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VII convegno nazionale fondazione AMD Baveno23-25 ottobre 2014 SUBITO DE disfunzioni sessuali e rischio cardiovascolare. Il ruolo dell ipogonadismo Giovanni Corona MD, PhD Endocrinology Unit Medical Department, Ospedale Maggiore Bologna, Italy jocorona@libero.it

Subito-DE study The SUBITO-DE study is an observational, multicenter, prospective study involving 27 Italian diabetes centers. Male patients recently diagnosed with T2DM were consecutively interviewed by their attending physician at the diabetes care centers and asked whether they had experienced a change in their sexual function or found it unsatisfactory. Those responding positively were then invited to participate in the study

Corona et al J Endocrinol Invest 2013;36:868

Screening: Do you suffer from any sexual dysfunction? yes No Would you want to discuss the problem? Stop Yes: V1 No: Stop 18 months of follow up V2

Data analyzed General characteristics of the subject Smoking and alcohol consumption Clinical history Depressive symptoms ( CES- D) Assessment of ED severity ( IIEF -EF ) Clinical history of DE ( treatment, response to treatment ). Evaluation of ejaculatory disorders, and sexual desire Evaluation of suspected androgen deficiency defined on the basis of ANDROTEST and Testosterone levels

North Investigator Emanuele Fraticelli Gianpaolo Magro Carlo B.Giorda Annamaria Chiambretti/Riccardo Fornengo Giorgio Viviani Andrea Corsi /Alberto Aglialoro Gianpaolo Testori Donatella Zavaroni Roberto Mingardi Alessandra Sforza/Giovanni Corona Centre Bra (CN) Cuneo Chieri (TO) Chivasso (TO) Genova Genova Milano Piacenza Vicenza Bologna

Centre Investigator Fabio Baccetti Sergio Leotta Rocco Bulzomi Angela Sabbatini Lelio Morviducci Centre Massa Carrara Roma Roma Palestrina (RM) Roma

South Investigator Rossella Iannarelli Vincenzo Paciotti Andrea Del Buono Gerardo Corigliano Gennaro Clemente Luciano Improta Salvatore Turco Sandro Gentile Stefano Albano/Marcello Sciaraffia Pietro Pata Domenico Cucinotta Carmelo De Francesco Centre l'aquila Avezzano (AQ) Cellola (CE) Napoli Salerno Santagnello (NA) Napoli Napoli Taranto Messina Messina Messina

2 Milano Chivasso Vicenza Torino Piacenza Bra Bologna Cuneo Genova Massa Carrara 2 27 centre involved Patients screened=1503 Patients enrolled=499 (33%) Mean age 58.8±8.8 years 3 Roma Palestrina L Aquila Avezzano Cellole 4 Napoli Salerno Taranto 3 Messina

N. pz screened n=1503 N=666 44.3% N=167 11.1% N=499 33.2% No ED ED Agree to be involved Not aggred

Type 1 diabetes Type 2 diabetes Age Total n. subjects %ED Total n. subjects %ED 45 884 13 677 16 46-55 267 43 2260 29 56-65 188 54 3975 42 66 44 66 1461 49 Fedele et al Int J Epidemiol 2000;29: 524

Yamada et al PLOS one 2012;7: e43763

What is the role of hypogonadism in T2DM CV risk?

2013 J Sex Med. 2013;10:245.

Recommendation 1: Definition of Testosterone Deficiency (TD) -TD is a clinical AND biochemical syndrome associated with age and comorbidities, and characterized by a deficiency of testosterone and relevant symptoms. It may affect the function of multiple organ systems, and result in significant detriment in the quality of life, including alterations in sexual function (EBMl 2). -TD results from defects at various levels of the hypothalamuspituitary-testes axis: abnormality in the testes (primary TD), pituitary or hypothalamic failure (secondary or tertiary TD) or a combination of the two (mixed TD) (EBMl1). TD may also result from an impairment of T action because of decreased bioavailability of the hormone (due to SHBG variations) or because of androgen receptor alterations (EBMl2). Buvat et al., J Sex Med. 2013;10:245

Recommendation 7: Threshold levels for the biochemical diagnosis of TD There are no generally accepted lower limits of normal total testosterone. There is, however, general agreement that: TT > 12 nmol/l (3.5 ng/ml or 350 ng/dl) does not usually require substitution (EBMI1) Based on the data of young hypogonadal men, men with TT < 8 nmol/l (2.3 ng/ml or 230 ng/dl) usually benefit from T treatment (EBMI1) Between these levels: measuring FT by equilibrium dialysis or calculating it from TT and SHBG levels may be helpful in case of TT between 8 and 12 nmol/l. A lower limit of 225 pmol/l (65 pg/ml) is accepted by many (EBMI3) A Testosterone Therapy trial for 3-6 months may be envisaged in those patients who are symptomatic, while alternative causes of the symptoms have been excluded (EBMI5). Beyond that time, T therapy would be continued only in case of substantial benefit Buvat et al., J Sex Med. 2013;10:245

