MICROVASCULAR COMPLICATIONS AND FOOT CARE: STANDARDSOF MEDICALCAREINDIABETESD2021 - DIABETES CARE
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Diabetes Care Volume 44, Supplement 1, January 2021 S151
11. Microvascular Complications American Diabetes Association
and Foot Care: Standards of
Medical Care in Diabetesd2021
Diabetes Care 2021;44(Suppl. 1):S151–S167 | https://doi.org/10.2337/dc21-S011
11. MICROVASCULAR COMPLICATIONS AND FOOT CARE
The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”
includes the ADA’s current clinical practice recommendations and is intended to
provide the components of diabetes care, general treatment goals and guidelines,
and tools to evaluate quality of care. Members of the ADA Professional Practice
Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc21-
SPPC), are responsible for updating the Standards of Care annually, or more
frequently as warranted. For a detailed description of ADA standards, statements,
and reports, as well as the evidence-grading system for ADA’s clinical practice
recommendations, please refer to the Standards of Care Introduction (https://doi
.org/10.2337/dc21-SINT). Readers who wish to comment on the Standards of Care
are invited to do so at professional.diabetes.org/SOC.
For prevention and management of diabetes complications in children and adoles-
cents, please refer to Section 13 “Children and Adolescents” (https://doi.org/10.2337/
dc21-S013).
CHRONIC KIDNEY DISEASE
Screening
Recommendations
11.1a At least annually, urinary albumin (e.g., spot urinary albumin-to-creatinine
ratio) and estimated glomerular filtration rate should be assessed in
patients with type 1 diabetes with duration of $5 years and in all patients
with type 2 diabetes regardless of treatment. B
11.1b Patients with diabetes and urinary albumin .300 mg/g creatinine and/or
an estimated glomerular filtration rate 30–60 mL/min/1.73 m2 should be
monitored twice annually to guide therapy. B
Treatment Suggested citation: American Diabetes Associa-
tion. 11. Microvascular complications and foot
Recommendations care: Standards of Medical Care in Diabetesd
2021. Diabetes Care 2021;44(Suppl. 1):S151–
11.2 Optimize glucose control to reduce the risk or slow the progression of S167
chronic kidney disease. A
© 2020 by the American Diabetes Association.
11.3a For patients with type 2 diabetes and diabetic kidney disease, consider use Readers may use this article as long as the work is
of a sodium–glucose cotransporter 2 inhibitor in patients with an estimated properly cited, the use is educational and not for
glomerular filtration rate $30 mL/min/1.73 m2 and urinary albumin profit, and the work is not altered. More infor-
.300 mg/g creatinine. A mation is available at https://www.diabetesjournals
.org/content/license.S152 Microvascular Complications and Foot Care Diabetes Care Volume 44, Supplement 1, January 2021
false-positive determinations as a result
11.3b In patients with type 2 diabetes 11.9 An ACE inhibitor or an angio-
of variation in urine concentration due
and diabetic kidney disease, tensin receptor blocker is not
to hydration (8).
consider use of sodium–glucose recommended for the primary
Normal UACR is defined as ,30 mg/g
cotransporter 2 inhibitors addi- prevention of chronic kidney
Cr, and high urinary albumin excretion is
tionally for cardiovascular risk disease in patients with diabe-
defined as $30 mg/g Cr. However, UACR
reduction when estimated glo- tes who have normal blood pres-
is a continuous measurement, and differ-
merular filtration rate and uri- sure, normal urinary albumin-to-
ences within the normal and abnormal
nary albumin creatinine are $30 creatinine ratio (,30 mg/g cre-
ranges are associated with renal and
mL/min/1.73 m2 or .300 mg/g, atinine), and normal estimated
cardiovascular outcomes (7,9,10). Fur-
respectively. A glomerular filtration rate. A
thermore, because of high biological var-
11.3c In patients with chronic kidney 11.10 Patients should be referred for
iability of .20% between measurements
disease who are at increased evaluation by a nephrologist if
in urinary albumin excretion, two of three
risk for cardiovascular events, they have an estimated glomer-
specimens of UACR collected within a 3- to
use of a glucagon-like peptide ular filtration rate ,30 mL/min/
6-month period should be abnormal be-
1 receptor agonist reduces renal 1.73 m2. A
fore considering a patient to have high or
end point, primarily albumin- 11.11 Promptly refer to a physician
very high albuminuria (1,2,11,12). Exer-
uria, progression of albumin- experienced in the care of kid-
cise within 24 h, infection, fever, conges-
uria, and cardiovascular events ney disease for uncertainty
tive heart failure, marked hyperglycemia,
(Table 9.1). A about the etiology of kidney
menstruation, and marked hypertension
11.4 Optimize blood pressure con- disease, difficult management
may elevate UACR independently of kid-
trol to reduce the risk or slow issues, and rapidly progressing
ney damage (13).
the progression of chronic kid- kidney disease. A
eGFR should be calculated from serum
ney disease. A
creatinine using a validated formula. The
11.5 Do not discontinue renin-
Epidemiology of Diabetes and Chronic Chronic Kidney Disease Epidemiology Col-
angiotensin system blockade
Kidney Disease laboration (CKD-EPI) equation is generally
for minor increases in serum
Chronic kidney disease (CKD) is diagnosed preferred (2). eGFR is routinely reported by
creatinine (,30%) in the ab-
by the persistent presence of elevated laboratories with serum creatinine, and
sence of volume depletion. A
urinary albumin excretion (albuminuria), eGFR calculators are available online at
11.6 For people with nondialysis-
low estimated glomerular filtration rate nkdep.nih.gov. An eGFR persistently ,60
dependent chronickidneydisease,
(eGFR), or other manifestations of kidney mL/min/1.73 m2 is considered abnormal,
dietary protein intake should
damage (1,2). In this section, the focus is though optimal thresholds for clinical di-
be approximately 0.8 g/kg body
on CKD attributed to diabetes (diabetic agnosis are debated in older adults (2,14).
