1 cardiovascular risk of glucose- lowering drugs josep redon. md, phd, faha scientific director...
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Cardiovascular risk of Glucose-Cardiovascular risk of Glucose-Lowering DrugsLowering Drugs
Josep Redon. MD, PhD, FAHAScientific DirectorResearch Foundation and Research InstituteINCLIVA. University of Valencia
Long-term CV and non-CV mortality Long-term CV and non-CV mortality in patients with type 2 diabetesin patients with type 2 diabetes
0 2
Increased risk of mortality
4 6 8 10
Patient-years* SMR (95% CI)
All-cause mortality
Women 2625 4.7 (3.9-5.8)**
Men 3183 3.0 (2.5-3.5)
All 5807 3.5 (3.1-4.0)
Cardiovascular mortality
Women 2591 7.2 (5.3-9.8)**
Men 3139 4.4 (3.4-5.6)
All 5730 5.2 (4.3-6.3)
Non-cardiovascular mortality
Women 2591 3.1 (2.3-4.2)
Men 3139 2.1 (1.6-2.7)
All 5730 2.4 (2.0-3.0)
Standardised mortality rates (SMR) for menand women with type 2 diabetes
*Follow-up from 1974-2005 for all-cause mortality and 1974-2004 for cardiovascular and non-cardiovascular mortality**p<0.01 for difference between men and women
Allemann S, et al. Swiss Med Wkly. 2009;139(39-40):576-83.
Potential contributors to accelerate Potential contributors to accelerate atherosclerosis and CV disease in Diabetesatherosclerosis and CV disease in Diabetes
Redon J et al. (submitted).
Type 1 DM
Late-onset central Late-onset central obesity and IRobesity and IR
Type 2 DM
Central obesity and IRCentral obesity and IR
Dyslipidemia*Dyslipidemia* Low-HDLLow-HDL Increased TGRL-CIncreased TGRL-C Postpandrial lipemiaPostpandrial lipemiaProimflamatory state*Proimflamatory state*Procoagulant state*Procoagulant state*
* Relate to insulin-resistance
HyperglycemiaNephropathyNephropathy
CV risk reduction with multiple intervention CV risk reduction with multiple intervention therapy in type 2 DMtherapy in type 2 DM
Gaede et al. N Engl J Med 2008 358:580-91
Factors which contribute to the final CV risk Factors which contribute to the final CV risk in diabetesin diabetes
GlucoseGlucoseLoweringLowering
DrugDrug
6
Interaction between Patient Interaction between Patient Characteristics Glucose Characteristics Glucose
Control Level and CV Risk Control Level and CV Risk ReductionReduction
Impact of intensive therapy of glucose control Impact of intensive therapy of glucose control in CV events in type 1 diabetes: DCCT studyin CV events in type 1 diabetes: DCCT study
DCCT/EDIC N Engl J Med 2008;353:2643-2653
Impact of intensive glucose control in CV Impact of intensive glucose control in CV events in diabetesevents in diabetes
DCCT/EDIC UKPDS ACCORD ADVANCE VADT
Subjects 1394 T1DM 3867 T2DM 10250 T2DM 11140 T2DM 1791 T2DM
Age, y 27 53 62 66 60
Follow-up 17 5.0 3.4 4.9 5.6
Targets HbA1c <6.05%FPG 70-120mg/L
FPG <6mmol/L
HbA1c <6% vs 7-7.9%
HbA1c <6.5% vs >6.5%
HbA1c <6% 1.5% reduction
DM time 6 0 10 7 10
CVD % 0 2 35 32 40
BP 115/73 135/82 136/75 145/81 132/76
LDL 109 mg/dl 3.5 mmol/L 2.7 mmol/L 3.1 mmol/L 2.8 mmol/L
HbA1c, % 9.1 7.1 8.3 7.5 9.4
Results 42% in CVD No difference Increased all mortality (1.22)
No difference No difference
Impact of intensive glucose control in CV Impact of intensive glucose control in CV events in diabetesevents in diabetes
DCCT/EDIC UKPDS ACCORD ADVANCE VADT
Subjects 1394 T1DM 3867 T2DM 10250 T2DM 11140 T2DM 1791 T2DM
