Screening and Management of Microvascular Complications of Diabetes Mellitus

Guidelines Being Compared:

1. American Association of Clinical Endocrinologists (AACE). American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract 2011 Mar-Apr;17(Suppl 2):1-53. [375 references]
2. University of Michigan Health System (UMHS). Management of type 2 diabetes mellitus. Ann Arbor (MI): University of Michigan Health System; 2012 Sep. 27 p. [17 references]

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  Nephropathy
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  Retinopathy
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  Neuropathy and Foot Care

Nephropathy

AACE (2011)

How Should Microvascular and Neuropathic Disease Be Prevented, Diagnosed, and Treated in Patients With DM? Diabetic Nephropathy Beginning 5 years after diagnosis in patients with T1DM and at diagnosis in patients with T2DM, an annual assessment of serum creatinine to estimate the GFR and urine albumin excretion should be performed to identify, stage, and monitor progression of diabetic nephropathy (Grade D; BEL 4). Patients with diabetic nephropathy should be counseled regarding the increased need for optimal glycemic control, blood pressure control, dyslipidemia control, and smoking cessation (Grade A; BEL 1). When therapy with ACE inhibitors or ARBs is initiated, renal function and serum potassium levels must be closely monitored (Grade A; BEL 1). Annual screening for microalbuminuria should be performed from the outset in patients with T2DM and beginning at puberty or 5 years after diagnosis in patients with T1DM. Measurement of the ACR (normal <30 mg albumin/g creatinine) in a random urine sample is acceptable for screening and obviates the need for the more cumbersome 24-hour or timed urine collections. Screening with a spot urine albumin level, if assessed by immunoassay or dipstick without the simultaneous measurement of urine creatinine, is suboptimal and fraught with errors. Albumin excretion can be increased by exercise, febrile illness, urinary tract infection, hematuria, severe hypertension, heart failure, and even high-grade hyperglycemia. Therefore, it is prudent to confirm albuminuria status with repeated testing before establishing a firm basis for therapeutic intervention for diabetic nephropathy. The National Kidney Foundation classification is based on GFR and the presence of kidney damage, as evidenced by abnormalities on pathologic, urine, blood, or imaging tests. The National Kidney Foundation classification differs from that based on albuminuria. The GFR (mL/min per 1.73 m2 body surface area)-based classification is as follows: Stage Description Stage 1: Kidney damage with normal or increased GFR >90 mL/min Stage 2: Kidney damage with mildly decreased GFR 60-89 mL/min Stage 3: Moderately decreased GFR 30-59 mL/min Stage 4: Severely decreased GFR 15-29 mL/min Stage 5: Kidney failure, GFR <15 mL/min or dialysis The finding that GFR may decline in adult patients with T2DM without concurrent increase in albumin excretion provides strong rationale for the use of GFR in screening for nephropathy. The GFR can be estimated from the measured serum creatinine level, using one of the standard formulas such as that from the MDRD. Thus, serum creatinine levels should be obtained and used for calculating the estimated GFR, at least annually, in all adults with DM, including those without evidence of albuminuria. Many laboratories now routinely report the estimated GFR, and the National Institutes of Health also has GFR calculators (http://www.nkdep.nih.gov ). Prevention of the development or progression of diabetic nephropathy includes optimal control of plasma glucose (A1C goal <7%) and blood pressure (blood pressure <130/80 mm Hg), inhibition of the renin-angiotensin-aldosterone system, and modification of other risk factors such as smoking and hyperlipidemia. Antihypertensive drugs that block the renin-angiotensin-aldosterone system provide adjunctive nephroprotective benefits besides their blood pressure-lowering effects. This property has been demonstrated for the ACE inhibitors and ARBs in patients with T1DM and T2DM. In selected cases (such as patients with massive proteinuria), combination therapy with an ACE inhibitor and an ARB may produce additive effects on blood pressure control and reduction of albuminuria. Aliskiren, an orally active direct renin inhibitor, may have a role as part of combination therapy in patients with DM and persistent albuminuria, despite treatment with an angiotensin inhibitor. There are no randomized prospective studies to inform best practices on how often to measure albumin excretion during renin-angiotensin-aldosterone system-blocking therapy in patients with microalbuminuria. Follow-up data can help direct drug titration in patients with persistent microalbuminuria, as there is some suggestion that normalization (or near-normalization) of albumin excretion may decrease the risks of progressive nephropathy and CVD. If the GFR continues to decrease despite excellent glycemic and blood pressure control, protein restriction may be of some benefit. The consensus recommendation is to prescribe a protein intake of approximately the adult recommended dietary allowance of 0.8 g/kg per day (approximately 10% of daily calories) in the patient with nephropathy. However, once the GFR begins to fall, further restriction to 0.6 g/kg per day may be beneficial in slowing the decline of GFR in selected patients. Referral to a nephrologist for the establishment of a firm diagnosis is indicated when the diagnosis of diabetic nephropathy is in doubt (e.g., patients with non-classic presentation, suspected IgA nephropathy, rapidly worsening nephropathy, active urinary sediment). Patients with advanced or severe kidney disease also should be cared for in consultation with a nephrologist. The timing of the referral to a nephrologist varies with the experience and comfort level of the DM caregiver in the management of kidney disease. The DM caregiver must be adept at delivering optimal management of risk factors for worsening nephropathy, such as hyperglycemia, hypertension, and dyslipidemia, to delay the progression of nephropathy for as long as possible. However, evidence suggests that referral of patients with stage 4 chronic kidney disease to a nephrologist is cost-effective and delays the time to dialysis treatment. Patients with stage 5 CKD require renal replacement therapy, and mortality while taking such therapy is higher in patients with DM than in patients without DM, largely because of CVD complications. Renal transplantation is the preferred replacement therapy for patient with DM who have end-stage kidney disease because long-term outcomes are superior to those achieved with dialysis. For patients with T1DM, the possibility of combined kidney-pancreas transplantation allows for considerably better outcomes.

