Transcript hypoglycaemia in the elderly - pace

Cardio Diabetes Master Class
Asian chapter
January 28-30 2011, Shanghai
Presentation topic
TZD’s in the management of diabetes & CV
disease: All about benefits and safety
Slide lecture prepared and held by:
Prof. John Betteridge, MD
University College London
London, United Kingdom
P H Y S I C IAN S ’ A CAD E M Y F O R CAR D I O VAS C U LAR E D U CAT I O N
Diabetes and Cardiovascular
Disease: Time To Act!
“With the rising tide of diabetes around the globe, the double jeopardy of
diabetes and cardiovascular disease is set to result in an explosion of
these and other complications- unless preventive action is taken.”
Prof Sir George Alberti, IDF President.
International Diabetes Federation
Glucose Toxicity
Retinopathy
Nephropathy
CH2OH
H
O
H
OH
H
OH
-cell
H
Neuropathy
OH
H
OH
damage
Hepatic and skeletal muscle
insulin resistance
Cardiovascular
disease
UKPDS:
Microvascular Complications, MI, and HbA1c
• Incidence rates by
updated HbA1c
• Adjusted for age, sex,
and ethnic group
• Expressed for white
men,
50–54 years old at
diagnosis; mean
diabetes duration 10
years
Adjusted incidence per
1000 patient years (%)
80
MI
Microvascular endpoints
60
40
20
0
5
6
7
8
9
10
Updated mean HbA1c
concentration (%)
Adapted from Stratton IM et al BMJ 2000;321:405-412.
11
UKPDS:
Endpoints by Glucose Treatment Group
Cause
Any diabetes-related*
MI
Stroke
PVD†
Microvascular
Intensive
rate/1000
patient-years
Conventional
rate/1000
patient-years
40.9
14.717.4
5.6
1.1
8.6
46.0
0.052
5.0
1.60
11.4
P
0.029
16
0.52
0.15
0.0099
% risk
reduction
12
–
–
25
*Combined microvascular and macrovascular events.
†Amputation or death from PVD.
.
UKPDS Group. Lancet 1998;352:837-53
Haemoglobin A1c: Cardiovascular Disease and
Mortality -The EPIC Study
• Design: Prospective population
study. 4662 men and 5570
8
women aged 45-79yrs, Norfolk
England
7
• Analysis: HbA1c and CVD risk
6
factors assessed 1995-1997.
CVD events and mortality
5
assessed during follow-up periodRR
to 2003
4
• Events: 806 CVD,
3
521 deaths
Age Adjusted RR by HbA1c
CHD CVD Death
MEN
2
1
0
5-
5.5-
6-
6.5-
5.4%
5.9%
6.4%
6.9
>7%
Khaw et al Ann Intern Med 2004; 141: 413
Known
DM
Conclusions:
RCTs of intensive versus standard glycaemic therapy have not shown a
significant reduction in CVD outcomes during the randomized period of the
trials.
NB Long-term follow-up of DCCT and UKPDS suggests that HbA1c around 7%
in years soon after diagnosis is associated with long-term risk reduction.
Less stringent HbA1c goals may be appropriate for patients with history of
severe hypoglycaemia, advanced CVD complications or extensive co-morbid
conditions or those with long-standing diabetes in whom the general goal is
difficult to maintain.