weight per day (the recommen-
ded daily allowance). A For kidney disease), which occurs in 20–40%
of patients with diabetes (1,3–5). CKD Diagnosis of Diabetic Kidney Disease
patients on dialysis, higher lev-
typically develops after diabetes duration Diabetic kidney disease is usually a clin-
els of dietary protein intake
of 10 years in type 1 diabetes but may be ical diagnosis made based on the pres-
should be considered, since
present at diagnosis of type 2 diabetes. ence of albuminuria and/or reduced
malnutrition is a major problem
CKD can progress to end-stage renal dis- eGFR in the absence of signs or symptoms
in some dialysis patients. B
ease (ESRD) requiring dialysis or kidney of other primary causes of kidney dam-
11.7 In nonpregnant patients with
transplantation and is the leading cause of age. The typical presentation of diabetic
diabetes and hypertension, ei-
ESRD in the U.S. (6). In addition, among kidney disease is considered to include a
ther an ACE inhibitor or an an-
people with type 1 or 2 diabetes, the long-standing duration of diabetes, ret-
giotensin receptor blocker is
presence of CKD markedly increases car- inopathy, albuminuria without gross he-
recommended for those with
diovascular risk and health care costs (7). maturia, and gradually progressive loss of
modestly elevated urinary albu-
eGFR. However, signs of CKD may be
min-to-creatinine ratio (30–299
Assessment of Albuminuria and present at diagnosis or without retinop-
mg/g creatinine) B and is strongly
Estimated Glomerular Filtration Rate athy in type 2 diabetes, and reduced
recommended for those with
Screening for albuminuria can be most eGFR without albuminuria has been fre-
urinary albumin-to-creatinine ra-
easily performed by urinary albumin-to- quently reported in type 1 and type 2
tio $300 mg/g creatinine and/or
creatinine ratio (UACR) in a random spot diabetes and is becoming more common
estimated glomerular filtration
urine collection (1,2). Timed or 24-h col- over time as the prevalence of diabetes
rate ,60 mL/min/1.73 m2. A
lections are more burdensome and add increases in the U.S. (3,4,15,16).
11.8 Periodically monitor serum cre-
little to prediction or accuracy. Measure- An active urinary sediment (containing
atinine and potassium levels for
ment of a spot urine sample for albumin red or white blood cells or cellular casts),
the development of increased
alone (whether by immunoassay or by rapidly increasing albuminuria or ne-
creatinine or changes in potas-
using a sensitive dipstick test specific for phrotic syndrome, rapidly decreasing
sium when ACE inhibitors, an-
albuminuria) without simultaneously mea- eGFR, or the absence of retinopathy
giotensin receptor blockers, or
suring urine creatinine (Cr) is less expen- (in type 1 diabetes) suggests alternative
diuretics are used. B
sive but susceptible to false-negative and or additional causes of kidney disease.care.diabetesjournals.org Microvascular Complications and Foot Care S153
For patients with these features, referral hemodynamics. In particular, many anti- and mortality (37–39). For patients with
to a nephrologist for further diagnosis, hypertensive medications (e.g., diuretics, eGFR ,60 mL/min/1.73 m2, appropriate
including the possibility of kidney biopsy, ACE inhibitors, and angiotensin receptor medication dosing should be verified,
should be considered. It is rare for pa- blockers [ARBs]) can reduce intravascular exposure to nephrotoxins (e.g., nonste-
tients with type 1 diabetes to develop volume, renal blood flow, and/or glomer- roidal anti-inflammatory drugs and io-
kidney disease without retinopathy. In ular filtration. There was concern that dinated contrast) should be minimized,
type 2 diabetes, retinopathy is only mod- sodium–glucose cotransporter 2 (SGLT2) and potential CKD complications should
erately sensitive and specific for CKD inhibitors may promote AKI through vol- be evaluated (Table 11.1).
caused by diabetes, as confirmed by ume depletion, particularly when com- The need for annual quantitative as-
kidney biopsy (17). bined with diuretics or other medications sessment of albumin excretion after di-
that reduce glomerular filtration; how- agnosis of albuminuria, institution of ACE
Staging of Chronic Kidney Disease ever, this has not been found to be true in inhibitors or ARB therapy, and achieve-
Stages 1–2 CKD have been defined by randomized clinical outcome trials of ad- ment of blood pressure control is a sub-
evidence of high albuminuria with eGFR vanced kidney disease (26) or high car- ject of debate. Continued surveillance
$60 mL/min/1.73 m2, while stages 3–5 diovascular disease risk with normal can assess both response to therapy and
CKD have been defined by progressively kidney function (27–29). Timely identifi- disease progression and may aid in as-
lower ranges of eGFR (18) (Fig. 11.1). At cation and treatment of AKI is important sessing adherence to ACE inhibitor or
any eGFR, the degree of albuminuria is because AKI is associated with increased ARB therapy. In addition, in clinical trials
associated with risk of cardiovascular risks of progressive CKD and other poor of ACE inhibitors or ARB therapy in
disease (CVD), CKD progression, and health outcomes (30). type 2 diabetes, reducing albuminuria
mortality (7). Therefore, Kidney Disease: Small elevations in serum creatinine from levels $300 mg/g Cr has been
Improving Global Outcomes (KDIGO) (up to 30% from baseline) with renin- associated with improved renal and car-
recommends a more comprehensive angiotensin system blockers (such as ACE diovascular outcomes, leading some to
CKD staging that incorporates albumin- inhibitors and ARBs) must not be con- suggest that medications should be ti-
uria at all stages of eGFR; this system is fused with AKI (31). An analysis of the trated to minimize UACR. However, this
more closely associated with risk but is Action to Control Cardiovascular Risk in approach has not been formally evalu-
also more complex and does not trans- Diabetes Blood Pressure (ACCORD BP) ated in prospective trials. In type 1 di-
late directly to treatment decisions (2). trial demonstrates that those random- abetes, remission of albuminuria may
Thus, based on the current classification ized to intensive blood pressure lowering occur spontaneously, and cohort studies
system, both eGFR and albuminuria with up to a 30% increase in serum evaluating associations of change in al-
must be quantified to guide treatment creatinine did not have any increase in buminuria with clinical outcomes have
decisions. This is also important since mortality or progressive kidney disease reported inconsistent results (40,41).
eGFR levels are essential to modify drug (32–36). Moreover, a measure of markers The prevalence of CKD complications
dosage or restrictions of use (Fig. 11.1) for AKI showed no significant increase of correlates with eGFR (42). When eGFR
(19,20). The degree of albuminuria may any markers with increased creatinine (34). is ,60 mL/min/1.73 m2, screening for
influence choice of antihypertensive Accordingly, ACE inhibitors and ARBs should complications of CKD is indicated (Table
(see Section 10 “Cardiovascular Disease not be discontinued for minor increases in 11.1). Early vaccination against hepatitis
and Risk Management,” https://doi.org serum creatinine (,30%), in the absence of B virus is indicated in patients likely to
/10.2337/dc21-S010) or glucose-lowering volume depletion. progress to ESRD (see Section 4 “Com-
medications (see below). Observed his- prehensive Medical Evaluation and As-
tory of eGFR loss (which is also associated Surveillance sessment of Comorbidities,” https://doi
with risk of CKD progression and other Albuminuria and eGFR should be mon- .org/10.2337/dc21-S004, for further in-
adverse health outcomes) and cause of itored regularly to enable timely diagno- formation on immunization).
