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Practical Diabetes Care, 3rd Ed., Excerpt #25: Diabetic Neuropathy Part 5 of 5

David Levy, MD, FRCP     

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Erectile dysfunction
This is the commonest neuropathic complication: 20% of men have erectile dysfunction (ED) at diagnosis, increasing to 34% at 12 years (UKPDS). The prevalence in a newly diagnosed Kuwaiti population was 30%, and nearly 50% in a large survey of Canadians attending their primary-care physicians [19]. The relationship between potency and peripheral neurological function is weak, but there is a large evidence base strongly relating ED to cardiovascular risk factors and the metabolic syndrome, the effects probably mediated through increasing impairment of endothelial function. This association is of less immediate interest to the patient than to his physician. However, diabetes carries an independent and disproportionate risk of ED (around threefold), and there is a very important link between ED and silent myocardial ischemia, and between ED and all-cause and cardiovascular death, the risk increasing with worsening degrees of ED [20]. Vigorous correction of cardiovascular risk factors is crucial, but apart from the 1-year data from the Look AHEAD study of intensive lifestyle intervention (see Chapter 5) there is little evidence that this translates into improved erectile function. In the ONTARGET/TRANSCEND studies, angiotensin blockade treatment over 5 years did not improve ED; nei- ther do statins. Fortunately, practice has been revolutionized by the PDE5 inhibitors, first introduced in 1998. Successful outcome of PDE5 inhibitor treatment improves compliance with other treatments, for example antihypertensive medication, resulting in better blood pressure control, and very importantly is independent of glycemic control [21].

History
Distinguish between ED and loss of libido; the latter may be psychogenic or, more rarely, endocrine in origin. Pain (e.g. Peyronie’s disease), significantly more common in diabetes, or balanitis, may be another factor. The duration of ED is not a reliable indicator of etiology.

Drug history
A detailed medication history is important:

  • antihypertensives (thiazides more likely to cause ED than beta-blockers);
  • psychotropics of all kinds (SSRIs are associated with ED, reduced libido and delayed ejaculation, and with reduced gonadotrophin and testosterone and elevated prolactin levels);
  • alcohol, tobacco, cannabis.

Examination

  • Peripheral pulses, abdominal aortic aneurysm, and arterial bruits.
  • Knee and ankle jerks, vibration sense at feet (though normal VPT does not exclude autonomic dysfunction).
  • Genitalia: testicular size, penile abnormalities.
  • Features of hypopituitarism.

Investigations
There is increasing interest in the hypogonadism associated with type 2 diabetes, and it is much more recognized than before, but the field is complicated by difficulties with definitions and continuing problems with the standardization of laboratory measurements of serum testosterone. However, there is reasonable agreement that total testosterone below 11 nmol/L (3.2 ng/mL) in the presence of sexual symptoms (absence of early morning erections, ED and lower frequency of sexual thoughts) identifies hypogonadism [22]. It is associated with increased visceral adiposity and the metabolic syndrome. Around one-quarter of type 2 males may be hypogonadal, about twice the rate in non-diabetic men [23]. However, the etiology is not clear, with no consistent patterns of gonadotrophins – various studies report low, normal or high val- ues. Perform a physical examination and check baseline endocrine tests (luteinizing hormone, testosterone, prolactin). Remember the association between genetic hemochromatosis, hypogonadism and type 2 diabetes. Diabetes does not confer protection against prolactinomas, other pituitary tumours or Kallmann’s syndrome, or other causes of primary hypogonadism (mumps orchitis, Klinefelter’s syndrome, itself associated with truncal obesity and insulin resistance, even when treated). A trial of testosterone replacement therapy is often warranted (British National Formulary, section 6.4.2), with appropriate monitoring, but is best done by an andrologist or a practitioner with experience of using the multiple products for testosterone replacement therapy now available.

PDE5 inhibitors (British National Formulary, section 7.4.5)
These drugs, of which three are currently available, increase the availability of vasodilatory nitric oxide by inhibiting cyclic AMP. The prototype drug, sildenafil, has been joined by vardenafil and the long-acting tadalafil. Sildenafil should be taken about an hour before intercourse; the others are effective within about 30 min. The only absolute contraindication is concomitant nitrate therapy (including nicorandil), which carries a risk of severe hypotension. They should not be taken at the same time as potent CYP3A4 inhibitors (erythromycin, ketoconazole, various antiretroviral agents, large quantities of grapefruit juice). There is some evidence that regular, as opposed to on-demand, use of these drugs is not only effective (especially with the long-acting tadalafil) but may improve outcomes through some form of ‘conditioning’. There is no clinically sig- nificant difference in the clinical outcomes with any agent; all are less effective in diabetes than in non-diabetic subjects (overall about 50% response rate, compared with 70–80%). Most patients will require the maximum recommended doses. If one agent is ineffective, it is worth trying another.