Evidence-based recommendations should be followed for blood pressure
management, statins smoking cessation, aspirin and healthy lifestyles
Skyler et al Diabetes Care 2009, 33: 187
Patho-physiology of Type 2 diabetes
Site of Action of Available Drugs
Decreased incretin
effect
Decreased glucose uptake
•GLP1-agonists
•DPP4-inhibitors
Increased lipolysis
•TZDs
•TZDs
•Metformin
Increased HGP
Hyperglycemia
•GLP1-agonists
•DPP4-inhibitors
•TZDs
•Metformin
Increased
glucagon
secretion
•GLP1-agonists
•DPP4-inhibitors
•Sulfonylureas
Decreased insulin
secretion
β and -cell dysfunction
Free Fatty Acids:
Insulin Resistance, IGT and Type 2 NIDDM
 Lipolysis
Muscle
 FFA mobilization
 FFA oxidation
 FFA oxidation
 Glucose utilization
Liver
Adiponectin
 Gluconeogenesis
Insulin 
Hyperglycaemia,Hyperinsulinaemia,IGT and Diabetes
Pioglitazone 30-45 mg/d Reduces Plasma Glucose,
Insulin and FFA and Increase Adiponectin in Diabetes
150
40
Insulin
( µU/mL )
Glucose
(mg/dL )
200
P=0.035
100
50
0.6
0.5
0.4
0.3
0.2
0.1
0.0
30
20
10
0
P=0.035
Adiponectin
( µg/mL )
FAs
( mEq/L)
0
P=0.08
25
20
15
10
5
0
P=0.0004
NAGASHIMA K et al. J Clin Invest 115:1323, 2005
Time to Primary Composite Endpoint*
Kaplan-Meier event rate
0.25
N events:
placebo
0.20
3-year estimate:
572 / 2633
23.5%
pioglitazone 514 / 2605
21.0%
0.15
0.10
Risk reduction : 10
HR
95% CI
p value
%
0.05
pioglitazone
vs placebo
0.0
N at Risk: 5238
0
5018
6
4786
4619
0.904 0.802, 1.018
4433
12
18
24
Time
from randomisation
(months)
4268
30
0.0951
693 (228)
36
*Death, non-fatal myocardial infarction (including silent MI), stroke, major leg amputation, acute
coronary syndrome, coronary or leg revascularisation
PROactive Total Events
Death
Non-fatal MI
ACS
Stroke
PCI/CABG
Major leg amputation
Leg revascularisation
Pioglitazone
177
131
65
92
195
28
115
803
Placebo
186
157
78
119
240
28
92
900
Time to : Death, MI ( excluding silent ) or Stroke
Secondary composite endpoint
0.15
N events:
placebo
3-year estimate:
358 / 2633
14.4%
pioglitazone 301 / 2605
12.3%
0.10
0.05
Risk reduction : 16
HR
95% CI
p value
%
pioglitazone
vs placebo
0.0
N at Risk: 5238
0
5102
6
4991
4877
0.841 0.722, 0.981
4752
12
18
24
Time
from randomisation
(months)
4651
30
0.0273
786 (256)
36
In high-risk patients with type 2 diabetes
and previous MI, pioglitazone significantly
reduced the occurrence of recurrent fatal
and nonfatal MI and ACS
Time to Fatal/Non-fatal MI
Patients with
previous MI
n=2445
Kaplan-Meier event rate
0.10
pioglitazone (65 / 1230)
placebo
(88 / 1215)
0.08
0.06
0.04
Risk reduction : 28
% HR 95% CI p value
0.02
pioglitazone vs
placebo
0.0
N at Risk: 2445
0
0.72
2387
2337
2293
2245
2199
6
12
18
24
30
0.52,
0.99
399 (139)
36
Time from Randomization (months)
0.045
In high-risk patients with type 2 diabetes
and previous stroke, pioglitazone
significantly reduced the occurrence of
recurrent fatal and nonfatal stroke.
Stroke, 2007;38:865-873
Time to Fatal or Non-Fatal Stroke in Patients
with Previous Stroke
Patients with previous
Stroke
n=984
Kaplan-Meier event rate
0.12
0.10
pioglitazone
(27 / 486)
placebo
(51 / 498)
0.08
0.06
0.04
Risk reduction : 47 %
0.02
pioglitazone vs placebo
0.00
N at Risk:
984
952
0
6
926
12
903
18
877
24
HR
95% CI
p value
0.53
0.34, 0.85
0.008
849
30
Time from Randomization (months)
132
36
Hazard Ratios for Cardiovascular
Events with Glitazones
Rosiglitazone
Metaanalysis Nissen et al.1
Myocardial Infarction (OR)
Metaanalysis Nissen et al.1
Cardiovascular Death (OR)
Metaanalysis Krall2
Myocardial Infarction (OR)
Metaanalysis FDA3
Myocardial Ischemia (OR)
Metaanalysis GSK4
Myocardial Ischemia (HR)
Data from Nissen + RECORD5
Myocardial Infarction (OR)
1.43
1.64
1.4
1.31
1.24
1.07
Cardiovascular Death´(OR)
Metaanalysis Singh6
1.42
Myocardial Infarction (HR)
Pioglitazone
0.90
PROactive7
Primary Endpoint (HR)
PROactive7
MI, Stroke and Death (HR)
PROactive MI-Subgroup8
Myocardial Infarction (HR)
Metaanalysis Lincoff et al9
MI, Stroke and Death (HR)
0.84
0.72
0.82
1
2
Hazard Ratio/Odds Ratio
Glitazones better
Glitazones worse
0
ç
1Nissen
SE and Wolski K. NEJM 2007; 356:2457-2471; 2Krall RL. Lancet 2007; 369:1995-1996; 3FDA-Homepage www.fda.gov;
CHICAGO:
Glycaemic Control Change in HbA1c
0.2
‡
A1C
change
from
baseline
(least
square
means,
%)
*
0
†
-0.2
-0.4
-0.6
Baseline
16
Glimepiride
24
32
40
Week
Pioglitazone
48
60
72
*P = 0.04; †P = 0.01; ‡P = 0.002 (treatment-group difference)
Mazzone T et al. JAMA. 2006.
