Transcript Glucose Lowering in Diabetes Mellitus

Glucose Lowering in Diabetes Mellitus:
Does it Increase or Decrease
CVD Mortality and/or Events?
Presenters:
Jeff Probstfield, MD—University of Washington
Irl B. Hirsch, MD—University of Washington
Eliot A. Brinton, MD—University of Utah
Paul Rosenblit, MD—University of California, Irvine
Moderator:
Eliot A. Brinton, MD—University of Utah
Glucose Lowering in Diabetes Mellitus: Does it Increase or Decrease
Total Mortality and/or CVD Events?
Jeff Probstfield, MD
Professor of Medicine in the Division of Cardiology
Adjunct Professor of Epidemiology,
Director of the Clinical Trials Division
University of Washington
Seattle, WA
ACCORD Trial Overall Goal
• To determine whether CVD event rates
can be reduced in people with diabetes by
intensively targeting three important CVD
risk factors: hyperglycemia, dyslipidemia,
and high blood pressure.
• Three trials in one research program
–Double 2 by 2 factorial design
Buse, JB, et al, AmJCard 2007 99:21i-33i.
DSMB Recommendation and NHLBI Decision
• NHLBI/NIH decision:
–Discontinue intensive glycemia treatment
–Transition all participants to the standard
glycemia treatment
–No interaction between BP and Lipid Trial
Components and Glycemia Intervention.
–Continue the BP and Lipid trials
• “These trials continue to address important
questions”
(NHLBI Press Release, February 6, 2008)
Glycemia Trial Research Question
• In middle aged/older people with type 2 DM
at high risk for a CVD event, does a
therapeutic strategy that targets an A1C <
6.0% reduce CVD event rates more than a
strategy that targets an A1C between 7.0% &
7.9% (with the expectation of achieving a
median level of 7.5%)?
Buse, JB, et al, AmJCard 2007 99:21i-33i.
Glycemia Trial Rationale
• Observational studies
supportive
– Each 1% higher A1C
associated with 18%
greater risk of CVD1
– CVD-glucose
relationship extends
into the normal range
• Clinical trials
inconclusive2
1. Selvin E, et al. Ann Intern Med. 2004;141:421-431.
2. Goff DC Jr, et al. Am J Cardiol. 2007;99[suppl]:4i-20i.
Study
Mean
A1C
(Intense)
Mean
A1C
(Control)
Relative
Risk
Reduction
for CVD
(95% CI)
UKPDS
(I/SU)
7.0%
7.9%
16% (0,29)
UKPDS (Met)
7.4%
8.0%
39% (11,59)
Kumamoto
7.1%
9.4%
46% (NS)
VACSDM
7.1%
9.3%
-56% (-170,10)
DIGAMI
7.1%
7.9%
29% (4,51)
UGDP(IVAR)
FPG
130-146
mg/dL
FPG
170-186
mg/dL
9% (NS)
Double 2 X 2 Factorial Design
BP
Lipid
Intensive Standard
(SBP<120) (SBP<140)
Intensive
Glycemia
(A1C<6%)
Standard
Glycemia
(A1C 7-7.9%)
Statin +
Statin +
Masked
Masked
Study Drug Study Drug
1178
1193
1383
1374
5128*
1184
1178
1370
1391
5123*
2362*
2371*
2753*
2765*
10,251
*Primary analyses compare the marginals for main effects
Buse, JB, et al, AmJCard 2007 99:21i-33i.
Participant Eligibility
•
•
•
•
•
•
•
•
Stable Type 2 Diabetes for 3+ months
A1C >7.5% AND <9% (more meds) OR <11% (fewer meds)
Age 40-79 + previous CVD events OR
Age 55-79 with:
– anatomical ASCVD, albuminuria, LVH OR
– > 2 CVD risk factors (dyslipidemia, hypertension,
smoking, obesity)
BMI < 45; Cr < 1.5 (133 uM)
No frequent/recent serious hypoglycemia
Able/willing to take insulin, do glucose monitoring
Eligible for BP or Lipid Trial
Buse, JB, et al, AmJCard 2007 99:21i-33i.
