The Metabolic Syndrome and its Components in Patients with Prostate Cancer on Androgen Deprivation Therapy mez-Caaman ~ o, Jose L. Alvarez-Ossorio, Juan Morote,* Antonio Go mez Veiga, Daniel Pesqueira, Angel Tabernero, Francisco Go Jose A. Lorente, Mariano Porras, Juan J. Lobato, Marı´a J. Ribal and Jacques Planas on behalf of the ANAMET Investigators Group From the Department of Urology, Hospital Vall d’Hebron and Universitat Auto´noma de Barcelona (JM, JP), Department of Urology, Hospital del Mar (JAL) and Department of Urology, Hospital Clı´nic i Provincial de Barcelona (MJR), Barcelona; Department of Radiation Oncology, Hospital Clı´nico Universitario Santiago de Compostela (AG-C) and Department of Urology, Hospital A Corun˜a (FGV), A Corun˜a; Department of Urology, Hospital Universitario Puerta del Mar, Cadiz (JLA-O); Department of Urology, Hospital Universitario Povisa, Pontevedra (DP); Department of Urology, Hospital Universitario La Paz, Madrid (AT); Department of Radiation Oncology, Hospital Universitario Virgen de la Arrixaca, Murcia (MP); and Department of Urology, Hospital General Universitario de Alicante, Alicante (JJL), Spain
Purpose: Androgen deprivation therapy may promote the development of the metabolic syndrome in patients with prostate cancer. We assessed the prevalence of the full metabolic syndrome and its components during the first year of androgen deprivation therapy. Materials and Methods: This observational, multicenter, prospective study included 539 patients with prostate cancer scheduled to receive 3-month depot luteinizing hormone-releasing hormone analogs for more than 12 months. Waist circumference, body mass index, lipid profile, blood pressure and fasting glucose were evaluated at baseline and after 6 and 12 months. The metabolic syndrome was assessed according to NCEP ATP III criteria (2001) and 4 other definitions (WHO 1998, AACE 2003, AHA/NHLBI 2005 and IDF 2005). Results: At 6 and 12 months after the initiation of androgen deprivation therapy, significant increases were observed in waist circumference, body mass index, fasting glucose, triglycerides, total cholesterol, and high-density and low-density lipoprotein cholesterol. No significant changes in blood pressure 130/85 or greater were detected. A nonsignificant increase of 3.9% in the prevalence of the full metabolic syndrome (ATP III) was observed (22.9% at baseline vs 25.5% and 26.8% at 6 and 12 months, respectively). The prevalence of the metabolic syndrome at baseline varied according to the definition used, ranging from 9.4% (WHO) to 50% (IDF). At 12 months significant increases in prevalence were observed with the WHO (4.1%) and AHA/NHLBI (8.1%) definitions. Conclusions: Androgen deprivation therapy produces significant early effects on waist circumference, body mass index, fasting glucose, triglycerides and cholesterol. The prevalence of and increase in the metabolic syndrome depend on the defining criteria. Counseling patients on the prevention, early detection and treatment of specific metabolic alterations is recommended.
Abbreviations and Acronyms AACE ¼ American Association of Clinical Endocrinologists ADT ¼ androgen deprivation therapy AHA/NHLBI ¼ American Heart Association/National Heart, Lung, and Blood Institute ATP III ¼ Adult Treatment Panel III BMI ¼ body mass index BP ¼ blood pressure CV ¼ cardiovascular CVD ¼ cardiovascular disease EBRT ¼ external beam radiotherapy HbA1c ¼ hemoglobin A1c HDL ¼ high-density lipoprotein IDF ¼ International Diabetes Federation LDL ¼ low-density lipoprotein LHRH ¼ luteinizing hormone-releasing hormone MetS ¼ metabolic syndrome NCEP ¼ National Cholesterol Education Program PCa ¼ prostate cancer
Accepted for publication December 17, 2014. Study received ethics committee approval. Supported by Ipsen Pharma, S.A., Barcelona, Spain. * Correspondence: Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, Passeig de la Vall d’Hebron 119-129, 08035 Barcelona, Spain (telephone: þ34 93 489 3000; FAX: þ34 93 489 4438; e-mail: [email protected]).
PSA ¼ prostate specific antigen RP ¼ radical prostatectomy SIR ¼ semi-interquartile range
See Editorial on page 1882. 0022-5347/15/1936-1963/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2014.12.086 Vol. 193, 1963-1969, June 2015 Printed in U.S.A.
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METABOLIC SYNDROME AND ANDROGEN SUPPRESSION THERAPY
Key Words: metabolic syndrome X, prostatic neoplasms, androgens
THE most common treatments for prostate cancer are surgery and radiotherapy. However, the use of androgen deprivation therapy, typically achieved through LHRH agonist administration, has increased steadily during the last 2 decades. ADT is the standard palliative treatment for metastatic PCa due to its ability to alleviate symptoms, prevent complications and modestly prolong survival. Evidence indicates that ADT improves disease-free and overall survival in patients with locally advanced PCa or high risk disease when combined with primary radiotherapy or as adjuvant therapy for pN1 disease after RP. In some cases ADT is used as an alternative to radiotherapy or surgery to treat localized disease. ADT is also commonly used to treat patients who experience biochemical relapse after primary treatment, although the evidence of clinical benefit is scant.1 LHRH agonists markedly reduce circulating testosterone, and this decrease can produce a wide range of adverse effects including sexual dysfunction, hot flushes, bone mass loss, sarcopenia, insulin resistance, lipid profile changes, anemia, fatigue, cognitive alterations and depression. As a result, patients who receive ADT have an increased risk of diabetes and cardiovascular disease.2 Given the overlap between these adverse effects and the risk factors that characterize the metabolic syndrome, including obesity, increased triglycerides, reduced high-density lipoproteins, hypertension and hyperglycemia, it has been suggested that ADT may also promote the development of MetS.3 Because the presence of MetS is known to double the risk of CVD, the most common noncancer cause of death in patients with PCa, the possible association between ADT and the metabolic syndrome raises concerns about the routine use of ADT.4 Given the close association between MetS and CVD, it is crucial to determine whether ADT increases the likelihood of MetS. Evidence of such an association is still inconclusive as most studies published to date have been retrospective or small.5e7 To address this knowledge gap we performed this multicenter prospective study to assess changes in the prevalence of full MetS (NCEP ATP III criteria, 2001) and its components in patients with PCa during the first year of ADT. A secondary objective was to evaluate changes in the lipid profile, HbA1c and C-reactive protein. Finally, because the prevalence of MetS can vary according to the particular definition used, we evaluated changes according to the 5 most commonly used definitions (ATP III 2001, WHO 1998, AACE 2003, AHA/NHLBI 2005 and IDF 2005).
