Il dr. ROBERTO TREVISAN dichiara di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche:

- NOVO- SANOFY- LILLY- NOVARTIS- ASTRA ZENECA- MEDTRONIC- MERCK- TAKEDA

MICROANGIOPATIA E MACROANGIOPATIA: DUE FACCE DELLA STESSA COMPLICANZA? Roberto TrevisanUOC Malattie Endocrine – DiabetologiaASST Papa Giovanni XXIII, Bergamo

2018: Riunione annuale del Gruppo di Studio SID “Diabete e Aterosclerosi”

TYPE 1 and TYPE 2 DIABETES ARE TWO DISEASES

WITH 2 DISTINCT PATHOGENIC SEQUENCES

LEADING TO 2 DISTINCT CLINICAL PRESENTATIONS

• MICROVASCULAR• MACROVASCULAR

1.0

0.9

0.8

0.7

0.6

0.50 1 2 3 4 5 6

Years

Su

rviv

al (

all-

cau

se m

orta

lity) Normoalbuminuria

(n=191)

Microalbuminuria(n=86)

Macroalbuminuria(n=51)

Proteinuria as a Risk Factor for Mortality in Type 2 DiabetesGall MA, et al. Diabetes. 1995;44:1303-1309.

Prevalence of retinopathy, neuropathy and cardiovascular disease in type 2 diabetic patients with

and without abnormal AER

0102030405060

Retinopathy Neuropathy CardiovascularDisease

%

AER<20mcg/min AER>20mcg/min

R. Trevisan, Diabetes Nutr. Metab 1996

Incidence (%) of Cardiovascular events in the HOPE study in diabetic patients

with and without microalbuminuria

Normo

0

10

30 Micro

MA, stroke, CV death

25

13,9

Mortality

18,6

9,3

Heart Failure

8,5

2,5

25

20

15

5

JAMA. 2001 Jul 25;286(4):421-6.

Increasing UACR is associated with mortality and ESRD in diabetes

3000

Adju

sted

HR

±95

% C

I

00.5

1248

163264

10 20 100030030UACR (mg/g)

No diabetes, 95% CIDiabetes, 95% CI

No diabetes, 95% CIDiabetes, 95% CI

0

1

1.52

4

8All-cause mortality

2.5 5 10 30 300 1000UACR (mg/g)

2.5 5 10 30 300 10000

1

1.52

4

8

UACR (mg/g)

Cardiovascular mortality

HRs adjusted for age, sex, race, smoking, history of cardiovascular disease, serum total cholesterol concentration, body-mass index and albuminuria

Includes data from participants with type 1 and type 2 diabetes

ESRD

Adju

sted

HR

±95

% C

IAd

just

ed H

R ±

95%

CI

Fox CS et al. Lancet 2012;380:1662

1,024,977 participants (128,505 with diabetes)

0

20

40

60

> 90 89-60 59-30 <30

Prev

alen

ce o

f CVD

(%)

eGFR, MDRD, ml/min/1.73m2

UAE <30 UAE 30-300 UAE > 300

The RIACE StudyCVD by eGFR and UAE

Nutr Metab Cardiovasc Dis. 2014 Aug;24(8):815-22.

BENEDICT: Measurable urinary albumin predicts cardiovascular risk among1208 normoalbuminuric patients with type 2 diabetesMedian follow-up 9.2 yrs

J Am Soc Nephrol. 2012; 23:1717-24

RIACE STUDY: Age- and sex-adjusted risk of major acute CVD events (OR [95% CI]) according to albuminuria deciles (mg/24 ore)

Solini A et al. Dia Care 2012;35:143-149

ONTARGET: Adjusted HR (95 CI %) of changes in UACR from baseline to 2-year visit for all-cause mortality, cardiovascular events and renal outcome after the 2-year visit with mean follow-up of 32 months in the whole study group (23480 pts)

J Am Soc Nephrol 22: 1353–1364, 2011

All Cause mortality

Cardiovascular death

Composite CV endpoints

Combined renal endpoints

Changes in Albuminuria predict Mortality and Morbidity

in patients with Vascular Disease

Retinopathy Predicts Cardiovascular Mortality in Type 2 Diabetic Men and Women

020406080

100120

All cause mortality CVD mortality CHD mortality

EVENT RATE 1000 persons/yrNo DR Background DR Proliferative DR

Diabetes Care 30:292–299, 2007

These associations were independent of current smoking, hypertension, total cholesterol, HDL cholesterol, glycemic control of diabetes, duration of diabetes, and proteinuria.

