RESTAURER LA SANTE DE L‘HOMME Syndrome métabolique, Dysfonction érectile et Syndrome de déficience en testostérone Pr. As. Mounir CHARIF CHEFCHAOUNI.

Présentation au sujet: "RESTAURER LA SANTE DE L‘HOMME Syndrome métabolique, Dysfonction érectile et Syndrome de déficience en testostérone Pr. As. Mounir CHARIF CHEFCHAOUNI."— Transcription de la présentation:

1 RESTAURER LA SANTE DE L‘HOMME Syndrome métabolique, Dysfonction érectile et Syndrome de déficience en testostérone Pr. As. Mounir CHARIF CHEFCHAOUNI XIIIéme Congrés National de Sexologie Marrakech, 24 Octobre 2009 Slide 1 “Restore the Man” is a presentation that explains the links and connections between the metabolic syndrome, erectile dysfunction and testosterone deficiency syndrome. 1

2 Les composants du syndrome métabolique : “Les tueurs silencieux“
Dyslipidemia Hypertension Insulin resistance Abdominal Obesity + Slide 2 It is very important to consider that the components of the metabolic syndrome are also referred to as “Silent Killers.” This is because most of these components can be present without any symptoms. For a long time, for example, dyslipidemia has been characterized by elevated cholesterol levels and these go unnoticed unless these levels are measured. The same goes for hypertension. An elevated blood pressure can exist for a long time without any symptoms, and insulin resistance, characterized by increasing blood glucose levels, can also be present without any symptoms. The only thing that is certainly visible is abdominal obesity. This, however, is not considered a disease but a cosmetic problem. 2

3 Définition du Syndrome métabolique par la Fédération Internationale du Diabète
Tour de taille:> 94 cm plus au moins deux des facteurs suivants: Chez l’homme * : 1. Triglycérides > 1,50 g/dl ou prise anti-cholestérolémiant 2. HDL-Cholestérol < 0,40 g/dl ou prise anti-cholestérolémiant 3. TA > 130 mmHg systolique et/ou 80mmHg pour la diastolique et/ou anti-hypertenseur 4. 1 g/l < glycémie <1,25 g/l ou diabète de type 2 diagnostiqué et traité Slide 3 The latest definition of the metabolic syndrome – and there have been several – is the one created by the International Diabetes Federation in This definition has several interesting aspects. It contains the same components as the previous definitions but the severity has been changed. For instance, waist circumference used to be 102 cm and it has now been lowered to 94 cm. This is also important because waist circumference has been considered one of many symptoms with the same ranking but now it ranks as number 1. In other words, there is no metabolic syndrome without visceral obesity, which waist circumference stands for. The other components are equally ranked, so two out of four need to be present to fulfill the definition of the metabolic syndrome: high triglycerides, low HDL-cholesterol and blood pressure above 130 over 85. The latter is also a stricter definition because it was previously 130 over 90. Fasting blood glucose is anything more than 100mg/dl, and this used to be 110. * Caucasians 3

4 LE TRIANGLE DES BERMUDES
Erectile Dysfunction TestosteroneDeficiency Syndrome Metabolic Syndrome Slide 4 Slide 4 shows that the metabolic syndrome, testosterone deficiency and erectile dysfunction are closely interrelated and we will now look at testosterone deficiency syndrome. 4

5 Ces 2 index de Masse Corporelle (IMC) ne sont pas égaux C‘est le tour de taille qui compte
189 cm, 93 kg = BMI 26 190 cm, 94 kg = BMI 26 Waist circumference > Testosterone < Slide 5 This is about the correlation between waist circumference and testosterone levels. Here we see two men who have exactly the same height, the same weight and the same body mass index. However, the one on the left hand side has a big belly (large waist circumference) and also has low testosterone levels, whereas the one on the right hand side has the same BMI, but he has a slim waist, is more muscular and he has higher testosterone levels. So, this shows that waist circumference is really a much more important measure than BMI. BMI was used for a long time to measure obesity or to reflect obesity but now it is generally agreed that waist circumference is the more important measure. 5

6 Index de masse corporelle et style de vie
Clear association between lack of exercise and elevated BMI BMI (kg/m2) Exercise (min/week) Television (h/day) 5.975 Men (Age years) <15 15-62 >62 ≥4 3-3,9 2-2,9 <2 25 26 27 27,5 26,5 25,5 Slide 6 This shows the clear association between lifestyle and body mass index. This publication from 2003 still uses body mass index. We can see on the left hand side the increasing body mass index as represented by the different columns. On the right hand side, you see the numbers of hours spent in front of the television. It shows that the more hours per day spent in front of the television, the higher the body mass index is. On the x-axis, you see the number of minutes spent exercising every week. Again, we see on the left hand side that very little time spent exercising is associated with a high body mass index, whereas longer periods of exercise is associated with a lower body mass index. Jakes et al. Eur J Clin Nutr 2003; 57: 6

7 Corrélation de la testostérone avec l‘IMC et le tour de taille
BMI: Waist circumference: Testosterone level Slide 7 This is a graphic illustration of the results of the Tromsø study which we will see on the next slide. This shows that testosterone levels are highest in those men who are slim and have a small waist, and that the larger the waist becomes, the lower the testosterone levels become. On the right hand side, you see men who are relatively obese. They have a high waist circumference but otherwise they are slim and, thus, non-muscular, non-athletic and have small shoulders. These are the men with the lowest testosterone levels. Modified from: Svartberg et al. Eur J Epidemiol 2004; 19, (Tromsø Study) 7

8 Tour de taille et testostérone
Lower limit of normal range 4 8 12 16 20 24 p < 0.001 <94 94 – 101.9 ≥102 Waist circumference (cm) Total Testosterone (nmol/L) n=666 n=536 n=346 14.7 12.7 11.0 1.584 Men (Age years) Slide 8 This is the Tromsø study from Johan Svartberg who showed clearly that men with a high waist circumference have the lowest relative testosterone levels. This is the negative association between total testosterone and waist circumference. The slimmest men with the lowest waist circumference have the highest testosterone levels, whereas those with a waist circumference above 102 cm tend to already be in the hypogonadial range. Svartberg et al. Eur J Epidemiol 2004; 19: (Tromsø-Studie) 8

9 Organes cibles de la testostérone et métabolites
DHT E2 T LDL HDL Slide 9 Slide 9 is an overview of all the organs that are affected by testosterone. These are the target organs of testosterone and its metabolites. We know that testosterone is metabolized into estradiol and DHT. Testosterone, estradiol and DHT work on numerous organs not related to sexual function, such as the liver, the vascular system, brain, bone, muscle and other functions. Most of the organs and tissues in the human body have testosterone and estrogen receptors.