MATERIALS AND METHODS Study Design and Participants This was a post-authorization, multicenter, prospective, open, observational study approved by the ethics committee of Vall d’Hebron Research Institute (Barcelona, Spain, Ref. # IPS-TRI-2008). Patients’ personal data were treated with strict confidentiality and delivered to third parties according to European Directive 95/46/CE and Spanish Law 15/1999. Patients with histologically confirmed PCa scheduled to receive 3-month depot LHRH agonists for more than 12 months were selected. Indications for ADT were established according to clinical criteria (table 1). Patients with previous ADT were excluded from study. All patients received 50 mg bicalutamide daily for 1 month. The first LHRH agonist administration was given between days 14 and 16. All components of MetS, as described in the NCEP ATP III definition,8 were assessed at baseline and after 6 and 12 months of followup. The NCEP ATP III definition includes the 5 risk factors of waist circumference greater than 102 cm, triglycerides 150 mg/dl or greater, HDL cholesterol less than 40 mg/dl, systolic/diastolic BP 130/85 mm Hg or greater and fasting glucose 110 mg/dl or greater. A diagnosis of MetS was made when 3 or more of these 5 factors were present. Several clinical parameters were assessed, including BMI, supplementary lipid profile (total cholesterol, HDL cholesterol and LDL cholesterol), HbA1c, C-reactive protein, PSA and total testosterone. Specific treatment rates of antidiabetic, antihypertensive and hypolipidemic agents were assessed at baseline and during followup. For the purposes of comparison, the prevalence of MetS was assessed according to the MetS definitions established by the WHO (1998), AACE (2003), AHA/NHLBI (2005) and IDF (2005).4
Table 1. Demographic and baseline characteristics of patients included in the final analysis Median SIR age (min-max) Median SIR ng/ml PSA (min-max) No. TNM classification at diagnosis (%): T1-2 N0 M0 T3-4 N0 M0 T1-4 N1 M0 T1-4 N0-1 M1 No. Gleason score at diagnosis (%): 6 or Less 7 8e10 No. indication for ADT (%): Primary treatment Biochemical failure with high risk of dissemination after RP Biochemical failure after EBRT No. Caucasian (%) No. regular exercise (%) No. smoker (%)
72.0 5.0 (45e86) 19.9 7.6 (1.1e1,181) 66 218 16 10
(21.3) (70.3) (5.2) (3.2)
5 205 100
(1.6) (66.1) (32.3)
215 55
(69.4) (17.7)
40 308 135 50
(12.9) (99.4) (43.6) (16.1)
METABOLIC SYNDROME AND ANDROGEN SUPPRESSION THERAPY
Statistical Analysis Summarized descriptive statistics are provided (number of subjects, mean, standard deviation, median, minimum, maximum) or frequency counts of the demographic and baseline data for the total populations included/treated. A 90% 2-sided CI was calculated for the difference between MetS prevalence at study initiation and completion (Newcombe’s method). If the upper limit of the CI was lower than the equivalence region (þ5%), the post-study prevalence would be considered no worse than at study initiation. The Wilcoxon signed-rank test was used for all other numerical comparisons with McNemar’s test used for categorical comparisons. The sample size was based on the upper limit of the unilateral CI. Based on 5,000 simulations (NewcombeWilson) 536 subjects were needed to estimate MetS prevalence at 30% (9), with a precision of 0.038 and a 10% dropout rate (0.05 2-sided alpha error, 80% power, 0.020 expected difference, 0.070 expected discordants and 0.290 expected agreement). Statistical analysis was performed with SASÒ version 9.2 according to specifications in the statistical analysis plan approved before database lock.
RESULTS From December 2008 to October 2009, 539 patients with prostate cancer were recruited. Nineteen patients were excluded from study because they received a different type of ADT. Overall 452 patients completed 1-year followup and 310 completed all required evaluations. The study flow chart and the reasons for exclusion from the final analysis are shown in figure 1. None of the patients were excluded for extreme manifestations of MetS or cardiovascular morbidity-mortality. ADT was the primary treatment in 215 cases (69.4%), whereas the other 55 (17.7%) and 40 (12.9%), respectively, had previously undergone RP or EBRT without
Figure 1. Patient disposition
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hormonotherapy. ADT was indicated in these cases due to biochemical failure and/or a high risk of dissemination. Baseline characteristics are summarized in table 1. Of the 310 patients evaluated in the final analysis 71 (22.9%) fulfilled the MetS diagnostic criteria (ATP III) before ADT. After 6 and 12 months 79 (25.5%) and 83 patients (26.8%), respectively, fulfilled the MetS criteria. The increase of 2.6 and 3.9 percentage points from baseline to 6 and 12-month followup was not significant (p¼0.0754 and p¼0.127, respectively, fig. 2). No significant differences in age, BMI or MetS rates at baseline were observed in patients who underwent primary treatment with ADT vs those previously treated with RP or EBRT. Table 2 summarizes changes in all parameters. At 6 months after ADT, 4 ATP III MetS components (waist circumference, HDL cholesterol, triglycerides and fasting glucose) increased significantly and remained significant at 12 months. The only MetS component that remained unchanged was systolic/ diastolic BP. Several other parameters also showed significant increases at months 6 and 12, including total cholesterol, LDL cholesterol, BMI and HbA1c. PSA and total testosterone decreased significantly while C-reactive protein remained unchanged. The MetS parameters with the most significant differences at month 12 vs baseline were waist circumference, fasting glucose and triglycerides. The percentage of patients with waist circumference greater than 102 cm increased from 52.3% (162) at baseline to 56.5% (175) at 12 months (p¼0.023). Fasting glucose levels of 110 mg/dl or greater increased from 36.8% (114) to 50.0% (155) (p¼0.006), while triglycerides 150 mg/dl or greater increased from 23.6% (73) to 30.7% (p¼0.010). In contrast, the percentage of patients with BP 130/85 mm Hg or greater or HDL cholesterol less than 40 mg/dl remained stable (fig. 2).
Figure 2. Metabolic syndrome and individual risk factors during 12 months of followup.
METABOLIC SYNDROME AND ANDROGEN SUPPRESSION THERAPY
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Table 2. Evolution of clinical and metabolic parameters and specific treatments 6 Mos
12 Mos
Baseline Median SIR (min-max): Abdominal perimeter (cm) BMI (kg/m2) Total cholesterol (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) Fasting glucose (mg/dl) HbA1c (%) Systolic BP (mm Hg) Diastolic BP (mm Hg) C-reactive protein (mg/l) Total testosterone (ng/ml) PSA (ng/ml) No. specific treatments (%): Hypolipidemic Antihypertensive Antidiabetic
103.0 7.0 (50.0e152.0) 27.9 2.4 (19.1e44.1) 205.7 23.5 (139.4e308.7) 50.9 7.5 (19.0e186.7) 129.7 20.4 (46.0e223.7) 90.0 28.0 (27.1e384.5) 103.0 11.5 (60.2e281.0) 5.7 0.4 (4.3e9.7) 145.0 12.5 (89.0e211.0) 80.0 5.7 (41.0e150.0) 2.7 2.0 (0.1e65.0) 444.5115.0 (186.0e1,212.0) 19.9 7.6 (0.1e1,181.0)
104.0 7.0 28.2 2.6 210.227.5 52.9 8.6 130.026.1 101.130.7 106.012.0 5.7 0.4 144.013.5 80.0 7.0 2.8 2.5 22.010.5 1.2 0.4
60 145 49
67 149 51
(19.3) (46.8) (15.8)
(77.5e136.0) (19.1e44.1) (136.8e381.4) (23.0e168.7) (44.9e232.6) (32.3e462.6) (69.0e280.0) (4.5e9.5) (96.0e231.0) (47.0e130.0) (0.1e144.1) (15.0e59.2) (0.0e85.0)
In parallel with increased cholesterol and triglyceride levels, the percentage of patients receiving hypolipidemic drugs also increased significantly from 19.3% (60 patients) at baseline to 22.6% (70) at 12 months (p¼0.002). The percentage of patients on antihypertensive or antidiabetic drugs remained stable (table 2). Depending on the MetS definition, the prevalence at baseline ranged from 9.4% (WHO 1998) to 50% (IDF 2005). After 12 months, increases in prevalence ranged from 3.9% (ATP III 2001) to 8.1% (AHA/NHLBI 2005). Significant increases were observed for the WHO (from 9.4% to 13.5%, p¼0.049) and AHA/NHLBI definitions (from 42.9% to 50.0%, p¼0.001, table 3).
