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Institute of Endocrine Sciences (C.L.R., V.V., P.B.-P., E.O., F.D., C.G., E.F., A.L., A.S., M.A.) and Occupational, Clinical and Environmental Epidemiology Research Center (A.B.), Fondazione Instituto di Ricovero e Cura a Carattere Scientifico Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, and Department of Endocrinology, Ospedale S. Giuseppe-Fatebenefratelli, AfaR (M.A.), University of Milan, 20122 Milan, Italy
Address all correspondence and requests for reprints to: Cristina L. Ronchi, Institute of Endocrine Sciences, Fondazione Instituto di Ricovero e Cura a Carattere Scientifico, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Via F. Sforza 35, 20122 Milan, Italy. E-mail: cristina.ronchi{at}unimi.it.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Objective: The objective of this study was to compare the long-term effects of SSTa treatment and successful surgery on GH/IGF-I secretion and cardiovascular risk parameters in acromegaly.
Design, Patients, and Intervention: This was a retrospective study of 36 acromegalic patients treated with SSTa and evaluated after a median of 66 months and of 33 sex-, age-, and body mass index-matched cured patients evaluated after a similar period of remission, all from the Institute of Endocrine Sciences (Milan, Italy).
Main Outcome Measures: The main outcome measures were fasting and post-oral load glucose homeostasis, hemoglobin A1c, insulin sensitivity and secretion by several indexes, lipid profile, and blood pressure.
Results: Fasting and areas under the glucose response curve rose in patients controlled (n = 29) and not controlled (n = 7) by SSTa, becoming higher than those in cured subjects. A 1% hemoglobin A1c increase was observed in all nondiabetic SSTa patients, but not in cured subjects. Basal insulin secretion and resistance, evaluated by homeostasis model assessment, decreased in all SSTa patients, whereas oral glucose tolerance test-derived insulin secretion and resistance, evaluated by insulinogenic index and oral glucose tolerance test-derived insulin secretion, improved only in SSTa-treated controlled patients. Triglycerides did not change during SSTa, whereas high-density lipoprotein cholesterol increased in SSTa-treated controlled patients. At the last visit, the contemporary presence of at least three cardiovascular risk factors was more frequent in patients treated with SSTa than in cured subjects.
Conclusions: SSTa therapy induces long-lasting disease control and improvement of insulin sensitivity and high-density lipoprotein cholesterol levels in responsive patients. The progressive glucose homeostasis alterations, observed independently from the degree of cure, suggest the need for glucose homeostasis and peripheral vascular complications monitoring during chronic SSTa treatment.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The aim of the present study was to investigate the effects of very long-term therapy with either o-LAR or l-SR on several disease-related cardiovascular risk factors in a large series of acromegalic patients. These results were compared with those obtained in a control group of well-matched, surgically cured patients who were reevaluated after a similar interval of time from the remission of disease.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Thirty-six consecutive patients with active acromegaly were studied before and during chronic treatment with depot SSTa (SSTa group). In particular, o-LAR was administered in 16 patients at 10–30 mg every 28 d, and l-SR was given to 20 patients, (60-mg l-SR microparticles every 21–28 d and 120 mg l-Autogel every 28–56 d in 16 and four patients, respectively). Thirty of these patients had previously undergone unsuccessful surgery, followed within 1–2 yr by radiotherapy in 18 cases (eight with conventional fractionated technique and 10 with 
-knife radiosurgery), whereas six were newly diagnosed (Table 1
). A group of 33 sex-, age-, and body mass index (BMI)-matched acromegalic patients who had undergone pituitary surgery, followed by radiotherapy in 12 cases (four with conventional fractionated technique and eight with -knife radiosurgery), and considered definitively cured according to current guidelines (23) was also evaluated as a control (cured group; Table 1). Eight patients treated with SSTa and six cured patients had one or more pituitary hormone deficiencies (not significantly different by Fisher’s exact test), in particular, hypoadrenalism (four SSTa and one cured), hypothyroidism (two SSTa and four cured), and hypogonadism [four SSTa (two men and two women) and one cured man], which were adequately substituted with the minimum required doses of cortisone acetate, levothyroxine, and testosterone/estroprogestinic, respectively.
