH treatment on fasting insulin was observed [+0.42 (0.23; 0.61)] (Table 3). The mean weighted difference in plasma insulin was 8.7 (7.0) pmol/liter between GH and placebo. This difference remained significant after exclusion of one large trial (7).

	Effects of the GH dose and treatment duration, gender, age, age at GHD onset, and trial designs

Top Abstract Introduction Subjects and Methods Results Body mass Lipids Blood pressure Glucose/insulin Effects of the GH... Discussion References

 
Effect of the GH dose (Table 4).

No significant relationship was observed between the GH dose and the effect size in meta-regression analysis. This result could be explained by a narrow dose distribution. A subgroup analysis was then done with trials using target doses of no more than 0.35 U/kg·wk and a target dose of 0.5 U/kg·wk. All effect sizes remained significant in the analysis of low-dose trials (Table 4). A smaller number of trials used high doses, and the effect size in this subgroup was significant only for fat mass, glucose, and insulin. A dose-dependent effect of GH was found on fat mass, with a lower effect size with low-dose GH [–0.2 (–0.4; –0.0)] than with high-dose GH [–0.6 (–1.0; –0.1)].

View this table: [in this window] [in a new window]   TABLE 4. Effect size (95% confidence interval) in subgroup analysis with trials using target doses of no more than 0.35 U/kg·wk, and with trials with a target dose of 0.5 U/kg·wk and with trials of short duration (<6 months) and with trials of longer duration (6 months)

Effect of the treatment duration (Table 4).

No significant relationship was observed between the treatment duration and the effect sizes in metaregression analysis. Thus, Table 4 shows only the results of subgroup analyses. All effect sizes remained significant in the analysis of trials with long-duration treatment. There were few short-term trials, explaining the smaller number of significant parameters. Overall, the results pointed to a greater effect of prolonged treatment on lean mass and diastolic blood pressure.

Effect of gender.

When comparing effects according to gender, a significant negative relationship was found only between proportion of women and the effect size for blood glucose (ß = –0.59, P = 0.03, adjusted R² = 0.30), suggesting a lesser effect in women than in men.

Effect of age.

A significant relationship was observed between mean age and the effect size for LDL cholesterol (ß = –0.60, P = 0.03, R² = 0.36) and total cholesterol (ß = –0.64, P < 0.04, R² = 0.41): the younger the patient, the stronger the effect.

Effect of age at GHD onset.

The relationship between the proportion of patients with adult-onset (vs. childhood-onset) GHD and the effect of GH treatment was significant for diastolic blood pressure (ß = –0.88, P = 0.02, R² = 0.71) and plasma insulin (ß = –0.76, P = 0.03, R² = 0.50), suggesting a greater beneficial effect on blood pressure and a lesser negative impact on insulin in patients with adult-onset GHD.

Effect of the trial design.

The overall effect size in subgroup analyses of parallel-group studies remained similar for all outcomes. There were few cross-over studies (one for cholesterol and lean body mass, two for insulin and glucose, and four for blood pressure), and the global effect sizes were not significant.

	Discussion

Top Abstract Introduction Subjects and Methods Results Body mass Lipids Blood pressure Glucose/insulin Effects of the GH... Discussion References

 
This systematic review of 37 blinded, randomized, placebo-controlled trials shows a small but statistically significant beneficial effect of GH treatment on lean and fat body mass, LDL and total cholesterol, and diastolic blood pressure in GH-deficient adults. In contrast, GH therapy significantly increased plasma glucose and insulin levels.

A major potential source of bias in systematic reviews is that trials with positive results are more likely to be published than trials with neutral or negative results. In our metaanalysis, this bias seems unlikely with regard to blood pressure and total and LDL cholesterol (rare significant results) and blood glucose and insulin (negative results). Furthermore, information provided to us by GH manufacturers suggests that most GH trials in this setting are published. Another limitation of metaanalyses is the variable quality of the selected trials. To minimize this problem, we selected only studies with protocols meeting strict methodological quality criteria. This, of course, does not rule out quality problems arising during the trials’ progress.

Lean body mass increased and fat mass decreased after GH treatment, whereas total body weight remained constant. These results support a beneficial effect of GH on the cardiovascular risk and were observed, whatever the method used to measure lean mass.

Effects on LDL cholesterol and total cholesterol were variable. Half the trials showed no significant difference between placebo and GH. However, the overall effect size suggests a beneficial effect of GH on these cardiovascular risk factors. In contrast, no effect on high-density lipoprotein cholesterol or triglyceride levels was observed.