DISCUSSION The present study is the first cohort study to our knowledge to prospectively analyze changes in the prevalence of MetS and its components after 12 months of ADT. The increase in MetS prevalence (ATP III) was nonsignificant. However, significant increases were observed when the WHO and AHA/ NHLBI definitions were used. More importantly, several components of the various MetS definitions, such as waist circumference, BMI, fasting glucose, hypertriglyceridemia and low HDL, showed significant early alterations during ADT. Worldwide the prevalence of MetS ranges from 20% to 30% of the adult population.9 Diagnosis requires 3 or more of the parameters of low serum HDL cholesterol, hypertension, and increases in waist circumference or BMI, serum triglycerides and fasting glucose.3,4,8 The clinical importance of
(21.6) (48.1) (16.4)
Mean % Change vs Baseline
p Value
þ1.4 þ1.4 þ5.6 þ8.5 þ2.9 þ7.6 þ4.2 þ1.3 þ0.3 þ0.7 þ0.3 94.5 88.2
0.001 0.001 0.001 0.001 0.004 0.001 0.001 0.032 0.808 0.790 0.898 0.001 0.001
105.0 6.0 28.4 2.8 211.124.9 52.9 8.7 132.021.5 104.229.9 106.013.0 5.8 0.4 146.012.5 80.0 7.6 2.7 2.0 20.010.9 0.9 0.1
0.008 0.046 0.157
70 149 51
þ7 (2.3) þ4 (1.3) þ2 (0.6)
(60.0e137.0) (18.7e47.0) (146.8e359.5) (16.0e149.9) (30.0e262.6) (29.7e444.0) (73.0e328.9) (3.7e11.3) (80.0e220.0) (48.0e120.0) (0.1e160.0) (15.0e89.3) (0.0e159.0) (22.6) (48.1) (16.4)
Mean % Change vs Baseline
p Value
þ1.6 þ2.3 þ5.8 þ7.7 þ3.0 þ12.6 þ4.7 þ3.4 þ0.2 þ0.4 0.1 94.7 91.2
0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.803 0.822 0.949 0.001 0.0001
þ10 (3.3) 0.002 þ4 (1.3) 0.046 þ2 (0.6) 0.157
these metabolic disorders involves their association with insulin resistance and CV related morbiditymortality, a relationship previously established in several prospective studies.3 Many studies have shown an association between ADT and an increased risk of CV morbidity10 and mortality.11 In fact, in light of these findings the U.S. Food and Drug Administration, American Heart Association, American Cancer Society, American Urological Association and American Society for Radiation Oncology have published reports to alert physicians to the possible CV risks of ADT.12 Despite these warnings, the link between ADT and CVD remains unclear. In fact, several studies have failed to confirm this association, and in a recent metaanalysis Nguyen et al emphasized that the available evidence remains insufficient to definitively associate ADT with increased CV mortality risk.13 As the authors noted, no prospective study, properly stratified according to patient history of CVD and diabetes status, has been performed to assess the influence of ADT on CV mortality. This theoretical association between ADT and CV morbidity-mortality could be explained by the fact Table 3. Changes in the prevalence of MetS after 1 year of ADT according to definition criteria No. Baseline (%) WHO (1998) ATP III (2001) AACE (2003) AHA/NHLBI (2005) IDF (2005)
29 71 104 133 155
* Significant difference.
(9.4) (22.9) (33.5) (42.9) (50.0)
No. After 12 Mos ADT (%) 42 83 119 158 173
(13.5) (26.8) (38.4) (51.0) (55.8)
% Increase
p Value
4.1 3.9 4.9 8.1 5.8
0.049* 0.075 0.211 0.001* 0.061
METABOLIC SYNDROME AND ANDROGEN SUPPRESSION THERAPY
that ADT promotes the development of metabolic disturbances, particularly insulin resistance.14,15 Consistent with observations from prospective studies that ADT increases abdominal fat and triglycerides while decreasing insulin sensitivity, cross-sectional studies have shown that men on ADT are more likely to meet the diagnostic criteria for MetS.16,17 While many studies have shown an association between ADT and certain MetS components, only 3 cross-sectional studies have assessed the prevalence of full MetS in patients with PCa receiving ADT (table 4).5e7 Braga-Basaria et al reported MetS (ATP III) prevalence rates in 3 groups, as 20 patients on ADT for 12 months or more (55%), 18 age matched men with nonmetastatic PCa who received local treatment (22%) and 20 age matched controls (20%).5 The men on ADT had a greater waist circumference, hyperglycemia and hypertriglyceridemia compared to controls, while hypertension and HDL cholesterol remained stable. Cleffi et al compared 54 patients with PCa after a mean of 15 months of ADT to 25 patients with PCa without ADT.6 The respective prevalence rates (IDF criteria) were 54% and 24%, and the percentage of patients on ADT with diabetes and central obesity increased the most, while BP, triglycerides and HDL cholesterol remained relatively stable. Morote et al retrospectively assessed the prevalence of MetS (ATP III) in 53 patients with PCa on ADT for 12 months or more vs 53 patients with PCa without ADT and 53 subjects without PCa (negative biopsy).7 The prevalence of MetS after any treatment was 32% in the nonPCa group, 36% in the nonADT group of patients with PCa and 51% in patients who received ADT. The largest changes observed from baseline were in waist circumference and fasting
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glucose. One notable finding was that the prevalence of MetS in the ADT group increased progressively with time, from 44% with 36 months or less of ADT to 57% with more than 36 months of ADT. Although the 23% baseline prevalence of MetS (ATP III) in patients with hormone na€ıve PCa in the present study was less than the expected 30%, it was in line with the expected rate for the age of our study population.3 The baseline prevalence of MetS ranged from 9.4% to 50% according to the definition used. Increases in waist circumference, fasting glucose and hypertriglyceridemia were early and highly significant. These findings are consistent with those reported in numerous cohort studies,18e23 in which these same 3 MetS components were the most affected by ADT. Depending on the definition, after 12 months of ADT the prevalence of MetS increased from 3.9% to 8.1%. In all 3 crosssectional studies that analyzed full MetS, the prevalence increased significantly after ADT. In the control groups the baseline prevalence ranged from 20% to 30% but increased to 50% or more in patients treated with ADT for 15 to 45 months. Moreover, as previously noted Morote et al found that prevalence increased according to the duration of ADT administration.7 The data from the previously mentioned studies, considered in light of the results presented here, suggest that ADT does not lead to the development of full MetS in patients with PCa, at least during the first year of treatment. However, we cannot rule out the possibility that MetS prevalence could increase with extended ADT. Regardless of whether ADT increases the prevalence of full MetS, the negative impact of ADT on several CV risk components of MetS (fasting glucose, hypertriglyceridemia, waist circumference and BMI)
Table 4. Summary of published data of metabolic disorders and full MetS References 19
Study Type
No. Cases
Mos ADT (range)
Smith et al Smith et al18
Cohort Cohort
22 40
3 12
Basaria et al20 Dockery et al21 Smith17 Smith et al14
Cross-sectional Cohort Cohort Cohort
20 31 79 25
45 3 12 3
(12e101)
Basaria et al15 Braga-Basaria et al5
Cross-sectional Cross-sectional
18 20
45 45
(12e101) (12e101)
Levy et al16 Smith et al26
Cohort Cohort
23 26
24 12
Galv~ao et al22 Hamilton et al23
Cohort Cohort
72 26
36 12
Cleffi et al6
Cross-sectional
54
15 (not reported)
Cross-sectional Cohort
53 310
7
Morote et al Present series
29 12
(12e64)
Significant Findings Fasting insulinemia þ64%, fat body mass þ8.4%, lean body mass 2.7% Total cholesterol þ9%, HDL þ11.3%, LDL þ7.3%, triglycerides þ26.5%, fat body mass þ9.4%, lean body mass 2.7%, BMI þ2.4% Fat body mass þ, BMI þ Total cholesterol þ7%, HDL þ20%, fasting insulinemia þ63% Fat body mass þ11%, lean body mass 3.8% Total cholesterol þ9.4%, HDL þ9.9%, triglycerides þ23%, fasting insulinemia þ23%, fat body mass þ4.3%, lean body mass 1.4% BMI þ, fasting glycemia þ, fasting insulinemia þ, leptin þ Full MetS 55% (control group 22%), BMI þ16.6%, waist circumference greater than 102 cm 45%þ, fasting glycemia 27.5%þ, triglycerides þ65.2% Fat body mass þ1.2%, lean body mass 1.1% BMI þ3.1%, fat body mass þ11.2%, lean body mass 3.6%, HDL þ9.7%, triglycerides þ19.4%, adiponectin þ36.4% Fat body mass þ13.8%, lean body mass 2.4% Total cholesterol þ11.2%, triglycerides þ46.6%, fat body mass þ14%, lean body mass 3.6%, BMI þ2.2%, leptin þ50.4% Full MetS 53% (control group 24%), waist circumference þ6.9%, fasting glycemia 110 mg/dl or greater þ13.9%, total cholesterol þ11.8% Full MetS 51% (control group 32%), ADT 12-36 mos 44%, more than 36 mos 57% Full MetS 23%-27%, waist circumference þ1.2%, total cholesterol þ3.8%, HDL þ7.7%, triglycerides þ7.2%, fasting glycemia þ1.6%
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METABOLIC SYNDROME AND ANDROGEN SUPPRESSION THERAPY
within 12 months of ADT administration is evident. However, some have suggested that the metabolic changes that accompany ADT are distinct from classically defined MetS.24 Although the metabolic alterations secondary to ADT share some of the features of classic MetS, there are important differences. In contrast to MetS, ADT may increase HDL cholesterol18,21,25 and subcutaneous (but not visceral) abdominal fat.18,26 Interestingly, none of the previously mentioned studies showed significant changes in BP.5e7,19,23,26 While classic MetS is associated with low levels of adiponectin27 and increased levels of C-reactive protein,28 ADT seems to increase adiponectin and leptin but not C-reactive protein.26 Our data confirm that ADT does not alter C-reactive protein levels during the first year. The present study has numerous strengths, primarily the prospective, longitudinal design and the large patient cohort. The main limitation in assessing the prevalence of MetS is that it varies according to the criteria used to define MetS. As our results show, the baseline prevalence and its increase during ADT vary greatly depending on the definition. Another limitation is the high dropout rate, although this characteristic is inherent in observational studies. Importantly, we verified that patients who dropped out and, therefore, were excluded from the final analysis, did not do so due to extreme manifestations of MetS or CV morbidity-mortality. Finally, some have raised doubts about the predictive value of MetS, with 1 study concluding that MetS adds no value to the traditional risk factors used to predict diabetes or CVD.29 A recent review of 2 large prospective studies showed that a MetS diagnosis was no better at predicting incident diabetes than fasting glucose levels greater than 110 mg/dl.30 This evidence has prompted the American Diabetes Association to recommend that all CV risk factors be assessed and treated, even when all diagnostic criteria for MetS are not present.29
CONCLUSIONS The findings reported here strongly suggest that ADT has an early and significant negative impact
on several important metabolic parameters associated with cardiovascular health. As our data show, the prevalence of MetS is highly influenced by the criteria used to define it, as is the magnitude of increases in MetS prevalence after 1 year of ADT.
