Microvascular Disease

Introduction

Microvascular complications may co-exist with or develop in patients with type 2 diabetes (T2D) include:

• Diabetic retinopathy
• Diabetic nephropathy
• Diabetic neuropathy:
  • Diabetic peripheral neuropathy
  • Mononeuropathy
  • Diabetic amyotrophy
  • Gastroparesis
  • Neurogenic bladder
  • CV autonomic neuropathy
  • Erectile dysfunction
  • Diabetic foot disorders.

Retinopathy, nephropathy and neuropathy are the major microvascular complications of T2D. While each microvascular diabetic complication has its own characteristic pathophysiological aspects, they ultimately share a common hyperglycemic etiology. However, other factors also have some influence over the onset and clinical course. Systemic hyperglycemia leads to increased intracellular glucose metabolism, disrupting physiological cell signaling, generating toxic metabolites and altering the cellular redox potential. These changes cause oxidative and ER stress and induce production of inflammatory cytokines, which in turn results in dysfunction both in the vascular endothelium and in specialized cells in the affected organs. The common etiology is reflected in the high degree of correlation among the diabetic microvascular complications; one systematic review and meta-analysis found that that the odds ratio (OR) for diabetic kidney disease is increased in patients with diabetic retinopathy (OR 4.64; P <0.01) and vice versa (OR 2.37; P <0.01). Furthermore, diabetic retinopathy is associated with diabetic neuropathy (OR 2.22; P <0.01) and vice versa (OR 1.73; P <0.01). The specific pathogenic outcomes are determined by the specific metabolic needs and protective responses of each organ.

Prevention, early detection, and aggressive treatment are essential to reduce associated morbidity and mortality. Good metabolic control has been clearly shown to prevent the development and delay the progression of these complications in both types of diabetes. Patients with a history of microvascular disease should undergo regular screening for other microvascular complications, given the shared etiology and known correlations.

Diabetic Retinopathy

The development and progression of retinopathy depend on the duration of diabetes and the duration and severity of hyperglycemia; nephropathy and hypertension are other important risk factors. Because diabetic retinopathy does not cause symptoms until it has reached an advanced stage, early and frequent evaluations for vision problems are critical. The following findings also support the importance of early detection:

• Diabetes is the leading cause (13%) of all new cases of blindness among adults aged 20 to 74
• Loss of vision associated with diabetic retinopathy and macular edema can be reduced by at least 50% with laser photocoagulation if identified in a timely manner.

Patients must be completely informed about the possible relationship between hyperglycemia and retinopathy, stressing the importance of promptly reporting any visual symptoms. Clinical trials have demonstrated that good glycemic control and lowering of blood pressure (BP) can delay the progression of diabetic retinopathy, with proper glycemic management having the added benefit of delaying or preventing its onset. Patients should therefore be encouraged to take any antihypertensive medications that have been prescribed and have access to a blood pressure cuff. Most importantly, patients should understand the potential visual complications associated with diabetic retinopathy and how to prevent or reduce the severity of these problems.

The three categories of diabetic retinopathy that are part of a continuum are:

• Nonproliferative or background
• Preproliferative
• Proliferative.

Nonproliferative

Background changes are the earliest stage of retinopathy and are characterized by microaneurysms and intraretinal “dot and blot” hemorrhages (Figure 24-1). If serous fluid leaks into the area of the maculae (where central vision originates), macular edema can occur and cause disruption in light transmission and visual acuity. Macular edema cannot be observed directly but is suggested by the presence of hard exudates close to the maculae. Any of these findings should prompt immediate referral to an ophthalmologist.

Preproliferative

Advanced background retinopathy with certain lesions is considered the preproliferative stage and indicates an increased risk of progression to proliferative retinopathy. This stage is characterized by “beading” of the retinal veins; soft exudates (also called “cotton-wool” spots that are ischemic infarcts of the inner retinal layers) (Figure 24-2); and irregular, dilated and tortuous retinal capillaries or occasionally newly formed intraretinal vessels. Any one of these signs suggests the need for further evaluation by an ophthalmologist.