UMHS (2012)

Annually Screen for microalbuminuria if not on an ACE inhibitor or ARB [IB]. Prescribe an ACE inhibitor or ARB for microalbuminuria or proteinuria [IA]. Serum creatinine and eGFR [ID]. Nephropathy Check spot urinary ACR (annually) if not on an ACE/ARB and without diagnosis of diabetic nephropathy. If >30 mg/gm, check UA to rule out asymptomatic UTI. Repeat spot urine ratio twice within 6 months. If 2 of 3 spot urine albumin/creatinine ratios >30 mg/dL: Check creatinine, electrolytes and eGFR [IDg] Begin ACE inhibitor or ARB [IAd] (if electrolytes allow use of ACE inhibitor). Recheck creatinine and electrolytes within 1–2 weeks of initiating therapy. g = studies in general population d = diabetes patient studies Rationale for Recommendations Microvascular Complications Nephropathy Yearly screening and treatment for microalbuminuria can reduce the incidence of renal failure. The spot urinary ACR is a simple method for testing for microalbuminuria. Because of day-to-day variation in urinary albumin excretion, if the first test is positive, the test should be repeated on at least two more occasions over a 3 to 6 month period. Two of three tests should be positive (>30 mg albumin per gm of creatinine) before microalbuminuria is considered present. Albuminuria is defined as albumin excretion >300 mg/day. Patients who are taking an ACE inhibitor or ARB or who have a diagnosis of diabetic nephropathy may not require yearly screening for microalbuminuria. Causes of elevated urinary albumin excretion in the absence of diabetic nephropathy include UTI, recent exercise, acute febrile illness, hematuria related to UTI or menses, and CHF. If screening microalbumin is >30 mg/dL, check urinalysis to assess for other causes. Microalbuminuria is a marker for greatly increased cardiovascular morbidity and mortality for patients with diabetes. Therefore, aggressive intervention is recommended to reduce all cardiovascular risk factors (e.g., lowering of LDL cholesterol, antihypertensive therapy, cessation of smoking, institution of regular physical activity, etc.) Patients with diabetes with a GFR <30-45 ml/min with or without nephrotic range proteinuria should be referred to a nephrologist for evaluation for other causes of nephropathy and for discussion of potential treatment options. Dietary protein restriction has been proven to be beneficial in patients with T1DM with proteinuria. This has not been clearly proven in patients with T2DM. Consider dietary referral to evaluate dietary protein in patients with proteinuria. ACE inhibitors reduce the rate of progression from microalbuminuria to overt proteinuria and diabetic nephropathy, independent of their effect on blood pressure. ARBs show similar benefits to ACE inhibitors in patients with T2DM and microalbuminuria and diabetic nephropathy. Direct comparisons between ACE inhibitors and ARBs have not been performed in patients with T2DM. ACE inhibitors and ARBs are regarded as functionally equivalent in protecting against diabetic nephropathy, although more evidence exists in the literature for therapy with an ARB to continue to show benefit even up to the development of end stage renal disease. An ACE inhibitor or an ARB should be used in all patients with microalbuminuria. Combination ACE/ARB therapy for patients with persistent albuminuria is NOT recommended. While the combination reduces proteinuria, it also increases renal failure and adverse events in patients with