Age, y 27 53 62 66 60
Follow-up 17 5.0 3.4 4.9 5.6
Targets HbA1c <6.05%FPG 70-120mg/L
FPG <6mmol/L
HbA1c <6% vs 7-7.9%
HbA1c <6.5% vs >6.5%
HbA1c <6% 1.5% reduction
DM time 6 0 10 7 10
CVD % 0 2 35 32 40
BP 115/73 135/82 136/75 145/81 132/76
LDL 109 mg/dl 3.5 mmol/L 2.7 mmol/L 3.1 mmol/L 2.8 mmol/L
HbA1c, % 9.1 7.1 8.3 7.5 9.4
Results 42% in CVD No difference Increased all mortality (1.22)
No difference No difference
Meta-analisis of RCT in macrovascular events Meta-analisis of RCT in macrovascular events with intensive glucose control: Main resultswith intensive glucose control: Main results
Ray KK et al Lancet 2009;373:1765-1772
Meta-analisis of RCT in macrovascular events Meta-analisis of RCT in macrovascular events with intensive glucose control: Main resultswith intensive glucose control: Main results
Tumbull FM et al. Diabetologica 2009;52:2288-2298
Hypoglycemia frequently occurs in intensive Hypoglycemia frequently occurs in intensive glucose control treatmentglucose control treatment
Disease duration and CV risk events in Disease duration and CV risk events in intensive glucose control therapy (VADT)intensive glucose control therapy (VADT)
Duckworth et al. N Engl J Med 2009;360:129-139
HbA1c goals and CV riskHbA1c goals and CV risk
15
Glucose-lowering drugs and Glucose-lowering drugs and
CV riskCV risk
Glucose metabolism abnormalities in type 2 Glucose metabolism abnormalities in type 2 diabetes and treatment approachesdiabetes and treatment approaches
Risk of all-cause mortality as a function of Risk of all-cause mortality as a function of HbAHbA1c1c and kind of treatment in T2DM and kind of treatment in T2DM
Adjusted for age, sex, smoking status, total cholesterol, cardiovascular risk and general morbidity*Truncated at lower quartile; †Truncated at upper quartile**p<0.01 vs the reference group (decile 4; median HbA1c 7.5)
Currie CJ, et al. Lancet 2010 ;375:481-9
6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5
2.4
2.2
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.66.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5
Insulin-based regimens (n=20,005)Metformin plus sulphonylureas (n=27,965)HbA1c (%) HbA1c (%)
HR
(9
5%
CI)
*
*
††
Adjusted HR for all-cause mortality by HbA1c deciles
**
****
**** **
**
Risk of CV fatal and non-fatal events in Risk of CV fatal and non-fatal events in T2DM treated with metformin or SUT2DM treated with metformin or SU
Roumie CL et al. Ann Intern Med 2012; 157: 601-610.
Risk of CV fatal and non-fatal events in Risk of CV fatal and non-fatal events in T2DM with or without previous MIT2DM with or without previous MI
No Prior MI Prior MI
Metformin
Gliclazide
Glimepiride
Glibenclamide
Glipizide
Tolbutamide
Repaglinide
0 1 2
MI, Stroke, and Cardiovascular Death
Hazard Ratios (95% confidence intervals)
11.29 (1.20, 1.39)1.18 (1.02, 1.36)1.16 (1.04, 1.29)1.24 (1.09, 1.40)1.17 (1.03, 1.33)0.87 (0.49, 1.54)
Metformin
Gliclazide
Glimepiride
Glibenclamide
Glipizide
Tolbutamide
Repaglinide
0 1 2
Hazard Ratios (95% confidence intervals)
1
1.22 (1.30, 1.46) 0.03
0.71 (0.52, 1.99) 0.04
1.10 (0.85, 1.41) 0.5
1.54 (1.12, 2.10) 0.008
1.44 (1.01, 2.05) 0.04
1.10 (0.67, 1.82) 0.69
MI, Stroke, and Cardiovascular Death
Schramm TK et al. Eur Heart J. 2011; 32:1900–1908.