Proliferative

Proliferative retinopathy is the final stage of this degenerative condition and imparts the most serious threat to vision. Neovascularization typically covers more than one third of the optic disk and may extend into the posterior vitreous. These fragile new vessels, which are prone to bleeding, probably develop in response to ischemia. Bleeding that occurs in the vitreous or preretinal space can cause visual symptoms such as “floaters” or “cobwebs” or retinal detachment that results from contraction of fibrous tissue. Sudden and painless vision loss usually is related to a major retinal hemorrhage.

Evaluation and Referral

Because visual acuity frequently changes in response to fluctuations in glycemic control (particularly extreme variations, e.g., low-to-high and high-to-low), the reason for any vision changes should be thoroughly investigated. All patients with diabetes should have annual eye examinations with complete visual history, visual acuity examinations and careful ophthalmoscopic examinations with dilated pupils. High-quality fundus photographs can detect most clinically significant diabetic retinopathy. Indications for referral to an ophthalmologist are shown in Table 24-1. Patients with type 1 diabetes should begin having annual eye examinations after 5 years of diabetes. Patients with T2D should have annual eye examinations starting at the time of diagnosis because of the probability that glucose intolerance was present for up to 4 to 7 years before the diagnosis of diabetes.

Treatment

An important reason for the early identification of diabetic retinopathy is that effective therapy exists for preventing vision loss, but not for reversing already established damage. Two large trials established the efficacy of laser photocoagulation surgery. The Diabetic Retinopathy Study (DRS) enrolled patients with proliferative diabetic retinopathy, and demonstrated that panretinal photocoagulation surgery reduced the risk of severe vision loss from 15.9% in untreated patients to 6.4% in treated patients. The Early Treatment Diabetic Retinopathy Study (ETDRS) enrolled patients with macular edema, and established that focal laser photocoagulation surgery reduced doubling of the visual angle (e.g., 20/50 to 20/100) from 20% in untreated patients to 8% in treated patients. The ETDRS trial also demonstrated a benefit of panretinal photocoagulation surgery in patients with high-risk proliferative diabetic retinopathy and for older-onset patients with severe nonproliferative diabetic retinopathy or less severe proliferative diabetic retinopathy.

Although panretinal and focal laser photocoagulation were the only standard treatment options for proliferative diabetic retinopathy and diabetic macular edema, laser therapy can be associated with significant adverse events and sometimes patients are unresponsive to treatment. For these reasons, several pharmacologic options are being investigated or developed for diabetic retinopathy. These options are primarily aimed at blocking intracellular signaling pathways or disrupting the inflammatory cascade.

Elevated retinal endothelial growth factor (VEGF) and neovascularization are associated with the pathogenesis of diabetic retinopathy. Several VEGF inhibitors have been developed and approved by the Food and Drug Administration (FDA) for diabetic retinopathy, including ranibizumab and aflibercept. Other anti-VEGF therapies are being developed, such as KH902, which acts as a VEGF receptor decoy by binding to VEGF. Data from multiple trials show that anti-VEGF agents have similar or superior visual acuity outcomes to panretinal laser over at least 2 years of follow-up. Furthermore, unlike laser-based interventions, anti-VEGF therapies do not reduce night and peripheral vision; therefore, they have largely replaced panretinal laser therapy as the current standard of care. Intraocular inflammation is another mechanism by which diabetic retinopathy develops. For this reason, corticosteroids (e.g., the FDA-approved dexamethasone and fluocinolone acetonide) and nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat diabetic macular edema. Several other therapeutic agents are being develop that block components of signaling pathways involved in the pathogenesis of diabetic retinopathy, but many are in early stages of development.

