Diabetes Microvascular Complications

EXECUTIVE SUMMARY

The total estimated cost for diabetes is $245 billion, with 43% of the cost coming from inpatient hospital care and 18% from prescriptions.

• Most complications can be prevented or delayed with targeted glucose control; every percentage point drop in HbA1c results in a 35% risk reduction of microvascular complications.
• Diabetic retinopathy is the most frequent cause of new-onset blindness in adults between 20-74 years of age. Screening should be done at diagnosis and annually if minimal or no disease is found.
• Diabetes kidney disease is the leading cause of chronic kidney disease in the United States, with African Americans three to five times more likely to develop diabetes kidney disease than Caucasians.
• Consultation with nephrologist when Stage 4 chronic kidney disease develops is associated with decreased morbidity, decreased healthcare costs, and delayed dialysis.
• Diabetes accounts for one-third of the cases of gastroparesis.
• Diabetic cheiropathy is a less-known complication characterized by the “prayer sign.”

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Diabetes mellitus is expensive, but most of the costs are attributed to complications and hospital care.¹ According to the American Diabetes Association (ADA), in 2012 the total estimated cost for diabetes was $245 billion.¹ An estimated 43% was from inpatient hospital costs and another 18% for prescriptions to manage the complications of diabetes.¹

Most of these complications can be prevented with targeted glucose control. Epidemiologic data demonstrate that for every percentage point decrease in hemoglobin A1c (HbA1c), a 35% risk reduction of microvascular complications occurs.² The good news is the complication rates in diabetes have been reduced,³ but this has been overtaken by the sheer increase in the number of people with diabetes who progress with complications.

Many people with type 2 diabetes may have a diabetes-related complication at the time of diagnosis. In both type 1 and type 2 diabetes, some of the complications, such as retinopathy and nephropathy, are silent. This requires an aggressive targeted approach because waiting for symptoms will be too late. Even diabetic neuropathy will be asymptomatic in up to 50% of people with measurable abnormalities.⁴

This article will review the recommendations from the ADA 2017 Standards of Care for microvascular complications and relevant position statements, and will highlight preventive screening and clinical pearls for the primary care physician treating patients with diabetes.

Diabetic Retinopathy

Diabetic retinopathy is a common microvascular complication of type 1 and type 2 diabetes. An estimated 3.7 million people globally are moderately to severely visually impaired because of diabetic retinopathy, and more than 800,000 people worldwide are blind because of diabetic retinopathy.⁵ It is the most frequent cause of new-onset blindness in adults between 20-74 years of age.⁶ Strong correlations have been made to glycemic control, blood pressure control, and duration of disease. Through early, regular screening and controlling of these risk factors, diabetic retinopathy may be detected and treated to prevent visual impairment.

Duration of diabetes is the greatest risk factor for diabetic retinopathy progression. In type 1 diabetes, retinopathy is rare in the first 3-5 years or before puberty.⁷ In the following 20 years, nearly all patients with type 1 diabetes will develop diabetic retinopathy.⁷ In patients with type 2 diabetes, as many as 21% will have some degree of retinopathy at the time of diagnosis.⁷ Chronic hyperglycemia, nephropathy, hypertension, and dyslipidemia are other factors that increase the risk of or are associated with diabetic retinopathy.⁸ Up to 50% of patients with albuminuria (regardless of estimated glomerular filtration rate [eGFR] level) will have retinopathy.⁹ Table 1 describes the different stages of retinopathy.

Pathophysiology. Mild, non-proliferative abnormalities characterized by increased vascular permeability can progress to moderate to severe nonproliferative diabetic retinopathy (NPDR).⁷ Proliferative diabetic retinopathy is characterized by the proliferation of new retinal blood vessels.⁷ Macular edema, which is central retinal thickening with exudation and edema, can present at any stage of retinopathy.⁷ Diabetic retinopathy can be accelerated by pregnancy, puberty, lack of glycemic control, hypertension, and cataract surgery.⁷

Preventing Diabetic Retinopathy. Glycemic control is key to the prevention of diabetic retinopathy. In the Diabetes Control and Complications Trial (DCCT), researchers evaluated the effect of tight glycemic control and progression from no or minimal retinopathy at baseline to moderate NPDR.¹⁰ For patients in the intensive therapy group with no retinopathy at baseline, the mean risk of retinopathy was reduced by 76% over 36 months.¹⁰ Among patients in the intensive therapy group who already presented with minimal-to-moderate NPDR, the risk of progression was reduced by 54% over those using conventional treatment.¹⁰ In the original Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, participants with type 2 diabetes for 10 years and known cardiovascular disease were randomized to intensive or standard therapy for glycemia, systolic blood pressure, and dyslipidemia. Four years later, retinopathy progression was reduced in those with prior intensive glycemic control, regardless of similar current HbA1c levels.¹¹ Similar legacy effects were not seen in those groups with intensive blood pressure control or on fenofibrate for dyslipidemia.¹¹

Screening. Since macular edema and proliferative diabetic retinopathy may be asymptomatic, screening is vital for early detection and treatment. For patients with type 1 diabetes, screening should be initiated five years after diagnosis.⁸ For those with type 2 diabetes, screening should be initiated at diagnosis.⁸ Screening should be completed by an ophthalmologist or optometrist who is experienced in diabetic retinopathy. The screening should be completed with the eyes dilated. If retinopathy is already present, referral to an ophthalmologist is recommended.⁸ Repeat evaluation should be done yearly if minimal or no disease is found.⁸

Pregnancy is a high-risk time for proliferative retinopathy. In pregnant women with preexisting type 1 or type 2 diabetes, eye examinations should be performed before conception or in the first trimester. The exams should be repeated each trimester and for one year postpartum.⁸ For those with gestational diabetes, no additional eye examinations are necessary after delivery.

