10. Microvascular Complications and Foot Care Diabetes Care 2017;40(Suppl. 1):S88 S98 DOI: /dc17-S013

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1 S88 Diabetes Care Volume 40, Supplement 1, January Mirovasular Compliations and Foot Care Diabetes Care 2017;40(Suppl. 1):S88 S98 DOI: /d17-S013 Amerian Diabetes Assoiation DIABETIC KIDNEY DISEASE 10. MICROVASCULAR COMPLICATIONS AND FOOT CARE Reommendations Sreening At least one a year, assess urinary albumin (e.g., spot urinary albumin to reatinine ratio) and estimated glomerular filtration rate in patients with type 1 diabetes with duration of $5 years, in all patients with type 2 diabetes, and in all patients with omorbid hypertension. B Optimize gluose ontrol to redue the risk or slow the progression of diabeti kidney disease. A Optimize blood pressure ontrol to redue the risk or slow the progression of diabeti kidney disease. A For people with nondialysis-dependent diabeti kidney disease, dietary protein intake should be approximately 0.8 g/kg body weight per day (the reommended daily allowane). For patients on dialysis, higher levels of dietary protein intake should be onsidered. B In nonpregnant patients with diabetes and hypertension, either an ACE inhibitor or an angiotensin reeptor bloker is reommended for those with modestly elevated urinary albumin to reatinine ratio ( mg/g reatinine) B and is strongly reommended for those with urinary albumin to reatinine ratio $300 mg/g reatinine and/or estimated glomerular filtration rate,60 ml/min/1.73 m 2. A Periodially monitor serum reatinine and potassium levels for the development of inreased reatinine or hanges in potassium when ACE inhibitors, angiotensin reeptor blokers, or diuretis are used. E Continuedmonitoringofurinary albumin to reatinine ratio in patients with albuminuria treated with an ACE inhibitor or an angiotensin reeptor bloker is reasonable to assess the response to treatment and progression of diabeti kidney disease. E An ACE inhibitor or an angiotensin reeptor bloker is not reommended for the primary prevention of diabeti kidney disease in patients with diabetes whohave normalbloodpressure, normalurinary albumin to reatinine ratio (,30 mg/g reatinine), and normal estimated glomerular filtration rate. B When estimated glomerular filtration rate is,60 ml/min/1.73 m 2, evaluate and manage potential ompliations of hroni kidney disease. E Patients should be referred for evaluation for renal replaement treatment if they have an estimated glomerular filtration rate,30 ml/min/1.73 m 2. A Promptly refer to a physiian experiened in the are of kidney disease for unertainty about the etiology of kidney disease, diffiult management issues, and rapidly progressing kidney disease. B Assessment of Albuminuria and Estimated Glomerular Filtration Rate Chroni kidney disease (CKD) is diagnosed by the presene of elevated urinary albumin exretion (albuminuria), low estimated glomerular filtration rate (egfr), or other manifestations of kidney damage (1,2). Diabeti kidney disease, or CKD attributed to diabetes, ours in 20 40% of patients with diabetes and is the leading Suggested itation: Amerian Diabetes Assoiation. Mirovasular ompliations and foot are. Se. 10. In Standards of Medial Care in Diabetesd2017. Diabetes Care 2017;40(Suppl. 1): S88 S by the Amerian Diabetes Assoiation. Readers may use this artile as long as the work is properly ited, the use is eduational and not for profit, and the work is not altered. More information is available at

2 are.diabetesjournals.org Mirovasular Compliations and Foot Care S89 ause of end-stage renal disease (ESRD) (1). Diabeti kidney disease typially develops after a diabetes duration of 10 years, or at least 5 years in type 1 diabetes, but may be present at diagnosis of type 2 diabetes. Sreening for albuminuria an be most easily performed by urinary albumin to reatinine ratio (UACR) in a random spot urine olletion (1,2). Timed or 24-h olletions are more burdensome and add little to predition or auray. Measurement of a spot urine sample for albumin alone (whether by immunoassay or by using a sensitive dipstik test speifi for albuminuria) without simultaneously measuring urine reatinine (Cr) is less expensive but suseptible to false-negative and falsepositive determinations as a result of variation in urine onentration due to hydration. Normal UACR is generally defined as,30 mg/g Cr, and inreased urinary albumin exretion is defined as $30 mg/g Cr. However, UACR is a ontinuous measurement, and differenes within the normal and abnormal ranges are assoiated with renal and ardiovasular outomes. Furthermore, beause of biologial variability in urinary albumin exretion, two of three speimens of UACR olleted within a 3- to 6-month period should be abnormal before onsidering a patient to have albuminuria. Exerise within 24 h, infetion, fever, ongestive heart failure, marked hyperglyemia, menstruation, and marked hypertension may elevate UACR independently of kidney damage. egfr should be alulated from serum Cr using a validated formula. The Chroni Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is generally preferred (2). egfr is routinely reported by laboratories with serum Cr, and egfr alulators are available from An egfr,60 ml/min/ 1.73 m 2 is generally onsidered abnormal, though optimal thresholds for linial diagnosis are debated (3). Urinary albumin exretion and egfr eah vary within people over time, and abnormal results should be onfirmed to stage CKD (1,2). Sine 2003, stage 1 2 CKD has been defined by evidene of kidney damage (usually albuminuria) with egfr $60 ml/min/1.73 m 2,while stages 3 5 CKD have been defined by progressively lower ranges of egfr (4) (Table 10.1). More reently, Kidney Disease: Improving Global Outomes (KDIGO) reommended a more omprehensive Table 10.1 Stages of CKD Stage Desription egfr (ml/min/1.73 m 2 ) 1 Kidney damage* with normal or inreased egfr $90 2 Kidney damage* with mildly dereased egfr Moderately dereased egfr Severely dereased egfr Kidney failure,15 or dialysis *Kidney damage is defined as UACR persistently $30 mg/g Cr or other abnormalities on pathologial, urine, blood, or imaging tests. Adapted from Levey et al. (4). CKD staging that inorporates albuminuria and is more losely assoiated with risks of ardiovasular disease (CVD) and CKD progression (2). It has not been determined whether appliation of the more omplex system aids linial are or improves health outomes. Diagnosis of Diabeti Kidney Disease Diabeti kidney disease is usually a linial diagnosis made based on the presene of albuminuria and/or redued egfr in the absene of signs or symptoms of other primary auses of kidney damage. The typial presentation of diabeti kidney disease is onsidered to