You are on page 1of 96

Hypogonadism and

Erectile Dysfunction
in Diabetic Men
Tarek Anis
Prof. Of Andrology, Cairo University
1

Disclosure
I have provided services (Speaker and investigator
in clinical trials) for Lilly, Pfizer, and Bayer.
For these activities, I have received appropriate
honorarium.
Slides of this presentation reflect my points of view
only and not those of Lilly

2

Why is it important
to screen for ED in
diabetic patients ?

3

Prevalence of Diabetes

Source : International Diabetes Federation
4

Prevalence of Diabetes
IDF estimates for 2010
19.5%
20

16.7%

15.2%

14.4%

15

13.1%
11%

10

5

0

U.A.E

Saudi Arabia

Bahrain

Kuwait

Oman

5.9%
Global Prevalence

6 of the top 10 countries

Egypt

IDF 2010
5

Prevalence of Diabetes
IDF estimates for 2012
24

23.7%

4 of the top 10 countries
23.4%

23.3%

23

22.4%
22

21

20

Kuwait

Saudi Arabia

Qatar

6

7

8

Bahrain

9
6

The top 10 countries for people
with diabetes (20-79 years)
0

25

50

75

92.3 M

China
63 M

India
24.1 M

USA
Brasil

13.4 M

Russa

12.7 M

Mexico

100

10.6 M

Indonesia

7.6 M

Egypt

7.5 M

Japan

7.1 M

Pakistan

6.6 M

Source IDF 2012

7

Diabeis is a Major Risk Factor
for ED
Odds ratio of ED

5
4

4.1

3

3.1

2.9

2

2.6
1.8

1
0

Diabetes 1,2

LUTs 2

Prostatic D 1

PVDs 1

1.7

1.6

Cardiac D 1 Dyslipidemia1 Hypertension 1,3

1.Martin-Morales A et al. J Urol. 2001;166:569-575.
2.Braun M et al. Int J Impot Res. 2000;12:305-311.
3.Laumann EO et al. JAMA. 1999;281:537-544.
4.Lewis RW. Urol Clin North Am. 2001;28:209-216.
8

Is Sex Important ?
1,000 sexually active
men (500) and women
(500) from different
cities in the ME region.

Algeria
Morocco

Lebanon
Egypt
United
Arab
Emirates
Kingdom
of Saudi
Arabia

Sexual Health and Overall
Wellness Survey In Africa and the
Middle East (AfME)
South Africa

9

Sex on the List of Life Priorities:
Importance vs. Satisfaction
100

98%

100
96%

75

75

50

50

25

25

0

Male

Female

Not at all important
Important

0

81%

81%

19%

19%

Male

Female

Not completely satisfied
Completely satisfied
10

Sex Ranks High on the List of
Life Priorities
Level of importance attributed to life priorities
Rank*

Men

Women

1st

Overall physical health

Family life

2nd

Work/career

Overall physical health

3rd

Sex

Love & romance

4th

Family life

Financial well-being

5th

Social life
Gaining wisdom
Financial well-being

Sex
Being a wife/partner
Social life
Work/Career

*Ranking based on perceived importance of a total of 18 life aspects

11

People Highly Satisfied with Erection
Enjoy Sexual Intercourse More Often

Frequency during past 4 weeks

15
12

12.5

12.2

9
6.8

6

6.7

3
0

Male
Female
Completely/very satisfied

Male
Female
Somewhat/not at all satisfied

12

13

ED Predicts Silent Myocardial Ischemia in
Apparently Uncomplicated Type 2 Diabetic
Patients
ED

33.8%

Silent Ischemia
N = 133

No ED

4.7%

No Ischemia
N = 127

Gazzaruso et al. Relationship between erectile dysfunction and silent myocardial ischemia in apparently uncomplicated
type 2 diabetic patients. Circulation 2004; 110 (1): 22-6.

14

ED Predicts Silent Myocardial Ischemia in
Apparently Uncomplicated Type 2 Diabetes
Myocardial ischemia at exercise ECG, 48-hour ambulatory ECG, and stress echocardiography

42.1%
88.2%

Erectile Dysfunction

Normal Erection

Gazzaruso et al. Relationship between erectile dysfunction and silent myocardial ischemia in apparently uncomplicated
type 2 diabetic patients. Circulation 2004; 110 (1): 22-6.
15

What Predicts Asymptomatic
Myocardial Ischemia ?
Odds Ratio

Erectile Dysfunction

14.8

Smoking

4.9

Microalbuminuria

3.7

Low HDL

3

high LDL

2.4

Multiple logistic regression modle: Age, diabetes duration, hypertension,
family history, smoking, microalbuminuria, HbA1c, BMI , cholesterol,
triglycerides, LDL , HDL, ED
Gazzaruso et al. Relationship between erectile dysfunction and silent myocardial ischemia in apparently uncomplicated
type 2 diabetic patients. Circulation 2004; 110 (1): 22-6.
16