Pregnancy in patients with preexisting type 1 or type 2 diabetes can result in rapid progression of diabetic retinopathy. This is especially true if there is poor glycemic control at the time of conception.¹⁴ Women with diabetes who are pregnant or planning to become pregnant should be advised about the risk of development or progression of diabetic retinopathy and the need for glycemic control prior to conception.⁸ However, an early worsening of retinopathy may occur with rapid implementation of intensive glycemic management if retinopathy already is present.⁸ Gestational diabetes does not appear to confer the same risk of developing diabetic retinopathy during pregnancy.⁸

Treatment. In addition to glycemic control, blood pressure control (< 140 mmHg systolic) also has been shown to decrease diabetic retinopathy progression, but there is no additional benefit of tight control of systolic blood pressure < 120 mmHg.¹² Fenofibrate also can slow diabetic retinopathy progression, especially with very mild NPDR, in patients with dyslipidemia.¹³ Aspirin was shown to have no effect on progression of retinopathy, development of vitreous hemorrhage, or duration of vitreous hemorrhage, and it may be used safely for other medical indications without ocular compromise.⁷

Treatment of patients with diabetes should include recommendations for exercise. Those with mild nonproliferative retinopathy can begin physical activity safely. However, patients with moderate nonproliferative retinopathy should avoid activities that greatly increase blood pressure, such as powerlifting.¹⁵ Patients with severe nonproliferative or unstable retinopathy should avoid any physical activity that is vigorous (jumping, jarring), any head-down activities, and breath holding.¹⁵ In the case of vitreous hemorrhage, no exercise should be done.¹⁵

Early detection of diabetic retinopathy is important because treatment can prevent or reverse vision loss. In the Diabetic Retinopathy Study (DRS), researchers found that photocoagulation surgery was an effective treatment for diabetic retinopathy. The Early Treatment Diabetic Retinopathy study and DRS showed photocoagulation decreased risk of vision loss, with the most benefit in patients who had more advanced baseline disease.^16,17 Current data provide evidence that intravitreal antivascular endothelial growth factor (anti-VEGF) agents are more effective in treating macular edema than monotherapy or combination therapy with laser coagulation.⁸ In addition, anti-VEGF can improve vision, whereas photocoagulation only prevents further vision loss.^18,19 One drawback to anti-VEGF is that it requires monthly intravitreal therapy during the first 12 months.

Clinical Pearls

• There are no specific signs or symptoms of early diabetic retinopathy.
• Screening for diabetic retinopathy should occur in patients:

- with type 1 diabetes five years after diagnosis.
- in patients with type 2 diabetes at diagnosis.

• Counseling and increased exams should be provided to diabetic women who plan to become or become pregnant, because diabetic retinopathy can accelerate rapidly during pregnancy.
• Tight glycemic control and blood pressure control (< 140 mmHg systolic) can prevent the development of diabetic retinopathy.
• Up to 50% of patients with albuminuria (regardless of eGFR level) will have retinopathy.⁹
• Treatment with photocoagulation can prevent progression of disease and anti-VEGF treatment can reverse vision loss from macular edema.

Diabetes Kidney Disease

Diabetes kidney disease (DKD), the preferred terminology by the ADA, is the leading cause of chronic kidney disease (CKD) in the United States.^20,21 DKD has significant long-term effects on the quality of life of patients with diabetes and is responsible for up to 40% of end-stage renal disease (ESRD).²⁰ Based on the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) and the ADA 2017 Standards of Care, this section will provide guidance on target HbA1c levels, medication management, and therapeutic treatment for patients with DKD.

The KDOQI stratifies target HbA1c level by the patient’s risk of hypoglycemia and comorbidities. This initiative is based on three publications demonstrating that glycemic control with HbA1c below 7% will prevent or decrease progression of kidney disease in patients with type 2 diabetes.^22,23,24 These studies are summarized in Table 2. The ADA recommends in patients at higher risk for hypoglycemia, the goal HbA1c should be raised above 7%.⁸ The KDOQI recommends patients with CKD Stage 4 and 5 who have limited life expectancy maintain an HbA1c greater than 7%.²⁵

Epidemiology. Males and females are equally affected by DKD.²⁰ The peak incidence for developing DKD is 15 years after diagnosis.²¹ African Americans are three to five times more likely to develop diabetic nephropathy than Caucasians.²⁰ Mexican Americans and Pima Indians also have a higher risk for developing DKD.²⁰

Proteinuria is a predictor of cardiovascular morbidity and all-cause mortality in diabetes.²¹ Presence of DKD is a factor for increased cardiovascular disease risk. Patients with DKD consistently face higher cardiovascular disease mortality rates.²⁶ Additionally, all-cause mortality is higher in patients with DKD.²¹

In type 1 diabetes, microvascular complications such as DKD begin to develop approximately 10-20 years after diagnosis; in type 2 diabetes, the exact onset often is unknown and thus warrants earlier screening.²⁷

Pathophysiology and Pathogenesis. Hyperglycemia is thought to induce three major histologic changes at the glomeruli leading to DKD: 1) mesangial expansion, 2) thickening of glomerular basement membrane, and 3) glomerular sclerosis.²⁸ Although the exact pathogenesis of why DKD occurs is unknown, it is thought that hyperglycemia initially causes hyperfiltration and renal injury as a result of histologic changes and activation of cytokines.²⁰ Typically, albuminuria may be the first sign of DKD.²⁹

This is further exacerbated as a result of comorbid conditions of hyperlipidemia, arteriosclerosis, hypertension, and obesity, which all contribute to renal injury and subsequent function decline. Central obesity leads to hypertension through hyperactivation of the renin-angiotensin-aldosterone system and the sympathetic nervous system.²⁰ Further, as the renal vasculature becomes arteriosclerotic, an increased progression of diabetic nephropathy occurs. An important distinguishing feature of diabetic nephropathy compared to other forms of CKD is that the glomeruli and kidneys usually are normal or increased in size initially.²⁰

Classification. Both eGFR and presence of albuminuria are used to stage CKD.^30,31 The eGFR is based on race, age, sex, weight, and serum creatinine levels. (See Table 3.) Historically, the term microalbuminuria was used to define moderately increased albumin levels. The National Kidney Foundation now recommends using the terms “mild,” “moderate,” or “severely increased” to describe albuminuria levels based on the levels depicted in Table 4.³¹ The albumin-to-creatinine ratio is the initial test used to detect albuminuria.

The two classification schemas represent the dual pathway to develop CKD. One is through elevation of creatinine and worsening of GFR. The other is through development of albuminuria. Increasing albuminuria often is followed by a decline in eGFR;³² however, this can be averted through the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) and glycemic control. (See Figure 1.)

Common Symptoms. Most people have no symptoms from diabetic nephropathy. Often, patients may have evidence or diagnosis of other microvascular complications.²⁰ Early DKD typically is asymptomatic. A late finding of DKD is foamy urine. Furthermore, if a patient is severely hypoalbuminemic, he or she may present with pedal edema and fatigue.²⁰ Patients with DKD typically have systemic hypertension. Patients with diabetic nephropathy typically also will present with retinopathy and neuropathy.⁸

Diagnostic Options. Since there are no symptoms, routine screening is critical. The ADA recommends yearly screening of a urinary albumin-to-creatinine ratio.⁸ In addition, at least yearly, the eGFR should be tested in patients with type 1 diabetes with duration of five years and among all patients with type 2 diabetes or patients with comorbid hypertension and diabetes.⁸ There is no clear recommendation for obtaining imaging, such as an ultrasound, for the diagnosis of DKD.