Measurement of bioactive or free testosterone www.issam.ch/freetesto.htm

Corona et al., Int J Androl. 2011;34:528

RANDOM-EFFECTS POOLED MEAN DIFFERENCE OF TOTAL TESTOSTERONE BETWEEN T2DM CASES AND CONTROLS FROM CROSS-SECTIONAL STUDIES All=27 Source Daubresse et al., 1978 Shahwan et al., 1978 Andò et al., 1984 Phillips, 1984 Small et al., 1987 Semple et al., 1988 Barret-Connor et al., 1990 Barret-Connor, 1992 Andersson et al., 1994 Tibblin et al., 1996 Defay et al., 1998* Defay et al., 1998** Chearskul et al., 2000 Jang et al., 2001 Zietz et al., 2000 Abou-Seif et al., 2001 Corrales et al., 2004 Svartberg et al., 2004 Achemlal et al., 2005 Chen et al., 2005 Pitteloud et al., 2005 Crawford et al., 2007 Selvin et al., 2007 Ibanez et al., 2008 OVERALL NO ED Daubresse et al., 1978 Shahwan et al., 1978 Corona et al., 2004 Corona et al., 2005 Rhoden et al., 2005 Hamdan et al., 2008 OVERALL ED OVERALL Overall -15,00 TT mean differences (nmol/l) -15-10 -5 0 5 10-10,00-5,00 0,00 5,00 10,00 Diff. in means LL, 95% CI UL, 95% CI -4,60-9,85 0,65-3,40-10,62 3,82-3,20-7,72 1,32-1,60-5,91 2,71-4,80-8,54-1,06-0,70-3,99 2,59-1,50-2,74-0,26-2,70-4,76-0,64-6,60-11,96-1,24-2,30-4,03-0,57-6,70-11,14-2,26-3,80-5,64-1,96-3,70-6,34-1,06-2,90-5,44-0,36-2,50-3,06-1,94-4,09-4,86-3,32-2,40-6,19 1,39-2,00-3,38-0,62 1,70-1,45 4,85-2,10-3,91-0,29-4,90-8,07-1,73-3,30-4,20-2,40-3,60-5,89-1,31-9,70-13,71-5,69-3,00-3,61-2,38-1,00-6,06 4,06-2,75-9,21 3,71-6,50-7,67-5,33-2,10-3,02-1,18-1,92-3,10-0,74-1,60-6,58 3,38-2,96-5,18-0,73-2,99-3,59-2,40-2.99-3.59-2.40 TT lower in cases TT higher in controls Corona et al., Int J Androl. 2011;34:528

Corona et al., J Sex Med 2014;11:2065

Total Testosterone (ng/ml) Prevalence of hypogonadism 4 < 3.5 3 < 3.0 2 < 2.311 15 25 35 45 %

Sweden Malmo Eight Countries/Cities in the European Male Ageing Study Estonia Tartu U.K. Manchester Russia Poland Lodz Belgium Leuven France Germany Hungary Szeged Spain Santiago Italy Florence n=3369

Wu et al., N Engl J Med. 2010;363:123

Testosterone totale (ng/ml) Prevalence of hypogonadism EMAS 4 < 3.5 3 < 3.0 2 < 2.311 15 25 35 45 %

Testosterone and type 2 diabetes mellitus 1. Hypogonadism is associated with T2DM

What about pre-diabetes conditions?

Glucose abnormalities in a consecutive series of 4351 patients with ED IFG/DM 2.1% No IFG/DM Established DM Newly diagnosed DM IFG (100-110 mg/dl) 59.2% 40.8% 19.6% 13.5% IFG (110-126 mg/dl) 5.6% Corona et al J Sex Med. 2012;9:1669

% ANDROTEST score Total Testosterone (nomol/l) cft (nomol/l) Adj. r=-0.052; p=0.006 Adj. r=-0.054; p=0.037 50 TT < 8 nm TT < 10.4 nm TT < 12 nm Adj. r=0.053; p< 0.008 40 30 20 10 0 < 100 1 101-109 2 110-125 3 4New ly Established 5 diagnosed Glycemia mg/dl DM < 100 101-109 110-125 New ly Established diagnosed Glycemia mg/dl DM Corona et al J Sex Med. 2012;9:1669

Testosterone and type 2 diabetes mellitus 1. Hypogonadism is associated with MetS and T2DM 2. Hypogonadism is associated with pre-diabetic conditions

RANDOM-EFFECTS MODEL OF TOTAL TESTOSTERONE IN INCIDENT CASES OF T2DM IN PROSPECTIVE STUDIES Source -6,000 TT mean differences (nmol/l) -5,000-4,000-3,000-2,000-1,000 0,000 1,000-6 -5-4 -3-2 -1 0 1 Diff. in means LL, 95% CI UL, 95% CI Haffner et al., 1996-0,700-2,037 0,637 Tibbling et al., 1996-3,700-5,501-1,899 Stellato et al., 2000-3,100-4,571-1,629 Laaksonen et al., 2004-2,600-4,462-0,738 OVERALL -2.46-3.85-1.07-2,456-3,845-1,066 TT Favorable TT Adverse Corona et al., Int J Androl. 2011;34:528

Who came first? MetS Hypogonadism

Corona et al., J Endocrinol Invest. 2011;34:557.

