Up to date in tema di Neuropatia Diabetica · (craniali e focali degli arti) • radiculopatie...

II SESSIONE: CONTROLLO GLICEMICO E COMPLICANZE DI SISTEMA

Up to date in tema di Neuropatia Diabetica

Vincenza Spallone

CONVEGNO CONGIUNTO AMD – SID UMBRIALa Diabetologia nel 2019 tra antichi problemi e nuove sfide

16 novembre 2019 - Perugia

Endocrinologia - Dipartimento di Medicina dei Sistemi

Disclosure

Negli ultimi due anni ho ricevuto compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche:

• Wörwag Pharma GmbH & Co, Germany • TRIGOcare International, Germany• Aziende Chimiche Riunite Angelini Francesco ACRAF SpA, Italia

Dichiara altresì il proprio impegno ad astenersi, nell’ambito dell’evento, dal nominare, inqualsivoglia modo o forma, aziende farmaceutiche e/o denominazione commerciale e dinon fare pubblicità di qualsiasi tipo relativamente a specifici prodotti di interesse sanitario(farmaci, strumenti, dispositivi medico-chirurgici, ecc.).


News• Nell’impatto clinico• Nello screening• Nella patogenesi• Nella gestione

Diabetic neuropathies are the most prevalent chronic complications ofdiabetes.This heterogeneous group of conditions affects different parts of the nervoussystem and presents with diverse clinical manifestations.The early recognition and appropriate management of neuropathy in the patient withdiabetes is important for a number of reasons.

Neuropatie diabetiche: classificazione

Neuropatie focali e multifocali• mononeuropatie (craniali e focali degli arti)• radiculopatie toracoaddominali• amiotrofia o radiculoplessopatia lombosacrale

Neuropatie non diabetiche associate al diabete• neuropatie da intrappolamento• CIDP (poliradiculopatia infiammatoria demielinizzante cronica)*

Adattata da: Thomas PK. Diabetes 46 Suppl 2:S54-S57, 1997; Boulton A et al Diabetes Care 28: 956-962, 2005; Pop-Busui R et al Diabetes Care 2017; 40:136-154

Polineuropatie simmetriche• sensitivomotoria cronica (dolorosa e non)• dolorosa acuta• autonomica

* Odds ratio 7.91 (Ng PS et al Neurology. 2019 Mar 12;92(11):e1188-e1194.)

Picco del dolore coincidente con nadir HbA1cReversibile con buon controllo entro 18 mesi

HbA1c

Pain

Ann Neurol 2010;67:534–541 Brain. 2015;138:43-52.

Rischio di TIND proporzionale alla riduzionedella HbA1c (a partire da ∆ HbA1c ≥2% a 3mesi)

Entro 6-8 settimane di miglioramento del controlloglicemico, dopo prolungato cattivo controllo

Dolore di elevata intensità con iperalgesia e allodinia e segni di danno delle piccole fibreSupposta attivazione della microglia con upregulation di citochine proinfiammatorie

Polineuropatia Diabetica

Polineuropatia simmetrica sensitivo-motorialunghezza-dipendente nei pazienti diabeticiattribuibile ad alterazioni metaboliche emicrovascolari conseguenti all’esposizione aiperglicemia cronica e a cofattori di rischiocardiovascolare.

Neuropatia Diabetica Dolorosa

Forma di polineuropatia simmetricasensitivomotoria cronica in cui è presentedolore neuropatico* come diretta conseguenzadelle anormalità del sistema somatosensitivoperiferico in persone diabetiche.

*Definizione di dolore neuropatico: “dolore che nasce come direttaconseguenza di una lesione o malattia del sistema somatosensitivo”(Treede R-D et al. Neurology 70: 1630-1635, 2008)

Tesfaye S et al Diabetes Care. 2010;33(:2285-93Spallone V. La neuropatia diabetica dolorosa. Elsevier Srl 2011, p.16-17Ziegler D et al Handb Clin Neurol. 2014;126:3-22.

15% PND non dolorosa15% PND dolorosa

Epidemiologia

70%30%

Polineuropatia diabetica: definizione ed epidemiologia

6,9

22,3519

21,3

34

23,828 28,2

23,1 24

36 36,2

30,6

0

5

10

15

20

25

30

35

40

Prev

alen

ce o

f DPN

(%)

PopulationPrimary

Care

Secondary Care

Prevalence of Diabetic Polyneuropathy (DPN) in Italy: findings from population-based, primary care and secondary care (diabetologists and neurologists)

studies

20% 28%

Spallone V, Vermigli C. Neuropatia e assistenza al diabetico. In Bonora E, Sesti G (Ed.). Società Italiana di Diabetologia. Il diabete in Italia. Ediz. Bononia University Press, Bologna 2016, p.233-253.

Truini A, Spallone V, Morganti R, Tamburin S, Zanette G, Schenone A, De Michelis C, Tugnoli V, Simioni V, Manganelli F, Dubbioso R, Lauria G, Lombardi R, Jann S, De Toni Franceschini L, TesfayeS, Fiorelli M, Spagnoli A, Cruccu G. On behalf of the Neuropathic Pain Special InterestGroup of the Italian Society of Neurology

Pain. 2018;159:2658-2666.

36

14,1

2,50

5

10

15

20

25

30

35

40 DPNPDPNSFN

%

• A cross-sectional multicentre study • 816 patients attending hospital diabetic outpatient clinics (123 with T1DM, 693 with T2DM)• Definite diagnosis of diabetic polyneuropathy (DPN), pure small-fibre polyneuropathy (SFN) and painful

polyneuropathy (PDPN) using a combined approach of clinical examination and diagnostic tests.

Prevalence of diabetic polyneuropathy (DPN), painful DPN (PDPN) and small-fibre polyneuropathy (SFN)

Diabetes Care 2017;40:1226–1232

In SEARCH study, in 1,734 youth with T1D (age 18, duration 7.2 years) and 258 with T2D (age22, duration 7.9 years) the prevalence and risk factors for diabetic polyneuropathy (DPN)(diagnosed with MNSI) were evaluated.

DPN prevalence7% in youth with T1D

22% in youth with T2D

7%

22%

Risk factorsin T1D: age, duration, smoking, DBP,obesity, LDL, triglycerides, and HDL;in T2D: age, male sex, duration, smoking,and HDL.Glycaemic control over time worse in DPNin T1D (OR: 1.53) but not in T2D.

Herder C, Roden M, Ziegler D

Trends in Endocrinology and Metabolism 2019

Neuropathy in the Elderly Population with Prediabetes and Diabetes

KORA (Cooperative Health Research in the Region of Augsburg, Germany): Participants aged 55 years were phenotyped forpossible DSPN by the Michigan Neuropathy Screening Instrument (MNSI) examination part.

1,2

3,74,25,7

8,7

14,813,3

21

0

5

10

15

20

25

30

MNSI≥2 and Pain in the feet MNSI ≥2 and Pain in the feet

NGTIFGIGTDM

% Prevalence Painful DPN

Diabetes Care 2019;42:240–247

In 503 partecipanti (età 62-81 anni) della coorte F4/FF4 dello studio KORA si valutava l’associazione tra misure antropometriche e lo sviluppodi polineuropatia sensitivo-motoria distale (DSPN), diagnosticata in base al Michigan Neuropathy Screening Instrument.

Dopo 6.5 anni, 127 casi di DSPNincidente.Sia l’obesità generale sia quellaaddominale erano associate allo sviluppodi DSPN.Due chemochine (CCL7 e CXCL10,neurotossiche in colture cellulari) e unmarker neurone specifico (DNER) sonostati identificati come possibili mediatoridella associazione tra obesità e DSPN,che spiegavano una proporzionedell’effetto totale dal 7% all’11% perbiomarker.

L’obesità generale e addominale erano associate con la DSPN nei partecipanti con e senza diabete, e questaassociazione era in parte mediata da marker infiammatori.

Onkhmdt qno` sh �ch adshb` �

' 2/ $ (Dolore

neuropatico(16%) Deficit

neuropaticiDisabilità

Tkbdqd

↑ Mortalità

↑ CostiCdoqdr r hnmd

↓ PnKHmedyhnmh Charcot

Amputazioni

Impatto clinico della Polineuropatia Diabetica

L nc-�c` �F qhdr �E@�ds�` k�Sdwsannj �ne�Ch adshb�Mdt qno` sgx+�1/ / 2Enqr aknl �BL �ds�` k�Ch adsnknf h �0887:�3090142,0151- (mortality)Bnoohmh�C�ds�` k�I �Bkhm�Dohcdl hnk�1/ / / :�429�408,412- (mortality)Gr t �V ,B�ds�` kEur J Neurol 2012; 19: 1192–1198. (mortality)Soedamah-Muthu SS et al Diabetes Care 2008; 31:1360–1366 (mortality)Brownrigg JRW et al Heart. 2014;100:1837-43 (CV events)Seferovic JP et al Diabetologia 2018;61:581–588 (mortality)Allet L et al. Diabetes Metab Res Rev. 2008;24:173-91. (falls)

Cadute

In 181 patients with diabetes, depression (according to BDI-II) is more severe in patients with painful (PDPN) compared to painless Diabetic Polyneuropathy (DPN)

Diab Vasc Dis Res. 2016; 3:418-428

Frequency of Depression (BDI-II score ≥13)

44%26% 10%

% *** **

BDI-II score in PDPN, DPN+ and DPN-

******

14.8±10.3 9.9±7.0

5.9±5.7

*** P<0.0001** P=0.004

DN4 is independently related to BDI-IIeven after adjusting for the CharlsonComorbidity Index, a measure of commoncomorbidities.

