1

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