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importanza del trattamento di altri fattori di rischio non convenzionali (trigliceridi, iperuricemia, infiammazione) nella riduzione della morbidità e mortalitàcardiovascolare
Catania4 novembre 2019
Andrea GiaccariCentro per le
Malattie Endocrinee Metaboliche
disclosure
Il dr. Andrea Giaccari dichiara di aver ricevuto negli ultimi due anni compensi ofinanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche:• Amgen• Astra Zeneca• Boehringer Ingelheim• Eli-Lilly• MSD• SanofiDichiara 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.).
Diabetes is associated with significant loss of life years
820,900 people in 97 prospective studies
Seshasai SR et al. NEJM 364:829, 2011
Non-vascular deathsVascular deaths
40 50 60 70 80 900Age (years)
0 40 50 60 70 80 90Age (years)
Year
s of
life
lost
0
1
2
3
4
5
6
7
0
1
2
3
4
5
6
7men women
a 50-year-old individual with diabetes and no history of vascular diseasewill die 6 years earlier compared to someone without diabetes
STENO 2: 21 years of follow up:cumulative CV event or death
Gaede P.et al.: Diabetologia 59:2298, 2016
25
50
75
100
0 4 208 12 160
%intensive
conventional7yrs
A conceptual look at vascular risk and its determinantsbefore and during the course of type 2 diabetes
Sattar N, Diabetologia 2013
diabetesdiagnosis
~ 8–10 years of diabeteshistory
coronary heart disease equivalent threshold
coro
nary
hea
rt d
isea
se r
isk
age
Risk Factors, Mortality, and CardiovascularOutcomes in Patients with Type 2 Diabetes
Acute myocardial infarction
Rawshani A et al. N Engl J Med 2018; 379: 633-644
HbA1c (mmol/mol)
SBP (mmHg)
LDL Chol (mmol/L)
Excess Mortality and risk factors
Glycemic control for CV risk reduction
Mannucci E et al. NMCD 2017
Blood pressure control for CV risk reduction
Frontoni S et al. NMCD 2014
DECLARE: hHF/CVD co-primary endpoint and risk factors
Wiviott SD et al. Online ahead of print. N Engl J Med. 2018
hHF/CVD
HR 95% CI P value
0.83 (0.73, 0.95) 0.005Patie
nts
with
eve
nt (
%)
6
0 1 2 3 4 5
4
2
0
Placebo (496 Events)
DAPA 10 mg (417 Events)
yearsM
ean
HbA
1c (
%) 8.3
8.0
7.7
7.5
DAPA 10 mg
Placebo
7.6
7.97.8
8.4
8.28.1
8.3
8.38.2 8.2 8.2 8.2
8.1
7.6 7.67.8
7.9 7.9
0 1 2 3 4
DAPA 10 mg
Placebo
Mea
n SBP
(mm
Hg)
134
133
132
136
135135
135135 135 135 135 135
132 132 132 132 132
years
DAPA 10 mg
Placebo
Mea
n Bod
y w
eigh
t (k
g)
89
87
88
91
90
9191
90 90 9089
8989
8888
8787
HbA1c
BW
SBP
Improvement in Cardiovascular Outcomes with Empagliflozin is independent of glycemic control
Inzucchi SE et al. Circulation 2018
LDL-C and CV events in interventional trialsEv
ent R
ate
(%)
30
25
20
15
10
5
0
lipid lowering
Placebo
4S
4S
LIPIDLIPID
CARE CAREHPS HPS
TNT (less-intense LDL-C management)TNT (intense LDL-C management)
Mean LDL-C (mg/dL)
IMPROVE-ITFOURIER
0 70 90 110 130 150 170 190 210
Effects of the SGLT2 inhibitor dapagliflozin onHDL chol, particle size, and chol efflux capacity, in T2DM
Fadini GP et al, Cardiovasc Diabetol 2017
altri meccanismi
• trigliceridi
• acido urico
• infiammazione
FIELD: no effect of fenfibrate (?)Cum
ulat
ive
risk
(%)
15
10
5
0
PlaceboFenofibrate
15
10
5
0
*Non-fatal MI:HR 0·76 (95% CI 0·62–0·94),p=0·010
†CHD death:HR 1·19 (95% CI 0·90–1·57), p=0·22
Cum
ulat
ive
risk
(%)
15
10
5
0HR 0·89 (95% CI 0·80–0·99),p=0·035
15
CHD events (non-fatal MI plus CHD death) Non-fatal MI and CHD death
Total CVD events Coronary revascularisation
10
5
0HR 0·79 (95% CI 0·68–0·93),p=0·003
*
†
0 43 5 621
0 43 5 621
0 43 5 621
0 43 5 621Cum
ulat
ive
risk
(%)
Cum
ulat
ive
risk
(%)
Keech A. et al. for the FIELD Investigators: Lancet 366(9500):1849, 2005
The FIELD Study (n: 9795 T2DM)Plasma concentration of lipids
Keech A. et al. for the FIELD Investigators: Lancet 366(9500):1849, 2005
PROVE IT-TIMI 22reaching target LDL alone with statin therapy does not achieve maximal CV
risk reduction if TGs are raised
-30
-25
-20
-15
-10
-5
0
Rela
tive
card
iova
scul
ar ri
sk re
duct
ion*
(%)
LDL ≥70TG ≥150
0%
LDL ≥70TG <150
LDL <70TG ≥150
LDL <70TG <150
-12%
p=0.017vs reference group(LDL ≥70, TG ≥150)
-28%
-16%-15%
≥200 (n=603)
<200(n=2,796)
PROVE IT-TIMI 22 study
30-d
ay ri
sk o