The effects of pharmacologic agents are transient, often making laser photocoagulation therapy necessary for more permanent regression of blood vessels. The RESTORE study demonstrated that combination therapy with laser photocoagulation and intravitreal ranibizumab provided greater improvements in best-corrected visual acuity (BCVA) than monotherapy alone. Another study, READ-2, found no difference in visual outcomes between combination and monotherapy groups, although combination therapy did improve BCVA and result in a greater decrease in macular edema. Further studies are required to clarify possible benefits of combination therapy.

Diabetic Nephropathy

Between 20% and 40% of patients with diabetes have diabetic kidney disease, the leading cause of end-stage renal disease. Nephropathy is progressive, takes years to develop and requires laboratory evaluation for early detection because it is generally asymptomatic in the early stages.

Structural and functional changes in the kidneys occur early in the course of poorly controlled diabetes but do not produce clinical symptoms. The first sign of nephropathy is persistent increased albuminuria (urine albumin-to-creatinine ratio [UACR] 30–299 mg/g), which is a marker for the development of diabetic kidney disease. Albuminuria is very strongly associated with coronary artery disease in patients with T2D. Hyperfiltration, indicated by an elevated CrCl, is also observed in early diabetic nephropathy. The important clinical point is that in this early stage of nephropathy, aggressive management may reverse or completely stabilize any abnormalities.

Microalbuminuria and macroalbuminuria are terms that were previously used to describe elevated albumin excretion rates of 30–299 mg/24 h and >300 mg/24 h, respectively. However, albuminuria occurs on a spectrum so these terms are no longer used. Instead, the term albuminuria is used and defined as UACR ≥30 mg/g.

The following conditions play a role in the development and acceleration of renal insufficiency:

• Chronic uncontrolled hyperglycemia
• Hypertension (virtually all patients who develop nephropathy also have hypertension [SBP >140 mm Hg, DBP >90 mm Hg])
• Neurogenic bladder leading to hydronephrosis and infections
• UTI and obstruction
• Nephrotoxic drugs (nonsteroidal anti-inflammatory drugs, chronic analgesic abuse, radiocontrast dyes [should be performed only when adequate hydration and diuresis can be assured and if no other diagnostic alternatives are available]).

Patients with diabetes often develop uremia at lower creatinine levels than patients with renal insufficiency resulting from other causes. Even with dialysis, the prognosis for patients with diabetes is worse than that for nondiabetic patients. Also, patients with diabetes tend to start dialysis earlier because they develop symptoms sooner than other patients with renal disease. Therefore, a renal transplant is the preferred method of treatment, if possible, at this stage.

Evaluation

All patients with T2D should be screened for evidence of nephropathy at least once a year. Screening should quantitatively assess both the UACR and estimated glomerular filtration rate (eGFR), since screening using albumin excretion rate alone has been shown to miss >20% of patients with progressive disease. For UACR, testing for both albumin and urine creatinine is recommended, since measuring urine albumin alone is susceptible to false-positive and false-negative results due to a variety of factors, including the concentration of urine. Random spot urine collection is the preferred method to access UACR. Two to three samples should be collected within a 3- to 6-month period before considering the development of albuminuria in patients, given that certain factors can interfere transiently with this evaluation (eg, exercise, infections, fever, uncontrolled diabetes, hypertension). The mean albumin excretion of three timed urine collections can be used to establish a diagnosis of albuminuria if the values are equivocal.

eGFR can be calculated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Complications associated with kidney disease correlates with kidney function, so screening for complications of CKD is indicated if eGFR is <60 mL/min/1.73 m² (Table 24-2). Patients with any abnormal kidney function tests should be referred early to a nephrologist.

It is important for physicians to inform patients with diabetes about the relationship between high BP and renal disease, and the benefits of maintaining glycemic control. Patients should be encouraged to have their BP checked regularly (in addition to obtaining their own BP cuff to measure BP at home), take antihypertensive medications that have been prescribed, monitor glucose levels frequently with self-monitoring of blood glucose (SMBG) or continuous glucose monitoring (CGM) and take any other measures to improve glycemia. The importance of reporting symptoms of urinary tract infection (UTI) should be emphasized, along with following proper treatment for this infection and avoiding nephrotoxic drugs.

Treatment

Treatment is aimed at early detection, prevention and aggressive management, focusing specifically on improving glycemic control, treating hypertension (e.g., with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB)) and evaluation for treatment with an sodium glucose cotransporter type 2 (SGLT2) inhibitor and/or finerenone. Consultation with a nephrologist and referral to a physician with experience in the management of kidney disease should be considered when advanced kidney disease develops. Also consider referral to an experienced physician when the etiology of the kidney disease is uncertain or if there are management issues (i.e., anemia, electrolyte disturbance).

Several glucose-lowering medications also have direct effects on the kidneys that can improve renal outcomes, including SGLT2 inhibitors and glucogonlike peptide 1 (GLP-1) receptor agonists. In EMPA-REG OUTCOME, empagliflozin reduced the risk of incident or worsening nephropathy by 39% compared to placebo. It also reduced the risk of doubling of serum creatinine accompanied by eGFR ≤45 mL/min/1.73 m² by 44%. In CANVAS, canagliflozin reduced the risk of progression of albuminuria by 27% and the risk of reduction in eGFR, ESRD, or death from ESRD by 40%.

In LEADER, liraglutide reduced the risk of new or worsening nephropathy by 22%. In SUSTAIN-6, semaglutide reduced the risk of new or worsening nephropathy by 36%. Several of these and other agents have also demonstrated protection against cardiovascular disease (CVD). In CREDENCE, canagliflozin was shown to be effective in reducing the composite of End-stage kidney disease (ESKD), a doubling of serum creatinine level, or death from renal or cardiovascular (CV) causes and the relative risk of ESKD. In the DAPA-CKD trial, dapagliflozin was shown to reduce the risk of a composite outcome of sustained decline in the eGFR of at least 50%, ESKD, or death from renal or CV causes. Finally, empagliflozin was shown to be efficacious in CKD in the EMPA-KIDNEY trial, which was stopped early because of positive results, although the results have not yet been published. Patient risk factors for both renal and CV disease should be taken into consideration when individualizing patient treatment plans.

Improving Glycemic Control

Considerable evidence supports the importance of optimizing glycemic control in delaying the development and slowing the progression of diabetic nephropathy. In the ACCORD, ADVANCE and UKPDS trials, intensive metabolic control was associated with a delay in the onset and progression of albuminuria and an improvement in eGFR in patients with T1D and T2D.

The benefits of improved glycemia appear to be greatest before the onset of albuminuria, since once overt diabetic nephropathy has developed, improved glycemia has modest benefits on the progression of renal disease. Research has revealed that the risk of developing albuminuria is substantially reduced at A1C <7%, so glycemic goals are aimed to meet this target (normal A1C is 4% to 6%).

Treating Hypertension

Controlling hypertension through aggressive therapeutic intervention can reduce proteinuria and considerably delay the progression of renal insufficiency. ACE inhibitors and ARBs offer effective antihypertensive effects in addition to significant delaying of the progression of diabetic nephropathy to end stage renal disease. ACE inhibitors and ARBs decrease proteinuria by minimizing efferent glomerular vasoconstriction and reducing glomerular hyperfiltration. In addition, ACE inhibitors can reduce CVD outcomes, including MI, stroke and death in patients with diabetes. ACE inhibitors and ARBs should be considered as first-line therapy in all nonpregnant, hypertensive patients with diabetes and urinary albumin excretion >300 mg/day. ACE inhibitors and ARBs are not recommended for the prevention of diabetic kidney disease in patients with diabetes and normal BP and normal urine albumin-creatinine ratio (UACR) (<30 mg/g).

When BP cannot be adequately controlled with the maximum dose of an ACE inhibitor or ARB, additional antihypertensive medications may be needed, such as calcium channel blocker (CCBs), or α-blockers (indapamide). Patients with renal insufficiency and hypertension may be given a diuretic as part of the antihypertensive regimen because of related sodium and fluid retention; a loop diuretic usually is necessary if the creatinine level exceeds 2 mg/dL. The combined use of different inhibitors of the renin-angiotensin system should be avoided (eg, an ACE inhibitor plus an ARB, a mineralocorticoid antagonist, or a direct renin inhibitor), since combination therapy provides no additional improvements compared with monotherapy and is associated with greater rates of adverse reactions.