Diabetologia. 2019 Jan 16.

Complication Crude mortalityrate per 1000 person-years

Mortalityrate ratio

No 4.56 REF

DKD 16.79 2.20

Retinopathy 7.13 1.02

Neuropathy 22.86 1.72

DKD + Retinopathy 28.37 2.25

DKD + Neuropathy 63.69 3.77

Neuropathy + Retinopathy

27.04 1.76

DKD + Neuropathyand Retinopathy

55.83 3.86

Hypothetical examples of mortality rates with different complication burdens.

Mortality rates and rate ratios for all-cause mortality according to concurrent microvascular complication burden

Observational clinical cohort included 3828 individuals with T1DM from the Steno Diabetes Center Copenhagen in 2001–2013. During 26,665 person-years of follow-up, 503 deaths occurred.

Neuropathy (Biothesiometer) and diabetic kidney disease are strong and independent risk markers of mortality in T1DM,whereas no evidence of higher mortality rate was found for retinopathy.The mortality risk with multiple complications does not exceed the risk with each complication separately.

Diabetologia 2018;61:581–588

Basta un sì a una di tre domande del questionario MNSI per aumentare del 50% la predizione del rischio cardiovascolare in pazienti con diabete di tipo 2 ad alto rischio

Analisi post-hoc del trial ALTITUDE in 8463 pazienti con diabete di tipo 2 e già malattia renale cronica e/o malattiacardiovascolare per valutare se l’auto-questionario MNSI-Q possa fornire informazioni sul rischio di morte e outcomecardiovascolari.

The association of answer ‘yes’ to any of the 3 questions with adverse outcomes

1 risposta positiva era associata a maggior rischio di outcome composito (HR 1.54), ospedalizzazione per scompenso(HR 1.74), infarto miocardico (HR 1.81), ictus (HR 1.75) e MACE (morte cardiovascolare, infarto e ictus non fatali) (HR1.49). Le associazioni erano più forti in presenza di tutte e tre le risposte positive.

3 domande associate all’outcome composito cardiovascolare:“Hai le gambe o i piedi addormentati?”“Hai mai avuto un’ulcera al piede?”“Ti fanno male le gambe quando cammini?”

20%

La prevalenza aumenta con• età: fino a 38% nel tipo 1 e 44% nel tipo 2• durata: fino a 35% nel tipo 1 e 65% nel tipo 2

Definizione ed epidemiologia della neuropatia autonomica nel diabete

Neuropatia autonomica diabetica

Disordine del sistema nervosoautonomo nell’ambito del diabete odelle alterazioni metaboliche delpre-diabete dopo esclusione di altrecause

Compromissione del controllo autonomicodel sistema cardiovascolare nell’ambito deldiabete dopo esclusione di altre cause.La CAN è comunemente documentata con Itest dei riflessi cardiovascolari

Neuropatia autonomica diabetica cardiovascolare (CAN)

Tesfaye S et al for The Toronto Neuropathy Expert Group. Diabetes Care 33:2285-2293, 2010Spallone V et al on behalf of the Toronto Consensus Panel on Diabetic Neuropathy. Diabetes Metab Res Rev 27:639–653,2011

Methods• 4 studies out of 14 considered both IFG and IGT;• CAN testing varied largely from CARTs to HRV measures.Findings• In 9 studies limited evidence of diminished HRV indices Vs. NGT;• When including both IFG and IGT, a trend toward worse or more widely

impaired autonomic indices in IGT Vs. IFG (Wu 2007; Dimova 2017) or inIGT+IFG Vs. isolated IFG and IGT (Ziegler 2015).

Epidemiology of cardiovascular autonomic neuropathy/dysfunction (CAN) in prediabetes

Ziegler D et al Diabetologia. 2015;58:1118-28 Wu JS et al J Clin Endocrinol Metab. 2007;92:3885-9Dimova R et al J Diabetes Complications. 2017;31:537-543Bernardi L et al Diabetes Metab Res Rev 2011;27:654-64Frontoni S et al Hypertension 2003, 41:1223-1227 Perciaccante A et al. BMC Cardiovasc Disord. 2006;6:19Wu JS et al J Clin Endocrinol Metab. 2007;92:3885-9

CARTs : cardiovascular autonomic testsHRV: heart rate variabilityIFG: impaired fasting glucoseIGT: impaired glucose toleranceNGT: normal glucose tolerance

Suggested meaning of association• Lower parasympathetic activity (Bernardi 2011);• Abnormal sympathetic predominance - in particular during the night (Frontoni 2003,

Perciaccante 2006, Wu 2007).Mediators of association• Independent correlates of autonomic indices: age, BMI, waist, other components of

metabolic syndrome, hypertension and antihypertensive drugs, fasting and 2h post loadglucose level.

Multiple factors in the relationship between metabolic syndrome and autonomic dysfunction

IFG-IGT

Insulin resistanceHyperinsulinemia

Obesity OSAS

Glucose variability

Inflammation

Neuroinflammation

Leptin

Hypertension

Dyslipidemia

MicrobiotaGutAutonomic

dysfunctionVagal depression

Sympathetic predominance

Metabolic effects

Cardiovascular effects

NAFLD

Greco C and Spallone V. Curr Diabetes Rev 2015;12:129-155; Lambert EA et al Am J Physiol Heart Circ Physiol 2015;309:H244–H258; Ziegler D et al J Clin Endocrinol Metab 2018;103:1130–1138; Frontoni S et al Hypertension 2003, 41:1223-1227; Paolisso G et al J Clin Endocrinol Metab 2000;85:1810–1814; Lieb DC et al Exp Diabetes Res. 2012;2012:878760.; Herder C et al. Heart2017;103:63–70; Hansen CS et al Cardiovasc Diabetol 2017;16:153; Abboud F and Kumar R Clin Invest. 2014;124:1454-1457; Guarino D et al Front. Physiol. 2017;8:665; Vinik AI et al Front.Neurosci. 2018;12:591; Ziegler D et al Metabolism. 2018;79:1-9.

Spallone V. Diabetes Metab J. 2019;43:3-30.

20%

Epidemiology of CAN in diabetes and prediabetes

11.4%

Diabetes Prediabetes*

Ziegler D et al Diabetologia. 2015;58:1118-28.

* Combined IFG+IGT

Progression of CAN↑ prevalence 4.6-6 % year

Prevalence of CAN in T2DM (%)

4,9

19,6

65

0

10

20

30

40

50

60

70

80

Baseline 5 years 10 years

HRV indices

Ratzmann KP et al J Diabetes Complications 1991; 5: 1-5.Zoppini G et al Diabetes Care. 2015;38:1487-93.Töyry JP et al Diabetes 1996; 45: 308-315.Ko SH et al Diabetes Care 2008; 31: 1832-1836

Prevalence at T2DM diagnosis CAN early 15.4 %CAN confirmed 1.7 % 17.2%

In the ADDITION Denmark cohort, 299 patients were evaluated for CAN at 6 and 13 years fromscreening-based T2DM diagnosis

Prevalence of confirmed CAN increasedfrom 9.1 to 15.1 with a total incidence of11.9% and an annual incidence of 1.8%.

Andersen ST, Witte DR, Fleischer J, Andersen H, Lauritzen T, JørgensenME, Jensen TS, Pop-Busui R, Charles M.

Diabetes Care. 2018;41:2586-2594.

% of Confirmed CAN

Characteristics of ADDITION• early screening-based diagnosis of T2DM• high intensity treatment from the diagnosis• good control of BG and risk factors during

the 13 yearsmight have attenuated CAN progression.Is this context representative of the present andfuture scenario of improved control in T2DM?

The heterogeneous course of CAN may challenge the present clinical approach of usingcategorical classification of CARTs for diagnosing CAN or the notion of CAN irreversibility.

In the ADDITION Denmark cohort, different trajectories in the CAN course were identified, with a number ofparticipants progressing to CAN and a number of those with CAN unexpectedly improving in CAN status: 8patients (28%) with confirmed CAN changed to no CAN.

Changes in CAN status on the basis of defined categories from the 6- to the 13-year follow-up

Andersen ST, Witte DR, Fleischer J, Andersen H,Lauritzen T, Jørgensen ME, Jensen TS, Pop-Busui R,Charles M.

Diabetes Care. 2018;41:2586-2594.

In 1,646 youth with T1DM (age 18, duration 8 years) and 252 with T2DM (age 22, duration 8years) of the SEARCH study, the prevalence and risk factors for cardiovascular autonomicneuropathy (CAN), defined as ≥3 abnormal HRV indices, were evaluated.

CAN prevalence12% in youth with T1DM17% in youth with T2DM

Risk factors (over time)in T1D: HbA1c, BP, triglycerides; in T2D: triglycerides, microalbuminuria

The prevalence of CAN in this multi-ethnic cohort ofadolescents and young adults with T1DM and T2DM in theUSA are comparable to those in adults with diabetes.Suboptimal glycaemic control and elevated triglycerideswere the modifiable risk factors associated with CAN.