ACCORD Outcomes
• Primary:
– First occurrence of nonfatal MI OR Nonfatal Stroke
OR CV Death
• Secondary/Other:
–
–
–
–
–
–
–
–
Each component of 10
Expanded CVD: 10 + Revasc & HF Hosp
Total mortality
Microvascular (nephropathy, neuropathy, eye)
Eye photo substudy (N = 3537)
HRQL (N = 2053); Cost (N = 4311)
MIND: cognition, brain volume (MRI)
Falls/Fractures/BMD
Buse, JB, et al, AmJCard 2007 99:21i-33i.
A1C Distribution
9
8
% of Participants
Standard Rx Goal
Intensive
Rx Goal
7
6
5
4
3
2
1
0
4
5
6
7
8
9
A1c
10
11
12
13
14
A1C Distribution: 48 Mo.
9
8
% of Participants
Standard Rx Goal
Intensive
Rx Goal
7
6
5
4
3
2
1
0
4
5
6
7
8
9
A1c
10
11
12
13
14
December 2007
Median A1C and Interquartile Ranges
ACCORD Study Group, NEJM 2008 358:2545-2549.
All Cause Mortality
1.41%/yr
1.14%/yr
HR = 1.22 (1.01-1.46)
P = 0.04
ACCORD Study Group, NEJM 2008 358:2545-2549.
Primary & Secondary Outcomes
Intensive
N (%)
Standard
N (%)
HR (95% CI)
P
352 (6.86)
371 (7.23)
0.90 (0.78-1.04)
0.16
Mortality
257 (5.01)
203 (3.96)
1.22 (1.01-1.46)
0.04
Nonfatal MI
186 (3.63)
235 (4.59)
0.76 (0.62-0.92) 0.004
Nonfatal Stroke
67 (1.31)
61 (1.19)
1.06 (0.75-1.50)
0.74
CVD Death
135 (2.63)
94 (1.83)
1.35 (1.04-1.76)
0.02
CHF
152 (2.96)
124 (2.42)
1.18 (0.93-1.49)
0.17
Primary
Secondary
ACCORD Study Group, NEJM 2008 358:2545-2549.
Primary & Secondary Outcomes
Intensive
N (%)
Standard
N (%)
HR (95% CI)
P
352 (6.86)
371 (7.23)
0.90 (0.78-1.04)
0.16
Mortality
257 (5.01)
203 (3.96)
1.22 (1.01-1.46)
0.04
Nonfatal MI
186 (3.63)
235 (4.59)
0.76 (0.62-0.92) 0.004
Nonfatal Stroke
67 (1.31)
61 (1.19)
1.06 (0.75-1.50)
0.74
CVD Death
135 (2.63)
94 (1.83)
1.35 (1.04-1.76)
0.02
CHF
152 (2.96)
124 (2.42)
1.18 (0.93-1.49)
0.17
Primary
Secondary
ACCORD Study Group, NEJM 2008 358:2545-2549.
Primary Outcome
2.29%/yr
2.11%/yr
HR = 0.90(0.78-1.04)
P = 0.16
ACCORD Study Group, NEJM 2008 358:2545-2549.
The Question:
Can the observed treatment group
difference in mortality be explained
by the observed postrandomization treatment group
difference in severe
hypoglycemia?
Severe Hypoglycemia Requiring Medical Assistance
Intensive Group Annual Incidence Rate = 3.3%
Standard Group Annual Incidence Rate = 1.0%
ACCORD Study Group, NEJM 2008 358:2545-2549.
Background: Mortality By Severe Hypoglycemia
Overall
Mortality
Rates
Never
Experienced a
Hypoglycemic Event
Experienced
Hypoglycemic Event
1.2% / year
3.3% / year
Intensive
Glycemia
1.3% / year
2.8% / year
Standard
Glycemia
1.1% / year
4.9% / year
Again, mortality is higher among participants who
had experienced a Severe Hypoglycemic Event,
regardless of treatment strategy
ACCORD Study Group, NEJM 2008 358:2545-2549.