inlude a long-standing duration of diabetes, retinopathy, albuminuria without hematuria, and gradually progressive kidney disease. However, signs of CKD may be present at diagnosis or without retinopathy in type 2 diabetes, and redued egfr without albuminuria has been frequently reported in type 1 and type 2 diabetes and is beoming more ommon over time as the prevalene of diabetes inreases in the U.S. (5 8). An ative urinary sediment (ontaining red or white blood ells or ellular asts), rapidly inreasing albuminuria or nephroti syndrome, rapidly dereasing egfr, or the absene of retinopathy (in type 1 diabetes) may suggest alternative or additional auses of kidney disease. For patients with these features, referral to a nephrologist for further diagnosis, inluding the possibility of kidney biopsy, should be onsidered. It is rare for patients with type 1 diabetes to develop kidney disease without retinopathy. In type 2 diabetes, retinopathy is only moderately sensitive and speifi for CKD aused by diabetes, as onfirmed by kidney biopsy (9). Surveillane Albuminuria and egfr should be monitored regularly to enable timely diagnosis of diabeti kidney disease, monitor progression of diabeti kidney disease, assess risk of CKD ompliations, dose drugs appropriately, and determine whether nephrology referral is needed (Table 10.2). Albuminuria and egfr may hange due to progression of diabeti kidney disease, development of superimposed kidney disease, or the effets of mediation, inluding many antihypertensive mediations (e.g., ACE inhibitors, angiotensin reeptor blokers [ARBs], and diuretis) and some gluose-lowering mediations (e.g., sodium gluose otransporter 2 [SGLT2] inhibitors). For patients with egfr,60 ml/min/1.73 m 2, appropriate mediation dosing should be verified, exposure to nephrotoxins (e.g., nonsteroidal antiinflammatory drugs and iodinated ontrast) should be minimized, and potential CKD ompliations should be evaluated. The need for annual quantitative assessment of albumin exretion after diagnosis of albuminuria, institution of ACE inhibitors or ARB therapy, and ahieving blood pressure ontrol is a subjet of debate. Continued surveillane an assess both response to therapy and disease progression and may aid in assessing adherene to ACE inhibitor or ARB therapy. In addition, in linial trials of ACE inhibitors or ARB therapy in type 2 diabetes, reduing albuminuria from levels $300 mg/g Cr has been assoiated with improved renal and ardiovasular outomes, leading some to suggest that mediations should be titrated to minimize UACR. However, this approah has not been formally evaluated in prospetive trials, and in type 1 diabetes, remission of albuminuria may our spontaneously and is not assoiated with improved linial outomes (10). The prevalene of CKD ompliations orrelates with egfr. When egfr is,60 ml/min/1.73 m 2, sreening for ompliations of CKD is indiated (Table 10.2). Early vaination

3 S90 Mirovasular Compliations and Foot Care Diabetes Care Volume 40, Supplement 1, January 2017 Table 10.2 Management of CKD in diabetes egfr (ml/min/1.73 m 2 ) Reommended management All patients Yearly measurement of UACR, serum Cr, potassium Referral to a nephrologist if possibility for nondiabeti kidney disease exists (duration of type 1 diabetes,10 years, persistent albuminuria, abnormal findings on renal ultrasound, resistant hypertension, rapid fall in egfr, or ative urinary sediment on urine mirosopi examination) Consider the need for dose adjustment of mediations Monitor egfr every 6 months Monitor eletrolytes, biarbonate, hemoglobin, alium, phosphorus, and parathyroid hormone at least yearly Assure vitamin D suffiieny Vainate against Hep B virus Consider bone density testing Referral for dietary ounseling Monitor egfr every 3 months Monitor eletrolytes, biarbonate, alium, phosphorus, parathyroid hormone, hemoglobin, albumin, and weight every 3 6 months Consider the need for dose adjustment of mediations,30 Referral to a nephrologist against hepatitis B virus is indiated in patients likely to progress to ESRD. Interventions Nutrition For people with nondialysis-dependent diabeti kidney disease, dietary protein intake should be approximately 0.8 g/kg body weight per day (the reommended daily allowane) (1). Compared with higher levels of dietary protein intake, this level slowed GFR deline with evidene of a greater effet over time. Higher levels of dietary protein intake (.20% of daily alories from protein or.1.3 g/kg/day) have been assoiated with inreased albuminuria, more rapid kidney funtion loss, and CVD mortality and therefore should be avoided. Reduing the amount of dietary protein below the reommended daily allowane of 0.8 g/kg/day is not reommended beause it does not alter glyemi measures, ardiovasular risk measures, or the ourse of GFR deline. Glyemia Intensive glyemi ontrol with the goal of ahieving near-normoglyemia has been shown in large prospetive randomized studies to delay the onset and progression of albuminuria and redued egfr in patients with type 1 diabetes (11,12) and type 2 diabetes (1,13 17). Insulin alone was used to lower blood gluose in the Diabetes Control and Compliations Trial (DCCT)/Epidemiology of Diabetes Interventions and Compliations (EDIC) study of type 1 diabetes, whileavarietyofagentswereusedinlinial trials of type 2 diabetes, supporting the onlusion that glyemi ontrol itself helps prevent diabeti kidney disease and its progression. The effets of gluoselowering therapies on diabeti kidney disease have helped define hemoglobin A1C targets (Table 6.2). Some gluose-lowering mediations also have effets on the kidney that are diret, i.e., not mediated through glyemia. For example, SGLT2 inhibitors redue renal tubular gluose reabsorption, intraglomerular pressure, and albuminuria and slow GFR loss through mehanisms that appear independent of glyemia (18 20). Gluagon-like peptide 1 reeptor agonists and dipeptidyl peptidase 4 inhibitors also have diret effets on the kidney and have been reported to improve renal outomes ompared with plaebo (21,22). Renal effets may be onsidered among other fators when seleting gluose-lowering mediations for individual patients (see Setion 8 Pharmaologi Approahes to Glyemi ). The presene of diabeti kidney disease affets the risks and benefits of intensive glyemi ontrol and a number of speifi gluose-lowering mediations. In the Ation to Control Cardiovasular Risk in Diabetes (ACCORD) trial of type 2 diabetes, adverse effets of intensive glyemi ontrol (hypoglyemia and mortality) were inreased among patients with kidney disease at baseline (23,24). Moreover, there is a lag time of at least 2 years in type 2 diabetes to over 10 years in type 1 diabetes for the effets of intensive gluose ontrol