Diabetes Mellitus and erectile dysfunction

Dr. Mohand Yaghi PgDip urol (MU) ChM urol (RCSEdin.)

Physiology of erection :

ED : The persistent inability to attain and maintain an erection sufficient for satisfactory sexual performance.

KUW: of 323 patients with DM 2, 31% had ED, IIEF-5 used. (The prevalence and predictors of erectile dysfunction in men with newly diagnosed with type 2 diabetes mellitus. BJU Int. 2007 Jan;99(1):130-4)

KSA: 376 pts, DM 2, 81% reported ED. (Erectile Dysfunction and Other Sexual Activity Dysfunctions among Saudi Type 2 Diabetic Patients. AlMogbel . Int J Health Sci (Qassim). 2014 Oct;8(4):347-59)

Risk factors – age, smoking, glu control, duration of DM & smoking, occupation, income, education.

Prevalence in DM

> 40 35 40-49 71 50-59 118 60-69 118 >70 34

beta blockers, diuretics, hydralazine, CCB Centrally acting: Methyldopa, Clonidine. Antidepressants: Benzodiazepines,

Phenothiazines, Haloperidol, Li, MAOIs, Tricyclics.

Hormones: anti-androgens, LHRH agonists Others: Cimetidine, Digoxin,

Metoclopromide, Statins.

Medications

Controversial Any drugs which lowers BP can cause ED (J.

Jensen et al. “The prevalence and etiology of impotence in 101 male hypertensive outpatients,” American Journal of Hypertension, vol. 12, no. 3, pp. 271–275, 1999)

small studies suggested that some antihypertensive drug classes could have less harmful or even beneficial effect on sexual function like CCB (C. A. Derby 2001), angiotensin II receptor blockers (M. Böhm et al. 2007) , and nebivolol (S. Bansal 1998)

Effect of Anti-hypertensives on ED

96 patients (all males, age 52+/-7 years) with newly diagnosed CVD and not suffering from ED.

Divided to 3 groups: group A didn’t know the drug, Group B knew the drug but not the side effect, Group C knew the drug and the side effects.

Results: ED in Group A 3.1%, group B 15.6%, group C 31.2%/

Silver et al. “Report of erectile dysfunction after therapy with beta-blockers is related to

patient knowledge of side effects and is reversed by placebo”.

Eur Heart J. 2003 Nov;24(21):1928-32.

Endothelial dysfunction, neuropathy, vascular changes. Penile tissue from diabetic men with ED demonstrates impaired

neurogenic and endothelium-mediated relaxation of smooth muscle. (aenz de Tejada I et al. 1989, N Engl J Med 320:1025 –1030, 1989)

Increased accumulation of advanced glycation end products (AGEs),23 and upregulation arginase, a competitor with nitric oxide synthase for its substrate L-arginine. (Seftel AD et al., Urology 50:1016 –1026, 1999)

decreased synthesis, release, or activity of nitric oxide through increased polyol pathway flux, intracellular accumulation of AGEs, activation of protein kinase C, and increased flux through the hexosamine pathway. (Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature 414:813 –820, 2001)

Effect of DM on ED

Experimental hyperglycemia may also affect cavernosal smooth muscle cell contractile responses.

penile smooth muscle has augmented force responses to vaconstrictors, possibly mediated by changes in expression of protein kinase C (Chitaley K et al., Nat Med7 : 119–122,2001)

Arterial morphology, flow, and diameter differ between diabetic and nondiabetic populations with ED. (Ruzbarsky V et al. Invest Urol 15::194 –199, 1997. Lehman TP et al., J Urol129 : 291–294,1983)

EAU guidelines 2015• History ( sexual relations, emotional status,

duration, rigidity, morning erection), IIEF-5, depression? Hypogonadism? IPSS.

• Physical exam.(GU, Vascular, neurology, endocrine).