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). In particular, the numbers of smoker patients (16 SSTa and 11 cured patients) or those with known positive family history for diabetes mellitus (12 and 15, respectively), blood hypertension (14 and 14, respectively), or dyslipidemia (six and three, respectively) were similar in the two series (all nonsignificantly different by Fisher’s exact test). Before SSTa treatment, glucose metabolism was abnormal in 11 patients [diabetes mellitus in seven and impaired glucose tolerance (IGT) in four, according to 1999 World Health Organization criteria]. Similarly, before surgery, 10 cured patients showed abnormal glucose metabolism [diabetes mellitus in one, IGT in eight, and impaired fasting glucose (IFG) in one]. At baseline, 20 SSTa patients and 15 cured patients were affected by systemic hypertension, treated by hypotensive drugs when necessary, whereas 24 and 29 patients, respectively, were affected by different types of dyslipidemia, in some cases treated by specific lipid-lowering drugs. The local ethical committee approved the study, and all subjects gave informed written consent. Study protocol and assays
All patients were periodically studied for the treatment efficacy by the evaluation of both serum GH (mean of at least five samples taken every 30 min during 2 h of saline infusion) measured by immunofluorometric assay (AutoDelfia, Wallac OY, Turku, Finland), and serum IGF-I was measured by RIA (Mediagnost, Tubingen, Germany), as previously described (24). The IGF-I values were compared with an appropriate age-adjusted range, as previously reported (25), and also expressed as an SD score. Patients also regularly underwent clinical examinations that included weight and height with calculation of BMI, waist circumference, and systolic and diastolic blood pressures measured according to the World Health Organization International Society of Hypertension Guidelines. Periodical laboratory assessment included fasting glucose (FG) and insulin levels (FI), glycosylated hemoglobin (HbA1c), lipid profile encompassing total cholesterol (TC), high-density cholesterol (HDLc), and triglycerides (TG) and fibrinogen. All these parameters were measured by standard procedures. Low-density lipoprotein cholesterol (LDLc) levels were evaluated by the formula: LDLc = TC – HDLc – TG/5. TG/HDLc ratio was calculated as a marker of cardiovascular risk, as previously described (26). FI was not measured in diabetic patients pharmacologically treated. A 2-h 75-g oral glucose tolerance test (OGTT) was performed in all nondiabetic patients for the evaluation of glucose and insulin levels. Basal hepatic insulin sensitivity was investigated by simple indexes derived from FG and FI, namely, the homeostasis model assessment [HOMA-S% = 22.5/FI (mU/liter) x FG (mmol/liter)] (27) and the quantitative insulin check index (QUICKI = 1/[log FG (mg/dl) + log FI (mU/liter)]) (28). The whole-body stimulated insulin sensitivity was measured by the composite index [insulin sensitivity index (ISI)] derived from the OGTT, proposed and validated against euglycemic hyperinsulinemic clamp by Matsuda et al. (OGTTISI = 10,000/square root of [FG x FI] x [mean glucose x mean insulin during OGTT]) (29). Basal and stimulated insulin secretion were investigated by simple formulas by the HOMA method (HOMA-B% = [(FI (mU/liter) x 20)/(FG (mmol/liter) – 3.5)]) (27) and by the insulinogenic index (IGI) proposed by Stumvoll et al. (30) ([IGI = insulin at time 30 – insulin at time 0 (pmol/liter)/glucose at time 30 (mmol/liter)]), respectively.
Patients were considered affected by hypertension and/or dyslipidemia according to Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults III (ATPIII) criteria (31), whereas glucose tolerance was defined according to World Health Organization criteria (32). In accordance with the newly proposed FG cutoff values for the diagnosis of altered glucose homeostasis and metabolic syndrome (33), patients with levels between 100 and 109 mg/dl (5.5 and 6.0 mmol/liter) were also counted as a separate group.
The study analyzed data obtained before and during chronic SSTa therapy, in particular, at 12 months and at the last follow-up visit, which corresponded to a median period of 66 months from the start of treatment (mean, 71.4 ± 25.5 months; range, 30–138 months). The cured group was evaluated at diagnosis and after a similar median period from definitive biochemical remission of disease (median, 80 months; mean, 86.7 ± 34.8; range, 30–150). The time from radiotherapy at last visit was also comparable between the two groups of patients (6.3 ± 3.3 in SSTa vs. 4.9 ± 4.6 yr in cured subjects; not significantly different by Fisher’s exact test).