to manifest as improved egfr outomes (17,25,26). Therefore, in some patients with prevalent diabeti kidney disease and substantial omorbidity, target A1C levels should be.7% (53 mmol/mol) (1,27). The gluose-lowering effets of SGLT2 inhibitors are blunted with redued egfr, but the renal and ardiovasular benefits of empagliflozin, ompared with plaebo, were not redued among trial partiipants with baseline egfr ml/min/1.73 m 2, ompared with partiipants with baseline egfr $60 ml/min/1.73 m 2 (19,28). With redued egfr, drug dosing may require modifiation (1). The U.S. Food and Drug Administration (FDA) revised guidane for the use metformin in diabeti kidney disease in 2016 (29), reommending use of egfr instead of serum Cr to guide treatment and expanding the pool of patients with kidney disease for whom metformin treatment should be onsidered. Revised FDA guidane states that metformin is ontraindiated in patients with an egfr,30 ml/min/ 1.73 m 2, egfr should be monitored while taking metformin, the benefits and risks of ontinuing treatment should be reassessed when egfr falls,45 ml/min/1.73 m 2, metformin should not be initiated for patients with an egfr,45 ml/min/1.73 m 2, and metformin should be temporarily disontinued at the time of or before iodinated ontrast imaging proedures in patients with egfr ml/min/ 1.73 m 2. Other gluose-lowering mediations also require dose adjustment or disontinuation at low egfr (1). Cardiovasular Disease and Blood Pressure Patients with diabeti kidney disease are at high risk of CVD. To redue ardiovasular risk, statin therapy and blood pressure treatment should be onsidered in patients with diabeti kidney disease. Blood pressure ontrol redues risk of ardiovasular events (30). Hypertension is a strong risk fator for the development and progression of diabeti kidney disease. Antihypertensive therapy redues the risk of albuminuria (30 32), and among patients with type 1 or 2 diabetes with established diabeti kidney disease (egfr,60 ml/min/1.73 m 2 and UACR $300 mg/g Cr), ACE inhibitor or ARB therapy redue the risk of progression to ESRD (33 35).

4 are.diabetesjournals.org Mirovasular Compliations and Foot Care S91 Blood pressure levels,140/90 mmhg in diabetes are reommended to redue CVD mortality and slow CKD progression. In individuals with albuminuria, who are at inreasedriskofcvdandckdprogression, lower blood pressure targets (e.g.,,130/80 mmhg) may be onsidered (36). Of note, there is an adverse safety signal in linial trials of diabeti kidney disease when diastoli blood pressure is treated to,70 mmhg and espeially,60 mmhg in older populations. As a result, linial judgment should be used when attempting to ahieve systoli blood pressure targets,130 mmhg to avoid diastoli blood pressure levels,60 70 mmhg. ACE inhibitors or ARBs are the preferred first-line agent for blood pressure treatment among patients with diabetes, hypertension, egfr,60 ml/min/1.73 m 2, and UACR $300 mg/g Cr beause of their proven benefits for prevention of CKD progression and major CVD events (37). In general, ACE inhibitors and ARBs are onsidered to have similar benefits (38)andrisks.Inthesettingoflower levels of albuminuria ( mg/g Cr), ACE inhibitor or ARB therapy has been demonstrated to redue progression to more advaned albuminuria ($300 mg/g Cr) and ardiovasular events but not progression to ESRD (37,39). While ACE inhibitors or ARB are often presribed for albuminuria without hypertension, linial trials have not been performed in this setting to determine whether this improves renal outomes. Absent kidney disease, ACE inhibitors or ARBs are useful to ontrol blood pressure but may not be superior to alternative lasses of antihypertensive therapy (40). In a trial of people with type 2 diabetes and normal urine albumin exretion, an ARB redued or suppressed the development of albuminuria but inreased the rate of ardiovasular events (41). In a trial of people with type 1 diabetes exhibiting neither albuminuria nor hypertension, ACE inhibitors or ARBs did not prevent the development of diabeti glomerulopathy assessed by kidney biopsy (42). Therefore, ACE inhibitors or ARBs are not reommended for patients without hypertension to prevent the development of diabeti kidney disease. Two linial trials studied the ombinations of ACE inhibitors and ARBs and found no benefits on CVD or diabeti kidney disease, and the drug ombination had higher adverse event rates (hyperkalemia and/or aute kidney injury) (43). Therefore, the ombined use of ACE inhibitors and ARBs should be avoided. Mineraloortioid reeptor antagonists (spironolatone, eplerenone, and finerenone) in ombination with ACE inhibitors or ARBs remain an area of great interest. Mineraloortioid reeptor antagonists areeffetiveformanagementofresistant hypertension, have been shown to redue albuminuria in short-term studies of diabeti kidney disease, and may have additional ardiovasular benefits (44 46). There has been, however, an inrease in hyperkalemi episodes in those on dual therapy, and larger, longer trials with linial outomes are needed before reommending suh therapy. Diuretis, alium hannel blokers, and b-blokers an be used as add-on therapy to ahieve blood pressure goals in patients treated with maximum doses of ACE inhibitors or ARBs (47) or as alternate therapy in the rare individual unable to tolerate ACE inhibitors and ARBs. Referral to a Nephrologist Consider referral to a physiian experiened in the are of kidney disease when there is unertainty about the etiology of kidney disease, diffiult management issues (anemia, seondary hyperparathyroidism, metaboli bone disease, resistant hypertension, or eletrolyte disturbanes), or advaned kidney disease (egfr,30 ml/min/1.73 m 2 ) requiring disussion of renal replaement therapy for ESRD. The threshold for referral may vary depending on the frequeny with whih a provider enounters patients with diabetes and kidney disease. Consultation with a nephrologist when stage 4 CKD develops (egfr #30 ml/min/1.73 m 2 ) has been found to redue ost, improve quality of are, and delay dialysis (48). However, other speialists and providers should also eduate their patients about the progressive nature of diabeti kidney disease, the kidney preservation benefits of proative treatment of blood pressure and blood gluose, and the potential need for renal replaement therapy. DIABETIC RETINOPATHY Reommendations Optimize glyemi ontrol to redue the risk or slow the progression of diabeti retinopathy. A Optimize blood pressure and serum lipid ontrol to redue the risk or slow the progression of diabeti retinopathy. A Sreening Adults with type 1 diabetes should have an initial dilated and omprehensive eye examination by an ophthalmologist or optometrist within 5 years