Mortality By Treatment Group and
Severe Hypoglycemia
Overall
Intensive
Glycemia
1.4% / year
Standard
Glycemia
1.1% / year
Hazard
Ratio
(257 Deaths)
(203 Deaths)
1.22 (1.01, 1.46)
Never
Experienced a
Hypoglycemic Event
Experienced
Hypoglycemic Event
1.3% / year
2.8% / year
(223 Deaths)
1.1% / year
(186 Deaths)
(34 Deaths)
4.9% / year
(17 Deaths)
1.24 (1.02, 1.50)
0.54 (030, 0.96)
Mortality Higher in
Intensive Group
Mortality Higher in
Standard Group
(95% CI)
Interaction P < 0.01
ACCORD Study Group, NEJM 2008 358:2545-2549.
Conclusions—I
Among participants who never had a severe
hypoglycemic event during follow-up, mortality
was greater in the intensive group.
However, among participants who had a
hypoglycemic event, mortality was greater in
the standard group
Participants who had experienced a severe
hypoglycemic event were more likely to die
• True for both treatment groups
ACCORD Study Group, NEJM 2008 358:2545-2549.
Conclusions—II
• We have not been able to identify a single agent, or
combination, that accounts for the imbalance in mortality.
– Exenatide  less mortality, but used rarely and more often in
Intensive Glycemia group
– Premixed Insulin  greater mortality, but used more often in
Standard Glycemia group
– Bolus Insulin  greater mortality, but no difference in mortality
hazard ratios by randomized group and we don’t know if the
relationship with mortality is a reflection of use or the participants to
whom it was given
– Approximately a 20% increase in mortality associated with
Intensive Glycemia even after controlling for participant
characteristics and post-randomization use of glycemia
medications.
ACCORD Study Group, NEJM 2008 358:2545-2549.
Identifying a “Cause” of the Higher Mortality
• ACCORD identified a previously unknown harm of a strategy
of intensive glucose lowering in high-risk individuals with
T2DM
• ACCORD was designed to test a therapeutic strategy, not
a specific component of the strategy or specific drug(s);
numerous factors differed between the randomized groups
• In a strategy trial, potential causes are difficult, if not
impossible, to separate out from other post-baseline factors
that differ by group
• Example: An ACCORD participant may or may not be on a
drug for various reasons, so we can’t separate out effects of
the drug from effects of patient characteristics that change
over time (some of which were not measured)
ACCORD Study Group, NEJM 2008 358:2545-2549.
Conclusion- what caused the difference ?
I It’s
T The
Strategy (the therapeutic approach to intensive glucose lowering)
S
I In
T This
P Population (with longstanding T2DM and CVD or CVD RFs)
I Intention
T To
analyses (comparing groups based on randomized
T Treat
assignment – the analysis that provides strong evidence of
causality)
ADVANCE Study Review:
Which A1c Targets and Which Drugs for Diabetes?
Irl B. Hirsch, MD
Professor of Medicine
Division of Metabolism, Endocrinology and Nutrition
University of Washington School of Medicine
Seattle, WA
Differences Between ACCORD/ADVANCE
BASELINE
# patients
ACCORD
ADVANCE
10,251
11,140
duration DM (yrs)
10
8
Hx macrovasc. Dz (%)
35
32
Baseline A1C (%)
8.1
7.2
target A1C (%)
<6
<6.5
insulin Rx (%)
77 vs. 55
41 vs. 24
TZD Rx (%)
92 vs. 58
17 vs. 11
Median A1C @ study end
6.4 vs. 7.5%
6.4 vs. 7.0%
DEATH: any cause
5.0 vs. 4.0%*
8.9 vs. 9.6%
Intervention
Outcome (intensive vs. standard)
NEJM 2008;358, 2630
*P<0.05
ADVANCE Primary Outcomes
ADVANCE Collaborative Group, NEJM 2008 358:2560-2572.
ADVANCE Primary Outcomes
ADVANCE Collaborative Group, NEJM 2008 358:2560-2572.
ADVANCE: Primary Outcomes
ADVANCE Collaborative Group, NEJM 2008 358:2560-2572.
ADVANCE: Secondary Endpoints
• All-cause mortality: P = NS
• Total renal events 11% RR with
intensive, P < 0.001
• Eye events: P = NS
• CHF, PVD, neuropathy: P = NS
ADVANCE Collaborative Group, NEJM 2008 358:2560-2572.
Candidate Mechanisms: TGC and CVD Events
– Hypoxia (remember the PDR story!)