12

17

0

2

4

6

8

10

12

14

16

18

20

Type 1 Type 2

CAN prevalence (%)

Jaiswal M, Divers J, Urbina EM, Dabelea D, Bell RA, Pettitt DJ, Imperatore G, Pihoker C, Dolan LM, Liese AD, Marcovina S, Linder B, Feldman EL, Pop-Busui R; SEARCH for Diabetes in Youth Study Group

Pediatr Diabetes. 2018;19:680-689.

Clinical impact of CANRecommendations• CAN is a risk marker of mortality (level A) as well as a risk marker and

likely a risk factor for cardiovascular morbidity (level B), and possibly aprogression promoter of diabetic nephropathy (level C).

Maser RE et al. Diabetes Care 2003; 26: 1895-1901; Vinik A and Ziegler D. Circulation 2007; 115: 387-397

RR = 3.65(95% C.I. 2.66-4.47)

Meta-analysis of 15 studies (1966-2001)

2900 patients followed for 1-16 years

Evidence that confirmed diagnosis of CAN (based on 2 abnormal CARTs) is anindependent predictor of mortality

CARTs and cardiovascular autonomic indexes (HRV, QT interval) in subsequent studies (2002-2010), including large trials as EURODIAB and ACCORD trial • predictors of mortality for any and cardiovascular causes• independently from multiple diabetes-related and traditional CV risk factors• relative risk from 1.5 to 7• combined indexes better predictors than single ones

CAN as a predictor of vascular morbidities

• Association with perioperative instability during surgery (in 7 out of 8 studies)

• Association with or independent predictor value for– silent myocardial ischemia (meta-analysis of 12 studies in 1468 patients with a

prevalence rate risk 1.96; DIAD study)

– coronary artery disease– cardiovascular morbidity (1 more study)– recurrent cardiovascular events (in 2 out of 3 studies)– stroke in type 2 diabetes (in 4 studies)

• Progression promoter of diabetic nephropathy (in 8 out of 9 studies mainly in type 1 diabetes)

• Independent predictor of severe hypoglycaemia (in 1 study) and of HbA1c instability (in 1 study)

Impact on glycaemiaYun JS et al Diabetes Care 2014;37:235-41.Yang Y et al Diabetes Metab J 2018;42:496-512

Impact on nephropathyOrlov S et al Clin J Am Soc Nephrol 10: 1136–1144, 2015;Tahrani AA et al Diabetologia. 2014;57:1249-56;Yun J-S et al Diab Res Clin Pract 2015;108:31-37

Impact on CVDBarthel P et al Diabetes Care 2011;34:1833–1837Karjalainen JJ et al Diabetes Care 2014;37:286–294 Cha SA et al PLoS One 2016; 11:e0164807;Cha SA et al Diabetes Res Clin Pract. 2018;143:159-169Yun J-S et al Cardiovasc Diabetol 2018;17:109

Updated from Spallone V et al on behalf of the Toronto Consensus Panel on Diabetic Neuropathy. Diabetes Metab Res Rev 27:639–653,2011

Abnormalities associated with CAN at the level of cardiovascular system and peripheral vascular function

Peripheral vascular function↑ Peripheral blood flow and warm skin↑ Arteriovenous shunting and swollen veins ↑ Venous pressure and oedema• Loss of protective cutaneous vasomotor

reflexes• Loss of venoarteriolar reflex with oedema and

microvascular damage↑ Capillary permeability• Medial arterial calcification

• Forms of cardiovascular morbidity• Risk markers or factors for mortality and morbidity• Potential pathogenetic link between CAN and mortality/morbidity

Cardiovascular system• Perioperative instability • Silent myocardial ischemia• Orthostatic hypotension• Resting tachycardia • QT interval prolongation• Nondipping, reverse dipping• Impaired BRS

• Sympatho-vagal imbalance• Cardiac sympathetic dysinnervation• Dysregulation of cerebral circulation• ⇓ Sympathetically mediated vasodilation of

coronary vessels• Left ventricular dysfunction • ↑ Arterial stiffness

Cardiovascular system• Perioperative instability • Silent myocardial ischemia

• Orthostatic hypotension• Resting tachycardia • QT interval prolongation• Nondipping, reverse dipping• Impaired BRS• Reduced HRV

Cardiovascular system• Perioperative unstability• Silent myocardial ischemia

Diabetes Metab Res Rev 27:654-664,2011 Diabetes Metab Res Rev 27:639–653,2011

Eur Heart J 2015; 36, 1609–1617

Ricci F, Fedorowski A, Radico F, Romanello M, Tatasciore A, Di Nicola M, Zimarino M, De Caterina R.

A meta-analysis of 13 prospective observational studies, including an overall population of 121,913 patients, with amedian follow-up of 6 years, on the association between prevalent OH, mortality, and incident major cardiac andcerebrovascular events (MACCE).

Pooled estimates of RRfor all-cause death were1.78 for patients <65years old, and 1.26 in theolder subgroup.

Orthostatic hypotension is associated with a significantly increased risk of all-causedeath, incident CHD, HF, and stroke.

RR=1.50 RR=2.25

RR=1.41 RR=1.64

All-cause mortality Heart-failure

CHD Stroke

Meta-analyses exploring the prognostic value of circadian rhythm of BP in the general population, independently of 24-h BP levels

There is evidence that nondipping has a predictive value for cardiovascular morbidity andmortality in the general population and hypertensive subjects

Spallone V. Curr Diab Rep 2018; 18:137In diabetes (mainly type 2 diabetes)

Relative Risk from 1.5 to 8

Emerging supposed mechanisms underlying the CAN-associated excess cardiovascular morbidity and mortality

• ↑ Coronary artery calcium score• possible role of CAN in the development of vascular calcification

• ↓ Coronary and myocardial blood flow regulation • coronary and myocardial microcirculation associated with cardiac

sympathetic innervation• ↑ Inflammation

• possible bidirectional relation between ANS and inflammation, given the autonomic control of inflammation

Coronary artery calcification and CANCalhoun HM et al Diabetes Care 2001; 24:1108–1114Thilo C et al Exp Clin Endocrinol Diabetes 2004;112:561-5Rodrigues TC et al Diabetes Technol Ther. 2010;12:963-9.Mogensen UM et al Diabetes 2012;61:1822-30Dayem SM et al Open Access Maced J Med Sci. 2015;3:681-8.Hjortkjær HØ et al Diab Vasc Dis Res. 2019;16:98-102.

Inflammation and CANLanza GA et al Eur Heart J 2007; 28:814-820Gonza lez-Clemente J-M et al Eur J Endocrinol. 2007;157:31-38. Lieb DC et al Exp. Diabetes Res. 2012; 2012, 1–8Pavlov, VA & Tracey KJ Nat. Rev. Endocrinol. 2012; 8:743–754Ziegler D et al PLoS ONE 2015;10: e0124242.

Cardiac blood flow regulation and CANvon Scholten BJ et al Diabetes 2016;65:3129–3138Zobel EH et al Diabetes 2019;68:1277–1286

ConclusionsDefinite CAN was an independent prognostic factorfor the development of severe hypoglycaemia inT2DM patients (Hazard ratio 2.43).

SH events (%)

894 T2DM patients (age: 55, duration: 9 yrs), followedfor 9.5 yrs, 31.4% with CAN.62 patients experienced 77 episodes of severehypoglycaemia (SH) (1.33 x 100 patient-years).


Cumulative incidence of SH according to CAN staging

Percentage of SH events according to CAN staging

Definite CANAdjusted HR 2.43

(95% CI 1.21-4.84)


News• Nell’impatto clinico

La neuropatia diabetica • si conferma la complicanza del diabete più comune • comincia presto nel diabete di tipo 1 e anticipa la comparsa del

diabete di tipo 2, con storia naturale non definita• ha ricadute rilevanti su qualità di vita e sopravvivenza • anche semplici misure di neuropatia funzionano come predittori di

mortalità e marker di rischio cardiovascolare e metabolico• i meccanismi noti ed emergenti dell’eccesso di mortalità e morbilità

documentano la pervasività del controllo nervoso

Recorded foot examination in 2016

17,714,9

22,2 20,3

0

10

20

30

40

50

Type 1 Type 2

2011

2016

+36.2%+25.4%

Change in foot examination from 2011 to 2016

Subjects monitored for retinopathy in 2016 Type 1: 46.2%Type 2: 36.2%

Assessment of AMD quality indicators in diabetes care in 222 diabetes centres in Italy in 2016

22.2% 20.3%

Lo screening della neuropatia deve essere eseguito in tutti i diabetici tipo 2 alla diagnosi e nei diabeticitipo 1 dopo 5 anni di malattia. Le successive valutazioni devono avere cadenza annuale.(Livello della prova VI, Forza della raccomandazione B)Polineuropatia simmetrica distale (DPN)Lo screening della polineuropatia sensitivo-motoria simmetrica distale cronica deve essere effettuatoutilizzando semplici test clinici, quali la valutazione della perdita della sensibilità pressoria almonofilamento di 10 g e della sensibilità vibratoria mediante diapason sul dorso dell’alluce,preferibilmente inseriti in un sistema strutturato a punteggio.(Livello della prova I, Forza della raccomandazione A)Gli esami elettrofisiologici non sono necessari per lo screening della polineuropatia diabeticamentre sono indispensabili per la diagnosi differenziale qualora le caratteristiche cliniche sianoatipiche.(Livello della prova VI, Forza della raccomandazione B)Qualora sia diagnosticata la polineuropatia diabetica, è utile che il diabetico sia inserito in unprogramma di prevenzione delle ulcerazioni che includa l’educazione.(Livello della prova VI, Forza della raccomandazione B)Per la diagnosi di polineuropatia diabetica dolorosa è necessaria la presenza di dolore neuropaticonella stessa localizzazione dei sintomi e segni neuropatici. L’identificazione del dolore neuropaticosi basa sulla storia e l’esame clinico, e si avvale dell’utilizzo di dispositivi di screening validati come ilDN4. La valutazione della risposta al trattamento del dolore neuropatico richiede una misuradell’intensità del dolore come la scala numerica a 11 punti di Likert.(Livello della prova III, Forza della raccomandazione A)