Does hypogonadism increase CV risk?

Corona et al., Eur J Endocrinol. 2011;165:687

Weighted differences (with 95% confidence interval [CI]) of mean total testosterone between non-angiographically documented CHD and controls from cross-sectional studies Source Poggi et al., 1976 Ben-Halim etal., 1978 Entrican et al., 1978 Luria et al., 1982 Labropoulos et al., 1982 Labropoulos et al., 1982* Zumoff et al., 1982* Phillips et al., 1983 Aksut etal., 1986 Aksut et al., 1986* Franzen et al., 1986 Franzen et al., 1986* Lichatenstein et al., 1987 Small et al., 1987 Phillips et al., 1988 Barrett-Connor et al., 1988 Sewdarsen et al., 1990 Hauner et al., 1991 Rice et al., 1993 Hautanen et al., 1994 Marques-Vidal et al., 1995 Phillips et al., 1996 Tripathi et al., 1998* Tripathi et al., 1998** Tripathi et al., 1998*** Chearskul et al., 2000 Mikulec et al., 2004 Cao et al., 2010 Overall CHD non-angio documented TT mean differences (nmol/l) -20-15 -10-5 0 5 10-20,00-15,00-10,00-5,00 0,00 5,00 10,00 Diff. in mean LL, 95% CI UL, 95% CI -8,75-13,91-3,59 0,00-2,94 2,94 2,35-0,31 5,01 1,32-4,06 6,70 3,00 0,27 5,73 1,80-0,38 3,98 1,46-1,43 4,35 0,80-0,86 2,46-6,36-8,63-4,10-7,16-10,03-4,28 3,00 0,57 5,43 2,00-0,43 4,43-1,10-1,81-0,39-3,30-7,12 0,52-0,69-2,57 1,18-0,04-1,18 1,10-1,51-2,64-0,38-1,40-2,85 0,05-2,15-3,53-0,76 0,50-1,71 2,71-0,40-1,95 1,15 2,64-2,01 7,29-13,85-15,68-12,02-13,43-14,97-11,89-13,56-15,59-11,53-5,81-7,92-3,70 0,31-0,77 1,39-4,06-5,30-2,82-2,33-3,99-0,68 Overall CHD non-angio-documented -2.33-3.99-0.68 Favours CHD Favors no CHD Corona et al., Eur J Endocrinol. 2011;165:687

Weighted differences (with 95% confidence interval [CI]) of mean total testosterone between angiographically documented CHD and controls from cross-sectional studies Source TT mean differences (nmol/l) -15-10 -5 0 5 10-15,00-10,00-5,00 0,00 5,00 10,00 Diff. in mean LL, 95% CI UL, 95% CI Luria et al., 1982 * 2,99-0,42 6,39 Zumoff et al., 1982-1,90-5,87 2,07 Barth et al., 1983-5,70-9,36-2,04 Hromadova et al., 1985-7,21-10,85-3,57 Sewdarsen et al., 1986-5,00-7,56-2,44 Chute et al., 1987-4,76-7,86-1,66 Hamalainen et al., 1987-0,70-4,36 2,96 Sewdarsen et al., 1988-3,80-6,88-0,72 Slowinska-Srzednicka et al., 1989-3,06-7,32 1,20 Zhao et al., 1998-5,56-7,80-3,32 Kabakci et al., 1999 1,74-0,28 3,76 English et al., 2000-2,00-4,09 0,09 Dobrzycki et al., 2003-9,30-11,97-6,63 Dunajska et al., 2004-3,60-7,25 0,05 Dunajska et al., 2004* -2,36-5,23 0,51 Fischer et al., 2004-0,60-2,08 0,88 Davoodi et al., 2007 0,78-0,64 2,20 He et al., 2007-0,28-2,08 1,53 Mohamad et al., 2007-4,50-6,48-2,52 Mohamad et al., 2007* -1,40-3,76 0,96 Turhan et al., 2007-3,48-5,76-1,20 Fallah et al., 2009 0,78-0,64 2,20 Overall Overall CHD CHD angio-documented -2,57-2.57-3,82-3.82-1,31-1.31 Favours CHD Favors no CHD Corona et al., Eur J Endocrinol. 2011;165:687

Weighted differences (with 95% confidence interval [CI]) of mean total testosterone between other CVD and controls from cross-sectional studies Source TT mean differences (nmol/l) -14-12 -10-8 -6-4 -2 0 2 4-14,00-12,00-10,00-8,00-6,00-4,00-2,00 0,00 2,00 4,00 Diff. in mean LL, 95% CI UL, 95% CI Taggart et al., 1980 0,10-2,15 2,35 Foresta et al., 1982-5,49-8,60-2,37 Elwan et al., 1990-0,87-4,67 2,93 Dash et al., 1991-6,60-12,26-0,94 Jeppesen et al., 1996-2,70-4,56-0,84 Price et al., 1997-1,30-3,52 0,92 Demirbag et al., 2005-8,02-11,73-4,31 Page et al., 2008-1,40-2,28-0,52 Overall other CVD -2.71-4.26-1.15 Overall other CVD -2,71-4,26-1,15 Favours other CVD Favors no other CVD Corona et al., Eur J Endocrinol. 2011;165:687

Is any relationship with incident CV diasese?