10 Signes de déficit en testostérone
Testosterone Deficiency Syndrome Psychologic Symptoms Sexual Symptoms Somatic Symptoms Sexual interest / libido  Number of morning erections  Potency  Irritability Nervousness Anxiety Depressive disorders Memory disturbances Lack of concentration Muscle pain Joint pain Excessive sweating Sleep disturbances Muscle strength Hot flashes Cardiovascular diseases Body weight  Osteopenia Chronic fatigue Slide 10 This is a list of symptoms that are associated with testosterone deficiency and this list could be continued. You see already that this is a long list and it lists the most important symptoms of testosterone deficiency. They can be divided into three major groups: psychological symptoms, somatic symptoms and sexual symptoms. And these are precisely the three domains of the Aging Male’s Symptoms scale. Under psychological symptoms, you see irritability, nervousness, anxiety and also depressive disorders which become increasingly important as men grow older. Somatic symptoms, muscle and joint pain, sleep disturbances, cardiovascular diseases and, in particular, increased body weight are among the most important symptoms. When it comes to sexual symptoms, one of the lead characteristics of testosterone deficiency is a decline in sexual interest and libido. A declining number of morning erections is also closely associated with testosterone deficiency. Heinemann et al. Aging Male 2001; 4: 14-21 Nieschlag et al. Aging Male 2005; 8: 56-58 10

11 Prevalence of symptomatic testosterone deficiency (%)
Prévalence en fonction de l‘âge du syndrome de déficience en testostérone 10 20 30 40 30-39 Age (years) Prevalence of symptomatic testosterone deficiency (%) n=5/435 1.475 Men (Age years) 40-49 50-59 60-69 70-79 n=18/434 n=27/333 n=17/187 n=19/86 Slide 11 This is about epidemiological evidence of the prevalence of testosterone deficiency. These data are from the famous longitudinal study, The Massachusetts Male Aging study, and it shows for the first time the association between not only laboratory levels of testosterone but also the symptoms. Hypogonadism is defined as a combination of symptoms and low chemical testosterone levels so it is the prevalence of those two together that defines testosterone deficiency syndrome in the Massachusetts Male Aging study. We see that the prevalence ranges between 5% and about 20% and it is clearly age-dependent, so we find the highest prevalence in the highest age group. Araujo et al. JCEM 2007; 92: 11

12 Niveau de la testostérone et symptômes
8 10 12 15 20 Total Testosterone (nmol/L) 434 Men (Age years) 69 Loss of libido** Loss of vigour** Increasing prevalence of symptoms with decreasing testosterone concentrations 84 Obesity ** Feeling depressed** Sleep disturbances* Hot flushes** Erectile Dysfunction* **p ≤ *p < 0.005 Lacking concentration* Diabetes mellitus type 2** 65 67 75 n= 74 Slide 12 The definition of Testosterone Deficiency Syndrome is quite controversial and one fact that makes it even more complicated than just discussing testosterone measurements in the laboratory is that there seem to be thresholds for individual symptoms. What we can see here is that symptoms such as loss of libido or loss of vigor occur already in the low normal range (if we consider the normal range to be between 12 and 35 nmol/l). Going below the threshold that is considered normal, we then see obesity, which occurs between 10 and 12 nmol/l. Below that, we see depressive symptoms, sleep disturbances, lack of concentration and type 2 diabetes occurring in the 8 and 10 nmol/l range. And under 8 nmol/l, we see hot flushes and erectile dysfunction. Zitzmann et al. J Clin Endocrinol Metab 2006; 91(11): 12

13 Quand faut-il doser la testostérone?
Prélèvement sanguin à 11H Variation diurne: entre 06H - 08H et 18H - 20H Elévation du taux le matin après un rapport sexuel Possibilité d’un seuil physiologique d’hypogonadisme l’après-midi Réduction de la testostérone totale et non de la fraction biodisponible par les statines

14 Quelle fraction de testostérone faut-il doser ?
3 fractions : T-SHBG = inactive = – 80٪ T- Libre = active = 2 – 3 ٪ T- Albumine = active = ٪ Mesurer testostérone totale Sujet âgé, diabétique : valeurs souvent borderline, doser Testostérone biodisponible

15 Associer un dosage du PSAT pour exclure le diagnostic de cancer de la prostate
Sujet > 50 ans En cas de traitement par testostérone, suivi par PSA trimestriel la 1ère année et puis annuel

16 Obésité abdominale Obésité viscérale, obésité centrale
Insulin Visceral Fat Testosterone Slide 13 When we examine the different components of the metabolic syndrome, we see that abdominal obesity -- which is also referred to as visceral obesity or central obesity -- is the essential component of the metabolic syndrome. No metabolic syndrome without abdominal obesity. This is an MRI scan from the University of Melbourne, Australia, which shows a cross section of the abdominal region. In the middle we see an orange zone. That is the visceral fat tissue within the abdominal cavity and between the abdominal organs. On the outside, we see a light blue layer, which is the subcutaneous fat tissue. This is not as much of a risk factor as the visceral fat, which is really the risk factor for cardiovascular and metabolic diseases and is correlated with high insulin levels and low testosterone levels. Courtesy of Rob McLachlan and Carolyn Allan, Monash University, Melbourne, Australia 16

17 Espérance de vie et niveau de la testostérone
Years Cumulative Survival ≥ 8.7 nmol/L (n=452) < 8.7 nmol/L (n=160) 858 Veterans (Age ≥ 40 years; ø 60 yrs) Total testosterone from at least 2 measurements 0.5 0.6 0.7 0.9 1.0 0.8 2 4 6 8 10 Slide 14 There is now increasing evidence from large cohorts of men that low testosterone levels are associated with higher mortality; or, looking at it from the other side, that higher testosterone levels predict greater longevity or longer life expectancy. This is quite interesting but this study came out first by Shores from the Seattle, Washington area, and was greeted with a lot of skepticism. But since then there have been three or four major longitudinal epidemiological studies, involving thousands of men, confirming these data, and this now seems to be a very well-accepted concept. The lower limit of normal was defined as a total testosterone level of less than 250 ng/dL (8.7 nmol/L) or a free testosterone level of less than 0.75 ng/dL (0.03 nmol/L). These levels were used as threshold levels because they have been identified as clearly low and generally associated with symptoms of hypogonadism, even in older men. Men were classified as having low testosterone levels if they had 2 low testosterone levels or if more than 2 levels were measured; most of the levels were low. Men were classified as having equivocal testosterone levels if they had at least 1 low and 1 normal level and if more than 2 levels were obtained, they had an equal number of low and normal testosterone levels. Men were classified as having normal testosterone levels if they had at least 2 normal testosterone levels and if more than 2 levels were obtained, most were normal. Shores et al. Arch Int Med 2006; 166: 1660 17

18 Testosterone concentration
La testostérone induit le développement de cellules musculaires à partir de cellules pluripotentes Testosterone concentration 0 nM 3 nM 30 nM 100 nM 300 nM MHC+ Myogenic cells 3 30 100 300 T (nM) 150 50 MHCII+ Area/field (μm2 x 103) ** *** 40 20 Fat cells/field 10 * Myogenic cells Fat cells Slide 15 This is about the mechanism of action of how testosterone influences body composition. It could be shown by Shally Bhasin’s group and Singh, a coworker who does all the laboratory work, that in the muscle there are pluripotent stem cells that can develop into either muscle cells or fat cells. And this group could show that in the presence of normal to higher testosterone levels, these stem cells develop into muscle cells or myogenic cells, whereas in the absence of testosterone or at low testosterone concentrations, they develop into fat cells. So this is a clear explanation as to why men with low testosterone develop more visceral fat, more fat tissue, than men with higher testosterone levels, who tend to have more muscle tissue. Singh et al. Endocrinology 2003; 144(11): Myogenic cells: ** p< 0,01; ***p< 0,001 Fat cells: *p = 0,02; **p< 0,004; ***p< 0,001 18