– Hypoglycemia (arrhythmias, brain
dysfunction, vasoconstriction, new data
leading to DAN)
– Obesity (3 drugs resulting in weight gain)
– Glucose variability in long-standing
diabetes (insulin deficiency)
Big Picture Messages
• T1 and T2DM: early meticulous glucose
control can prevent microvascular and
neuropathic complications
• T1DM: early meticulous glucose control
appears to prevent CVD many years
later
• T2DM: early meticulous glucose control
appears to prevent both micro- and
macrovascular disease in T2DM
The Benefit of Early Aggressive Glycemic Control
• Metabolic memory
• “Legacy effect”
Big Picture Message
• T2DM: patients with known CVD or long
durations of DM may be harmed by
meticulous control; although the
mechanism(s) for this are not known,
the leading candidate mechanism is
hypoglycemia
More Big Picture Messages
• T1DM: impact of glycemia on microvascular
disease not present after 20-25 years
(probably true for T2DM too)
• After long duration of either T1 or T2DM (or
known CVD), it appears BP, LDL-C and ASA
use better predict CVD mortality than A1C
• Impact of hypoglycemia is not consistent
between populations (under 5 year-olds,
geriatrics, inpatient)
SO WHAT A1C TARGETS?
My Take, At Least While We Are Awaiting ADA/AACE
Consensus Statements on T2DM Targets
• < 10 years T2DM AND no CVD: Target at least
< 7%
– 1st line: metformin
– 2nd line: SFU, sitagliptin, exenatide, basal insulin
(A1C < 9%)
– 3rd line: physiologic insulin therapy
• 10-15 years T2DM AND no CVD:
– No change from above but this population will be
more likely to require insulin to reach A1C target
Possible Strategy
• > 15 years T2DM OR known CVD: 7-7.5%
A1C
– Drugs with less risk of hypoglycemia
• Metformin, SFU unlikely to be effective with longer
durations of DM
• Little data for TZDs, exenatide, sitagliptin
– Greatest risk of hypoglycemia with insulin, but also
greatest likelihood of efficacy to consistent A1C levels
• Less hypoglycemia with basal insulin alone, but
some prandial insulin required as duration of DM
and A1C increases
• Don’t use basal insulin to replace prandial needs!
Conclusion
• The 4 recent studies do not negate the years of research
from other clinical trials
• Different populations appear to have different A1C targets
– It appears the same in the inpatient population!
• It is difficult to recommend a generalization of one drug vs.
another (depending on the situation) as there are so many
variables and little clinical trial data to guide us
– General: hypoglycemia, weight gain, pregnancy, cost
– Specific: GI tolerability, edema, bone fx, increase CVD
risk (?)
Conclusion
• Insulin is always an option, is underutilized, and needs to be used in a
physiologic manner in patients with
severe insulin deficiency
– In patients with known vascular disease,
even more modest A1C targets require the
use of insulin analogues (as opposed to
human insulins) due to the consistent data
showing less hypoglycemia even though
there are no differences in A1C.
Effects of Intensive vs. Standard Glucose Control on
Cardiovascular Disease:
the VA Diabetes Trial (VADT)
Eliot A. Brinton, MD
Diplomate, American Board of Clinical Lipidology
Associate Professor, University of Utah
Director, Metabolism Section of Cardiovascular Genetics
Salt Lake City, UT
VADT: Design
Subject Inclusion:
• DM-2 on insulin or unresponsive to maximal doses
oral agents
• Central A1c > 7.5%, or local A1c > 8.3%
• No major CV events in last 6 months (MI, CVA, CV
surgery)
• Creatinine < 1.6 mg/dL, ALT < 3x ULN
• N=1791 (20 centers)