Baseline weighted differences (with 95% confidence interval) of mean total testosterone (TT) between patients with incident overall mortality and controls TT mean differences (nmol/l) Source -6-5 -4-3 -2-1 0 Diff. in mean LL, 95% CI UL, 95% CI Letonen et al., 1996-2,90-5,39-0,41 Khaw et al., 2007-0,90-1,38-0,42 Corona et al., 2010-2,10-3,87-0,33 OVERALL -1,53-2,69-0,37 Higher ovreall mortality Lower overall mortality Corona et al., Eur J Endocrinol. 2011;165:1

Baseline weighted differences (with 95% confidence interval) of mean total testosterone (TT) between patients with incident CV mortality and controls TT mean differences (nmol/l) Source -7-6 -5-4 -3-2 -1 0 1 Diff. in mean LL, 95% CI UL, 95% CI -7,00-6,00-5,00-4,00-3,00-2,00-1,00 0,00 1,00 Barrett-Connor et al., 1988-0,61-1,86 0,64 Khaw et al., 2007-1,00-1,66-0,34 Corona et al., 2010-3,00-6,53 0,53 OVERALL -0,97-1,55-0,40 Higher any CVD mortality Lower any CVD mortality Corona et al., Eur J Endocrinol. 2011;165:1

Baseline weighted differences (with 95% confidence interval) of mean total testosterone (TT) between patients with incident MACE and controls TT mean differences (nmol/l) Source -12-10 -8-6 -4-2 0 2 4 Diff. in mean LL, 95% CI UL, 95% CI -12,00-10,00-8,00-6,00-4,00-2,00 0,00 2,00 4,00 Cauley et al., 1987 Phillips et al., 1988 Contoreggi et al., 1990 Yarnell et al., 1993 Hautanen et al 1994 Mikulec et al., 2004 Yeap et al., 2009 Corona et al., 2010 Overall 0,60-1,47 2,67-0,69-2,83 1,44 0,35-1,79 2,49 0,10-1,19 1,39 0,50-1,71 2,71-10,10-10,77-9,44-1,00-2,02 0,02-0,70-1,85 0,45-1,40-5,23 2,44 Higher any CVD incidence Lower any CVD incidence Corona et al., Eur J Endocrinol. 2011;165:1

Any data in DM?

Subito DE: V2 data N=450 90.2% N=43 N=6 8.2% 1.2% No V2 Yes V2 Dead Lost at follow up

V2 data: incident events N=43 8.2% N=450 90.2% N=6;1.2% N=25; 5.6% N=15; 3.3% Dyslipidemia No V2 Yes V2 Arterial hypertension MACE

VERY HIGH DOSE OF TRT. CV-related events in: 4 of 14 subjects (29%) with T levels > 1000 ng/dl 7 of 46 subjects (15%) with T levels < 500 ng/dl COMPOSITE RISK FOR ADVERSE EVENTS (including peripheral oedema) ELDERLY MEN WITH LIMITED MOBILITY

Vigen et al., JAMA. 2013; 310:1829

Kaplan-Meier Survival Curves With Testosterone Therapy Evaluated as a Time-Varying Covariate Vigen et al., JAMA. 2013; 310:1829

Cohort study of the risk of acute non-fatal myocardial infarction (MI) following an initial TT prescription (N = 55,593) in a large health-care database. Incidence rate of MI in the 90 days following the initial prescription (postprescription interval) compared with the rate in the one year prior to the initial prescription (pre-prescription interval) (post/pre). Finkle et al., PLoS ONE. 2014; 9: e85805

testosterone & heart Is testosterone administration associated with incidence of composite CV events? BMC Med. 2013; 11: 108. Published online 2013 April 18. doi: 10.1186/1741-7015-11-108 PMCID: PMC3648456 Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials Lin Xu, 1 Guy Freeman, 1 Benjamin J Cowling, 1 and C Mary Schooling 1,2 placebo-controlled, randomized studies 12 wks or more 27 trials 2994 men 180 adverse events

Xu et al., BMC Medicine 11:108, 2013

[01-31-2014] The U.S. Food and Drug Administration (FDA) is investigating the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products. We have been monitoring this risk and decided to reassess this safety issue based on the recent publication of two separate studies that each suggested an increased risk of cardiovascular events among groups of men prescribed testosterone therapy. We are providing this alert while we continue to evaluate the information from these studies and other available data, and will communicate our final conclusions and recommendations when the evaluation is complete.

Until evidence from large randomized trials becomes available, the Endocrine Society believes that patients should be made aware of the potential risk of cardiovascular events in middle-aged and older men who are taking or considering testosterone therapy for age-related decline in testosterone levels and symptoms.