Differential Diagnosis. Some red flags may suggest that diabetes is not the only cause of CKD. If a person has advanced CKD without evidence of other microvascular complications, this is a warning. Overt proteinuria with sudden onset (less than five years after the onset of diabetes) of urine sediment with dysmorphic red cells and casts, or an abrupt decline in GFR, suggests a kidney disease of nondiabetic etiology.²⁰ Serum or urinary electrophoresis may be done if there is a concern for multiple myeloma. The absence of albuminuria with a reduced eGFR and diabetes needs investigation for other causes of CKD than DKD.²¹ Table 5 lists red flags that suggest a nondiabetic glomerular disease.

Treatment. A hallmark of diabetes nephropathy is management of glucose, salt reduction, blood pressure, and dyslipidemia. Furthermore, patients should avoid nephrotoxic medications and supplements such as aminoglycosides and nonsteroidal anti-inflammatories. Patients should be referred to a nephrologist at stage IV kidney disease or if rapidly declining kidney function occurs. Other indications for referral depend on the complexity of the case. Newer oral medications for diabetes may help prevent the progression of renal failure.

Glycemic Control. Drug selection, monitoring, and pharmacology all are affected in patients with diabetic nephropathy. As a patient’s eGFR declines, some oral agents will require dose adjustment. Insulin remains the central therapy for glucose control in patients with diabetes and advanced CKD.³¹ Table 6 shows the recommended dose adjustments for antiglycemic medications in patients with renal disease. In 2016, both empagliflozin and canagliflozin were shown to reduce progression of CKD and microalbuminuria.^33,34 Empagliflozin lowered rates of nephropathy progression and reduced risk of major adverse cardiovascular events compared to placebo when added to standard type 2 diabetes care in the landmark Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG) outcome study.³³

Blood Pressure. Treatment for blood pressure should begin at 140/90 mmHg for patients with diabetes and diabetic kidney disease.³⁷ The United Kingdom Prospective Diabetes Study (UKPDS) found a 12% reduction of risk of diabetic complications with each 10 mmHg drop in systolic pressure until pressure was 120 mmHg.³⁸ The medications of choice remain ACE inhibitors or ARBs for individuals with hypertension and diabetes, DKD, and CKD. ACE inhibition has been shown to delay the development of DKD when initiated in patients with mildly elevated albuminuria. Creatinine may climb by up to 30% at initiation of an ACE inhibitor or ARB.³⁹ Consider evaluating for other underlying renal diseases if the creatinine elevates more than this.

The KDOQI recommends against giving ACE/ARBs to type 2 diabetes patients who are normotensive and normoalbuminuric patients.^40,41,42 ACE inhibitors or ARBs are suggested for diabetes patients who are normotensive with microalbuminuria.^31,37 There is no specific dose or titration for these individuals. Dual blockade of the renin-angiotensin system by both ACE and ARBs is not recommended because of the increased risk for hyperkalemia, impaired renal function, and hypotension.⁴³

Salt Reduction. The 2012 Reduction of Endpoints in Non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) Trial and Irbesartan Diabetic Nephropathy Trial (IDNT) demonstrated that low-sodium diets increased ARB nephroprotective and cardioprotective effects in patients with type 2 diabetes and diabetic nephropathy.^44,45

Renal Dialysis and Renal Transplant. Patients with ESRD should be referred to nephrology. Options for treatment include peritoneal dialysis or hemodialysis, renal transport, or the option to stop treatment and begin palliative or hospice care. One observational study found that patients who started dialysis at a younger age (< 60 years of age) had poorer survival.⁴⁶

Referral. Figure 1 includes indications for referral based on GFR and albuminuria classification. Consider other causes of kidney disease unrelated to diabetes, especially in patients with type 1 diabetes where the onset of retinopathy does not precede development of nephropathy.²¹ Nephrologists can help clarify diagnosis, control resistant hypertension and hyperkalemia, and prepare patients for dialysis.⁸

One also must consider that the development of nephropathy may not be related to the diabetes itself. In patients with type 1 diabetes, the onset of retinopathy usually precedes the development of nephropathy.⁴⁷ An individual who presents with nephropathy but no retinopathy should have an evaluation for other causes. Referral to a nephrologist should be made to establish the cause of nephropathy when it is uncertain or when there are difficult-to-manage, DKD-related issues, including anemia, hyperparathyroidism, and advancing kidney disease with an eGFR < 30 mL/min/1.73 m².⁸ Having a consulting nephrologist when Stage 4 CKD develops (eGFR < 30 mL/min/1.73 m²) is associated with decreased morbidity, decreased healthcare costs, and delayed dialysis.⁴⁸ Consider a referral at Stage 3B to prepare patients earlier and for nephrology to maximally medically treat.

Clinical Pearls

• Yearly DKD screening for DKD should occur through urinary albumin testing and a measurement of eGFR.
• Blood pressure and glucose control can provide prevention of nephropathy progression. Maintain blood pressure < 140/90 mmHg in patients with diabetes and CKD. ACE inhibitors or ARBs should be the treatment of choice.
• ACE inhibitors and ARBs should not be used to prevent nephropathy if blood pressure and protein excretion are normal. ACE inhibitors and ARBs should not be used in combination.
• Patients with CKD stages 3-5 have an increased risk of hypoglycemia. Caution should be used with oral agents such as sulfonylureas.
• In some patients with CKD, it is appropriate to set the target HbA1c > 7%, especially when the risk of hypoglycemia is great.

Diabetic Peripheral Neuropathy

A widely accepted definition of diabetic peripheral neuropathy (DPN) in clinical practice is “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes.”⁴⁹ The ADA classification of distal symmetric polyneuropathy is: 1) primarily small-fiber neuropathy, 2) primarily large-fiber neuropathy, and 3) mixed small- and large-fiber neuropathy (most common).

