Current Diabetes Reports (2019) 19:86

https://doi.org/10.1007/s11892-019-1212-8

MICROVASCULAR COMPLICATIONS—NEUROPATHY (R POP-BUSUI, SECTION EDITOR)

Epidemiology of Peripheral Neuropathy and Lower Extremity

Disease in Diabetes
Caitlin W. Hicks 1 & Elizabeth Selvin 2

# Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract
Purpose of Review Diabetic peripheral neuropathy eventually affects nearly 50% of adults with diabetes during their lifetime and
is associated with substantial morbidity including pain, foot ulcers, and lower limb amputation. This review summarizes the
epidemiology, risk factors, and management of diabetic peripheral neuropathy and related lower extremity complications.
Recent Findings The prevalence of peripheral neuropathy is estimated to be between 6 and 51% among adults with diabetes
depending on age, duration of diabetes, glucose control, and type 1 versus type 2 diabetes. The clinical manifestations are
variable, ranging from asymptomatic to painful neuropathic symptoms. Because of the risk of foot ulcer (25%) and amputation
associated with diabetic peripheral neuropathy, aggressive screening and treatment in the form of glycemic control, regular foot
exams, and pain management are important. There is an emerging focus on lifestyle interventions including weight loss and
physical activity as well.
Summary The American Diabetes Association has issued multiple recommendation statements pertaining to diabetic neuropa-
thies and the care of the diabetic foot. Given that approximately 50% of adults with diabetes will be affected by peripheral
neuropathy in their lifetime, more diligent screening and management are important to reduce the complications and health care
burden associated with the disease.

Keywords Peripheral neuropathy . Lower extremity disease . Type 1 diabetes . Type 2 diabetes . Microvascular complications

Introduction reported symptoms [1••]. The estimated prevalence of periph-

eral neuropathy among adults with diabetes in the USA is
Diabetic peripheral neuropathy is defined as, “the presence of 28% [1••, 2].
symptoms and/or signs of peripheral nerve dysfunction in The consequences of diabetic peripheral neuropathy can be
people with diabetes after the exclusion of other causes” devastating. Approximately 50% of people with diabetes will
[1••]. The diagnosis relies on both clinical signs as well as develop a foot ulcer during their lifetime [3–5], and diabetes is
quantitative testing and may be present despite a lack of a leading cause of lower limb amputation [6]. In addition,
neuropathic pain and decreased sensation can contribute to
This article is part of the Topical Collection on Microvascular an array of pour outcomes including falls, impaired quality
Complications—Neuropathy of life, restrictions in activities of daily living, and depressive
symptoms [7].
* Elizabeth Selvin While peripheral neuropathy can occur in adults without
eselvin@jhu.edu diabetes, the prevention and management of peripheral neu-
Caitlin W. Hicks ropathy in diabetes is largely focused on glycemic control.
chicks11@jhmi.edu Pain management also remains an important component in
1
the management of diabetic neuropathy [1••], and there is an
Division of Vascular Surgery and Endovascular Therapy, Johns
emerging focus on lifestyle interventions including weight
Hopkins University School of Medicine, 600 N Wolfe Street, Halsted
668, Baltimore, MD 21287, USA loss and physical activity [1••, 8].
2 Herein, we summarize the epidemiology, risk factors, and
Department of Epidemiology, Johns Hopkins Bloomberg School of
Public Health, 2024 E. Monument St., Suite 2-600, management of diabetic peripheral neuropathy and related
Baltimore, MD 21287, USA lower extremity complications.
 86 Page 2 of 8 Curr Diab Rep (2019) 19:86