Prospective, randomized study of:
• Intensive vs. standard glycemic Rx, 5-7.5 years
• Background good diet & lifestyle + Rx BP & lipids
(both arms)
• 1o endpoint: CVD composite
Abraira, C, et al, J Diab. Complic, 2003; 17: 314
VADT: Design (cont’d)
Primary outcome
• Composite of: MI, CVA, CVD Death, CHF, PCI,
CABG, “Inoperable” CAD, LE revascularization or
amputation for ischemia
Secondary outcomes
• Total mortality
• Angina
• TIA
• Claudication
• Critical limb ischemia
• Retinopathy
• Nephropathy
• Neuropathy
• Quality of life
• Cognitive function
• Cost-effectiveness
Abraira, C, et al, J Diab. Complic, 2003; 17: 314
VADT: Baseline Subject Characteristics
(similar in both arms)
•
•
•
•
•
•
Sex: 97% male
Age: 60.4 + 9.5 y
DM Duration: 11.5 + 7.7 y
BMI: 31.3 + 4.6 kg/m2
A1c: 9.4 + 1.5%
Race
–
–
–
–
Non-Hispanic, White: 62%
African-American: 17%
Hispanic: 16%
Other: 5%
• Smoking history
– Current: 17%
– Former: 55%
– Never: 28%
Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
VADT: Glycemic Rx and Results
A1c Goal by Study Arm
Intensive: <7%
Standard: 8-9%
Method (same in both Rx arms):
1. Metformin (BMI>27) or glimepiride (BMI<27)
2. Rosiglitazone
3. Insulin
4. Other oral agents
5. Toolbox: add any other drugs to get to Rx goals
On-study A1c by Study Arm
Intensive: 6.9%
Standard: 8.4%
Abraira, C, et al, J Diab. Complic, 2003; 17: 314
VADT: Primary Endpoint
Treatment
Standard
Intensive
N
Incidence
%
N
Incidence
%
P-value
899
263
29.3
892
231
25.9
0.11
Non-significant trend towards 12% decrease in
CVD (composite) with intensive glycemic control
Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
VADT: Antiplatelet/Anticoagulant,
Statins and Cigarette Use (%)
100
90
80
70
60
50
40
30
20
10
0
Antiplatelet/Anticoagulant
STD
INT
STD
INT
STD
INT
Statins
Ye
ar
6
Ye
ar
5
Ye
ar
4
Ye
ar
3
Ye
ar
2
Ye
ar
1
Ba
se
lin
e
Cigarette Smoking
Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
VADT: On-Study LDL-C (Median/IQR mg/dL)
130
110
STD
INT
90
70
Ye
ar
~30% ↓
in LDL-C
6
Ye
ar
5
Ye
ar
4
Ye
ar
3
Ye
ar
2
Ye
ar
1
B
as
el
in
e
50
Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
VADT: On-Study HDL-C (Median/IQR mg/dL)
50
45
40
STD
INT
35
30
Ye
ar
6
Ye
ar
5
Ye
ar
4
Ye
ar
3
Ye
ar
2
Ye
ar
1
B
as
el
in
e
25
~18% ↑
in HDL-C
Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
VADT: On-Study TG (Median/IQR mg/dL)
260
220
180
STD
INT
140
100
60
e
in
l
e
s
Ba
1
ar
e
Y
2
ar
e
Y
3
ar
e
Y
4
ar
e
Y
5
ar
e
Y
6
ar
e
Y
~21% ↓
in TG
Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
Predictors of Initial 1o Outcome Event
(Treatment by Duration Interaction)
Variable
HR
Lower CI
Upper CI
p-value
Prior CV event
3.30
2.50
3.69
<.0001
Age
HDL
HbA1c
1.33
0.83
1.09
1.19
0.76
1.02
1.49
0.91
1.16
<.0001
<.0001
0.01
Hypoglycemia
DM DurationStd. Rx
DM DurationIntens. Rx
2.07
1.14
3.77
0.02
1.01
0.99
1.02
0.5
1.03
1.02
1.05
<.0001
Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
CVD Hazard Ratio Intensive/Standard Rx
VADT: Intensive Glycemia Rx Beneficial
if Started Early
(DM Duration <15 years)
No correlation
in Std. Rx group
p<0.0001
DM Duration (years)
Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
http://www.diabetes.org/diabetesconnect/brousethe2008webcastcollection. Accessed July 2008
VADT: Severe Hypoglycemia
Impaired
Consciousness
Std. Rx
Intens. Rx
Loss of
Consciousness
Std. Rx
Intens. Rx
Severe
Hypoglycemia*
Std. Rx
Intens. Rx
N
Incidence
%
p
899
892
79
178
8.8
20.0
<0.01
899
892
39
91
4.3
10.2
<0.01
899
892
87
188
9.7
21.1
<0.01
*Either impaired or total loss of consciousness. Some subjects had both.
Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
Predictors of All-Cause Mortality
Variable
HR
Prior event
1.90
1.40
2.58
<.0001
Age
2. 41
2.00
2.91
<.0001
Smoker
1.70
1.16
2.48
0.006
1.17
1.06
1.29
0.002
5.9
2.1
16.1
0.001
1.28
0.40
4.05
0.7
Baseline
HbA1c
Hypoglycemia*
(Std Rx)
Hypoglycemia
(Intens. Rx)
Lower CI Upper CI
p-value
*Also predicted primary endpoint (CVD composite) and CVD death.
Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
Veterans Affairs Diabetes Trial
Effect of Rosiglitazone on Time to CVD Death
(Non-randomized Rx)
Unadjusted
4 mg
8 mg
Adjusted: baseline*
4 mg
8 mg
Adjusted: baseline and time covariates**
4 mg
8 mg
Hazard Ratio:
0.5
1.0
1.5
*Baseline covariates: age, baseline insulin use, prior event, smoker, baseline SBP
**Baseline and time-dependent covariates: age, baseline insulin Rx, prior CVD, smoker
In the VADT, it was better to be on Rosiglitazone than not.
Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
http://www.diabetes.org/diabetesconnect/brousethe2008webcastcollection. Accessed July 2008
Veterans Affairs Diabetes Trial
Effect of Rosiglitazone on Time to MI
(Non-randomized Rx)
Unadjusted
4 mg
8 mg
Adjusted: baseline*
4 mg
8 mg
Adjusted: baseline and time covariates**
4 mg
8 mg
Hazard Ratio:
0.5
1.0
1.5
*Baseline covariates: age, baseline insulin use, prior event, smoker, baseline SBP
**Baseline and time-dependent covariates: age, baseline insulin Rx, prior CVD, smoker
In the VADT, it was better to be on Rosiglitazone than not.
Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
http://www.diabetes.org/diabetesconnect/brousethe2008webcastcollection. Accessed July 2008
VADT: Conclusions
Intensive Glycemic Rx reduces CVD if:
• Started early in the course of DM (<12y)
• Less aggressive goal (<7% vs. <6)
• TZD (rosiglitazone) included in Rx
• Hypoglycemia avoided (std Rx only?)
• Added to aggressive Rx of lipids & BP
(especially if HDL-C increases)
per Brinton, EA; after Duckworth, W and Abraira, C, Oral Presentations ADA Mtg 6/08.
Are ‘Blood Glucose Control’ Trials Less than 10 years Duration
Long Enough to Show CVD Benefit?:
Time to Benefit and “Legacy Effect” of Lower Glycemia
Paul D. Rosenblit MD, PhD, FACE
Private Solo Practice
Endocrinology, Diabetes and Metabolism, and
Clinical Professor of Medicine
Univ. of California, Irvine School of Medicine
DCCT/EDIC: Lower Glycemia in DM-1
Diabetes Control & Complications Trial (Randomized Intervention) /
Epidemiology of Diabetes Interventions & Complications (Observational F/U)
Conventional
Intensive
Conventional
Intensive
11
10
8.9%
10
mean 8.2%
9
A1c
(%) 8
Between group
A1c difference 1.8%
7.9%
7
7.1%
Normal  6.05
6
5
7.8%
8
0
1
2
3
6
Normal
4
5
6
DCCT Study yr
mean 8.0%
7
8
9 10
1
2
3
4
5
6
7
8
EDIC yr
Adapted from DCCT Research Group. N Engl J Med 1993;329:977-986
DCCT/EDIC Study Research Group, N Engl J Med 2005; 353:2643-2653
Lower Glycemia in DM-1 Decreases CVD
But Benefits are Delayed (DCCT-EDIC)
0.10
0.08
Intervention ----------------Follow-up------------------
0.06
Conventional
treatment
MACE
(NF MI,
CVA, or 0.04
CVD death)
↓57% RRR
p=0.02)
0.02
Intensive treatment
0.00
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
No. at Risk
Years since entry
Intensive
705
686
640
118
Conventional
721
694
637
96
DCCT/EDIC Study Research Group, N Engl J Med 2005; 353:2643-53.