Incidence per 1000 person-years

Incidence of Coronary Artery Disease
with Respect to Age and Erectile
Dysfunction Status
48.52

29.63

27.15

23.97

23.3

10.72
5.09
0.94
40-45

50-59

60-69

≥ 70

Age

Inman BA, Sauver JL, Jacobson DJ, McGree ME, Nehra A, Lieber MM, Roger VL, Jacobsen SJ. A population-based,
longitudinal study of erectile dysfunction and future coronary artery disease. Mayo Clin Proc 2009; 84 (2): 108-13.
17

Why ED occurs before other
Vascular Symptoms?
Early

The small diameter of the
cavernosal arteries.
The penis is a vascular organ,
sensitive to changes in oxidative
stress and NO levels.
The high content of endothelium
and smooth muscle on a per gram
tissue basis (compared to other
organs).

Late

Penile artery
1-2 mm
ED
Coronary
3-4 mm
angina/infarction
Carotid
5-7 mm
Stroke

Femoral
6-8 mm
Claudication

Montorsi et al. The Artery Size
Hypothesis: A Macrovascular Link
Between Erectile Dysfunction and
Coronary Artery Disease. Curr Opin
Urol. Am J Cardiol 2005;96:19M–23M.
18

Health Related Quality Of Life In Men With
ED And Diabetes
With ED

1,456 patients, of whom 500 patients had
ED at baseline and 192 patients
developed ED during the followup.

1.48

1.50

Change in SF-36 Sum Score

The onset of ED was associated with
marked worsening in physical and social
functioning, general health perception, as
well as in the summary physical and
mental components scores. The
development of ED was also associated
with a significant increase in depressive
symptoms.

Without ED

Change in QOL over 3 years

No changes in patients without ED
ED at baseline, a worsening in all SF-36
scales.

Incident ED

0.75
0
-0.75

-0.46
-1.21

-1.50

-1.22

-1.81
-2.25

Mental

-2.08

Physical

-3.00

SF-36 Domain

De Berardis G et al. Longitudinal Assessment of Quality of Life in Patients With Type 2 Diabetes and Self- Reported
Erectile Dysfunction. Diabetes Care. 2005; 28:2637-2643.
19

Diabetes, Depression and
Erectile Dysfunction
Diabetes doubles the odds of depression.
There is strong predictive value of depressive symptoms in the
incidence of ED among diabetic men
The development of ED worsens existing depressive
symptoms
ED because of diabetes can generate anxiety, making the
condition worse
Depression, and anxiety are associated with more diabetic
complications and poor glycemic control
Malavige LS, Levy JC. Erectile dysfunction in diabetes mellitus. J Sex Med 2009; 6 (5): 1232-47.
20

Do Diabetic Men
Address ED with their
Physicians ?

21

Only 47 % of Diabetic men with ED discuss
their sexual function with their physician

38%

40
30

21%

21%

20
10
0

7%

MD Busy

7%

3%
MD Female

Embarrassed

Not importatnt

3%
MD didn’t Ask Not Appropriate

Other

Zweifler J, Padilla A, Schafer S., Barriers to recognition of erectile dysfunction among diabetic
Mexican-American men. J Am Board Fam Pract. 1998 Jul-Aug;11(4):327-30.

22

How to Measure
Erectile Function ?

23

How to Measure Erectile Function

Body weight

Blood pressure

Erectile Function

10

24

24

International Index of Erectile
Function (IIEF)
The IIEF is a 15-question instrument that addresses the relevant
domains of male sexual function.
Responses are scored using a five-point scale, with a score of 1
representing the worst response (almost never/never), and a score
of 5 representing the best response (almost always/always).
The 15 questions fall into five domains of sexual function: erectile
function (questions 1–5 and 15), orgasmic function (questions 9–
10), sexual desire (questions 11–12), intercourse satisfaction
(questions 6–8) and overall satisfaction (questions 13–14).
The total score of erectile function domain is 30, men scoring less
or equal to 25 are classified as having ED
Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function
(IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49 (6): 822-30.
25

IIEF Erectile Function Domain
Score

26

How to Measure Erectile
Function
Sexual Encounter Profile (SEP)
SEP2. Were you able to insert your penis into your partner’s vagina?
Yes/No
SEP3. Did your erection last long enough to have successful
intercourse?
Yes/No

Global Assessment Questionnaire (GAQ)
Has the treatment you have been taking improved your erections?
Yes/No
27

Erection Hardness Scale
A Validated Measure of Erection Hardness

Penis is larger but
not hard

Penis is hard
but not hard
enough for penetration

Penis is hard
enough for
penetration
but not
completely
hard

Penis is
completely
hard and
fully rigid

Goldstein et al. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med 1998;
338 (20): 1397-404. Mulhall et al. Validation of the erection hardness score. J Sex Med 2007; 4 (6): 1626-34.

