This module will discuss the pathogenesis, clinical presentation, and treatment of three complications of diabetes mellitus: diabetic retinopathy, diabetic nephropathy, and diabetic neuropathies.
This module will discuss the pathogenesis, clinical presentation, and treatment of three complications of diabetes mellitus: diabetic retinopathy, diabetic nephropathy, and diabetic neuropathies.
After completing this continuing education course, the participant will be able to meet the following objectives:
Diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy are common complications of type 1 and type 2 diabetes mellitus (DM). These pathologies are often referred to as microvascular complications because they are characterized by damage to the microvasculature of the eyes, kidneys, and nervous system. They are a significant cause of morbidity and mortality, and they are quite serious because:
There are many factors that contribute to the development of and risk for these complications, but chronic hyperglycemia - and the duration and level of hyperglycemia - is the primary cause of diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.3-5 However, although chronic hyperglycemia is the primary cause of diabetic neuropathy, nephropathy, and retinopathy, the damage to eyes, kidneys, and neurological system is from complex pathologic processes that apart from elevated blood glucose, play an important role in the pathogenesis and progression of diabetic neuropathy, nephropathy, and retinopathy.5 In addition, there is evidence that these pathologic processes:
These points are not encouraging, and good glycemic control is not a guarantee that diabetic retinopathy will not happen.8 However, it is important to remember that controlling blood glucose can considerably reduce the incidence and progression of diabetic retinopathy,9 but early detection, very rigorous and intensive glycemic control, are necessary to prevent diabetic retinopathy.
A 55-year-old male with a PMH of type 2 diabetes mellitus is admitted to a hospital for complaints of pain and decreased sensation in both feet and occasional episodes of blurred vision. His medications include metformin and glipizide. His blood pressure is 172/88 mm Hg; his fasting serum glucose is 256 mg/dL; his HbA1c is 9.5%, and his weight is 97 kg. An exam and nerve conduction studies of his lower extremities reveal decreased pain sensation and diminished nerve conduction. An ophthalmologic exam reveals decreased visual acuity and new and extensive retinal vascular growth. The physician increases the dose of metformin and prescribes insulin and a small dose of an ACE inhibitor. The patient is encouraged to exercise, and the dietary department provides him with a weight-reducing diet. At a follow-up nine months after discharge, the patient has lost 7 kg, his blood pressure is 144/76, and his fasting serum glucose is 118 mg/dL, and hid HbA1c is 7.0%. The retinal vascular growth has not diminished, but it has not extended, and the patient reports that he has increased sensation and decreased pain in both feet.
A 77-year-old female with a PMH of HTN and type 2 diabetes is admitted to a hospital for treatment of a non-healing ulcer of her foot. On admission it is noted that her fasting serum glucose is 221 mg/dL; her HbA1c is 10.1%; her blood pressure is 181/82, and; her serum BUN and creatinine are elevated, 52 mg/dL and 4.3 mg/dL, respectively. She is taking metformin, glipizide, enalapril, and HCTZ. Insulin and amlodipine are added to her medication regimen. Intensive therapy directed by the diabetic nurse specialist succeeds in healing the ulcer. But although the new medications succeed in decreasing her blood pressure and blood sugar, her renal function gets worse, and the patient must undergo twice-weekly hemodialysis.
Diabetic retinopathy is a very common complication of diabetes. Diabetic retinopathy is microangiopathy, a disease that weakens and damages the arterioles, capillaries, and venules in the retina.10 The pathogenesis of diabetic retinopathy is not completely understood. As with the other diabetic complications discussed in this module, chronic hyperglycemia is the primary cause of diabetic retinopathy,11 but there are many complex pathological processes that, apart from elevated blood glucose, play an important role in the pathogenesis and progression of diabetic retinopathy.4,11,12 Some of these biochemical, hemodynamic, hormonal, and metabolic processes are:
These pathologic processes cause fibrosis, hemorrhages, ischemia, macular edema, microaneurysms, the growth of new blood vessels (neovascularization), and occlusions to the retinal vasculature,1 and eventually, the signs and symptoms of diabetic retinopathy. Whitehead et al. state the “. . .biology of DR is hugely complex”,4 and an in-depth discussion would be quite lengthy; a brief description of the accumulation of advanced glycation end products is provided as an example.