after the onset of diabetes. B Patients with type 2 diabetes should have an initial dilated and omprehensive eye examination by an ophthalmologist or optometristatthetimeofthediabetes diagnosis. B If there is no evidene of retinopathy for one or more annual eye exams and glyemia is well ontrolled, then exams every 2 years may be onsidered. If any level of diabeti retinopathy is present, subsequent dilated retinal examinations should be repeated at least annually by an ophthalmologist or optometrist. If retinopathy is progressing or sight-threatening, then examinations will be required more frequently. B While retinal photography may serve as a sreening tool for retinopathy, it is not a substitute for a omprehensive eye exam. E Women with preexisting type 1 or type 2 diabetes who are planning pregnany or who are pregnant should be ounseled on the risk of development and/or progression of diabeti retinopathy. B Eye examinations should our before pregnany or in the first trimester in patients with preexisting type 1 or type 2 diabetes, and then patients should be monitored every trimesterandfor1yearpostpartum as indiated by the degree of retinopathy. B Promptly refer patients with any level of maular edema, severe nonproliferative diabeti retinopathy (a preursor of proliferative diabeti retinopathy), or any proliferative diabeti retinopathy to an ophthalmologist who is knowledgeable and experiened in the management of diabeti retinopathy. A Laser photooagulation therapy is indiated to redue the risk of vision

5 S92 Mirovasular Compliations and Foot Care Diabetes Care Volume 40, Supplement 1, January 2017 loss in patients with high-risk proliferative diabeti retinopathy and, in some ases, severe nonproliferative diabeti retinopathy. A Intravitreal injetions of anti vasular endothelial growth fator are indiated for entral-involved diabeti maular edema, whih ours beneath the foveal enter and may threaten reading vision. A The presene of retinopathy is not a ontraindiation to aspirin therapy for ardioprotetion, as aspirin does not inrease the risk of retinal hemorrhage. A Diabeti retinopathy is a highly speifi vasular ompliation of both type 1 andtype2diabetes,withprevalene stronglyrelatedtoboththeduration of diabetes and the level of glyemi ontrol. Diabeti retinopathy is the most frequent ause of new ases of blindness among adults aged years in developed ountries. Glauoma, atarats, and other disorders of the eye our earlier and more frequently in people with diabetes. In addition to diabetes duration, fators that inrease the risk of, or are assoiated with, retinopathy inlude hroni hyperglyemia (49), nephropathy (50), hypertension (51), and dyslipidemia (52). Intensive diabetes management with the goal of ahieving near-normoglyemia has been shown in large prospetive randomized studies to prevent and/or delay the onset and progression of diabeti retinopathy and potentially improve patient-reported visual funtion (14,53 55). Lowering blood pressure has been showntodereaseretinopathyprogression, although tight targets (systoli blood pressure,120 mmhg) do not impart additional benefit (54). ACE inhibitors and ARBsarebotheffetivetreatmentsindiabeti retinopathy (56). In patients with dyslipidemia, retinopathy progression may be slowed by the addition of fenofibrate, partiularly with very mild nonproliferative diabeti retinopathy (NPDR) at baseline (52). Several ase series and a ontrolled prospetive study suggest that pregnany in patients with type 1 diabetes may aggravate retinopathy and threaten vision, espeially when glyemi ontrol is poor at the time of oneption (57,58). Laser photooagulation surgery an minimize the risk of vision loss (58). Sreening The preventive effets of therapy and the fat that patients with proliferative diabeti retinopathy (PDR) or maular edema may be asymptomati provide strong support for sreening to detet diabeti retinopathy. An ophthalmologist or optometrist who is knowledgeable and experiened in diagnosing diabeti retinopathy should perform the examinations. If diabeti retinopathy is present, prompt referral to an ophthalmologist is reommended. Subsequent examinations for patients with type 1 or type 2 diabetes are generally repeated annually for patients with minimal to no retinopathy. Exams every 2 years maybeost-effetiveafteroneormore normal eye exams, and in a population with well-ontrolled type 2 diabetes, there was essentially no risk of development of signifiant retinopathy with a 3-year interval after a normal examination (59). More frequent examinations by the ophthalmologist will be required if retinopathy is progressing. Retinal photography with remote reading by experts has great potential to provide sreening servies in areas where qualified eye are professionals are not readily available (60,61). Highquality fundus photographs an detet most linially signifiant diabeti retinopathy. Interpretation of the images should be performed by a trained eye are provider. Retinal photography may also enhane effiieny and redue osts when the expertise of ophthalmologists an be used for more omplex examinations and for therapy (62). In-person exams are still neessary when the retinal photos are of unaeptable quality and for follow-up if abnormalities are deteted. Retinal photos are not a substitute for omprehensive eye exams, whih should be performed at least initially and at intervals thereafter as reommended by an eye are professional. Results of eye examinations should be doumented and transmitted to the referring health are professional. Type 1 Diabetes Beause retinopathy is estimated to take at least 5 years to develop after the onset of hyperglyemia, patients with type 1 diabetes should have an initial dilated and omprehensive eye examination within 5 years after the diagnosis of diabetes (63). Type 2 Diabetes Patients with type 2 diabetes who may have had years of undiagnosed diabetes and have a signifiant risk of prevalent diabeti retinopathy at the time of diagnosis should have an initial dilated and omprehensive eye examination at the time of diagnosis. Pregnany Pregnany is assoiated with a rapid progression of diabeti retinopathy (64,65). Women with preexisting type 1 or type 2 diabetes who are planning pregnany or who have beome pregnant should be ounseled on the risk of development and/or progression of diabeti retinopathy. In addition, rapid implementation of intensive glyemi management in the setting of retinopathy is assoiated with early worsening of retinopathy (58). Women who develop gestational diabetes mellitus do not require eye examinations during pregnany and do not appear to be at inreased risk of developing diabeti retinopathy during pregnany (66). Two of the main motivations for sreening for