19 Dysfonction érectile et syndrome métabolique
Erectile Dysfunction Metabolic Syndrome TestosteroneDeficiency Syndrome Slide 17 Now let’s look into the association between the metabolic syndrome and erectile dysfunction. 19

20 Définition de la dysfonction érectile
“Incapacité d’obtenir et de maintenir une érection suffisante pour permettre une performance satisfaisante” Slide 18 Erectile dysfunction is defined as the inability to achieve and maintain an erection sufficient to permit satisfactory sexual performance. International Educational Initiative on Erectile Function, 2001 20

21 Prévalence de la dysfonction érectile en Allemagne “étude Cologne”
2.3 9.5 15.7 34.4 53.4 10 20 30 40 50 60 30-39 40-49 50-59 60-69 70-80 Prevalence of ED (%) Crude prevalence of ED in Germany: 19.2% 4.489 Men Age group Slide 19 There are numerous studies and the Cologne study is one of them. Conducted in Cologne, Germany, it shows the crude prevalence of erectile dysfunction in different age groups. It is quite low in the age group 30 to 39, and then it increases by decade, so erectile dysfunction is clearly an age-associated condition. Braun et al. Int J Impotence Res 2000; 12: 21

22 154 ED patients (mean age 53.5 years)
Association entre syndrome métabolique et sévérité de la dysfonction érectile ED Patients (%) 20 40 60 80 40.2 37.7 22.1 52.3 34.1 13.6 Fasting glucose > 110 mg/dl Insulin resistance Metabolic syndrome 8.3 21.7 70.0 mild moderate severe Severity of ED 100 154 ED patients (mean age 53.5 years) Slide 20 This slide shows the association between the metabolic syndrome or components of the metabolic syndrome, such as glucose levels, and the severity of erectile dysfunction. So you can see that with the increasing levels of glucose on the left hand part of the slide, there is more severe erectile dysfunction. The same goes for insulin resistance and the presence or absence of the metabolic syndrome. So these co-morbidities are clearly associated with the severity of erectile dysfunction. Bansal et al. J Sex Med 2005; 2: 22

23 27.839 Men from 8 countries (age 20-75 years)
Prévalence de la DE en fonction des facteurs de comorbidités étude MALES Affected Men (%) 10 20 30 40 Hypertension CHD/ A. pectoris High cholesterol Diabetes mellitus 19 7 16 4 36 17 29 14 Men without ED n=23.416 Men with ED n=4.422 Men from 8 countries (age years) * Slide 21 One can also look at this phenomenon from a different perspective. This is a large study which was conducted by Bayer years ago – the so-called MALES study – which was a worldwide study with almost 28,000 men. And when you look at men with and without erectile dysfunction, you always see that men with erectile dysfunction have a much higher prevalence of these co-morbidities than men without erectile dysfunction. You look at hypertension, coronary heart disease -- that is what CHD stands for -- high cholesterol levels -- also called dyslipidemia -- and diabetes, and, in every single one of these co-morbidities, the prevalence is much higher in men who have erectile dysfunction compared to those who don’t. Rosen et al. Curr Med Res Opin 2004; 20: p < vs. Men without ED 23

24 Prévalence de la DE chez les patients avec une HTA et/ou un diabète
Representative sample of Men (mean age 58.9 years) Proportion of men with ED Hypertension n=3.906 Diabetes mellitus n=2.377 Both n=917 67.4% 78% 70.6% Slide 22 This is another multi-national study from Europe. What we see here is that when we look at men with co-morbidities -- hypertension, diabetes or even both taken together -- the prevalence of ED is very very high. About 67% of men with hypertension have erectile dysfunction. This goes up to more than 70% in type 2 diabetes, and when both of these conditions are present, almost 80% of men have erectile dysfunction. Giuliano et al. Urology 2004; 64: 24

25 Prévalence de la DE chez les patients avec une maladie coronarienne aigue ou chronique
ED Prevalence (%) 20 40 60 80 Without CHD* n=95 95 men without coronary alteration (controls) and 285 CHD patients (ø age 53.6 – 55.4 years) 24 22 55 65 Acute CHD and 1 stenotic artery and 2 stenotic arteries Chronic CHD p=0.002 p=0.0004 p=0.82 p=0.99 Slide 23 This is about the association between erectile dysfunction and coronary heart disease. Coronary heart disease is characterized by atherosclerosis of the coronary arteries and whenever a coronary artery is closed by more than 75%, this is referred to as a stenotic artery. And here we see the association between the prevalence of erectile dysfunction and different grades of coronary heart disease. Starting from the left hand side -- men without coronary heart disease -- 24% of them have erectile dysfunction. So this is like a control group. If there is one stenotic artery, it is the same number. There is no statistical difference between these two. However, as this disease progresses and we see two or more stenotic arteries, the prevalence of erectile dysfunction jumps to more than half of these men affected by atherosclerosis of the coronary arteries. * CHD = coronary heart disease Montorsi et al. Eur Heart J 2006; 27: 25

26 Endothelial Dysfunction Cardiovascular events
La dysfonction endothéliale est le précurseur des événements vasculaires Smoking Diabetes Dyslipidemia Hypertension Obesity Endothelial Dysfunction Atherosclerosis Cardiovascular events ED Slide 24 There is a very close correlation between erectile dysfunction and endothelial dysfunction. Endothelial dysfunction is the result of different co-morbidities as well as poor lifestyle choices. We see here that all these different lifestyle factors, or risk factors, such as smoking, hypertension, diabetes, dyslipidemia and obesity, have an impact on endothelial function. The endothelium is the inner layer of the blood vessel that contributes to the reactivity and elasticity of these blood vessels and, as a result, to the blood flow. If the endothelium is impaired, this is the beginning of atherosclerosis and reduced blood flow, especially in the periphery. This affects the penis and the coronary arteries, as well. Thus, atherosclerosis resulting from endothelial dysfunction is a precursor of cardiovascular diseases. Sasayama et al. Circ J 2003; 6: 26

27 Pourquoi la DE se produit avant les maladies cardiovasculaires?
Hypothèse: diamétre artériel A. pectoris, myocardial infarction Erectile dysfunction TIA Apoplex Claudicatio intermittens Penile artery Ø1-2mm Coronary artery Ø3-4mm Carotis interna Ø5-7mm Femoral artery Ø6-8mm Clinical sequelae of significant obstruction Slide 26 One of the hypotheses that attempts to explain why erectile dysfunction is a predictor of coronary artery disease and other cardiovascular diseases is based on the fact that the penile arteries are the smallest arteries in the body. Penile arteries have a diameter of 1 to 2 millimeters and if they start clotting due to atherosclerotic processes, they will be the first to lead to symptoms. In other words, if a small artery clots you will quickly see symptoms. The larger arteries, however, need more time because this is usually a progressive process. About 5 to 10 years after penile arteries develop problems, the coronary arteries follow. Then, of course, it goes further down the road to the large internal carotis and the femoral arteries which may then lead to claudicatio and other symptoms if the process is far advanced, but it all starts with symptoms deriving from the small arteries. Modified after Montorsi et al. Am J Cardiol 2005; 96: 19M-23M 27