Hazard Ratio for incident cardiovascular disease events in Type 2diabetic patients in relation to diabetic retinopathy status at baseline

0

1

2

3

4

5

Men (n=1302) Women (n=801)

Bck RetProl Ret

Targher, Diabetic Medicine 2008; 25: 45

Proliferative Diabetic Retinopathy in Type 2 Diabetes is related toCoronaryArtery Calcium in the VADT

Diabetes Care May 2008 vol. 31 no. 5 952-957

Survival curves of Type 2 diabetic patients with overt proteinuriaIn relation to retinopathy status

Follow-up (years)

05

100

75

50

25

10 15 20

%

R. Trevisan, Diabetes Care 2002; 25 : 2026-31.

Without Retinopathy

With Retinopathy

Association between retinal disease and risk of diabetes-related complications

Risk with retinal disease vs no retinal disease

Cardiovascular disease 4.1-fold higher incidence (type 1 DM)2.3-fold higher incidence (type 2 DM)

Heart failure 2.7-fold higher incicence (type 2 DM)

Macroalbuminuria 3.2-fold higher incidence (type 1 DM)

Chronic Kidney Disease 2.8-fold higher incidence (type 1 DM)1.4-fold higher incidence (type 2 DM)

Neuropathy 1.8-fold higher incidence (type 2 DM)

Lower Limb amputations 25.0-fold higher incidence (type 1 DM)5.0-fold higher incidence (type 2 DM)

Skeletal fractures 5.4-fold higher incidence (type 1 DM)5.3-fold higher incidence (type 2 DM)

Non-alcoholic fatty liver disease 3.3-fold higher incidence (type 1 DM)1.8-fold higher incidence (type 2 DM)

Lancet Diabetes Endocrinol 2013; 1: 71–78

Incidence Rate of CHD Events: The role of microvascular complications

05

10152025303540

All CHD AMI

No micro

Micro

Per 1

000

pers

on-y

ear

No micro

Micro

p=0.002 p=0.003

All CHD AMI

No micro

Micro

No micro

Micro

p<0.001 p=0.003

FemalesMales

Avogaro et al. for the DAI study. Diabete Care, 2007

Lancet Diabetes Endocrinol 2016; 4: 588–97

• A population-based cohort of patients with type 2 diabetes from the UK Clinical Practice Research Datalink (n=49 027).

• Median follow-up of 5.5 years. • 2822 (5.8%) individuals experienced a primary outcome (a composite of

cardiovascular death, non-fatal myocardial infarction, or non-fatal ischaemic stroke).

Adjusted hazard ratio for the primary outcome (cardiovascular mortality, non-fatal myocardial infarction, or non-fatal ischaemicstroke) by cumulative burden of microvascular disease and per 1 SD difference in values for established risk factors*

Lancet Diabetes Endocrinol 2016; 4: 588–97

1 SD of each established risk factor is: blood pressure 13.5/8.4 mmHg ;LDL cholesterol 0.9 mmol/L; BMI 6.3 kg/m2; HbA1c 1.3% .

Adjusted event rates for the primary outcome (cardiovascular mortality, non-fatal myocardial infarction, or non-fatalischaemic stroke) by cumulative burden of microvascular disease andestablished risk factor goals

Lancet Diabetes Endocrinol 2016; 4: 588–97

ADVANCE: Cumulative incidence of outcomes during follow-up according to status of microvascular and macrovascular disease at baseline.