Types and Presentation of Diabetic Peripheral Control and Complications Trial/Epidemiology of Diabetes
Neuropathy Interventions and Complications (DDCT/EDIC) Study, the
prevalence of diabetic peripheral neuropathy among adults
There are several forms of diabetic peripheral neuropathy with type 1 diabetes was 6% at baseline and increased to
[1••]. The most common type is distal symmetric 30% after 13–14 years of follow-up [27]. The prevalence of
polyneuropathy which can be classified as primarily small- peripheral neuropathy among adults with type 1 diabetes in
fiber, primarily large-fiber, or mixed small and large fibers the Pittsburgh Epidemiology of Diabetes Complications was
[1••], and accounts for approximately 75% of all diabetic neu- 34% and increased significantly with age (18–29 years, 18%;
ropathies [9, 10]. Distal symmetric polyneuropathy causes ≥ 30 years, 58%) [28]. The prevalence of diabetic peripheral
neuropathic pain symptoms in approximately 10 to 30% of neuropathy among youths with type 1 diabetes (mean age
affected patients depending on the population studied [2, 15.7 years) was 8.2% in the SEARCH for Diabetes in Youth
11–16]. The pain may be described as a burning or stabbing Study [29].
pain, numbness, hyperesthesia, or a deep ache. It is often The prevalence of diabetes peripheral neuropathy is some-
worse at night and usually affects the lower legs and feet, what higher among persons with type 2 diabetes. In the
although in some patients, the hands may be affected as well SEARCH for Diabetes in Youth Study, peripheral neuropathy
[17]. was present in 26% of youths with type 2 diabetes [29]. In the
Atypical forms of diabetic peripheral neuropathy include Action to Control Cardiovascular Risk in Diabetes
mononeuropathies (i.e., mononeuritis multiplex), (poly) (ACCORD) trial, peripheral neuropathy was present in 42%
radiculopathies, and treatment-induced neuropathies [1••]. of adults with type 2 diabetes at baseline [30]. This is similar
Mononeuropathies are closely associated with diabetes [9] to the 39% prevalence reported in the Veteran Affairs Diabetes
and tend to affect the median, ulnar, radial, or common pero- Trial [31]. In the Bypass Angioplasty Revascularization
neal nerves [18]. Cranial nerve involvement is extremely rare Investigation 2 Diabetes (BARI 2D) trial, 51% of adults with
and usually presents as an acute mononeuropathy affecting type 2 diabetes had a history of peripheral neuropathy at base-
cranial nerves III, IV, VI, or VII [18]. Diabetic radiculopathies line [32].
typically involve the lumbosacral plexus and present primarily The burden of diabetic peripheral neuropathy is higher in
as unilateral thigh pain and weight loss with subsequent motor older age and among adults with long-standing type 1 or type
weakness [1••, 19, 20]. Treatment-induced neuropathy is a 2 diabetes [26, 33, 34]. There is some evidence to suggest that
rare iatrogenic event that [17] occurs in patients following diabetic peripheral neuropathy may occur less frequently in
periods of extreme metabolic dysregulation (i.e., Asian populations, although this finding has not been consis-
ketoacidosis), or following a sudden and substation change tent [25]. Most estimates suggest that approximately 50% of
in glycemic control (i.e., insulin neuritis). Each of the atypical adults with diabetes will be affected by diabetic peripheral
diabetic peripheral neuropathies are largely self-limited and neuropathy over the course of their lifetime [3–5].
will resolve over several months with supportive care, medical
management, and physical therapy [18–21]. Etiology and Risk Factors for Diabetic Peripheral
Other diabetic neuropathies include autonomic neuropa- Neuropathy
thies that affect the cardiovascular, gastrointestinal, and uro-
genital systems. Adults with diabetes may also suffer from Diabetic peripheral neuropathy is thought to be caused by
sudomotor dysfunction, hypoglycemia unawareness, and ab- nerve dysfunction and cell death that results from oxidative
normal pupillary function [1••]. These neuropathies share a stress and inflammation [35]. Hyperglycemia, dyslipidemia,
similar diffuse pathophysiology with distal symmetric and insulin resistance all contribute to dysregulation of meta-
polyneuropathy, but are largely non-sensory. bolic pathways that collectively cause an imbalance in the
mitochondrial redox state, thereby leading to excess formation
Epidemiology of Diabetic Peripheral Neuropathy of mitochondrial and cytosolic reactive oxygen species [36].
This leads to a loss of axonal energy stores and axonal injury,
Diabetic peripheral neuropathy is the most common form of promoting peripheral neuropathy [35]. The earliest changes of
neuropathy worldwide [22•]. In a landmark historical cohort diabetic peripheral neuropathy occur at the level of unmyelin-
study of 4400 adults with diabetes from France who were ated C fibers, resulting in pain, allodynia, and hyperesthesias
followed prospectively from 1947 to 1973, 50% of partici- [37]. Mild segmental axonal demyelination then occurs,
pants developed peripheral neuropathy by the end of the followed by frank axonal degeneration of myelinated fibers
25 years of follow-up [23]. More recent cross-sectional studies as demyelination surpasses remyelination [38]. These changes
from the USA and Europe have reported a prevalence of dia- lead to a progressive loss of distal sensation in a distal-to-
betic peripheral neuropathy ranging from 6 to 51% depending proximal course along the nerve that defines diabetic periph-
on the population studied [2, 5, 24–26]. In the Diabetes eral neuropathy.
Curr Diab Rep (2019) 19:86 Page 3 of 8 86

Randomized clinical trials have demonstrated the benefit of electrophysiologic studies [49]. Symptomatic