kidney damage (including possible causes sis of CKD, monitor progression of CKD,
other than diabetes) may also affect these detect superimposed kidney diseases Interventions
decisions (21). including AKI, assess risk of CKD compli- Nutrition
cations, dose drugs appropriately, and For people with nondialysis-dependent
Acute Kidney Injury determine whether nephrology referral CKD, dietary protein intake should be
Acute kidney injury (AKI) is diagnosed is needed. Among people with existing ;0.8 g/kg body weight per day (the
by a 50% or greater sustained increase in kidney disease, albuminuria and eGFR recommended daily allowance) (1). Com-
serum creatinine over a short period of may change due to progression of CKD, pared with higher levels of dietary pro-
time, which is also reflected as a rapid development of a separate superim- tein intake, this level slowed GFR decline
decrease in eGFR (23,24). People with posed cause of kidney disease, AKI, with evidence of a greater effect over
diabetes are at higher risk of AKI than or other effects of medications, as time. Higher levels of dietary protein
those without diabetes (25). Other risk noted above. Serum potassium should intake (.20% of daily calories from pro-
factors for AKI include preexisting CKD, also be monitored for patients treated tein or .1.3 g/kg/day) have been asso-
the use of medications that cause kidney with ACE inhibitors, ARBs, and diuretics ciated with increased albuminuria, more
injury (e.g., nonsteroidal anti-inflammatory because these medications can cause rapid kidney function loss, and CVD mor-
drugs), and the use of medications that hyperkalemia or hypokalemia, which tality and therefore should be avoided.
alter renal blood flow and intrarenal are associated with cardiovascular risk Reducing the amount of dietary proteinS154 Microvascular Complications and Foot Care Diabetes Care Volume 44, Supplement 1, January 2021
Figure 11.1—Risk of chronic kidney disease (CKD) progression, frequency of visits, and referral to nephrology according to glomerular filtration rate
(GFR) and albuminuria. The GFR and albuminuria grid depicts the risk of progression, morbidity, and mortality by color, from best to worst (green,
yellow, orange, red, dark red). The numbers in the boxes are a guide to the frequency of visits (number of times per year). Green can reflect CKD with
normal eGFR and albumin-to-creatinine ratio only in the presence of other markers of kidney damage, such as imaging showing polycystic kidney disease
or kidney biopsy abnormalities, with follow-up measurements annually; yellow requires caution and measurements at least once per year; orange
requires measurements twice per year; red requires measurements three times per year; and dark red requires measurements four times per year.
These are general parameters only, based on expert opinion, and underlying comorbid conditions and disease state as well as the likelihood of impacting
a change in management for any individual patient must be taken into account. “Refer” indicates that nephrology services are recommended. *Referring
clinicians may wish to discuss with their nephrology service, depending on local arrangements regarding treating or referring. Reprinted with
permission from Vassalotti et al. (22).
below the recommended daily allowance and progression of albuminuria and re- glucose control to manifest as improved
of 0.8 g/kg/day is not recommended duced eGFR in patients with type 1 di- eGFR outcomes (53,58,59). Therefore, in
because it does not alter glycemic mea- abetes (47,48) and type 2 diabetes some patients with prevalent CKD and
sures, cardiovascular risk measures, or (1,49–55). Insulin alone was used to substantial comorbidity, target A1C lev-
the course of GFR decline (43). lower blood glucose in the Diabetes els may be less intensive (1,60).
Restriction of dietary sodium (to Control and Complications Trial (DCCT)/ Direct Renal Effects of Glucose-Lowering
,2,300 mg/day) may be useful to control Epidemiology of Diabetes Interventions Medications
blood pressure and reduce cardiovascu- and Complications (EDIC) study of type 1 Some glucose-lowering medications also
lar risk (44,45), and restriction of dietary diabetes, while a variety of agents were have effects on the kidney that are direct,
potassium may be necessary to control used in clinical trials of type 2 diabetes, i.e., not mediated through glycemia. For
serum potassium concentration (25,37–39). supporting the conclusion that glyce- example, SGLT2 inhibitors reduce renal
These interventions may be most important mic control itself helps prevent CKD and tubular glucose reabsorption, weight, sys-
for patients with reduced eGFR, for whom its progression. The effects of glucose- temic blood pressure, intraglomerular
urinary excretion of sodium and potassium lowering therapies on CKD have helped pressure, and albuminuria and slow GFR
may be impaired. For patients on dialysis, define A1C targets (see Table 6.2). loss through mechanisms that appear in-
higher levels ofdietary protein intake should The presence of CKD affects the risks dependent of glycemia (28,61–64). More-
be considered, since malnutrition is a major and benefits of intensive glycemic con- over, recent data support the notion that
problem in some dialysis patients (46). trol and a number of specific glucose- SGLT2 inhibitors reduce oxidative stress in
Recommendations for dietary sodium lowering medications. In the Action to the kidney by .50% and blunt increases in
and potassium intake should be individ- Control Cardiovascular Risk in Diabetes angiotensinogen as well as reduce NLRP3
ualized on the basis of comorbid con- (ACCORD) trial of type 2 diabetes, ad- inflammasome activity (65–67). Glucagon-
ditions, medication use, blood pressure, verse effects of intensive glycemic con- like peptide 1 receptor agonists (GLP-1
and laboratory data. trol (hypoglycemia and mortality) were RAs) also have direct effects on the kidney
Glycemic Targets increased among patients with kidney and have been reported to improve renal
Intensive glycemic control with the goal disease at baseline (56,57). Moreover, outcomes compared with placebo (68–71).
of achieving near-normoglycemia has there is a lag time of at least 2 years in Renal effects should be considered when
been shown in large prospective ran- type 2 diabetes to over 10 years in type selecting antihyperglycemia agents (see
domized studies to delay the onset 1 diabetes for the effects of intensive Section 9 “Pharmacologic Approaches tocare.diabetesjournals.org Microvascular Complications and Foot Care S155
Table 11.1—Selected complications of chronic kidney disease These analyses were limited by eval-
Complication Medical and laboratory evaluation
uation of study populations not selected
primarily for CKD and examination of
Elevated blood pressure .140/90 mmHg Blood pressure, weight
renal effects as secondary outcomes.
Volume overload History, physical examination, weight However, all of these trials included large
Electrolyte abnormalities Serum electrolyte numbers of people with stage 3a (eGFR
Metabolic acidosis Serum electrolytes 45–59 mL/min/1.73 m2) kidney disease.
Anemia Hemoglobin; iron testing if indicated In addition, subgroup analyses of CAN-
Metabolic bone disease Serum calcium, phosphate, PTH, vitamin 25(OH)D VAS and LEADER suggested that the renal
Complications of chronic kidney disease (CKD) generally become prevalent when estimated benefits of canagliflozin and liraglutide
glomerular filtration rate falls below 60 mL/min/1.73 m2 (stage 3 CKD or greater) and become were as great or greater for participants
more common and severe as CKD progresses. Evaluation of elevated blood pressure and volume with CKD at baseline (29,70) and in CAN-
overload should occur at every clinical contact possible; laboratory evaluations are generally
indicated every 6–12 months for stage 3 CKD, every 3–5 months for stage 4 CKD, and every 1– VAS were similar for participants with or
3 months for stage 5 CKD, or as indicated to evaluate symptoms or changes in therapy. PTH, without atherosclerotic cardiovascular
parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D. disease (ASCVD) at baseline (79).