Statistical analysis
Data are expressed as the mean ± SD unless otherwise stated. Data were tested for normality of distribution by Kolmogorov-Smirnov test and log-transformed to obtain normal distribution when necessary. Statistical analysis was carried out using paired two-tailed Student’s t test to compare baseline characteristics of the two groups of patients. The pattern of the recorded glucose and insulin values over the time of the OGTT was assessed by a one-way ANOVA for repeated measurements model, followed by Bonferroni’s post hoc test. The areas under the response curve (AUC) of glucose and insulin during OGTT were estimated according to the trapezoidal method. Fisher’s exact test was used to analyze differences in the number of patients with different metabolic abnormalities. Linear regression analysis was performed to determine correlation coefficients between different parameters. Multivariable regression models were used to evaluate the association between treatment group and glucose homeostasis after controlling for multiple variables potentially associated with glycemia control. Multivariate models included either plasma FG or AUCGLUC as the dependent variable and patient group, IGF-I, GH, IGI, HOMA-B, and BMI as independent variables. ß Coefficients and related SE values obtained from the models are reported. P < 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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During SSTa therapy, 29 patients reached GH levels below 2.5 µg/liter and IGF-I levels in the normal range for age [controlled (SSTa-C); 81% of the total], whereas seven reached only poor GH and/or IGF-I control [not controlled (SSTa-NC); 19%]. The total time of follow-up during SSTa was comparable in these two subgroups of patients. Both GH and IGF-I significantly decreased in SSTa-C and SSTa-NC after 12 months; afterward, GH remained stable until the last follow-up visit, whereas IGF-I further decreased in SSTa-C, remaining within the normal range in all patients (Fig. 1). In particular, GH and IGF-I were similar in SSTa-C and cured patients at the last visit. No difference in IGF-I reduction was observed between the 18 SSTa patients who received and the 18 who did not receive radiotherapy. Similarly, no differences were found between newly diagnosed and previously operated/irradiated SSTa patients or between o-LAR and l-SR/Autogel.
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BMI values significantly increased until the last visit in all groups, in particular, from 27 ± 4 to 28 ± 4 kg/m2 in SSTa-C (P < 0.05), from 28 ± 4 to 31 ± 6 kg/m2 in SSTa-NC (P < 0.05), and from 26 ± 4 to 27 ± 5 kg/m2 in cured subjects (P < 0.05 vs. baseline and NS vs. SSTa-C and -NC). However, waist circumference values did not change in any group throughout the duration of the study.
Glucose metabolism
Plasma FG levels similarly and progressively increased over time in SSTa-C and SSTa-NC, becoming at the last visit higher in SSTa-NC compared with SSTa-C and in both cases higher than those recorded in cured subjects (Fig. 1). In the multivariable models, the difference between SSTa-C and SSTa-NC disappeared, suggesting that it was due to associated changes in the parameters included in the model (with IGF-I as the best predictor, P < 0.05). The difference between SSTa-C and cured subjects was still present in this analysis (P < 0.005) even if slightly decreased (ß coefficient, 14.7 ± 6.0 to 11.3 ± 3.0); IGF-I was always the best predictor (P < 0.05). A significant positive correlation was observed between FG and GH/IGF-I levels during SSTa treatment (r = 0.53; P < 0.005 and r = 0.54; P < 0.05, respectively; data not shown).
Plasma HbA1c levels progressively rose until the last visit from 4.7 ± 0.7% to 5.7 ± 0.5% in SSTa-C and from 4.8 ± 0.7% to 6.1 ± 1.5% in SSTa-NC (both P < 0.05); they were abnormal in six of 29 SSTa-C (20% of total) and two of five SSTa-NC (40%), whereas they did not change in cured subjects (5.1 ± 0.8% vs. 5.6 ± 0.9%; not significantly different), being abnormal in two of 33 subjects (6%). HbA1c also increased in four previously diabetic patients (two SSTa-C and two SSTa-NC) and remained stable in the other three.