Records identified through different sources N=2747 UNPUBLISHED Studies N=649 Ongoing N=202 Records removed: No Clinical Trials N=2287 No Human species N =2 No English language N=13 No Male subjects N=145 No results available N=372 No placebo N=26 W omen N=21 No T arm N=27 Full-text articles assessed for eligibility N=300 Full-text articles excluded: Women N=4 No T use included N=45 No RCT N=21 No placebo (or p-only) arm N=108 No T-only arm N=4 Study duplicates N=18 Study assessed for eligibility N=1 Studies included in qualitative synthesis N=101 Studies excluded (see table 6) N=26 Studies included in quantitative synthesis (meta-analysis) N=75 Corona et al., 2014

Primary end-point: MACE cardiovascular death, non-fatal myocardial infarction stroke, acute coronary syndromes and/or heart failure reported as serious adverse events Secondary end-points: all cardiovascular-related events (anything reported as such by the authors): events reported as cardiac disorders, cardiovascular complaints, cardiovascular event vascular disorders, cardiac or cardiovascular event description fell within the International Statistical Classification of Disease (ICD) version 10 chapter IX (I00 toi99) Corona et al., Expert Opin Drug Saf. 2014 Aug 19:[Epub ahe

Is testosterone administration associated with CV outcomes? (MACE)

Source MH-OR LL UL p 0,00 0,01 Odds ratio for MACE 0,10 1,00 10,00 100,00 0.01 0.1 1 10 100 1000,00 TS #Events # Patients Placebo #Events # Patients Copenaghen SG 1986 (27) 1,97 0,08 48,82 0,68 Hall et al., 1996 (30) 0,32 0,01 8,23 0,49 Sih et al., 1997 (32) 0,88 0,05 15,33 0,93 Snyder et al., 1999 (36) 2,04 0,18 23,17 0,57 English et al., 2000 (38) 3,12 0,12 80,39 0,49 Seidman et al., 2001 (43) 0,41 0,02 10,83 0,59 Steidle et al., 2003 (48) 2,83 0,11 70,27 0,53 Armory et al., 2004 (50) 3,13 0,12 80,68 0,49 Kenny et al., 2004 (52) 0,23 0,01 7,05 0,40 Svartberg et al., 2004 (56) 0,29 0,01 7,74 0,46 Brockenbrough et al., 2006 (59) 3,75 0,36 39,59 0,27 Malkin et al., 2006 (65) 2,17 0,19 25,01 0,53 Nair et al., 2006 (68) 5,70 0,26 123,78 0,27 Svartberg et al., 2008 (77) 3,16 0,12 82,64 0,49 Chapman et al., 2009 (80) 1,00 0,05 20,83 1,00 Legros et al., 2009 (81) 1,01 0,04 25,01 1,00 Aversa et al., 2010 (85) 0,08 0,00 2,07 0,13 Aversa et al., 2010 (86) 0,07 0,00 1,97 0,12 Basaria et al., 2010 (10) 13,39 0,74 240,78 0,08 Kalinchenko et al., 2010 (88) 0,21 0,01 5,15 0,34 Srinivas-Shankar et al., 2010 (89) 1,01 0,14 7,31 0,99 Ho et al., 2011 (91) 1,00 0,06 16,37 1,00 Jones et al., 2011 (92) 0,51 0,05 5,75 0,59 Kaufman et al., 2011 (93) 0,87 0,04 18,48 0,93 Behere et al., 2012 (95) 2,95 0,12 72,91 0,51 Hildreth et al., 2013 (97) 0,15 0,02 1,53 0,11 Overall 1,01 0,57 1,77 0,98 1 134 0 87 0 35 1 35 1 17 1 15 2 54 1 54 1 25 0 25 0 13 1 17 1 106 0 99 1 24 0 24 0 6 1 5 0 15 1 14 3 19 1 21 2 37 1 39 2 30 0 32 1 19 0 19 1 6 1 6 1 237 0 79 0 40 1 10 0 42 1 10 6 106 0 103 0 113 1 71 2 136 2 138 1 60 1 60 1 108 2 112 2 234 0 40 1 183 0 179 1 96 3 47 31 1895 20 1341 Placebo TS Corona et al., 2014

Source # Trials MH-OR LL UL p 0,00 Odds ratio for MACE 0,01 0,10 1,00 10,00 0.01 0.1 1 10 100 100,00 1000,00 TS #Events # Patients Placebo #Events # Patients AMI 14 0,68 0,30 1,52 0,34 11 1086 11 747 Acute coronary syndrome 15 0,92 0,43 1,97 0,83 18 1093 11 738 Stroke 5 0,82 0,24 2,83 0,76 3 244 4 242 New heart failure 3 1,64 0,25 10,63 0,60 3 387 0 193 CV mortality 13 1,14 0,49 2,66 0,76 11 1173 8 928 Placebo TS Corona et al., Expert Opin Drug Saf. 2014 Aug 19:[Epub ahe