28 La Dysérection est un marqueur précoce des maladies coronariennes
162 angiographically assessed men with symptomatic CHD (mean age yearse) CHD-severity n ED-Prevalence 1 stenotic artery 56 18% mean prevalence 46% 2-3 stenotic arteries 53 57% Chronic angina 66% Slide 27 When we look at studies where the outcome from this hypothesis can be demonstrated, we see that the severity of coronary heart disease correlates with the prevalence of ED. We have seen this in the previous slide from a slightly different perspective, but what we see is that if one coronary artery is stenotic, there is an ED prevalence of 18 percent, but if it is 2 to 3 stenotic arteries, then the ED prevalence is much higher. In other words, when we look at the summary, in 71% of patients with chronic angina, ED has preceded this event, and the mean interval is about two years. In 71% of patients with chronic angina ED preceded CHD (mean interval 25 months) Montorsi et al. Eur Urol 2005; Suppl 4(3): 341, Abstr 695 28

29 Change in lifestyle and additional interventions
Sur le chemin des maladies cardiovasculaires Quelles sont les opportunités pour intervenir ? Lifestyle Lack of exercise Overeating Smoking Stress Metabolic syndrome Cardiovascular events Myocardial infarction Stroke Testosterone deficiency Change in lifestyle Change in lifestyle and additional interventions Erectile Dysfunction Substitution Early marker of CHD e.g. PDE-5-Inh. Slide 28 This slide demonstrates the pathway to disease. When you look at the right hand side, there are the cardiovascular events -- myocardial infarction and stroke -- dramatic events that are potentially lethal. But the groundwork for these events has been laid about 20 to 25 years before. Then we go to the left hand side of the slide where we see lifestyle, lack of exercise, overeating, smoking and stress. These are the factors that eventually lead, after a long period of time, to such potentially lethal events as myocardial infarction and stroke. In an ideal world, we would intervene quite early, which means that if we see that there is an unhealthy lifestyle, we would talk to the patient, educate the patient and change his behavior. But this is extremely difficult for two reasons. Number one, it is very difficult to change habits. Number two, we don’t even see these patients, because these patients don’t consider themselves sick, so they would never present at the doctor’s office. So the next opportunity arises when these patients develop the metabolic syndrome and one of the very early symptoms characterizing the metabolic syndrome is erectile dysfunction. Erectile dysfunction may therefore be the first symptom that men with the metabolic syndrome experience. So there is a second chance for intervention if men present with erectile dysfunction, a second chance for doctors, for health care professionals, to educate them about lifestyle changes. And if we generate enough data and look at the existing data, there is also the chance to do testosterone substitution if there is a testosterone deficiency. This may also contribute to improvement of the metabolic syndrome. So these are several steps of intervention that are possible to prevent such major lethal or potentially lethal dramatic events as myocardial infarction and stroke. Modified after Makhsida et al. J Urol 2005; 174: 29

30 Déficience en testostérone et syndrome métabolique
Erectile Dysfunction TestosteroneDeficiency Metabolic Syndrome Slide 29 Now let’s look at the link between the metabolic syndrome and testosterone deficiency. 30

31 Exercice physique et équilibre alimentaire
Traitement par la testostérone en cas de déficit symptomatique en testostérone Slide 30 Of course, and most doctors would agree on this, exercise and healthy diet is certainly the best way to treat or prevent the metabolic syndrome. However, if symptomatic testosterone deficiency is proven by the presence of symptoms and low testosterone levels, testosterone treatment may be considered. 31

32 Le traitement de base du syndrome métabolique
Weight reduction Reduction of insulin resistance Decrease of hyperinsulinemia Decrease of hypertriglyceridemia Increase of HDL Decrease of blood pressure ca. 5% of body weight (ca. 3-5 kg) Physical exercise e.g., 30 minutes 4 days per week Slide 31 Let’s look at the effects of changes in lifestyle -- of physical exercise and weight reduction. We see here that these interventions alone -- and we are not talking about huge efforts but, for example, four days per week, 30 minutes of physical exercise and we are talking about a weight reduction of about 5% of body weight -- would lead, as it has been shown in many studies, to a reduction of insulin resistance, a decrease in hyperinsulinemia, a decrease of hypertriglyceridemia and an increase of HDL and a decrease in blood pressure. So, if people would be reasonable and would change their lifestyles, they could probably make major progress on their therapeutic pathway without any medical intervention. 32

33 Exercice physique et équilibre alimentaire
Traitement par la testostérone en cas de déficit symptomatique en testostérone Slide 32 However, exercise and healthy diet is something that is usually not done. Even if the patients show an initial motivation to start exercising and improving their nutrition, after a few weeks or months, they usually fall back into their old habits. Based on recent study results, it might be advisable to offer to these patients testosterone treatment to help them in this process. Of course, testosterone treatment is indicated only in proven symptomatic testosterone deficiency. 33

34 Effets potentiels de la testostérone sur...
Masse graisseuse et tour de taille Lipides Tension arterielle Insulino-résistance et glycémie Slide 35 So let’s look together at obesity, which is the essential component of the metabolic syndrome, as we have seen previously. 34

35 40 Men with testosterone deficiency syndrome
La testostérone soutient la réduction à long terme de la masse graisseuse 40 Men with testosterone deficiency syndrome 20 22 24 26 28 30 32 12 54 90 Body fat mass (%) Weeks -25% Slide 36 One of our pivotal studies to achieve the approval for Nebido was a head to head comparison between testosterone enanthate, the old testosterone, and the testosterone undecanoate in Nebido. What we see in this study, conducted in Cologne, is that there is a consistent and progressive effect on the reduction of body fat. These were 40 men with severe hypogonadism, and we can see that within approximately two years of treatment, these men progressively lost 25% of their body fat, which is quite impressive. Open label, randomised Week 0-30: testosterone enanthate or testosterone undecanoate i.m. Week 31-90: testosterone undecanoate i.m. (Nebido®) Freude et al. The Aging Male 2006; 9(1):15; DEXA-Messung 35

36 Baseline testosterone (nmol/L)
La testostérone réduit la masse graisseuse indépendamment de l‘âge et du taux sanguin de base de la testostérone 362 patients with late-onset testosterone deficiency (age: years, T: < 15 nmol/L) placebo Total cohort Age (years Baseline testosterone (nmol/L) <65 ≥65 <10 10-<12 12-<15 1% testosterone gel -3 -2 -1 1 2 Δ Fat mass (kg) n= 170 177 115 112 55 65 62 69 38 54 70 -4 *** * Slide 37 Recently, we finalized a study using Testogel – testosterone gel – in elderly men. There were around 360 elderly patients with late onset testosterone deficiency. Interestingly, this is one of the largest studies on the elderly population and it was done placebo-controlled for the first half year. What we saw in this study is quite interesting and slightly controversial when compared to previously published data. The total cohort lost fat mass in the magnitude of kg. However, this was independent of age. We also see on the right hand panel that this was independent of baseline testosterone levels. So those men with very low testosterone levels -- below benefited equally as well as those with low normal testosterone levels. We decided to include men with low normal testosterone levels -- up to 15 nmol/l -- and it was quite surprising to see that those men with the low normal testosterone levels had the same loss of fat mass as those with very low testosterone levels. European Testogel®-Study, Bouloux et al. J Men‘s Health & Gender 2007; 4(3): ***p<0, *p<0,05 36