28

Epidemiology of
Diabetic Erectile
Dysfunction
29

Prevalence of ED in Diabetic Men
Study, Country

ED prevalence

Age

Duration of
Diabetes

HbA1c

Methodology and scales

UK, McCulloch et al.

35%

20-59

NK

NK

Self-reported nonvalidated

Italy, De Berardis et al.

Frequently 34%
Occasionally 24%

62 ± 10

10 ± 9

NK

Self-reported nonvalidated
questionnaire

Italy, Fedele et al.

36%

NK

NK

NK

Direct questioning by
interviewers at 178 centers

USA, Bacon et al.

45.8%

65.8

NK

NK

Self-reported nonvalidated
questionnaire

Hong Kong, Siu et al.

63.6%

58.3 ± 10

5

7.7 ± 1.5

Direct questioning by the
interviewer

S. Korea, Cho et al

65.4%

53.8 ± 6.6

6

7.93

Telephone and face-to-face
interview modified IIEF5

France, Giuliano et al.

71% IIEF5
67% on questioning

59 ± 9

NK

7.6 ± 1.5

IIEF5 and direct questioning

Sri Lanka, Malavige et al.

73.1%

55.6 ± 10.4 7.2

7.2 ± 1.6

IIEF5

Saudi Arabia, El-Sakka et al.

86.1%

53.7 ± 10.8 11 ± 8

NK

IIEF, erectile function domain

Japan, Sasaki et al.

90%

59 ± 8

>8

IIEF5

NK

Malavige LS, Levy JC. Erectile dysfunction in diabetes mellitus. J Sex Med 2009; 6 (5): 1232-47.
30

Prevalence of ED in
Diabetic Men
The prevalence of ED among diabetic men varies from 35% to
90%.
In the Massachusetts male aging study, ED was 3 times more
common in diabetic compared with non-diabetic men
ED occurs 10–15 years earlier in diabetic than in non-diabetic
men.
ED in men with diabetes is more severe and is less responsive to
oral treatment than non-diabetic men with ED.
Diabetes is commonly associated with comorbidities such as
hypertension, hyperlipidaemia, and the metabolic syndrome,
which are recognized independent risk factors for ED.
Malavige LS, Levy JC. Erectile dysfunction in diabetes mellitus. J Sex Med 2009; 6 (5): 1232-47.
31

Prevalence of ED in Diabetic
Men
12% of men who present with ED were found to have previously
undiagnosed DM
Men with type 1 DM were at a significantly higher risk for ED (RR, 3.0)
compared with men with type 2 DM (RR, 1.3)
Men with Type 2 DM had an increasingly greater risk of ED with
increased duration since diagnosis, particularly for men whose DM
was diagnosed >20 years previously
The incidence of insulin resistance is three times higher in men with
ED
The RR for ED in men with DM increases with coexisting
cardiovascular disease, renal disease, diabetic foot and retinal disease
Malavige LS, Levy JC. Erectile dysfunction in diabetes mellitus. J Sex Med 2009; 6 (5): 1232-47.
32

Diabetes Mellitus as risk factors
for ED in Upper Egypt
Diabetic

21.4%

658 men with erectile
dysfunction

Non diabetic
3.7%

821 age-matched
controls

Diabetes Mellitus (OR = 5.4) is a significant risk factors for ED
Zedan et al. Cigarette smoking, hypertension and diabetes mellitus as risk factors for erectile dysfunction in upper
Egypt. East Mediterr Health J 2010; 16 (3): 281-5.
33

The Pathophysiology
of ED in Diabetes

34

Pathophysiology of Diabetes
Induced ED
Neuropathy(
Cavernosal(
smooth(muscle(
structural/
func&onal(
changes(

Endothelial(
dysfunc&on(

Hormonal(
changes(

Diabe&c(
ED(

Psychological(
effects(

Malavige LS, Levy JC. Erectile dysfunction in diabetes mellitus. J Sex Med 2009; 6 (5): 1232-47.
35

Pathophysiology of Diabetes
Induced ED
AGEs(and(oxygen(
free(radicals(
Up3regulated(
RhoA/Rho3kinase(
pathway(

Impaired(NO(
synthesis(

Increased(
endothelin(and(
endothelin3B(
receptor(binding(
sites(

Diabe&c(
ED(

Impaired(cGMP3
dependent(
protein(kinase31(

Thorve VS, Kshirsagar AD, Vyawahare NS, Joshi VS, Ingale KG, Mohite RJ. Diabetes-induced erectile dysfunction:
epidemiology, pathophysiology and management. J Diabetes Complications 2011 Mar-Apr; 25 (2): 129-36.
36

Peripheral and Autonomic
Neuropathy
The neuropathy is attributable to microvasculopathy and
nerve toxicity that arise from several mechanisms:

-Increased oxidative stress
-Accumulation of AGEs
-Impaired axonal transport
-Increased flux through the polyol pathway
-Altered protein kinase C, and polyADP-ribose polymerase
activities.