Advanced Glycation End Products
When blood glucose is chronically elevated, proteins and lipids can be modified by the addition of a sugar molecule. This process is called glycosylation, and the compounds that are formed by glycosylation are called advanced glycation end products, or AGEs. Advanced glycation end products are naturally produced, but the level of AGEs in people who have diabetes and chronically elevated blood glucose is quite high,11,12 and this causes two primary effects. First, AGEs alter the structure and function of proteins, damaging retinal cell membranes and the retinal vasculature.4 Second, high levels of AGEs cause the production of reactive oxygen species, oxidative stress, and inflammation.4,12 The retinal vasculature is quite vulnerable to these harmful effects of AGEs6, and in addition, high levels of AGEs may also participate/sustain some of the other pathological processes that cause diabetic retinopathy.
Epidemiologic studies illustrate three key points about diabetic retinopathy:
In the United States, diabetic retinopathy is the leading cause of blindness and visual impairment in people ages 20-742,8 and for people who have diabetes, the incidence of blindness is 25 times that of the general population.11 Within 20 years of the diagnosis, almost every patient who has type 1 diabetes and between 50%-80% of those who have type 2 diabetes will have some degree of diabetic retinopathy8, and there is evidence suggesting that for some patients, diabetic retinopathy had begun four to seven years before they were diagnosed with diabetes.1 Factors that increase the risk of diabetic retinopathy are listed in Table 1.3-16 Note: The issue of intensive control of hyperglycemia and diabetic retinopathy will be discussed later.
Diabetic retinopathy is usually categorized as non-proliferative or proliferative (the proliferative form, PDR, is characterized by the growth of new blood vessels), and it is classified as mild, moderate, severe, or very severe.1 A patient’s clinical presentation may not fit neatly into a specific category or level of severity, but these distinctions help practitioners determine the risk for progression and choose follow-up and treatment strategies. Non-proliferative retinopathy can progress to proliferative form - more likely if the disease is severe or very severe - proliferative retinopathy can occur in the absence of non-proliferative diseases, and macular edema can occur in both.1 Patients who have the advanced stages of proliferative diabetic retinopathy have traditionally been the most at-risk for developing visual abnormalities, but it has become evident that patients with milder forms have visual dysfunction as well.17 Very few patients who have diabetic retinopathy have symptoms until the late stages of the disease;1 at that point patients can have blurred vision, floaters, partial loss of vision, and poor night vision.18 The diagnosis of diabetic retinopathy can be made by fundoscopic examination using a slit lamp or an ophthalmoscope. Diagnosis can also be made using fluorescein angiography, wide and ultra-widefield fundus fluorescein angiography, and optical coherence tomography.19,20
Diabetic retinopathy causes many pathological changes in the eye, and diabetic macular edema is one of the most common and most serious of these changes.17,21 The macula is an anatomically distinct region of the retina that provides the eye with high-acuity visual ability. Thickening and disruption of the retinal vasculature causes a breakdown of the blood-retinal-barrier and subsequently, edema that is localized to the macula.1,17,21 Diabetic macular edema is the leading cause of blindness in patients who have diabetic retinopathy,21 and it can be a complication of non-proliferative and proliferative retinopathy.1,22 The longer someone has diabetes the greater the risk of developing macular edema and after 25 years approximately 30% of people who have diabetes, type 1 or type 2, will have macular edema;21 other risk factors include a high A1C and the severity of DR.21 Unfortunately for many patients diabetic macular edema is chronic and progressive and improvement in the condition does not occur.22-24