• Lab. (HBA1c, FBG, lipids profile, morning Testosterone, PSA, TFTs). Prolactin & LH if Testosterone is low.

Investigations

Nocturnal penile tumescence and rigidity test (NPTR)- erection with 60% of rigidity for > 10min. (Rigiscan)

Intra-cavernous injection test- functional test. Duplex US- PSF > 30cm/s, end-diastolic

velocity < 3cm/s. Internal pudendal Arteriography- rarely

performed only perform reconstruction surgery.

Psychiatric assessment- specially in young pts.

Specialized diagnostic tests

Treatment

Life style changes particularly important in individuals with ED and comorbidities like DM/HT. Increase PDE5Is response.

Derby CA, Mohr BA, Goldstein I, et al. Modifiable risk factors and erectile dysfunction: can lifestyle changes modify risk? Urology 2000 Aug;56(2):302-6. Prospective study, 1097 pts, age (40-70),

examined life changes in smoking, physical activity, alcohol consumption, obesity.

Results: Only obesity (p 0.006), and physical activity (p 0.01) were associated with ED.

Life style

RCT, single blinded, 110 obese pts, age 35-55.

After 2 yrs, BMI decreased from 36.9 to 31.2 in the interventional arm.

IIEF-5 increased from 13 to 17 17 men reported IIEF score of 22 or higher. Conclusion: 1/3 of the pts reported

improvement in sexual activity after weight loss .

Esposito K, Giugliano F, Di Palo C, et al. Effect of lifestyle changes on erectile dysfunction in obesemen: a randomized controlled trial. JAMA 2004 Jun;291(24):2978-84.

Sildenafil (Viagra) : first PDEIs 1998, doses 25, 50, 100 mg.

Initiation dose 50mg, effect starts from 30-60min., may last for 12 hrs.

In patients with diabetes, 66.6% reported improved erections (GAQ) and 63% successful intercourse attempts compared to 28.6% and

33% of men taking placebo.

Stuckey BG, Jadzinsky MN, Murphy LJ, et al. Sildenafil citrate for treatment of erectile dysfunction in men with type 1 diabetes: results of a randomized controlled trial. Diabetes Care 2003 Feb;26(2):279-84.

1st line treatment -Oral therapy

Effect after 30min, peak after 2 hours, maintained eff. Up to 36 hrs. absorption not affected by fatty food like Viagra/Levitra.

10, 20mg approved. Initial dose 10mg. Diabetics- 64% reported improved erections versus

25% of patients in the control group. But diabetic pts remain poor responders to ON

DEMAND Tadalafil (45% for 10mg and 50% for 20mg) Fonseca V, Seftel A, Denne J, et al. Impact of diabetes mellitus on the severity of erectile dysfunction and response to treatment: analysis of data from tadalafil clinical trials. Diabetologia 2004 Nov;47(11):1914-23.

Tadalafil (Cialis)

Starts 30min., 5mg, 10mg, 20mg approved from “on-demand”.

diabetic patients remain poor responders to on-demand with a successful intercourse rates increasing from 23% with placebo to 49% and 54% with 10 and 20 mg of Vardenafil on-demand.

Vardenafil (Levitra)

Highly selective PDE5Is, fast ( 15-30min), lasts for > 6hrs, half-life 6-17hrs.

Side effects is lower than other PDE5. Recommended dose 100mg (15-30min before

intercourse). Success rates: 41.3%, 57.1%, and 57.0% for

avanafil 50 mg, 100 mg, and 200 mg respectively in the general population with ED. (Goldstein et al. 2012b).

34.4% and 40.0% for 100 mg and 200 mg in men with diabetes (89.5% type 2). Goldestein et al. 2012b

New Face – Avanafil (Pedra)

Daily tadalafil led to a significantly higher IIEF score and higher completion of successful intercourse attempts compared to on-demand tadalafil. McMahon C. Comparison of efficacy, safety and tolerability of on-demand tadalafil and daily dosed tadalafil for the treatment of erectile dysfunction. J Sex Med 2005 May;2(3):415-25.