f dea
th, M
I or r
ecur
rent
AC
S (%
)
20.3
13.5
+56%p=0.001
0
5
10
25
15
20
On-treatment TG mmol/L in patients with LDL-C <70 mg/dL
For people at target LDL, those with low TGs have an additional 12% reduction in cardiovascular risk versus those with raised TGs
Miller A et al. J Am Coll Cardiol 2008
REDUCE-IT: primary endpoint (MACE-3)patients with established CVD or with diabetes and other risk factors, receiving statin and triglyceride level of 135 to 499 mg/dl and a LDL cholesterol level of 41 to 100 mg/dl
N Engl J Med. 2018 Nov 10. doi: 10.1056/NEJMoa1812792
2 g of icosapentethyl twice daily
placebo
Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol
The STRENGTH Trial
Nicholls SJ et al, Clinical Cardiology 2018
altri meccanismi
• trigliceridi
• acido urico
• infiammazione
uric acid and cardiovascular risk
Feig DI et al.: NEJM 359:1811, 2008 doi: 10.1056/NEJMra0800885
Uric acid is an independent risk factor for declinein kidney function, CV events and mortality in T1DM
HR per doubling of uric acid
Pyleman-Lyberg S et al, Diabetes Care 2019
Elevated serum uric acid is associatedwith greater risk for hypertension and diabetic kidney disease,
in obese adolescents with type 2 diabetes, duration <2 yrs (n: 539)TODAY study (average FU 5.7 yrs)
Bjornstad P et al, Diabetes Care 2019
Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitorson serum uric acid level: A meta-analysis of randomized controlled trials
Zhao Y et al, DOM 2018
Uric acid and the cardio-renal effects of SGLT2 inhibitors
Bailey CJ et al, Diabetes Obes Metab 2019
Uric acid and the cardio-renal effects of SGLT2 inhibitors
Bailey CJ et al, Diabetes Obes Metab 2019
Preventing Early Renal Loss in type 1 diabetes (PERL):A Randomized Double-Blinded Trial of Allopurinol
NCT02017171: double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40–99.9 mL/min/1.73 m2, SUA ‡4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ‡3 mL/min/1.73 m2/year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period.; iGFR: iohexol GFR;
Afkarian M, … and Doria A; Diabetes Care 42:1454, 2019 doi: 10.2337/dc19-0342
altri meccanismi
• trigliceridi
• acido urico
• infiammazione
Targeting inflammation to reduce CV disease risk:a realistic prospect?
Welsh P, Br J Pharmacol 2017
Pro-atherogenic and inflammatory pathways targetedby prospective anti-atherosclerotic antibodies and inhibitors
Welsh P, Br J Pharmacol 2017
Antiinflammatory Therapy with Canakinumabfor Atherosclerotic Disease (the CANTOS trial)
Ridker PM, et al. N Engl J Med 2017
Antiinflammatory Therapy with Canakinumabfor Atherosclerotic Disease (the CANTOS trial)
Primary End Point with Canakinumab, 150 mg, vs. Placebonon fatal myocardial infarction, nonfatal stroke, or cardiovascular death
Key Secondary End Point with Canakinumab, 150 mg, vs. Placeboadditionally included hospitalization for unstable angina that led to urgent
revascularization
Ridker PM, et al. N Engl J Med 2017
Greater risk reduction with greater hsCRP reduction(the CANTOS trial)
Ridker PM, et al. Circulation 2018
Canakinumab was equally effective in preventing major cardiovascular eventsin patients with diabetes, pre-diabetes and normoglycemia at study enter
Everett BM, et al. J Am Coll Cardiol 2018
Cardiovascular event reduction with no change in LDLC:additive effects of inflammation inhibition to lipid lowering
Ridker PM, J Am Coll Cardiology 2018
Even
t Rat
e (%
)
30
25
20
15
10
5
0
0 70 90 110 130 150 170 190
lipid lowering
Placebo
4S
4S
LIPIDLIPID
CARE CAREHPS HPS
TNT (less-intense LDL-C management)TNT (intense LDL-C management)
Mean LDL-C (mg/dL)
IMPROVE-ITFOURIER
CANTOS
210
Dapagliflozin suppresses oxidative stress and inflammatorygene expression in cultured proximal tubular epithelial cells
0.2 nM 2.0 nM 20.0 nM
Terami N, PLOS ONE 2014
Atherosclerosis patients with “residual inflammatory risk”are more common that patients with “residual cholesterol risk”
Ridker PM, et al. Circulation Res 2017Pradhan A, et al. Circulation 2018
Redefining residual risk:moving toward personalized medicine
Ridker PM, et al. J Am Coll Cardiology 2018
altri meccanismi
• trigliceridi
• acido urico
• infiammazione
• altro?