Pathophysiology and Pathogenesis. The development and progression of DPN arise from the complex relationships between the nerves and their surrounding cells.⁵⁰ Both vascular factors and metabolic interactions contribute to all stages of DPN.⁵¹ The generally accepted understanding in human diabetes leading to the development of DPN is the complex interaction among hyperglycemia, duration of diabetes, age-related neuronal damages, the degrees of blood pressure and blood lipid control, and weight.^52,53,54,55 Hyperglycemia activates numerous biochemical pathways that determine the metabolic state of a nerve cell and combines with impaired nerve perfusion, contributing to the progression of neuropathies. A landmark trial, the DCCT, supports the significance of hyperglycemia in the pathogenesis of neuropathy.^10,56,57 Another hyperglycemia-related mechanism leading to DPN is hyperglycemia-induced oxidative and nitrosative stress with an increase in free radical production.^58,59

In addition to hyperglycemia, low-grade inflammation recently has been suggested to possibly play an important role in the pathogenesis of diabetic neuropathies, leading to deficits in peripheral and autonomic nerve fibers.^51,60 The complex array of metabolic and vascular factors triggers the imbalance between damages and repairs in nerve fibers, specifically affecting distal sensory fibers and contributing to the gradual loss of sensation that manifests the clinical symptoms of diabetic polyneuropathy.^58,61

Common Symptoms. When inquiring about symptoms of DPN experienced, make note of the location (most likely felt in hands and feet), precipitating factors, characteristics of the discomforts, as well as the onset and frequency of nocturnal exacerbation since symptoms are patient-specific.⁴ Both small and large fibers are affected by elevated blood glucose, and the symptoms experienced vary depending on the class of sensory fibers affected. When the affected nerve fibers are predominantly small, the symptoms triggered are usually pain (sticking, lancinating, prickling, burning, aching, boring, and excessively sensitive), dysesthesias (unpleasant sensations of burning, tingling, prickling, and stabbing), and numbness.⁴

The intensity of the discomfort can range from feeling minor abnormal sensations to being disabled by the pain that can be exacerbated at night and disturbing sleep, which has been shown to be associated with depression due to a perception of lowered quality of life.⁴

On the other hand, when large fibers predominantly are affected, patients might feel numbness and tingling in their extremities, experience unsteady gait, and lose balance (leading to potential falls).⁴ Some patients might experience the worsening of symptoms as their blood glucose levels decline due to intensifying therapeutic management of diabetes. Patients might be asymptomatic but with various degrees of sensory loss; an undesirable outcome of severe sensory loss due to diabetic neuropathy can be painless injury, leading to an increased risk of foot ulceration or, in serious cases, amputation.⁶²

The most common form of diabetic peripheral neuropathy is distal symmetric polyneuropathy with a progressive loss of sensory nerve fibers.⁴ The typical “stocking” pattern bilaterally is created by the damages that occur on the most distal portions of the longest nerves (being affected first).^63,64,65 As time progresses, a “stocking-glove” pattern, promoting sensory loss and typical symptoms of DNP, results from proximal proceeding of nerve deficits.⁴

Clinical Diagnosis. A clinical diagnosis of DPN can be made based on neuropathic signs and symptoms of a patient with diabetes after excluding other causes of neuropathy.⁶⁶ Asymptomatic diabetic peripheral neuropathy can occur in up to 50% of those who have this complication; therefore, implementation of preventive foot care is essential, especially for those who are at high risk for injuries due to insensate feet.⁴ Annual screening for DPN should be performed in all patients with diabetes by pinprick, temperature, vibration perception (using a 128-Hz tuning fork), 10-g monofilament pressure sensation, and ankle deep tendon reflexes; potential foot ulcers can be predicted by a loss of 10-g monofilament sensation (loss of protective sensation) and a reduced perceived vibration.⁶³ The ADA’s Standards of Medical Care in Diabetes—2017 continues to recommend a yearly 10-g monofilament test for the purpose of identifying patients at risk of developing ulceration and amputation.⁸ In addition, the 2017 ADA guidelines recommend screening for DPN at diagnosis of type 2 diabetes and five years after the diagnosis of type 1 diabetes.⁸

In 2009, the Toronto Consensus Panel on Diabetic Neuropathies updated diagnostic criteria to provide diagnostic categories. In addition, several well-validated screening instruments can be included by healthcare providers in the diagnosing process, including the Michigan Neuropathy Screening Instrument (MNSI), the Toronto Clinical Neuropathy Score, and the Utah Neuropathy Scale. Table 7 describes other causes of neuropathy that should be excluded.

Diagnostic Studies. Several diagnostic tests exist to confirm the presence of DPN. Nerve conduction studies have been considered for years to be the gold standard diagnostic test for DPN because of their objective measures without patients’ responses, leading to high reliability.⁴ Quantitative Sensory Testing evaluates patients’ abilities to detect light touch, vibration, and temperature discrimination, involving a certain level of subjectivity.⁴ Other methods, including skin biopsy and Intraepidermal Nerve Fiber Density and Corneal Confocal Microscopy, have not been used routinely in clinical practice but can be used in clinical trials.⁴

Treatment Options: Pharmacological Treatment. The pharmacological treatment of DPN is for symptomatic improvement, so the medications used are not intended to prevent progression. Table 8 summarizes medications from the three most commonly used classes (anticonvulsants, antidepressants, and opioids) to control neuropathic symptoms. Although several agents commonly are used as the initial approach for DPN management, only pregabalin and duloxetine have been FDA-approved for the management of this condition; thus, either of these agents is recommended as the initial choice for symptomatic neuropathic pain.⁴ Gabapentin, although not FDA-approved to be used in DPN management, often is used as an initial approach, which has a comparative efficacy with the FDA-approved agents. Tricyclic antidepressants (e.g., amitriptyline) — non-FDA-approved DPN agents — are effective in managing DPN, but they should be used with caution because of a higher risk of side effects.

The American Academy of Neurology (AAN) guideline recommends the following topical agents: capsaicin and isosorbide dinitrate spray (moderate evidence) and Lidoderm patch (weak evidence).⁶⁹ Oxcarbazepine, lamotrigine, lacosamide, clonidine, pentoxifylline, and mexiletine are not recommended in the AAN guideline in treating DPN.⁶⁹

In addition, opioids have been recommended by some to use in refractory DPN. The opioids recommended by the AAN guideline include dextromethorphan (400 mg/day), morphine sulfate (titrated to 120 mg/day), and oxycodone (mean 37 mg/day, max 120 mg/day); however, there are no sufficient data to suggest using one agent over the other.⁶⁹ The authors of this paper recommend only using opioids in severe refractory cases with close monitoring of patients who gain true functional improvement from opioids. The authors follow the 2016 position statement by the Centers for Disease Control and Prevention that opioids have limited long-term use in non-cancer type pain.⁷⁰

One of the challenges in DPN pharmacological treatment is inadequate head-to-head studies incorporating quality-of-life outcomes.⁴ A recent study comparing an eight-week therapy among high-dose pregabalin, high-dose duloxetine, or in a combination found no significant differences in average pain change between monotherapy and combination therapy.⁷¹ More studies comparing two active agents are needed to provide insight into improving the care for those who suffer from diabetic peripheral neuropathy.