diabeti retinopathy are to prevent loss of vision and to intervene with treatment when vision loss an be prevented or reversed. Photooagulation Surgery Two large trials, the Diabeti Retinopathy Study (DRS) in patients with PDR and the Early Diabeti Retinopathy Study (ETDRS) in patients with maular edema, provide the strongest support for the therapeuti benefits of photooagulation surgery. The DRS (67) showed that panretinal photooagulation surgery redued the risk of severe vision loss from PDR from 15.9% in untreated eyes to 6.4% in treated eyes with the greatest benefit ratiointhosewithmoreadvanedbaseline disease (dis neovasularization or vitreous hemorrhage). The ETDRS also verified the benefits of panretinal photooagulation for high-risk PDR and in older-onset patients with severe NPDR or less-than-high-risk PDR. Panretinal laser photooagulation is still ommonly used to manage ompliations of diabeti retinopathy that involve retinal neovasularization and its ompliations. Anti Vasular Endothelial Growth Fator While the ETDRS (68) established the benefit of foal laser photooagulation

6 are.diabetesjournals.org Mirovasular Compliations and Foot Care S93 surgery in eyes with linially signifiant maular edema (defined as retinal edema loated at or within 500 mm of the enter of the maula), urrent data from well-designed linial trials demonstrate that intravitreal anti vasular endothelial growth fator (anti-vegf) agents provide a more effetive treatment regimen for entral-involved diabeti maular edema than monotherapy or even ombination therapy with laser (69 71). In both trials, laser photooagulation surgery was benefiial in reduing the risk of further visual loss in affeted patients but generally not benefiial in reversing already diminished auity. Now, anti-vegf improves vision and has replaed the need for laser photooagulation in the vast majority of patients with diabeti maular edema in most ases (72). Most patients require near-monthly administration of intravitreal therapy with anti-vegf agents during the first 12 months of treatment with fewer injetions needed in subsequent years to maintain remission from entralinvolved diabeti maular edema. Intravitreous anti-vegf therapy is also a potentially viable alternative treatment for PDR (73). Other emerging therapies for retinopathy that may use sustained intravitreal delivery of pharmaologi agents are urrently under investigation. NEUROPATHY Reommendations Sreening All patients should be assessed for diabeti peripheral neuropathy starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes and at least annually thereafter. B Assessment for distal symmetri polyneuropathy should inlude a areful history and assessment of either temperature or pinprik sensation (small-fiber funtion) and vibration sensation using a 128-Hz tuning fork (for large-fiber funtion). All patients should have annual 10-g monofilament testing to identify feet at risk for uleration and amputation. B Symptoms and signs of autonomi neuropathy should be assessed in patients with mirovasular and neuropathi ompliations. E Optimize gluose ontrol to prevent or delay the development of neuropathy in patients with type 1 diabetes A andtoslowtheprogression of neuropathy in patients with type 2 diabetes. B Assess and treat patients to redue pain related to diabeti peripheral neuropathy B and symptoms of autonomi neuropathy and to improve quality of life. E Either pregabalin or duloxetine are reommended as initial pharmaologi treatments for neuropathi pain in diabetes. A The diabeti neuropathies are a heterogeneous group of disorders with diverse linial manifestations. The early reognition and appropriate management of neuropathy in the patient with diabetes is important. 1. Diabeti neuropathy is a diagnosis of exlusion. Nondiabeti neuropathies may be present in patients with diabetes and may be treatable. 2. Numerous treatment options exist for symptomati diabeti neuropathy. 3. Up to 50% of diabeti peripheral neuropathy (DPN) may be asymptomati. If not reognized and if preventive foot are is not implemented, patients are at risk for injuries to their insensate feet. 4. Reognition and treatment of autonomi neuropathy may improve symptoms, redue sequelae, and improve quality of life. Speifi treatment for the underlying nerve damage, other than improved glyemi ontrol, is urrently not available. Glyemi ontrol an effetively prevent DPN and ardia autonomi neuropathy (CAN) in type 1 diabetes (74,75) and may modestly slow their progression in type 2 diabetes (16) but does not reverse neuronal loss. Therapeuti strategies (pharmaologi and nonpharmaologi) for the relief of painful DPN and symptoms of autonomi neuropathy an potentially redue pain (76) and improve quality of life. Diagnosis Diabeti Peripheral Neuropathy Patients with type 1 diabetes for 5 or more years and all patients with type 2 diabetes should be assessed annually for DPN using the medial history and simple linial tests. Symptoms vary aording to the lass of sensory fibers involved. The most ommon early symptoms are indued by the involvement of small fibers and inlude pain and dysesthesias (unpleasant sensations of burning and tingling). The involvement of large fibers may ause numbness and loss of protetive sensation (LOPS). LOPS indiates the presene of distal sensorimotor polyneuropathy and is a risk fator for diabeti foot uleration. The following linial tests may be used to assess smalland large-fiber funtion and protetive sensation: 1. Small-fiber funtion: pinprik and temperature sensation 2. Large-fiber funtion: vibration pereption, 10-g monofilament, and ankle reflexes 3. Protetive sensation: 10-g monofilament These tests not only sreen for the presene of dysfuntion but also predit future risk of ompliations. Eletrophysiologial testing or referral to a neurologist is rarely needed, exept in situations where the linial features are atypial or the diagnosis is unlear. In all patients with diabetes and DPN, auses of neuropathy other than diabetes should be onsidered, inluding toxins (alohol), neurotoxi mediations (hemotherapy), vitamin B12 defiieny, hypothyroidism, renal disease, malignanies (multiple myeloma, bronhogeni arinoma), infetions (HIV), hroni inflammatory demyelinating neuropathy, inherited neuropathies, and vasulitis (77). Diabeti Autonomi Neuropathy The symptoms and signs of autonomi neuropathy should be eliited arefully during the history and physial examination. Major linial manifestations of diabeti autonomi neuropathy inlude hypoglyemia unawareness, resting tahyardia, orthostati hypotension, gastroparesis, onstipation, diarrhea, feal inontinene, eretile dysfuntion, neurogeni bladder, and sudomotor dysfuntion with either inreased or dereased sweating.