37 Effet de la testostérone sur le tour de taille
n=20 (18-74 years, ø age: 41 years) Open label, randomised; Testosterone undecanoatei.m. (Nebido®) for 90 weeks 95 97 98 100 102 104 Waist circumference (cm) 96 99 101 103 Testosterone undecanoate i.m. (weeks) 12 30 54 90 94 93 IDF target Slide 38 In half of the patients who participated in the comparison trial between testosterone enanthate and testosterone undecanoate that I showed few slides ago, we also had waist circumference measurements. This was not part of the original protocol so we only did this with a few patients. And when we re-analyzed the data retrospectively, it was quite interesting to see that the waist circumference of these patients had shrunk considerably. It is also interesting to note that during the first 30 weeks of treatment, there was no change in waist circumference, but after that, waist circumference dropped continuously, and after 90 weeks of treatment, the patients had lost on average 6 cm of waist circumference, which is quite impressive because they did not undergo a special diet and exercise program. Freude et al. Aging Male 2006; 9(1): 15 37

38 Waist circumference (cm) Lifestyle* + 1% Testosterone Gel
Effet de la testostérone plus régime alimentaire/exercice physique sur le tour de taille en cas de diabète de type 2 Pilot study: 32 newly diagnosed type 2 diabetics (35-70 years) 105.7 85 90 95 100 105 110 115 Waist circumference (cm) Lifestyle* alone n=16 99 107.9 Lifestyle* + 1% Testosterone Gel 93.3 -6.7 cm -14.6 cm IDF target baseline 12 months * * ‡ 1% Testosterone Gel (Testogel®) 50 mg/d; *Lifestyle = 3x 30 min Walking + 3x 15 min muscle training per week; Low calorie and low carbohydrate nutrition (no diet); contact by telephone/sms 2x per week No diabetic complications; no drug treatment for diabetes Slide 39 A very important study was conducted by Prof. Heufelder in Munich, comparing men with a newly diagnosed type 2 diabetes who were on lifestyle changes alone with those on a combination of lifestyle changes and testosterone. All these men had low testosterone to begin with and all of them were quite obese, as you can see here, with waist circumferences between 105 and 110 cm. Now, these men underwent a not-very-vigorous, very light, diet and exercise program. However, it was very well-conducted, as these men were highly motivated, well-educated and it was made sure that they followed the regimen, having been contacted at least twice a week over the entire period of observation. On the left hand side, you see the group that was exposed to lifestyle changes alone -- diet and exercise – and on the right hand side, you see the same diet and exercise changes plus the addition of Testogel, which was administered in low doses. It was not uptitrated -- just a standard dose of 50 mg per day. And you find that after one year of treatment, both regimens were quite successful. The men on lifestyle changes alone lost 6.7 cm. However, those who received testosterone in addition to the lifestyle and exercise changes lost more than double -- that is, 14.6 cm waist circumference -- which is quite dramatic and which is highly significantly different from the diet and exercise alone group. Heufelder et al. Endocrine Society Abstract Book 2007: 151 *p<0,05 vs. baseline; ‡p<0,05 between groups 38

39 Effets potentiels de la testostérone sur...
Masse graisseuse et tour de taille Lipides Tension arterielle Insulino-résistance et glycémie Slide 40 Now let’s look at the lipid component of the metabolic syndrome and the effect of testosterone on lipid pattern. 39

40 Lifestyle* + 1% testosterone gel
Effet de la testostérone plus régime alimentaire/exercice physique sur les triglycérides en cas de diabète de type 2 chez l‘homme 304 Triglyzeride (mg/dl) 100 150 200 250 300 350 Lifestyle* alone n=16 205 279 Lifestyle* + 1% testosterone gel 139 * ‡ * IDF target Pilot study: 32 newly diagnosed type 2 diabetics (35-70 years) baseline 12 months 1% Testosterone Gel (Testogel®) 50 mg/d; *Lifestyle = 3x 30 min Walking + 3x 15 min muscle training per week; Low calorie and low carbohydrate nutrition (no diet); contact by telephone/sms 2x per week No diabetic complications; no drug treatment for diabetes Slide 41 We continue with the same study by Prof. Heufelder -- life style alone versus lifestyle plus testosterone. Let’s look at tryglycerides, one of the components of the metabolic syndrome. You’ll remember that the metabolic syndrome comprises triglycerides and HDL cholesterol as the two components that are important in terms of risk for cardiovascular diseases and metabolic diseases. So again, on the left hand side, you see the effect of lifestyle alone on triglyceride levels -- a significant reduction in triglyeride levels. However, when testosterone was added, the reduction was far more pronounced and the target set by the International Diabetes Federation definition was reached in the majority of these patients. Heufelder et al. Endocrine Society Abstract Book 2007: 151 *p<0,05 vs. baseline; ‡p<0,05 between groups

41 Lifestyle* + 1% testosterone gel
Effet de la testostérone plus régime alimentaire/exercice physique sur le cholestérol-HDL en cas de diabète de type 2 chez l‘homme 38.6 HDL-C (mg/dl) Lifestyle* alone n=16 47.2 40.7 Lifestyle* + 1% testosterone gel 57.5 * ‡ * IDF target 20 30 40 50 60 70 10 Pilot study: 32 newly diagnosed type 2 diabetics (35-70 years) baseline 12 months 1% Testosterone Gel (Testogel®) 50 mg/d; *Lifestyle = 3x 30 min Walking + 3x 15 min muscle training per week; Low calorie and low carbohydrate nutrition (no diet); contact by telephone/sms 2x per week No diabetic complications; no drug treatment for diabetes Slide 42 Let’s see what happens with HDL cholesterol. Again, we see an improvement in both groups. Exercise alone improved HDL above the threshold set by the IDF definition. However, when testosterone was added, the increase in HDL-cholesterol was more pronounced, which is really a very good sign because HDL is considered to be beneficial to the cardiovascular system and HDL should be as high as possible. Heufelder et al. Endocrine Society Abstract Book 2007: 151 *p<0,05 vs. baseline; ‡p<0,05 between groups

42 Effets potentiels de la testostérone sur...
Masse graisseuse et tour de taille Lipides Tension arterielle Insulino-résistance et glycémie. Slide 43 This is about the effects of testosterone on blood pressure. 42

43 Diastolic Blood Pressure (mmHg)
Effet de la testostérone sur la pression diastolique chez l‘homme avec une obésité abdominale 85 placebo n=16 86 87 testosterone gel 82 * IDF target 27 men with abdominal obesity (ø age 57.7 years; WHR >0.9, BMI <35, T <20 nmol/L) testosterone Gel or placebo for 9 months Diastolic Blood Pressure (mmHg) 80 84 88 90 baseline 9 months Slide 44 The first study ever to mention any effect of testosterone on blood pressure was done by Per Mårin and the group of Per, Bjœrntorp who were looking into obesity. Their research was focused on obesity -- particularly visceral obesity -- and they already recognized in the early ‘90s the association between testosterone and obesity. And these were men who were treated with testosterone. This was an early version of our current Testogel-or-placebo study and for the first time, it was published that testosterone had a beneficial effect on diastolic blood pressure and there was a significant reduction of diastolic blood pressure in the testosterone group. Mårin et al. Obesity Res 1993; 1(4): * p<0.05