Non-pharmacological Treatment. Procedures. The ANN guideline suggests considering percutaneous electrical nerve stimulation for three to four weeks for the treatment of DPN.⁶⁹ A pilot, two-style acupuncture, randomized, controlled trial⁷² and a single-blind, placebo-controlled, randomized trial⁷³ evaluating the effectiveness of acupuncture in DPN both showed improvements in outcome measures associated with pain. However, further studies are needed to confirm the role of acupuncture in DPN management.

Alpha-lipoic Acid. Some evidence suggests the use of antioxidant alpha-lipoic acid might help reduce free radical-mediated oxidative stress and provide the following benefits: targeting the pathogenesis, slowing the development, and improving symptoms of DPN.^74,75

Prevention. Lifestyle modifications, focusing on healthy diet and physical activity, continuously have been shown to decrease the prevalence of diabetes and its complications, including diabetic peripheral neuropathy.⁶⁸ Intensive glycemic control has been shown to help lower the risk of diabetic neuropathy in patients with diabetes through improving nerve function.^61,76,77 The DCCT established the role of glycemic control in preventing and ceasing diabetic neuropathy progression in type 1 diabetes.^10,56

Clinical Pearls

• Up to 50% of patients might have painless or asymptomatic peripheral neuropathy.
• Patients with neuropathy are recommended to receive foot care education (daily self-inspection of feet) and regular podiatric care for select patients.
• Patients with DPN who exhibit signs of loss of protective sensation with or without deformity should be advised to follow up with a physician every three to six months for preventive measures.⁶⁴
• To effectively manage symptoms of DPN, a multidisciplinary approach becomes essential; this comprehensive approach might include pharmacological, psychological, and/or physical therapy.
• A new position statement on diabetic neuropathy published by the ADA recommends screening for DPN in patients with prediabetes exhibiting symptoms of peripheral neuropathy.⁴
• Specialty care is needed for people with peripheral disease, non-sensory neuropathy, or Charcot foot.

Gastroparesis

Another form of diabetes neuropathy is gastroparesis. This condition is associated with upper gastrointestinal symptoms including nausea, vomiting, early satiety or postprandial fullness, abdominal pain, and bloating, but in the absence of outlet obstruction. Although there are a number of causes of gastroparesis, it has been estimated that diabetes accounts for about a third of all cases.⁷⁸

Pathophysiology. Proposed pathophysiologic mechanisms for diabetic gastroparesis include impaired glycemic control, vagal or prevertebral sympathetic ganglia neuropathy, abnormalities of interstitial cells of Cajal, loss of nitric oxide synthase, and, possibly, myopathy.^79,80

Clinical Presentation. Early in this condition, patients are usually asymptomatic. There is not a linear relationship between symptoms and severity of the neuropathy. The wide variety in symptoms makes it hard to diagnose the condition. Other clinical presentations include anorexia, malnutrition, weight loss, and hypoglycemia from the mismatch of absorption of food and insulin. Pain actually may be under-reported but significant for many people. In an NIH-funded consortium, 72% of patients with gastroparesis had abdominal pain.⁸¹ This was the dominant symptom in 18% of these patients. Pain was induced by eating (72%), was nocturnal (74%), and interfered with sleep (66%) for these patients.⁸¹

How common is diabetes gastroparesis? The cumulative 10-year incidence of gastroparesis has been estimated at 5.2% in type 1 diabetes and 1% in type 2 diabetes among community patients with diabetes.⁸² Other studies have found rates to be between 5-12%.^83,84 However, rates are much higher when the diagnosis is based on symptoms rather than the gastric-emptying study.

Gastroparesis is more common in type 1 diabetes than type 2 diabetes, and it is most commonly seen after the person has had diabetes for more than 10 years and has developed the other microvascular complications of retinopathy, nephropathy, and peripheral neuropathy. If a patient presents with gastroparesis earlier than expected, other etiologies should be explored, most commonly perioperative vagal nerve injury or pharmacologic effects from incretin-based agents — glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl-peptidase 4 inhibitors (DPP-4 inhibitors).

Once a patient develops symptoms from gastroparesis, the symptoms typically persist and are stable over 12-25 years. This is true even if there is improved glucose control,⁸⁵ except in the case of a pancreas and kidney transplant.⁸⁶ Although there is no clear evidence that gastroparesis increases mortality itself, it does substantially reduce all aspects of quality of life.⁸⁷

Diagnostics. A number of tests can help with the diagnosis. The gold standard for this diagnosis is gastroesophageal scintigraphy. It is noninvasive, tests physiology, and provides quantitative results. Gastroparesis can be diagnosed if there is at least 35% retention of a standard low-fat meal four hours post-ingestion.⁸⁰

To provide the most accurate test results, the pretest protocol should include discontinuing all motility-altering medications for at least two to three days before testing, including prokinetics, opiates, and anticholinergics. Incretin agents, such as GLP-1 agonists and DPP-4 inhibitors, also should be stopped, as they are known to delay gastric emptying. Hyperglycemia also has been shown to delay gastric emptying, and the glucose should be below 275 mg/dL before beginning the study.^79,88

Patients should refrain from smoking and consuming alcohol on the test day, as both may slow gastroesophageal emptying.⁸⁹ In addition, GLP-1RAs can exacerbate gastroparesis because they slow gastric emptying. Further, some people may have subclinical gastroparesis that is uncovered when a GLP-1RA is started.

Treatment. The treatment of gastroparesis depends largely on the severity of symptoms. The general principles for treatment include supportive treatments (fluids, electrolytes, glucose control, and nutrition), medical treatments (prokinetics, antiemetics, and pain relief), and invasive treatments (surgery, Botox injections, gastric pacing, or electrical stimulation).⁷⁹

Supportive treatment usually is started in the hospital and is focused on normalization of fluid, electrolyte, and nutritional disorders. When providing nutritional support, enteral feeding is preferred to parenteral feeding, as it is more physiologic and may help maintain bowel flora. Further, dietary changes can be very helpful in gastroparesis. Low-fiber, low-fat, low-residue diets are recommended for patients with gastroparesis.⁸⁵ High-fiber diets can increase symptoms, as they require more digestion.