Impact of different oral glucose-lowering Impact of different oral glucose-lowering drugs on CV risk of T2DMdrugs on CV risk of T2DM
Tzoulaki et al BMJ 2009;339:b4731
Haza
rd r
ati
o (
95
% C
l) (
log
scale
)
1st generation
sulphonylureas vs
metform
in
2.0
1.0
1.5
0.5
2nd generation
sulphonylureas vs
metform
in
All rosig
litazone* v
s
metform
in
All pioglita
zone*
vs metfo
rmin
All rosig
litazone*
vs all p
ioglitazone* Other
combinations†
vs metfo
rmin
n = 6053, 1st generation sulphonylureas; n= 58,095, 2nd generation sulphonylureas; n= 8442, rosiglitazone; n = 9640, rosiglitazone combination; n = 3816, pioglitazone monotherapy or combination; n = 37,253, other drugs or combinations; n = 68,181, metformin*Any therapy (monotherapy and combinations)†Other drugs and combinations of any oral antidiabetes drugs excluding rosiglitazone and pioglitazone
Increased risk of allcause mortality
Decreased risk of all cause mortality
All cause mortality
Impact of different oral glucose-lowering Impact of different oral glucose-lowering drugs on CV risk of T2DMdrugs on CV risk of T2DM
Tzoulaki et al BMJ 2009;339:b4731
n = 6053, 1st generation sulphonylureas; n= 58,095, 2nd generation sulphonylureas; n= 8442, rosiglitazone; n = 9640, rosiglitazone combination; n = 3816, pioglitazone monotherapy or combination; n = 37,253, other drugs or combinations; n = 68,181, metformin*Any therapy (monotherapy and combinations)†Other drugs and combinations of any oral antidiabetes drugs excluding rosiglitazone and pioglitazone
Increased risk of MI
Decreased risk of MI
Haza
rd r
ati
o (
95
% C
l) (
log
scale
)
1st generation
sulphonylureas vs
metform
in
2.0
1.0
1.5
0.5
2nd generation
sulphonylureas vs
metform
in
All rosig
litazone* v
s
metform
in
All pioglita
zone*
vs metfo
rmin
All rosig
litazone*
vs all p
ioglitazone* Other
combinations†
vs metfo
rmin
Myocardial infarction
Impact of different oral glucose-lowering Impact of different oral glucose-lowering drugs on CV risk of T2DMdrugs on CV risk of T2DM
Tzoulaki et al BMJ 2009;339:b4731
n = 6053, 1st generation sulphonylureas; n= 58,095, 2nd generation sulphonylureas; n= 8442, rosiglitazone; n = 9640, rosiglitazone combination; n = 3816, pioglitazone monotherapy or combination; n = 37,253, other drugs or combinations; n = 68,181, metformin*Any therapy (monotherapy and combinations)†Other drugs and combinations of any oral antidiabetes drugs excluding rosiglitazone and pioglitazone
Congestive heart failure
Increased risk of CHF
Decreased risk of CHF
Haza
rd r
ati
o (
95
% C
l) (
log
scale
)
1st generation
sulphonylureas vs
metform
in
2.0
1.0
1.5
0.5
2nd generation
sulphonylureas vs
metform
in
All rosig
litazone* v
s
metform
in
All pioglita
zone*
vs metfo
rmin Other
combinations†
vs metfo
rmin
Factors related to the impact of different Factors related to the impact of different glucose-lowering drugs on CV riskglucose-lowering drugs on CV risk
Comparative risk of hypoglycemia with Comparative risk of hypoglycemia with glucose-lowering drugsglucose-lowering drugs
MET vs MET + TZD
SU vs REPAG
SU vs MET
SU vs TZD
SU + TZD vs SU
SU + MET vs SU
SU + MET vs MET
GLIB vs other SU
Weighted absolute risk difference
Drug 1 less riskof hypoglycemia
Drug 1 greater riskof hypoglycemia
0.00 (−0.01-0.01)
0.02 (−0.02-0.05)
0.04 (0.00-0.09)
0.09 (0.03-0.15)
0.08 (0.00-0.16)
0.11 (0.07-0.14)
0.14 (0.07-0.21)
0.03 (0.00-0.05)
3 (1557)
5 (1495)
8 (2026)
5 (1921)
3 (1028)
8 (1948)
9 (1987)
6 (2238)
Pooled effect(95% CI)
Studies(participants)
0.05 0.1 0.15 0.20
Bolen S, et al. Ann Intern Med. 2007; 147: 386-399.HypoglycemiaHypoglycemia
Meta-analysis of effect of antidiabetes Meta-analysis of effect of antidiabetes therapies on hypoglycaemiatherapies on hypoglycaemia
Phung OJ, et al. JAMA 2010;303(14):1410-8
*I2=50-75%; **I2≥75% I2>50% was considered to represent important statistical heterogeneitySU, sulphonylurea; TZD, thiazolidinediones; AGI, -glucosidase inhibitor; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1
TZDs
All drugs
SUs
Glinides
0 2
Increased risk of hypoglycaemia vs placebo
No. trials
AGIs
DPP-4 inhibitors
GLP-1 analogues
4 6 8 44
19
RR (95% CI)
3
2
2
8
2
1.43 (0.89 to 2.30)