diabetes, without any benefits on cardiovascular or renal outcomes. Other antihypertensives including beta-blockers and non-dihydropyridine classes of calcium channel blockers (NDCCB) can reduce the level of albuminuria, but no studies to date have demonstrated a reduction in the rate of fall of GFR. Some members of the dihydropyridine class of calcium channel blockers (e.g., nifedipine, felodipine) may increase urinary albumin excretion, and should be avoided in patients with microalbuminuria. Control of blood pressure is important. Recommended blood pressure goals in patients with diabetes and chronic kidney disease are: <140/80 if urine albumin excretion <30 mg/24 hours <130/80 if urine albumin excretion >30 mg/24 hours In normotensive patients with microalbuminuria, target dosages of ACE inhibitors are difficult to define. Some experts recommend titrating medications upward until a normal albuminuria is seen or side effects occur.

Retinopathy (Back to top)

AACE (2011)

How Should Microvascular and Neuropathic Disease Be Prevented, Diagnosed, and Treated in Patients With DM? Diabetic Retinopathy At the time of diagnosis, patients with T2DM should be referred to an experienced ophthalmologist or optometrist for annual dilated eye examination (Grade D; BEL 4). In patients with T1DM, a referral should be made within 5 years of diagnosis (Grade B; BEL 2). Women who are pregnant and have DM should be referred for frequent/repeated eye examinations during pregnancy and 1 year postpartum (Grade C; BEL 3). Patients with active retinopathy should have examinations more frequently than once a year, as should patients receiving vascular endothelial growth factor therapy (Grade D; BEL 4). Optimal glucose, blood pressure, and lipid control should be implemented to slow the progression of retinopathy (Grade D; BEL 4).

UMHS (2012)

Retinopathy Perform dilated retinal exam by eye care specialist [IBd] every 2-3 years if previous eye exam was normal and good glucose and blood pressure control. Otherwise annually or more frequently as recommended by the eye care provider. If retinopathy: Treatment per ophthalmology [AId] Consider improving glycemic control [IAd] d = diabetes patient studies Rationale for Recommendations Retinopathy Dilated retinal examination reduces the incidence of severe visual loss by allowing timely treatment (e.g., laser photocoagulation, anti-VEGF intraocular injections) of proliferative retinopathy and macular edema. Optimal screening intervals for retinopathy depend on the risk in the individual patient. Patients who have been diagnosed with retinopathy should be screened at least annually, and many will require much more frequent examination depending on the degree of retinal abnormality. Patients have a low risk of developing retinopathy that will require treatment over the short term if they (a) have no retinopathy on a baseline retinal exam by an expert and (b) have reasonable glucose and blood pressure control. These patients can be screened less frequently, at 2 to 3 year intervals. For measuring quality of care for diabetes, the HEDIS interval for retinal examinations is biannually for patients with previous normal eye exam and at least annually for patients with abnormal eye exam. Unless the primary caregiver has been specifically trained to perform dilated retinal examinations, the accuracy of fundoscopic examination is poor. Thus, all screening should be performed by a trained eye-care professional.