These changes start in individuals with impaired glucose
tolerance, well before the diagnosis of diabetes is
established
37

Hypogonadism in
Diabetic Men

38

Pooled Mean Difference of Testosterone
Levels Between Type 2 Diabetes Cases and
Controls
43 prospective and crosssectional studies including
6427 men
In all cross sectional
studies diabetic men had
lower T levels
Prospective studies have
shown that men with
higher testosterone levels
had a 42% lower risk of
type 2 diabetes
Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2
diabetes: a systematic review and meta-analysis. JAMA 2006; 295 (11): 1288-99.
39

Mechanisms by which testosterone may decrease
insulin resistance
Pluripotent
cell

Adipocyte

Myocyte
︎ Mitochondrial
function

➡︎ Tg uptake
︎ Lipolysis

Testosterone
➡︎ Total fat mass

︎ Lean body mass

Decreased insulin resistance
Grossmann M. Testosterone and glucose metabolism in men: current concepts and controversies. J Endocrinol
2014; 220 (3): R37-55
40

Testosterone and insulin resistance: a bilateral relationship
Type 2 diabetes/metabolic syndrome

Insulin
resistance
Muscle
Cytokines

SHBG

Decreased
myocyte
differentiation/
mitochondrial
function

Stimulation of adipocyte
differentiation and triglyceride uptake

Visceral adipose
tissue
Cytokines
Insulin
Leptin
Ghrelin

Testosterone

HPT
axis

Kisspeptin
Luteinizing hormone

Symptoms/
end organ
deficits

Age/comorbidities

Grossmann M. Testosterone and glucose metabolism in men: current concepts and controversies. J Endocrinol
2014; 220 (3): R37-55
41

Hypogonadism and Diabetes
Levels of testosterone are frequently low in men with type 2
DM; most of these men have symptoms of hypogonadism,
including ED and decreased libido
Obesity and age are associated with low testosterone levels in
men with DM.
Even after adjustment for age and BMI, the prevalence of
hypogonadism in the diabetic men was higher than that in
nondiabetic men
The average decline of free testosterone concentrations was
7.8 pg/ml per decade in nondiabetic men and 8.4 pg/ml per
decade in diabetic men.
42

Prevalence of Subnormal Free Testosterone
Concentrations Stratified by BMI
Non diabetic

Diabetic

Prevalence of Hypogonadism

60
50

50%
44%

40
30
20

26%

44%

40%

29%

1,849 men (1,451
non-diabetic and
398 diabetic)

10
0

Lean

Overweight

(BMI <25 kg/m2)

(BMI 25–30 kg/m2)

Obese
(BMI ≥30 kg/m2)

Dhindsa et al. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes
Care 2010; 33 (6): 1186-92.
43

Prevalence of Subnormal Free Testosterone
Concentrations Stratified by Age
Prevalence of Hypogonadism

Non diabetic

Diabetic

70

*

60
50
40
30

*

20

1,849 men (1,451
non-diabetic and
398 diabetic)

*

10
0

45-52 years

53-59 years

60-68 years

69-90 years

Dhindsa et al. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes
Care 2010; 33 (6): 1186-92.
44

Androgens Maintain Penile
Tissues Structure and Function
Androgens maintain vascular endothelial structure and
function
Androgens maintain tunica albuginea structural integrity and
connective tissue matrix fibro-elastic properties
Androgens regulate differentiation of pluripotent precursor
cells into trabecular smooth muscle, and maintain smooth
muscle structure and function
Androgens maintain penile cavernosal and dorsal nerves
structure and function
Traish,AM, 2008. Androgens Play a Pivotal Role in Maintaining Penile Tissue Architecture and Erection: A Mini
Review. Published-Ahead-of-Print on September 18, 2008 by Journal of Andrology
45

Testosterone Restores PDE5 Inhibitors
Responsiveness in Hypogonadal Patients with
Erectile Dysfunction
Authors

No. of
subjects

Hypogonadism PDE5 I response at
baseline

Overall
efficacy

Aversa et al.

20

No

Failure

80%

Kalinchenko et al.

120

Yes

Failure

70%

Shabsigh et al.

75

Yes

Failure

70%

Chatterjee et al.

12

Yes

Not evaluated

100%

Shamloul et al.

40

PADAM

Greenstein et al.

49

Yes

Not evaluated

63%

Hwang et al.

32

Yes

Failure

57%

Rosenthal et al.

24

Yes

Failure

92%

Tas et al.