ACKNOWLEDGMENTS Bradley Londres provided editorial assistance.
APPENDIX Members of the Spanish ANAMET Working Group: Jose Ma Saladie, Hospital Universitari Germans Trias i Pujol, Barcelona; Gemma Sancho, Hospital de la Santa Creu I Sant Pau, Barcelona; Humberto Villavicencio, Fundacion Puigvert, Barcelona; Jose Segarra, Hospital Universitari Joan XXIII, Tarragona; Jose Comet, Hospital Universitari Dr. Josep Trueta, Girona; Dr. Jose Francisco Suarez, Hospital Universitari de Bellvitge, Barcelona; Dr. Ma Jose Ribal, Hospital Clınic I Provincial, Barcelona; Dr. Jose Antonio Llorente, Hospital del Mar, Barcelona; Dr. Juan Urıa, Hospital General de Vic, Barcelona; Dr. Jesus Guajardo, Hospital Universitari Arnau de Vilanova, Barcelona; Dr. Antonio Gomez Caama~no, Hospital Clınico Universitario de Santiago, A Coru~na; Dr. Camilo Garcıa Freire, Hospital de Conxo, A Coru~na; Dr. Antonio Ojea, Hospital Xeral-Cıes de Vigo, Pontevedra; Dr. Juan Mata, Hospital Meixoeiro, Pontevedra; Dr. Ma Luisa Vazquez, Hospital Meixoeiro, Pontevedra; Dr. Francisco Gomez Veiga, Hospital Juan Canalejo, A Coru~na; Dr. Daniel Pesqueira, Policlınico de Vigo, Pontevedra; Dr. Juan Pablo Ciria, Hospital Virgen de Aranzazu, San Sebastian; Dr. Roberto Llarena, Hospital de Cruces, Bilbao; Dr. Jesus Miguel Unda, Hospital de Basurto, Bilbao; Dr. Angel Jose Tabernero, Hospital Universitario de La Paz, Madrid; Dr. Angel Silmi, Hospital Clınico San Carlos, Madrid; Dr. Carlos Hernandez, Hospital Gregorio Mara~non, Madrid; Dr. Alfredo Rodrıguez Antolın, Hospital 12 de Octubre, Madrid; Dr. Miguel Julian Mora, Hospital de La Princesa, Madrid; Dr. Almudena Zapatero, Hospital de La Princesa, Madrid; Dr. Ana Maria Perez, Fundacion Jimenez Dıaz, Madrid; Dr. Joaquin Carballido, Hospital Puerta de Hierro, Madrid; Dr. Ma Jose Ortiz, Hospital Universitario Virgen del Rocıo, Sevilla; Dr. Jose Luis Alvarez-Ossorio, Hospital Universitario Puerta del Mar, Cadiz; Dr. Alvaro Juarez, Hospital General Jerez de la Frontera, Cadiz; Dr. Juan Jose Lobato, Hospital General Universitario de Alicante, Alicante; Dr. Juan Fernando Jimenez, Hospital Universitario La Fe, Valencia; Dr. Alejandro Tormo, Hospital Universitario La Fe, Valencia; Dr. Eduardo Solsona, Instituto Valenciano de Oncologıa, Valencia; Dr. Manuel Casa~na, Instituto Valenciano de Oncologıa, Valencia; Dr. Manuel Rivas, Hospital de Cabue~nes, Gijon; Dr. Ramon Abascal, Hospital Universitario Central de Oviedo, Oviedo; Dr. Pedro Prada, Hospital Universitario Central de Oviedo, Oviedo; Dr. Jose Amon, Hospital Universitario Rio Hortega, Valladolid; Dr. Pedro Rodrıguez, Hospital Universitario de La Laguna, Tenerife; Dr. Claudio Oton, Hospital Universitario de La Laguna, Tenerife; Dr. Reinaldo Marrero, Hospital Dr. Negrın, Las Palmas de Gran Canaria; Dr. Mariano Porras, Hospital Virgen de La Arrixaca, Murcia; Dr. Marino Perez, Hospital Virgen de La Arrixaca, Murcia; Dr. Victor Macıas, Hospital Clınico Universitario de Salamanca, Salamanca; and Dr. Miguel Angel Barranco, Hospital de Mataro, Barcelona.
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3. Eckel RH, Grundy SM and Zimmet PZ: The metabolic syndrome. Lancet 2005; 365: 1415.
undergoing long-term androgen-deprivation therapy. J Clin Oncol 2006; 24: 3979.
4. Galassi A, Reynolds K and He J: Metabolic syndrome and risk of cardiovascular disease: a meta-analysis. Am J Med 2006; 119: 812.
6. Cleffi S, Neto AS, Reis LO et al: Androgen deprivation therapy and morbid obesity: do they share cardiovascular risk through metabolic syndrome? Actas Urol Esp 2011; 35: 259.
5. Braga-Basaria M, Dobs AS, Muller DC et al: Metabolic syndrome in men with prostate cancer
7. Morote J, Ropero J, Planas J et al: Metabolic syndrome in patients with prostate cancer
METABOLIC SYNDROME AND ANDROGEN SUPPRESSION THERAPY
undergoing androgen suppression. Actas Urol Esp 2014; 38: 285. 8. Grundy SM, Brewer HB Jr, Cleeman JI et al: Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/ American Heart Association conference on scientific issues related to definition. Circulation 2004; 109: 433. 9. Ford ES, Giles WH and Dietz WH: Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287: 356. 10. Keating NL, O’Malley AJ, Freedland SJ et al: Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst 2010; 102: 39. 11. Nguyen PL, Chen MH, Beckman JA et al: Influence of androgen deprivation therapy on allcause mortality in men with high-risk prostate cancer and a history of congestive heart failure or myocardial infarction. Int J Radiat Oncol Biol Phys 2012; 82: 1411. 12. Levine GN, D’Amico AV, Berger P et al: Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. CA Cancer J Clin 2010; 60: 194. 13. Nguyen PL, Je Y, Schutz FA et al: Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA 2011; 306: 2359.