Neuropathy and Foot Care (Back to top)

AACE (2011)

How Should Microvascular and Neuropathic Disease Be Prevented, Diagnosed, and Treated in Patients With DM? Diabetic Neuropathy Diabetic painful neuropathy is diagnosed clinically and must be differentiated from other painful conditions(Grade D; BEL 4). Interventions that reduce oxidative stress, improve glycemic control, and/or improve dyslipidemia and hypertension might have a beneficial effect on diabetic neuropathy (Grade A; BEL 1). Exercise and balance training may also be beneficial (Grade C; BEL 3). Tricyclic antidepressants, anticonvulsants, and serotonin and norepinephrine reuptake inhibitors are useful treatments (Grade A; BEL 1). Large-fiber neuropathies are managed with strength, gait, and balance training; pain management; orthotics to treat and prevent foot deformities; tendon lengthening for pes equinus from Achilles tendon shortening; and/or surgical reconstruction and full contact casting as needed (Grade A; BEL 1). Small-fiber neuropathies are managed with foot protection (e.g., padded socks), supportive shoes with orthotics if necessary, regular foot and shoe inspection, prevention of heat injury, and use of emollient creams; however, for pain management, the medications mentioned above must be used (Grade A; BEL 1).

UMHS (2012)

Neuropathy Perform foot exam: (1) inspect and check pulse (each visit if patient has a history of neuropathy; otherwise annually), and (2) monofilament (annually), see Table 11 in the original guideline document [IBd]. If structural abnormality: Prescription for customized shoe and/or orthotics Consider podiatry referral If neuropathy: Optimize glycemic control [IAd] Treatment of painful neuropathy if indicated If not sensitive to monofilament: Education regarding proper foot care and increased risk of ulceration Consider podiatry referral If foot ulcer: Prescription for customized shoe and/or orthotics Aggressive wound care with close follow up Refer to a multidisciplinary team specializing in the care of diabetic foot ulcers [IAd] g = studies in general population d = studies in patients with diabetes Rationale for Recommendations Neuropathy Diabetic neuropathy is reported in up to half of patients with diabetes. Most have loss of sensation, only a minority experience pain. Patients often describe pain as burning, shock sensation, or stabbing. Evidence indicates early detection of diabetic neuropathy results in fewer foot ulcers and amputations. Attention should be paid to the etiology of pain in diabetic feet. Occasionally, mechanical factors rather than neuropathy are the mechanism underlying pain. Diabetic Foot Care. Foot care includes examination, preventive care, consideration of orthotic footwear, and treatment of foot ulcers. Examination. Patients with diabetes need visual foot inspection, checking of pulses and sensory annually, and with every routine visit if they have abnormalities. Inspection should also include identifying areas of callus formation, claw toe deformity, prominent metatarsal heads (or other bony prominences), and other structural changes. Three simple tests detect peripheral neuropathy: pressure sensation, vibration sensation and temperature/pain perception. Sensory testing with a 5.07 (10g) nylon monofilament should be done yearly to identify insensate feet without protective sensation. Instructions on "How to Use a Monofilament" are in Table 11 of the original guideline document. Individuals with insensitive feet are considered to be at high risk of developing foot ulcers and other related complications. Education. Education regarding appropriate foot care should be provided. All patients need education regarding optimal foot and nail care, which includes daily inspection and appropriately fitting shoes. To minimize the risk of trauma, patients should be counseled to avoid walking barefoot and those with neuropathy should avoid high-impact exercise and the use of hot water. Footwear. Orthotic footwear should be