2.63 (0.76 to 9.13)**
7.92 (1.45 to 43.21)
0.60 (0.08 to 4.55)
0.67 (0.30 to 1.50)
0.94 (0.42 to 2.12)
Relative risk (RR; 95% CI) of hypoglycaemia versus placebo
2 2.04 (0.50 to 8.23)
Decreased risk of hypoglycaemia vs placebo
HypoglycemiaHypoglycemia
Risk of hypoglycaemia with glucose-lowering Risk of hypoglycaemia with glucose-lowering drugsdrugs
HypoglycemiaHypoglycemia
Meta-analysis of effect of antidiabetes Meta-analysis of effect of antidiabetes therapies on weight changetherapies on weight change
Phung OJ, et al. JAMA 2010;303(14):1410-8
Weighted mean difference (WMD) in change from baseline in body weight (kg) versus placebo
All drugs SUs Glinides TZDs AGIs
WM
D (
mean;
95
% C
I)
vs
pla
ceb
o
No. trials
DPP-4inhibitors
GLP-1analogues
12 2 2 1 1 4 2
-3
-2
-1
3
0
1
2
***
*I2=50-75%; **I2≥75% I2>50% was considered to represent important statistical heterogeneitySU, sulphonylurea; TZD, thiazolidinediones; AGI, -glucosidase inhibitor; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1
Changes in body weightChanges in body weight
Risk of weight gain with glucose-lowering Risk of weight gain with glucose-lowering drugsdrugs
Changes in body weightChanges in body weight
Blood pressure reduction with glucose-Blood pressure reduction with glucose-lowering drugslowering drugs
Effect on other CVRFEffect on other CVRF
Different impact of rosiglitazone and Different impact of rosiglitazone and pioglitazone in CV riskpioglitazone in CV risk
Erdmann E et al. Curr Cardiology Rev 2009;5:155-165Specific molecule effectSpecific molecule effect
Different impact of rosiglitazone and Different impact of rosiglitazone and pioglitazone in lipid profilepioglitazone in lipid profile
TZDs vs placeboTZDs vs placebo PioglitazonePioglitazone RosiglitazoneRosiglitazone
Total cholesterolTotal cholesterol NeutralNeutral RaisedRaised
LDLLDL NeutralNeutral RaisedRaised
HDLHDL RaisedRaised RaisedRaised
TriglyceridesTriglycerides ReducedReduced NeutralNeutral
HbA1cHbA1c ↓ ↓ 1–1.5%1–1.5% ↓ ↓ 1–1.5%1–1.5%
Aljada et al. PPAR Research 2009Specific molecule effectSpecific molecule effect
Different impact of rosiglitazone and Different impact of rosiglitazone and pioglitazone in gene expressionpioglitazone in gene expression
Erdmann E et al. Curr Cardiology Rev 2009;5:155-165Specific molecule effectSpecific molecule effect
Sitagliptine (DDP-4 inhibitor) improves endothelial Sitagliptine (DDP-4 inhibitor) improves endothelial function and reduce atherosclerosisfunction and reduce atherosclerosis
Matsubara J et al. J Am Coll Cardiol 2012;59:265–76
Lireglutide (GLP-1) reduces vascular Lireglutide (GLP-1) reduces vascular inflammatory markersinflammatory markers
Forst T et al. Diabetic Med 2012
Gliptins and CV risk factors in type 2 diabetes.
Ussher JR and Drucker DJ. Endocrine Reviews 2012; 33: 187-215.
Ongoing trials of CV outcomes with several classic and new glucose-lowering drugs
Trial Investigational vs comparator
ORIGIN Insulin glargine
ACE Acarbose vs placebo
TOSCA-IT Thiazolinedinediones vs SU
TECOS Sitagliptin vs placebo
SAVOR-TIMI 53 Saxagliptin vs placebo
CAROLINA Linagliptin vs glimepiride
EXAMINE Alogliptina vs placebo
CANVAS Canagliflozin vs placebo
Ongoing trials of CV outcomes with several classic and new glucose-lowering drugs
Trial Investigational vs comparator
EXSCEL Exenatide vs placebo
LEADER Liraglutide vs placebo
ELIXA Lixasenatide vs placebo
REWIND Dulaglutide vs placebo
To take homeTo take home
● Diabetes is a high CV risk conditionDiabetes is a high CV risk condition
● Hypoglycemia and side effects of the glucose-Hypoglycemia and side effects of the glucose-lowering drugs can blunt the CV risk reductionlowering drugs can blunt the CV risk reduction
● HbA1c should be tailored to the individual HbA1c should be tailored to the individual patientpatient
● New molecular targets expand potential CV and New molecular targets expand potential CV and renal protectionrenal protection
● The potential impact of new glucose-lowering The potential impact of new glucose-lowering agents in CV risk should be explored in the agents in CV risk should be explored in the forthcoming studiesforthcoming studies