14. Smith MR, Lee H and Nathan DM: Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab 2006; 91: 1305. 15. Basaria S, Muller DC, Carducci MA et al: Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgendeprivation therapy. Cancer 2006; 106: 581. 16. Levy ME, Perera S, van Londen GJ et al: Physical function changes in prostate cancer patients on androgen deprivation therapy: a 2-year prospective study. Urology 2008; 71: 735. 17. Smith MR: Changes in fat and lean body mass during androgen-deprivation therapy for prostate cancer. Urology 2004; 63: 742. 18. Smith MR, Finkelstein JS, McGovern FJ et al: Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab 2002; 87: 599. 19. Smith JC, Bennett S, Evans LM et al: The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer. J Clin Endocrinol Metab 2001; 86: 4261. 20. Basaria S, Lieb J, Tang AM et al: Long-term effects of androgen deprivation therapy in prostate cancer patients. Clin Endocrinol (Oxf) 2002; 56: 779. 21. Dockery F, Bulpitt CJ, Agarwal S et al: Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia. Clin Sci (Lond) 2003; 104: 195. 22. Galv~ao DA, Spry NA, Taaffe DR et al: Changes in muscle, fat and bone mass after 36 weeks of maximal androgen blockade for prostate cancer. BJU Int 2008; 102: 44.
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23. Hamilton EJ, Gianatti E, Strauss BJ et al: Increase in visceral and subcutaneous abdominal fat in men with prostate cancer treated with androgen deprivation therapy. Clin Endocrinol 2011; 74: 377. 24. Saylor PJ and Smith MR: Metabolic complications of androgen deprivation therapy for prostate cancer. J Urol, suppl., 2013; 189: S34. 25. Eri LM, Urdal P and Bechensteen AG: Effects of the luteinizing hormone-releasing hormone agonist leuprolide on lipoproteins, fibrinogen and plasminogen activator inhibitor in patients with benign prostatic hyperplasia. J Urol 1995; 154: 100. 26. Smith MR, Lee H, McGovern F et al: Metabolic changes during gonadotropin-releasing hormone agonist therapy for prostate cancer. Cancer 2008; 112: 2188. 27. Trujillo ME and Scherer PE: Adiponectinejourney from an adipocyte secretory protein to biomarker of the metabolic syndrome. J Intern Med 2005; 257: 167. 28. Haffner SM: The metabolic syndrome: inflammation, diabetes mellitus, and cardiovascular disease. Am J Cardiol 2006; 97: 3A. 29. Kahn R, Buse J, Ferrannini E et al: The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005; 28: 2289. 30. Sattar N, McConnachie A, Shaper AG et al: Can metabolic syndrome usefully predict cardiovascular disease and diabetes? Outcome data from two prospective studies. Lancet 2008; 371: 1927.
Purpose: Androgen deprivation therapy may promote the development of the metabolic syndrome in patients with prostate cancer. We assessed the prevalence of the full metabolic syndrome and its components during the first year of androgen deprivation therapy. Materials and Methods: This observational, multicenter, prospective study included 539 patients with prostate cancer scheduled to receive 3-month depot luteinizing hormone-releasing hormone analogs for more than 12 months. Waist circumference, body mass index, lipid profile, blood pressure and fasting glucose were evaluated at baseline and after 6 and 12 months. The metabolic syndrome was assessed according to NCEP ATP III criteria (2001) and 4 other definitions (WHO 1998, AACE 2003, AHA/NHLBI 2005 and IDF 2005). Results: At 6 and 12 months after the initiation of androgen deprivation therapy, significant increases were observed in waist circumference, body mass index, fasting glucose, triglycerides, total cholesterol, and high-density and low-density lipoprotein cholesterol. No significant changes in blood pressure 130/85 or greater were detected. A nonsignificant increase of 3.9% in the prevalence of the full metabolic syndrome (ATP III) was observed (22.9% at baseline vs 25.5% and 26.8% at 6 and 12 months, respectively). The prevalence of the metabolic syndrome at baseline varied according to the definition used, ranging from 9.4% (WHO) to 50% (IDF). At 12 months significant increases in prevalence were observed with the WHO (4.1%) and AHA/NHLBI (8.1%) definitions. Conclusions: Androgen deprivation therapy produces significant early effects on waist circumference, body mass index, fasting glucose, triglycerides and cholesterol. The prevalence of and increase in the metabolic syndrome depend on the defining criteria. Counseling patients on the prevention, early detection and treatment of specific metabolic alterations is recommended.
Abbreviations and Acronyms AACE ¼ American Association of Clinical Endocrinologists ADT ¼ androgen deprivation therapy AHA/NHLBI ¼ American Heart Association/National Heart, Lung, and Blood Institute ATP III ¼ Adult Treatment Panel III BMI ¼ body mass index BP ¼ blood pressure CV ¼ cardiovascular CVD ¼ cardiovascular disease EBRT ¼ external beam radiotherapy HbA1c ¼ hemoglobin A1c HDL ¼ high-density lipoprotein IDF ¼ International Diabetes Federation LDL ¼ low-density lipoprotein LHRH ¼ luteinizing hormone-releasing hormone MetS ¼ metabolic syndrome NCEP ¼ National Cholesterol Education Program PCa ¼ prostate cancer
Accepted for publication December 17, 2014. Study received ethics committee approval. Supported by Ipsen Pharma, S.A., Barcelona, Spain. * Correspondence: Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, Passeig de la Vall d’Hebron 119-129, 08035 Barcelona, Spain (telephone: þ34 93 489 3000; FAX: þ34 93 489 4438; e-mail: [email protected]).
PSA ¼ prostate specific antigen RP ¼ radical prostatectomy SIR ¼ semi-interquartile range
See Editorial on page 1882. 0022-5347/15/1936-1963/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2014.12.086 Vol. 193, 1963-1969, June 2015 Printed in U.S.A.
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METABOLIC SYNDROME AND ANDROGEN SUPPRESSION THERAPY
Key Words: metabolic syndrome X, prostatic neoplasms, androgens
THE most common treatments for prostate cancer are surgery and radiotherapy. However, the use of androgen deprivation therapy, typically achieved through LHRH agonist administration, has increased steadily during the last 2 decades. ADT is the standard palliative treatment for metastatic PCa due to its ability to alleviate symptoms, prevent complications and modestly prolong survival. Evidence indicates that ADT improves disease-free and overall survival in patients with locally advanced PCa or high risk disease when combined with primary radiotherapy or as adjuvant therapy for pN1 disease after RP. In some cases ADT is used as an alternative to radiotherapy or surgery to treat localized disease. ADT is also commonly used to treat patients who experience biochemical relapse after primary treatment, although the evidence of clinical benefit is scant.1 LHRH agonists markedly reduce circulating testosterone, and this decrease can produce a wide range of adverse effects including sexual dysfunction, hot flushes, bone mass loss, sarcopenia, insulin resistance, lipid profile changes, anemia, fatigue, cognitive alterations and depression. As a result, patients who receive ADT have an increased risk of diabetes and cardiovascular disease.2 Given the overlap between these adverse effects and the risk factors that characterize the metabolic syndrome, including obesity, increased triglycerides, reduced high-density lipoproteins, hypertension and hyperglycemia, it has been suggested that ADT may also promote the development of MetS.3 Because the presence of MetS is known to double the risk of CVD, the most common noncancer cause of death in patients with PCa, the possible association between ADT and the metabolic syndrome raises concerns about the routine use of ADT.4 Given the close association between MetS and CVD, it is crucial to determine whether ADT increases the likelihood of MetS. Evidence of such an association is still inconclusive as most studies published to date have been retrospective or small.5e7 To address this knowledge gap we performed this multicenter prospective study to assess changes in the prevalence of full MetS (NCEP ATP III criteria, 2001) and its components in patients with PCa during the first year of ADT. A secondary objective was to evaluate changes in the lipid profile, HbA1c and C-reactive protein. Finally, because the prevalence of MetS can vary according to the particular definition used, we evaluated changes according to the 5 most commonly used definitions (ATP III 2001, WHO 1998, AACE 2003, AHA/NHLBI 2005 and IDF 2005).
