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Marco Giorgio BaroniDipartimento di Medicina Sperimentale
Sapienza Universitagrave di Roma
Roma 21 maggio 2019
Obiettivi nel paziente con diabete tipo 2 la glicemia non basta
Il sottoscritto Marco Giorgio Baroni
dichiara di aver ricevuto negli ultimi due anni compensio finanziamenti dalle seguenti Aziende Farmaceuticheeo Diagnostiche
- Sanofi- Novo Nordisk- Abbott- Mundi Pharma- MSD
Dichiara altresigrave il proprio impegno ad astenersi nellrsquoambito dellrsquoevento dal nominare in qualsivoglia modo o forma aziende farmaceutiche eo denominazione commerciale e di non fare pubblicitagrave di qualsiasi tipo relativamente a specifici prodotti di interesse sanitario (farmaci strumenti dispositivi medico-chirurgici ecc)
Effect of Glucose-Lowering Drugs on 3-Point MACE in T2DM Patients
Study Year Glucose-loweringdrug HR 95 CI P-value
PROACTIVE 2005 Pioglitazone 084 072 - 098 002
ORIGIN 2012 Insulin glargine 102 094 - 111 NS
DEVOTE 2017 Insulin degludec 091 078 - 106 NS
SAVOR 2013 Saxagliptin 100 089 - 112 NS
EXAMINE 2013 Alogliptin 096 080 - 115 NS
TECOS 2015 Sitagliptin 098 089 - 108 NS
ELIXA 2015 Lixisenatide 102 089 - 117 NS
EMPA-REG 2015 Empagliflozin 086 074 - 099 0038
06 1 12CV mortality non-fatal MI non-fatal stroke Favors study drug Favors placebo
Effect of Glucose-Lowering Drugs on 3-Point MACE in T2DM Patients
Study Year Glucose-loweringdrug HR 95 CI P-value
PROACTIVE 2005 Pioglitazone 084 072 - 098 002
ORIGIN 2012 Insulin glargine 102 094 - 111 NS
DEVOTE 2017 Insulin degludec 091 078 - 106 NS
SAVOR 2013 Saxagliptin 100 089 - 112 NS
EXAMINE 2013 Alogliptin 096 080 - 115 NS
TECOS 2015 Sitagliptin 098 089 - 108 NS
ELIXA 2015 Lixisenatide 102 089 - 117 NS
EMPA-REG 2015 Empagliflozin 086 074 - 099 0038
LEADER 2016 Liraglutide 087 078 - 097 001
SUSTAIN-6 2016 Semaglutide 074 058 - 095 002
CANVAS 2017 Canagliflozin 086 075 - 097
06 1 12CV mortality non-fatal MI non-fatal stroke Favors study drug Favors placebo
Effect of GLP-1 RAs on CVD outcome
Bethel MA et al Lancet 2018
Effect of GLP-1 RAs on CVD outcome
Bethel MA et al Lancet 2018
Quali meccanismi
Age (yrs)
LDL-cholesterol mmoll)Systolic BP (mmHg)
UKPS 23 Risk Factors for CHD
Turner RC et al BMJ 1999316823-828
HbA1c ()
Estim
ated
HREs
timat
edHR
Estim
ated
HREs
timat
edHR
Adjusted Hazard Ratios for Outcomes According to Age Category and Number of Risk-Factor Variables outside Target Ranges (HbA1c LDL Album BP smoke)
Rawshani A et al N Engl J Med 2018379633-644
The Potential Mechanisms of Cardiovascular Benefits of Glucagon-like Peptide-1 Receptor Agonists
PotentialCardiovasculareffects of GLP-
1 receptoragonists
Glucose
Body weightVisceral fat
LDL CholesterolTriglycerides
AlbuminuriaGFR
Cardiac function
Cardiac Ischemia
Atherosclerosis
Blood Pressure
METABOLIC CARDIOVASCULAR
Relative Importance of Risk Factors for Predicting Death from Any Cause Acute Myocardial Infarction Stroke and Hospitalization for Heart Failure amongPatients with Type 2 Diabetes with or without Preexisting Conditions
Rawshani A et al N Engl J Med 2018379633-644
Association between Levels of Glycated Hemoglobin Systolic Blood Pressure and LDL Cholesterol and Death from Any Cause Acute Myocardial Infarction Stroke and Heart Failure in Patients with Type 2 Diabetes
Rawshani A et al N Engl J Med 2018379633-644
Quale riduzione del rischio cardiovascolare egrave stata ottenuta con il trattamento intensivo della glicemia
1 gt302 gt503 lt104 2
Residual vascular risk for macrovascolar complications in type 2 diabetic patients as reported in randomized controlled trials thatcompared more intensive glucose control vs less intensive glucosecontrol
Turnbull FM et al Diabetologia 2009Giugliano D et al Endocrine 2018
Leader Estimated mean values from randomization to end of trial for glycated hemoglobin
Glycated Hemoglobin and Body Weight in SUSTAIN 6
Marso SP et al N Engl J Med 2016