23

Yes

Not evaluated

34%

Failure

Improved

Adopted from Greco EA, Spera G, Aversa A: Combining testosterone and PDE5 inhibitors in erectile dysfunction:
basic rationale and clinical evidences. Eur Urol. 2006 Nov;50(5):940-7
46

Hypogonadism among Jordanian
Men with Type 2 Diabetes
1049 men with type 2 diabetes

36.4%

total T<3 ng/ml

29%

Symptoms of Hypogonadism

Alhayek et al., Hypogonadism among Jordanian men with type 2 diabetes: Prevalence and
associated factor, Int J Diab Mellitus (2011)
47

Long-Term Treatment with Testosterone Undecanoate
Improves Metabolic Control and Erectile
Function in Hypogonadal Men with Type 2 Diabetes
Single-center, cumulative, prospective, observational
registry study of 340 hypogonadal men (total
testosterone ≤ 12.1 nmol/L = 348.3 ng/dl) from a
single urological practice.
120 men (35.3%) had T2D.
All men received testosterone undecanoate injections
for up to 7 years.
All men were treated for their T2D by their respective
family physician.
Saad F, Haider A, Doros G, Traish A. 16th World Meeting on Sexual Medicine, São Paulo, Brazil, from 8 – 12
October 2014.
48

Saad F, Haider A, Doros G, Traish A. 16th World Meeting on Sexual Medicine, São Paulo, Brazil, from 8 – 12
October 2014.
49

Saad F, Haider A, Doros G, Traish A. 16th World Meeting on Sexual Medicine, São Paulo, Brazil, from 8 – 12
October 2014.
50

Saad F, Haider A, Doros G, Traish A. 16th World Meeting on Sexual Medicine, São Paulo, Brazil, from 8 – 12
October 2014.
51

Patients Reaching HbA1c Target of ≤ 6.5%
at Various Time Points
97%

96%
80%

20%
4%
Baseline
no (n=115)

Yes (n=5)

3%
66 months
no (n=12)

Yes (n=48)

84 months
no (n=1)

Yes (n=28)

Saad F, Haider A, Doros G, Traish A. 16th World Meeting on Sexual Medicine, São Paulo, Brazil, from 8 – 12
October 2014.
52

Saad F, Haider A, Doros G, Traish A. 16th World Meeting on Sexual Medicine, São Paulo, Brazil, from 8 – 12
October 2014.
53

Saad F, Haider A, Doros G, Traish A. 16th World Meeting on Sexual Medicine, São Paulo, Brazil, from 8 – 12
October 2014.
54

Saad F, Haider A, Doros G, Traish A. 16th World Meeting on Sexual Medicine, São Paulo, Brazil, from 8 – 12
October 2014.
55

Saad F, Haider A, Doros G, Traish A. 16th World Meeting on Sexual Medicine, São Paulo, Brazil, from 8 – 12
October 2014.
56

Saad F, Haider A, Doros G, Traish A. 16th World Meeting on Sexual Medicine, São Paulo, Brazil, from 8 – 12
October 2014.
57

Saad F, Haider A, Doros G, Traish A. 16th World Meeting on Sexual Medicine, São Paulo, Brazil, from 8 – 12
October 2014.
58

Saad F, Haider A, Doros G, Traish A. 16th World Meeting on Sexual Medicine, São Paulo, Brazil, from 8 – 12
October 2014.
59

Onset of effects of testosterone and time
span until maximum effects
Sexual interest and desire
Sexual thoughts and fantasy
Erectile
function

Morning erections

Satisfaction with sex life

Number of
erections / week

Sexual activity/
ejaculations
Saad F et al. Eur J Endocrinol 2011;165:675-685
60

Management of
Diabetic Men with
Erectile Dysfunction

61

WHO Treatment Recommendation
1

2

3

Risk Factor Modification
Intracavernosal Penile
injection
prosthesis
Lifestyle Modification
Drug Therapy Modifications MUSE
Revascularization
medicated urethral
Androgen Replacement
system for erection
Vacuum device
Oral PDE5 Inhibitors

≈ 90 %

≈5%

Transdermal
testosterone
Stop
smoking
Sildenafil
Antihypertensives/diuretics
Control
of(Viagra)
blood
glucose
Gel
or scrotal,
buccal, and non-scrotal
Reduce
weight
Tadalafil
(Cialis)
Selective
serotonin-reuptake
inhibitors patches
Dyslipidaemia
Intramuscular
(IM)(eg,
injection
Exercise
regularly
Vardenafil
(Levitra)
Hormonal
agents
anti-androgens)
Hypertension
Subcutaneous
implant
Follow
healthy diet
H2-receptor
Oraladequate
testosterone
Get
sleep
Limit or avoid alcohol