Screening for a disease is recommended when certain conditions are present, including (but not limited to):
Diabetic retinopathy is a disease that meets these criteria, particularly in that the majority of patients who have diabetic retinopathy are asymptomatic until they develop macular edema or proliferative retinopathy,26 and screening for diabetic retinopathy has been proven to prevent vision loss.26 Although certain parameters should be used to guide screening for diabetic retinopathy, the optimal approach is to screen patients on a case by case basis. A single approach to screening for a patient population that differs significantly in factors like duration of diabetes and co-morbidities that affect the development and progression of the disease is not ideal,25 and diabetic retinopathy screening recommendations are most useful when they provide advice specific to each patient about when and how often to screen. The American Diabetes Association recommends26:
Treatment of diabetic retinopathy begins with therapies that prevent the disease from developing, and the two primary preventive approaches are glycemic control and blood pressure control.8,27 Good glycemic control and blood pressure control have been shown to reduce the incidence and progression of diabetic retinopathy in both type 1 and type 2 diabetes,8 and there is evidence that suggests that both treatments together are more effective than if either one is applied alone.8,27
Dyslipidemias are very common in patients who have diabetes, they are considered a risk factor for developing diabetic retinopathy, and lipid-lowering therapy is often prescribed to diabetic patients. Lipid-lowering therapy and treatment with fenofibrate to lower serum triglyceride level may slow the progression of diabetic retinopathy and prevent the need for treatment,28-30 but there is no conclusive evidence that either one prevents diabetic retinopathy.8
The four commonly used and effective therapies for the treatment of diabetic retinopathy and macular edema are intravitreal anti-vascular endothelial growth factor (VEGF) medications, focal photocoagulation therapy with laser, pan-retinal photocoagulation, and vitrectomy. These can be used alone or as adjuncts to each other, and the choice of treatment depends on the type of diabetic retinopathy, the severity of the disease, and whether there is macular damage.
VEGF inhibitors: Vascular endothelial growth factor is a protein that stimulates angiogenesis, the growth of new blood vessels. Production of VEGF is increased when the retinal tissues are hypoxic, and the new blood vessels can cause edema, increase capillary permeability, and they can rupture very easily. The VEGF inhibitors like bevacizumab and ranibizumab are monoclonal antibodies that bind to and inhibit VEGF, thus preventing angiogenesis. The VEGF inhibitors have been successfully used for patients who have non-proliferative and proliferative diabetic retinopathy (the evidence for their use in PDR is less robust), alone or as an adjunct to pan-retinal photocoagulation and/or vitrectomy and they can slow the rate of progression of the disease and may decrease its severity, as well.8,31 The VEGF inhibitors have been proven to be superior to focal laser photocoagulation for treating diabetic macular edema,32-34 at least as effective as pan-retinal photocoagulation at treating proliferative diabetic retinopathy without macular edema,35,36 and they are now considered first-line treatment.32-34
The VEGF inhibitor medications that are commonly used to treat diabetic retinopathy are aflibercept, bevacizumab, pegaptanib, and ranibizumab but only pegaptanib and ranibizumab are FDA-approved for the treatment of diabetic retinopathy, and macular edema,8 and VEGF inhibitors and focal laser photocoagulation are often used together.32 Using a VEGF is done by application of a topical anesthetic and a topical antibiotic, a local injection of an anesthetic is administered, and then the eye is injected with a VEGF. Multiple injections are often needed, and the common side effects include conjunctival hemorrhage, infection, and eye pain.