UKPDS: Lower Glycemia in DM-2
with Intensive Intervention
Over 10 years HbA1c was 7·0% (6·2–8·2) in the intensive group
compared with 7·9% (6·9–8·8) in the conventional group
9
Average
between
group A1c
difference
= 0.9%
Conventional
8
Median
A1c (%)
Intensive
(Sulfonylurea
or Insulin)
7
6
0
0
3
6
9
12
15
Years from randomization
UKPDS Group. Lancet. 1998;352:837-853.
UKPDS: Aggregate Clinical Endpoints in Glucose Control
Study with Between Group HbA1c Difference of Only 0.9%
After Mean 10-Years’ Follow-Up
Relative risk* (95% CI)
Reduced
0.5 risk
RR
P value
Any diabetes-related endpoint
0.88
0.029
Diabetes-related deaths
0.90
0.34
All-cause mortality
0.94
0.44
Myocardial infarction
0.84
0.052
Stroke
1.11
0.52
Microvascular
0.75
0.0099
*vs. conventional policy.
Favors
Intensive
1
Increased
risk
2
Favors
Conventional
Microvascular, NOT Macrovascular, events were reduced in UKPDS trial
UKPDS Group. Lancet. 1998;352:837-853
UK Prospective Diabetes Study
and Long-Term F/U
Interventional Trial (Randomized, Blinded), 1977-1997
 N=5,102, newly-diagnosed DM-2 (recruited 1977-1991)
 Median randomized follow-up 10 y (6-20 y)
10-y Post-Trial Monitoring, 1997-2007*
 Annual follow-up (UKPDS clinic-based x 5y, then
questionnaire-based x 5y more)
Median total follow-up 17 y (16-30 y)
*no attempts to maintain previously assigned therapies.
Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:
UKPDS Post-Trial Follow-Up A1c
UKPDS
HbA1c
diff. 0.9%
end of
trial
UKPDS results
presented
Mean (95%CI)
UKPDS website-- http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/
Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:
UKPDS “Legacy Effect” of Earlier Glucose Control
with Insulin or Sulfonylurea
Aggregate Endpoint
Interv.
-1997
F/U
-2007
Any diabetes related endpoint
RRR:
P:
12%
0.029
9%
0.040
Microvascular disease
RRR:
P:
25%
0.0099
24%
0.001
Myocardial infarction
RRR:
P:
16%
0.052
15%
0.014
All-cause mortality
RRR:
P:
6%
0.44
13%
0.007
RRR = Relative Risk Reduction, P = Log Rank
Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:
UKPDS: “Legacy Effect” of Earlier Glucose Control
with Metformin in Overweight Patients
Aggregate Endpoint
Interv.
-1997
F/U
-2007
Any diabetes related endpoint
RRR:
P:
32%
0.0023
21%
0.013
Microvascular disease
RRR:
P:
29%
0.19
16%
0.31
Myocardial infarction
RRR:
P:
39%
0.010
33%
0.005
All-cause mortality
RRR:
P:
36%
0.011
27%
0.002
RRR = Relative Risk Reduction, P = Log Rank
Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:
UKPDS Post-Trial Follow-up Blood Pressure
UKPDS
results
presented
Mean (95%CI)
UKPDS website-- http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/
Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:
UKPDS: No “Legacy Effect” of Earlier BP Control
Aggregate Endpoint
Interv.
-1997
F/U
-2007
Any diabetes related endpoint
RRR:
P:
24%
0.0046
7%
0.31
Microvascular disease
RRR:
P:
37%
0.0092
16%
0.17
Myocardial infarction
RRR:
P:
21%
0.13
10%
0.35
All-cause mortality
RRR:
P:
18%
0.17
11%
0.18
RRR = Relative Risk Reduction, P = Log Rank
Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:
UKPDS CVD (Diabetes-Related Deaths) and Trial Duration
at Curve Separation: What are your expectations for
ACCORD, ADVANCE and VADT
Proportion
of patients
with events
UKPDS 15 yrs, mean F/U 10
Conventional (n=411)
Intensive (n=951)
Metformin (n=342)
35%
30%
M vs. C
P=0.017
7.9
yrs 0.9
7.0
M vs. I I vs. C
P=0.11 P=0.029
Standard A1c
Trial
Between group
A1c difference
20%
Intensive A1c
10%
0%
0
3
6
9
12
15
Years from randomization
UKPDS Group. Lancet. 1998;352:854-865.