≈5%

62
62

Tadalafil

Vardenafil

Sildenafil
63

Mechanism of action
Sexual
Stimulation

Endothelial cell

Cavernous
nerve

Stimulation
Inhibition

Smooth muscle cell
Endoplasmic
reticulum
Nitric
oxide

Decreased
Ca2+

cGMP-specific
protein Kinase

Guanylate
cyclase

cGMP

GTP

Ca2+

K+

Smooth muscle
relaxation

PDE5
5’ GMP

K+
PDE5 inhibitor
site of action

Ca2+

64

Chemical Structure
O

O
O

N

HN

O

N

HN
N

N

O

O

N

N

N

O

N

O

S

O

N

HN

N

N

O

S O

H
N

H 2N

O
0H

O
O

O
O

N

Sildenafil

N

Vardenafil

N

N

Tadalafil

P

O
0H

cGMP

65

Pharmacokinetic Profile

∆ C max with food

t max (h)
t 1/2 (h)
Presence in the body (h)
Therapeutic window (h)

Sildenafil

Tadalafil

Vardenafil

➡︎29%

no change

➡︎20%

1

2

1

3-5
24
4

17.5
72
24

~4
24
4
66

67

Impact of Metabolic Control of Patients
With Diabetes II-associated ED
159 ED male patients with DM were enrolled in a prospective
study.
Erectile function was assessed using the IIEF score
Diabetes control was instituted using lifestyle modification in
addition to oral hypoglycemic agents and/or insulin therapy.
At baseline, 3- and 6-month visits, patients were assessed for
control of DM, ED severity, and total testosterone, and insulin
assessment.

El-Sakka AI, Sayed HM, Tayeb KA. Androgen pattern in patients with type 2 diabetes-associated erectile
dysfunction: impact of metabolic control. Urology 2009; 74 (3): 552-9.
68

Impact of Metabolic Control of
Patients With Diabetes II-associated ED
HbA1c

Testosterone

5.7%

5.3

4.7

HbA1c

4.3

5.3%

Baseline

3 month

Total T ng/mL

6.7%

6 month

El-Sakka AI, Sayed HM, Tayeb KA. Androgen pattern in patients with type 2 diabetes-associated erectile
dysfunction: impact of metabolic control. Urology 2009; 74 (3): 552-9.
69

Impact of Metabolic Control of
Patients With Diabetes II-associated ED
HbA1c

IIEF Score
17.8
15.3

12.4

6.7%

Baseline

5.7%

3 month

5.3%

6 month

El-Sakka AI, Sayed HM, Tayeb KA. Androgen pattern in patients with type 2 diabetes-associated erectile
dysfunction: impact of metabolic control. Urology 2009; 74 (3): 552-9.
70

Adherence to Mediterranean Diet in
Men with Type 2 Diabetes

Adherence to a
Mediterranean diet was
assessed by a 9-point
scale (range of scores, 0–9, with
higher scores indicating greater
adherence).

ED was assessed with
the IIEF-5 score.

ED

100

Normal

75
63.2%
50

56.9%

51.1%

25
0

0-3

4-6

Prevalence of ED

555 men with type 2
diabetes.

7-9

Mediterranean-diet score

Giugliano et al. Adherence to Mediterranean diet and erectile dysfunction in men with type 2 diabetes.
J Sex Med 2010; 7 (5): 1911-7.
71

PDE5 Inhibitors for
Diabetic ED

72

PDE5 Inhibitors for Diabetic ED
PDE5 inhibitors are generally safe and well- tolerated by
diabetic men.
All three PDE5 inhibitors have been evaluated for ED in
diabetic patients and shown to have similar levels of
efficacy.
There have been no head-to-head comparative studies
for the three drugs.
All PDE5 inhibitors are less efficacious in diabetic men.
Generally, diabetic patients require the maximum dose of
each agent, ie sildenafil 100 mg, vardenafil 20 mg, and
tadalafil 20 mg
73

Sildenafil Efficacy for the
Treatment of ED in Men DM
268 diabetic men with ED randomized to receive either sildenafil
given in a dose-escalation manner, or placebo, for 12 weeks
% of patients reporting improvement
10%
56%

Placebo

Sildenafil

Rendell et al. Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized
controlled trial. Sildenafil Diabetes Study Group. JAMA 1999; 281 (5): 421-6.
74

Sildenafil Efficacy for the Treatment
of ED in Men with Type II DM
International Index of Erectile Function at baseline and
week 12 prospective, self- reported, flexible-dose study
Erectile function score
IIEF-EF*

30
25
20

18.3

15
10

9.2

5

IIEF-EF
Erectile function
domain
Q 1 to 5 and 15,
maximum score
30

0

BaseLine

Endpoint

Behrend et al. Sildenafil in the treatment of erectile dysfunction in men with diabetes: demand, efficacy and patient
satisfaction. Int J Impot Res 2005 May-Jun; 17 (3): 264-9
75

Intercourse Satisfaction
International Index of Erectile Function at baseline and
week 12 prospective, self- reported, flexible-dose study
Intercourse satisfaction
score

15

10

8
5
4.3

Intercourse
satisfaction
score
Q 6 to 8,
maximum score
15

0

BaseLine

Endpoint

Behrend et al. Sildenafil in the treatment of erectile dysfunction in men with diabetes: demand, efficacy and patient
satisfaction. Int J Impot Res 2005 May-Jun; 17 (3): 264-9
76