44 Testosterone undecanoate i.m. (months)
Effet de la testostérone sur la pression diastolique chez les hommes avec une DE et un déficit en testostérone 122 patients with erectile dysfunction (T < 12 nmol/L) Blood pressure (mmHg) Testosterone undecanoate i.m. (months) 70 90 100 120 140 80 110 130 135.8 84.4 126 79 3 6 9 12 15 syst diast 150 Slide 45 It took more than ten years to get confirmation of these early observations and we now know from a lot of groups that used testosterone in men with metabolic syndrome and in men with obesity that there is indeed a beneficial effect on blood pressure of a magnitude that is really clinically relevant and that supports the use of anti-hypertensives. This is a cohort of 122 men presenting to a urologist’s office with the complaint of erectile dysfunction. The majority of these men were quite obese and they all had low testosterone. When they received treatment with Nebido for 15 months, we see a drop in both systolic and diastolic blood pressure. The systolic blood pressure drop is about 10 points and in diastolic blood pressure, we find a drop of about 5 points. Again, clinically, this is highly relevant and desirable. Yassin and Saad, J Urol 2007; 177(4): 288 44

45 Effets potentiels de la testostérone sur...
Masse graisseuse et tour de taille Lipides Tension arterielle Insulino-résistance et glycémie Slide 46 What effect does testosterone have on insulin resistance and glucose levels? 45

46 Individual measurements Insulin requirement (IU)
Effet du blocage androgénique dans le cancer de la prostate sur le contrôle glycémique 29 insulin dependent type 2 diabetics (58-84 years, ø age 75 years) with prostate cancer under medical androgen deprivation therapy HbA1c (%) Individual measurements t1 t2 t3 t4 t5 Retrospective study; individually different times of measurement during a period of 24 months Insulin requirement (IU) 20 30 50 10 40 60 * ** 4 6 2 8 12 70 Slide 47 This represents a new way to look at the effects of testosterone deficiency and, I think, one that is very important. With testosterone, we have a very unique opportunity, because men with advanced prostate cancer routinely receive androgen deprivation therapies. They usually receive a medical castration, which used to be done surgically, but they are all in some way deprived of their testosterone levels. In other words, they are in an artificial state of testosterone deficiency. And what happens with these men? These are data from a German group from North Germany. These were patients with type 2 diabetes at the time they were diagnosed with prostate cancer. And then they were put on androgen deprivation therapy by means of a GnRH or LHRH analogue. And then the diabetic parameters of these men were monitored over time. It was quite interesting to see that the HbA1c level -- that is, the most important parameter of control of blood sugar -- increased after androgen deprivation therapy, after their testosterone was taken away, and it increased continuously despite the fact that these men were treated by diabetologists and all the diabetes medications were continuously administered subject to the needs of the patient. There was no way anymore to get the blood sugar under control. This is the increase of Hb1Ac levels under an artificial testosterone deficiency state. And, at the same time, when we look at the right hand panel, you see that every 3 months -- the interval between examinations – these patients needed more and more insulin. So despite the fact that they were under fairly good control by diabetologists, there was no way to control insulin resistance or to control blood sugar. Haider et al. Aging Male 2007; 10(4): * p<0.01; ** p=0.000

47 HbA1c sous traitement par la testostérone
* Double-blind, placebo controlled, cross-over study; 3 months treatment, 1 month wash-out 24 type 2 diabetics with testosterone deficiency (HbA1c ≤ 9.5 %; years, ø age 64 years) HbA1c (%) 6,8 7,0 7,2 7,4 7,6 7,8 Placebo Testosterone baseline 3 months Slide 48 Not many studies have been done with testosterone in men with type 2 diabetes. There are just a few. And this is one I would like to show you because this study is a particularly well-controlled study. There are a small number of patients but it is a double-blind, placebo-controlled crossover study. All the patients have been on testosterone for three months, off testosterone for three months, and then the patients were crossed over so every patient received either placebo or testosterone and everybody served as their own control. Now, when we look at the development of glucose control or HbA1c levels, we see that those who received testosterone for only three months had a significant reduction in HbA1c levels and an improvement of glycemic control which again is of a magnitude that is quite desirable and which can also be achieved by specific medications for this condition. Kapoor et al. Eur J Endocrin 2006; 154: 899 * p<0.03 47

48 Lifestyle* + 1% testosterone gel
Effet de la testostérone plus régime alimentaire ⁄ exercice physique sur HbA1c en cas de diabète de type 2 7.6 HbA1c (%) 5 6 7 8 9 Lifestyle* alone n=16 7.1 7.5 Lifestyle* + 1% testosterone gel 6.3 * ‡ * IDF target Pilot study: 32 newly diagnosed type 2 diabetics (35-70 years) baseline 12 months Slide 49 And now we come back to the Heufelder study where diet and exercise alone were compared to diet and exercise plus testosterone. They also measured HbA1c levels. So again, we see on the left hand side that the glycemic control responded favorably to diet and exercise alone. This is a reduction of HbA1c levels by about 0.5 %, which is very nice and which is something that every doctor would welcome in their patients. However, on the right hand side, we see a much better reduction of HbA1c levels when testosterone was added, from 7.5 to in other words a reduction of more than 1%. This is highly desirable as some studies have clearly demonstrated that a reduction of HbA1c levels by 1% has a dramatic effect on all risks of any outcome of diabetes that you can think of. For example, a reduction of 1 % HbA1c means a reduction of the risk of amputation in late stage diabetes by more than 40%. 1% Testosterone Gel (Testogel®) 50 mg/d; *Lifestyle = 3x 30 min Walking + 3x 15 min muscle training per week; Low calorie and low carbohydrate nutrition (no diet); contact by telephone/sms 2x per week No diabetic complications; no drug treatment for diabetes Heufelder et al. Endocrine Society Abstract Book 2007: 151 *p<0,05 vs. baseline; ‡p<0,05 between groups 48

49 Syndrome de déficience en testostérone : Les points forts
Le déficit en testostérone n‘est pas un phénomène isolé, mais associé à d‘autres facteurs de comorbidités. Des études épidémiologiques montrent l‘association de l‘hypotestostéronémie et l‘obésité abdominale, HTA, dyslipidémie et le diabète de type 2. La normalisation de la testostéronémie est associée à l‘amélioration des composants du syndrome métabolique. L‘impact majeur et futur du traitement par la testostérone n‘est pas le bien être, mais la prévention et le traitement des facteurs de risques. Slide 50 In summary, testosterone deficiency is not an isolated phenomenon. It is associated with co-morbidities. In other words, we don’t see perfectly healthy men in their 50s or 60s who have a testosterone deficiency. It is almost always associated with co-morbidities, particularly the components described in the metabolic syndrome. Epidemiological studies -- and this is not some studies but all the studies that have looked into these correlations -have shown associations between low testosterone and co-morbid conditions, and, again, particularly the components of the metabolic syndrome. What we see from the studies that have been done so far is that a normalization of testosterone levels is associated with improvement of all the factors of the metabolic syndrome and I emphasize the word all because it is not one or two but it is really every single component of the metabolic syndrome that responds favorably to the normalization of testosterone levels. And that is why the future of testosterone treatment is not about the lifestyle and well-being of the elderly but about prevention and treatment of potentially life-threatening co-morbidities. 49