MATERIALS AND METHODS Study Design and Participants This was a post-authorization, multicenter, prospective, open, observational study approved by the ethics committee of Vall d’Hebron Research Institute (Barcelona, Spain, Ref. # IPS-TRI-2008). Patients’ personal data were treated with strict confidentiality and delivered to third parties according to European Directive 95/46/CE and Spanish Law 15/1999. Patients with histologically confirmed PCa scheduled to receive 3-month depot LHRH agonists for more than 12 months were selected. Indications for ADT were established according to clinical criteria (table 1). Patients with previous ADT were excluded from study. All patients received 50 mg bicalutamide daily for 1 month. The first LHRH agonist administration was given between days 14 and 16. All components of MetS, as described in the NCEP ATP III definition,8 were assessed at baseline and after 6 and 12 months of followup. The NCEP ATP III definition includes the 5 risk factors of waist circumference greater than 102 cm, triglycerides 150 mg/dl or greater, HDL cholesterol less than 40 mg/dl, systolic/diastolic BP 130/85 mm Hg or greater and fasting glucose 110 mg/dl or greater. A diagnosis of MetS was made when 3 or more of these 5 factors were present. Several clinical parameters were assessed, including BMI, supplementary lipid profile (total cholesterol, HDL cholesterol and LDL cholesterol), HbA1c, C-reactive protein, PSA and total testosterone. Specific treatment rates of antidiabetic, antihypertensive and hypolipidemic agents were assessed at baseline and during followup. For the purposes of comparison, the prevalence of MetS was assessed according to the MetS definitions established by the WHO (1998), AACE (2003), AHA/NHLBI (2005) and IDF (2005).4
Table 1. Demographic and baseline characteristics of patients included in the final analysis Median SIR age (min-max) Median SIR ng/ml PSA (min-max) No. TNM classification at diagnosis (%): T1-2 N0 M0 T3-4 N0 M0 T1-4 N1 M0 T1-4 N0-1 M1 No. Gleason score at diagnosis (%): 6 or Less 7 8e10 No. indication for ADT (%): Primary treatment Biochemical failure with high risk of dissemination after RP Biochemical failure after EBRT No. Caucasian (%) No. regular exercise (%) No. smoker (%)
72.0 5.0 (45e86) 19.9 7.6 (1.1e1,181) 66 218 16 10
(21.3) (70.3) (5.2) (3.2)
5 205 100
(1.6) (66.1) (32.3)
215 55
(69.4) (17.7)
40 308 135 50
(12.9) (99.4) (43.6) (16.1)
METABOLIC SYNDROME AND ANDROGEN SUPPRESSION THERAPY
Statistical Analysis Summarized descriptive statistics are provided (number of subjects, mean, standard deviation, median, minimum, maximum) or frequency counts of the demographic and baseline data for the total populations included/treated. A 90% 2-sided CI was calculated for the difference between MetS prevalence at study initiation and completion (Newcombe’s method). If the upper limit of the CI was lower than the equivalence region (þ5%), the post-study prevalence would be considered no worse than at study initiation. The Wilcoxon signed-rank test was used for all other numerical comparisons with McNemar’s test used for categorical comparisons. The sample size was based on the upper limit of the unilateral CI. Based on 5,000 simulations (NewcombeWilson) 536 subjects were needed to estimate MetS prevalence at 30% (9), with a precision of 0.038 and a 10% dropout rate (0.05 2-sided alpha error, 80% power, 0.020 expected difference, 0.070 expected discordants and 0.290 expected agreement). Statistical analysis was performed with SASÒ version 9.2 according to specifications in the statistical analysis plan approved before database lock.
RESULTS From December 2008 to October 2009, 539 patients with prostate cancer were recruited. Nineteen patients were excluded from study because they received a different type of ADT. Overall 452 patients completed 1-year followup and 310 completed all required evaluations. The study flow chart and the reasons for exclusion from the final analysis are shown in figure 1. None of the patients were excluded for extreme manifestations of MetS or cardiovascular morbidity-mortality. ADT was the primary treatment in 215 cases (69.4%), whereas the other 55 (17.7%) and 40 (12.9%), respectively, had previously undergone RP or EBRT without
Figure 1. Patient disposition
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hormonotherapy. ADT was indicated in these cases due to biochemical failure and/or a high risk of dissemination. Baseline characteristics are summarized in table 1. Of the 310 patients evaluated in the final analysis 71 (22.9%) fulfilled the MetS diagnostic criteria (ATP III) before ADT. After 6 and 12 months 79 (25.5%) and 83 patients (26.8%), respectively, fulfilled the MetS criteria. The increase of 2.6 and 3.9 percentage points from baseline to 6 and 12-month followup was not significant (p¼0.0754 and p¼0.127, respectively, fig. 2). No significant differences in age, BMI or MetS rates at baseline were observed in patients who underwent primary treatment with ADT vs those previously treated with RP or EBRT. Table 2 summarizes changes in all parameters. At 6 months after ADT, 4 ATP III MetS components (waist circumference, HDL cholesterol, triglycerides and fasting glucose) increased significantly and remained significant at 12 months. The only MetS component that remained unchanged was systolic/ diastolic BP. Several other parameters also showed significant increases at months 6 and 12, including total cholesterol, LDL cholesterol, BMI and HbA1c. PSA and total testosterone decreased significantly while C-reactive protein remained unchanged. The MetS parameters with the most significant differences at month 12 vs baseline were waist circumference, fasting glucose and triglycerides. The percentage of patients with waist circumference greater than 102 cm increased from 52.3% (162) at baseline to 56.5% (175) at 12 months (p¼0.023). Fasting glucose levels of 110 mg/dl or greater increased from 36.8% (114) to 50.0% (155) (p¼0.006), while triglycerides 150 mg/dl or greater increased from 23.6% (73) to 30.7% (p¼0.010). In contrast, the percentage of patients with BP 130/85 mm Hg or greater or HDL cholesterol less than 40 mg/dl remained stable (fig. 2).
Figure 2. Metabolic syndrome and individual risk factors during 12 months of followup.
METABOLIC SYNDROME AND ANDROGEN SUPPRESSION THERAPY
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Table 2. Evolution of clinical and metabolic parameters and specific treatments 6 Mos
12 Mos
Baseline Median SIR (min-max): Abdominal perimeter (cm) BMI (kg/m2) Total cholesterol (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) Fasting glucose (mg/dl) HbA1c (%) Systolic BP (mm Hg) Diastolic BP (mm Hg) C-reactive protein (mg/l) Total testosterone (ng/ml) PSA (ng/ml) No. specific treatments (%): Hypolipidemic Antihypertensive Antidiabetic
103.0 7.0 (50.0e152.0) 27.9 2.4 (19.1e44.1) 205.7 23.5 (139.4e308.7) 50.9 7.5 (19.0e186.7) 129.7 20.4 (46.0e223.7) 90.0 28.0 (27.1e384.5) 103.0 11.5 (60.2e281.0) 5.7 0.4 (4.3e9.7) 145.0 12.5 (89.0e211.0) 80.0 5.7 (41.0e150.0) 2.7 2.0 (0.1e65.0) 444.5115.0 (186.0e1,212.0) 19.9 7.6 (0.1e1,181.0)
104.0 7.0 28.2 2.6 210.227.5 52.9 8.6 130.026.1 101.130.7 106.012.0 5.7 0.4 144.013.5 80.0 7.0 2.8 2.5 22.010.5 1.2 0.4
60 145 49
67 149 51
(19.3) (46.8) (15.8)
(77.5e136.0) (19.1e44.1) (136.8e381.4) (23.0e168.7) (44.9e232.6) (32.3e462.6) (69.0e280.0) (4.5e9.5) (96.0e231.0) (47.0e130.0) (0.1e144.1) (15.0e59.2) (0.0e85.0)
In parallel with increased cholesterol and triglyceride levels, the percentage of patients receiving hypolipidemic drugs also increased significantly from 19.3% (60 patients) at baseline to 22.6% (70) at 12 months (p¼0.002). The percentage of patients on antihypertensive or antidiabetic drugs remained stable (table 2). Depending on the MetS definition, the prevalence at baseline ranged from 9.4% (WHO 1998) to 50% (IDF 2005). After 12 months, increases in prevalence ranged from 3.9% (ATP III 2001) to 8.1% (AHA/NHLBI 2005). Significant increases were observed for the WHO (from 9.4% to 13.5%, p¼0.049) and AHA/NHLBI definitions (from 42.9% to 50.0%, p¼0.001, table 3).