7 S94 Mirovasular Compliations and Foot Care Diabetes Care Volume 40, Supplement 1, January 2017 Cardia Autonomi Neuropathy CAN is assoiated with mortality independently of other ardiovasular risk fators (78,79). In its early stages, CAN may be ompletely asymptomati and deteted only by dereased heart rate variability with deep breathing. Advaned disease may be assoiated with resting tahyardia (.100 bpm) and orthostati hypotension (a fall in systoli or diastoli blood pressure by.20 mmhg or.10 mmhg, respetively, upon standing without an appropriate inrease in heart rate). CAN treatment is generally foused on alleviating symptoms. Gastrointestinal Neuropathies Gastrointestinal neuropathies may involve any portion of the gastrointestinal trat with manifestations inluding esophageal dysmotility, gastroparesis, onstipation, diarrhea, and feal inontinene. Gastroparesis should be suspeted in individuals with errati glyemi ontrol or with upper gastrointestinal symptoms without another identified ause. Exlusion of organi auses of gastri outlet obstrution or pepti uler disease (with esophagogastroduodenosopy or a barium study of the stomah) is needed before onsidering a diagnosis of or speialized testing for gastroparesis. The diagnosti gold standard for gastroparesis is the measurement of gastri emptying with sintigraphy of digestible solids at 15-min intervals for 4 h after food intake. The use of 13 Cotanoiaidbreathtest is emerging as a viable alternative. Genitourinary Disturbanes Diabeti autonomi neuropathy may also ause genitourinary disturbanes, inluding sexual dysfuntion and bladder dysfuntion. In men, diabeti autonomi neuropathy may ause eretile dysfuntion and/or retrograde ejaulation (76). Female sexual dysfuntion ours more frequently in those with diabetes and presents as dereased sexual desire, inreased pain during interourse, dereased sexual arousal, and inadequate lubriation (80). Lower urinary trat symptoms manifest as urinary inontinene and bladder dysfuntion (noturia, frequent urination, urination urgeny, and weak urinary stream). Evaluation of bladder funtion should be performed for individuals with diabetes who have reurrent urinary trat infetions, pyelonephritis, inontinene, or a palpable bladder. Glyemi Control Near-normal glyemi ontrol, implemented early in the ourse of diabetes, has been shown to effetively delay or prevent the development of DPN and CAN in patients with type 1 diabetes (81 84). Although the evidene for the benefit of near-normal glyemi ontrol is not as strong for type 2 diabetes, some studies have demonstrated a modest slowing of progression without reversal of neuronal loss (16,85). Speifi gluoselowering strategies may have different effets. In a post ho analysis, partiipants, partiularly men, in the Bypass Angioplasty Revasularization Investigation in Type 2 Diabetes (BARI 2D) trial treated with insulin sensitizers had a lower inidene of distal symmetri polyneuropathy over 4 years than those treated with insulin/sulfonylurea (86). Neuropathi Pain Neuropathi pain an be severe and an impat quality of life, limit mobility, and ontribute to depression and soial dysfuntion (87). No ompelling evidene exists in support of glyemi ontrol or lifestyle management as therapies for neuropathi pain in diabetes or prediabetes, whih leaves only pharmaeutial interventions. Pregabalin and duloxetine have reeived regulatory approval by the FDA, Health Canada, and the European Mediines Ageny for the treatment of neuropathi pain in diabetes. The opioid tapentadol has regulatory approval in the U.S. and Canada, but the evidene of its use is weaker (88). Comparative effetiveness studies and trials that inlude quality-of-life outomes are rare, so treatment deisions must onsider eah patient s presentation and omorbidities and often follow a trial-and-error approah. Given the range of partially effetive treatment options, a tailored and stepwise pharmaologi strategy with areful attention to relative symptom improvement, mediation adherene, and mediation side effets is reommended to ahieve pain redution and improve quality of life (89 91). Pregabalin, a alium hannel a2-d subunit ligand, is the most extensively studied drug for DPN. The majority of studies testing pregabalin have reported favorable effets on the proportion of partiipants with at least 30 50% improvement in pain (88,90,92 95). However, not all trials with pregabalin have been positive (88,90,96,97), espeially when treating patients with advaned refratory DPN (94). Adverse effets may be more severe in older patients (98) and may be attenuated by lower starting doses and more gradual titration. Duloxetine is a seletive norepinephrine and serotonin reuptake inhibitor. Doses of 60 and 120 mg/day showed effiay in the treatment of pain assoiated with DPN in multienter randomized trials, although some of these had high drop-out rates (88,90,95,97). Duloxetine also appeared to improve neuropathyrelated quality of life (99). In longer-term studies, a small inrease in A1C was reported in people with diabetes treated with duloxetine ompared with plaebo (100). Adverse events may be more severe in older people, but may be attenuated with lower doses and slower titrations of duloxetine. Tapentadol is a entrally ating opioid analgesi that exerts its analgesi effets through both m-opioid reeptor agonism and noradrenaline reuptake inhibition. Extended-release tapentadol was approved by the FDA for the treatment of neuropathi pain assoiated with diabetes based on data from two multienter linial trials in whih partiipants titrated to an optimal dose of tapentadol were randomly assigned to ontinue that dose or swith to plaebo (101,102). However, both used a design enrihed for patients who responded to tapentadol and therefore their results are not generalizable. A reent systemati review and meta-analysis by the Speial Interest Group on Neuropathi Pain of the International Assoiation for the Study of Pain found the evidene supporting the effetiveness of tapentadol in reduing neuropathi pain to be inonlusive (88). Therefore, given the high risk for addition and safety onerns ompared with the relatively modest pain redution, the use of tapentadol ER is not generally reommended as a firstor seond-line therapy. Triyli antidepressants, gabapentin, venlafaxine, arbamazepine, tramadol, and topial apsaiin, although not approved for the treatment of painful DPN, may be effetive and onsidered for the treatment of painful DPN (76,88,90).