The AUCGLUC progressively and similarly increased in SSTa-C and SSTa-NC, becoming higher than in the cured group (Fig. 1). In the multivariable models, the difference between SSTa-C and cured subjects became nonsignificant, with IGF-I and HOMA-B% as the most important predictors (both P = 0.05). The entire glucose response curve after OGTT showed a significant decrease in cured (P < 0.05 vs. before surgery) and a significant increase in all SSTa-treated patients (P < 0.05 vs. before SSTa and cured subjects; Fig. 2).
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Serum FI levels significantly and similarly decreased in all groups of patients (data not shown). The entire insulin response to glucose load showed an early and temporary decrease at 30 min in SSTa-C (P < 0.05 vs. before SSTa) and a late and prolonged decline in cured subjects (P < 0.05 vs. before surgery), whereas it showed an increase in SSTa-NC, with a peak at 30 min (P < 0.05 vs. pre-SSTa and cured subjects; Fig. 2).
As expected, HOMA-B% significantly fell in all SSTa groups, whereas IGI sharply decreased only in SSTa-C, becoming in both cases lower than those observed in cured patients (Fig. 4). All insulin sensitivity indexes, such as HOMA-S%, QUICKI, and OGTTISI, significantly increased in SSTa-C and cured groups, but not in SSTa-NC (Fig. 4). HOMA-S% also negatively correlated with IGF-I levels (P < 0.05; r = 0.41; data not shown). No significant differences were found in glucose tolerance/insulin sensitivity between o-LAR and l-SR/Autogel or between newly diagnosed and previously unsuccessfully treated SSTa patients.
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At the last visit, mean diastolic blood pressure values did not change in any group, whereas mean systolic slightly decreased only in cured patients (Table 2). The overall blood pressure worsened in 11 SSTa (six normotensive and five hypertensive) and in eight cured patients (six normotensive and two hypertensive), whereas it improved only in four cured controls. Serum HDLc levels significantly increased at the last visit in SSTa-C and cured subjects, including diabetic patients, whereas TG and LDLc levels decreased only in cured subjects and SSTa-C, respectively (Table 2). The TG/HDL ratio and TC did not change in any group (Table 2). The lipid profile worsened in 10 patients (five dyslipidemic and five normolipidemic) during SSTa, whereas it improved in 21 dyslipidemic patients (seven SSTa and 14 cured).
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). No significant correlations between all these metabolic factors and glucose homeostasis/insulin resistance parameters or GH/IGF-I levels were found. No differences between o-LAR and l-SR were observed.
At the last visit, the contemporary presence of at least three cardiovascular risk factors, recognized according to the ATPIII report (31), was more frequent in SSTa (eight SSTa-C and four SSTa-NC) than in cured subjects (n = 4; P < 0.05 vs. SSTa, by Fisher’s exact test; Fig. 3B).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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We evaluated insulin release and hepatic or whole body insulin sensitivity by a number of indexes, derived from glucose and insulin values, that have been previously validated in healthy subject and different insulin-resistant populations, such as diabetic, obese, and acromegalic patients (29, 30, 31, 41). In particular, HOMA-S% and HOMA-B% reproduce insulin sensitivity and secretion under fasting conditions, respectively, whereas OGTTISI and IGI reflect insulin sensitivity and secretion after oral glucose load administration, respectively. Using this approach, basal insulin secretion significantly decreased during SSTa therapy in both SSTa-C and SSTa-NC, whereas insulin release after glucose load significantly decreased only in SSTa-C, becoming lower than that in cured patients. Also, the overall insulin response to OGTT during SSTa therapy showed a significant decrease only in SSTa-C. Therefore, the glucose deterioration found in controlled patients seems to be at least partially due to a deep and prevalently postload insulin suppression. The multivariate analysis showed that HOMA-B% together with IGF-I were the most important predictors of the differences in AUCGLUC between SSTa-C and SSTa-NC. Consistent with the involvement of insulin reduction in glucose metabolism deterioration during SSTa therapy, a recent study by Barkan et al. (42) demonstrated that the glucose improvement in acromegalic patients converted from SSTa to pegvisomant was strictly associated with insulin increase.
