Antidiabetic medications and heart disease

26th April 2014, Kuwait

Prof. Dr. Oliver Schnell

Diabetes Research Group e.V.at the Helmholtz Center Munich,

Germany

Schramm TK et al., Circulation, 2008; 117: 1945

Diabetes = CAD risk equivalent

Estimated future years of life lost owing to diabetes

Diabetes mellitus, fasting glucose, and risk of cause-specific death

The Emerging Risk Factors Collaboration. NEJM 2011; 364: 829-841

HR for major causes of death, according to baseline levels of fasting glucose

The Emerging Risk Factors Collaboration. NEJM 364 (2011) 829-841

Diabetes mellitus, fasting glucose, and risk of cause-specific death

14%

4%

16%

12%

4%

10%

5%

11%

0%

5%

10%

15%

20%

25%

1999 2001 1999 2001

Ho

sp

ita

l Mo

rta

lity

D

ND

< 24h 24h

p=0.027

p=0.01

The Munich Myocardial Infarction Registry: Reduction of hospital mortality in patients with acute myocardial infarction

Sch

nell

O e

t al

., D

iabe

tes

Car

e 2

004

27:

455-

460

Diabetes and diffuse CHD

• Female, 58 years

• HbA1c: 8.4 %

• Duration of diabetes: 15 years

• Acute myocardial infarction (MI)

• Angiogram: diffuse coronary artery disease

Left coronary arteryRight coronary artery

8%

21%

16%

25%

35%

28%

19%

11%9%

7%

22%

14%

8%

3%

7%

0%

5%

10%

15%

20%

25%

30%

35%

40%

1st 2nd 3rd 4th 5th

CRP quintiles

Mo

rta

lity

All

D

ND

The Munich Myocardial Infarction Registry:CRP-levels and mortality in diabetic

and non-diabetic patients

Otter W, Winter M, Doering W, Standl E, Schnell ODiabetes Care 2007; 30: 3080 - 3082

* *** ** **

***

**

P for trend vs. lowest quintile: * P < 0,05, ** P < 0,01, *** P < 0,001

Impact of diabetes, C-reactive protein and kidney function on hospital mortality in acute myocardial infarction

Schnell O et al, Diab Vasc Dis Res 2010; 7: 225-230

The Silent Diabetes Study Extent of CAD as detected by (a) OGTT Patients without known diagnosis of DM

undergoing coronary angiography in relation to severity and (b) HbA1c

a.)a.)

b.)b.)

Doerr R et al. Diabetologia. 2011; 54:2923-30

Hospital mortality and stroke:Diabetic patients vs. non-diabetic patients

Braun K, Otter W, Sandor S, Standl E, Schnell O. Diab Res Clin Pract 98 (2012): 164-168Braun K, Otter W, Sandor S, Standl E, Schnell O. Diab Res Clin Pract 98 (2012): 164-168

All patients

Diabetic patients

Non-diabetic patients

Total mortality Mortality ≤ 24 h

Increase in postprandial blood glucose precedes preprandial blood glucose elevation

Monnier L et al, Diabetes Care 2007 (30) 263-269

HbA1c: blue < 6,5 %, red 6,5 – 7 %, green 7,1 – 8 %, orange 8,1 – 9%, brown 9,1 % and higher

Breakfast

Duration of diabetes

Glu

cose

mm

ol/l

preprandial postprandial

Morning

NAVIGATOR: No effect of nateglinide on prevention of diabetes nor CV outcomes

The NAVIGATOR Study Group, NEJM 2010, published online on March 14

Years of Follow-up

Pro

po

rtio

n w

ith e

ven

ts

0.0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 7

Glargine

Standard Care

# at Risk 1 2 3 4 5 6 7

G

SC

6264 6057 5850 5619 5379 5151 3611 766

6273 6043 5847 5632 5415 5156 3639 800

Time to Adjudicated Primary Outcome 1 - CV Death MI Stroke

Adj. HR 1.02 (0.94, 1.11)Log Rank P = 0.63

1st Co-primary endpoint: MI, Stroke, or CV Death

N E

ngl J

Med

201

2; 3

67:3

19-3

28N

Eng

l J M

ed 2

012;

367

:319

-328

Multifactorial intervention in type 2 diabetes: The Steno 2 study

Composite endpointCV-death, MI or stroke, CABG or PCI, limb amputation or vascular surgery

Gaede et al N Engl J Med 2008;358:580-91

Steno 2 Study – 13 year follow up: negative trends in weight management may have challenged the benefits of blood glucose lowering therapy

Gaede et al N Engl J Med 2008;358:580-91

ACCORD: Primary Endpoints Subgroups

The Action to Control Cardiovascular Risk in Diabetes Study Group, N Engl J Med 2008;358:2545–59

Evidence of benefit for • Patients without preexisting cardiovascular events• Patients with baseline HbA1c<8%

ACCORDACCORDACCORDACCORD VADTVADTVADTVADT ADVANCEADVANCEADVANCEADVANCE

p< 0.01 p<0.001p<0.001

Severe Hypoglycemic episodes in ACCORD, VADT, ADVANCE

0

2

4

6

8

10

12

Mor

talit

y (%

)

<81 81 - 99 100 - 125 126 - 150 151 - 199 >199

(n=62) (n=123) (n=280) (n=186) (n=200) (n=196)

Glucose levels (mg/dl)

Pinto DS, et al. J Am Coll Cardiol 2005;461:178-80.

Mortality and blood glucose in patients with ST elevation MI

Effect of experimental hypoglycaemia on QT interval

5.0 mM 2.5 mM

QTc, corrected QT interval from baseline; HR, heart rate

QTc 610 msHR 61 bpm

QTc 456 msHR 66 bpm

A B

Marques et al. Diabet Med 1997;14:648–54

ADA / EASD position statement:Approach to management of hyperglycemia

Inzucchi SE et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).

Diabetologia DOI 10.1007/s00125-012-2534-0

after Drucker DJ. Gastroenterology 2007; 132:2131-2167

T1/2= 1-2 min

GLP-1 receptor-dependent

Metabolic effects

Metabolic and cardiovascular effects of GLP-1

Cardiovascular effects

GLP-1 receptor-

independent

Cardiovascular effects

GLP-1 Receptors are Present in Cardiovascular Tissues

Ban et al; Circulation 2008

GLP-1-Receptor; greenVascular/cardiac smooth muscle; redNuclei: blue

Mesenteric artery(medial smooth muscle cells)

Microvascular endothelium; Coronary smooth muscle

Cardiomyocytes

Endocardium

Infarct size is reduced with liraglutide at 28 days post MI in mice

*p<0.05 vs. placebo

Liraglutide

Infa

rct

size

(%

)

*

0

10

20

30

Placebo

Infarct

Noyan-Ashraf et al. Circulation 2007;116(Suppl)

Infarct

Initial Combination Therapy With Sitagliptin Plus Metformin Provided Sustained HbA1c Reductions Through 104 Weeks1

APT=all-patients-treated; bid=twice daily; LS=least-squares; qd=once daily. 1. Williams-Herman D et al. Diabetes Obes Metab. 2010;12(5):442–451.

Sitagliptin 100 mg qd (n=50)Metformin 500 mg bid (n=64) Sitagliptin 50 mg bid + metformin 1000 mg bid (n=105)Metformin 1000 mg bid (n=87)

Sitagliptin 50 mg bid + metformin 500 mg bid (n=96)

ExtensionStudy

24-WeekPhase

ContinuationPhase

LS

Mea

n H

bA

1c C

han

ge

Fro

m B

asel

ine,

%

–1.2

–1.1

–1.3

–1.4

–1.7

Mean baseline HbA1c = 8.5%–8.7%

0 6 12 18 24 30 38 46 54 62 70 78 91 1046.0

6.5

7.0

7.5

8.0

8.5

9.0

Weeks

APT Population (Extension Study)

Sitagliptin vs Glipizide: Weight Change and Incidence of Hypoglycemia1

Pat

ien

ts W

ith

at

Lea

st 1

Ep

iso

de

, %

APaT Population(Patients Inadequately Controlled on Metformin)

Sitagliptin + metformin

Glipizide + metformin

5,3

34,1

0

10

20

30

40

All Patients

Between-groups difference = –28.8% (95% CI: –33.0, –24.5)

n=588 n=584

APaT=all-patients-as-treated; CI=confidence interval; LS=least-squares. 1. Seck T et al. Int J Clin Pract. 2010;64(5):562–576.

LS

Mea

n (

±95%

CI)

Bo

dy

We

igh

t C

han

ge

Fro

m B

asel

ine,

kg

Between-groups difference = –2.3 kg(95% CI: –3.0, –1.6)

Hypoglycemia over 104 weeksBody weight at week 104

n=253 n=261

–1.6

0,7

–2,5

–2,0

–1,5

–1,0

–0,5

0,0

0,5

1,0

1,5

2,0

Sitagliptin vs Glipizide in Patients With T2DM

and End-Stage Renal Disease on Dialysis: HbA1c 54 Weeks1

CI=confidence interval; FAS=full analysis set; LOCF=last observation carried forward.aMean dose of glipizide was 5.3 mg per day.1. Data on file, MSD.

FAS/LOCF Population

0.0

−0.1

−0.2

−0.3

−0.4

−0.5

−0.6

−0.7

−0.8

−0.9

−1.00 6 12

Sitagliptin Glipizidea

18 24

Week

Cha

nge

From

Bas

elin

e, %

30 36 42 48 54

Δ = 0.15% (−0.18, 0.49)

Δ (95% CI)

Baseline HbA1c; sitagliptin = 7.89%; glipizide = 7.77%

Dosage of sitagliptin in patients with renal impairment

Mild renal insufficiency (CrCl ≥50 mL/min) No dosage adjustment required

Moderate renal insufficiency (CrCl ≥30 to <50 mL/min) 50 mg once daily

Severe renal insufficiency (CrCl <30 mL/min), end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis Sitagliptin may be administered without regard to the timing of hemodialysis

25 mg once daily

Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of sitagliptin treatment and periodically thereafter

JANUVIA Prescribing information; revised 04/2012http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf JANUVIA Prescribing information; revised 04/2012http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf

aMinimum of 2,000 patients on metformin monotherapy.bIf eGFR is ≥50 mL/min/1.73 m2, dose of sitagliptin = 100 mg/d; if eGFR is 30 to <50 mL/min/1.73 m2, dose of sitagliptin = 50 mg/d; if eGFR is <30 mL/min/1.73 m2 during the study, dose reduced to 25 mg/d. TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; T2DM = type 2 diabetes mellitus; CVD = cardiovascular disease; R = randomization; AHA = antihyperglycemic agent; HbA1c = hemoglobin A1C; ADA = American Diabetes Association; V = visit; M = month;T = telephone contact (study participants will also see their usual-care physician regularly); AV = annual visit; eGFR = estimated glomerular filtration rate. 1. Green JB et al. Am Heart J. 2013;166:983–989.e7.

R

Patients aged ≥50 years with T2DM, pre-existing CVD, and:HbA1c 6.5%–8.0% (48–64 mmol/mol) and dose-stable for ≥3 months on:

– Metformin, pioglitazone, or sulfonylurea as monotherapy or any dual combination therapya

OR– Insulin alone or in

combination with metformin

Sitagliptinb

Placebo

V2M4

V3M8 Brief Visit

M18Brief Visit

M30Brief Visit

M42

TM15

TM21

TM27

TM33

TM39

TM45

Additional oral AHA agents or insulin added according to usual care to target HbA1c goals according to current guidelines (eg, ADA)

Continue metformin and/or pioglitazone and/or sulfonylurea, and/or insulin

Visit 1Randomization

(Day 1)

End of Study VisitAV

M48AV

M36AV

M24AV

M12

TECOS: Summary of Study Design1

TECOS: Selected Inclusion and Exclusion Criteria1

Inclusion criteria included:• Aged ≥50 years with type 2 diabetes• Documented vascular disease in the coronary, cerebral, or peripheral arteries• Patients with inadequate control (HbA1c of 6.5%–8.0%) for at least 3 months

despite:– Stable-dose monotherapy or dual combination therapy with metformin, pioglitazone,

and/or a sulfonylurea– Stable dose of insulin as monotherapy or in combination with stable dose of metformin

Exclusion criteria included:• Patient has a history of type 1 diabetes mellitus or ketoacidosis• Patient is not able to take sitagliptin• Patient has taken an approved or investigational DPP-4 inhibitor agent, GLP-1

analogue, or a TZD other than pioglitazone within the past 3 months

TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; HbA1c = hemoglobin A1C; DPP-4 = dipeptidyl peptidase; GLP-1 = glucagon-like peptide-1; TZD = thiazolidinedione. 1. Green JB et al. Am Heart J. 2013;166:983–989.e7.

Anti-hyperglycemic therapy in Type 2 Diabetes

Inzucchi SE et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).

Diabetologia DOI 10.1007/s00125-012-2534-0

• Recent guidelines emphasize an individualized treatment approach in type 2 diabetes focussing on pts. with vascular complications

• In diabetic heart disease, treatment strategies, which are not accompanied by hypoglycemia and weight gain are required.

• DPP-4 inhibition with sitagliptin has shown to be associated with– reduction of fasting and postprandial blood glucose– reduction of HbA1c

• As compared to sulfonylureas, sitagliptin provides similar efficacy in reducing HbA1c in patients uncontrolled on metformin, but with no weight gain and fewer reported hypoglycemic episodes

• Sitagliptin has been shown to be efficacious and well tolerated in patients with insulin therapy or renal impairment

• The potential for cardiovascular protection is currently being studied in TECOS

Take home messages