Several large clinical trials of SGLT2
inhibitors focused on patients with ad-
Glycemic Treatment,” https://doi.org/10 A1C or cannot use or tolerate metformin. vanced CKD, and assessment of primary
.2337/dc21-S009). SGLT2 inhibitors reduce risks of CKD renal outcomes are completed or ongo-
progression, CVD events, and hypogly- ing. Canagliflozin and Renal Events
Selection of Glucose-Lowering Medications cemia. GLP-1 RAs are suggested because in Diabetes with Established Nephrop-
for Patients With Chronic Kidney Disease they reduce risks of CVD events and athy Clinical Evaluation (CREDENCE), a
For patients with type 2 diabetes and hypoglycemia and appear to possibly placebo-controlled trial of canagliflozin
established CKD, special considerations slow CKD progression (77). among 4,401 adults with type 2 diabetes,
for the selection of glucose-lowering A number of large cardiovascular out- UACR $300 mg/g Cr, and mean eGFR
medications include limitations to avail- comes trials in patients with type 2 di- 56 mL/min/1.73 m2 with a mean albu-
able medications when eGFR is dimin- abetes at high risk for CVD or with existing minuria level of over 900 mg/day, had a
ished and a desire to mitigate high risks of CVD examined kidney effects as second- primary composite end point of ESRD,
CKD progression, CVD, and hypoglycemia ary outcomes. These trials include EMPA- doubling of serum creatinine, or renal
(72,73). Drug dosing may require modifi- REG OUTCOME [BI 10773 (Empagliflozin) or cardiovascular death (26,80). It was
cation with eGFR ,60 mL/min/1.73 m2 (1). Cardiovascular Outcome Event Trial in stopped early due to positive efficacy and
The U.S. Food and Drug Administration Type 2 Diabetes Mellitus Patients], CAN- showed a 32% risk reduction for devel-
(FDA) revised its guidance for the use of VAS (Canagliflozin Cardiovascular Assess- opment of ESRD over control (26). Ad-
metformin in CKD in 2016 (74), recom- ment Study), LEADER (Liraglutide Effect ditionally, the development of the primary
mending use of eGFR instead of serum and Action in Diabetes: Evaluation of end point, which included chronic dialysis
creatinine to guide treatment and ex- Cardiovascular Outcome Results), and for $30 days, kidney transplantation or
panding the pool of patients with kidney SUSTAIN-6 (Trial to Evaluate Cardiovascu- eGFR ,15 mL/min/1.73 m2 sustained
disease for whom metformin treatment lar and Other Long-term Outcomes With for $30 days by central laboratory as-
should be considered. The revised FDA Semaglutide in Subjects With Type 2 sessment, doubling from the baseline
guidance states that metformin is contra- Diabetes) (63,68,71,78). Specifically, com- serum creatinine average sustained for
indicated in patients with an eGFR ,30 pared with placebo, empagliflozin reduced $30 days by central laboratory assess-
mL/min/1.73 m2; eGFR should be mon- the risk of incident or worsening nephrop- ment, or renal death or cardiovascular
itored while taking metformin; the ben- athy (a composite of progression to death, was reduced by 30%. This benefit
efits and risks of continuing treatment UACR .300 mg/g Cr, doubling of serum was on background ACE inhibitor or ARB
should be reassessed when eGFR falls to creatinine, ESRD, or death from ESRD) by therapy in .99% of the patients (26).
,45 mL/min/1.73 m2 (75,76); metformin 39% and the risk of doubling of serum Moreover, in this advanced CKD group,
should not be initiated for patients with creatinine accompanied by eGFR #45 mL/ there were clear benefits on cardiovas-
an eGFR ,45 mL/min/1.73 m2; and min/1.73 m2 by 44%; canagliflozin reduced cular outcomes demonstrating a 31% re-
metformin should be temporarily discon- the risk of progression of albuminuria by duction in cardiovascular death or heart
tinued at the time of or before iodinated 27% and the risk of reduction in eGFR, failure hospitalization and a 20% reduc-
contrast imaging procedures in patients ESRD, or death from ESRD by 40%; liraglu- tion in cardiovascular death, nonfatal
with eGFR 30–60 mL/min/1.73 m2. tide reduced the risk of new or worsening myocardial infarction, or nonfatal stroke
Within these constraints, metformin nephropathy (a composite of persistent (26,81,82).
should be considered the first-line treat- macroalbuminuria, doubling of serum cre- In addition to renal effects, some SGLT2
ment for all patients with type 2 diabetes, atinine, ESRD, or death from ESRD) by 22%; inhibitors and GLP-1 RAs have demon-
including those with CKD. and semaglutide reduced the risk of new strated cardiovascular benefits. Namely,
SGLT2 inhibitors and GLP-1 RAs should or worsening nephropathy (a composite of in EMPA-REG OUTCOME, CANVAS, LEADER,
be considered for patients with type 2 persistent UACR .300 mg/g Cr, doubling and SUSTAIN-6, empagliflozin, canagli-
diabetes and CKD who require another of serum creatinine, or ESRD) by 36% (each flozin, liraglutide, and semaglutide,
drug added to metformin to attain target P , 0.01). respectively, each reduced cardiovascularS156 Microvascular Complications and Foot Care Diabetes Care Volume 44, Supplement 1, January 2021
events, evaluated as primary outcomes, with eGFR $30 mL/min/1.73 m2 and normotensive with or without high al-
compared with placebo (see Section demonstrated benefit in subgroups buminuria (formerly microalbuminuria)
10 “Cardiovascular Disease and Risk Man- with low eGFR) (28,29,84). Canagliflozin (97,98).
agement,” https://doi.org/10.2337/dc21- was recently approved to be started Absent kidney disease, ACE inhibitors
S010 for further discussion). While the down to eGFR levels of 30 mL/min/ or ARBs are useful to control blood
glucose-lowering effects of SGLT2 inhib- 1.73 m2. Some GLP-1 RAs may be used pressure but have not proven superior
itors are blunted with eGFR ,45 mL/ with lower eGFR, but most require dose to alternative classes of antihypertensive
min/1.73 m2, the renal and cardiovas- adjustment. therapy, including thiazide-like diuretics
cular benefits were still seen down to and dihydropyridine calcium channel
Cardiovascular Disease and Blood Pressure
eGFR levels of 30 mL/min/1.73 m2 with blockers (99). In a trial of people with
Hypertension is a strong risk factor for
no significant change in glucose (26,28,47, type 2 diabetes and normal urine albu-
the development and progression of CKD
49,56,60,71,78). Most participants with min excretion, an ARB reduced or sup-
(85). Antihypertensive therapy reduces
CKD in these trials also had diagnosed pressed the development of albuminuria
the risk of albuminuria (86–89), and
ASCVD at baseline, though ;28% of CANVAS but increased the rate of cardiovascular
among patients with type 1 or 2 diabetes
participants with CKD did not have di- events (100). In a trial of people with
with established CKD (eGFR ,60 mL/
agnosed ASCVD (29). type 1 diabetes exhibiting neither albu-
Based on evidence from the CREDENCE min/1.73 m2 and UACR $300 mg/g Cr),
minuria nor hypertension, ACE inhibitors
trial and secondary analyses of cardiovas- ACE inhibitor or ARB therapy reduces the
or ARBs did not prevent the development
cular outcomes trials with SGLT2 inhib- risk of progression to ESRD (90–92).