glucose control of slowing the progression of microvascular mononeuropathy is less common, occurring in approximately
disease in diabetes, including peripheral neuropathy [39]. In 0.9% of adults with type 1 diabetes and 1.3% of adults with
the DCCT trial of 1441 adults with type 1 diabetes, intensive type 2 diabetes, compared with 0–1% of adults without dia-
insulin therapy (versus conventional therapy) reduced the risk betes [48, 50]. Risk factors of mononeuropathy are similar to
of clinical neuropathy by 60% after 6.5 years of follow-up those for diabetic peripheral neuropathy and include longer
[40]. The benefits of strict glycemic control persisted long- duration of diabetes, female sex, and higher body mass index
term, as demonstrated in the observational follow-up of the [49, 51, 52].
DCCT/EDIC participants, with a reduction in the risk of dia-
betic peripheral neuropathy in the intensively treated versus Epidemiology of Lower Extremity Complications
conventional group that persisted after the end of the trial in Diabetes
(relative risk reduction of 30% during years 6.5 to 14) [27].
Among adults with type 2 diabetes, both the KUMAMOTO Peripheral neuropathy can cause a range of complications,
Trial [41] and the UK Prospective Diabetes Study (UKPDS) including chronic pain, foot ulcers, foot infections, and ampu-
[42, 43] demonstrated fewer microvascular complications, in- tations. The estimated global prevalence of diabetic foot ulcers
cluding peripheral neuropathy, among patients treated with is 6%, with major risk factors including older age, lower body
intensive versus conventional glucose control. In addition, mass index, longer duration of diabetes, hypertension, diabetic
median motor nerve conduction studies [41] and vibration retinopathy, and smoking [53]. Approximately 25% of people
perception threshold [42, 43] were significantly improved in with diabetes will develop a foot ulcer during their lifetime
patients treated with intensive therapy in the KUMAMOTO [54], which can progress to infection and limb amputation in
and UKPDS studies, respectively. In a recent Cochrane review severe cases. Ninety percent of hospital admissions for diabet-
and meta-analysis of data from 17 randomized trials (7 in ic foot ulcers are related to peripheral neuropathy and infec-
people with type 1 diabetes, 8 in people with type 2 diabetes, tion, and diabetes accounts for 83% of all major amputations
and 2 in both types) evaluating the association of glucose in the USA [55]. Based on data from the Consensus
control with diabetic peripheral neuropathy, enhanced glucose Development Conference on Diabetic Foot Wound Care, it
control significantly reduced the risk of clinical neuropathy as is estimated that approximately 14–24% of people with a foot
well as nerve conduction and vibration threshold abnormali- ulcer will ultimately require an amputation [56]. Thus, early
ties in type 1 diabetes. The risk of clinical neuropathy was also diagnosis and treatment are essential. Implementation of reg-
reduced in type 2 diabetes, although this was not statistically ular foot exams among adults with diabetes has been shown to
significant (P = 0.06) [44]. reduce the rate of foot ulcers in a variety of populations
In addition to age, duration of diabetes, and glucose con- [57–59], and is essential to preventing progression of the dis-
trol, diabetic peripheral neuropathy is linked to cardiometa- ease to infection or lower limb amputation.
bolic disease and is associated with modifiable cardiovascular Patients with diabetic peripheral neuropathy who are at the
risk factors, including elevated triglyceride levels, body mass highest risk for developing foot ulcers that lead to amputation
index, smoking, and hypertension [45, 46]. Prevalent cardio- include those with a prior history of foot ulcers, a structural
vascular disease is associated with nearly twice the risk of foot deformity, peripheral artery disease, visual impairment,
diabetic peripheral neuropathy, even after accounting for stan- diabetic nephropathy, poor glycemic control, and smoking
dard cardiovascular risk factors [45]. The temporality of these [60••]. While all patients should have annual foot exams and
associations and causal mechanisms linking peripheral neu- appropriate management of diabetic peripheral neuropathy,
ropathy with cardiovascular disease are less clear, but could be patients with major risk factors should be educated on ampu-
due to the presence of subclinical atherosclerosis and/or mi- tation risk and referred for dedicated foot care and surveillance
crovascular disease that contribute to both progressive cardio- whenever possible. Effective patient education has been
vascular and peripheral neuropathy morbidity [47]. shown to reduce the incidence of foot ulcers and amputations
by as much as 50% [61].
Epidemiology of Mononeuropathies
Treatment Approaches for Diabetic Peripheral
Mononeuropathies, which affect less than 10% of patients, Neuropathy
generally present with acute symptoms affecting the medial,
ulnar, radial, or common peroneal nerve distributions [17]. Peripheral neuropathy is usually an irreversible disease, ex-
The prevalence of mononeuropathy is higher in adults with cept in rare instances. The treatment is largely supportive and
diabetes compared with those without [9, 48]. In the Early aims to prevent progression of disease and related complica-
Diabetes Intervention Trial, median nerve mononeuropathy tions [62]. The three main principles of treatment for periph-
was diagnosed in 23% of adults with diabetes based on eral neuropathy are glycemic control, foot care, and pain
 86 Page 4 of 8 Curr Diab Rep (2019) 19:86

