Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda...
Transcript of Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda...
![Page 1: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/1.jpg)
Gabriele PerrielloDipartimento di Medicina Interna
Azienda Ospedaliera-Universitaria di Perugia
Metformina, sulfoniluree, pioglitazone
![Page 2: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/2.jpg)
![Page 3: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/3.jpg)
![Page 4: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/4.jpg)
Hypoglycemic therapy and CV riskCombination of SUs and Metformin may be Linked to Higher Risk for
CVD and All-cause Mortality*
CI=confidence interval; CVD=cardiovascular disease; met=metformin; NS=not specified; SU=sulfonylureas*Composite end point of CVD hospitalizations or CVD mortality – only statistically significantly increased end point.
Rao A, et al. Diabetes Care. 2008; 31: 1672–1678.
Meta-analysis data from 9 clinical studies
1.041.860.961.382.241.861.521.43
(0.62, 1.75)(1.33, 2.61)(0.82, 1.12)(1.13, 1.69)(1.26, 3.99)(1.03, 3.35)(0.84, 2.76)(1.10, 1.85)
SU combo with metbetter than comparators
SU combo with metworse than comparators
Relative risk(95% CI)
Risk ratios for composite end point of CVD hospitalizations or CVD mortality*
0.25 1.00 4.00
Source study reference
Bruno (1999)Olsson (2000)
Johnson (2005)Koro (2005)
Evans (2006a)Evans (2006b)Evans (2006c)
Overall
![Page 5: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/5.jpg)
Change From Baseline in LVEF (Primary Endpoint) and Other Echocardiographic Measurements (n=254)
J Am Coll Cardiol HF 2017
p = 0.007
p = 0.062 p = 0.002
![Page 6: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/6.jpg)
Lancet Diabetes Endocrinol 2017
First occurrence of all-cause death, non-fatal myocardial infarction (including silent
myocardial infarction), non-fatal stroke, or urgent coronary revascularisation
N=3028 pts. with T2DM
![Page 7: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/7.jpg)
Cardiovascular history of patients in TOSCA and VIVIDD
![Page 8: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/8.jpg)
Lancet Diabetes Endocrinol 2017
![Page 9: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/9.jpg)
Failure of hypoglycaemic treatment was defined as HbA1c of 8% (64 mmol/mol) or above on two consecutive visits 3 months apart
Lancet Diabetes Endocrinol 2017
![Page 10: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/10.jpg)
P10
Cardiovascular risk related to glitazone use in T2DM
Study N° CV event OR (95% CI)Nissen and Wolski 42 AMI 1.43* (1.03-1.98)NEJM 356:2457, 2007 (27847) CV death 1.64 (0.98-2.74)
Home et al. - AMI 1.16 (0.75-1.81)NEJM 357:28, 2007 (4447) CHF 2.24* (1.27-3.97)
CV death 0.97 (0.73-1.29)
Diamond et al. 42 AMI 1.26 (0.99-1.69)Ann Int Med; 147:578, 2007 (27847) CV death 1.17 (0.77-1.77)
Singh et al. 4 AMI 1.42* (1.06-1.91)JAMA 298:1189, 2007 (14291) CHF 2.09* (1.52-2.88)
CV death 0.90 (0.63-1.26)
Lincoff et al. 19 MACE 0.82* (0.72-0.94)JAMA 298:1180, 2007 (16390) CHF 1.41* (1.14-1.76)
Lago et al. 7 CHF 1.72* (1.21-2.42)Lancet 370:1129, 2007 (20191) CV death 0.93 (0.67-1.29)
![Page 11: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/11.jpg)
P11
RR 1.41 (1.11 ÷1.80)RRI 41% (10÷80)
ARI 1.6%–NNH 60 (35÷200)
Incidence Rate ≈ 18 x 1000 pty
Congestive Heart Failure inthe PROACTIVE Study
Lancet 2005; 366 October 8: 1279–89
ARR 2.1%–NNT 48 (26÷405)
![Page 12: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/12.jpg)
Potenziali down-sides cardiovascolari delle sulfoniluree, glinidi e pioglitazone nel diabete mellito tipo 2
Potenziale problema Evitare o riconsiderare l’uso di
Incremento ponderale Sulfoniluree e glinidi, TZD
Ipoglicemia Sulfoniluree e glinidi
Ritenzione idrica/edema, alterata natriuresi Pioglitazone
Disfunzione endoteliale Sulfoniluree (esclusa gliclazide)
Scompenso cardiaco Pioglitazone
Ridotta funzione renale Sulfoniluree
Ryden L, et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 2007;28:88-136.
