Post on 04-Aug-2020
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!