DISCUSSION The present study is the first cohort study to our knowledge to prospectively analyze changes in the prevalence of MetS and its components after 12 months of ADT. The increase in MetS prevalence (ATP III) was nonsignificant. However, significant increases were observed when the WHO and AHA/ NHLBI definitions were used. More importantly, several components of the various MetS definitions, such as waist circumference, BMI, fasting glucose, hypertriglyceridemia and low HDL, showed significant early alterations during ADT. Worldwide the prevalence of MetS ranges from 20% to 30% of the adult population.9 Diagnosis requires 3 or more of the parameters of low serum HDL cholesterol, hypertension, and increases in waist circumference or BMI, serum triglycerides and fasting glucose.3,4,8 The clinical importance of
(21.6) (48.1) (16.4)
Mean % Change vs Baseline
p Value
þ1.4 þ1.4 þ5.6 þ8.5 þ2.9 þ7.6 þ4.2 þ1.3 þ0.3 þ0.7 þ0.3 94.5 88.2
0.001 0.001 0.001 0.001 0.004 0.001 0.001 0.032 0.808 0.790 0.898 0.001 0.001
105.0 6.0 28.4 2.8 211.124.9 52.9 8.7 132.021.5 104.229.9 106.013.0 5.8 0.4 146.012.5 80.0 7.6 2.7 2.0 20.010.9 0.9 0.1
0.008 0.046 0.157
70 149 51
þ7 (2.3) þ4 (1.3) þ2 (0.6)
(60.0e137.0) (18.7e47.0) (146.8e359.5) (16.0e149.9) (30.0e262.6) (29.7e444.0) (73.0e328.9) (3.7e11.3) (80.0e220.0) (48.0e120.0) (0.1e160.0) (15.0e89.3) (0.0e159.0) (22.6) (48.1) (16.4)
Mean % Change vs Baseline
p Value
þ1.6 þ2.3 þ5.8 þ7.7 þ3.0 þ12.6 þ4.7 þ3.4 þ0.2 þ0.4 0.1 94.7 91.2
0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.803 0.822 0.949 0.001 0.0001
þ10 (3.3) 0.002 þ4 (1.3) 0.046 þ2 (0.6) 0.157
these metabolic disorders involves their association with insulin resistance and CV related morbiditymortality, a relationship previously established in several prospective studies.3 Many studies have shown an association between ADT and an increased risk of CV morbidity10 and mortality.11 In fact, in light of these findings the U.S. Food and Drug Administration, American Heart Association, American Cancer Society, American Urological Association and American Society for Radiation Oncology have published reports to alert physicians to the possible CV risks of ADT.12 Despite these warnings, the link between ADT and CVD remains unclear. In fact, several studies have failed to confirm this association, and in a recent metaanalysis Nguyen et al emphasized that the available evidence remains insufficient to definitively associate ADT with increased CV mortality risk.13 As the authors noted, no prospective study, properly stratified according to patient history of CVD and diabetes status, has been performed to assess the influence of ADT on CV mortality. This theoretical association between ADT and CV morbidity-mortality could be explained by the fact Table 3. Changes in the prevalence of MetS after 1 year of ADT according to definition criteria No. Baseline (%) WHO (1998) ATP III (2001) AACE (2003) AHA/NHLBI (2005) IDF (2005)
29 71 104 133 155
* Significant difference.
(9.4) (22.9) (33.5) (42.9) (50.0)
No. After 12 Mos ADT (%) 42 83 119 158 173
(13.5) (26.8) (38.4) (51.0) (55.8)
% Increase
p Value
4.1 3.9 4.9 8.1 5.8
0.049* 0.075 0.211 0.001* 0.061
METABOLIC SYNDROME AND ANDROGEN SUPPRESSION THERAPY
that ADT promotes the development of metabolic disturbances, particularly insulin resistance.14,15 Consistent with observations from prospective studies that ADT increases abdominal fat and triglycerides while decreasing insulin sensitivity, cross-sectional studies have shown that men on ADT are more likely to meet the diagnostic criteria for MetS.16,17 While many studies have shown an association between ADT and certain MetS components, only 3 cross-sectional studies have assessed the prevalence of full MetS in patients with PCa receiving ADT (table 4).5e7 Braga-Basaria et al reported MetS (ATP III) prevalence rates in 3 groups, as 20 patients on ADT for 12 months or more (55%), 18 age matched men with nonmetastatic PCa who received local treatment (22%) and 20 age matched controls (20%).5 The men on ADT had a greater waist circumference, hyperglycemia and hypertriglyceridemia compared to controls, while hypertension and HDL cholesterol remained stable. Cleffi et al compared 54 patients with PCa after a mean of 15 months of ADT to 25 patients with PCa without ADT.6 The respective prevalence rates (IDF criteria) were 54% and 24%, and the percentage of patients on ADT with diabetes and central obesity increased the most, while BP, triglycerides and HDL cholesterol remained relatively stable. Morote et al retrospectively assessed the prevalence of MetS (ATP III) in 53 patients with PCa on ADT for 12 months or more vs 53 patients with PCa without ADT and 53 subjects without PCa (negative biopsy).7 The prevalence of MetS after any treatment was 32% in the nonPCa group, 36% in the nonADT group of patients with PCa and 51% in patients who received ADT. The largest changes observed from baseline were in waist circumference and fasting
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glucose. One notable finding was that the prevalence of MetS in the ADT group increased progressively with time, from 44% with 36 months or less of ADT to 57% with more than 36 months of ADT. Although the 23% baseline prevalence of MetS (ATP III) in patients with hormone na€ıve PCa in the present study was less than the expected 30%, it was in line with the expected rate for the age of our study population.3 The baseline prevalence of MetS ranged from 9.4% to 50% according to the definition used. Increases in waist circumference, fasting glucose and hypertriglyceridemia were early and highly significant. These findings are consistent with those reported in numerous cohort studies,18e23 in which these same 3 MetS components were the most affected by ADT. Depending on the definition, after 12 months of ADT the prevalence of MetS increased from 3.9% to 8.1%. In all 3 crosssectional studies that analyzed full MetS, the prevalence increased significantly after ADT. In the control groups the baseline prevalence ranged from 20% to 30% but increased to 50% or more in patients treated with ADT for 15 to 45 months. Moreover, as previously noted Morote et al found that prevalence increased according to the duration of ADT administration.7 The data from the previously mentioned studies, considered in light of the results presented here, suggest that ADT does not lead to the development of full MetS in patients with PCa, at least during the first year of treatment. However, we cannot rule out the possibility that MetS prevalence could increase with extended ADT. Regardless of whether ADT increases the prevalence of full MetS, the negative impact of ADT on several CV risk components of MetS (fasting glucose, hypertriglyceridemia, waist circumference and BMI)
Table 4. Summary of published data of metabolic disorders and full MetS References 19
Study Type
No. Cases
Mos ADT (range)
Smith et al Smith et al18
Cohort Cohort
22 40
3 12
Basaria et al20 Dockery et al21 Smith17 Smith et al14
Cross-sectional Cohort Cohort Cohort
20 31 79 25
45 3 12 3
(12e101)
Basaria et al15 Braga-Basaria et al5
Cross-sectional Cross-sectional
18 20
45 45
(12e101) (12e101)
Levy et al16 Smith et al26
Cohort Cohort
23 26
24 12
Galv~ao et al22 Hamilton et al23
Cohort Cohort
72 26
36 12
Cleffi et al6
Cross-sectional
54
15 (not reported)
Cross-sectional Cohort
53 310
7
Morote et al Present series
29 12
(12e64)
Significant Findings Fasting insulinemia þ64%, fat body mass þ8.4%, lean body mass 2.7% Total cholesterol þ9%, HDL þ11.3%, LDL þ7.3%, triglycerides þ26.5%, fat body mass þ9.4%, lean body mass 2.7%, BMI þ2.4% Fat body mass þ, BMI þ Total cholesterol þ7%, HDL þ20%, fasting insulinemia þ63% Fat body mass þ11%, lean body mass 3.8% Total cholesterol þ9.4%, HDL þ9.9%, triglycerides þ23%, fasting insulinemia þ23%, fat body mass þ4.3%, lean body mass 1.4% BMI þ, fasting glycemia þ, fasting insulinemia þ, leptin þ Full MetS 55% (control group 22%), BMI þ16.6%, waist circumference greater than 102 cm 45%þ, fasting glycemia 27.5%þ, triglycerides þ65.2% Fat body mass þ1.2%, lean body mass 1.1% BMI þ3.1%, fat body mass þ11.2%, lean body mass 3.6%, HDL þ9.7%, triglycerides þ19.4%, adiponectin þ36.4% Fat body mass þ13.8%, lean body mass 2.4% Total cholesterol þ11.2%, triglycerides þ46.6%, fat body mass þ14%, lean body mass 3.6%, BMI þ2.2%, leptin þ50.4% Full MetS 53% (control group 24%), waist circumference þ6.9%, fasting glycemia 110 mg/dl or greater þ13.9%, total cholesterol þ11.8% Full MetS 51% (control group 32%), ADT 12-36 mos 44%, more than 36 mos 57% Full MetS 23%-27%, waist circumference þ1.2%, total cholesterol þ3.8%, HDL þ7.7%, triglycerides þ7.2%, fasting glycemia þ1.6%
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METABOLIC SYNDROME AND ANDROGEN SUPPRESSION THERAPY
within 12 months of ADT administration is evident. However, some have suggested that the metabolic changes that accompany ADT are distinct from classically defined MetS.24 Although the metabolic alterations secondary to ADT share some of the features of classic MetS, there are important differences. In contrast to MetS, ADT may increase HDL cholesterol18,21,25 and subcutaneous (but not visceral) abdominal fat.18,26 Interestingly, none of the previously mentioned studies showed significant changes in BP.5e7,19,23,26 While classic MetS is associated with low levels of adiponectin27 and increased levels of C-reactive protein,28 ADT seems to increase adiponectin and leptin but not C-reactive protein.26 Our data confirm that ADT does not alter C-reactive protein levels during the first year. The present study has numerous strengths, primarily the prospective, longitudinal design and the large patient cohort. The main limitation in assessing the prevalence of MetS is that it varies according to the criteria used to define MetS. As our results show, the baseline prevalence and its increase during ADT vary greatly depending on the definition. Another limitation is the high dropout rate, although this characteristic is inherent in observational studies. Importantly, we verified that patients who dropped out and, therefore, were excluded from the final analysis, did not do so due to extreme manifestations of MetS or CV morbidity-mortality. Finally, some have raised doubts about the predictive value of MetS, with 1 study concluding that MetS adds no value to the traditional risk factors used to predict diabetes or CVD.29 A recent review of 2 large prospective studies showed that a MetS diagnosis was no better at predicting incident diabetes than fasting glucose levels greater than 110 mg/dl.30 This evidence has prompted the American Diabetes Association to recommend that all CV risk factors be assessed and treated, even when all diagnostic criteria for MetS are not present.29
CONCLUSIONS The findings reported here strongly suggest that ADT has an early and significant negative impact
on several important metabolic parameters associated with cardiovascular health. As our data show, the prevalence of MetS is highly influenced by the criteria used to define it, as is the magnitude of increases in MetS prevalence after 1 year of ADT.
ACKNOWLEDGMENTS Bradley Londres provided editorial assistance.
APPENDIX Members of the Spanish ANAMET Working Group: Jose Ma Saladie, Hospital Universitari Germans Trias i Pujol, Barcelona; Gemma Sancho, Hospital de la Santa Creu I Sant Pau, Barcelona; Humberto Villavicencio, Fundacion Puigvert, Barcelona; Jose Segarra, Hospital Universitari Joan XXIII, Tarragona; Jose Comet, Hospital Universitari Dr. Josep Trueta, Girona; Dr. Jose Francisco Suarez, Hospital Universitari de Bellvitge, Barcelona; Dr. Ma Jose Ribal, Hospital Clınic I Provincial, Barcelona; Dr. Jose Antonio Llorente, Hospital del Mar, Barcelona; Dr. Juan Urıa, Hospital General de Vic, Barcelona; Dr. Jesus Guajardo, Hospital Universitari Arnau de Vilanova, Barcelona; Dr. Antonio Gomez Caama~no, Hospital Clınico Universitario de Santiago, A Coru~na; Dr. Camilo Garcıa Freire, Hospital de Conxo, A Coru~na; Dr. Antonio Ojea, Hospital Xeral-Cıes de Vigo, Pontevedra; Dr. Juan Mata, Hospital Meixoeiro, Pontevedra; Dr. Ma Luisa Vazquez, Hospital Meixoeiro, Pontevedra; Dr. Francisco Gomez Veiga, Hospital Juan Canalejo, A Coru~na; Dr. Daniel Pesqueira, Policlınico de Vigo, Pontevedra; Dr. Juan Pablo Ciria, Hospital Virgen de Aranzazu, San Sebastian; Dr. Roberto Llarena, Hospital de Cruces, Bilbao; Dr. Jesus Miguel Unda, Hospital de Basurto, Bilbao; Dr. Angel Jose Tabernero, Hospital Universitario de La Paz, Madrid; Dr. Angel Silmi, Hospital Clınico San Carlos, Madrid; Dr. Carlos Hernandez, Hospital Gregorio Mara~non, Madrid; Dr. Alfredo Rodrıguez Antolın, Hospital 12 de Octubre, Madrid; Dr. Miguel Julian Mora, Hospital de La Princesa, Madrid; Dr. Almudena Zapatero, Hospital de La Princesa, Madrid; Dr. Ana Maria Perez, Fundacion Jimenez Dıaz, Madrid; Dr. Joaquin Carballido, Hospital Puerta de Hierro, Madrid; Dr. Ma Jose Ortiz, Hospital Universitario Virgen del Rocıo, Sevilla; Dr. Jose Luis Alvarez-Ossorio, Hospital Universitario Puerta del Mar, Cadiz; Dr. Alvaro Juarez, Hospital General Jerez de la Frontera, Cadiz; Dr. Juan Jose Lobato, Hospital General Universitario de Alicante, Alicante; Dr. Juan Fernando Jimenez, Hospital Universitario La Fe, Valencia; Dr. Alejandro Tormo, Hospital Universitario La Fe, Valencia; Dr. Eduardo Solsona, Instituto Valenciano de Oncologıa, Valencia; Dr. Manuel Casa~na, Instituto Valenciano de Oncologıa, Valencia; Dr. Manuel Rivas, Hospital de Cabue~nes, Gijon; Dr. Ramon Abascal, Hospital Universitario Central de Oviedo, Oviedo; Dr. Pedro Prada, Hospital Universitario Central de Oviedo, Oviedo; Dr. Jose Amon, Hospital Universitario Rio Hortega, Valladolid; Dr. Pedro Rodrıguez, Hospital Universitario de La Laguna, Tenerife; Dr. Claudio Oton, Hospital Universitario de La Laguna, Tenerife; Dr. Reinaldo Marrero, Hospital Dr. Negrın, Las Palmas de Gran Canaria; Dr. Mariano Porras, Hospital Virgen de La Arrixaca, Murcia; Dr. Marino Perez, Hospital Virgen de La Arrixaca, Murcia; Dr. Victor Macıas, Hospital Clınico Universitario de Salamanca, Salamanca; and Dr. Miguel Angel Barranco, Hospital de Mataro, Barcelona.
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