![Page 13: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/13.jpg)
DIMISEM Perugia 2002
![Page 14: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/14.jpg)
University Group Diabetes Program
Meinert et al. 1970
![Page 16: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/16.jpg)
MYOCARDIAL ISCHAEMIC PRE-CONDITIONING
“Phenomenon by which a brief episod (s) of myocardial ischaemia increases the ability of the heart to tolerate a subsequent prolonged
period of ischaemia”
‘Murry et al, 1986’
![Page 17: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/17.jpg)
Beneficial effects of myocardial ischaemic preconditioning
• Resistance to hypoxic injury• Slow energy metabolism• Improve post-ischaemic function• Protect coronary endothelium• ↑Post-ischaemic tension in atrial
trabeculae muscle• ↓Reperfusion arrythmias
![Page 18: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/18.jpg)
ISCHAEMIC PRE-CONDITIONINGMEDIATORS
ATP sensitive K+
channels(K+ ATPS)
Protein Kinase C(PKC)
Sarcolemmal:1. Blocked by
sulfonylureas
Mitochondrial:1. Opened by diazoxide2. Blocked by 5-HD
![Page 19: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/19.jpg)
HRs for all outcomes associated with glyburide and glimepiride compared with gliclazide, glipizide, and tolbutamide
Diabetes Care Publish Ahead of Print, published online September 1, 2017
![Page 20: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/20.jpg)
Metformin vs other OHAsAggregate Endpoint p
Any diabetes related endpoint 0.0034Diabetes related deaths 0.11All cause mortality 0.021Myocardial infarction 0.12Stroke 0.032Peripheral vascular disease 0.62Microvascular 0.39
UKPDS 34, Lancet 1998; 352: 854-65
![Page 21: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/21.jpg)
Riduzione del rischio cardiovascolare indiretta e diretta della metformina
Obiettivo Indiretta (dipendente dalla riduzione della
glicemia)
MET vs CONV
Diretta (indipendente dalla riduzione della
glicemia)
MET vs INT
Ogni evento legato al diabete
↓ 32%; p=0,002 ↓ 25%; p=0,003
Morti legate al diabete ↓ 42%; p=0,017 p=NSMortalità per tutte le cause ↓ 36%; p=0,011 ↓ 28%; p=0,021
Infarto del miocardio ↓ 39%; p=0,01 p=NS
Ictus cerebrale p=NS ↓ 56%; p=0,032Arteriopatia periferica p=NS p=NS
UKPDS 34, Lancet 1998; 352: 854-65
![Page 22: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/22.jpg)
In cardiopathic type 2 diabetic patients…
• Metformin remains first-line therapeutic agent for its potential cardioprotective action
• Pioglitazone is not recommended for possibly causing heart failure
• Sulfonylureas should be avoided because of their negative effect on the heart and hypoglycemic burden
![Page 23: Gabriele Perriello - Sid Italia · Gabriele Perriello. Dipartimento di Medicina Interna. Azienda Ospedaliera- Universitaria di Perugia. Metformina, sulfoniluree, pioglitazone. Hypoglycemic](https://reader031.fdocuments.in/reader031/viewer/2022020318/5c65966909d3f2916e8d01c9/html5/thumbnails/23.jpg)
Effect of Glucose-Lowering Drugs on 3-Point MACE* in T2DM Patients
HR 95% CIlowering drug value
0.6Favors study drug
1 1.2Favors placebo
*CV mortality, non-fatal MI, non-fatal stroke
Study Glucose- P-
PROACTIVE Pioglitazone 0.84 0.72-0.98
Saxagliptin 1.00 0.89-1.12
Alogliptin 0.96 0.80-1.15
Sitagliptin 0.99 0.89-1.10
Lixisenatide 1.02 0.89-1.17
Liraglutide 0.87 0.78-0.97
Semaglutide 0.74 0.58-0.95
Empagliflozin 0.86 0.74-0.99
_J 0.027
NS
NS
NS
NS
0.010
0.020
0.038
SAVOR
EXAMINE
TECOS
ELIXA
_J
_J
LEADER
SUSTAIN-6
EMPA-REG
CVOT (3 MACE)