Alternative to on-demand dosing of tadalafil for couples who prefer spontaneous rather than scheduled sexual activities

Double-blind, placebo-controlled study of 298 men with diabetes and ED, 2.5 and 5 mg tadalafil once daily for 12 weeks was efficacious and well tolerated.

Hatzichristou D, Gambla M, Rubio-Aurioles E, et al. Efficacy of tadalafil once daily in men with diabetes mellitus and erectile dysfunction. Diabet Med 2008 Feb;25(2):138-46.

On-demand or chronic use of PDE5 inhibitors ???

Between 70-90% of patients choose Tadalafil (Cialis).

1. von Keitz A, Rajfer J, Segal S et al. A multicenter, randomized, double-blind, crossover study to evaluate patient preference for tadalafil and sildenafil. Eur Urol 2004; 45: 499-507.

2. Stroberg P, Murphy A, Costigan T. Switching patients with erectile dysfunction from sildenafil citrate to tadalafil: results of a European multicenter, open-label study of patient preference. Clin Ther 2003; 25: 2724-37.

3. Eardley I, Mirone V, Montorsi F et al. An open-label, multicentre, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in men nave to phosphodiesterase 5 inhibitor therapy. BJU Int2005; 96: 1323-32.

Which PDE5 inhibitor??

Doesn’t increase MI, or time to ischemia in pts with stable angina. In fact, there is evidence that PDE5Is improve exercise test.

Nitrates contraindicated If patient on PDE5Is develops angina,

Nitroglycerine should be given 24hrs (Viagra)/48hrs (Cialis)

α-Blockers + PDE5Is (Viagra) = orthostatic hypotension (first 4 hrs)

patients should be stable on α-blocker therapy prior to initiating combined treatment, and that the lowest dose should be started initially of PDE5Is

Safety of oral therapy

Empty stomach, no alcohol, no fatty food, sexual stimulation, appropriate time for absorption (AT LEAST 60min required for men using Sildenafil and Vardenafil, and up to 2 h being required for men using tadalafil), adequate dose.

Lack of response

Alprostadil (Caverject)- PGE1 most efficacious as monotherapy at a dose

of 5-40 μg, starts 5-15min. Efficacy rates for intracavernous alprostadil

of > 70% in general ED populations, as well as CVD, DM.

sexual activity after 94% of the injections and satisfaction rates of 87-93.5% in patients and 86-90.3% in partners.

2nd line therapy (injections)

Penile pain (50%), prolonged erections (5%), priapism (1%), fibrosis (2%), hypotension.

Pain can be alleviated with the addition of sodium bicarbonate or local anaesthesia.

Cavernosal fibrosis clears within a few months after temporary discontinuation of the injection.

Contraindications: bleeding disorders, risk of priapism.

Drop-out rates of 41-68%, with most dropouts occurring within the first 2-3 months.

Complications

MUSE- Erections sufficient for intercourse are achieved in 30-65.9%, constricting ring increase the response

local pain (29-41%) and dizziness with possible hypotension (1.9-14%). Penile fibrosis and priapism(< 1%), urethral bleeding (5%) and urinary tract infections (0.2%).

alternative to intracavernous injections in patients who prefer a less-invasive and less effective treatment.

Intra-urethral injections

Penile Prosthesis – inflatable, malleable devices.

For non-responders to oral therapy or who prefer a permanent solution.

Peno-scrotal approach or infrapubic approach. Highest satisfaction rates (92-100% in patients

and 91-95% in partners). Complications: mechanical failure (>5% after

5yrs), infection (2-3%), diabetics have the same incidents.

3rd line treatment

ED evaluation is crucial in patients over 40. ED is treatable condition. Life style changes make some difference. Doctor-patient relationship and

communication is essential. Variety of ED treatments exists.

Take home message

Thank you