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Sara BelcastroSCDU Endocrinologia, Diabetologia e Metabolismo
Università di Torino
sara.belcastro@unito.it
Congresso Congiunto AMD-SID-SIEDP-ANIED-OSDIGenova 26 ottobre 2019
Sistema nervoso centrale: effetti sulle patologie cerebrovascolari e sulle malattie degenerative del sistema nervoso
Terapie del diabete: certezze consolidate e nuove prospettive
Dr. Sara Belcastro declares to have received in the last two yearscompensation or financing from the following pharmaceutical and/or
diagnostic companies: Merck, Novartis, Boehringer, Lilly, Mundipharma, Novo Nordisk and Bruno.
Disclosure
Ischaemic heart disease is the leading cause of mortality in patients with T2D
35%
15%10%
40%
Low Wang CC et al. Circulation 2016;133:2459–502
Non-cardiovascular causes
Ischaemic heartdisease
Other heart disease(predominantly congestive)
Stroke
Despite management of modifiable risk, placebo-treated patients were still at risk of CV and renal events
aEvent rate ranges are taken from values reported for the placebo groups in the CANVAS Program, EMPA-REG OUTCOME and DECLARE-TIMI 58 CV outcome trials; bComponents of the renal composite endpoint differed slightly across trials. CANVAS: 40% reduction in eGFR, renal replacement therapy or renal death; EMPA-REG Outcome: 40% reduction in eGFR (to < 60 ml/min/1.73 m2), end stage renal disease or renal death; DECLARE-TIMI 58: Doubling of serum creatinine accompanied by eGFR of ≤ 45 ml/min/1.73 m2, initiation renal replacement therapy or renal death. CV, cardiovascular; HF, heart failure, MI, myocardial infarction. 1. Zinman B et al. N Engl J Med 2015;373:2117–28; 2. Neal B et al.N Engl J Med 2017;377:644–57; 3. Wiviott SD et al. N Engl J Med 2019;380:347–57; 4. Wanner C et al. N Engl J Med 2016;375:1801–2
CV event rates in placebo-treated patients in CV outcome trials
CV deatha
7–20patients per
1000 patient-years1-3
Non-fatal strokea
7–9patients per
1000 patient-years1-3
Non-fatal MIa
12–19patients per
1000 patient-years1-3
Hospitalizationfor HFa
9–15patients per
1000 patient-years1-3
Renal compositea,b
7–12patients per
1000 patient-years2–4
Modifiable risk factors were addressed in patients with T2D in CV outcomes trials
aAverage of placebo-group populations from CANVAS Program, DECLARE-TIMI 58, EMPA-REG OUTCOME and overall population for VERTIS CV, CV outcomes trials bAverage of placebo-group populations from CANVAS Program, EMPA-REG Outcome and overall population for DECLARE-TIMI 58 and VERTIS CV. BMI; BMI, body mass index; CV, cardiovascular, RAS, renin–angiotensin system1. Zinman B et al. N Engl J Med 2015;373:2117–28; 2. Neal B et al. N Engl J Med 2017;377:644–57; 3.
4. Cannon CP et al. Am Heart J 2018;206:11–23; 5. Raz I et al. Diabetes Obes Metab 2018;20:1102–10.Wiviott SD et al. N Engl J Med
2019;380:347–57;
Total cholesterol1,2,4,5,b Blood pressure1–4,a Obesity (BMI)1–4,a HbA1c1–4,a
Range: 4.2–4.4 mmol/L Systolic range: 133–137Diastolic range: 77–78
30.7–32.0 kg/m2 8.1–8.3% (65–67 mmol/mol)
Management of modifiable risk factors in CV outcomes trial populations1–5
Statin use ranged from 75–81% of patients across
CVOTs1–4a
Anti-thrombotic use ranged from 61–90%
of patients across CVOTs1–4a
RAS-inhibitor use ranged from 80–81%
of patients across CVOTs1–4a
β-blocker use ranged from 53–69% of patients across
CVOTs1–4a
Diuretic use ranged from 41–45% of patients across
CVOTs1–4a
Hyperglycaemia is a strong predictor of stroke or acute MI among patients with T2D
Patients with T2D: n = 271 174GFR, glomerular filtration rate; LDL, low-density lipoprotein; MI, myocardial infarction
1. Rawshani A et al. N Engl J Med 2018;379:633-44
Stroke MIHbA1c
Systolic blood pressureDuration of diabetes
Physical activityAtrial fibrillation
IncomeMarital status
SmokingEstimated GFR
Lipid-lowering medicationBlood pressure medication
LDL cholesterolDiastolic blood pressure
Body mass indexHeart failureAlbuminuria
EducationImmigrant
0.000 0.005
Increasing importance
0.010 0.015R2
0.000 0.005
Increasing importance
0.010 0.020R2
0.015
HbA1cSystolic blood pressure
LDL cholesterolPhysical activity
SmokingDuration of diabetes
Estimated GFRIncome
Diastolic blood pressureHeart failure
Blood pressure medicationMarital status
EducationAlbuminuria
Lipid-lowering medicationImmigrant