Medications. Prokinetics: In the United States metoclopramide and erythromycin are the most commonly used medications to treat gastroparesis. However, metoclopramide has a black box warning because of the risk of tardive dyskinesia. Development of this condition is directly related to the duration of metoclopramide use and the number of doses taken. When using this medication, it is best to use it only in symptomatic patients and start with the lowest effective dose 15 minutes before meals. Drug holidays sometimes can help to prolong the duration of effects.⁹⁰

Domperidone is a more selective dopamine agonist that is equally effective to metoclopramide but has fewer central nervous system side effects.⁹¹

Antiemetics: Antiemetics can be used to help with symptoms. However, the risk of medication interactions is significant and should be monitored carefully.

Pain management can be a challenge in patients with gastroparesis. Tricyclic antidepressants often are used as first-line therapy for pain in gastroparesis. Second-line approaches are the weak mu-opioid receptor agonist, tramadol, which also releases serotonin and inhibits the reuptake of norepinephrine, and the gamma-aminobutyric acid analog, gabapentin. However, using narcotics in gastroparesis is not recommended, as it can contribute to constipation and worsening symptoms.

Invasive treatments: Botox injections are used commonly in the treatment of gastroparesis, but their use is not supported in clinical trials.^92,93

The gastric electrical stimulation device was FDA-approved under a humanitarian device exemption in 2000.⁹⁴ The gastric electrical stimulation device delivers high-frequency, low-energy electrical stimulation to the stomach. It is more helpful in diabetic gastroparesis than idiopathic gastroparesis. A meta-analysis showed substantial benefits in patient symptoms. The exact mechanism of its benefit is still not known.⁹⁵ It has been proposed that gastric electrical stimulation results in changes in the central mechanisms that control nausea and vomiting, increases vagal function, and results in decreased sensitivity to distension.⁹⁷ Patients who respond well typically respond quickly. This has led some to recommend a trial with temporary electrode placement first before long-term implementation.

Clinical Pearls

• Diabetic gastroparesis is more common in people with long-standing diabetes and those with other microvascular complications.
• The gold standard diagnosis for gastroparesis is gastroesophageal scintigraphy.
• Low-fiber, low-fat, low-residue diets are recommended in diabetic gastroparesis.
• Pharmacologic and interventional treatments have limited benefits and significant long-term risk.

Diabetic Cheiroarthropathy

One of the lesser-known diabetes complications is cheiroarthropathy. This condition is characterized by limited joint mobility due to thickening of skin in people with long-standing diabetes. It likely was the first complication identified from type 1 diabetes. Prevalence rates vary widely from 8-50%.⁹⁸

Cheiroarthropathy is believed to be caused by the glycosylation and cross-linking of collagen. It can affect the skin and tendons, and can result in limited joint mobility, most commonly extension of the fingers, stiffness, and pain. The classic physical exam sign for diabetic cheiropathy is the “prayer sign.” In this condition, a person is unable to fully flatten his or her hands to “pray” leaving a gap between the fingers of the left and right hand. There is evidence that those who develop cheiropathy have a three times greater risk of microvascular complications.⁹⁹

Diabetic cheiropathy typically is worse in those with long-standing or poorly controlled glycemia. Fortunately, many people experience relief of symptoms and improved mobility when glucose control improves.¹⁰⁰

Conclusion

Management of diabetes complications requires a multidisciplinary team. Early screening of retinopathy, nephropathy, and neuropathy is essential, given the asymptomatic nature of the disease. The hallmark of diabetes management for all complications continues to be glycemic and blood pressure control.