Focal laser photocoagulation therapy: For many years focal laser photocoagulation therapy has been a standard treatment for diabetic macular edema.8,32 This technique cauterizes retinal blood vessels, reducing areas of ischemia and thus decreasing VEGF production. It can reduce the risk of moderate vision loss and blindness, but it seldom will improve a patient’s vision32 and VEGF inhibitors are now the treatment of choice for diabetic macular edema.32-34 However, focal laser photocoagulation still has an important role as an adjunct to treatment with VEGF inhibitors; the combination provides a synergistic effect and can help reduce adverse effects of both therapies.33
Pan-retinal photocoagulation: Pan-retinal photocoagulation has long been the standard therapy for proliferative diabetic retinopathy without macular edema.8,35,36 Unlike focal photocoagulation, the pan-retinal technique is more extensive, less focused, and treats more areas of the retina and not just the maculae. This technique can be very effective at reducing vision loss.8
Vitrectomy: Surgery is an option for patients who have diabetic macular edema or proliferative retinopathy, and specific complications like retinal detachment and vitreous hemorrhage,8,37 and the pars plana vitrectomy is the most commonly performed procedure. Pars plana vitrectomy involves removal of vitreous gel through the pars plana, a structure which is part of the ciliary body; this is the basic procedure, and there are several ways it can be done. The pars plana vitrectomy can be used for patients who have not responded to laser photocoagulation, intravitreal steroids, or VEGF inhibitors,37,38 and for certain patients who have proliferative retinopathy, vitrectomy can improve vision.8 The effectiveness of vitrectomy for treating macular edema is less certain. Some researchers have found that the technique improves visual acuity while others have not; vitrectomy may be no more effective for treating macular edema than laser therapy or waiting,8,39,40 and the incidence and seriousness of some of the complications associated with the procedure like retinal detachment and recurrent vitreous hemorrhage are not insignificant.37 These reported differences in effectiveness can be explained in part by the patient selection and vitrectomy may benefit only a small number of patients who have macular edema.8
Intravitreal injections of glucocorticoids have been used to treat macular edema and proliferative retinopathy,8 but they are considered a second-line therapy that is used only if other treatments do not work.8,21,33 Intravitreal glucocorticoids are less effective than other therapies; improvements are relatively short-term. This therapy is associated with a high incidence of serious adverse effects like cataract formation and glaucoma,8,21,33 and a recent 2018 literature review concluded that combining intravitreal glucocorticoids with VEGF inhibitors was no more effective than VEGF inhibitors alone and was associated with a high risk of complications.41
Diabetic nephropathy is a common complication of both type 1 and type 2 diabetes.42,43 Approximately 40% of all diabetic patient develop nephropathy,44 in the United States diabetic nephropathy accounts for approximately 30%-40% of all cases of end-stage renal disease (ESRD),44 and it is the most common cause of chronic kidney disease.43 Diabetic nephropathy is an independent risk factor for the development of cardiovascular disease,45 and patients who have diabetic nephropathy almost always have other microvascular complications.42
Diabetic nephropathy is characterized by structural changes in the kidneys that cause glomerular hyperfiltration, increased proteinuria and albumin excretion, and reduced glomerular filtration rate (GFR).44 The primary causes of diabetic nephropathy are hyperglycemia and genetic susceptibility, 5,46 and these are the initiating forces of the hemodynamic, inflammatory, and metabolic processes that cause the pathologic changes to renal tissue and vasculature.5,42,44
Risk factors for the development of diabetic nephropathy include:42-44,46
Diabetic nephropathy is a progressive disease that is characterized by increased urinary albumin excretion, declining glomerular GFR, abnormal urinary protein excretion, and elevated blood pressure,42,47 and the clinical course of diabetic nephropathy is often described as having five stages5,47:
The American Diabetes Associations recommends that patients who have type 1 diabetes for ≥ five years should have a spot check of urinary albumin and GFR measurement.48 For patients who have type 2 diabetes, these tests should be done once a year and done once a year if the diabetic patient has hypertension.48
Treatment of diabetic nephropathy is intended to slow and hopefully stop the progression of renal damage, and this is done with glycemic control and treatment of hypertension; weight loss and controlling dyslipidemia are often used as well, but their benefits are uncertain.