Atrial fibrillationBody mass index
Elevated risk of mortality and cardiovascular morbidity in patients with T2D
1. Rawshani A et al. N Engl J Med 2018;379:633–44
0.8
1.0
2.0
Haza
rd ra
tio
0.0
LDL cholesterol (mmol/L)
1.2
1.6
2.5 5.0 7.5
Systolic blood pressure (mmHg)Glycated haemoglobin (mmol/mol)
100 150 200
50 75 100
Death from any cause
0.8
1.0
2.5
Haza
rd ra
tio
0.0
1.5
2.0
2.5 5.0 7.5
100 150 200
50 100 150
Acute myocardial infarction
3.0
0.8
1.0
2.0
0.0
1.2
1.6
2.5 5.0 7.5
100 150 200
50 100 150
Stroke
1.0
4.0
0.0
2.0
3.0
2.5 5.0 7.5
100 150 200
50 100 150
Heart failure
Haza
rd ra
tio
Haza
rd ra
tio
DPP4 is do not increase or decrease the overall risk of CV events
Study SAVOR-TIMI 531,4
(N = 16 492)EXAMINE2,4
(N = 5380)TECOS3,4
(N = 14 671)
DPP4i Saxagliptin Alogliptin Sitagliptin
Study population History of established CV disease or multiple CV risk factors
Acute MI or unstable angina requiring hospitalization
Pre-existing CV disease
3-P MACE 1.00a,b (0.89–1.12) 0.96a,b (upper ≤ 1.16) 0.99a,b (0.89–1.10)
CV death 1.03 (0.87–1.22) 0.79 (0.60–1.04) 1.03 (0.89–1.19)
Fatal or non-fatal MI 0.95 (0.80–1.12) 1.08 (0.88–1.33)c 0.95 (0.81–1.11)
Fatal or non-fatal stroke 1.11 (0.88–1.39) 0.91 (0.55–1.50)c 0.97 (0.79–1.19)
Hospitalization for HF 1.27a (1.07–1.51) – 1.00 (0.83–1.20)
All-cause death 1.11 (0.96–1.27) 0.88 (0.71–1.09) 1.01 (0.90–1.14)
1. Scirica BM et al. N Engl J Med 2013;369:1317–26; 2. White WB et al. N Engl J Med 2013;369:1327–35;3. Green JB et al. N Engl J Med 2015;373:232–42; 4. Son JW, Kim S. Diabetes Metab J 2015;39:373–83
HRs (95% CI) for DPP4i CV outcomes trial endpoints
GLP1RAs have variable effects on CV outcomes
Study ELIXA1
(N = 6068)LEADER2
(N = 9340)SUSTAIN-63
(N = 3297)EXSCEL4
(N = 14 752)HARMONY5
(N = 9463)
GLPIRA Lixisenatide Liraglutide Semaglutide sc Exenatide Albiglutide
Study population T2D and acute coronary syndrome
T2D and high CV risk
T2D T2D with or without previous CV disease
T2D and CV disease
Primary endpointa 1.02 (0.89–1.17)b 0.87b,c (0.78–0.97) 0.74b,c (0.58–0.95) 0.91b,c (0.83–1.00) 0.78b,c (0.68–0.90)
CV death 0.98 (0.78–1.22) 0.78b (0.66–0.93) 0.98 (0.65–1.48) 0.88 (0.76–1.02) 0.93 (0.73–1.19)
Non-fatal MI 1.03 (0.87–1.22) 0.88 (0.75–1.03) 0.74 (0.51–1.08) 0.97d (0.85–1.10) 0.75b,d (0.61–0.90)
Non-fatal stroke 1.12 (0.79–1.58) 0.89 (0.72–1.11) 0.61b (0.38–0.99) 0.85d (0.70–1.03) 0.86d (0.66–1.14)
Hospitalization for HF 0.96 (0.75–1.23) 0.87 (0.73–1.05) 1.11 (0.77–1.61) 0.94 (0.78–1.13) –
All-cause death 0.94 (0.78–1.13) 0.85b (0.74–0.97) 1.05 (0.74–1.50) 0.86 (0.77–0.97) 0.95 (0.79–1.16)
1. Pfeffer MA et al. N Engl J Med 2015;373:2247–57; 2. Marso SP et al. N Engl J Med 2016;375:311–22; 3. Marso SP et al. N Engl J Med 2016;375:1834–44; 4. Holman RR et al. N Engl J Med 2017;377:1228–39; 5. Hernandez AF et al. Lancet 2018;392:1519 –29
HRs (95% CI) for GLP1RA CV outcomes trial endpoints
J. Lovshin and David Cherney Diabetes 2015
SGLT2 inhibitors and risk of stroke in patients with type 2 diabetes: A systematic review and meta-analysis
Diabetes, Obesity and Metabolism, Volume: 20, Issue: 8
Inzucchi SE Endocrinol Metab Clin N Am 2018
Proposed glucose-lowering strategy in T2DM with CVD favoring agents demostrated to improve CV outcomes
Il passaporto di un farmaco antidiabetico Ottimizzazione del compenso glico-metabolico
Riduzione di peso
No ipoglicemia
Sicurezza CV o superiorità!
Manegevolezza
Effetti extraglicemici …capacità di modificare la storia naturale della malattia
Y. Seino, D.Yabe Journal of Diabetes Investigation 2013
GLP-1 RA Neuroprotection
Adapted from: Kim DS. et al.,Cell. Transplantation, 2017, Vol 26(9) 1560-1571
Y. Seino, D.Yabe Journal of Diabetes Investigation 2013
Exenatide had positive effects onpratically defined off-medicationmotor scores in Parkinson’s disease,which were sustained beyond theperiod of exposure. Exenatiderepresents a major new avenue forinvestigation in Parkinson’s disease,and effects on everyday symptomsshould be examined in longer-termtrials.
D. Athauda et al. The Lancet Vol 390. 2017
IY Simsir et al . Diabetes & Metabolic Syndrome Review 2018
Study ongoing…
«Sapere che sappiamo quel che sappiamo, e sapere che nonsappiamo quel che non sappiamo; questa è la vera conoscenza».
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