management. Glycemic control has not been shown to effec- majority of these costs are attributable to the treatment of foot
tively reduce the symptoms among patients with peripheral ulcers with superimposed infections and their complications,
neuropathy [44], and thus, both glycemic control and foot care which is estimated to cost more than $13,000 per admission
efforts are largely preventative. There is emerging evidence [77]. The estimated combined direct and indirect costs asso-
that lifestyle interventions including weight loss and physical ciated with diabetic peripheral neuropathy were estimated to
activity may be helpful for managing painful peripheral neu- be between $3000 and $4000 per patient per year in 2009 [74],
ropathy, although the data are preliminary [1••, 8, 63]. and have likely increased in the ensuing decade.
Pharmacologic treatment is indicated for the treatment of
painful diabetic peripheral neuropathy and has been shown to Quality of Life and Functional Impact of Diabetic
be effective in a number of randomized controlled trials and Peripheral Neuropathy
systematic reviews [1••, 64]. The American Diabetes
Association recommends medications for the relief of symp- There are also indirect costs associated with diabetic periph-
toms related to diabetic peripheral neuropathy, which have eral neuropathy that are more challenging to calculate, includ-
been shown to improve patients’ quality of life [1••, 60••]. ing loss of productivity, loss of quality of life, rehabilitation
Currently, only duloxetine and pregabalin are approved by costs, and personal expenditures [17]. The physical and men-
the US Food and Drug Administration (FDA) for the treat- tal components of quality of life are significantly altered
ment of diabetic peripheral neuropathic pain [65, 66]. among patients with painful diabetic peripheral neuropathy
Tricyclic antidepressants have been shown to reduce neuro- [78], and concomitant anxiety, depression, and sleep distur-
pathic pain, but are not currently approved by the FDA for this bance are reported in 43% of affected patients [79].
indication largely due to their risk of serious side effects [1••, Employment status is affected in 35 to 43% of patients [79,
67, 68]. Pain management with tramadol or oxycodone has 80], with employed patients reporting an average of 5.5
also been shown to lower pain scores and improve physical missed workdays per month due to pain [80].
function in some patients [69, 70]. However, opioids have In addition to impaired quality of life, patients with diabetic
addictive properties and should not be used as first- or peripheral neuropathy also have an increased risk of falls due
second-line therapy for neuropathic pain [1••, 71]. to balance challenges [81–83]. The risk of balance impairment
Despite a large body of evidence and professional treat- is particularly high for patients with severe diabetic peripheral
ment guidelines on the medical management of painful dia- neuropathy, older age, and concomitant depression [81]. As a
betic peripheral neuropathy [1••, 60••], current medication result, falls and fractures are frequent among affected patients
prescribing patterns are inconsistent. In a study of claims- [84], occurring in an estimated 25% of adults ≥ 65 years with
based data among a cohort of 666 patients with diabetic pe- diabetes compared with 18% among similar adults without
ripheral neuropathy, 43% received pharmacologic agents diabetes [85]. Diabetic peripheral neuropathy is associated
within 1 year of diagnosis [72]. Of these, 53% were prescribed with a risk of major fractures due to falls [86, 87], potentially
an opioid, including 33% who were prescribed an opioid as a because patients tend to have falls that are sideways, as op-
first-line agent. Antidepressants were prescribed in 26% of posed to forward or backward [82].
cases, followed by anticonvulsants (23%), non-steroidal anti-
inflammatory drugs (19%), and muscle relaxants (5%). FDA- Screening and Prevention for Diabetic Peripheral
approved duloxetine and pregabalin were only prescribed in Neuropathy
1% and 6% of cases, respectively [72]. Continuous treatment
with duloxetine has been shown to be associated with a reduc- Due to the substantial impact that diabetic peripheral neurop-
tion in opioid use compared with treatment with other modal- athy has on patients’ health, quality of life, and health care
ities [73, 74], and higher average daily doses of duloxetine are costs, the American Diabetes Association currently recom-
associated with higher treatment compliance and lower health mends that screening for diabetic peripheral neuropathy be
care costs [74]. In contrast, inappropriate or excessive performed in all adults at the time of diabetes diagnosis, and
medication-taking behaviors occur in 5 to 24% of patients annually thereafter [60••]. Despite these recommendations,
with chronic opioid prescriptions, and the prevalence of opi- data from the National Health and Nutrition Examination
oid addiction ranges from 36 to 50% [71, 75]. Surveys (2005–2010) demonstrated that 28.6% of adults with
diagnosed diabetes reported they had not had a health profes-
Economic Impact of Diabetic Peripheral Neuropathy sional check their feet for sores or irritation in the past year
[88]. Similarly, data from the Centers for Disease Control and
The US health care burden of diabetic peripheral neuropathy Prevention showed that the age-adjusted percentage of adults
is substantial, estimated to be $10.9 billion per year overall with diagnosed diabetes who received a foot exam in the last
[76]. As much as 27% of direct medical costs related to dia- year was only 67.5% in 2010 [89]. Although there was an ~
betes may be related to peripheral neuropathy [76]. The 20% increase in the percentage of foot exams performed for
Curr Diab Rep (2019) 19:86 Page 5 of 8 86