Glycemic control: Intensive insulin therapy, aka strict glycemic control, is often used to treat diabetes and if it is applied in the early stages of diabetic nephropathy, intensive glycemic control can help prevent some of the pathologic changes of the disease, e.g., the development of microalbuminuria.49,50 However, the effectiveness of strict glycemic control for preventing the development of diabetic nephropathy and its progression is most strong for type 1 diabetes, and the benefits of this approach for patients who have type 2 diabetes has not been conclusively proved.47,49-51 In addition, there is no evidence that strict glycemic control helps preserve GFR or prevent the development of ESRD and if the patient has well established CKD, strict glycemic control is likely to be ineffective and may be harmful.50
Blood pressure control: Hypertension is a common co-morbidity in patients who have type 1 and type 2 diabetes, and it is a significant risk factor for the development and progression of diabetic nephropathy.48 In patients with type 1 or type 2 and moderate albuminuria, antihypertensive therapy with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) can provide significant protection against the development of progressive nephropathy.48,52-54 For patients who have type 1 or type 2 diabetes and definitive signs of diabetic kidney disease (eGFR <60 mL/min/1.73 m2 and UACR ≥300 mg/g Cr), treatment with an ACE inhibitor or an ARB therapy reduces the risk of progression to ESRD.48
The American Diabetes Association recommends ACE inhibitors or an ARB as first-line treatment for diabetic patients who have hypertension, an estimated GFR (eGFR) <60 mL/min/1.73 m2, and a UACR ≥300 mg/g Cr, and the ACE inhibitors and the ARBs seem to be equally safe and effective for this purpose.48,55 An ACE inhibitor and an ARB should not be used together to treat diabetic hypertension as this increases the risk for hyperkalemia and acute kidney injury 48,56 and neither should be used if the diabetic patient has normal blood pressure, normal UACR (<30 mg/g Cr) and normal eGFR.48
Non-dihydropyridine calcium channel blockers, diltiazem and verapamil, have been shown to have renal protective effects, and the combination of verapamil and an ACE inhibitor may have an additive effect, but at this time calcium channel blockers are considered second-line treatment for diabetic patients who have hypertension.49,57,58 Mineralocorticoid antagonists like spironolactone used in combination with other renin-angiotensin blockers can reduce albuminuria, but using both together increases the risk of hyperkalemia.59
Diabetic medications: The American Diabetes Association recommends considering the use of a sodium-glucose cotransporter 2 inhibitor or a glucagon-like peptide 1 receptor agonist, or both, for patients who have type 2 diabetes and chronic kidney disease.60
Sodium-glucose co-transporter 2 inhibitors have been shown to reduce the progression of kidney disease, reduce serious end-points of kidney disease like the need for dialysis, and improve markers of diabetic kidney disease like serum creatinine level and urinary albumin excretion.49,61
Recommendations for the use of glucagon-like peptide 1 receptor agonists are less enthusiastic. A 2019 systematic review and metaanalysis of the research concluded that the effect of these drugs on microvascular complications of diabetes is controversial, they appear to be safe for treating diabetic patients who have CKD, and that studies have shown only minimal improvement in urinary albumin excretion and no clinically important effect on GFR. And it is important to note that the American Diabetes Association only recommended considering the use of a sodium-glucose cotransporter 2 inhibitor or a glucagon-like peptide 1 receptor agonist and that the Association noted that “. . . additional clinical trials are needed to more rigorously assess the benefits and risks of these classes of drugs among people with CKD.”60
Treating dyslipidemia and weight loss: Treating dyslipidemias is a primary part of diabetes care, but there is limited information about the protective effect of lipid-lowering therapy against the development and/or progression of diabetic nephropathy. Several clinical trials that used fenofibrate and post-hoc analysis of the data from this research found that fenofibrate reduced the progression of GFR decline and reduced urinary albumin excretion, but it did not prevent the development of CKD or ESRD.63
Weight loss has many benefits for diabetic patients, but there is very little information on weight loss and diabetic nephropathy and no conclusive evidence that it can preserve renal function in these patients.
Diabetic neuropathies are the most common complications of type 1 and type 2 diabetes.64 In developed countries, they are the most common cause of neuropathies,65,66 and they are a common cause of serious morbidities like chronic pain and amputation. Approximately 6%-29% of diabetic patients have some form of neuropathy when they are first diagnosed as having diabetes,67,68 and approximately 50% of all diabetic patients will eventually develop a neuropathy.69,70
The diabetic neuropathies can affect autonomic, motor, or sensory nerves. They are quite complex, and there are many sub-types. There are several classification schemes used to categorize diabetic neuropathies: by way of their anatomical distribution (e.g., proximal versus distal); by the pattern of symptoms (e.g., acute, versus chronic), or; by the nature of the symptoms (e.g., painful versus non-painful, focal versus non-focal, and autonomic or peripheral, motor, or sensory).65,66
A discussion of all the sub-types of diabetic neuropathy would be quite lengthy, and it is most practical to divide the diabetic neuropathies into peripheral and autonomic forms. This module will provide information about the most common forms of diabetic neuropathy, chronic distal, symmetric polyneuropathy and autonomic neuropathies.