Associated diaseses Source # Trials MH-OR LL UL p 0,00 Odds ratio for MACE 0,01 0,10 1,00 10,00 100,00 0.01 0.1 1 10 100 1000,00 TS #Events # Patients Placebo #Events # Patients Elderly men 10 1,22 0,49 3,03 0,67 Men with CVD 2 2,48 0,35 17,45 0,36 Frail men 5 2,25 0,72 7,08 0,17 Men with metabolic diseases 4 0,19 0,04 0,85 0,03 13 954 6 549 3 62 1 64 13 401 4 355 1 303 5 203 Hypogonadism status Mixed population 14 1,26 0,58 2,73 0,56 TT < 12 nm 12 0,84 0,32 2,23 0,73 15 1066 11 865 16 829 9 476 da qui Type of support Drug company not supported 12 0,94 0,39 2,24 0,88 Drug company supported 14 1,07 0,51 2,24 0,86 10 437 8 332 21 1458 12 1009 Trial duration 12 weeks 4 1,02 0,20 5,29 0,98 >12 weeks 22 1,01 0,55 1,84 0,98 2 147 2 145 29 1746 18 1196 Placebo TS Corona et al., 2014

Source MH-OR LL UL p Odds ratio for MACE in Metabolic disease 0,00 0,01 0,10 1,00 10,00 100,00 0.01 0.1 1 10 100 TS #Events # Patients Placebo #Events # Patients Aversa 2010 JSM 0,08 0,00 2,07 0,13 0 40 1 10 Aversa 2010 JEI 0,07 0,00 1,97 0,12 0 42 1 10 Kalinchenko 2010 0,21 0,01 5,15 0,34 0 113 1 71 Jones et al., 2011 0,51 0,05 5,75 0,59 1 108 2 112 Overall 0,19 0,04 0,85 0,03 1 303 5 203 Placebo TS Corona et al., 2014

Is testosterone administration associated with CV outcomes? (any adverse event)

Source MH-OR LL UL p Copenaghen SG 1986 (27) 2,22 0,78 6,31 0,13 Hall et al., 1996 (30) 0,19 0,01 4,08 0,29 Sih et al.,1997 (32) 0,88 0,05 15,33 0,93 Snyder et al., 1999 (36) 1,96 0,61 6,29 0,26 English et al.,2000 (38) 5,43 0,25 118,96 0,28 Seidman et al., 2001 (43) 0,41 0,02 10,83 0,59 Steidle et al., 2003 (48) 4,76 0,23 100,40 0,32 Armory et al., 2004 (50) 5,44 0,25 119,63 0,28 Kenny et al., 2004 (52) 0,23 0,01 7,05 0,40 Svartberg et al., 2004 (56) 0,29 0,01 7,74 0,46 Brockenbrough et al., 2006 (59) 1,20 0,34 4,18 0,77 Malkin et al., 2006 (65) 0,86 0,24 3,10 0,82 Merza et al.,2006 (67) 0,30 0,01 7,85 0,47 Nair et al., 2006 (68) 1,32 0,39 4,50 0,66 Okun et al., 2006 (69) 0,46 0,04 5,75 0,55 Emmelot-Vonk et al., 2008 (75) 2,35 0,59 9,33 0,22 Svartberg et al., 2008 (77) 3,16 0,12 82,64 0,49 Caminiti et al., 2009 (78) 2,06 0,18 23,83 0,56 Chapman et al., 2009 (80) 1,00 0,05 20,83 1,00 Legros et al., 2009 (81) 1,01 0,04 25,01 1,00 Aversa et al., 2010 (85) 0,08 0,00 2,07 0,13 Aversa et al., 2010 (86) 0,07 0,00 1,97 0,12 Basaria et al., 2010 (10) 6,05 2,22 16,51 0,00 Kalinchenko et al., 2010 (88) 0,12 0,01 2,59 0,18 Srinivas-Shankar et al., 2010 (89) 2,60 0,49 13,61 0,26 Ho et al., 2011 (91) 1,00 0,14 7,34 1,00 Jones et al.,2011 (92) 0,40 0,14 1,19 0,10 Kaufman et al., 2011 (93) 1,49 0,33 6,71 0,60 Hoyos et al., 2012 (94) 3,18 0,13 81,01 0,48 Hildreth et al., 2013 (97) 0,14 0,04 0,48 0,00 NCT00957528 0,88 0,05 16,74 0,93 Overall 1,07 0,69 1,65 0,76 0,00 Odds ratio for overall CV events 0,01 0,10 1,00 10,00 100,00 0.01 0.1 1 10 100 1000,00 TS #Events # Patients Placebo #Events # Patients 16 134 5 87 0 35 2 35 1 17 1 15 9 54 5 54 2 25 0 25 0 13 1 17 2 106 0 99 2 24 0 24 0 6 1 5 0 15 1 14 9 19 9 21 5 37 6 39 0 20 1 19 7 30 6 32 1 15 2 15 7 120 3 117 1 19 0 19 2 35 1 35 1 6 0 6 1 237 0 79 0 40 1 10 0 42 1 10 25 106 5 103 0 113 2 71 5 136 2 138 2 60 2 60 5 108 12 112 17 234 2 40 1 33 0 34 4 96 11 47 1 9 1 8 126 1944 83 1390 Placebo TS Corona et al., 2014