adults with diabetes between 1994 and 2010 [89], there is still Association about the workup and management of diabetic
neuropathy.
substantial room for improvement. As of 2014, the Centers for
2. Gregg EW, Gu Q, Williams D, de Rekeneire N, Cheng YJ, Geiss L,
Medicaid and Medicare Services included an annual foot ex- et al. Prevalence of lower extremity diseases associated with normal
am in primary care as a clinical quality measure [90]. To glucose levels, impaired fasting glucose, and diabetes among U.S.
qualify, the foot exam must include a visual inspection, sen- adults aged 40 or older. Diabetes Res Clin Pract. 2007;77(3):485–8.
sory exam with monofilament testing, and assessment of low- https://doi.org/10.1016/j.diabres.2007.01.005.
3. Boulton AJ. Diabetic neuropathy and foot complications. Handb
er extremity pulses. An adequate foot exam can be performed Clin Neurol. 2014;126:97–107. https://doi.org/10.1016/B978-0-
in 3 min [91] and should be implemented as a regular compo- 444-53480-4.00008-4.
nent in the physical exam. 4. Boulton AJ. The pathway to foot ulceration in diabetes. Med Clin
North Am. 2013;97(5):775–90. https://doi.org/10.1016/j.mcna.
2013.03.007.
5. Kumar S, Ashe HA, Parnell LN, Fernando DJ, Tsigos C, Young RJ,
Conclusions et al. The prevalence of foot ulceration and its correlates in type 2
diabetic patients: a population-based study. Diabet Med.
1994;11(5):480–4.
The American Diabetes Associations has issued multiple rec- 6. Margolis DJ, Jeffcoate W. Epidemiology of foot ulceration and
ommendation statements pertaining to diabetic neuropathies amputation: can global variation be explained? Med Clin
and the care of the diabetic foot [1••, 60, 92]. Each of these North Am. 2013;97(5):791–805. https://doi.org/10.1016/j.
mcna.2013.03.008.
focus on the importance of glycemic control and foot care for
7. Vileikyte L, Leventhal H, Gonzalez JS, Peyrot M, Rubin RR,
the prevention and treatment of diabetic peripheral neuropa- Ulbrecht JS, et al. Diabetic peripheral neuropathy and depressive
thy. Given that approximately 50% of adults with diabetes will symptoms: the association revisited. Diabetes Care. 2005;28(10):
be affected by peripheral neuropathy in their lifetime, more 2378–83. https://doi.org/10.2337/diacare.28.10.2378.
diligent screening and management of the diabetic population 8. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin
JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes
are important to reduce the complications and health care bur- with lifestyle intervention or metformin. N Engl J Med.
den associated with the disease. 2002;346(6):393–403. https://doi.org/10.1056/NEJMoa012512.
9. Albers JW, Pop-Busui R. Diabetic neuropathy: mechanisms,
Acknowledgments We thank Dr. Andrew Boulton for his review of and emerging treatments, and subtypes. Curr Neurol Neurosci Rep.
insights regarding this manuscript. 2014;14(8):473. https://doi.org/10.1007/s11910-014-0473-5.
10. Dyck PJ, Albers JW, Andersen H, Arezzo JC, Biessels GJ, Bril V,
Funding Information Dr. Selvin was supported by grants K24 et al. Diabetic polyneuropathies: update on research definition, di-
DK106414 and R01 DK089174 from the National Institutes of Health agnostic criteria and estimation of severity. Diabetes Metab Res
(NIDDK) related to this topic. Rev. 2011;27(7):620–8. https://doi.org/10.1002/dmrr.1226.
11. Partanen J, Niskanen L, Lehtinen J, Mervaala E, Siitonen O,
Uusitupa M. Natural history of peripheral neuropathy in patients
Compliance with Ethical Standards with non-insulin-dependent diabetes mellitus. N Engl J Med.
1995;333(2):89–94. https://doi.org/10.1056/
Conflict of Interest Caitlin W. Hicks declares that she has no conflict of NEJM199507133330203.
interest. Elizabeth Selvin is a PI of grants from the Foundation for the 12. Jambart S, Ammache Z, Haddad F, Younes A, Hassoun A, Abdalla
National Institutes of Health and the National Kidney Foundation, but K, et al. Prevalence of painful diabetic peripheral neuropathy
that is unrelated to this topic. among patients with diabetes mellitus in the Middle East region. J
Int Med Res. 2011;39(2):366–377.10.1177/147323001103900204.
Human and Animal Rights and Informed Consent This article does not 13. Hall GC, Carroll D, Parry D, McQuay HJ. Epidemiology and
contain any studies with human or animal subjects performed by any of treatment of neuropathic pain: the UK primary care perspec-
the authors. tive. Pain. 2006;122(1–2):156–62. https://doi.org/10.1016/j.
pain.2006.01.030.
14. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, et al.
The prevalence by staged severity of various types of diabetic neu-
References ropathy, retinopathy, and nephropathy in a population-based cohort:
the Rochester Diabetic Neuropathy Study. Neurology. 1993;43(4):
817–24. https://doi.org/10.1212/wnl.43.4.817.
Papers of particular interest, published recently, have been 15. Davies M, Brophy S, Williams R, Taylor A. The prevalence, sever-
highlighted as: ity, and impact of painful diabetic peripheral neuropathy in type 2
diabetes. Diabetes Care. 2006;29(7):1518–22. https://doi.org/10.
• Of importance 2337/dc05-2228.
•• Of major importance 16. Daousi C, MacFarlane IA, Woodward A, Nurmikko TJ, Bundred
PE, Benbow SJ. Chronic painful peripheral neuropathy in an urban
1.•• Pop-Busui R, Boulton AJ, Feldman EL, Bril V, Freeman R, Malik community: a controlled comparison of people with and without
RA, et al. Diabetic neuropathy: a position statement by the diabetes. Diabet Med. 2004;21(9):976–82. https://doi.org/10.1111/
American Diabetes Association. Diabetes Care. 2017;40(1):136– j.1464-5491.2004.01271.x.
54. https://doi.org/10.2337/dc16-2042 This article describes the 17. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R,
most recent position statment from the American Diabetes et al. Diabetic neuropathies: a statement by the American Diabetes
 86 Page 6 of 8 Curr Diab Rep (2019) 19:86