REFERENCES

1. American Diabetes Association. Cost of Diabetes. Available at: http://www.diabetes.org/advocacy/news-events/cost-of-diabetes.html?referrer=https://www.google.com/. Updated June 22, 2015. Accessed Feb. 8, 2017.
2. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998;352:837-853.
3. Gregg EW, Yanfed L, Wang J. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med 2014;370:1514-1523.
4. Pop-Busui R, Boulton A, Feldman E, et al. Diabetes neuropathy: A position statement by the American Diabetes Association. Diabetes Care 2017;40:136-154.
5. Leasher JL, Bourne RR, Flaxman SR, et al. Global estimates on the number of people blind or visually impaired by diabetic retinopathy: A meta-analysis from 1990 to 2010. Diabetes Care 2016;39:1643-1649.
6. National Eye Institute. Facts about diabetic eye disease. Available at: https://nei.nih.gov/health/diabetic/retinopathy. Updated Sept. 2015. Accessed Feb. 8, 2017.
7. Fong, DS, Aiello L, Gardner TW, et al. Retinopathy in diabetes. Diabetes Care 2004;27(Suppl 1):S84-S87.
8. American Diabetes Association. Standards of Medical Care in Diabetes-2017. Diabetes Care 2017;40:(Suppl 1):S4-S5.
9. Doggen K, Nobels F, Scheen AJ, et al. Cardiovascular risk factors and complications associated with albuminuria and impaired renal function in insulin-treated diabetes. J Diabetes Complications 2013;27:370-375.
10. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986.
11. Action to Control Cardiovascular Risk in Diabetes Follow-On (ACCORDION) Eye Study Group and the Action to Control Cardiovascular Risk in Diabetes Follow-On (ACCORDION) Study Group. Persistent effects of intensive glycemic control on retinopathy in type 2 diabetes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) follow-on study. Diabetes Care 2016;39:1089-1100.
12. ACCORD Study Group, ACCORD Eye Study Group, Chew EY, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363:233-244.
13. Chew EY, Davis MD, Danis RP, et al. The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study. Ophthalmology 2014;121:2443-2451.
14. Diabetes Control and Complications Trial Research Group. Effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial. Diabetes Care 2000;23:1084-1091.
15. Colberg SR, Sigal RJ, Yardley JE, et al. Physical activity/exercise and diabetes: A position statement of the American Diabetes Association. Diabetes Care 2016;39:2065-2079.
16. The Diabetic Retinopathy Study Research Group. Preliminary report on effects of photocoagulation therapy. Am J Ophthalmol 1976;81:383-396.
17. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796-1806.
18. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: Results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012;119:789-801.
19. Wong TY, Cheung CMG, Larsen M, et al. Diabetic retinopathy. Nat Rev Disease Prim doi:10.1038/nrdp.2016.12; published online March 17, 2016.
20. Batuman V, Soman AS, Schmidt RJ, Soman SS. Diabetes nephropathy. Medscape Available at: http://emedicine.medscape.com/article/238946-overview. Updated Sept. 30, 2016. Accessed Feb. 12, 2017.
21. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic kidney disease: A report from an ADA Consensus Conference. Diabetes Care 2014;37:2864-2883. https://doi.org/10.2337/dc14-1296
22. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-2572.
23. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129-139.
24. Ismail-Beigi F, Craven T, Banerji MA, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: An analysis of the ACCORD randomised trial. Lancet 2010;376:419-430.
25. National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis 2012;60:850-886.
26. Fox CS, Matsushita K, Woodward M, et al. Chronic Kidney Disease Prognosis Consortium. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: A meta-analysis. Lancet 2012;380:1662-1673.
27. Hahr AJ, Molitch ME. Management of diabetes mellitus in patients with chronic kidney disease. Clin Diabetes Endocrinol 2015. doi: 10.1186/s40842-015-0001-9.
28. Alsaad KO, Herzenberg AM. Distinguishing diabetic nephropathy from other casues of glomerulosclerosis: An update. J Clin Pathol 2007;60:18-26.
29. Narva AS, Bilous RW. Laboratory assessment of diabetic kidney disease. Diabetes Spectr 2015;28:162-166.
30. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-612.
31. National Kidney Foundation. KDOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 Suppl 1):S1-S266.
32. de Boer IH, Rue TC, Cleary PA, et al. Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria: An analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort. Arch Intern Med 2011;171:412-420.
33. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323-334.
34. Heerspink HJL, Desai M, Jardine M, et al. Canagliflozin slows progression of renal function decline independently of glycemic effects. J Am Soc Nephrol 2016;28:1-8.
35. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed Oct. 31, 2016.
36. Micromedex Solutions. Truven Health Analytics, Inc. Ann Arbor, MI. Available at: http://www.micromedexsolutions.com. Accessed Oct. 31, 2016.
37. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults. JAMA 2014;311:507-520.
38. King P, Peacock I, Donnelly R. The United Kingdom Prospective Diabetes Study (UKPDS): Clinical and therapeutic implications for type 2 diabetes. Br J Clin Pharmacol 1999;48:643-648.
39. Jackevicius CA, Wong J, Aroustamian I, et al. Rates and predictors of ACE inhibitor discontinuation subsequent to elevated serum creatinine: A retrospective cohort study. BMJ Open 2014;4:e005181.
40. Mauer M, Zinman B, Gardiner R, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med 2009;361:40-51.
41. Bilous R, Chaturvedi N, Sjølie AK, et al. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: Three randomized trials. Ann Intern Med 2009;151:11-20.
42. Haller H, Ito S, Izzo JL Jr, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011;364:907-917.
43. Makani H, Bangalore S, Desouza KA, et al. Efficacy and safety of dual blockade of the renin-angiotensin system: Meta-analysis of randomised trials. BMJ 2013;346:f360.
44. Miao Y, Ottenbros SA, Laverman GD, et al. Effect of a reduction in uric acid on renal outcomes during losartan treatment: A post-hoc analysis of the reduction of endpoints in non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan Trial. Hypertension 2011;58:2-7.
45. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Eng J Med 2001;354:851-860.
46. Adler A, Casula A, Steenkamp R, et al. Association between glycemia and mortality in diabetic individuals on renal replacement therapy in the U.K. Diabetes Care 2014;37:1304-1311.
47. Sharma SG, Bomback AS, Radhakrishnan J, et al. The modern spectrum of renal biopsy findings in patients with diabetes. Clin J Am Soc Nephrol 2013;8:1718-1724.
48. Smart NA, Dieberg G, Ladhani M, Titus T. Early referral to specialist nephrology services for preventing the progression to end-stage kidney disease. Cochrane Database Syst Rev 2014;6:CD007333.
49. Boulton AJM, Gries FA, Jervell JA. Guidelines for the diagnosis and outpatient management diabetic peripheral neuropathy. Diabet Med 1998;15:508-514.
50. O’Brien PD, Hinder LM, Sakowski SA, Feldman EL. ER stress in diabetic peripheral neuropathy: A new therapeutic target. Antioxid Redox Signal 2014;21:621-633.
51. Cameron NE, Cotter MA. Pro-inflammatory mechanisms in diabetic neuropathy: Focus on the nuclear factor kappa B pathway. Curr Drug Targets 2008;9:60-67.
52. Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005;352:341-350.
53. Wiggin TD, Sullivan KA, Pop-Busui R, et al. Elevated triglycerides correlated with progression of diabetic neuropathy. Diabetes 2009;58:1634-1640.