of diabetic glomerulopathy assessed by
itors, cardiovascular and renal events are Moreover, antihypertensive therapy re-
kidney biopsy (97). This was further
reduced with SGLT2 inhibitor use in pa- duces risks of cardiovascular events (86).
supported by a similar trial in patients
tients down to an eGFR of 30 mL/min/ Blood pressure levels ,140/90 mmHg
with type 2 diabetes (98). Therefore, ACE
1.73 m2, independent of glucose-lowering are generally recommended to reduce
inhibitors or ARBs are not recommended
effects (81,82). CVD mortality and slow CKD progression
for patients without hypertension to pre-
While there is clear cardiovascular risk among all people with diabetes (89). Lower vent the development of CKD.
reduction associated with GLP-1 RA use blood pressure targets (e.g., ,130/80 Two clinical trials studied the combi-
in patients with type 2 diabetes and CKD, mmHg) should be considered for patients nations of ACE inhibitors and ARBs and
the proof of benefit on renal outcome will based on individual anticipated benefits found no benefits on CVD or CKD, and the
come with the results of the ongoing and risks. Patients with CKD are at in- drug combination had higher adverse
FLOW (A Research Study to See How creased risk of CKD progression (particu- event rates (hyperkalemia and/or AKI)
Semaglutide Works Compared with Pla- larly those with albuminuria) and CVD and (101,102). Therefore, the combined use
cebo in People With Type 2 Diabetes and therefore may be suitable in some cases of ACE inhibitors and ARBs should be
Chronic Kidney Disease) trial with inject- for lower blood pressure targets, espe- avoided.
able semaglutide (83). As noted above, cially in those with $300 mg/g Cr Mineralocorticoid receptor antago-
published data address a limited group of albuminuria. nists (spironolactone, eplerenone, and
CKD patients, mostly with coexisting ACE inhibitors or ARBs are the pre- finerenone) in combination with ACE in-
ASCVD. Renal events have been exam- ferred first-line agent for blood pressure hibitors or ARBs remain an area of great
ined, however, as both primary and sec- treatment among patients with diabetes, interest. Mineralocorticoid receptor an-
ondary outcomes in published large trials. hypertension, eGFR ,60 mL/min/1.73 m2, tagonists are effective for management of
Also, adverse event profiles of these and UACR $300 mg/g Cr because of their resistant hypertension, have been shown
agents must be considered. Please refer proven benefits for prevention of CKD to reduce albuminuria in short-term stud-
to Table 9.1 for drug-specific factors, progression (90–93). In general, ACE in- ies of CKD, and may have additional
including adverse event information, hibitors and ARBs are considered to have cardiovascular benefits (103–105). There
for these agents. Additional clinical trials similar benefits (94,95) and risks. In the has been, however, an increase in hyper-
focusing on CKD and cardiovascular out- setting of lower levels of albuminuria (30– kalemic episodes in those on dual therapy,
comes in CKD patients are ongoing and 299 mg/g Cr), ACE inhibitor or ARB therapy and larger, longer trials with clinical out-
will be reported in the next few years. has been demonstrated to reduce pro- comes are needed before recommending
For patients with type 2 diabetes and gression to more advanced albuminuria such therapy.
CKD, the selection of specific agents may ($300 mg/g Cr) and cardiovascular
depend on comorbidity and CKD stage. events but not progression to ESRD Referral to a Nephrologist
SGLT2 inhibitors may be more useful for (93,96). While ACE inhibitors or ARBs Consider referral to a physician experi-
patients at high risk of CKD progression are often prescribed for high albuminuria enced in the care of kidney disease when
(i.e., with albuminuria or a history of without hypertension, outcome trials there is uncertainty about the etiology
documented eGFR loss) (Fig. 9.1) be- have not been performed in this setting of kidney disease, for difficult manage-
cause they appear to have large bene- to determine whether this improves re- ment issues (anemia, secondary hyper-
ficial effects on CKD incidence. The SGLT2 nal outcomes. Moreover, two long-term, parathyroidism, metabolic bone disease,
inhibitors empagliflozin and dapagliflo- double-blind studies demonstrate no resistant hypertension, or electrolyte
zin are approved by the FDA for use with renoprotective effect of either ACE in- disturbances), or when there is advanced
eGFR $45 mL/min/1.73 m2 (though piv- hibitors or ARBs in type 1 and type kidney disease (eGFR ,30 mL/min/
otal trials for each included participants 2 diabetes among those who were 1.73 m2) requiring discussion of renalcare.diabetesjournals.org Microvascular Complications and Foot Care S157
replacement therapy for ESRD (2). The Laser photocoagulation surgery can min-
should be monitored every tri-
threshold for referral may vary depend- imize the risk of vision loss (116). How-
mester and for 1 year post-
ing on the frequency with which a pro- ever, intervention is not appropriate
partum as indicated by the
vider encounters patients with diabetes during pregnancy. This problem often
degree of retinopathy. B
and kidney disease. Consultation with a resolves after pregnancy and so does
nephrologist when stage 4 CKD develops not require treatment.
The preventive effects of therapy and the
(eGFR ,30 mL/min/1.73 m2) has been
fact that patients with proliferative di-
found to reduce cost, improve quality of Screening
abetic retinopathy (PDR) or macular
care, and delay dialysis (106). However, Recommendations edema may be asymptomatic provide
other specialists and providers should 11.14 Adults with type 1 diabetes strong support for screening to detect
also educate their patients about the should have an initial dilated diabetic retinopathy.
progressive nature of CKD, the kidney and comprehensive eye exam- Diabetic retinopathy screening should
preservation benefits of proactive treat- ination by an ophthalmologist be performed using validated approaches
ment of blood pressure and blood glu- or optometrist within 5 years and methodologies. Youth with type 1
cose, and the potential need for renal after the onset of diabetes. B or type 2 diabetes are also at risk for
replacement therapy. 11.15 Patients with type 2 diabetes complications and need to be screened
should have an initial dilated for diabetic retinopathy (117). If dia-
and comprehensive eye exam- betic retinopathy is evident on screening,
DIABETIC RETINOPATHY
ination by an ophthalmologist prompt referral to an ophthalmologist
Recommendations or optometrist at the time of is recommended. Subsequent examina-
11.12 Optimize glycemic control to the diabetes diagnosis. B tions for patients with type 1 or type 2
reduce the risk or slow the 11.16 If there is no evidence of ret- diabetes are generally repeated annually
progression of diabetic reti- inopathy for one or more an- for patients with minimal to no retinop-
nopathy. A nual eye exams and glycemia is athy. Exams every 1–2 years may be cost-
11.13 Optimize blood pressure and well controlled, then screening effective after one or more normal eye
serum lipid control to reduce every 1–2 years may be con- exams, and in a population with well con-
the risk or slow the progression sidered. If any level of diabetic trolled type 2 diabetes, there was essentially
of diabetic retinopathy. A retinopathyispresent,subsequent no risk of development of significant reti-
dilated retinal examinations nopathywitha3-year intervalaftera normal
should be repeated at least examination (118). Less frequent intervals
Diabetic retinopathy is a highly specific
annually by an ophthalmologist have been found in simulated modeling to
vascular complication of both type 1 and
or optometrist. If retinopathy is be potentially effective in screening for
type 2 diabetes, with prevalence strongly
progressing or sight-threaten- diabetic retinopathy in patients without
related to both the duration of diabetes
ing, then examinations will be diabetic retinopathy (119). More frequent
and the level of glycemic control (107).