Association. Diabetes Care. 2005;28(4):956–62. https://doi.org/10. Nerv Syst. 2009;14(1):1–13. https://doi.org/10.1111/j.1529-8027.

2337/diacare.28.4.956. 2009.00200.x.
18. Smith BE. Focal and entrapment neuropathies. Handb Clin Neurol. 33. Tovi J, Svanborg E, Nilsson BY, Engfeldt P. Diabetic neuropathy in
2014;126:31–43. https://doi.org/10.1016/B978-0-444-53480-4. elderly type 2 diabetic patients: effects of insulin treatment. Acta
00003-5. Neurol Scand. 1998;98(5):346–53.
19. Dyck PJ, Windebank AJ. Diabetic and nondiabetic lumbosacral 34. Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH.
radiculoplexus neuropathies: new insights into pathophysiology A multicentre study of the prevalence of diabetic peripheral neu-
and treatment. Muscle Nerve. 2002;25(4):477–91. ropathy in the United Kingdom hospital clinic population.
20. Massie R, Mauermann ML, Staff NP, Amrami KK, Mandrekar JN, Diabetologia. 1993;36(2):150–4.
Dyck PJ, et al. Diabetic cervical radiculoplexus neuropathy: a dis- 35. Feldman EL, Nave KA, Jensen TS, Bennett DLH. New hori-
tinct syndrome expanding the spectrum of diabetic radiculoplexus zons in diabetic neuropathy: mechanisms, bioenergetics, and
neuropathies. Brain. 2012;135(Pt 10):3074–88. https://doi.org/10. pain. Neuron. 2017;93(6):1296–313. https://doi.org/10.1016/j.
1093/brain/aws244. neuron.2017.02.005.
21. Gibbons CH, Freeman R. Treatment-induced neuropathy of diabe- 36. Sajic M. Mitochondrial dynamics in peripheral neuropathies.
tes: an acute, iatrogenic complication of diabetes. Brain. Antioxid Redox Signal. 2014;21(4):601–20. https://doi.org/10.
2015;138(Pt 1):43–52. https://doi.org/10.1093/brain/awu307. 1089/ars.2013.5822.
22.• Iqbal Z, Azmi S, Yadav R, Ferdousi M, Kumar M, Cuthbertson DJ, 37. Green AQ, Krishnan S, Finucane FM, Rayman G. Altered C-fiber
et al. Diabetic peripheral neuropathy: epidemiology, diagnosis, and function as an indicator of early peripheral neuropathy in individ-
pharmacotherapy. Clin Ther. 2018;40(6):828–49. https://doi.org/ uals with impaired glucose tolerance. Diabetes Care. 2010;33(1):
10.1016/j.clinthera.2018.04.001 This article provides a 174–6. https://doi.org/10.2337/dc09-0101.
comprehensive literature review on the treatment of 38. Malik RA, Veves A, Walker D, Siddique I, Lye RH, Schady W,
neuropathic pain in diabetic peripheral neuropathy. et al. Sural nerve fibre pathology in diabetic patients with mild
23. Pirart J. Diabetes mellitus and its degenerative complications: a neuropathy: relationship to pain, quantitative sensory testing and
prospective study of 4,400 patients observed between 1947 and peripheral nerve electrophysiology. Acta Neuropathol.
1973 (3rd and last part) (author’s transl). Diabete Metab. 2001;101(4):367–74.
1977;3(2–4).
39. Ang L, Jaiswal M, Martin C, Pop-Busui R. Glucose control and
24. Tesfaye S, Stevens LK, Stephenson JM, Fuller JH, Plater M,
diabetic neuropathy: lessons from recent large clinical trials. Curr
Ionescu-Tirgoviste C, et al. Prevalence of diabetic peripheral neu-
Diab Rep. 2014;14(9):528. https://doi.org/10.1007/s11892-014-
ropathy and its relation to glycaemic control and potential risk
0528-7.
factors: the EURODIAB IDDM Complications Study.
40. Diabetes Control and Complications Trial Research Group, Nathan
Diabetologia. 1996;39(11):1377–84.
DM, Genuth S, Lachin J, Cleary P, et al. The effect of intensive
25. Abbott CA, Malik RA, van Ross ER, Kulkarni J, Boulton AJ.
treatment of diabetes on the development and progression of long-
Prevalence and characteristics of painful diabetic neuropathy in a
term complications in insulin-dependent diabetes mellitus. N Engl J
large community-based diabetic population in the U.K. Diabetes
Med. 1993;329(14):977–86. http s://doi.org/10.1056 /
Care. 2011;34(10):2220–4. https://doi.org/10.2337/dc11-1108.
NEJM199309303291401.
26. Cabezas-Cerrato J. The prevalence of clinical diabetic
polyneuropathy in Spain: a study in primary care and hospital 41. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S,
clinic groups. Neuropathy Spanish Study Group of the Spanish et al. Intensive insulin therapy prevents the progression of diabetic
Diabetes Society (SDS). Diabetologia. 1998;41(11):1263–9. microvascular complications in Japanese patients with non-insulin-
27. Martin CL, Albers JW, Pop-Busui R, Group DER. Neuropathy and dependent diabetes mellitus: a randomized prospective 6-year
related findings in the diabetes control and complications trial/ study. Diabetes Res Clin Pract. 1995;28(2):103–17.
epidemiology of diabetes interventions and complications study. 42. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year
Diabetes Care. 2014;37(1):31–8. https://doi.org/10.2337/dc13- follow-up of intensive glucose control in type 2 diabetes. N Engl J
2114. Med. 2008;359(15):1577–89. https://doi.org/10.1056/
28. Maser RE, Steenkiste AR, Dorman JS, Nielsen VK, Bass EB, NEJMoa0806470.
Manjoo Q, et al. Epidemiological correlates of diabetic neuropathy. 43. Effect of intensive blood-glucose control with metformin on com-
Report from Pittsburgh Epidemiology of Diabetes Complications plications in overweight patients with type 2 diabetes (UKPDS 34).
Study. Diabetes. 1989;38(11):1456–61. https://doi.org/10.2337/ UK Prospective Diabetes Study (UKPDS) Group. Lancet.
diab.38.11.1456. 1998;352(9131):854–865.
29. Jaiswal M, Lauer A, Martin CL, Bell RA, Divers J, Dabelea D, et al. 44. Callaghan BC, Little AA, Feldman EL, Hughes RA. Enhanced
Peripheral neuropathy in adolescents and young adults with type 1 glucose control for preventing and treating diabetic neuropathy.
and type 2 diabetes from the SEARCH for Diabetes in Youth Cochrane Database Syst Rev. 2012;(6):CD007543.https://doi.org/
follow-up cohort: a pilot study. Diabetes Care. 2013;36(12):3903– 10.1002/14651858.CD007543.pub2.
8. https://doi.org/10.2337/dc13-1213. 45. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-
30. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen Tirgoviste C, et al. Vascular risk factors and diabetic neuropathy. N
RM, et al. Effect of intensive treatment of hyperglycaemia on mi- Engl J Med. 2005;352(4):341–50. https://doi.org/10.1056/
crovascular outcomes in type 2 diabetes: an analysis of the NEJMoa032782.
ACCORD randomised trial. Lancet. 2010;376(9739):419–30. 46. Wiggin TD, Sullivan KA, Pop-Busui R, Amato A, Sima AA,
https://doi.org/10.1016/S0140-6736(10)60576-4. Feldman EL. Elevated triglycerides correlate with progression of
31. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven diabetic neuropathy. Diabetes. 2009;58(7):1634–40. https://doi.org/
PD, et al. Glucose control and vascular complications in veterans 10.2337/db08-1771.
with type 2 diabetes. N Engl J Med. 2009;360(2):129–39. https:// 47. Pinto A, Tuttolomondo A, Di Raimondo D, Fernandez P, La Placa
doi.org/10.1056/NEJMoa0808431. S, Di Gati M, et al. Cardiovascular risk profile and morbidity in
32. Pop-Busui R, Lu J, Lopes N, Jones TL, Investigators BD. subjects affected by type 2 diabetes mellitus with and without dia-
Prevalence of diabetic peripheral neuropathy and relation to glyce- betic foot. Metabolism. 2008;57(5):676–82. https://doi.org/10.
mic control therapies at baseline in the BARI 2D cohort. J Peripher 1016/j.metabol.2008.01.004.
Curr Diab Rep (2019) 19:86 Page 7 of 8 86