Associated diaseses Source # Trials MH-OR LL UL p 0,00 Odds ratio for overall CVD 0,01 0,10 1,00 10,00 0.01 0.1 1 10 100 100,00 TS #Events # Patients Placebo #Events # Patients Elderly men 11 1,13 0,58 2,22 0,71 Men with CVD 3 1,28 0,44 3,71 0,65 Frail men 5 2,62 1,38 4,96 0,00 Men with metabolic diseases 5 0,33 0,14 0,82 0,02 52 890 31 487 9 94 7 98 56 395 22 349 6 336 16 237 Hypogonadism status Mixed population 18 1,26 0,84 1,90 0,27 TT < 12 nm 13 0,80 0,30 2,15 0,66 67 1072 49 879 61 849 34 495 Type of support Drug company not supported 14 1,33 0,82 2,15 0,25 52 575 32 474 Drug company supported 17 1,02 0,51 2,04 0,96 76 1343 51 900 Trial duration 12 weeks 2 0,18 0,02 1,81 0,15 0 53 2 27 >12 weeks 29 1,14 0,73 1,77 0,56 128 1868 81 1347 Placebo TS Corona et al., 2014

Corona et al., 2014

EFFECTS OF TRT ON DM & MetS PATIENT RESULTS FROM META-ANALYSIS EVALUATION

Patients with metabolic syndrome and or type 2 diabetes Study (Ref.) Boyanov et al 2003 Kapoor et al., 2006 La Vignera et al., 2008 Heufelder et al., 2009 Aversa et al., 2010 Gopal et al., 2010 Jones et al., 2011 Aversa et al., 2011 Tishova et al., 2011 Location Sofia, Bulgaria Sheffield, UK Catania, Italy Munich, Germany Rome, Italy Mumbai, India Multicenter Rome, Italy Moscow, Russia # patients (ID/C) 24/24 12/12 7/5 16/16 32/10 11/11 103/102 40/10 105/65 Hypogonadism cut off Trial duration (weeks) TT TT TT TT TT cft TT TT TT <15 nm <12 nm <8 nm <12 nm <11 nm <225 pm < 11 nm <11 nm < 12 nm 12 12 52 52 52 12 52 104 30 Drugs O-TU i.m T T gel 1% T gel 1% TU i.m T T gel 2% TU TU Dose 120 mg daily 200 mg/ 2weeks 50 mg/ daily 50 mg/ daily 1000 mg/ 12 weeks 200 mg/ 2weeks 60mg/ Daily 1000 mg/ 12 weeks 1000 mg/ 12 weeks Comparator No TRT group Placebo No TRT group No TRT group Placebo Placebo Placebo Placebo Placebo IDF-MetS Metabolic NCEP-ATPIII- T2DM with with or T2DM T2DM IDF-MetS T2DM characteristics MetS IDF-MetS without T2DM IDF-MetS IDF-MetS MetS n=483 patients; mean follow up 37 weeks Corona et al., Best Pract Clin Endocrinol & Metab 2013;27;557

Effects of TRT on metabolic parameter in patients with MetS Source -1,50 Glycaemia mean differences (mmol/l) -1,00-0,50-1.5-1.0-0.5 0 0.5 1.0 0,00 0,50 1,00 Diff. in mean LL, 95% CI UL, 95% CI p Heufelder et al., 2009-0,60-1,15-0,05 0,03 Aversa et al., 2010-0,60-1,35 0,15 0,12 Jones et al., 2011-0,31-1,33 0,71 0,55 Aversa et al., 2011-0,70-0,96-0,44 0,00 Tishova et al., 2011-0,04-0,49 0,41 0,86 Overall -0,48-0,78-0,19 0,00 Favours no TRT Favors TRT Corona et al., Best Pract Clin Endocrinol & Metab 2013;27;557

Effects of TRT on metabolic parameter in patients with MetS HOMA index mean differences Source -6-5 -4-3 -2-1 0 1 2 3-6,00-5,00-4,00-3,00-2,00-1,00 0,00 1,00 2,00 3,00 Diff. in mean LL, 95% CI UL, 95% CI p La Vignera et al., 2009-2,22-3,62-0,81 0,00 Heufelder et al., 2009-2,22-3,08-1,35 0,00 Aversa et al., 2010-1,80-2,62-0,98 0,00 Jones et al., 2011-0,05-2,31 2,21 0,97 Aversa et al., 2011-2,85-5,04-0,66 0,01 Tishova et al., 2011-0,32-0,53-0,11 0,00 Overall -1,54-2,59-0,50 0,00 Favours TRT Favors no TRT Corona et al., Best Pract Clin Endocrinol & Metab 2013;27;557

Effects of TRT on metabolic parameter in patients with MetS Triglycerides mean differences (nmol/l) Source -1,20-1,00-0,80-0,60-0,40-0,20-1.2-1.0-0.8-0.6-0.4-0.2 0 0.2 0.4 0.6 0.8 0,00 0,20 0,40 0,60 0,80 Diff. in mean LL, 95% CI UL, 95% CI p La Vignera et al., 2009-0,48-0,82-0,14 0,01 Heufelder et al., 2009-0,80-1,08-0,52 0,00 Aversa et al., 2010 0,00-0,43 0,43 1,00 Jones et al., 2011-0,25-0,65 0,15 0,22 Aversa et al., 2011-0,10-0,79 0,59 0,78 Tishova et al., 2011-0,52-0,98-0,06 0,03 Overall -0,40-0,66-0,14 0,00 Favours TRT Favors no TRT Corona et al., Best Pract Clin Endocrinol & Metab 2013;27;557