CHICAGO:
Treatment effect on posterior wall mean CIMT
0.016
0.012
Mean
change
from
baseline
(least
squares,
mm)
0.008
P = 0.02
0.004
0
-0.004
-0.008
-0.012
Baseline
Glimepiride
Week 24
Week 48
Week 72
Pioglitazone
CIMT = carotid intima-media thickness
Mazzone T et al. JAMA. 2006.
Objective:
Will pioglitazone stabilize carotid artery vulnerable plaque in patients with
acute coronary syndromes (ACS) and type 2 diabetes.
Population:
61 patients with type 2 diabetes, age 63yrs, approx 70% male and echo lucent
carotid plaques within 5 days of ACS. Random allocation to
pioglitazone 15-30mg/day or matching placebo.
Methods:
Vulnerable carotid plaques were assessed by measuring plaque echolucency
using carotid ultrasound with integrated back scatter (IBS)
An increase in IBS reflects an increase in plaque echogenicity.
Echolucent plaques with low IBS represent identify lipid and macrophage-rich lesions,
unstable plaques
PROactive
Metabolic Effects of Pioglitazone
HbA1c
- 0.5%
HDL-cholesterol
+ 8.9%
LDL-cholesterol
Triglycerides
Systolic BP
Weight
+ 2.3%
- 13.2
- 3 mmHg
+ 4 kg
Change in LDL cholesterol, Particle size,
Apoprotein B and Particle Concentration
23.3
Pioglitazone
Rosiglitazone
15.7*
12.0
2.4** 1.7
11.5
1.5*
n= n=
363 356
*p<0.001 and **p=0.005
between treatment groups
n= n=
333 325
n=
333
n=
325
Apo B
concentration
LDL particle
size
-7.8*
LDL particle
25
20
15
10
5
0
-5
-10
LDL-C
Change
from baseline
at week 24
(%)
n=
346
n=
334
Goldberg et al. Diabetes Care 2005; 28: 1547-1554
Goldberg et al. Circulation 2005; 111: 1727–1728
CHF
CHF
Death
Lancet, 2007; 370: 1129-1136
P=0.007
More pioglitazone (5.7%)
than placebo patients
(4.1%) had episode of
serious heart failure,
(requiring hospitalization
or life threatening) but
there was no difference in
mortality p=0.639
Erdmann et al Diabetes Care 30:2773–2778, 2007
The Development of Heart failure on Pioglitazone in
PROactive did not affect subsequent prognosis
Placebo
Pioglitazone
Kaplan Meier estimates of time from serious heart failure to allcause mortality
Erdmann et al Diabetes Care 30:2773–2778, 2007
Whole body glucose disposal and Myocardial
glucose utilization during hyperinsulinaemic clamp
FDG uptake using Positron Emission Tomography
Whole body
glucose disposal
p<0.05
between treatment
differences
Myocardial glucose
utilization
JACC, 2007; 50: 2051
Hyperaemic Myocardial Blood Flow
Before and After Pioglitazone
p<0.05
between
treatment
differences
JACC, 2007; 50: 2051
•
•
Setting:
UK general practice research dta
Objective:
To investigate risk of incident MI, congestive heart failure and all cause mortality
associated with prescription of oral anti diabetes drugs
Design:
Retrospective cohort study
Setting:
UK general practice research data base 1990-2005
Participants:
91521 people with diabetes
Methods:
Person time intervals for drug treatment were categorised by drug class
excluding non-drug intervals and intervals for insulin
3588 MIs, 6900 CCF, 18548 deaths