48. Hanewinckel R, Ikram MA, Van Doorn PA. Peripheral neuropa- Rehabilitation. PM R. 2011;3(4):345–52, 352 e341–321. https://
thies. Handb Clin Neurol. 2016;138:263–82. https://doi.org/10. doi.org/10.1016/j.pmrj.2011.03.008.
1016/B978-0-12-802973-2.00015-X. 65. Onakpoya IJ, Thomas ET, Lee JJ, Goldacre B, Heneghan CJ.
49. Albers JW, Brown MB, Sima AA, Greene DA. Frequency of me- Benefits and harms of pregabalin in the management of neuropathic
dian mononeuropathy in patients with mild diabetic neuropathy in pain: a rapid review and meta-analysis of randomised clinical trials.
the early diabetes intervention trial (EDIT). Tolrestat Study Group BMJ Open. 2019;9(1):e023600. https://doi.org/10.1136/bmjopen-
For Edit (Early Diabetes Intervention Trial). Muscle Nerve. 2018-023600.
1996;19(2):140–6. https://doi.org/10.1002/(SICI)1097- 66. Ormseth MJ, Scholz BA, Boomershine CS. Duloxetine in the man-
4598(199602)19:2<140::AID-MUS3>3.0.CO;2-E. agement of diabetic peripheral neuropathic pain. Patient Prefer
50. O’Hare JA, Abuaisha F, Geoghegan M. Prevalence and forms of Adherence. 2011;5:343–56. https://doi.org/10.2147/PPA.S16358.
neuropathic morbidity in 800 diabetics. Ir J Med Sci. 1994;163(3): 67. Kvinesdal B, Molin J, Froland A, Gram LF. Imipramine treatment
132–5. of painful diabetic neuropathy. JAMA. 1984;251(13):1727–30.
51. Vinik AI, Holland MT, Le Beau JM, Liuzzi FJ, Stansberry KB, 68. Max MB, Culnane M, Schafer SC, Gracely RH, Walther DJ,
Colen LB. Diabetic neuropathies. Diabetes Care. 1992;15(12): Smoller B, et al. Amitriptyline relieves diabetic neuropathy pain
1926–75. https://doi.org/10.2337/diacare.15.12.1926. in patients with normal or depressed mood. Neurology.
52. Vinik A, Mehrabyan A, Colen L, Boulton A. Focal entrapment 1987;37(4):589–96. https://doi.org/10.1212/wnl.37.4.589.
neuropathies in diabetes. Diabetes Care. 2004;27(7):1783–8. 69. Gimbel JS, Richards P, Portenoy RK. Controlled-release oxyco-
https://doi.org/10.2337/diacare.27.7.1783. done for pain in diabetic neuropathy: a randomized controlled trial.
53. Zhang P, Lu J, Jing Y, Tang S, Zhu D, Bi Y. Global epidemiology of Neurology. 2003;60(6):927–34. https://doi.org/10.1212/01.wnl.
diabetic foot ulceration: a systematic review and meta-analysis 0000057720.36503.2c.
(dagger). Ann Med. 2017;49(2):106–16. https://doi.org/10.1080/ 70. Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P,
07853890.2016.1231932. et al. Double-blind randomized trial of tramadol for the treatment of
54. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in the pain of diabetic neuropathy. Neurology. 1998;50(6):1842–6.
patients with diabetes. JAMA. 2005;293(2):217–28. https://doi. https://doi.org/10.1212/wnl.50.6.1842.
org/10.1001/jama.293.2.217.
71. Hojsted J, Sjogren P. Addiction to opioids in chronic pain patients: a
55. Hicks CW, Selvarajah S, Mathioudakis N, Sherman RE, Hines KF,
literature review. Eur J Pain. 2007;11(5):490–518. https://doi.org/
Black JH 3rd, et al. Burden of infected diabetic foot ulcers on
10.1016/j.ejpain.2006.08.004.
hospital admissions and costs. Ann Vasc Surg. 2016;33:149–58.
72. Patil PR, Wolfe J, Said Q, Thomas J, Martin BC. Opioid use in the
https://doi.org/10.1016/j.avsg.2015.11.025.
management of diabetic peripheral neuropathy (DPN) in a large
56. American Association of Diabetes, Consensus Development
commercially insured population. Clin J Pain. 2015;31(5):414–24.
Conference on Diabetic Foot Wound Care: 7–8 April 1999,
https://doi.org/10.1097/AJP.0000000000000124.
Boston, Massachusetts. Am Diabetes Assoc Diabetes Care.
1999;22(8):1354–60. https://doi.org/10.2337/diacare.22.8.1354. 73. Zhao Y, Wu N, Chen S, Boulanger L, Police RL, Fraser K. Changes
57. Brem H, Sheehan P, Rosenberg HJ, Schneider JS, Boulton AJ. in opioid use and healthcare costs among U.S. patients with diabetic
Evidence-based protocol for diabetic foot ulcers. Plast Reconstr peripheral neuropathic pain treated with duloxetine compared with
Surg. 2006;117(7 Suppl):193S–209S; discussion 210S–211S. other therapies. Curr Med Res Opin. 2010;26(9):2147–56. https://
https://doi.org/10.1097/01.prs.0000225459.93750.29. doi.org/10.1185/03007995.2010.503140.
58. Boodoo C, Perry JA, Leung G, Cross KM, Isaranuwatchai W. Cost- 74. Wu N, Chen S, Boulanger L, Fraser K, Bledsoe SL, Zhao Y.
effectiveness of telemonitoring screening for diabetic foot ulcer: a Duloxetine compliance and its association with healthcare costs
mathematical model. CMAJ Open. 2018;6(4):E486-E494.https:// among patients with diabetic peripheral neuropathic pain. J Med
doi.org/10.9778/cmajo.20180088 E c o n . 2 0 0 9 ; 1 2 ( 3 ) : 1 9 2 – 2 0 2 . h t t p s : / / d o i . o rg / 1 0 . 3 111 /
59. Lim JZ, Ng NS, Thomas C. Prevention and treatment of diabetic 13696990903240559.
foot ulcers. J R Soc Med. 2017;110(3):104–109.10.1177/ 75. Martell BA, O’Connor PG, Kerns RD, Becker WC, Morales KH,
0141076816688346. Kosten TR, et al. Systematic review: opioid treatment for chronic
60.•• American Association of Diabetes. 11. Microvascular complica- back pain: prevalence, efficacy, and association with addiction. Ann
tions and foot care: standards of medical care in diabetes-2019. Intern Med. 2007;146(2):116–27. https://doi.org/10.7326/0003-
Diabetes Care. 2019;42(Suppl 1):S124–38. https://doi.org/10. 4819-146-2-200701160-00006.
2337/dc19-S011 This article describes the most recent 76. Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The
recommendations from the American Diabetes Association health care costs of diabetic peripheral neuropathy in the US.
about the workup and management of microvascular Diabetes Care. 2003;26(6):1790–5. https://doi.org/10.2337/
complications and foot care in adults with diabetes. diacare.26.6.1790.
61. Boulton AJ. Lowering the risk of neuropathy, foot ulcers and am- 77. Hicks CW, Selvarajah S, Mathioudakis N, Perler BA, Freischlag
putations. Diabet Med. 1998;15(Suppl 4):S57–9. https://doi.org/10. JA, Black JH 3rd, et al. Trends and determinants of costs associated
1002/(SICI)1096-9136(1998120)15:4+<S57::AID-DIA741>3.0. with the inpatient care of diabetic foot ulcers. J Vasc Surg.
CO;2-D. 2014;60(5):1247–1254 e1242. https://doi.org/10.1016/j.jvs.2014.
62. Boulton AJ, Kempler P, Ametov A, Ziegler D. Whither pathoge- 05.009.
netic treatments for diabetic polyneuropathy? Diabetes Metab Res 78. Van Acker K, Bouhassira D, De Bacquer D, Weiss S, Matthys K,
Rev. 2013;29(5):327–33. https://doi.org/10.1002/dmrr.2397. Raemen H, et al. Prevalence and impact on quality of life of periph-
63. Smith AG, Russell J, Feldman EL, Goldstein J, Peltier A, Smith S, eral neuropathy with or without neuropathic pain in type 1 and type
et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes 2 diabetic patients attending hospital outpatients clinics. Diabetes
Care. 2006;29(6):1294–9. https://doi.org/10.2337/dc06-0224. Metab. 2009;35(3):206–13. https://doi.org/10.1016/j.diabet.2008.
64. Bril V, England J, Franklin GM, Backonja M, Cohen J, Del Toro D, 11.004.
et al. Evidence-based guideline: treatment of painful diabetic neu- 79. Tolle T, Xu X, Sadosky AB. Painful diabetic neuropathy: a cross-
ropathy: report of the American Academy of Neurology, the sectional survey of health state impairment and treatment patterns. J
American Association of Neuromuscular and Electrodiagnostic Diabetes Complications. 2006;20(1):26–33. https://doi.org/10.
Medicine, and the American Academy of Physical Medicine and 1016/j.jdiacomp.2005.09.007.
 86 Page 8 of 8 Curr Diab Rep (2019) 19:86

80. McDermott AM, Toelle TR, Rowbotham DJ, Schaefer CP, Dukes Endocrinol (Oxf). 2012;77(1):51–5. https://doi.org/10.1111/j.
EM. The burden of neuropathic pain: results from a cross-sectional 1365-2265.2011.04222.x.
survey. Eur J Pain. 2006;10(2):127–35. https://doi.org/10.1016/j. 88. Selvin E, Narayan KM, Huang ES. Chapter 41: Quality of care in
ejpain.2005.01.014. people with diabetes. In: Cowie CCCS, Menke A, Cissell MA,
81. Timar B, Timar R, Gaita L, Oancea C, Levai C, Lungeanu D. The Eberhardt MS, Meigs JB, Gregg EW, Knowler WC, Barrett-
impact of diabetic neuropathy on balance and on the risk of falls in Connor E, Becker DJ, Brancati FL, Boyko EJ, Herman WH,
patients with type 2 diabetes mellitus: a cross-sectional study. PLoS Howard BV, Narayan KMV, Rewers M, Fradkin JE, editors.
One. 2016;11(4):e0154654. https://doi.org/10.1371/journal.pone. Diabetes in America, 3rd ed. NIH Pub No. 17–1468. 3rd ed.
0154654. Bethesda, MD: National Institutes of Health; 2018.
82. Brown SJ, Handsaker JC, Bowling FL, Boulton AJ, Reeves ND. 89. Centers for Disease Control and Prevention (CDC). Age-adjusted
Diabetic peripheral neuropathy compromises balance during daily percentage of adults aged 18 years or older with diagnosed diabetes
activities. Diabetes Care. 2015;38(6):1116–22. https://doi.org/10. receiving a foot exam in the last year, United States, 1994–2010
2337/dc14-1982. https://www.cdc.gov/diabetes/statistics/preventive/fx_foot.
83. Schwartz AV, Vittinghoff E, Sellmeyer DE, Feingold KR, de htm2014 Last updated 2014. Accessed 03/07/2019.
Rekeneire N, Strotmeyer ES, et al. Diabetes-related complications, 90. Centers for Medicare and Medicaid Services (CMS). Proposed clin-
glycemic control, and falls in older adults. Diabetes Care. ical quality measures for 2014. http://www.cms.gov/Medicare/
2008;31(3):391–6. https://doi.org/10.2337/dc07-1152. Quality-Initiatives-Patient-Assessment-Instruments/
84. Schneider AL, Williams EK, Brancati FL, Blecker S, Coresh J, QualityMeasures/Downloads/Eligible-Providers-2014-Proposed-
Selvin E. Diabetes and risk of fracture-related hospitalization: the EHR-Incentive-Program-CQM.pdf 2014 Updated 2014. Accessed
Atherosclerosis Risk in Communities Study. Diabetes Care. 03/02/2019.
2013;36(5):1153–8. https://doi.org/10.2337/dc12-1168. 91. Miller JD, Carter E, Shih J, Giovinco NA, Boulton AJ, Mills JL,
85. Yang Y, Hu X, Zhang Q, Zou R. Diabetes mellitus and risk of falls et al. How to do a 3-minute diabetic foot exam. J Fam Pract.
in older adults: a systematic review and meta-analysis. Age Ageing. 2014;63(11):646–56.
2016;45(6):761–7. https://doi.org/10.1093/ageing/afw140. 92. American Association of Diabetes. Peripheral arterial disease in
86. Janghorbani M, Van Dam RM, Willett WC, Hu FB. Systematic people with diabetes. Diabetes Care. 2003;26(12):3333–41.
review of type 1 and type 2 diabetes mellitus and risk of fracture. https://doi.org/10.2337/diacare.26.12.3333.
Am J Epidemiol. 2007;166(5):495–505. https://doi.org/10.1093/
aje/kwm106. Publisher’s Note Springer Nature remains neutral with regard to jurisdic-
87. Kim JH, Jung MH, Lee JM, Son HS, Cha BY, Chang SA. Diabetic tional claims in published maps and institutional affiliations.
peripheral neuropathy is highly associated with nontraumatic frac-
tures in Korean patients with type 2 diabetes mellitus. Clin