Chronic, distal symmetric polyneuropathy is the most common type of diabetic neuropathy,64,65 and it accounts for approximately 75% of all diabetic neuropathies.68
This form of diabetic neuropathy is caused by an imbalance between nerve damage and repair,71 and as with the other diabetic microvascular complications, hyperglycemia is the primary cause,72 initiating and sustaining pathologic processes like oxidative stress, inflammation, and accumulation of AGEs that damage nerve cells.72
Factors that increase the risk of developing chronic distal symmetric polyneuropathy include:67,72
The onset of chronic, distal symmetric polyneuropathy is slow and insidious,73 and as many as 50% of patients who have the disease are asymptomatic, but a physical examination will reveal signs of mild to moderately severe sensory loss.60,73 Signs and symptoms begin in the toes and feet, move up into the legs, fingers, and hands and occasionally chest and abdomen, and patients who have this neuropathy are more likely to experience the following signs and symptoms:60,65,67,73 these are sometimes categorized as negative or positive, i.e., numbness and tingling or pain.
Chronic, distal symmetric polyneuropathy alone is a painful and potentially disabling condition, but it can cause several serious complications, as well: diabetic foot ulcer and falls and fractures.
Diabetic foot ulcer occurs at least once in approximately 15%-25% of all patients who have diabetes,74,75 and it is the most common cause of non-traumatic amputation.76 A recent (2018) study by Kim et al. found that in patients who had a diabetic foot wound and specific risk factors, the incidence of a major amputation was 38.2%.74
The presence of diabetic neuropathy increases the risk of amputation 10-15-fold compared to non-diabetics,74 diabetic foot wounds account for approximately 25% of all hospital admission in diabetic patients,77 and the presence of a diabetic ulcer has been associated with a two-fold increase in mortality, regardless of the presence of other risk factors.75 Factors that increase the risk for developing a diabetic foot ulcer and/or amputation include, but are not limited to CHF, foot deformity, high A1C, infections, male gender, peripheral arterial disease (PAD), prior ulcer or amputations, trauma, and smoking.74,76-78
Diabetic neuropathy is an independent risk factor for falls,79 and compared to people who do not have diabetes, patients who have diabetic neuropathy are estimated to be five to 15 times more likely to fall.80,81 Factors that contribute to falls/increased risk for falling include loss of pain, sensation and temperature discrimination; balance and posture problems; gait changes; the presence of diabetic retinopathy; and (possibly) vestibular damage.74,79-81
The American Diabetes Association defines chronic, distal symmetric polyneuropathy as “. . . the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes.”82 The signs and symptoms are considered chronic when they have been present for greater than three to six months.67
Chronic, distal symmetric polyneuropathy is a diagnosis of exclusion that is based on clinical findings.82 A patient history is obtained, a physical examination is performed, and then tests for touch perception, pain perception, reflexes, and temperature discernment tests are done.67
Recommendations for screening are listed below.73,82 There are also screening tests available like the Michigan Neuropathy Screening Instrument and the Utah Early Neuropathy Screening Instrument; these can be quite helpful for clinicians as they include detailed instructions for the physical examination, pertinent questions for the patient history, and a list of the tests that should be done and how to evaluate the results.72
Treatment of chronic, distal, symmetrical polyneuropathy begins with glycemic control. Several large studies and reviews have shown that for patients who have type 1 diabetes, early and strict control of blood glucose can prevent distal symmetric neuropathy, delay its onset and slow its progression.60 For patients who have type 2 diabetes, glycemic control may slow the progression of distal symmetric neuropathy, but the preventive effect of glycemic control is not especially strong in type 2 diabetes and for type 1 and type 2 diabetics, glycemic control cannot reverse pre-existing nerve damage.60
Approximately 25%-30% of patients who have diabetes have painful diabetic neuropathy. For many patients, the pain is self-limiting and will resolve,84 but patients who do have painful diabetic neuropathy can benefit from pain control. Drugs and therapies that are used alone or in combination to treat painful diabetic neuropathy include (but are not limited to):84