8 are.diabetesjournals.org Mirovasular Compliations and Foot Care S95 Orthostati Hypotension Treating orthostati hypotension is hallenging. The therapeuti goal is to minimize postural symptoms rather than to restore normotension. Most patients require both nonpharmaologi measures (e.g., ensuring adequate salt intake, avoiding mediations that aggravate hypotension, or using ompressive garments over the legs and abdomen) and pharmaologi measures. Physial ativity and exerise should be enouraged to avoid deonditioning, whih is known to exaerbate orthostati intolerane, and volume repletion with fluids and salt is ritial. Midodrine and droxidopa are approved by the FDA for the treatment of orthostati hypotension. Gastroparesis for diabeti gastroparesis may be very hallenging. Dietary hanges may be useful, suh as eating multiple small meals and dereasing dietary fat and fiber intake. Withdrawing drugs with adverse effets on gastrointestinal motility inluding opioids, antiholinergis, triyli antidepressants, gluagon-like peptide 1 reeptor agonists, pramlintide, and possibly dipeptidyl peptidase 4 inhibitors, may also improve intestinal motility (103,104). In ases of severe gastroparesis, pharmaologi interventions are needed. Only metolopramide, a prokineti agent, is approved by the FDA for the treatment of gastroparesis. However, the level of evidene regarding the benefits of metolopramide for the management of gastroparesisisweak,andgiventheriskforserious adverse effets (extrapyramidal signs suh as aute dystoni reations, drug-indued parkinsonism, akathisia, and tardive dyskinesia), its use in the treatment of gastroparesis beyond 5 days is no longer reommended by the FDA or the European Mediines Ageny. It should be reserved for severe ases that are unresponsive to other therapies (104). Eretile Dysfuntion s for eretile dysfuntion may inlude phosphodiesterase type 5 inhibitors, intraorporeal or intraurethral prostaglandins, vauum devies, or penile prostheses. As with DPN treatments, these interventions do not hange the underlying pathology and natural history of the disease proess but may improve the patient s quality of life. FOOT CARE Reommendations Perform a omprehensive foot evaluation at least annually to identify risk fators for ulers and amputations. B All patients with diabetes should have their feet inspeted at every visit. C Obtain a prior history of uleration, amputation, Charot foot, angioplasty or vasular surgery, igarette smoking, retinopathy, and renal disease and assess urrent symptoms of neuropathy (pain, burning, numbness) and vasular disease (leg fatigue, laudiation). B The examination should inlude inspetion of the skin, assessment of foot deformities, neurologial assessment (10-g monofilament testing with at least one other assessment: pinprik, temperature, vibration, or ankle reflexes), and vasular assessment inluding pulses in the legs and feet. B Patients with symptoms of laudiation or dereased or absent pedal pulses should be referred for ankle-brahial index and for further vasular assessment as appropriate. C A multidisiplinary approah is reommended for individuals with foot ulers and high-risk feet (e.g., dialysis patients and those with Charot foot, prior ulers, or amputation). B Refer patients who smoke or who have histories of prior lowerextremity ompliations, loss of protetive sensation, strutural abnormalities, or peripheral arterial disease to foot are speialists for ongoing preventive are and lifelong surveillane. C Provide general preventive foot self-are eduation to all patients with diabetes. B The use speialized therapeuti footwear is reommended for high-risk patients with diabetes inluding those with severe neuropathy, foot deformities, or history of amputation. B Foot ulers and amputation, whih are onsequenes of diabeti neuropathy and/or peripheral arterial disease (PAD), are ommon and represent major auses of morbidity and mortality in people with diabetes. Early reognition and treatment of patients with diabetes and feet at risk for ulers and amputations an delay or prevent adverse outomes. The risk of ulers or amputations is inreasedinpeoplewhohavethefollowing risk fators: Poor glyemi ontrol Peripheral neuropathy with LOPS Cigarette smoking Foot deformities Preulerative allus or orn PAD History of foot uler Amputation Visual impairment Diabeti nephropathy (espeially patients on dialysis) Cliniians are enouraged to review Amerian Diabetes Assoiation sreening reommendations for further details and pratial desriptions of how to perform omponents of the omprehensive foot examination (105). Evaluation for Loss of Protetive Sensation All adults with diabetes should undergo a omprehensive foot evaluation at least annually. Detailed foot assessments may our more frequently in patientswithhistoriesofulersoramputations, foot deformities, insensate feet, and PAD (106). Foot inspetions should our at every visit in all patients with diabetes. To assess risk, liniians should ask about history of foot ulers or amputation, neuropathi and peripheral vasular symptoms, impaired vision, renal disease, tobao use, and foot are praties. A general inspetion of skin integrity and musuloskeletal deformities should be performed. Vasular assessment should inlude inspetion and palpation of pedal pulses. The neurologial exam performed as part of the foot examination is designed to identify LOPS rather than early neuropathy. The 10-g monofilament is the most useful test to diagnose LOPS. Ideally, the 10-g monofilament test should be performed with at least one other assessment (pinprik, temperature or vibration sensation using a 128-Hz tuning fork, or ankle reflexes). Absent monofilament sensation suggests LOPS, while at least two normal tests (and no abnormal test) rules out LOPS.