prescribed to accommodate major foot deformities and cushion pressure areas. Most insurance plans, including Medicare, cover therapeutic footwear for patients with diabetic neuropathy or deformity. For others with less deformity, athletic shoes with sufficient room for the toes and forefoot and cushioned socks are appropriate. Foot ulcers. Detection and early treatment of foot ulcers is of paramount importance, as foot ulcers are among the most common reasons for hospitalization among people with diabetes. Foot ulcers are the leading cause of lower extremity amputations and up to 85% of amputations can be avoided with patient education on foot care, medical professional monitoring and early intervention. Should a foot ulcer be found, infection and vascular status should be carefully evaluated and early treatment should be undertaken with aggressive wound care, orthotic prescriptions or casting to offload the ulcer, antibiotics, and revascularization when necessary. Studies have shown that patients with diabetic foot ulcers have the best outcomes if managed by a multidisciplinary team that specializes in diabetic foot care. Treatment of painful diabetic peripheral neuropathy. Optimizing glycemic control is of paramount importance in slowing the progression of established diabetic neuropathy. NSAIDs should be used cautiously for chronic neuropathic pain due to their GI and renal side effects that are of concern in this population. First line therapies for the treatment of diabetic peripheral neuropathy supported by the literature include TCAs, gabapentin, pregabalin, and duloxetine. TCAs may be used to treat painful neuropathy and their use is supported by research. They should be used with caution in the elderly, started at low doses and titrated to maximize pain relief while minimizing side effects of dry mouth, sedation, orthostatic hypotension and constipation. Nortriptyline is the preferred tricyclic as it has fewer anticholinergic properties. It can be started at dinner at a dose of 10-25 mg and titrate up as tolerated to maximum of 150 mg/day. Gabapentin at 1600 mg/day as divided doses or more may be required. Sedation is a side effect that limits its use. Pregabalin (150-300 mg/day as divided doses) is FDA-approved and is less sedating. Duloxetine (60 mg-120 mg/day) and venlafaxine (75-450 mg/day), SNRIs are useful in treating patients with co-morbid depression. SSRIs and trazodone are not as effective in treating painful diabetic peripheral neuropathy. Lidocaine 5% patches have been proven to relieve diabetic peripheral neuropathy pain and improve quality of life ratings. No side effects were found with the regimen of up to 3 patches worn 12 hours overnight and removed. Other agents. Among other agents, including carbamazepine (200-600 mg/day) and valproate (500 mg/day) have been shown to decrease diabetic peripheral neuropathy. Their use is limited by their side effect profiles. Opioids. As a last option, opioids may be considered, though general use is discouraged. Tramadol is a weak opioid and dose of 37.5 mg tramadol with 325 mg acetaminophen showed an improvement in diabetic peripheral neuropathy compared to placebo. Refer to the NGC summary of the UMHS guideline Managing chronic non-terminal pain in adults including prescribing controlled substances. Acupuncture and transcutaneous electrical nerve stimulation (TENS). Several studies have shown the efficacy of using traditional acupuncture for the treatment of painful diabetic neuropathy. TENS has also been evaluated and has been shown to reduce lower extremity pain associated with diabetic peripheral neuropathy.

Internet citation: National Guideline Clearinghouse (NGC). Guideline synthesis: Screening and management of microvascular complications of type 2 diabetes mellitus. In: National Guideline Clearinghouse (NGC) [Web site]. Rockville (MD): Agency for Healthcare Research and Quality (AHRQ); 2010 May (revised 2014 Oct). [cited YYYY Mon DD]. Available: http://www.guideline.gov.