GLP-1 receptor agonists glucose control
Magnitude of cardioprotection and HbA1c loweringwith GLP-1 receptor agonists
Taylor SI GLP-1 receptor agonists differentiation within the class Lancet 2018
prim
aryo
utco
me
card
iova
scul
arde
ath
stro
ke
myo
card
ialin
farc
tion
Harmony Outcomes HbA1c and body weight
HbA1c Body weight
Magnitude of cardioprotection and HbA1c loweringwith GLP-1 receptor agonists
Taylor SI GLP-1 receptor agonists differentiation within the class Lancet 2018
GLP-1 targets multiple organs to improve glucosecontrol in T2DM
The Potential Mechanisms of Cardiovascular Benefits of Glucagon-like Peptide-1 Receptor Agonists
PotentialCardiovasculareffects of GLP-
1 receptoragonists
Glucose
Body weightVisceral fat
LDL CholesterolTriglycerides
AlbuminuriaGFR
Cardiac function
Cardiac Ischemia
Atherosclerosis
Blood Pressure
METABOLIC CARDIOVASCULAR
Quali sono gli effetti degli analoghi del GLP-1 sullrsquoassetto lipidico
1 Modesta riduzione di colesterolo e trigliceridi2 Riduzione significativa del colesterolo3 Riduzione significativa dei trigliceridi4 Riduzione HDL
GLP-1 receptor agonists impact on blood lipids
bull Network meta analysis of 35 trials with Liraglutide Exenatide Taspoglutide
bull Effectsbull HDL = -232 to -502 mgdl (NS)
bull LDL = -309 to -618 mgdl (NS)
bull TC = -618 to -1044 mgdl (NS)
bull TG = -2657 to -4340 mgdl (NS)
Clinical TherapeuticsVolume 37 Number 1 2015
GLP-1 receptor agonists
The Potential Mechanisms of Cardiovascular Benefits of Glucagon-like Peptide-1 Receptor Agonists
PotentialCardiovasculareffects of GLP-
1 receptoragonists
Glucose
Body weightVisceral fat
LDL CholesterolTriglycerides
AlbuminuriaGFR
Cardiac function
Cardiac Ischemia
Atherosclerosis
Blood Pressure
METABOLIC CARDIOVASCULAR
Anti-Atherosclerotic potential of GLP-1 action
GLP-1RndashDependent Intracellular Signal Pathways in the Cardiomyocyte
Potential Role of Epicardial Adipose Tissue in the Heart
Epicardial Adipose Tissue Mediates the Effect of Chronic SystemicInflammatory Disorders to Cause Coronary Atherosclerosis AtrialArrhythmias and Heart Failure With Preserved Ejection Fraction
Packer M JACC 2018
GLP-1
Metabolic pathways associated to GLP-1R and GLP-2R levels in EAT from CAD patients
Dozio E Int J Cardiol 2019
Epicardial fat thickness (yellow filling between the white arrows) before (on the left) and after 3 months of liraglutide combinedwith metformin treatment (on the right) in the same patient
Iacobellis G Obesity 2017
The Potential Mechanisms of Cardiovascular Benefits of Glucagon-like Peptide-1 Receptor Agonists
PotentialCardiovasculareffects of GLP-
1 receptoragonists
Glucose
Body weightVisceral fat
LDL CholesterolTriglycerides
AlbuminuriaGFR
Cardiac function
Cardiac Ischemia
Atherosclerosis
Blood Pressure
METABOLIC CARDIOVASCULAR
Quali sono gli effetti degli analoghi del GLP-1 sulla pressione arteriosa sistolica
1 Nessun effetto2 Riduzione di 3-4 mmHg3 Riduzione 7-8 mmHg4 Aumento di 1-2 mmHg
SUSTAIN-6 - Systolic Blood Pressure
0
Overall mean at baseline 1356 mmHg
104
ETD ndash259[ndash409ndash108]
ETD ndash127[ndash277023]
Marso SP et al N Engl J Med 20163751834-1844
Meta-analysis of Change in Systolic (top) and Diastolic Blood Pressure (mmHg) in T2DM Patients Treated with GLP1-Ra
Visboll T et al BMJ 2012344d7771 doi 101136bmjd7771
- 357 mmHg
- 138 mmHg
LEADER amp SUSTAIN 6 ndash Renal Outcomes
SUSTAIN-6 - New or Worsening Nephropathy
LEADER - Time to first renal event
Placebo
Semaglutide
HR 06495 CI (046minus088)
p=0005
Marso SP et al N Engl J Med 2016375311-22 Marso SP et al N Engl J Med 20163751834-1844
Effects of glucagon-like peptide 1 (GLP-1) and GLP-1 receptoragonists (GLP-1RAs) on renal haemodynamics in diabetes
Effect of 3h GLP-1 infusion on Urine Fluid and Electrolyte Output in Healthy Subjects
P=00009
P=00013 P=00004
P=02595
Gutzwiller J-P et al J Clin Endocrinol Metab 2004893055ndash3061