Effects of TRT on metabolic parameter in patients with MetS Corona et al., Best Pract Clin Endocrinol & Metab 2013;27;557

Testosterone and type 2 diabetes mellitus 1. Hypogonadism is associated with MetS and T2DM 2. Hypogonadism is associated with pre-diabetic conditions 3. Hypogonadism predicts T2DM but T2DM predicts hypogonadism 4. Having MACE decreases T by 2-3 nmoles/l 5. T is associated with incident overall and CV mortality but not incident MACE in longitudinal studies 6. TRT does not increase CV risk : possible protective effects in metabolic subjects 7.TRT in MetS is able to improve glyco-metabolic control ( fasting glycaemia), insulin resistance ( triglycerides, HOMA), fat mass ( waist)

Patients with metabolic syndrome and or type 2 diabetes Study (Ref.) Boyanov et al 2003 Kapoor et al., 2006 La Vignera et al., 2008 Heufelder et al., 2009 Aversa et al., 2010 Gopal et al., 2010 Jones et al., 2011 Aversa et al., 2011 Tishova et al., 2011 Location Sofia, Bulgaria Sheffield, UK Catania, Italy Munich, Germany Rome, Italy Mumbai, India Multicenter Rome, Italy Moscow, Russia # patients (ID/C) 24/24 12/12 7/5 16/16 32/10 11/11 103/102 40/10 105/65 Hypogonadism cut off Trial duration (weeks) TT TT TT TT TT cft TT TT TT <15 nm <12 nm <8 nm <12 nm <11 nm <225 pm < 11 nm <11 nm < 12 nm 12 12 52 52 52 12 52 104 30 Drugs O-TU i.m T T gel 1% T gel 1% TU i.m T T gel 2% TU TU Dose 120 mg daily 200 mg/ 2weeks 50 mg/ daily 50 mg/ daily 1000 mg/ 12 weeks 200 mg/ 2weeks 60mg/ Daily 1000 mg/ 12 weeks 1000 mg/ 12 weeks Comparator No TRT group Placebo No TRT group No TRT group Placebo Placebo Placebo Placebo Placebo IDF-MetS Metabolic characteristics T2DM T2DM NCEP-ATPIII- MetS T2DM with IDF-MetS IDF-MetS T2DM with or without IDF-MetS IDF-MetS T2DM Type 2 diabetes n=263 patients; mean follow up 28 weeks Corona et al., Best Pract Clin Endocrinol & Metab 2013;27;557

Effects of TRT on metabolic parameter in patients with T2DM Corona et al., Best Pract Clin Endocrinol & Metab 2013;27;557

Effects of TRT on metabolic parameter in patients with T2DM Source Glycaemia mean differences (mmol/l) -4-3 -2-1 0 1 2-4,00-3,00-2,00-1,00 0,00 1,00 2,00 Diff. in mean LL, 95% CI UL, 95% CI p Boyanov et al., 2003-2,00-3,09-0,91 0,00 Kapoor et al., 2006-1,35-3,33 0,63 0,18 Heufelder et al., 2009-0,60-1,15-0,05 0,03 Gopal et al., 2010-1,98-3,66-0,30 0,02 Jones et al., 2011-0,17-1,42 1,08 0,79 Overall -1,09-1,84-0,35 0,00 Favours TRT Favors no TRT Corona et al., Best Pract Clin Endocrinol & Metab 2013;27;557

Effects of TRT on metabolic parameter in patients with T2DM Source Triglycerides mean differences (nmol/l) -2.0-1.5-1.0-0.5 0 0.5 1-2,00-1,50-1,00-0,50 0,00 0,50 1,00 Diff. in mean LL, 95% CI UL, 95% CI p Boyanov et al., 2003-0,51-0,92-0,10 0,02 Kapoor et al., 2006-0,20-1,23 0,83 0,70 Heufelder et al., 2009-0,80-1,08-0,52 0,00 Gopal et al., 2010-0,82-1,61-0,03 0,04 Jones et al., 2011-0,29-0,75 0,17 0,22 Overall -0,60-0,83-0,37 0,00 Favours TRT Favors no TRT Corona et al., Best Pract Clin Endocrinol & Metab 2013;27;557

V1 Previous use of ED therapy (All 21%) Frequente Sildenafil Tadalfil Vardenafil PGE1 Testosterone Occasionale %

Efficacia PDE5ì V2 vs V1 Sildenafil Tadalfil Ottima Vardenafil Buona Scarsa 0 5 10 15 %

V2 Previous use of ED therapy (All 38.2 vs 21%) Frequente Sildenafil Tadalfil Vardenafil PGE1 Testosterone Occasionale 0 2 4 6 8 10 12 %

Ringraziamenti Prof. CB Giorda Prof. D Cucinotta Dott. P Guida Dott.ssa E Nada SUBITO-DE study group