9 S96 Mirovasular Compliations and Foot Care Diabetes Care Volume 40, Supplement 1, January 2017 Evaluation for Peripheral Arterial Disease Initial sreening for PAD should inlude a history of dereased walking speed, leg fatigue, laudiation, and an assessment of the pedal pulses. Ankle-brahial index testing should be performed in patients with symptoms or signs of PAD. Patient Eduation All patients with diabetes and partiularly those with high-risk foot onditions (history of uler or amputation, deformity, LOPS, or PAD) and their families should be provided general eduation about risk fators and appropriate management (107). Patients at risk should understand the impliations of foot deformities, LOPS, and PAD; the proper are of the foot, inluding nail and skin are; and the importane of foot monitoring on a daily basis. Patients with LOPS should be eduated on ways to substitute other sensory modalities (palpation or visual inspetion using an unbreakable mirror) for surveillane of early foot problems. The seletion of appropriate footwear and footwear behaviors at home should also be disussed. Patients understanding of these issues and their physial ability to ondut proper foot surveillane and are should be assessed. Patients with visual diffiulties, physial onstraints preventing movement, or ognitive problems that impair their ability to assess the ondition of the foot and to institute appropriate responses will need other people, suh as family members, to assist with their are. People with neuropathy or evidene of inreased plantar pressures (e.g., erythema, warmth, or alluses) may be adequately managed with well-fitted walking shoes or athleti shoes that ushion the feet and redistribute pressure. People with bony deformities (e.g., hammertoes, prominent metatarsal heads, bunions) may need extrawide or deep shoes. People with bony deformities, inluding Charot foot, who annot be aommodated with ommerial therapeuti footwear, will require ustom-molded shoes. Speial onsideration and a thorough workup should be performed when patients with neuropathy present with the aute onset of a red, hot, swollen foot or ankle, and Charot neuroarthropathy should be exluded. Early diagnosis and treatment of Charot neuroarthropathy is the best way to prevent deformities that inrease the risk of uleration and amputation. The routine presription of therapeuti footwear is not generally reommended. However, patients should be provided adequate information to aid in seletion of appropriate footwear. General footwear reommendations inlude a broad and square toe box, laes with three or four eyes per side, padded tongue, quality lightweight materials, and suffiient size to aommodate a ushioned insole. Use of ustom therapeuti footwear an help redue the risk of future foot ulers in high-risk patients (106,108). Most diabeti foot infetions are polymirobial, with aerobi gram-positive oi. Staphylooi and Streptooi are the most ommon ausative organisms. Wounds without evidene of softtissue or bone infetion do not require antibioti therapy. Empiri antibioti therapy an be narrowly targeted at gram-positive oi in many patients with aute infetions, but those at risk for infetion with antibioti-resistant organisms or with hroni, previously treated, or severe infetions require broader-spetrum regimens and should be referred to speialized are enters (109). Foot ulers and wound are may require are by a podiatrist, orthopedi or vasular surgeon, or rehabilitation speialist experiened in the management of individuals with diabetes (109). Referenes 1. Tuttle KR, Bakris GL, Bilous RW, et al. Diabeti kidney disease: a report from an ADA Consensus Conferene. Diabetes Care 2014;37: National Kidney Foundation. KDIGO 2012 linial pratie guideline for the evaluation and management of hroni kidney disease. Kidney Int Suppl 2013;3: Delanaye P, Glassok RJ, Pottel H, Rule AD. An age-alibrated definition of hroni kidney disease: rationale and benefits. Clin Biohem Rev 2016;37: Levey AS, Coresh J, Balk E, et al. National Kidney Foundation pratie guidelines for hroni kidney disease: evaluation, lassifiation, and stratifiation. Ann Intern Med 2003;139: de Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss NS, Himmelfarb J. Temporal trends in the prevalene of diabeti kidney disease in the United States. JAMA 2011;305: Afkarian M, Zelnik LR, Hall YN, et al. Clinial manifestations of kidney disease among US adults with diabetes, JAMA 2016; 316: Kramer HJ, Nguyen QD, Curhan G, Hsu C-Y. Renal insuffiieny in the absene of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA 2003;289: Molith ME, Steffes M, Sun W, et al. Development and progression of renal insuffiieny with and without albuminuria in adults with type 1 diabetes in the Diabetes Control and Compliations Trial and the Epidemiology of Diabetes Interventions and Compliations study. Diabetes Care 2010;33: He F, Xia X, Wu XF, Yu XQ, Huang FX. Diabeti retinopathy in prediting diabeti nephropathy in patients with type 2 diabetes and renal disease: a meta-analysis. Diabetologia 2013;56: de Boer IH, Gao X, Cleary PA, Bebu I, Lahin JM, Molith ME, et al. Albuminuria hanges and ardiovasular and renal outomes in type 1 diabetes: the DCCT/EDIC study. Clin J Am So Nephrol 2016;11: DCCT/EDIC Researh Group. Effet of intensive diabetes treatment on albuminuria in type 1 diabetes: long-term follow-up of the Diabetes Control and Compliations Trial and Epidemiology of Diabetes Interventions and Compliations study. Lanet Diabetes Endorinol 2014;2: DCCT/EDIC Researh Group, de Boer IH, Sun W, et al. Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. N Engl J Med 2011;365: UK Prospetive Diabetes Study (UKPDS) Group. Effet of intensive blood-gluose ontrol with metformin on ompliations in overweight patients with type 2 diabetes (UKPDS 34). Lanet 1998;352: UK Prospetive Diabetes Study (UKPDS) Group. Intensive blood-gluose ontrol with sulphonylureas or insulin ompared with onventional treatment and risk of ompliations in patients with type 2 diabetes (UKPDS 33). Lanet 1998;352: ADVANCE Collaborative Group, Patel A, MaMahon S, et al. Intensive blood gluose ontrol and vasular outomes in patients with type 2 diabetes. N Engl J Med 2008;358: Ismail-Beigi F, Craven T, Banerji MA, et al. Effet of intensive treatment of hyperglyaemia on mirovasular outomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lanet 2010;376: Zoungas S, Chalmers J, Neal B, et al. Follow-up of blood-pressure lowering and gluose ontrol in type 2 diabetes. N Engl J Med 2014;371: Cherney DZI, Perkins BA, Soleymanlou N, et al. Renal hemodynami effet of sodium-gluose otransporter 2 inhibition in patients with type 1 diabetes mellitus. Cirulation 2014;129: Wanner C, Inzuhi SE, Lahin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375: Heerspink HJL, Desai M, Jardine M, Balis D, Meininger G, Perkovi V. Canagliflozin slows progression of renal funtion deline independently of glyemi effets. J Am So Nephrol. 18 August 2016 [Epub ahead of print]. DOI: /ASN MarsoSP,DanielsGH,Brown-FrandsenK,etal. Liraglutide and ardiovasular outomes in type 2 diabetes. N Engl J Med 2016;375: Cooper ME, Perkovi V, MGill JB, et al. Kidney disease end points in a pooled analysis of