required more frequently. B examinations by the ophthalmologist will be
Diabetic retinopathy is the most frequent
11.17 Programs that use retinal pho- required if retinopathy is progressing.
cause of new cases of blindness among
tography (with remote reading Retinal photography with remote
adults aged 20–74 years in developed
or use of a validated assess- reading by experts has great potential
countries. Glaucoma, cataracts, and other
ment tool) to improve access to provide screening services in areas
disorders of the eye occur earlier and
to diabetic retinopathy screen- where qualified eye care professionals
more frequently in people with diabetes.
ing can be appropriate screen-
In addition to diabetes duration, fac- are not readily available (112,113). High-
ing strategies for diabetic
tors that increase the risk of, or are quality fundus photographs can detect
retinopathy. Such programs
associated with, retinopathy include most clinically significant diabetic reti-
need to provide pathways for
chronic hyperglycemia (108), nephropa- nopathy. Interpretation of the images
timely referral for a compre-
thy (109), hypertension (110), and dysli- should be performed by a trained eye
hensive eye examination when
pidemia (111). Intensive diabetes care provider. Retinal photography may
indicated. B
management with the goal of achieving also enhance efficiency and reduce costs
11.18 Women with preexisting type
near-normoglycemia has been shown in when the expertise of ophthalmologists
1 or type 2 diabetes who are
large prospective randomized studies to can be used for more complex examina-
planning pregnancy or who are
prevent and/or delay the onset and pro- tions and for therapy (120,121). In-person
pregnant should be counseled
gression of diabetic retinopathy and po- exams are still necessary when the retinal
on the risk of development
tentially improve patient reported visual photos are of unacceptable quality and for
and/or progression of diabetic
function (50,112–114). follow-up if abnormalities are detected.
retinopathy. B
Several case series and a controlled Retinal photos are not a substitute for
11.19 Eye examinations should oc-
prospective study suggest that preg- comprehensive eye exams, which should
cur before pregnancy or in the
nancy in patients with type 1 diabetes first trimester in patients with be performed at least initially and at
may aggravate retinopathy and threaten preexisting type 1 or type 2 intervals thereafter as recommended
vision, especially when glycemic control is diabetes, and then patients by an eye care professional. Artificial in-
poor at the time of conception (115,116). telligence systems that detect more thanS158 Microvascular Complications and Foot Care Diabetes Care Volume 44, Supplement 1, January 2021
mild diabetic retinopathy and diabetic manage complications of diabetic retinop-
experienced in the management
macular edema authorized for use by athy that involve retinal neovasculariza-
of diabetic retinopathy. A
the FDA represent an alternative to tra- tion and its complications.
11.21 The traditional standard treat-
ditional screening approaches (122). How- Anti–Vascular Endothelial Growth Factor
ment, panretinal laser photoco-
ever, the benefits and optimal utilization Treatment
agulation therapy, is indicated
of this type of screening have yet to be Recent data from the Diabetic Retinop-
to reduce the risk of vision loss
fully determined. Artificial intelligence athy Clinical Research Network and
in patients with high-risk prolif-
systems should not be used for patients others demonstrate that intravitreal
erative diabetic retinopathy and,
with known retinopathy, prior retinopa- injections of anti–vascular endothelial
in some cases, severe nonproli-
thy treatment, or symptoms of vision growth factor (anti-VEGF) agent, specif-
ferative diabetic retinopathy. A
impairment. Results of eye examinations ically ranibizumab, resulted in visual acu-
11.22 Intravitreous injections of anti–
should be documented and transmitted ity outcomes that were not inferior to
vascular endothelial growth
to the referring health care professional.
factor are not inferior to tradi- those observed in patients treated with
Type 1 Diabetes tional panretinal laser photoco- panretinal laser at 2 years of follow-up
Because retinopathy is estimated to take at agulation and are also indicated (128). In addition, it was observed that
least 5 years to develop after the onset of to reduce the risk of vision loss patients treated with ranibizumab tended
hyperglycemia, patients with type 1 diabe- in patients with proliferative to have less peripheral visual field loss,
tes should have an initial dilated and com- diabetic retinopathy. A fewer vitrectomy surgeries for secondary
prehensive eye examination within 5 years 11.23 Intravitreous injections of anti– complications from their proliferative
after the diagnosis of diabetes (123). vascular endothelial growth fac- disease, and a lower risk of developing
tor are indicated for central diabetic macular edema. However, a
Type 2 Diabetes
involved diabetic macular edema, potential drawback in using anti-VEGF
Patients with type 2 diabetes who may which occurs beneath the foveal therapy to manage proliferative disease
have had years of undiagnosed diabetes center and may threaten reading is that patients were required to have a
and have a significant risk of prevalent vision. A greater number of visits and received a
diabetic retinopathy at the time of di- 11.24 The presence of retinopathy is greater number of treatments than is
agnosis should have an initial dilated and not a contraindication to aspi- typically required for management with
comprehensive eye examination at the rin therapy for cardioprotection,
time of diagnosis. panretinal laser, which may not be optimal
as aspirin does not increase the for some patients. Other emerging thera-
Pregnancy risk of retinal hemorrhage. A pies for retinopathy that may use sustained
Pregnancy is associated with a rapid pro- intravitreal delivery of pharmacologic
gression of diabetic retinopathy (124,125). Two of the main motivations for screen- agents are currently under investigation.
Women with preexisting type 1 or type 2 ing for diabetic retinopathy are to pre- The FDA approved ranibizumab for the
diabetes who are planning pregnancy or vent loss of vision and to intervene with treatment of diabetic retinopathy in 2017.
who have become pregnant should be treatment when vision loss can be pre- While the ETDRS (129) established the
counseled on the risk of development and/ vented or reversed. benefit of focal laser photocoagulation
or progression of diabetic retinopathy. surgery in eyes with clinically significant
Photocoagulation Surgery
In addition, rapid implementation of macular edema (defined as retinal edema
Two large trials, the Diabetic Retinopathy
intensive glycemic management in located at or within 500 mm of the center
Study (DRS) in patients with PDR and the
the setting of retinopathy is associated of the macula), current data from well-
with early worsening of retinopathy Early Treatment Diabetic Retinopathy
designed clinical trials demonstrate that
(116). Women who develop gestational Study (ETDRS) in patients with macular
intravitreal anti-VEGF agents provide a
diabetes mellitus do not require eye edema, provide the strongest support for
more effective treatment regimen for
examinations during pregnancy and do the therapeutic benefits of photocoag-
central-involved diabetic macular edema
not appear to be at increased risk of ulation surgery. The DRS (127) showed in
than monotherapy or even combination
developing diabetic retinopathy during 1978 that panretinal photocoagulation therapy with a laser (130,131). There are
pregnancy (126). surgery reduced the risk of severe vision currently three anti-VEGF agents com-
loss from PDR from 15.9% in untreated monly used to treat eyes with central-
Treatment
eyes to 6.4% in treated eyes with the involved diabetic macular edemad
greatest benefit ratio in those with more bevacizumab, ranibizumab, and afliber-
Recommendations advanced baseline disease (disc neovas- cept (107).
11.20 Promptly refer patients with cularization or vitreous hemorrhage). In In both the DRS and the ETDRS, laser
any level of macular edema, 1985, the ETDRS also verified the ben- photocoagulation surgery was beneficial
severe nonproliferative diabetic efits of panretinal photocoagulation in reducing the risk of further visual loss in
retinopathy (a precursor of pro- for high-risk PDR and in older-onset affected patients but generally not bene-
liferative diabetic retinopathy), patients with severe nonproliferative ficial in reversing already diminished acu-
or any proliferative diabetic ret-
diabetic retinopathy or less-than- ity. Anti-VEGF therapy improves vision and
inopathy to an ophthalmolo-
high-risk PDR. Panretinal laser photo- has replaced the need for laser photoco-
gist who is knowledgeable and
coagulation is still commonly used to agulation in the vast majority of patientscare.diabetesjournals.org Microvascular Complications and Foot Care S159
with diabetic macular edema (132). Most 2. Up to 50% of diabetic peripheral where the clinical features are atypical or
patients require near-monthly adminis- neuropathy may be a symptomatic. If the diagnosis is unclear.
tration of intravitreal therapy with anti- not recognized and if preventive foot In all patients with diabetes and DPN,
VEGF agents during the first 12 months of care is not implemented, patients are at causes of neuropathy other than diabetes
treatment, with fewer injections needed in risk for injuries to their insensate feet. should be considered, including toxins (e.g.,
subsequent years to maintain remission 3. Recognition and treatment of auto- alcohol), neurotoxic medications (e.g., che-
from central-involved diabetic macular nomic neuropathy may improve symp- motherapy), vitamin B12 deficiency, hypo-
edema. toms, reduce sequelae, and improve thyroidism, renal disease, malignancies
Adjunctive Therapy quality of life. (e.g., multiple myeloma, bronchogenic car-
Lowering blood pressure has been shown cinoma), infections (e.g., HIV), chronic in-
to decrease retinopathy progression, al- Specific treatment for the underlying flammatory demyelinating neuropathy,
though tight targets (systolic blood pres- nerve damage, other than improved inherited neuropathies, and vasculitis
sure ,120 mmHg) do not impart additional glycemic control, is currently not avail- (138). See the American Diabetes Asso-
benefit (113). ACE inhibitors and ARBs are able. Glycemic control can effectively ciation (ADA) position statement “Dia-
both effective treatments in diabetic reti- prevent diabetic peripheral neuropathy betic Neuropathy” for more details (137).
nopathy(133).Inpatientswithdyslipidemia, (DPN) and cardiac autonomic neuropa-
retinopathy progression may be slowed by thy (CAN) in type 1 diabetes (135,136) Diabetic Autonomic Neuropathy
and may modestly slow their progression The symptoms and signs of autonomic
the addition of fenofibrate, particularly with
in type 2 diabetes (52), but it does not neuropathy should be elicited care-
very mild nonproliferative diabetic retinop-
reverse neuronal loss. Therapeutic strat- fully during the history and physical
athy at baseline (111,134).
egies (pharmacologic and nonpharmaco- examination. Major clinical manifesta-
logic) for the relief of painful DPN and tions of diabetic autonomic neuropathy
NEUROPATHY symptoms of autonomic neuropathy can include hypoglycemia unawareness, rest-
Screening potentially reduce pain (137) and im- ing tachycardia, orthostatic hypotension,
prove quality of life. gastroparesis, constipation, diarrhea,
Recommendations
fecal incontinence, erectile dysfunction,
11.25 All patients should be assessed
neurogenic bladder, and sudomotor dys-
for diabetic peripheral neuropa-
Diagnosis function with either increased or de-
thy starting at diagnosis of type 2
Diabetic Peripheral Neuropathy creased sweating.
diabetes and 5 years after the
Patients with type 1 diabetes for 5 or Cardiac Autonomic Neuropathy. CAN is
diagnosis of type 1 diabetes and
more years and all patients with type 2 associated with mortality independently of
at least annually thereafter. B
diabetes should be assessed annually for other cardiovascular risk factors (139,140).
11.26 Assessment for distal symmetric
DPN using the medical history and simple In its early stages, CAN may be completely
polyneuropathy should include a
clinical tests (137). Symptoms vary ac- asymptomatic and detected only by de-
careful history and assessment of
cording to the class of sensory fibers creased heart rate variability with deep
either temperature or pinprick
involved. The most common early symp-
sensation (small fiber function) breathing. Advanced disease may be asso-
toms are induced by the involvement of ciated with resting tachycardia (.100 bpm)
and vibration sensation using a
small fibers and include pain and dyses- and orthostatic hypotension (a fall in systolic
128-Hz tuning fork (for large-
thesia (unpleasant sensations of burning or diastolic blood pressure by .20 mmHg
fiber function). All patients
and tingling). The involvement of large or .10 mmHg, respectively, upon standing
should have annual 10-g mono-
fibers may cause numbness and loss of
filament testing to identify without an appropriate increase in heart
protective sensation (LOPS). LOPS indi- rate). CAN treatment is generally focused on
feet at risk for ulceration and
cates the presence of distal sensorimotor alleviating symptoms.
amputation. B
polyneuropathy and is a risk factor for
11.27 Symptoms and signs of auto- Gastrointestinal Neuropathies. Gastroin-
diabetic foot ulceration. The following
nomic neuropathy should be testinal neuropathies may involve any
clinical tests may be used to assess small-
assessed in patients with mi- portion of the gastrointestinal tract
and large-fiber function and protective
crovascular complications. E with manifestations including esophageal
sensation:
dysmotility, gastroparesis, constipation,
The diabetic neuropathies are a hetero- 1. Small-fiber function: pinprick and diarrhea, and fecal incontinence. Gastro-
geneous group of disorders with diverse temperature sensation paresis should be suspected in individ-
clinical manifestations. The early recog- 2. Large-fiber function: vibration per- uals with erratic glycemic control or with
nition and appropriate management of ception and 10-g monofilament upper gastrointestinal symptoms with-
neuropathy in the patient with diabetes 3. Protective sensation: 10-g monofilament out another identified cause. Exclusion of
is important. organic causes of gastric outlet obstruc-
These tests not only screen for the tion or peptic ulcer disease (with eso-
1. Diabetic neuropathy is a diagnosis of presence of dysfunction but also predict phagogastroduodenoscopy or a barium
exclusion. Nondiabetic neuropathies future risk of complications. Electrophys- study of the stomach) is needed before
may be present in patients with di- iological testing or referral to a neurologist considering a diagnosis of or specialized
abetes and may be treatable. is rarely needed, except in situations testing for gastroparesis. The diagnosticS160 Microvascular Complications and Foot Care Diabetes Care Volume 44, Supplement 1, January 2021
gold standard for gastroparesis is the different effects. In a post hoc analysis, Duloxetine is a selective norepineph-
measurement of gastric emptying with participants, particularly men, in the rine and serotonin reuptake inhibitor.
scintigraphy of digestible solids at 15-min Bypass Angioplasty Revascularization In- Doses of 60 and 120 mg/day showed
intervals for 4 h after food intake. The use vestigation in Type 2 Diabetes (BARI 2D) efficacy in the treatment of pain associ-
of 13C octanoic acid breath test is emerg- trial treated with insulin sensitizers ated with DPN in multicenter random-
ing as a viable alternative. had a lower incidence of distal symmet- ized trials, although some of these had
Genitourinary Disturbances. Diabetic auto- ric polyneuropathy over 4 years than high drop-out rates (150,152,157,159).
nomic neuropathy may also cause gen- those treated with insulin/sulfonylurea Duloxetine also appeared to improve
itourinary disturbances, including sexual (147). neuropathy-related quality of life (162).
dysfunction and bladder dysfunction. In In longer-term studies, a small increase in
Neuropathic Pain
men, diabetic autonomic neuropathy A1C was reported in people with diabetes
Neuropathic pain can be severe and can treated with duloxetine compared with
may cause erectile dysfunction and/or impact quality of life, limit mobility, and
retrograde ejaculation (137). Female sex- placebo (163). Adverse events may be
contribute to depression and social dys- more severe in older people but may be
ual dysfunction occurs more frequently function (148). No compelling evidence
in those with diabetes and presents attenuated with lower doses and slower
exists in support of glycemic control or titration of duloxetine.
as decreased sexual desire, increased lifestyle management as therapies for
pain during intercourse, decreased sex- Tapentadol is a centrally acting opioid
neuropathic pain in diabetes or predia- analgesic that exerts its analgesic effects
ual arousal, and inadequate lubrication
betes, which leaves only pharmaceutical through both m-opioid receptor agonism
(141). Lower urinary tract symptoms
interventions (149). and noradrenaline reuptake inhibition.
manifest as urinary incontinence and
Pregabalin and duloxetine have re- Extended-release tapentadol was ap-
bladder dysfunction (nocturia, frequent
ceived regulatory approval by the FDA,
urination, urination urgency, and weak proved by the FDA for the treatment
Health Canada, and the European Med-
urinary stream). Evaluation of bladder of neuropathic pain associated with di-
icines Agency for the treatment of neu-
function should be performed for indi- abetes based on data from two multi-
ropathic pain in diabetes. The opioid
viduals with diabetes who have recurrent center clinical trials in which participants
tapentadol has regulatory approval in
urinary tract infections, pyelonephritis, titrated to an optimal dose of tapentadol
the U.S. and Canada, but the evidence
incontinence, or a palpable bladder. were randomly assigned to continue that
of its use is weaker (150). Comparative
dose or switch to placebo (164,165).
Treatment effectiveness studies and trials that include
However, both used a design enriched
Recommendations
quality-of-life outcomes are rare, so treat-
for patients who responded to tapenta-
11.28 Optimize glucose control to pre- ment decisions must consider each pa-
dol and therefore their results are not
vent or delay the development tient’s presentation and comorbidities and
generalizable. A recent systematic review
of neuropathy in patients with often follow a trial-and-error approach.
and meta-analysis by the Special Interest
type 1 diabetes A and to slow Given the range of partially effective treat-
Group on Neuropathic Pain of the Inter-
the progression of neuropathy in ment options, a tailored and stepwise
national Association for the Study of Pain
patients with type 2 diabetes. B pharmacologic strategy with careful atten-
found the evidence supporting the ef-
11.29 Assessandtreatpatientstoreduce tion to relative symptom improvement,
fectiveness of tapentadol in reducing neu-
pain related to diabetic peripheral medication adherence, and medication
ropathic pain to be inconclusive (150).
neuropathy B and symptoms of side effects is recommended to achieve
Therefore, given the high risk for addiction
autonomic neuropathy and to im- pain reduction and improve quality of life
and safety concerns compared with the
prove quality of life. E (151–153).
relatively modest pain reduction, the use of
11.30 Pregabalin, duloxetine, or ga- Pregabalin, a calcium channel a2-d
extended-release tapentadol is not gener-
bapentin are recommended subunit ligand, is the most extensively
ally recommended as a first-or second-line
as initial pharmacologic treat- studied drug for DPN. The majority of
therapy. The use of any opioids for man-
ments for neuropathic pain in studies testing pregabalin have reported
agement of chronic neuropathic pain car-
diabetes. A favorable effects on the proportion of
ries the risk of addiction and should be
participants with at least 30–50% im-
avoided.
Glycemic Control provement in pain (150,152,154–157).
Tricyclic antidepressants, venlafaxine,
Near-normal glycemic control, imple- However, not all trials with pregabalin
carbamazepine, and topical capsaicin,
mented early in the course of diabetes, have been positive (150,152,158,159),
although not approved for the treat-
has been shown to effectively delay or especially when treating patients with
ment of painful DPN, may be effective
prevent the development of DPN and advanced refractory DPN (156). Adverse
and considered for the treatment of
CAN in patients with type 1 diabetes effects may be more severe in older
painful DPN (137,150,152).
(142–145). Although the evidence for patients (160) and may be attenuated
the benefit of near-normal glycemic con- by lower starting doses and more gradual Orthostatic Hypotension
trol is not as strong for type 2 diabetes, titration. The related drug, gabapentin, Treating orthostatic hypotension is chal-
some studies have demonstrated a mod- has also shown efficacy for pain control in lenging. The therapeutic goal is to mini-
est slowing of progression without re- diabetic neuropathy and may be less mize postural symptoms rather than to
versal of neuronal loss (52,146). Specific expensive, although it is not FDA ap- restore normotension. Most patients re-
glucose-lowering strategies may have proved for this indication (161). quire both nonpharmacologic measuresYou can also read