Monotherapy with any drug will provide at best 50% effectiveness for 50% of patients,85 and as there is very little head-to-head research comparing the effectiveness of one medication to another, so the best approach is to be aware of the limitations of drug therapy, to monitor the patient for improvement or failure closely, and be willing to use a different approach/different drug if necessary. Combination therapy may be more effective than monotherapy, but the evidence supporting this is sparse.84
There are three medications that have an FDA labeled use for treating painful diabetic neuropathy, duloxetine, pregabalin, and tapentadol.60,84 All three have been shown to provide an acceptable level of pain relief (e.g., pregabalin provides a 30%-50% decrease in pain intensity), they are more effective than placebo, and they are effective for a significant number of patients.86-89 Clinicians should remember that tapentadol is an opioid analgesic and can cause gastrointestinal distress, respiratory depression, and tolerance. Pregabalin has abuse potential and because of its adverse effect profile of dizziness and somnolence, many patients cannot and will not tolerate the drug.88
The tricyclic antidepressants (TCAs) like amitriptyline and desipramine have been used for many years to treat painful diabetic neuropathy and with good effect.84 Common adverse effects of the TCAs include dry mouth, dizziness, and somnolence.83,84 Patients may find these adverse effects difficult to tolerate, and the drop-out rate of patients taking TCAs can be as high as >38%.90 In addition, there are many precautions and warnings associated with the TCAs that limit their use, like the presence of glaucoma, heart failure, and unstable angina.83
Periodic assessment and preventive care of a diabetic patient’s feet and patient education about self-care should be considered mandatory for diabetic patients. The American Diabetes Association’s recommendations for assessment and referral are:60
Self-care is an important part of preventing diabetic foot ulcer.60,78The patient should be made aware that because of poor circulation, diminished sense of temperature discrimination, and loss of sensory and pain receptors he/she may not know when the feet have been injured, so preventive care and daily foot inspections are critically important. A patient education program should include the following points:60,78
In diabetic patients, an imbalance between the sympathetic and parasympathetic branches of the autonomic nervous can have significant adverse effects on homeostasis, and diabetic autonomic neuropathies can affect any organ that has autonomic innervation. These diabetic complications are most often present when the patient has a peripheral neuropathy, and they rarely occur alone.91 Diabetic autonomic neuropathy can be sub-clinical or clinical92, and the initial signs and symptoms of a diabetic autonomic neuropathy are usually mild and may be overlooked, but the disease is progressive and eventually, serious effects can occur. Subclinical evidence of these neuropathy sub-types has been seen within one year of the diagnosis of type 2 diabetes and within 2 years of the diagnosis of type 1 diabetes.93
As with all diabetic microvascular complications, hyperglycemia is a primary cause of autonomic diabetic neuropathies, and chronically elevated serum glucose initiates and sustains the (previously discussed) pathologic processes that are the basis of the signs and symptoms of the disease.93 Vascular risk factors, high body mass, high triglyceride levels, hypertension, and smoking may also increase the risk of developing diabetic autonomic neuropathy.92
The incidence of diabetic autonomic neuropathies varies considerably depending on the organ system affected and the diagnostic criteria used, but the autonomic neuropathies are not uncommon; cardiovascular autonomic neuropathy has been noted in 7% of all diabetic patients at the time of diagnosis of diabetes, and a 16%- 20% prevalence of this sub-type has been confirmed in several studies.93
The sub-categories of diabetic autonomic neuropathy are:92
Cardiovascular autonomic neuropathy: Cardiovascular autonomic neuropathy (CAN) is caused by impaired autonomic control of the cardiovascular system, and it is the most common of the diabetic autonomic neuropathies;93 in older patients who have a long duration of diabetes, the prevalence has been reported to be as high as 65%.93