Limiting Protein Intake

Some initial clinical trials demonstrated that limiting dietary protein intake could slow the progression of albuminuria, glomerular filtration rate (GFR) decline and the occurrence of end-stage renal disease. However, more recent trials have provided conflicting results. Currently, the American Diabetes Association (ADA)-recommended daily allowance of protein is approximately 0.8 g/kg body weight per day, for people with non-dialysis-dependent diabetic kidney disease. This level has shown to slow GFR decline compared with higher levels of protein intake. The ADA does not recommend reducing the amount of dietary protein any lower, since it does not improve glycemic measures, CV risk, or GFR decline.

Diabetic Neuropathy

The various diabetic neuropathies are one of the more common yet distressing long-term complications of diabetes. The prevalence varies with the severity and duration of hyperglycemia, and affects >50% of patients with longstanding T1D and T2D. Diabetic neuropathies can be focal or diffuse and are categorized into different syndromes according to neurologic distribution, each with symptoms corresponding to the affected region. Examples of diabetic neuropathies are shown in Table 24-3.

Glycemic control is capable of modestly slowing the development of diabetic peripheral neuropathy and CV autonomic neuropathy in patients with T2D, but cannot reverse the loss of neurons. Other than glycemic control, there are no specific treatments available for underlying nerve damage. However, pharmacologic and nonpharmacologic strategies do exist and are recommended for the relief of symptoms related to painful neuropathy, since these can improve the quality of life patients. Management approaches to select types of diabetic neuropathies are discussed below.

Diabetic Peripheral Neuropathy (DPN)

Symptoms will vary according to the type of sensory fibers affected. Common symptoms involving small fibers include pain, dysesthesias and numbness. Sensory loss initially affects the distal lower extremities, and ascends with disease progression, affecting the hands once reaching mid-calf. Patients should be screened once a year for symptoms of DPN using simple clinical tests, such as assessment of pinprick sensation, light touch perception using a 10-g monofilament, ankle reflexes and vibration threshold using a 128-Hz tuning fork. Distal regions should be assessed first, followed by more proximal assessment to gauge the progression of DPN.

Causes of neuropathy other than diabetes should always be considered (e.g., heavy metal poisoning, alcohol abuse, B12 deficient, neurotoxic medications). The three components of treatment include glycemic control, foot care and treatment of pain. As previously discussed, enhanced glucose control has been demonstrated to significantly improve measures of neuropathy. Foot care is important because sensory loss predisposes patients to ulcer formation. Patients should inspect their feet daily for injuries, cracked skin, or early signs of infections.

Neuropathic pain can be sudden and severe in patients with DPN, and is associated with a lower quality of life, social dysfunction, depression and limited mobility. Several drugs have been approved specifically for relief of pain associated with DPN (e.g., tapentadol, pregabalin, duloxetine), but none are effective at completely relieving pain. Other treatment options include other antidepressants (eg, amitriptyline, venlafaxine), other anticonvulsants (e.g., sodium valproate) and capsaicin cream. Opioids can also be considered, but their use is more controversial.

The ADA recommends that treatment decisions should be individualized to the patient, considering there is no best option for pain relief. A stepwise pharmacologic strategy should be used, with close monitoring of relative symptom improvement, side effects and adherence. If neuropathic pain persists despite the outlined treatments, referral to a specialist, addition of a transcutaneous nerve stimulation (TENS) unit, acupuncture, or a series of local nerve blocks may be helpful, although the prognosis for pain relief in these patients is poor.