Mohammedi et al. Cardiovasc Diabetol (2017) 16:95

absence of both macrovascular and microvascular disease

presence of microvascular disease alone

presence of macrovascular disease alone

presence of both macrovascular and microvascular disease

General features of hyperglycemia-induced tissuedamage

Circ Res. 2010;107:1058-1070

La Microangiopatia Diabetica“Esposizione” al diabete e sue conseguenze

The total glycemic exposure (A1c and durationof diabetes) explains only ∼ 11% of the variation in retinopathy risk in the complete cohort of DCCT.Other factors explain the remaining 89% of the variation in risk among subjectsindependent of A1c.

Diabetes 44: 968-983, 1995

IperglicemiaIpertensioneProteinuriaFumoRidotta fuzione renaleDislipidemia Fattori geneticiDisfunzione endotelialeInsulino-resistenza

Fattori di rischio cardiovascolare = Fattori di rischio microangiopatico

The Metabolic Syndrome and Complications in Type 2 Diabetes

816

23

52

06 7

21

0

10

20

30

40

50

60

PDR neuropathy Microalb CVD

%

MS+ MS-

B Isomaa et al. Diabetologia 2001: 44: 1148

NASH and complications in Type 2 Diabetes

39

11

2015

34

5

15

9

05

1015202530354045

BDR PDR Microalb CKD

%

NASH+ NASH-

The association between NASH and diabetic complicationswas independent of age, sex, BMI, waist, BP, diabetes duration, Lipids, HbA1c, smoking and medication use

G Targher et al. Diabetologia 2008: 51: 444

0

2

4

6

8

10

12

Controls DM2 normo DM2 micro DM2 macro DM2 PDR

Glu

cose

disp

osal

(mg/

Kg/

min

)

R Trevisan, Diabetes 2006

Type 2 diabetic patients with increased AER and PDR have a greater insulin resistance

Time to chronic kidney disease (at least stage 3B) in the ANDIS cohort

Time to coronary events in the ANDIS cohort

Lancet Diabetes Endocrinol 2018:S2213-8587(18)30051-2

Most resistant to insulin

autoimmune diabetes

severe insulin-deficient diabetes

mild obesity-related diabetes

Mild age-related diabetes

0.0 2.5 5.0 7.5 10.0 12.5-5

0

5

10

15

Whole-body glucose disposal(mg/kg/min)

∆M

BP

(mm

Hg)

r = - 0.51P = 0.03

INSULIN RESISTANCE IS A MAJOR DETERMINANT OF BLOOD PRESSURE INCREASE AFTER A HIGH SODIUM DIET

R. Trevisan, Diabetologia 2004

0.0 2.5 5.0 7.5 10.0 12.5-100

-75

-50

-25

0 r = 0.59p < 0.05

Glucose disposal rate (mg/kg/min)

% c

hang

e in

FB

F

RELATIONSHIP BETWEEN TOTAL GLUCOSE DISPOSAL RATE AND PERCENTCHANGE IN FOREARM BLOOD FLOW AFTER L-NMMA INFUSION

IN TYPE 2 DIABETIC PATIENTS

Insulin resistance isassociated with a

reduced NO availability

R. Trevisan, 2004

Insulin-resistance: Mechanisms of Micro- and Macrovascular damage

Abdominal adiposity ↓ Ch-HDL ↑ Trigliceride ↑ Blood Pressure Higher nocturnal BP Sodium sensitivity Endothelial dysfunction Reduced EPC Arterial stiffness Renal dysfunction High uric acid

CONCLUSIONS

There is a cluster of micro/macroangioapthy in diabetes

Microangiopathy predicts macroangiopathy

Insulin resistance is associated with microangiopathy in both type 1 and type 2 diabetes.

Insulin resistance (and endothelial dysfunction) is closely associated to microvascular disease and may represent the common risk factor/process underlying the association between microangiopathy and cardiovascular disease

Grazie per la vostra attenzione!