UKPDS CVD (Diabetes-Related Deaths) and Trial Duration
at Curve Separation: What are your expectations for
ACCORD, ADVANCE and VADT
Proportion
of patients
with events
UKPDS 15 yrs, mean F/U 10
Conventional (n=411)
Intensive (n=951)
Metformin (n=342)
35%
30%
M vs. C
P=0.017
Standard A1c
Trial
Between group
A1c difference
20% ADVANCE
Intensive A1c
ACCORD, ADVANCE and
VADT trials were much
shorter than 10 years;
likely far too short to show
reduction in CVD with
intensive glycemic
control.
VADT
10%
7.9
yrs 0.9
7.0
M vs. I I vs. C
P=0.11 P=0.029
7.3
0.8
6.5
8.4
1.5
6.9
7.5
ACCORD 1.1
6.4
0%
0
3
6
9
12
15
Years from randomization
UKPDS Group. Lancet. 1998;352:854-865.
Risk Reduction of Micro- and Macrovascular Complications
and Diabetes-related Death in 110 (lean) T2DM patients by
Intensive Insulin Therapy over 10 years of the Kumamoto
Study. Conventional 9.4% and Intensive 7.1%
Between Group HbA1c diff. was 2.3%
Retinopathy
• Progression of retinopathy
• Photocoagulation
Nephropathy
• Progression of nephropathy
Neuropathy
• Clinical neuropathy
Macrovascular Disease
• Macrovascular complications
• Diabetes-related death
Mean RRR
6 years
10 years
65%*
40%*
67%**
77%*
57%*
66%**
58-80%*
64%**
46%NS
---
54%*
81%*
*p<0.05
**p<0.03
Ohkubo Y, Kishikawa H, Araki E, et al. Diabetes Res Clin Pract 1995;28:103-117
Wake N, Hisashige A, Katayama T et al. Diabetes Res Clin Pract 2000; 48: 201–210
Steno-2 Study Design
• DM-2 (N = 160)
• Rx arms:
• Intensive Multifactorial Management Rx of Glucose, Lipids, BP,
etc, per Steno Diabetes Center
• Conventional Rx per pt’s GP
• PROBE (Prospective, Randomized, Open, Blinded Endpoint study)
Conventional Rx
80
Randomized
Microvascular
Macrovascular
Endpoint examinations
80
4 years
8 years
Intensive Rx
Gæde P, et al, NEJM 2003;348:383-393
STENO-2: Total Mortality by Rx Arm Over Time
Intensive vs. Conventional HR: ~2
year 4
1.0
0.5
7.8
13.3
50% decrease in total mortality w/ Intensive Rx
seen only after >10 years f/u (avg 13.3 y)
Gæde P, et al, NEJM. 2008;358:580-591
STENO-2: CVD Events by Rx Arm Over Time
~50% decrease in CVD events w/ Intensive Rx
seen only after >7 years f/u (avg 13.3 y)
Gæde P, et al, NEJM. 2008;358:580-591
Summary and Conclusions:
Time-Course of CVD Prevention in DM
Glycemic Control—
• Microvascular benefits: accrue relatively early (<6y in DCCT,
UKPDS, Kumamoto, ADVANCE, STENO-2)
• Macrovascular benefits:
– Were NOT seen in trials <10y Rx w/ A1c diff. 0.8-1.8%
(ACCORD, ADVANCE, VADT, DCCT, UKPDS)
– WERE seen at 10 y w/ A1c diff 2.3% (Kumamoto)
– WERE seen at >10 y even after glycemic difference lost—
so-called “Metabolic Memory” or “Legacy Effect” (Steno-2,
UKPDS-Metformin, UKPDS-10+8.5y-F/U, DCCT-17y-F/U)
– Total mortality increased at <5 y (Steno-2, ACCORD), but
decreased at >10 y (Steno-2-13.3y-F/U, UKPDS-10+8.5yF/U)
BP Control—no “Legacy Effect” after end of intervention
UKPDS-10+8.5y-F/U)
Combined Intensive BP-BG control vs standard BP-BG control
reduced CV Mortality and All-cause mortality (ADVANCE),
consistent with imperative multifactorial approach (STENO-2)