54. Stella P, Ellis D, Maser RE, Orchard TJ. Cardiovascular autonomic neuropathy (expiration and inspiration ratio) in type 1 diabetes. Incidence and predictors. J Diabetes Complications 2000;14:1-6.
55. Witten DR, Tesfaye S, Chaturvedi N, et al. Risk factors for cardiac autonomic neuropathy in type 1 diabetes mellitus. Diabetologia 2005;48:164-171.
56. Diabetes Control and Complication Trial (DCCT) Research Group. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol 1995;38:869-880.
57. Diabetes Control and Complication Trial (DCCT) Research Group. The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT). Diabetologia 1998;41:416-423.
58. Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: Mechanisms to management. Pharmacol Ther 2008;120:1-34.
59. Vincent AM, Callaghan BC, Smith AL, Feldman EL. Diabetic neuropathy: Cellular mechanisms a therapeutic target. Nat Rev Neurol 2011;7:573-583.
60. Kellogg AP, Wiggin T, Larkin D, et al. Protective effects of cyclooxygenase-2 gene inactivation against peripheral nerve dysfunction and intraepidermal nerve fibers loss in experimental diabetes. Diabetes 2007;56:2997-3005.
61. Callaghan BC, Cheng HT, Stables CL, et al. Diabetic neuropathy: Clinical manifestations and current treatments. Lancet Neurol 2012;11:521-534.
62. Boulton AJM, Kirsner RS, Vileikyte L. Clinical practice: Neuropathic diabetic foot ulcers. N Eng J Med 2004;351:48-55.
63. Boulton AJM, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: A statement by the American Diabetes Association. Diabetes Care 2005;28:956-962.
64. Boulton AJM, Armstrong DG, Albert SF, et al. Comprehensive foot examination and risk assessment: A report of the task force of the foot care interest group of the American Diabetes Association, with endorsement by the American Association of Clinical Endocrinologists. Diabetes Care 2008;31:1679-1685.
65. Tesfaye S, Boulton AJ, Dyck PJ, et al. Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 2010;33:2285-2293.
66. Dyke PJ, Albers JW, Andersen H, et al. Diabetic polyneuropathies: Update on research definition, diagnostic criteria and estimation of severity. Diabetes Metab Res Rev 2011;27:620-628.
67. Freeman R. Not all neuropathy is diabetes is of diabetic etiology: Differential diagnosis of diabetic neuropathy. Curr Diabe Rep 2009;9:423-431.
68. Balducci S, Iacobellis G, Parisi L, et al. Exercise training can modify the natural history of diabetic peripheral neuropathy. J Diabetes Complications 2006;20:216-223.
69. Bril V, England J, Franklin GM, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy. Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2011;76:1758-1765.
70. Dowell D, Haegerich TM, Chou R. CDC Guideline for prescribing opioids for chronic pain – United States 2016. MMWR Recomm Rep 2016;65:1-49.
71. Tesfaye S, Wilhelm S, Lledo A, et al. Duloxetine and pregabalin: High-dose monotherapy or their combination? The “COMBO-DN study” – a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. Pain 2013;154:2616-2625.
72. Ahn AC, Bennani T, Freeman R, et al. Two styles of acupuncture for treating painful diabetic neuropathy – a pilot randomized control trial. Acupunct Med 2007;25:11-17.
73. Garrow A, Xing M, Vere J, et al. Role of acupuncture in the management of diabetic painful neuropathy (DPN): A pilot RCT. Acupunct Med 2014;32:242-249.
74. Ziegler D, Nowak H, Kempler P, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: A meta-analysis. Diabet Med 2004;21:114-121.
75. Ziegler D, Low PA, Litchy WJ, et al. Efficacy and safety of antioxidant treatment with alpha-lipoic acid over 4 years in diabetic polyneuropathy: The NATHAN 1 trial. Diabetes Care 2011;34:2054-2060.
76. Kuwabara S, Ogawara K, Harrori T, et al. The acute effects of glycemic control on axonal excitability in human diabetic nerves. Intern Med 2002;41:360-365.
77. Peltier A, Goutman SA, Callaghan BC. Painful diabetic neuropathy. BMJ 2014;348:g1799.
78. Soykan I, Sivri B, Sarosiek I, et al. Demography, clinical characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis. Dig Dis Sci 1998;43:2398-2404.
79. Camilleri M, Bharucha AE, Farrugia G. Epidemiology, mechanisms, and management of diabetic gastroparesis. Clin Gastroenterol Hepatol 2011;9:5-12.
80. Shin AS, Camilleri M. Diagnostic assessment of diabetic gastroparesis. Diabetes 2013;62:2667-2673.
81. Hasler WL, Wilson L, Parkman HP, Lee L. Importance of abdominal pain as a symptom in gastroparesis: Relation to clinical factors, disease severity, quality of life, gastric retention, and medication use. Gastroenterology 2010;138. doi: 10.1016/S0016-5085(10)62131-2.
82. Choung RS, Locke GR 3rd, Schleck CD, et al. Risk of gastroparesis in subjects with type 1 and 2 diabetes in the general population. Am J Gastroenterol 2012;107:82-88.
83. Maleki D, Locke GR III, Camilleri M, et al. Gastrointestinal tract symptoms among persons with diabetes mellitus in the community. Arch Intern Med 2000;160:2808-2816.
84. Bytzer P, Talley NJ, Leemon M, et al. Prevalence of gastrointestinal symptoms associated with diabetes mellitus: A population-based survey of 15,000 adults. Arch Intern Med 2001;161:1989-1996.
85. Jones KL, Russo A, Berry MK, et al. A longitudinal study of gastric emptying and upper gastrointestinal symptoms in patients with diabetes mellitus. Am J Med 2002;113:449-455.
86. Gaber AO, Hathaway DK, Abell T, et al. Improved autonomic and gastric function in pancreas-kidney vs kidney-alone transplantation contributes to quality of life. Transplant Proc 1994;26:515-516.
87. Punkkinen J, Färkkilä M, Mätzke S, et al. Upper abdominal symptoms in patients with Type 1 diabetes: Unrelated to impairment in gastric emptying caused by autonomic neuropathy. Diabet Med 2008;25:570-577.
88. Schvarcz E, Palmer M, Aman J, et al. Physiological hyperglycemia slows gastric emptying in normal subjects and patients with insulin-dependent diabetes mellitus. Gastroenterology 1997;113:60-66.
89. Miller G, Palmer KR, Smith B, et al. Smoking delays gastric emptying of solids. Gut 1989;30:50-53.
90. Rao AS, Camilleri M. Review article: Metoclopramide and tardive dyskinesia. Aliment Pharmacol Ther 2010;31:11-19.
91. Patterson D, Abell T, Rothstein R, et al. A double-blind multicenter comparison of domperidone and metoclopramide in the treatment of diabetic patients with symptoms of gastroparesis. Am J Gastroenterol 1999;94:1230-1234.
92. Arts J, Holvoet L, Caenepeel P, et al. Clinical trial: A randomized-controlled crossover study of intrapyloric injection of botulinum toxin in gastroparesis. Aliment Pharmacol Ther 2007;26:1251-1258.
93. Friedenberg FK, Palit A, Parkman HP, et al. Botulinum toxin A for the treatment of delayed gastric emptying. Am J Gastroenterol 2008;103:416-423.
94. Humanitarian Device Exemption for Enterra Device. Fed Reg 2000;65:78495-78496.
95. O’Grady G, Egbuji JU, Du P, et al. High-frequency gastric electrical stimulation for the treatment of gastroparesis: A meta-analysis. World J Surg 2009;33:1693-1701.
96. Reddymasu SC, Sarosiek I, McCallum RW. Severe gastroparesis: Medical therapy or gastric electrical stimulation. Clin Gastroenterol Hepatol 2010;8:117-124.
97. McCallum RW, Dusing RW, Sarosiek I, et al. Mechanisms of symptomatic improvement after gastric electrical stimulation in gastroparetic patients. Neurogastroenterol Motil 2010;22:161-167.
98. Douloumpakas I, Pyrpasopoulou A, Triantafyllou A, et al. Prevalence of musculoskeletal disorders in patients with type 2 diabetes mellitus: A pilot study. Hippokratia 2007;11:216-218.
99. Rosenbloom AL, Silverstein JH, Lezotte DC. Limited joint mobility in childhood diabetes mellitus indicates increased risk for microvascular disease. N Engl J Med 1981;305;191-194.
100. Lister DM, Graham-Brown RAC, Burden AC. Resolution of diabetic cheiroarthropathy. Br Med J 1986;293:1537.