Sildenafil Citrate Efficacy for the
Treatment of ED in Men with Type II DM
5

Baseline

Placibo

Sildenafil

4
3.42

3.35

3
2

1.77

1.86

1.84
1.49

1
0

IIEF Q3
The ability to achieve an erection
sufficient for sexual intercourse

Double-blind,
placebo-controlled
trial
219 patients were
randomized to
sildenafil or
matching placebo
for 12 weeks

IIEF Q4
The ability to maintain an
erection after penetration

Boulton AJ, Selam JL, Sweeney M, Ziegler D. Sildenafil citrate for the treatment of erectile dysfunction in men with
Type II diabetes mellitus. Diabetologia 2001; 44 (10): 1296-301
77

Sildenafil Citrate Efficacy for the
Treatment of ED in Men with Type II DM
30

Erectile Function Domain,Questions 1 to 5 and 15

24

20.4
18

12

10.4

11.5

6

0

Baseline

Placebo

Sildenafil

Boulton AJ, Selam JL, Sweeney M, Ziegler D. Sildenafil citrate for the treatment of erectile
dysfunction in men with Type II diabetes mellitus. Diabetologia 2001; 44 (10): 1296-301
78

Sildenafil Citrate Efficacy for the
Treatment of ED in Men with Type II DM
Affirmative responses to the GEQ
(Has treatment improved your erections?)
Yes

100

No

75
50

65%

25
0

11%

Sildenafil

Placebo

Boulton AJ, Selam JL, Sweeney M, Ziegler D. Sildenafil citrate for the treatment of erectile
dysfunction in men with Type II diabetes mellitus. Diabetologia 2001; 44 (10): 1296-301
79

Efficacy of Sildenafil Citrate in
Treatment of ED in Type 2 Diabetes
382 diabetic men with ED randomized to receive either sildenafil
given in a dose-escalation manner, or placebo, for 12 weeks
Mild
100

Moderate
41.9%

Severe
25.9%

80
13.3%

60

50.3%

60.7%

40
20
0

7.9%

Before Treatment

After Treatment

El-Sakka AI. Efficacy of sildenafil citrate in treatment of erectile dysfunction: effect of type 2 diabetes. Eur Urol 2004;
46 (4): 503-9.
80

Vardenafil Efficacy for the Treatment
of ED in Diabetic Patients
In a multicenter, placebo-controlled, double-blind study, 452 diabetic
patients were randomised to placebo, vardenafil 10 mg or 20 mg

% of patients reporting improvement
13%

57%
72%

Placebo

10 mg

20 mg

Goldstein et al. Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men
with diabetes: a multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care 2003; 26 (3): 777-83.
81

Tadalafil Efficacy for the Treatment
of ED in Diabetic Patients
In a placebo-controlled, double-blind study, 191 diabetic patients were
randomised to placebo, Tadalafil 10 mg or 20 mg

% of patients reporting improvement
25%
56%

Placebo

10 mg

64%

20 mg

Sáenz de Tejada I, Anglin G, Knight JR, Emmick JT. Effects of tadalafil on erectile dysfunction in men with diabetes.
Diabetes Care 2002; 25 (12): 2159-64.
82

Impact of DM on the severity of ED
and response to treatment
Placebo

Tadalafil 10 mg

Tadalafil 20 mg

30

IIEF-EF

25
19.2

20
15

21.6

19.9

23.9

15.7
13.4

10
5
0

Diabetic

Non Diabetic

Fonseca V, Seftel A, Denne J, Fredlund P. Impact of diabetes mellitus on the severity of erectile
dysfunction and response to treatment: analysis of data from tadalafil clinical trials. Diabetologia
2004; 47 (11): 1914-23.
83

Impact of DM on the severity of ED
and response to treatment

SEP-2

Placebo
100
90
80
70
60
50
40
30
20
10
0

Tadalafil 10 mg

Tadalafil 20 mg

75.3%
59.5%

82.7%

64.7%
52.8%

35.8%

Diabetic

Non Diabetic

Fonseca V, Seftel A, Denne J, Fredlund P. Impact of diabetes mellitus on the severity of erectile
dysfunction and response to treatment: analysis of data from tadalafil clinical trials. Diabetologia
2004; 47 (11): 1914-23.
84

Impact of DM on the severity of ED
and response to treatment

SEP-3

Placebo
100
90
80
70
60
50
40
30
20
10
0

Tadalafil 10 mg

Tadalafil 20 mg

70.6%

60.9%
48.6%

52.8%
33.2%

21.5%

Diabetic

Non Diabetic

Fonseca V, Seftel A, Denne J, Fredlund P. Impact of diabetes mellitus on the severity of erectile
dysfunction and response to treatment: analysis of data from tadalafil clinical trials. Diabetologia
2004; 47 (11): 1914-23.
85