Raccomandazioni sulla neuropatia diabetica

Lo screening della polineuropatia sensitivo-motoria simmetrica distale cronica deve essereeffettuato utilizzando semplici test clinici, quali la valutazione della perdita della sensibilitàpressoria al monofilamento di 10 g e della sensibilità vibratoria mediante diapason suldorso dell’alluce, preferibilmente inseriti in un sistema strutturato a punteggio.(Livello della prova I, Forza della raccomandazione A)

Sede Alluce dorso

Stimoli 10 (3 falsi)

Insensibilità 0 risposte corrette

Riduzione <8 risposte corrette

Screening Neuropatia

Strumentario per esame neurologicoMonofilamento 10 g

Modalità di valutazione di sintomi e segni per lo screening della polineuropatia diabetica

Diab Res Clin Pract 2016; 115:150-156

Aim: alternative, simple and rapid test for the screening of distal symmetrical polyneuropathy (DSPN), for use in local primary care facilities.3883 patients with T2DM, aged 18–80 years, from 21 hospitals underwent nerve conduction study (as the gold standard) and clinical assessments of ankle reflexes (AR) and thermal (T), vibration (V), pressure (P), and pinprick (PP) sensations.

Test Time (sec)

AR (Ankle Reflex) 53

T (Thermal) 30

V (Vibration) 81

PP (Pinprick) 23

P (Monofilament) 86

AR+T+V 2 min 44 sec

AR+T+V+PP+P 4 min 33 sec

•Need for more than one test (low sensitivity)•Combinations of AR+PP T+V and AR+T+V the two most efficient and not different between them

•Correspondence between AR+T+V and AR+PP+P+V+T in 100% of probable clinical DSPN, in 84.05% of possible clinical DSPN, and in 96.84% of no DSPN

Conclusions: Combined AR + T + V assessment is avaluable tool for screening DSPN, potentiallydecreasing costs to local primary care facilities andmaking care more available to underservedpopulations.

Corneal Confocal Microscopy (CCM) Advantages• non invasive, rapid (2 min), reiterative

good reproducibility• moderate-high sensitivity and specificity for

DPN • availability of worldwide normative

reference values

Characteristics• images of corneal structure and nerves• manual and automated image analysis system • parameters: nerve fiber density (number/mm2),

length and branch density

Abnormalities of CCM morphometric variables• Correlate with IENF loss and other measures of small fibre function• Are associated with severity of DPN • Are more marked in painful DPN• Are associated with CAN• Are present early in the course if disease• Identify patients at risk to develop DPN• Identify prediabetic patients at risk to develop diabetesCorneal fibre density improves (earlier than other measures) after • combined pancreas/kidney transplantation (6 and 12 months)• bariatric surgery • ARA 290 treatment• Insulin pump

Quattrini C et al Diabetes 2007; 56: 2148–2154Mehra S et al Diabetes Care 2007; 30: 2608–2612Efron N et al Eye Contact Lens 2010; 36: 245–248Tavakoli M et al Diabetes Care 2010; 33:1792–1797Dabbah MA et al Med Image Comput Assist Interv 2010; 13(Pt 1):300–7Malik R et al Diabetes Metab Res Rev 2011; 27: 678–684Tavakoli M et al Diabetes 2013; 62:254-260

Chen X et al Diabetes Care 2015;38:1138–1144Ziegler D et al Diabetes 2014; 63:2454-2463Asghar O et al Diabetes Care. 2014; 37: 2643–2646Ferdousi M et al 2015Bitirgen G et al Diabetic Med 2014; 31: 431-8Petropoulos IN et al PLoS One. 2015; 10: e0123517Pritchard N et al Diabetes Care. 2015;38:671-5

Lovblom et al Can J Diab 2015; 2671: S1499 Azmi S et al Diabetes Care 2015;38:1502–1508Brines M et al Mol Med. 2015;20:658-66.Tavakoli M et al Diabetes Care 2015;38:838-43Ahmed A et al Diabetes Care 2012; 35:821–828Pritchard N et al Diab Res Clin Pract 2014; 104:248-256Sivaskandarajah GA et al Diabetes Care 2013;36:2748–55

Ziegler D et al. Diabetes 2014;63:2454-2463

Diabetic patient

Control subject

CORNEAThe most dense innervation7000 nociceptors/mm2

Azmi S, Jeziorska M, Ferdousi M, Petropoulos IN, PonirakisG, Marshall A, Alam U, Asghar O, Atkinson A, Jones W, Boulton AJM, Brines M, Augustine T, Malik RA.

Diabetologia. 2019 Aug;62(8):1478-1487.

Longitudinal least mean squares change from baseline values

Longitudinal observational study examined neuropathic symptoms, deficits, QST, NCS, CCM and skin biopsy results in 32 control participants, 29individuals with type 1 diabetes and severe DPN and 36 individuals with T1DM after simultaneous pancreas kidney transplantation (SPK)

SPK is associated with early and maintained small nerve fibre regeneration in the cornea and skin (measure of more distalintraepidermal nerve regeneration), followed by an improvement in neuropathic symptoms and peroneal nerveconduction velocity. We argue for the inclusion of CCM and skin biopsy as co-primary endpoints, to provide an earlygo/no go signal for clinical trials of disease-modifying therapies.

05

10152025

Baseline 12months

36months

Mean dendritic length in SPK

***

Douleur Neuropathique en 4 questions (DN4): versione italiana

Bouhassira D et al. Pain 2005Perez C et al. Health Qual Life Outcomes 2007Spallone V et al. Diabet Med 2012

• Sensibilità 80-83%, specificità 78-91% Vs. diagnosi clinica

• 2 domande con 7 item su tipo di dolore e sintomi sensitivi positivi associati (DN4-Interview)

• 3 item di esame neurologico nell’area del dolore

• Cut-off 4 suggerisce un dolore neuropatico

Lo screening della neuropatia deve essere eseguito in tutti i diabetici tipo 2 alla diagnosi e nei diabeticitipo 1 dopo 5 anni di malattia. Le successive valutazioni devono avere cadenza annuale.(Livello della prova VI, Forza della raccomandazione B)Polineuropatia simmetrica distale (DPN)Lo screening della polineuropatia sensitivo-motoria simmetrica distale cronica deve essere effettuatoutilizzando semplici test clinici, quali la valutazione della perdita della sensibilità pressoria almonofilamento di 10 g e della sensibilità vibratoria mediante diapason sul dorso dell’alluce,preferibilmente inseriti in un sistema strutturato a punteggio.(Livello della prova I, Forza della raccomandazione A)Gli esami elettrofisiologici non sono necessari per lo screening della polineuropatia diabeticamentre sono indispensabili per la diagnosi differenziale qualora le caratteristiche cliniche sianoatipiche.(Livello della prova VI, Forza della raccomandazione B)Qualora sia diagnosticata la polineuropatia diabetica, è utile che il diabetico sia inserito in unprogramma di prevenzione delle ulcerazioni che includa l’educazione.(Livello della prova VI, Forza della raccomandazione B)Per la diagnosi di polineuropatia diabetica dolorosa è necessaria la presenza di dolore neuropaticonella stessa localizzazione dei sintomi e segni neuropatici. L’identificazione del dolore neuropaticosi basa sulla storia e l’esame clinico, e si avvale dell’utilizzo di dispositivi di screening validati come ilDN4. La valutazione della risposta al trattamento del dolore neuropatico richiede una misuradell’intensità del dolore come la scala numerica a 11 punti di Likert.(Livello della prova III, Forza della raccomandazione A)

Raccomandazioni sulla neuropatia diabetica

Per la diagnosi di polineuropatia diabetica dolorosa è necessaria la presenza di doloreneuropatico nella stessa localizzazione dei sintomi e segni neuropatici. L’identificazione deldolore neuropatico si basa sulla storia e l’esame clinico, e si avvale dell’utilizzo di dispositivi discreening validati come il DN4. La valutazione della risposta al trattamento del doloreneuropatico richiede una misura dell’intensità del dolore come la scala numerica a 11 punti diLikert.(Livello della prova III, Forza della raccomandazione A)

Diabet Med. 2017;34:834-838

COMPASS 31 shows a fair diagnostic accuracy for the presence of CAN in 73 patients with diabetes

Conclusions COMPASS 31 can represent a valid, easy-to-use, quantitative assessment tool for autonomic symptoms indiabetic neuropathy, with a fair diagnostic accuracy for CAN.