In most studies, mild fluid retention was observed and led to a reduction in the GH dose or withdrawal of patients from the trial. In one trial, GH treatment was associated with hypertension (10). On the contrary, another trial (23) showed a significant beneficial effect of GH on diastolic blood pressure. The overall effect size supports this result, with a decrease in diastolic blood pressure and no change in systolic blood pressure on GH. The relationship between blood pressure and GH therapy may be due to stimulation of the renin-aldosterone system (55), an increase in nitric oxide formation (15), or a decrease in intima-media thickness (56). However, this effect was observed during long-term treatment (at a time when fluid homeostasis had normalized) rather than during shorter treatment, suggesting that an effect of GH on blood vessels is more likely (57). It is noteworthy that GH effects on blood pressure were mentioned in only eight trial reports, even though blood pressure is probably monitored in all trials, suggesting that no significant effect was noted in most studies.

It has been suggested that GH treatment may impair glucose tolerance and even lead to diabetes (58). In one trial (14), two cases of incident diabetes were reported. However, the effect of GH on fasting insulin and glucose concentrations varied among the studies. The overall effect sizes in this review suggest significant increases in both insulin and glucose concentrations during GH treatment. The insulin-antagonistic effect of GH likely explains this finding (58). However, it must be emphasized that the mean glucose concentration remained in the normal range. Our results do not support previous suggestions that insulin resistance falls during low-dose and long-term GH therapy (31, 59). Men were more sensitive to the effect of GH on insulin sensitivity in our analysis. A similar gender difference in the response to GH treatment has been described with regard to lean body mass and fat mass (60) and is in keeping with the higher GH dose requirements in women than in men. However, very few studies with a prolonged follow-up (12 months) were included in this metaanalysis, and it must be pointed out that in the only trial reporting the effect of GH on this outcome, deleterious effects on insulin were not maintained at 12 and 18 months (14). Thus, studies with direct measurement of insulin sensitivity in patients treated on long-term with GH are needed before drawing firm conclusions about the effect (or absence of effect) of GH on this parameter in patients with GHD, despite a clear reduction in visceral fat.

Lower target doses are required to prevent adverse effects such as fluid retention and glucose elevation. However, our results suggest that, even at low doses, GH treatment is associated with elevated glucose and insulin concentrations, which are considered as cardiovascular risk factors. On the contrary, significant beneficial GH effects on cardiovascular risk factors such as lipid parameters and fat mass persisted at lower doses, even though the effect on fat mass tended to be weaker. Thus, the overall cardiovascular benefit of low-dose GH remains uncertain. However, taking into account the risk of cancer with GH treatment (61), the currently recommended use of low doses seems fully justified. Another important issue in all the trials reporting the effects of GH is the fact that many patients reduced the GH doses (due to side effects or according to IGF-I measurement), the final doses they achieved being lower than the target doses in a substantial number of patients. The issue of physiologic or pharmacological response to treatment is important. In this setting, it would have been interesting to study the dose-effect relationship in terms of IGF-I Z score, which takes into account the variance of age. Unfortunately, in the majority of studies, IGF-I was given in absolute terms, without any reference to normal age-adjusted ranges, which could have permitted a calculation of a SD score.

Our results suggest that young patients may be more sensitive than older patients to GH treatment. This negative relationship with age emerged for total and LDL cholesterol and has previously been described for lean body mass (33, 34).

Beneficial effects on body mass, cholesterol, and blood pressure increased with the duration of treatment, whereas adverse effects (on insulin and glucose) remained at a similar level. However, the results of subgroup analyses must be interpreted with caution because they involved a lower number of trials. Furthermore, long-term treatment usually corresponded to trials that did not exceed 6 months in duration.

We observed a difference between patients with adult-onset and childhood-onset GHD with regard to insulin and blood pressure. In contrast to previous studies (7, 20), GH treatment seemed to be more beneficial in adults with adult-onset GHD than in adults with childhood-onset GHD. We found no difference in GH effects between patients with multiple hormone deficiency and those with isolated GHD. However, the very small number of patients with isolated GH deficiency in most trials rules out firm conclusions.

In conclusion, this metaanalysis of blinded, placebo-controlled clinical trials shows that GH treatment has beneficial effects on lean body mass, fat mass, total and LDL cholesterol, and diastolic blood pressure in GH-deficient adults. GH may also have beneficial effects on other cardiovascular risk factors, such as fibrinogen (33), inflammatory parameters (14), cardiac function (62, 63), and intima-media thickness (56). As expected, GH reduced insulin sensitivity, whatever the dose and duration of treatment. Overall, however, the global cardiovascular benefit of GH treatment in adults remains to be determined in large, long-term trials with appropriate clinical end points.

	Acknowledgments

 
The authors thank Professor P. Sonksen, and Drs. G. Johannsson, L. Thuesen, N. Vahl, H. Simpson, C. Florkowski, and J. Mesa for their kind response to requests for new information about their data.

	Footnotes

 
Abbreviations: BMI, Body mass index; GHD, GH deficiency; LDL, low-density lipoprotein.

Received May 14, 2003.

Accepted February 18, 2004.

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Top Abstract Introduction Subjects and Methods Results Body mass Lipids Blood pressure Glucose/insulin Effects of the GH... Discussion References

 

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