Mononeuropathy

These neuropathies can occur in virtually any cranial or peripheral nerve, are asymmetric and have an abrupt onset. Cranial mononeurop­athies are the most common, particularly those involving the third and sixth cranial nerves, causing extraocular muscle motor paralysis and peripheral palsies. Patients can develop palsies involving the peroneal (foot drop), median and ulnar nerves. Spontaneous recovery over 3 to 6 months is typical. Patients with diabetes are more prone to developing compression neuropathies such as carpal tunnel syndrome.

Diabetic Amyotrophy

This neuropathy is often asymmetric, is more common in men and is often characterized by severe pain, muscle wasting in the pelvic girdle and quadricep muscles and mild sensory involvement. This condition usually is self-limiting, with complete recovery typically occurring in 6 to 12 months. Treatment is focused on maintaining glycemic control and symptomatic relief using physical therapy and analgesics.

Gastroparesis

This neuropathy should be suspected in patients with nausea, vomiting, early satiety, abdominal distention and bloating following a meal and is secondary to delayed emptying and retention of gastric contents. The delay in gastric emptying usually is asymptomatic, although glycemic control can be affected. Postprandial hypoglycemia and delayed hyperglycemia develop when the balance between exogenous insulin administration and nutrient absorption is disrupted because of gastric stasis. Therefore, gastroparesis should be considered even in the absence of GI symptoms in a patient who suddenly develops unexplainable poor glycemic control after having had satisfactory control.

Primary treatment is focused on optimizing glucose control with insulin; secondary treatment involves dietary modifications. Patients are encouraged to have multiple, small, low-fat, low-residue meals (6 to 8/day). When patients remain symptomatic despite these measures, treatment with the following prokinetic agents is recommended:

• Erythromycin is a motilin receptor agonist that improves gastric emptying. Both oral and IV regimens are effective, but long-term effectiveness of oral therapy is limited by tachyphylaxis. Common side effects are nausea and vomiting.
• Oral metoclopramide HCl is generally used with caution because of adverse reactions (nervousness, anxiety, dystonic effects and the potential for irreversible tardive dyskinesia). In 2009, the FDA required a boxed warning on metoclopramide-containing drugs due to their long-term and high-dose risks.
• Domperidone is not approved for sale in the US, and distribution of domperidone-containing drugs is illegal. However, the FDA recognizes that patients 12 years of age or older with certain GI conditions, including patients with gastroparesis, may benefit from treatment with domperidone. These patients may gain access to domperidone through an expanded access investigational new drug application.

Neurogenic Bladder

Bladder dysfunction is estimated to affect approximately 25% of patients with T2D. It usually first manifests as diminished bladder sensation, which delays micturition reflexes. This leads to overstretched bladder and reduced contractility leading to increased urinary retention. Common symptoms of bladder dysfunction include a weak stream, straining and hesitation.

Confirmation of this diagnosis requires demonstration of cystometric abnormalities and large residual urine volume. Most medical treatment is inadequate, although scheduling frequent voidings every 3 to 4 hours combined with bethanechol 10 to 50 mg 3 to 4 times daily supplemented by small doses of phenoxybenzamine may be helpful. Intermittent catheterization may be necessary if patients do not respond to pharmacologic therapy because chronic urinary retention can lead to UTI, lower urinary tract lithiasis and epidermoid bladder carcinoma.

Cardiovascular Autonomic Neuropathy (CAN)

CAN is a clinically important diabetic autonomic neuropathy associated with mortality. Early stages may be asymptomatic, and later stages are characterized by disturbing and disabling autonomic symptoms, orthostatic hypotension and resting tachycardia (>100 bpm). Multifactorial CV risk intervention has been shown to impede the progression and development of CAN in patients with T2D, and consists of targeting glucose, lipids, BP and lifestyle factors (e.g., smoking).

Typical treatment of orthostatic hypotension includes elevating the head of the bed, compression stockings for lower limbs and torso, supplementary salt intake and the use of fludrocortisone (0.05 mg initially with gradual increases of 0.1 mg up to 0.5 to 1 mg). This pharmacologic therapy should be used cautiously in patients with cardiac disease because it causes sodium and water retention and may precipitate congestive heart failure (CHF).

Erectile Dysfunction (ED)

Erectile dysfunction, or impotence, is defined as the consistent inability of a man to attain or keep an erection for satisfactory sexual intercourse. It is a couples’ disorder, as both patient and partner suffer. Diabetic impotence is usually caused by circulatory and nervous system abnormalities and is a very common complaint in the male diabetic population. The prevalence of ED increases with age, reaching 52% in men with diabetes aged 55 to 59 years. Other factors associated with ED in diabetic patients include longstanding diabetes, poor glycemic control and retinopathy. There is no indication that intensive glycemic control can improve or reverse ED once it develops.

The classic clinical picture includes a patient with normal sexual desire but the inability to physically act on that desire. If a patient says that he has morning erections, he can masturbate without problems, or his libido is abnormally low, look for other causes of impotence such as psychological problems or a low androgen state. Orgasm and ejaculation are usually normal. Even if the patient does not have any psychological problems that could cause the impotence, he may develop a secondary psychological fear of failure that could complicate the clinical picture.

The diagnosis can be made in most cases by a good sexual, psychosocial and medical history, a physical examination and laboratory tests. Despite the prevalence of this disorder, nearly all patients can be successfully treated with either nonsurgical or surgical means, none of which are specific for patients with diabetes.

Hyperprolactinemia is also an uncommon cause of impotence. Hemochromatosis is a condition that is underdiagnosed and is associated with impotence and glucose intolerance. Serum iron stores, including ferritin levels, are abnormally high in this disorder. If the patient has femoral bruits and/or peripheral occlusive disease, a vascular workup may help identify the cause of impotence.

It is important to be sure the patient is not taking any medications that can cause impotence such as β-blockers, thiazide diuretics, or SSRIs. ACE inhibitors, ARBs, CCBs and α-blockers do not generally cause impotence.

Testosterone is an important regulator of sexual function in men, and low testosterone often coexists with ED in middle-aged and older men. Testosterone level should be measured for some men to rule out a low androgen state, which is rarely a cause for impotence. If testosterone levels are low on several occasions, testosterone replacement by injection or via a scrotal or skin patch, is suggested. Combination therapy using testosterone plus a PDE-5 inhibitor is becoming more common, although conflicting data exist about its efficacy.

Until the late 1990s, there were no truly effective oral medications for erectile dysfunction (ED). Since then, the convenience and outcomes of the treatment of ED have improved considerably as a result of the availability of the class of drugs called phosphodiesterase-type 5 (PDE-5) inhibitors, which include sildenafil (Viagra), vardenafil (Levitra), tadalafil (Cialis) and avanafil (Stendra). All improve erectile function in the same basic way, by inactivating cyclic GMP thereby resulting in an increase in nitric oxide levels leading to relaxation of the vessels that supply blood to the erectile tissue in the penis. The PDE-5 inhibitors may not automatically trigger erections; sexual stimulation is also usually needed to start the process.

Many clinical trials have shown PDE-5 inhibitors improve erectile function regardless of the underlying cause or causes, including diabetes. Although all of these PDE-5 inhibitors increase the number and quality of erections and sexual experiences in men with diabetes, they have slightly different chemical structures that affect how quickly they work and how quickly they wear off (Table 24-4). Which drug may be best for an individual patient is not known since there have been no studies that compared these medications.

The side effects of the PDE-5 inhibitors relate to their vasodilatory effects and include headaches, lightheadedness, dizziness, flushing, distorted vision and in some instances syncope. Men at highest risk for syncope are those taking nitrates, so men are cautioned against combined use of a PDE-5 inhibitors and a nitrate. Although it previously appeared as though PDE-5 inhibitors could have adverse effects in individuals with coronary disease, the consensus position of the ADA and the American College of Cardiology is that they are safe in individuals with stable coronary artery disease who are not taking nitrates.

Intracavernosal injection of vasoactive agents such as papaverine or prostaglandins can be self-administered and work by relaxing corporal smooth muscle. Intracavernosal injections will work best in patients with diabetic impotence whose arterial inflow and corporal veno-occlusion mechanism are normal. Side effects include the formation of painless fibrotic nodules within the corpora cavernosa and priapism. Titration guidelines should be followed when initiating therapy. Despite the route of administration, patient acceptance is also good. The Medical Urethral System for Erection (MUSE) is also available.

Other therapies exist but are rarely used. These include penile prostheses, penile revascularization, and the placement of a constricting band at the base of the penis to maintain an erection, with or without a vacuum device to apply negative pressure. Because of their ease of use and safety, PDE-5 inhibitors are considered first-line therapy.

Diabetic Foot Disorders

More than half of all nontraumatic amputations in the United States occur in individuals with diabetes, and the majority of these could have been prevented with proper foot care. Efforts aimed at prevention, early detection and treatment of diabetic foot disorders can have a significant impact on the incidence of these problems.

Detection and Treatment

The physician and patient must diligently examine the patient’s feet on a regular basis for signs of redness or trauma, especially if neuropathy is present. Autonomic neuropathy causes decreased sweating and dry skin that can result in cracked, thickened skin that is susceptible to infection and ulceration. History of foot ulcers, previous amputation, foot deformities, peripheral vascular disease, visual impairment, diabetic nephropathy, poor glycemic control and cigarette smoking are also factors that contribute to the risk of ulcers or amputation. Foot pressure that is abnormally distributed predisposes a neuropathic patient to pressure ischemia and skin breakdown.

Loss of protective sensation can be assessed using one or more of five clinical tests: use of a 10-g monofilament, vibration testing using a 128-Hz tuning fork, tests of pinprick sensation, ankle reflex assessment and testing vibration perception threshold with a biothesiometer. Ideally, two or more of these tests are performed, with one using Semmes Weinstein (SW) monofilaments, which are available in three thicknesses: 1-g fiber (SW 4.17 rating), 10-g fiber (SW 5.07 rating) and 75-g fiber (SW 6.10 rating). The following evaluation procedure has been recommended: place the monofilament against the skin and apply pressure to different areas of the bottom of the foot until the filament buckles. The patient should be able to feel the monofilament when it buckles and identify the location being tested. The 5.07-thickness monofilament, which is equivalent to 10-g of linear pressure, detects the presence or absence of protective sensation and is useful for identifying a foot at risk for ulceration and in need of special care.

The prevalence of peripheral arterial disease is high in patients with diabetes, but many remain asymptomatic. For this reason, all adults with diabetes should undergo annual comprehensive foot evaluations, or more frequently in patients with histories of ulcers, amputations, foot deformities, insensate feet, or peripheral arterial disease (PAD). Foot inspections should occur at every visit. ankle-brachial index (ABI) testing should be performed in patients with symptoms or signs of PAD. Patients with significant symptoms or a positive ABI should be referred for further vascular assessment and consider exercise, medications and surgical options

Daily inspection of feet, especially if the patient is insensate, can help detect early skin lesions and proper footwear can minimize the development of foot problems. Patients should be taught to cut toenails straight across, not trim calluses themselves, regularly wash their feet with warm water and mild soap and avoid going barefoot or wearing constricting shoes. Minor wounds that are not infected can be treated with mild antiseptic solution, daily dressing changes and foot rest. Patient guidelines for care of the diabetic foot are shown in Table 24-5.

Podiatrists should be consulted for assistance with more serious foot problems and for regular nail and callus care in high-risk individuals. If an ulcer develops, the skin must be debrided and the pressure alleviated; infections should be treated promptly with medications appropriate for the offending organism. Antibiotic therapy is not required for wounds without evidence of soft-tissue or bone infection. Healing is facilitated by bed rest with foot elevation and the use of an orthopedic walking cast to relieve pressure but allow mobility. IV antibiotics, surgical debridement, distal arterial revascularization and local foot-sparing surgery may help prevent amputation in cases of seriously infected foot ulcers.