potential and novel pathways associated with CV effects of SGLT2-i
other
glucoseinsulin
uric acid
triglyceridesHDLLDLoxi-
dativestress
body weightvisceral fat
autonomicnerv. sys.
blood pressureart. stiffness
albuminuria
Inzucchi SE, et al. Diab Vasc Dis Res 12:90; 2015
Hematocrit over time in patients treatedwith empagliflozin and placebo.
Mixed-model repeated-measures analysis using all data up to individual trial completionin patients treated with one or more doses of study drug who had a baseline and post-baseline
measurement
Inzucchi SE et al. Diabetes Care 2018
EMPA-REG outcome trialchanges in markers of plasma volume are the most important mediators of
the reduction in risk of CV death with empagliflozin versus placeboUnivariate mediation analysis of risk of CV death with empagliflozin vs. placebo: time-dependent
covariate analysis adjusting for the updated mean of each variable
Inzucchi SE et al. Diabetes Care 2018
DECLARE: co-primary outcomes
N at risk is the number of subjects at risk at the beginning of the period. 2-sided p-value is displayed; HR, CI, and p-value are from cox proportional hazard model.CV, cardiovascular; Dapa, dapagliflozin; hHF, hospitalization for heart failure; MACE, major adverse cardiac eventWiviott SD et al. Online ahead of print. N Engl J Med. 2018
hHF/CVD
HR 95% CI P value
0.83 (0.73, 0.95) 0.005Patie
nts
with
eve
nt (
%)
6
0 1 2 3 4 5
4
2
0
Placebo (496 Events)
DAPA 10 mg (417 Events)
yearsPa
tient
s w
ith e
vent
(%
)
10.0
0 1 2 3 4 5
7.5
5.0
2.5
0.0
Placebo (803 Events)
DAPA 10 mg (756 Events)
MACE
HR 95% CI P value
0.93 (0.84, 1.03) 0.172
years
years 20.50
placebo semaglutide
1 1.5
patie
nts
with
eve
nt (
%)
SUSTAIN6: MACE (primary outcome)CV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke
Marso SP et al.: NEJM 375:1834, 2016
Hazard ratio, 0.74 (95% CI, 0.58–0.95) P<0.001 for noninferiorityP=0.02 for superiority
10
8
6
4
1
0
years 310
placebo pioglitazone
2
patie
nts
with
eve
nt (
%)
PROACTIVE: MACE (primary outcome failed)CV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke
Hazard ratio, 0.82 (0.70-0.97)p=0.02
15
10
5
0
Wilcox R. et al AHJ 155:712, 2008
glycosuria
increased FFAoxidation
improved cellular metabolism
weight loss
reducedcaloric intake
reduced FFAstorage
weight loss
new s.c.adipocytes
improved FFAstorage
weight gain
reduced CV risk
SGLT inhibitors GLP-1 RAs TZDs
Giaccari A. DOM 21:2211, 2019doi: 10.1111/dom.13814
Composite cardiovascular risk factor target achievement and its predictorsin US adults with diabetes: The Diabetes Collaborative Registry
(n: 74 393 patients, mean age 69.0 years, 41.0% women)
Fan W et al. DOM 2019
…nel frattempo
Conclusioni
• non basta più ottenere soltanto il goal glicemico, quello pressorio e quello lipidico
• dobbiamo volere di più e pretendere che le molecole che utilizziamo ci garantiscano una protezione cardiovascolare globale
• dobbiamo lavorare per comprendere meglio i meccanismi implicati nel rischio cardiovascolare del diabete e sviluppare strategie terapeutiche ad hoc
• utilizziamo i farmaci giusti (e ne abbiamo!)• arriviamo a goal con glicemia, pressione e lipidi