Signs and symptoms of CAN include exercise intolerance, orthostatic hypotension, postural tachycardia, resting QT prolongation, and tachycardia.92-94 This is a very serious complication of diabetes, and patients who have CAN have a five-fold increase in mortality risk, succumbing to arrhythmias, myocardial ischemia, and sudden death.93,94
Gastrointestinal autonomic neuropathy: Diabetic neuropathy of the gastrointestinal (GI) tract affects motor and sensory function of the gut.95 Gastroesophageal reflux (GERD), gastroparesis, and chronic diarrhea are the primary manifestations of diabetic GI neuropathy, and signs and symptoms may be very mild, the patient may be asymptomatic, or she/he may have severe and debilitating GI distress.92,95 Patients may have abdominal pain, anorexia, decreased bowel motility, decreased esophageal transit time, diarrhea, constipation, and pre-mature satiety.93,95
Genitourinary autonomic neuropathy: Diabetic autonomic neuropathy has been associated with an increased incidence of genitourinary disorders like bladder dysfunction, dyspareunia, erectile dysfunction, sexual dysfunction, and urinary incontinence.92 These disorders have complex etiologies, and the contribution of diabetic autonomic neuropathy to genitourinary complications of diabetes has not been clearly outlined and is not completely understood.96,97
Metabolic: Patients who have diabetes and diabetic autonomic neuropathy may develop an abnormal response to hypoglycemia that is characterized by decreased glucagon and epinephrine excretion, a phenomenon that is called hypoglycemia-associated autonomic failure.92,98 This change in the normal compensatory response to hypoglycemia both causes hypoglycemia and decreases the patient’s awareness that he/she is hypoglycemic. It may be caused, in part, by diabetic autonomic neuropathy but the mechanism of action is unknown.98
Pupillary: Diabetic autonomic neuropathy may cause changes in pupillary adaptation that make activities like night driving more difficult.92,99
Sudomotor and vasomotor: Loss of sudomotor function caused by diabetic autonomic neuropathy may decrease the ability to sweat and the body’s ability to regulate temperature.
Diabetic autonomic neuropathy can cause abnormal vasomotor function and reflexes, particularly in the peripheral capillaries and arterioles.100
Diagnosis of diabetic autonomic neuropathies relies on a clinical examination and testing.92 Commonly used tests include:
Treatment of diabetic autonomic neuropathies is primarily preventive and symptomatic.92,93,101,102 Behavioral interventions such as dietary changes, maintaining a strict urination schedule, and close attention to postural shifts can be used for patients who have gastrointestinal, bladder, or cardiovascular autonomic neuropathy, respectively, and drug therapy can be used for specific signs and symptoms. Reducing hyperlipidemia, blood pressure control and smoking cessation may help prevent the progression of some forms of the disease.92 Glucose control can help prevent the progression of diabetic autonomic neuropathy, and it is the foundation of diabetes treatment, but the aggressive lowering of the A1C is associated with a specific risk connected to diabetic neuropathies. Studies and clinical experience have shown that when A1C is rapidly reduced some patients may develop autonomic and/or peripheral neuropathy,92,103 a phenomenon called treatment-induced diabetic neuropathy (TIND).92,103 Gibbons (2017) writes“. . . a decrease in the glycosylated hemoglobin A1C of more than 3 points in 3 months in individuals with chronic hyperglycemia increases the risk of developing TIND.”103
Diabetic complications of nephropathy, neuropathy, and retinopathy cause significant morbidity and as the incidence of diabetes - particularly type 2 diabetes - is steadily increasing, these complications will likely become increasingly common, and nursing knowledge of diabetes - which evidence suggests is not always at an optimal level104,105 – is a crucial for identifying and treating these complications.
The available treatments can delay the onset and slow the progression of diabetic complications, but the most important mode of treatment and prevention is tight glycemic control. There is clear evidence that strict control of serum glucose (along with blood pressure control, weight loss, and diet) can prevent the development of these complications and can decrease their progression if they are present. Because these diabetic complications have an insidious onset and often do not respond to therapy, it is vital that at-risk patients: