Antidiabetic medications
and heart disease
26th April 2014, Kuwait
Prof. Dr. Oliver Schnell
Diabetes Research Group e.V.
at the Helmholtz Center Munich,
Germany
Diabetes = CAD risk equivalent
Schramm TK et al., Circulation, 2008; 117: 1945
Diabetes mellitus, fasting glucose,
and risk of cause-specific death
Estimated future years of life lost owing to diabetes
The Emerging Risk Factors Collaboration. NEJM 2011; 364: 829-841
Diabetes mellitus, fasting glucose,
and risk of cause-specific death
HR for major causes of death, according to baseline levels of fasting glucose
The Emerging Risk Factors Collaboration. NEJM 364 (2011) 829-841
25%
D
Hospital Mortality
p=0.027
ND
20%
p=0.01
15%
16%
14%
11%
12%
10%
10%
5%
5%
4%
4%
0%
1999
< 24h
2001
1999
2001
 24h
Schnell O et al., Diabetes Care 2004 27: 455-460
The Munich Myocardial Infarction
Registry: Reduction of hospital mortality in
patients with acute myocardial infarction
Diabetes and diffuse CHD
Right coronary artery
•
Female, 58 years
•
HbA1c: 8.4 %
•
Duration of diabetes: 15 years
•
Acute myocardial infarction (MI)
•
Angiogram: diffuse coronary
artery disease
Left coronary artery
The Munich Myocardial Infarction Registry:
CRP-levels and mortality in diabetic
and non-diabetic patients
40%
35%
**
* 25%
*
*
19%
Mortality
30%
*
25%
21%
20%
16%
15%
10%
**
*
28%
**
35%
**
22%
ND
14%
11%
7% 8% 7%
9%
8%
3%
5%
0%
1st
2nd
3rd
4th
5th
CRP quintiles
P for trend vs. lowest quintile:
* P < 0,05, ** P < 0,01, *** P < 0,001
All
D
Otter W, Winter M, Doering W, Standl E, Schnell O
Diabetes Care 2007; 30: 3080 - 3082
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.)
b.)
Doerr R et al. Diabetologia. 2011; 54:2923-30
Hospital mortality and stroke:
Diabetic patients vs. non-diabetic patients
All patients
Diabetic patients
Non-diabetic patients
Total mortality
Mortality ≤ 24 h
Braun K, Otter W, Sandor S, Standl E, Schnell O. Diab Res Clin Pract 98 (2012): 164-168
Increase in postprandial blood glucose precedes
preprandial blood glucose elevation
Breakfast
postprandial
Glucose mmol/l
preprandial
Morning
Duration
of diabetes
HbA1c: blue < 6,5 %, red 6,5 – 7 %, green 7,1 – 8 %, orange 8,1 – 9%,
brown 9,1 % and higher
Monnier L et al, Diabetes Care 2007 (30) 263-269
NAVIGATOR: No effect of nateglinide
on prevention of diabetes nor CV outcomes
The NAVIGATOR Study Group, NEJM 2010, published online on March 14
# at Risk
1
2
3
4
5
6
7
G
6264
6057
5850
5619
5379
5151
3611
766
SC 6273
6043
5847
5632
5415
5156
3639
800
0.3
N Engl J Med 2012; 367:319-328
0.2
Adj. HR 1.02 (0.94, 1.11)
Log Rank P = 0.63
Glargine
0.1
Standard Care
0.0
Proportion with events
0.4
0.5
1st Co-primary
MI, Stroke,
orDeath
CV MIDeath
Timeendpoint:
to Adjudicated Primary
Outcome 1 - CV
Stroke
0
1
2
3
4
Years of Follow-up
5
6
7
Multifactorial intervention
in type 2 diabetes: The Steno 2 study
Composite endpoint
CV-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
Evidence of benefit for
• Patients without preexisting cardiovascular events
• Patients with baseline HbA1c<8%
The Action to Control Cardiovascular Risk in Diabetes Study Group,
N Engl J Med 2008;358:2545–59
Severe Hypoglycemic episodes
in ACCORD, VADT, ADVANCE
ACCORD
VADT
ADVANCE
p<0.001
p< 0.01
p<0.001
Mortality and blood glucose
in patients with ST elevation MI
12
Mortality (%)
10
8
6
4
2
0
<81
(n=62)
81 - 99 100 - 125 126 - 150 151 - 199
(n=123)
(n=280)
(n=186)
(n=200)
>199
(n=196)
Glucose levels (mg/dl)
Pinto DS, et al. J Am Coll Cardiol 2005;461:178-80.
Effect of experimental hypoglycaemia
on QT interval
A
5.0 mM
QTc 456 ms
HR 66 bpm
B
2.5 mM
QTc 610 ms
HR 61 bpm
QTc, corrected QT interval from baseline; HR, heart rate
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
Metabolic and cardiovascular effects of GLP-1
Metabolic effects
GLP-1 receptordependent
Cardiovascular
effects
T1/2= 1-2 min
GLP-1
receptorindependent
Cardiovascular
effects
after Drucker DJ. Gastroenterology 2007; 132:2131-2167
GLP-1 Receptors are Present in
Cardiovascular Tissues
Cardiomyocytes
Microvascular endothelium;
Coronary smooth muscle
Endocardium
Mesenteric artery
(medial smooth muscle cells)
Ban et al; Circulation 2008
GLP-1-Receptor; green
Vascular/cardiac smooth muscle; red
Nuclei: blue
Infarct size is reduced with liraglutide
at 28 days post MI in mice
Infarct
Infarct
*p<0.05 vs. placebo
Infarct size
(%)
30
*
20
10
0
Placebo
Liraglutide
Noyan-Ashraf et al. Circulation 2007;116(Suppl)
Initial Combination Therapy With Sitagliptin Plus Metformin
Provided Sustained HbA1c Reductions Through 104 Weeks1
LS Mean HbA1c Change From Baseline, %
APT Population (Extension Study)
Sitagliptin 100 mg qd (n=50)
Sitagliptin 50 mg bid + metformin 500 mg bid (n=96)
Metformin 500 mg bid (n=64)
Metformin 1000 mg bid (n=87)
Sitagliptin 50 mg bid + metformin 1000 mg bid (n=105)
9.0
24-Week
Phase
8.5
Continuation
Phase
Extension
Study
Mean baseline HbA1c = 8.5%–8.7%
8.0
–1.1
7.5
–1.2
7.0
–1.3
–1.4
6.5
–1.7
6.0
0
6 12 18 24 30
38
46
54
Weeks
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.
62
70
78
91
104
Sitagliptin vs Glipizide: Weight Change
and Incidence of Hypoglycemia1
Body weight at week 104
Hypoglycemia over 104 weeks
Between-groups difference = –2.3 kg
(95% CI: –3.0, –1.6)
Between-groups difference = –28.8%
(95% CI: –33.0, –24.5)
2,0
0,7
40
1,5
1,0
0,5
n=253
0,0
–0,5
–1,0
–1,5
–2,0
–2,5
n=261
Patients With
at Least 1 Episode, %
LS Mean (±95% CI) Body Weight
Change From Baseline, kg
APaT Population
(Patients Inadequately Controlled on Metformin)
Sitagliptin + metformin
–1.6
34,1
30
20
10
5,3
n=588
n=584
0
Glipizide + metformin
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.
All Patients
Sitagliptin vs Glipizide in Patients With T2DM
and End-Stage Renal Disease on Dialysis: HbA1c 54 Weeks1
FAS/LOCF Population
Baseline HbA1c; sitagliptin = 7.89%; glipizide = 7.77%
Change From Baseline, %
0.0
−0.1
−0.2
−0.3
−0.4
−0.5
−0.6
Δ (95% CI)
Δ = 0.15%
(−0.18, 0.49)
−0.7
−0.8
−0.9
−1.0
0
6
12
18
24
30
36
42
Week
Sitagliptin
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.
Glipizidea
48
54
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
25 mg once daily
Sitagliptin may be administered without regard to the timing of hemodialysis
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 04/2012
http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf
TECOS: Summary of Study Design1
Patients aged ≥50 years with
T2DM, pre-existing CVD, and:
HbA1c 6.5%–8.0%
(48–64 mmol/mol) and dosestable for ≥3 months on:
– Metformin, pioglitazone, or
sulfonylurea as
monotherapy or any dual
combination therapya
OR
– Insulin alone or in
combination with
metformin
Sitagliptinb
R
Placebo
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 1
Randomization
V2
(Day 1)
M4
aMinimum
V3
M8
AV
M12
T
M15
T
M21
Brief Visit
M18
AV
M24
T
M27
T
M33
Brief Visit
M30
AV
M36
T
M39
T
M45
Brief Visit
M42
End of
Study
AV Visit
M48
of 2,000 patients on metformin monotherapy.
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.
bIf
1. Green JB et al. Am Heart J. 2013;166:983–989.e7.
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
Take home messages
• 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