50 Traitement de la dysfonction érectile par les inhibiteurs de la PDE 5
Slide 51 The therapy of ED with PDE-5 inhibitors. 50

51 Les inhibiteurs de la PDE 5 dans le traitement de la dysfonction érectile
Option thérapeutique orale la plus efficace. Les trois molécules (Sildenafil, Tadalafil, Vardénafil) ont une efficacité similaire et un bon profil de tolérance. Elles ont des différences pharmacologiques avec des répercussions cliniques différentes. Il y a des différences pertinentes dans la préférence des patients comme le montrent de nombreuses études. Slide 52 After their introduction in 1998, PDE-5 inhibitors have been proven to be the most effective oral therapeutic option for the treatment of ED. All three available components -- Sildenafil, Tadalafil and Vardenafil (there are a few more now but certainly not available worldwide) -- have shown similar efficacy and good tolerability. There are, however, pharmacologic differences with clinical relevance. There are differences in patient preference as demonstrated in direct head-to-head comparison studies. 51

52 Inhibiteurs de la PDE 5 : les récepteurs et leur inhibition potentielle.
Minutes 50 100 150 200 10 20 60 80 40 30 % bound Sildenafil Tadalafil Vardenafil 25 75 3 6 9 12 15 % PDE 5-inhibition Concentration of PDE 5-inhibitors (nM) Vardenafil 0.09 Tadalafil 1.8 Sildenafil 3.7 IC50 (nM) Of the three PDE-5-inhibitors, vardenafil shows the tightest and longest binding to the PDE-5 receptor After 30 minutes, 60% of vardenafil is still bound, but only 25% of tadalafil and 12% of sildenafil I. Receptor binding to PDE-5* II. Compound concentration* Slide 53 Preclinical research with all the PDE-5 inhibitors clearly shows that Vardenafil is the most potent PDE-5 inhibitor when it comes to the various parameters that were tested in the lab, such as binding to the receptor, the concentration of PDE-5 inhibitors over time and the intensity of the inhibition of the target enzyme. Blount et al. Mol Pharmacol 2004; 66: * in vitro studies IC50=compound concentration at which PDE5 activity is blocked by 50% 52

53 Inhibiteurs de la PDE 5 : début et durée d‘action
Inhibitor Onset of Effect Duration of Effect Vardenafil 10 Minutes1 up to 12 hours2 Tadalafil 16 Minutes 24-36 hours Sildenafil 14 Minutes 4-8 hours Slide 54 Several studies have also investigated the onset of action after intake of one of the three PDE-5 inhibitors and it has been shown that Vardenafil acts quicker than the other two after as little as 10 minutes and the duration is up to 12 hours. There it is between the other two components, Sildenafil and Tadalafil. So Vardenafil has a quick onset of action and a medium duration of action. 1 Montorsi et al. J Sex Med 2004; 1: 2 Porst et al. MMW 2005 53

54 Inhibiteurs de la PDE 5 : Relation effet-dose
% „Yes" Responses Efficacy of medium and low doses in relationship to the highest investigated dose according to GAQ* *GAQ – Global Assessment Question: „Has the treatment you have been taking over the past 4 weeks improved your erections?″ Efficacy of the highest investigated dose set to 100% 100 82.7 61.7 91.6 66.6 95 82.5 20 40 60 80 High Dose Medium Dose Low Dose Tadalafil Sildenafil Vardenafil Slide 55 This slide shows that, compared to the other two components, Vardenafil is truly effective at very low doses. You can see here that if we set the effect arbitrarily at 100 for the highest dose of each compound and then we go to the medium and low dose, you see that the lower the dose gets, the higher the relative potency and the relative effectiveness of Levitra becomes. And this was assessed with the so-called global assessment question, which is, “has the treatment you have been taking over the past 4 weeks improved the erections?” So Vardenafil is highly effective even at low doses. 5, 10, 20 mg (Tadalafil), Brock et al. J Urol 2002; 168: , 50, 100 mg (Sildenafil), Goldstein et al. N Engl J Med 1998; May 14; 338 (20): 5, mg (Vardenafil), Porst et al. Int J Imp Res 2001;13 54

55 CONFIRMED : étude comparant Vardénafil-Sildénafil
4 weeks therapy 1 week wash-out Vardenafil 20mg Sildenafil 100mg without ED therapy R ED patients with diabetes mellitus or/and hypertension or/and hyperlipidemia Double blind, cross-over, 4-week no-treatment phase before first examination, two 4-week treatment phases, in between 1 week wash-out Primary end point: proof of non-inferiority as a prerequisite for Secondary end points: difference in patient preference n = 1.057 Slide 56 This is about the CONFIRMED trial, one of the very few direct head-to-head comparison trials between two different PDE-5 inhibitors and certainly the best-designed study. These are patients with erectile dysfunction who have received either Levitra 20 mg or Sildenafil 100 mg. These are the highest doses and all patients have been on both drugs at different points in time. There was a one week washout period in between. Then they were asked about their preference and of course there was the IIEF Index of erectile dysfunction and the score for erectile function was assessed and so on. So this is one of the very few, and certainly the best-conducted, direct head-to-head comparison trial between two PDE-5 inhibitors. Rubio-Aurioles et al. J Sex Med 2006; 3: 55

56 CONFIRMED : Préférence globale
Patients (%) n.s. 38.9 34.5 26.6 10 20 30 40 Vardenafil preferred Sildenafil No preference n=248 These non-confirmatory tests were done after the primary test hypothesis (noninferiority of vardenafil) had been fulfilled Slide 57 Patient preference in this CONFIRMED trial showed that there is a slight but non-significant preference for Vardenafil over Sildenafil. Almost 27 % of the patients said they did not have any preference. In other words, there is a tendency towards a slight preference for Vardenafil over Sildenafil. Rubio-Aurioles et al. J Sex Med 2006; 3: 56

57 Dysfonction érectile et syndrome métabolique : Etudes Vardénafil
Efficacité du vardénafil chez les patients avec DE associée à l‘un des composants du syndrome métabolique Diabète Type 2 Diabète Type 1 HTA Dyslipidémie Slide 58 How about the effects of Vardenafil in patients with components of the metabolic syndrome and other co-morbidities, such as type 1 diabetes? 57