Adverse effects common to all three include headache, dyspepsia, nausea, visual disturbances, flushing, nasal congestion, back pain and myalgia. Non-arteritic ischemic optic neuropathy, usually unilateral, has been rarely reported with sildenafil and tadalafil (see Chapter 9). It presents with blurred vision or visual field loss within hours of taking the drug; recovery is variable. Vascular risk factors including diabetes and a history of myocardial infarction and hypertension are associated with this form of optic neuropathy, so the causal association is not clear.

Other approaches
Sublingual apomorphine is less effective than the PDE5 inhibitors, but can be used in patients taking nitrates. It is no longer available in the UK. Intracavernosal injections, intraurethral alprostadil, vacuum tumescence devices and surgical implants have a limited place, but all require specialist andrologist referral after documented failure of PDE5 inhibitors used properly at the maximum recommended (or tolerated) doses. Combination therapy may be helpful. There is a hint that successful treatment of OSA improves erectile function.

Gastrointestinal dysfunction
Gastroparesis is failure of stomach emptying, through a combination of vagal neuropathy, reduction in gastric pacemaker cells and neurohormonal changes. Acute elevations in blood glucose levels also delay gastric emptying. Early on there may be only slight fullness or early satiety after meals; more advanced symptoms are episodic nausea and vomiting, leading to ketoacidosis (sometimes recurrent and frequent), weight loss and malnutrition. Vomiting on an empty stomach first thing in the morning suggests a non-neuropathic cause [24]. In longstanding type 1 diabetes, consider gastroparesis if glycemic control worsens abruptly, especially if there is unexpected hypoglycemia (mismatch of food absorption and mealtime insulin) or recurrent ketoacidosis precipitated by vomiting. Bear in mind the association between significant eating disorders, advanced microvascular complications and gastroparesis. In type 2 diabetes, enquire carefully about symptoms of gastroparesis before starting GLP-1 analogues, which act in part through delaying gastric emptying, and use with caution in patients with advanced peripheral neuropathy – GLP-1 analogues may uncover advanced but asymptomatic autonomic dysfunction (see Chapter 6).

Management of gastroparesis
Upper gastrointestinal endoscopy may show concurrent pathologies, or retained food residue. Quantify the delayed gastric emptying with a nuclear medicine study (the percentage of a standard radiolabelled solid meal retained after 4 hours should be less than 10%). Drug treatment is often unsatisfactory, but try metoclopramide 5–10 mg t.d.s. (not in patients under 20 years old), or preferably domperidone 10–20 mg t.d.s. before meals. Erythromycin (a motilin agonist) increases gastric emptying but itself can cause nausea. Low-dose erythromycin suspension (e.g. 125 mg t.d.s.) before meals has been reported to be effective and well tolerated for several months. Inpatients can be given intravenous erythromycin (e.g. 3 mg/kg body weight 8-hourly).

Promptly admit patients with episodic vomiting for intravenous fluids and insulin. Detailed dietary advice is needed. Because liquid emptying is less affected than solid, suitable liquid enteral supplements may be helpful during exacerbations not requiring hospitalization. For intractable cases, an implantable gastric pacemaker is available. While it does not decrease overall symptoms, it reduces the frequency of vomiting.

Large bowel involvement
Constipation is common, as a result of large bowel atony. Diarrhoea is episodic, lasting a few days, then remitting. It characteristically occurs at night, when it may be associated with fecal incontinence. Weight loss and malabsorption do not occur. Episodic severe diarrhoea, like gastroparesis, is more common in middle-aged type 1 patients with very long duration of diabetes and other evidence of microvascular complications. Bacterial overgrowth is said to be common, and a 7–10 day course of oxytetracycline or erythromycin (each 250 mg q.d.s.) relieves symptoms in about 50%. Patients should keep a supply in reserve at home. Intractable diabetic diarrhoea may respond to treatment with somatostatin analogues.

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David Levy, MD, FRCP, Consultant Physician, Gillian Hanson Centre, Whipps Cross University Hospital; Honorary Senior Lecturer
Queen Mary University of London London, UK

This edition first published 2011, © 2011 by David Levy. 1st edition 1998 (Greenwich Medical Media/Cambridge University Press) 2nd edition 2006 (Altman Publications)