Another possible mechanism of glucose worsening in SSTa-C may be represented by the possible incomplete normalization of the 24-h GH secretion profile obtained by SSTa treatment with respect to successful surgery (43). This assumption was also supported by the multivariate analysis data indicating that IGF-I was the best predictor of FG differences between SSTa-C and SST-NC. Accordingly, Van Thiel et al. (44) recently reported that a typical acromegaly-related complication, such as diastolic cardiac dysfunction, still persisted despite successful long-term octreotide treatment, suggesting an incomplete restoration of the physiological GH secretion pattern.
Basal and postload insulin sensitivity significantly improved in patients responsive to SSTa, confirming previous findings obtained by euglycemic clamp (14, 20). Furthermore, they reached values similar to those observed in cured patients, in contrast with previously reported data (19, 45). Moreover, HOMA-S% significantly correlated with IGF-I levels, supporting the strict connection between disease control and insulin sensitivity. In this view, the significant rise in HDLc levels found in both SSTa-C and cured patients seemed to closely reflect improvement in insulin sensitivity (26, 46). The observed improvement was of particular relevance, because HDLc levels exceeded the current cutoff values recommended to reduce cardiovascular risk (31).
No significant differences were observed in diastolic and systolic blood pressures between patients controlled by SSTa or surgery, thus confirming a substantially similar role of the two different therapeutic options on systemic pressure control (11, 15, 17, 47). Finally, this study investigated the number of patients with at least three cardiovascular risk markers of those reported by ATPIII (34), because it is widely recognized that they synergistically act to amplify the cardiovascular morbidity (48). This number was significantly higher in the SSTa group compared with the surgically cured one. Long-term epidemiological studies are needed to clarify the real influence of chronic SSTa administration on minor/major cardiovascular events and premature mortality, taking into account the positive effect on HDLc levels and insulin sensitivity accompanying the negative consequence on glucose homeostasis.
In conclusion, 6-yr SSTa therapy induced long-lasting disease control in responsive patients accompanied by improvements in insulin sensitivity and HDLc levels similar to those produced by successful surgery. However, SSTa therapy by causing a deep postglucose insulin suppression in well-responsive patients and persistent GH-dependent insulin resistance in uncontrolled ones caused a progressive glucose tolerance impairment, independently from the degree of GH/IGF-I control. Thus, strict monitoring of glucose homeostasis and peripheral micro- and macrovascular complications during chronic SSTa treatment is highly recommended.
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Acknowledgments |
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Footnotes |
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First Published Online November 1, 2005
Abbreviations: AUC, Area under the response curve; AUCGLUC, area under the glucose response curve; -B, basal insulin secretion; BMI, body mass index; FG, fasting glucose; FI, fasting insulin; HbA1c, hemoglobin A1c; HDLc, high-density lipoprotein cholesterol; HOMA, homeostasis model assessment; IFG, impaired fasting glucose; IGI, insulinogenic index; IGT, impaired glucose tolerance; ISI, insulin sensitivity index; LDLc, low-density lipoprotein cholesterol; l-SR, lanreotide; o-LAR, octreotide; OGTT, oral glucose tolerance test; QUICKI, quantitative insulin check index; -S, stimulated insulin secretion; SSTa, somatostatin analog; SST-C, SSTa-treated, controlled patients; SST-NC, SSTa-treated, uncontrolled patients; TC, total cholesterol; TG, triglycerides.
Received July 29, 2005.
Accepted October 20, 2005.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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), after 12 months of therapy (
), and at the last visit (
). Dotted lines represent normal cutoff values. To convert IGF-I and glucose concentrations to nanomoles per liter and millimoles per liter, divide the concentration in micrograms per liter by 7.741 and the concentration in milligrams per deciliter by 18, respectively. *, P < 0.05 vs. baseline; **, P < 0.005 vs. baseline; 
, P < 0.05 vs. baseline and after 12 months of therapy.
, last visit evaluation. To convert glucose and insulin concentrations to nanomoles per liter and picomoles per liter, divide the concentration in milligrams per deciliter by 18 and multiply the concentration in milliunits per liter by 7.14, respectively. *, P < 0.05 vs. before therapy in every group, by one-way ANOVA for repeated measures.
, FG between 100–109 mg/dl; 
, IFG;