58 Vardénafil dans la DE chez le diabétique
452 patients with erectile dysfunction and diabetes (HbA1c ≤12%, 88% type 2) Placebo (mean IIEF-EF score) Erectile function Vardenafil 10 mg 20 mg after 12 weeks of therapy 6 10 14 18 22 12.6 17.1 19.0 Score <11 = severe ED baseline * * ‡ Slide 59 One of the early studies with Levitra was done with patients with diabetes -- both type 1 and type 2 diabetes -- and Vardenafil was used in different doses versus placebo. This is the erectile function score of the IIEF-EF after 12 weeks of therapy and we clearly see that there is a clear advantage of Vardenafil over placebo. You also see that it is a very difficult-to-treat patient group. The highest dose of Vardenafil is more effective than the 10mg dose. Prospective, randomized, multi-center, double-blind; 12 weeks treatment with 10 or 20 mg vardenafil (PRN) or placebo least-squares mean IIEF-EF domain scores at week 12; IIEF-EF: erectile function, orgasm, sexual desire, intercourse satisfaction , overall sexual satisfaction; related to the previous 4 weeks Goldstein et al. Diabetes Care 2003; 26: *p< vs placebo; ‡p<0.03 vs 10 mg vardenafil 58

59 Vardénafil dans la DE et le diabète de type 1
Multi-center, randomized, double-blind, placebo-controlled parallel group study; 12 week treatment with vardenafil (dose titration) or placebo; SEP = Sexual Encounter Profile 452 type 1 diabetic men (HbA1c <12%) with ED; no previous use of PDE 5 inhibitors SEP 3: Ability to successfully complete intercourse SEP 2: Ability to penetrate baseline week 4 week 8 week 12 ** * SEP3 % "ja" 20 40 60 80 SEP2 % "ja" 28 13 39 47 50 26 25 18 52 41 71 Placebo Vardenafil Slide 60 One of the few studies done in patients with type 1 diabetes also shows that Vardenafil is highly effective in these patients. This was assessed by two questions, SEP 2 and SEP 3, from the sexual encounter profile, which is about achieving an erection and the maintenance of the erection to successfully completed intercourse. Ziegler et al. J Sex Med 2006; 3: *p< vs placebo; **p= vs placebo 59

60 Vardénafil dans la DE et HTA
338 ED patients with controlled hypertension on at least one antihypertensive Multi-center, randomized, double-blind, placebo-controlled parallel group study; 12 week treatment with vardenafil (dose titration) or placebo; ITT-collective Placebo Vardenafil SEP3 % "yes" Base- line 4 8 Week 12 * 35 18 62 66 68 32 20 40 60 100 LOCF 67 SEP2 % "yes" 50 80 83 84 58 56 49 SEP 3: Ability to successfully complete intercourse SEP 2: Ability to penetrate Slide 61 A specific study was conducted on men with hypertension -- one of the underlying conditions, one of the components, of the metabolic syndrome. This was a multi-center trial in Germany, published in 2005, and again we see a very good response rate -- over 80 % for the SEP 2 question about the ability to penetrate in men with hypertension. When it comes to SEP 3, there are still very good success rates over placebo -- slightly lower than for SEP 2. SEP 3 , about the completion of successful intercourse -- is really the critical question. And here we see slightly lower success rates but still highly effective responses compared to placebo. van Ahlen et al. J Sex Med 2005; 2: *p< vs placebo 60

61 Vardénafil dans la DE et la dyslipidémie
386 ED patients with hyperlipidemia (at least 1 statin) Prospective, randomized, double-blind, placebo-controlled parallel group study; 12 weeks treatment with vardenafil (titration regimen) or placebo; SEP = Sexual Encounter Profile ; LOCF = Last Observation Carried Forward Erectile function Placebo Vardenafil SEP3 % "yes" 20 40 60 80 33.8 66.7 LOCF IIEF-EF domain score 14.8 22.0 * SEP 3: Ability to successfully complete intercourse Slide 62 This is the most recent study of men with hyperlipidemia, one of the co-morbidities, one of the factors, of the metabolic syndrome. The study was done in the United States with almost 400 patients and it clearly shows very good effectiveness of Levitra in men with hyperlipidemia. Miner et al. J Sex Med 2008; 5: *p<0.01 vs. pacebo 61

62 Dysfonction érectile : Points forts
Syndrome métabolique est un facteur de risque de la DE DE est le premier symptome de l‘athèrosclèrose DE : occasion pour le diagnostic des facteurs de risque cardiovasculaires et les composants du syndrome métabolique Vardénafil est efficace dans le traitement de la DE associée à HTA, diabète et la dyslipidémie. Vardénafil augmente le nombre d‘EPCS. Slide 66 In summary, the metabolic syndrome is a risk factor for erectile dysfunction, and erectile dysfunction is an early symptom of atherosclerotic disease. In ED patients, the diagnosis of typical co-morbidities and cardiovascular risk factors is of utmost importance, and Vardenafil is effective also in patients with ED and metabolic co-morbidities such as diabetes, dyslipidemia and hypertension, as specific studies have pointed out. Finally, Vardenafil increases the number of endothelial progenitor cells and this is related to the so- called endothelial repair. 62

63 Résumé Treat ED and check for T
Association entre la DE, Hypotestostéronémie et les conditions du syndrome métabolique : obésité centrale, HTA, dyslipidémie et diabète de type 2. DE est souvent la 1ère manifestation de ces comorbidités : portail de la santé de l’homme DE est l’occasion pour le médecin d’avoir une approche plus ciblée sur la santé de l’homme Lors de la prescription d’un inhibiteur PDE 5, pensez à prescrire un dosage de la testostérone, surtout devant la présence du syndrome métabolique. Slide 68 In order to summarize what we have heard about both testosterone deficiency syndrome and erectile dysfunction, we can say that many epidemiological studies consistently show associations between ED, low testosterone and co-morbid conditions, especially central obesity, hypertension, dyslipidemia and type 2 diabetes. Erectile dysfunction is often the first manifestation of these co-morbidities and therefore ED is considered the portal to men’s health. ED should prompt physicians to take a more holistic approach to men’s health. In other words, it is not sufficient to just treat erectile dysfunction but it is very important to look behind erectile dysfunction and see what other conditions exist that are potentially life-threatening. For men presenting with erectile dysfunction, prescription of a PDE-5 inhibitor and, during the same visit, drawing a blood sample for measuring testosterone and other parameters, is a good strategy, especially with men with central obesity and other underlying conditions. So if you want to summarize the whole presentation, I think a good way to simplify it is to say “Treat ED and check for T,” where T not only stands for testosterone but also for other things, such as lipids, glucose, and blood pressure. So this is very important not only for the patient but also for the physician who wants to keep the patient and not send him away with just a prescription for Levitra. Rather, he wants the patient to come back so he can look at what other conditions may exist. This is why this sentence, thus simplified, says it very well -- “Treat ED and check for T.” Treat ED and check for T 63

64 Take-Home Message Restore the Man Mesurer chez vos patients
Tour de taille Pression arterielle Lipides Glycémie (1-1,25g ⁄ l) HbA1c Testostérone totale Slide 69 As a take home message, what a physician should do with a patient presenting with ED is measure waist circumference -- very inexpensive, very quickly done -- measure blood pressure, again a routine thing that a doctor does in his office, and take a blood sample to measure lipids, fasting glucose, HbA1c and total testosterone, because all these parameters are risk factors for metabolic and cardiovascular diseases. So, coming back to the title of our presentation, what we want to emphasize and we want to advise is: “Restore the Man.” Restore the Man 64