Salvage of On-demand Tadalafil
Failures with Daily Tadalafil

McMahon C. Efficacy and safety of daily tadalafil in men with erectile dysfunction previously
unresponsive to on-demand tadalafil. J Sex Med 2004; 1 (3): 292-300.
86

Salvage of On-demand Tadalafil
Failures with Daily Tadalafil
30

IIEF-EF

25

23.1

22.4

10 mg

20 mg

20

14.9

15
10

10.3

5
0

Base line

on demand 20 mg

Daily
McMahon C. Efficacy and safety of daily tadalafil in men with erectile dysfunction previously
unresponsive to on-demand tadalafil. J Sex Med 2004; 1 (3): 292-300.
87

Penetration Success (SEP2)

Salvage of On-demand Tadalafil
Failures with Daily Tadalafil
100
90
80
70
60
50
40
30
20
10
0

66%

21%

Base line

62%

28%

on demand 20 mg

10 mg

20 mg
Daily

McMahon C. Efficacy and safety of daily tadalafil in men with erectile dysfunction previously
unresponsive to on-demand tadalafil. J Sex Med 2004; 1 (3): 292-300.
88

Intercourse Completion (SEP3)

Salvage of On-demand Tadalafil
Failures with Daily Tadalafil
100
90
80
70
60
50
40
30
20
10
0

58%

14%
Base line

52%

21%

on demand 20 mg

10 mg

20 mg
Daily

McMahon C. Efficacy and safety of daily tadalafil in men with erectile dysfunction previously
unresponsive to on-demand tadalafil. J Sex Med 2004; 1 (3): 292-300.
89

Intercourse Completion (SEP3)

Salvage of On-demand Tadalafil
Failures with Daily Tadalafil
100
90
80
70
60
50
40
30
20
10
0

69%

63%

42%

on demand 20 mg

10 mg

20 mg
Daily

McMahon C. Efficacy and safety of daily tadalafil in men with erectile dysfunction previously
unresponsive to on-demand tadalafil. J Sex Med 2004; 1 (3): 292-300.
90

Approaches to improve responsiveness of
diabetes-induced ED to PDE5 inhibitor therapy
Education about most effective protocol for use of PDE5 inhibitors
Normalizing testosterone level
Improvement in overall health (decreasing adiposity, improving
cardiorespiratory fitness, and controlling hyperglycemia and dyslipidemia)
Higher dosing of PDE5 inhibitors and use of different inhibitors
Chronic daily treatment with PDE5 inhibitors
Combining PDE5 inhibitor therapy with other therapies.
Potential therapeutic utility of nebivolol (a highly selective β1adrenoceptor antagonist with NO–mediated vasodilatory properties) as
an adjunct to PDE5 inhibitors1.
1. Martínez-Salamanca et al. Nebivolol potentiates the efficacy of PDE5 inhibitors to relax corpus cavernosum and penile
arteries from diabetic patients by enhancing the NO/cGMP pathway. J Sex Med 2014; 11 (5): 1182-92.
91

PDE5 inhibitors Diminish Microalbuminuria
and A1c % in Patients with Type 2 Diabetes

mg/L/24 h

Placebo
20
18
16
14
12
10
8
6
4
2
0

50 mg Sildenafil for one month
18.82

17.60

13.28
9.15

Before Treatment

After Treatment

Grover-Pa´ez et al., Sildenafil citrate diminishes microalbuminuria and the percentage of A1c in male patients with
type 2 diabetes, Diab. Res. Clin. Pract. (2007), doi:10.1016/j.diabres.2007.02.006
92

PDE5 inhibitors Diminish Microalbuminuria
and A1c % in Patients with Type 2 Diabetes
Placebo

50 mg Sildenafil for one month

10
9

A1c (%)

8
7
6

8.08%
7.15%

8.3%
7.49%

5
4
3
2
1
0

Before Treatment

After Treatment

Grover-Pa´ez et al., Sildenafil citrate diminishes microalbuminuria and the percentage of A1c in male patients with
type 2 diabetes, Diab. Res. Clin. Pract. (2007), doi:10.1016/j.diabres.2007.02.006
93

Conclusions

94

Conclusions
Erectile dysfunction in men with diabetes is likely to become
a more serious problem in the future with the rapidly
increasing prevalence and earlier onset of diabetes.
The aetiology of ED in diabetes is multifactorial.
Diabetic ED is more severe and more resistant to treatment.
Optimal glycaemic control, management of associated
comorbidities, and lifestyle modification should be
recommended to all patients.

95

Conclusions
Psychosexual and relationship counseling would be
beneficial for men with such coexisting problems.
Hypogonadism should be identified and may need
treatment.
PDE5 inhibitors are safe and effective for the
management of ED in diabetic men
A maximal dose of PDE5 inhibitors is often needed.
Testosterone replacement for hypogonadal men with
T2D restores erectile function and improves metabolic
control.
96