OR: odds ratioPPV: positive predictive valueNPV: negative predictive valueLR+: likelihood ratio for positive resultLR-: likelihood ratio for negative result

At the Cut-off of 16 and 17 COMPASS 31 Total Weighted have acceptable sensitivity for CAN

CAN

CAN confirmed

True

pos

itive

frac

tion

(Sen

sitiv

ity)

True negative fraction (1-Specificity)

AUC = 0.748 ± 0.068 (95% CI 0.599-0.861)

COMPASS 3131 items, 6 domains

Orthostatic intolerance

Vasomotordysfunction

Secretomotor dysfunction

Gastrointestinalsymptoms

Badderdysfunction

Pupillomotor dysfunction

6 weighted subscale scores and 1 total

CAN assessment: signsConclusions• Resting heart rate is not a specific sign of CAN (class IV). • Orthostatic hypotension (class III), QTi prolongation (class II), and

reverse dipping on ABPM are specific but insensitive indices of CAN (class III).

Recommendations• Regardless of the presence of orthostatic symptoms, the orthostatic

hypotension test is recommended yearly … (level B).• In presence of unexplained tachycardia (level C), QTi

prolongation (level B), or reverse dipping (level C)referral for CAN testing is advisable

Test Sensitivity Specificity

OH 31% 98%

QTc >441 28% 86%

BP rising pattern 26% 95%

Spallone V et al. Clin Auton Res 2009;19:58-64Whitsel EA et al. Diabetes Care 2000 ; 23:241-7Spallone V et al. J Hum Hypertension 2007; 21:381-6

Cardiovascular autonomic reflex testsConclusions• The following CARTs are the gold standard for clinical autonomic testing: heart rate response to deep breathing, standing, and Valsalva manoeuvre, and blood pressure response to standing (class II).

• These CARTs are sensitive, specific, reproducible, easy to perform, safe, and standardized (classes II-III). Recommendations• Diagnosis of CAN is based on the use of CARTs …. (level A).• Performance of CARTs should be standardized and the influence of confounding variables minimized (level A).

• Age-related normal ranges of heart rate tests are strictly required (level A).

DB

LS

VM

OH

Guidelines of scientific societies on screening and diagnosis of CAN in clinical practice

AACE: American Association of Clinical EndocrinologistsACE: American College of EndocrinologyADA: American Diabetes AssociationAMD: Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi)CARTs: Cardiovascular Reflex TestsCV: CardiovascularSID: Italian Society of Diabetology (Società Italiana di Diabetologia)

Toronto Consensus

(2011)

Position Statement ADA

(2017)

Position Statement AACE/ACE

(2018)

SID/AMD Standards

(2018)

Symptoms Screening Screening Screening Screening

Signs Screening ScreeningDiagnosis

Screening Screening

CARTs Gold standard for diagnosis

Possible In asymptomatic

patients

Screening Diagnosis

HRV (time- and frequency-domain indices)

Prognostic information

Research In addition to CARTs

Research

Candidates In particular in those at greater risk for CAN; universal

screening of symptoms and signs

In presence of microvascular

complications and/or hypoglycaemia unawareness

Those with type 2 from

diagnosis, or type 1 after 5

years

In particular in presence of high

CV risk and complications


A clinical screening score for the risk of diabetic cardiovascular autonomic neuropathy in type 2 diabetesAbbatepassero A, D’Amato C, Izzo V, Staltari MT, Seminara G, Greco C, Lauro D, Spallone V 29th Annual Meeting Neurodiab, Sitges, Spain

CAN risk score

Variable Score

Insulin treatment Yes 2

HbA1c >8% 1

Heart rate (bpm) ≥80 1

Microalbuminuria Yes 1

Retinopathy Yes 3

Cardiovascular disease Yes 1

Physical Activity No 1

CAN risk score is correlated with CARTs score

Area under the ROC curve (AUC) of CAN risk score for CAN and confirmed CAN

Diagnostic performance for CAN of CAN risk score (cut-off 4)

This CAN risk score may help in identifying asymptomatic individuals ata higher risk of CAN to be referred with priority for CARTs performance

In 173 subjects with T2DM (17 with early and 16 with confirmed CAN), a CAN risk score was built based onclinical variables, micro- and macroangiopathic complications and resting HR.

CAN Sensitivity (%) Specificity (%) PPV (%) NPV (%)

CAN risk score 66.7 75.7 39.3 90.6

Confirmed CAN Sensitivity (%) Specificity (%) PPV (%) NPV (%)

CAN risk score 81.3 72.6 23.2 97.4

Attempts at addressing the need for accessibility and affordability of cardiovascular reflex tests

• Reduction of the number of repetitions of tests, and use of a mini-battery of 2-3 CARTs (no unanimity on the best tests)

• Use of reference ranges derived from literature and obtained with different methodology

• Substitution of CARTs with HRV indices measured on short ECG recordings (2-5 min)• Development of handheld devices and technical advancement (telemetry, mobile

derived approaches)

Mustonen J et al Clin Physiol 1989. 9:249-257.May O et al J Diab Complic 2000; 14:7-12Lambrecht R et al Auton Neurosci. 2007;131:102-6.Fleischer J et al J Diabetes Sci Technol 2011;5:107-112Pafili K et al Rev Diabet Stud 2015; 12: 213-9.Stranieri A et al Artif Intell Med 2013. 58:185-193.Charles et al Diabetologia 2013;56:101–108 Bellavere F et al Acta Diabetol 2018; August 29

Prerequisite: validation Vs. gold standard and age-related reference values

Sudomotor function assessment and Corneal Confocal Microscopy for the screening and diagnosis of CAN

Neuropad

Sensitivity 59-89%; specificity 27-78%

Spallone V et al Diabet Med 2009Papanas N et al Diabet Med 2013

Corneal confocal microscopy

Sensitivity 86-100%; specificity 56-78%Tavakoli M et al Muscle Nerve 2015

Test AUC Sensitivity Specificity

CCM 0.89-0.91 86-100 56-78


ESC hands 0.74-0.78 45-58 76-96

ESC feet 0.66-0.92 60-83 69-76

Sensitivity 60-83%; specificity 69-76%

Electrochemical Sweat Conductance (ESC)

Selvarajah D et al PLoS One. 2015 Greco C et al Neurodiab 2018


Neuropad 0.71 59-89 27-78

• La valutazione dei sintomi e segni neuropatici resta la modalità discreening della neuropatia diabetica raccomandata per affidabilitàdiagnostica e facilità di uso.

• Diagnosi e valutazione del dolore neuropatico ineludibile.• Tentativi di facilitazione della diagnosi di CAN sono in corso

(conciliando praticabilità con accuratezza e rilevanza clinica).• Metodiche promettenti con accesso ancora limitato (manca

evidenza conclusiva di predittività di outcome).• Identificare le barriere all’implementazione: costi, carico di lavoro,

inerzia, percezione di inutilità, bisogni educativi insoddisfatti.• Necessità di studi di costo-efficacia per la CAN.


News• Nello screening

Risk factors and clinical correlates of DPN

• Height 7, 9

• Male sex (type 2) 11, 15

• Female sex (type 2) 16

• BMI, weight, obesity 9, 11, 12, 15

• Abdominal obesity 1, 2, 7,12

• Dyslipidemia (low HDL 3,11,12, high Triglycerides 3, 8,11, high Cholesterol 6,11)• Physical inactivity 2• Severe ketoacidosis• Cardiovascular disease• Peripheral vascular disease 1, 2

• Low C peptide levels (type 1) 4• Hypoinsulinemia and insulin treatment (type 2) 5• Alcohol• Vitamin D deficit 10

Shaw JE et al. Textbook of Diabetic Neuropathy Thieme 2003; Tesfaye S et al. NEJM 2005; Ziegler D et al Handb Clin Neurol. 2014;126:3-22.1Ziegler D et al. Diabetes Care 2008; 2Ziegler D et al. Eur J Pain 2009; 3Van Acker K et al. Diabetes & Metabolism 2009; 4Panero F et al. DiabetesCare 2009; 5Pop-Busui R et al J Peripheral Nerv Syst 2009; 6Sibal L et al Ann NY Acad Sci 2006; 7Davis TME et al Diabetologia 2008; 8Wiggin TDet al Diabetes 2009; 9Sun JK et al Diabetes Care 2011; 10 Lv WS et al J Endocrinol Invest 2015; 38:513–518; 11Jaiswal M et al Diabetes Care2017;40:1226–1232; 12Andersen ST et al Diabetes Care 2018; 13Liu X et al PLoS ONE 14(2): e0212574; 14Lai Y-R et al Front Neurosci 2019; 13:90;15Truini A et al PAIN 2018; 16 Gylfadottir SS et al Pain 2019

• Diabetes duration 11, 13, 15, 16

• Glycaemic control 11, 12, 13, 15• glycaemic variability (preliminary and controversial data) 14

• Retinopathy13, 15, nephropathy14, 15, autonomic neuropathy• Hypertension (type 1), blood pressure 11

• Age 9, 11, 13, 15, 16

• Smoking (type 1) 11, 16

In 191 patients with diabetes, BMI was the only clinical independent predictor of PDPN in a multiple logistic regression in addition to sensorimotor deficit severity (as MDNS).

Eur J Pain 2011;15:153-60.

BMI according to the presence of PDPN or DPN

MDNS: Michigan Diabetic Neuropathy Score

PDPN DPN+ DPN-

Correlation between pain intensity and the severity of sensorimotor deficits (MDNS)

• A cross-sectional multicentre study • 816 patients from hospital diabetic outpatient clinics • Definite diagnosis of DPN, SFN and PDPN

DPN: associated with male sex, age, diabetes duration, glycaemic control and microvascular complicationsSFN: unrelated to demographic variables and diabetes severityPDPN: female sex the only risk factor (compared to painless DPN)

P1 No DPN Vs. painful DPN; P2 painful Vs. painless DPN

Truini A, Spallone V, Morganti R, Tamburin S, Zanette G, Schenone A, De Michelis C, Tugnoli V, Simioni V, Manganelli F, Dubbioso R, Lauria G, Lombardi R, Jann S, De Toni Franceschini L, Tesfaye S, Fiorelli M, Spagnoli A, Cruccu G. On behalf of the Neuropathic Pain Special Interest of the Italian Society of Neurology

Pain. 2018;159:2658-2666.

PAIN 2018; 159:469–480

Pain in Neuropathy Study: cohort of 189 patients with definite DPN (78 without and 111 with painful DPN).

Electrophysiological characterization of 2 of the novelvariants (M1852T and T1596I) demonstrated that gain offunction changes as a consequence of markedly impairedchannel fast inactivation.

Rare NaV1.7 variants might contribute to the development of neuropathic pain in patients with DPN

In 10 with painful DPN (and not in thosewith painless DPN), 12 rare variants in thevoltage-gated sodium channel NaV1.7 wereidentified (7 not previously linkedneuropathic pain).

Possible contributors to pain development in painful DPNHyperglycaemia + cardiovascular risk factors

Peripheral nerve damage (small and large fibres)

DPN

Painful DPN

Obesity

Metabolic derangement

Glycaemic oscillations•+oxidative stress •+inflammation

Central Nervous System Changes•pain matrix and thalamic excitability•regional volume loss

Genetics• nociceptor excitability• pain modulation• neurotransmission• regeneration• gene expression

Sex/Gender• genetics• psychosocial aspects

Psychosocial aspects• depression• anxiety• catastrophizing• sleep disturbance• social support• comorbidities

Spallone V. Pain-free Vs. painful diabetic peripheral neuropathy

Management of DSPNRecommendations• Tight glucose control targeting near-normal glycemia in patients with type 1 diabetes

dramatically reduces the incidence of distal symmetric polyneuropathy and is recommended for distal symmetric polyneuropathy prevention in type 1 diabetes. A

• In patients with type 2 diabetes with more advanced disease and multiple risk factors and comorbidities, intensive glucose control alone is modestly effective in preventing distal symmetric polyneuropathy and patient-centered goals should be targeted. B

• Lifestyle interventions are recommended for distal symmetric polyneuropathy prevention in patients with prediabetes/metabolic syndrome and type 2 diabetes. B

Pathogenetic TherapiesDespite the recent major advances in elucidating the pathogenesis of diabeticneuropathy, there remains a lack of treatment options that effectively target the naturalhistory of DSPN or reverse DSPN once established.

Studi di efficacia dell‘attività fisica nella polineuropatia diabetica

PND: polineuropatia diabetica; VPT: soglia di percezione vibratoria; ENG: elettroneurografia; MDNS: Michigan Diabetic Neuropathy Score;VCM: velocità di conduzione motoria; VCS: velocità di conduzione sensitiva

Esercizio fisico da solo o integrato in intervento su stile di vita • favorisce reinnervazione cutanea in neuropatia delle piccole fibre nel prediabete (Smith

2006)• previene lo sviluppo di polineuropatia in pazienti con diabete (Balducci 2006)• migliora i sintomi e la sensibilità al monofilamento in persone obese o sovrappeso con

diabete di tipo 2 (Look AHEAD 2017)• riduce il dolore neuropatico (Kluding 2012) e migliora la conduzione nervosa in pazienti

con polineuropatia diabetica (Kluding 2012, Gholami 2018)

Agent RCTs(patients)

Findings (SMD, CI) Conclusion Evidencestrength

Alpha-lipoic acid 5 (984) -2.64 to - 0.54 Effectiveshort-term

Low

Acetyl-L-Carnitine 1 (333) -3.6 (-3.99 to -3.29) Inconclusive Insufficient

Benefits and Harms of Non-pharmacologic Treatment Options (Alpha-Lipoic Acid, Acetyl-L-Carnitine) To Improve Symptoms of Diabetic Peripheral Neuropathy

Alpha-lipoic acid was more effective than placebo for reducing pain, althoughstudies were short-term (<3 months) (low strength of evidence). There were fewadverse effects.However, these studies were all conducted by the same investigator and hadmethodologic and reporting limitations.The only long-term study had a high dropout rate.Alpha-lipoic acid was not effective for numbness and paresthesia.

Agency for Healthcare Research and Quality Publication No. 17-EHC005-EF. March 2017

Farmaci per il dolore neuropatico della neuropatia diabetica dolorosa (NDD) raccomandatidalle Società Scientifiche (dal 2010 in poi)

Linee Guida Trattamento di TCA SNRI(duloxetina. venlafaxina)

α2-δ ligandi(gabapentin, pregabalin)

Oppioidi

NICE 2010 NDD(non specialisti)

1ª linea(amitriptilina)

1ª linea(duloxetina)

2ª linea 2ª linea(tramadolo)

EFNS 2010 Doloreneuropatico/NDD

1ª linea 1ª linea 1ª linea 2ª linea(tramadolo)

TEPDN 2010 NDD 1ª linea 1ª linea(duloxetina)

1ª linea 2ª linea

AACE 2011 NDD 1ª linea 1ª linea(duloxetina)

1ª linea 2ª linea

AAN 2011 NDD 2ª linea(amitriptilina)

2ª linea 1ª linea(pregabalin)

2ª linea

SFD 2011 NDD 1ª linea(amitriptilina,

clomipramina)


1ª linea 2ª linea

NICE 2013 Dolore neuropatico(non specialisti)

1ª linea(amitriptilina)


1ª linea 2ª linea(tramadolo)

NeuPSIG IASP 2015

Dolore neuropatico 1ª linea 1ª linea 1ª linea 2ª linea(tramadolo)

ICCPN 2016 Dolore neuropatico 1ª linea 1ª linea 1ª linea 2ª linea(tramadolo)

ADA 2017 NDD 2ª linea 1ª linea(duloxetina)

1ª linea(pregabalin)

3ª linea(tramadolo

tapentadolo)

AACE: American Association of Clinical EndocrinologistsADA: American Diabetes AssociationAAN: American Academy of NeurologyEFNS: European Federation of Neurological SocietiesIASP: International Association for the Study of Pain

ICCPN: Italian Consensus Conference on Pain in NeurorehabilitationNICE: National Institute for Health and Clinical ExcellenceSFD: French-speaking Society of DiabetologyTEPDN: Toronto Expert Panel on Diabetic Neuropathy

Aggiornato da Spallone V. Curr Diab Rep 12:403-413, 2012

Number needed to treat (NNT) per una riduzione del 50% del dolore, number needed to harm (NNH) per i farmaci di 1ª e 2ª linea nel trattamento del dolore neuropatico periferico secondo le review Cochrane

disponibili.

Dati ottenuti nella NDD, nella Nevralgia posterpetica (NPE) o in dolore neuropatico di varia eziologia (NP). N.D.: non disponibile.*1 solo RCT** per Responder 30%, ed evidenza di qualità molto bassa

Aggiornato da Spallone V. Curr Diab Rep. 2012;12:403-13

4,5

4,3

4,2

6,1

6,6

5,2

11,5

5,7

4,4

6,3

5,9

4,5

5

5,1

0 2 4 6 8 10 12

Capsaicina 8%

Oxycodone SR

Tramadol

Pregabalin

Gabapentin

Venlafaxine

Duloxetine

AmitriptylineNumber Needed to Treat

Number Needed to Harm

IASP strongly advocates for access to opioids for the humane treatment ofsevere short-lived pain, using reasonable precautions to avoid misuse,diversion, and other adverse outcomes.At the same time, IASP recommends caution when prescribing opioids forchronic pain.There may be a role for medium-term, low-dose opioid therapy in carefullyselected patients with chronic pain who can be managed in a monitoredsetting. However, with continuous longer-term use, tolerance, dependence,and other neuroadaptations compromise both efficacy and safety.Chronic pain treatment strategies that focus on improving the quality of life,especially those integrating behavioral and physical treatments, arepreferred.IASP also strongly advocates for continued research to identify ways tominimize opioid risk and find effective alternatives to opioids for thetreatment of various pain problems.

February 2018

Prospettive nel trattamento della PDPN• Fenotipizzazione del dolore neuropatico per scelta mirata del trattamento

(Demant 2014) (ma fenotipo del nocicettore irritabile raro nella PDPN)• Genotipizzazione per terapia basata sui meccanismi: trial con bloccante

NaV1.7 nella PDPN inefficace (ma no inclusione per varianti gene SCN9A) (McDonnell 2018)

• Ricerca di biomarker per identificare i pazienti a rischio o predire quelli responsivi nei trial clinici e per comprendere la patogenesi

• Ottimizzazione dei percorsi terapeutici: combinazione dei farmaci (Selvarajah 2018)

• Ricerca di nuovi farmaci• Approccio multidimensionale e multidisciplinare alla persona con dolore

neuropatico, considerando bisogni del paziente e risorse disponibili

McDonnell A et al Pain. 2018;159:1465-1476Demant DT et al Pain 2014; 155: 2263–2273Selvarajah D et al. Trials 2018; 19:578

Up to date in tema di Neuropatia DiabeticaNews• Nella gestione (della DPN)

Approccio multidimensionale e interdisciplinare alla persona con diabete e dolore neuropatico cronico

PersonaComorbilità generali

•Obesità•Complicanze micro- e macrovascolari

Aspetti psicocognitivi• Rabbia• Sfiducia• Disfunzione cognitiva

Aspetti sociali• Isolamento• Disagio familiare • Disagio sociale

Aspetti funzionali• Rischio cadute• visus

Comorbilità dolore correlate•Disturbi sonno•Depressione•Ansia

Professionisti•Team diabetologico •Neurologo•Terapista del dolore•MMG• Fisiatra• Fisioterapista• Psicologo/Psichiatra• Geriatra• Assistente sociale• Nutrizionista/dietista

Team piede diabetico• Diabetologo• Podologo• Infermiere• Chirurgo

Caregiver• Familiari• Badante

Strumenti• Terapia diabete• Farmacoterapia DN• Terapie fisiche DN• Fisioterapia/riabilitazione• Terapie complementari• Counselling/supporto

psicosociale

Spallone V e Cefalo CMA GIDM 2018;38:127-141

Search for Diabetic neuropathy 22.10.2019

34 trial per neuropatia diabetica• 11 con farmaci• 1 con terapia cellulare• 1 con immunoglobuline nella TIND• 10 con terapie fisiche• 1 con agopuntura• 6 con esercizio fisico, fisioterapia,

terapie cognitivo-comportamentali

Bönhof GJ et al Endocr Rev. 2019;40:153-192.

Vie cellulari coinvolte nella patogenesi della neuropatia diabetica

38

62

0102030405060708090

100

% Pain Treatment

Yes Not

0

5

10

15

20

25

% Medication use

Population-based study KORA F4 Survey (Germany): 1076 older persons (233 with diabetes).14% had distal sensorimotor neuropathy (bilateral impairment of foot-vibration perception and/or of foot-pressuresensation), of which 66 had pain level during the last 4 weeks of ≥4.

Under- and inappropriate treatment even when pain intensity is ≥4

Meisinger C, Bongaerts BWC, Heier M, Amann U, Kowall B, Herder C, Rückert-Eheberg IM, Rathmann W, Ziegler D.

Pharmacoepidemiol Drug Saf. 2018;27:806-814.

Emerging clinical correlates and predictors of CAN

• Residual β-cell function (cross-sectional data in type 2)• Glycaemic variability (increasing preliminary not homogeneous data)• Neck circumference (cross-sectional data in type 2)• Vitamin B12 deficiency (preliminary cross-sectional data)• High and low vitamin D levels (preliminary cross-sectional data)• Low bilirubin level (preliminary cross-sectional data in type 2)• Oxidative stress biomarkers (preliminary data)• Inflammation biomarkers (preliminary data, mainly in type 2)• Genetic susceptibility (GST, MIR146a, MIR 27a and MIR499 gene)

(cross-sectional data)

β-cell functionYang X et al Neurosci. Bull. 2019, 35:25–33 BG variability type 1 diabetesSiegelaar SE et al Diabetologia 2009; 52:2229–2232Lachin JM et al Diabetes Care 2017;40:777–783Nyiraty S et al Front. Endocrinol. 2018; 9:174.BG variability type 2 diabetesDi Flaviani A et al Diabetes Care. 2011;34:1605-9 Kalopita S et al J Diabetes Res. 2014;2014:835392 Jun JE et al. Cardiovascular Diabetology 2015; 14:70Xu W et al Int J Cardiol. 2016;215:263-8. Fleischer J et al Diabetes Care 2015 Apr; 38(4): 682-688 Klimontov VV et al. Springerplus. 2016;5:337. Fleischer J et al J Diabetes Complications 2017; 31:1389–1393Neck circumfereneTahrani A et al J Diabetes Res. 2017;2017:1273789.

Vitamin B12 and DHansen CS et al J Diabetes Complications. 2016 Aug 30;Maser RE et al Endocr Pract. 2015;21:174-81Hansen CS et al Diabet Med. 2017;34:364-371Jung C-H et al Diab Vasc Dis Res 2015; 12:342-351BilirubinChung JO et al Diabet Med. 2014;31:185-91.Inflammation biomarkersHerder C et al Heart 2017;103:63-70.Hansen CS et al Cardiovasc Diabetol 2017;16:153Fleischer J et al J Diabetes Complications 2017; 31:1389–1393Oxidative stress biomarkersZiegler D et al Acta Diabetol. 2015;52:65-72.Genetic susceptibilityVojtkova J et al J Diabetes Complications. 2013;27:44-8.Ciccacci C et al J Diabetes Complications 2018; 32:11-17Ciccacci C et al Acta Diabetol. 2014; 51:663-71

Acta Diabetol 2014;51:663-71.

Ciccacci C, Morganti R, Di Fusco D, D'Amato C, Cacciotti L,Greco C, Rufini S, Novelli G, Sangiuolo F, Marfia GA, BorgianiP, Spallone V.

In 150 participants with T2DM the polymorphisms in MIR146a and MIR499A gene were analysed toevaluate their association with susceptibility to CAN.

Independent associations of MIR146a SNPs with CAN susceptibility

Association of rs3746444 GG genotype of MIR499A genewith a higher risk of CAN development and a greater CANseverity

Genetic variability in miRNA genes (MIR146a, and MIR499A) might be involved in diabeticneuropathies susceptibility (through changes in respective miRNAS expression)

Ciccacci C, Latini A, Greco C, Politi C, D'Amato C,Lauro D, Novelli G, Borgiani P, Spallone V.

J Diabetes Complications 2018;32:11-17

Management of CAN: prevention and pathogenetic treatmentConclusions • Intensive diabetes therapy retards the development of CAN in type 1 diabetes (level A). • Intensive multifactorial cardiovascular risk intervention retards the development and

progression of CAN in type 2 diabetes (level B). • Lifestyle intervention may improve HRV in pre-diabetes (level B) and diabetes (level B).

Treatment of diabetic autonomic neuropathyRecommendations• Optimize glucose control as early as possible to prevent or delay the development of

cardiovascular autonomic neuropathy in people with type 1 diabetes. A• Consider a multifactorial approach targeting glycemia among other risk factors to prevent

cardiovascular autonomic neuropathy in people with type 2 diabetes. C• Consider lifestyle modifications to improve cardiovascular autonomic neuropathy in

patients with prediabetes. C


Effects of weight loss and physical exercise on cardiovascular autonomic function in diabetes

Voulgari C et al Metab Clin Exp. 2013;62:609–21; Villafaina S et al Curr Diab Rep 2017;17: 110; Röling M et al Curr Diab Rep 2017; 17: 125; Bhati P et al Diabetes Metab Syndr 2018; 12:69–78

4 reviews, including 25 studies (≈ 700 patients), mainly in T2DM without CAN, only 6 RCTsResults• Significant improvement in HRV and BRS• Supervised exercise better than not supervised• Endurance exercise and intense combined exercise (resistance and aerobic

training) effective• Length of session of 45-75 min, frequency of more than 3 days/week, duration of

intervention of more than 3-4 months effective

Conclusion: low-grade evidence of moderate beneficial effect on HRV indicesexists in T2DM (without CAN or with early CAN)

7 studies, most uncontrolled and non randomized• including 132 obese and/or overweight subjects with T2DM;• with a follow-up of 3-12 months;• weight loss obtained by bariatric surgery or caloric restriction diet;• weight loss of at least 10% was effective;• very-low-calorie diet equivalent to Roux-en-Y gastric bypass.

HRV LF HF LF:HFDB VRMSNANA

Weight loss associated with (increased parasympathetic indices of HRV, improvement in

sympathovagal balance, reduced sympathetic activity)

Alam I et al Auton Neurosci. 2009;151:168-73.Sjoberg N et al J Appl Physiol (1985). 2011;110:1060-4.Maser RE et al Surg Obes Relat Dis. 2013;9:221-6.Kokkinos A et al Obes Surg. 2013;23:31-8.

Lips MA et al Eur J Endocrinol. 2013;169:383-90.Straznicky N et al. Front. Physiol. 2016;7:516. Casellini CM et al PLoS ONE 2016; 11(5): e0154211.

Treatment of orthostatic hypotension

Non-pharmacological measures •discontinue exacerbating drugs•adequate intake of fluid and salt•bed tilt-up•elastic stockings and abdominal binder•physical counter-manoeuvres Pharmacological measures•Midodrine (FDA), fludrocortisone•acarbose, octeotride, desmopressin, erythropoietin

Treatment is recommended only in symptomatic forms.Objective: to minimize symptoms (not to normalize BP fall).

Spallone V et al Diabetes Metab Res Rev 27:639–653,2011;Figueroa JJ et al Cleve Clin J Med. 2010;77:298-306;Maule S et al Cardiovasc Hematol Disord Drug Targets. 2007;7:63-70;Freeman R N Engl J Med. 2008;358:615-24;Low P et al J Clin Neurol. 2015;11:220-6;Wieling W et a J Intern Med. 2015;277:69-82.www.syncopedia.org and www.stars.org.uk, respectively.Pop-Busui R et al Diabetes Care 2017; 40:136-154.Gibbons CH et al J Neurol 2017;264:1567-1582Fanciulli A Clin Auton Res. 2018 May 15.

Studies in diabetes exploring the effects on BP levels and outcomes of bedtime administration of antihypertensive drugs

Preliminary findings in diabetes confirm that bedtime administration of antihypertensive drugs canimprove the day-night pattern of BP, by acting mainly on night-time BP and in presence of nondipping.Conclusive evidence on the protection of this regimen on hard outcomes is lacking, as with thehypertensive population.

Spallone V. Curr Diab Rep 2018; 18:137

• Supporto all’efficacia dell’intervento sullo stile di vita, soprattutto in fasi precoci (prediabete, no CAN)

• Conferma del ruolo preventivo del controllo glicemico nel diabete di tipo 1, evidenza limitata per l’intervento intensivo nel diabete di tipo 2

• No evidenze su terapie patogenetiche• Nuovi biomarker aprono a prospettive terapeutiche • Trattamento sintomatico delle forme cliniche disponibile


News• Nella gestione (della CAN)

• Precocità: anche nei giovani e nel prediabete• Sfidato il dogma dell’irreversibilità della CAN e possibile efficacia di

approcci preventivi precoci• Molteplici ricadute cliniche e ruolo di marker prognostico• Screening e diagnosi: urgenza di semplificazione e adattabilità a risorse e

contesti diversi e al profilo di rischio individuale• Trattamenti per le forme sintomatiche – dolorose ed autonomiche –

disponibili ma di efficacia limitataProspettive• ricerca mirata a nuovi target (infiammazione), outcome intermedi precoci,

marcatori di rischio e di risposta• strategie per implementare screening e diagnosi e il trattamento delle

forme cliniche• promuovere formazione

Non solo luce riflessa, ma attenzione nella pratica, nella formazione, nella ricerca

Up to date in tema di Neuropatia DiabeticaConclusioni

Grazie a

Grazie per l’attenzione

Dipartimento di Medicina dei Sistemi, Endocrinologia e Neurologia

Gerola MarfiaRoberto Morganti

Cinzia D’AmatoCarla Greco

Laura CacciottiFederica Di Gennaro

Susanna LongoDiana Corradini

Alice SunChiara CefaloValentina Izzo

Maria Teresa StaltariDipartimento di Medicina e

Prevenzione, GeneticaPaola BorgianiCinzia CiccacciAndrea Latini

Gruppo di Studio NeuropatiaDiabetica SID

Università di PaviaLuciano Bernardi

Pietro CortelliGiulia Pierangeli

Giorgio CruccuAndrea Truini

Neuropathy Study Group of EASD (NEURODIAB)

AINV Associazione Italiana per lo studio del sistema NeuroVegetativo

Interaction between SGLT2i and Sympathetic Nervous System

C57BL6/J high-fat diet (HFD) mice

NE SGLT2

In vitro study In vivo study

Human proximal tubule cells

Dapaglifozin Tyrosine hydroxylaseNE

Matthews WB et al J Hypertens 2017; 35:2059–2068

Diuretic-induced hypovolemia MSNA

Human T2DM4 days of empagliflozin (25 mg) = MSNAweight BP

diuresisKimmerly DS et al Am J Physiol Heart Circ Physiol. 2002;282:H645-55.Jordan J et al J Am Soc Hypertens. 2017;11:604-612.

Sympathetic fibers Na reabsorption

Nauria

Proximal tubule

Di Bona G et al Am J Physiol Regul Integr Comp Physiol 2010; 298: R245–R253Ghezzi C et al Diabetologia 2018; 61:2087–2097

SGLT2i


Interaction between Sympathetic Nervous System and SGLT2i

Unresolved questions• Do SGLT2is exert an inhibiting effect on SNS in conditions of sympathetic overactivity

like T2DM?• Is this another mechanism underlying the cardiovascular protection of SGLT2is?

Metabolic syndrome rats

Trials in T2DM

Rahman A et al. Clin Exp Pharmacol Physiol 2017; 44:522–5.Chilton R et al Diabetes Obes Metab. 2017;19:1620-1624.

Dipping restorationSGLT2i

No preferential effect on nighttime BP

SGLT2i


GLP-1 Receptor Agonists and autonomic nervous systemMice and

ratsGLP-1 RA HR, HRV

GLP-1 RA

Central administration

Central and peripheral administration

SNS

Suggested mechanisms

GLP-1 RA

GLP-1 RA

insulin Vagus, SNSSNS

Heart (atrial GLP-1 R)

Discrepancies in the available preclinical and clinical findings suggesting possible species-specific patterns of GLP1 receptors inaddition to differences between GLP1-Ras (Nakatani Y et al Diabetes Care 2016;39:e22-23; Cacciatori V et al J Endocr Soc 2017; 2:53-62; Nyström T et al Endocrinol Diab Metab. 2019;2:e00058; Brock C et al Br J Clin Pharmacol. 2019 Jul 24.)Unmet needs: Conclusive data on the mechanisms of GLP-1 RAs effects on BP and HR

Direct action

Valensi P et al Diabetologia 2013; 56:1196–1200.; Baggio LL et al Mol Metab. 2017;6:1339-1349; Smits MM et al Eur J Endocrinol 2017; 176:77-86.

Yamamoto H et al J Clin Invest. 2002;110:43-52.Gardiner SM et al Br J Pharmacol. 2008;154:60-71.

GLP-1 RA HR, MSNA

GLP-1 RA

Infusion

HR (+ 3 bpm), HRV, BP Cardiovascular outcomes

Healthy humans

Trials in T2DM Chronic administration

Bharucha AE et al Am J Physiol Regul Integr Comp Physiol 2008; 295: R874–R880; Kumarathurai P et al Diabetes Care 2017;40:117–124; Sun F et al Diabetes Res Clin Pract. 2015;110:26-37.; Smits MM et al Br J Clin Pharmacol 2015; 81:613-620

Modified from Spallone V. Diabetes Metab J. 2019;43:3-30.

Treatment of symptomatic forms of diabetic autonomic neuropathy

Orthostatic HypotensionNon-pharmacological measures • discontinue exacerbating drugs• adequate intake of fluid and salt• bed tilt-up• elastic stockings and abdominal binder• physical counter-manoeuvres Pharmacological measures• midodrine, fludrocortisone• acarbose, octeotride, desmopressin, erythropoietin Gastrointestinal Dysfunction

Gastroparesis•prokinetic drugs: domperidone, erythromycin•antiemetic drugs•Gastric Electric Stimulation (GES); surgery Diarrhoea• loperamide, intermittent antibiotics, octreotideConstipation: laxatives

Urogenital DysfunctionHyperactive bladder-neurogenic bladder:

anticholinergic drugs, intermittent catheterization, sacral neuromodulation

Erectile dysfunction: PDE-5 inhibitors

Hyperhidrosis• iontophoresis•botulinum injections•anticholinergic drugs

Treatment may alleviate symptoms and minimize their impact on quality of life

Non-dipping• ≥1 antihypertensive drug at bedtimeSupine HypertensionNon-pharmacological measures • bed tilt-up• snack or alcohol at bedtimePharmacological measures (caution) • low dose transdermal nitrates• short-acting antihypertensive drug at bedtime

PAIN 2014; 155: 2263–2273

Randomised, double-blind, placebo-controlled, and phenotype-stratified study with 26-week treatment periods ofoxcarbazepine (1800-2400 mg) and placebo in 97 with peripheral neuropathic pain due to polyneuropathy, surgical ortraumatic nerve injury, or postherpetic neuralgia.

Oxcarbazepine is more efficacious for relief of peripheral neuropathic pain in patients withthe irritable Vs. the non-irritable nociceptor phenotype.

Non-irritable nociceptorN=52

Irritable nociceptorN=31

Irritable nociceptor: small fibers preserved (thermal thresholds) plus allodynia and hyperalgesia

Non-irritable nociceptor(deafferentation): sensory loss no hyperalgesia

NNT 13

NNT 3.9

Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W.

Cochrane Database of Systematic Reviews 2018, CD012182.

16 studies with 1750 participants, only one in PDPN (negative)

Authors' conclusionsThe potential benefits of cannabis-based medicine (herbal cannabis, plant-derived orsynthetic THC, THC/CBD oromucosal spray) in chronic neuropathic pain might beoutweighed by their potential harms. The quality of evidence for pain relief outcomesreflects the exclusion of participants with a history of substance abuse and othersignificant comorbidities from the studies, together with their small sample sizes.

Single-arm, open-label trial of seal oil omega-3 polyunsaturated fatty acids (ω-3 PUFA) 2330mg/die supplementation for 1 year, in 40 individuals with T1DM with and without DPNaccording to Toronto Clinical Neuropathy Score ≥1.

Conclusions: 12 months of ω-3 supplementation was associated with increase in CNFL in T1DM.

Corneal nerve fiber length (CNFL) increased29% (p<0.002) after 12 months ofsupplementation. There was no change innerve conduction or sensory function

Lewis EJH, Perkins BA, Lovblom LE, Bazinet RP, Wolever TMS, Bril V.

Neurology. 2017;88:2294-2301.

Up to date in tema di Neuropatia Diabetica · (craniali e focali degli arti) • radiculopatie...

Documents

Transcript of Up to date in tema di Neuropatia Diabetica · (craniali e focali degli arti) • radiculopatie...