Glucose Lowering in Diabetes Mellitus: Does it Increase or Decrease
CVD Mortality and/or Events? Presenters:
Jeff Probstfield, MD—University of WashingtonIrl B. Hirsch, MD—University of Washington
Eliot A. Brinton, MD—University of UtahPaul 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, MDProfessor of Medicine in the Division of Cardiology
Adjunct Professor of Epidemiology,Director of the Clinical Trials Division
University of WashingtonSeattle, WA
• 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
ACCORD Trial Overall Goal
Buse, JB, et al, AmJCard 2007 99:21i-33i.
• 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)
DSMB Recommendation and NHLBI Decision
• 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%)?
Glycemia Trial Research Question
Buse, JB, et al, AmJCard 2007 99:21i-33i.
• 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
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)
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.
Glycemia Trial Rationale
IntensiveGlycemia(A1C<6%) 5128*
StandardGlycemia(A1C 7-7.9%) 5123*
LipidStatin + Masked Study Drug
Statin + Masked Study Drug
BPIntensive(SBP<120)
Standard(SBP<140)
2765*2753*2362* 2371*
1178 1193
11781184
1374
13911370
1383
10,251*Primary analyses compare the marginals for main effects
Double 2 X 2 Factorial Design
Buse, JB, et al, AmJCard 2007 99:21i-33i.
• 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
Participant Eligibility
Buse, JB, et al, AmJCard 2007 99:21i-33i.
• Primary: – First occurrence of nonfatal MI OR Nonfatal Stroke
OR 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
ACCORD Outcomes
Buse, JB, et al, AmJCard 2007 99:21i-33i.
01
234
567
89
4 5 6 7 8 9 10 11 12 13 14
A1c
% o
f Par
ticip
ants
Intensive Rx Goal
Standard Rx Goal
A1C Distribution
01
23
45
67
89
4 5 6 7 8 9 10 11 12 13 14
A1c
% o
f Par
ticip
ants
Intensive Rx Goal
Standard Rx Goal
December 2007
A1C Distribution: 48 Mo.
Median A1C and Interquartile Ranges
ACCORD Study Group, NEJM 2008 358:2545-2549.
1.41%/yr
1.14%/yr
HR = 1.22 (1.01-1.46)P = 0.04
All Cause Mortality
ACCORD Study Group, NEJM 2008 358:2545-2549.
IntensiveN (%)
StandardN (%) HR (95% CI) P
Primary 352 (6.86) 371 (7.23) 0.90 (0.78-1.04) 0.16
Secondary
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 Outcomes
ACCORD Study Group, NEJM 2008 358:2545-2549.
IntensiveN (%)
StandardN (%) HR (95% CI) P
Primary 352 (6.86) 371 (7.23) 0.90 (0.78-1.04) 0.16
Secondary
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 Outcomes
ACCORD Study Group, NEJM 2008 358:2545-2549.
2.29%/yr
2.11%/yr
HR = 0.90(0.78-1.04)P = 0.16
Primary Outcome
ACCORD Study Group, NEJM 2008 358:2545-2549.
Can the observed treatment group difference in mortality be explained by the observed post-randomization treatment group difference in severe hypoglycemia?
The Question:
Intensive Group Annual Incidence Rate = 3.3%Standard Group Annual Incidence Rate = 1.0%
Severe Hypoglycemia Requiring Medical Assistance
ACCORD Study Group, NEJM 2008 358:2545-2549.
NeverExperienced a
Hypoglycemic EventExperienced
Hypoglycemic Event
OverallMortalityRates
1.2% / year 3.3% / year
Again, mortality is higher among participants who had experienced a Severe Hypoglycemic Event,
regardless of treatment strategy
Background: Mortality By Severe Hypoglycemia
IntensiveGlycemia 1.3% / year 2.8% / year
StandardGlycemia 1.1% / year 4.9% / year
ACCORD Study Group, NEJM 2008 358:2545-2549.
OverallNever
Experienced a Hypoglycemic Event
ExperiencedHypoglycemic Event
Intensive Glycemia
1.4% / year(257 Deaths)
1.3% / year(223 Deaths)
2.8% / year(34 Deaths)
Standard Glycemia
1.1% / year(203 Deaths)
1.1% / year(186 Deaths)
4.9% / year(17 Deaths)
HazardRatio(95% CI)
1.22 (1.01, 1.46) 1.24 (1.02, 1.50) 0.54 (030, 0.96)
Mortality By Treatment Group andSevere Hypoglycemia
Mortality Higher inIntensive Group
Mortality Higher inStandard Group
Interaction P < 0.01ACCORD Study Group, NEJM 2008 358:2545-2549.
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 groupParticipants who had experienced a severe hypoglycemic event were more likely to die
• True for both treatment groups
Conclusions—I
ACCORD Study Group, NEJM 2008 358:2545-2549.
• 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.
Conclusions—II
ACCORD Study Group, NEJM 2008 358:2545-2549.
• 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)
Identifying a “Cause” of the Higher Mortality
ACCORD Study Group, NEJM 2008 358:2545-2549.
I T S
I T P
I T T
It’sTheStrategy (the therapeutic approach to intensive glucose lowering)
InThisPopulation (with longstanding T2DM and CVD or CVD RFs)
IntentionToTreat analyses (comparing groups based on randomized assignment –
the analysis that provides strong evidence of causality)
Conclusion- what caused the difference ?
ADVANCE Study Review: Which A1c Targets and Which Drugs for Diabetes?
Irl B. Hirsch, MDProfessor of Medicine
Division of Metabolism, Endocrinology and NutritionUniversity of Washington School of Medicine
Seattle, WA
Differences Between ACCORD/ADVANCEBASELINE ACCORD ADVANCE
# patients 10,251 11,140
duration DM (yrs) 10 8
Hx macrovasc. Dz (%) 35 32
Baseline A1C (%) 8.1 7.2
Intervention
target A1C (%) <6 <6.5
insulin Rx (%) 77 vs. 55 41 vs. 24
TZD Rx (%) 92 vs. 58 17 vs. 11
Outcome (intensive vs. standard)
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%
NEJM 2008;358, 2630 *P<0.05
ADVANCE Collaborative Group, NEJM 2008 358:2560-2572.
ADVANCE Primary Outcomes
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 under-
utilized, 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 UtahDirector, Metabolism Section of Cardiovascular Genetics
Salt Lake City, UT
VADT: DesignSubject 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
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: Design (cont’d)
• 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%
VADT: Baseline Subject Characteristics (similar in both arms)
Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
VADT: Glycemic Rx and Results
A1c Goal by Study ArmIntensive: <7%Standard: 8-9%Method (same in both Rx arms):1. Metformin (BMI>27) or glimepiride (BMI<27)2. Rosiglitazone3. Insulin4. Other oral agents5. Toolbox: add any other drugs to get to Rx goalsOn-study A1c by Study ArmIntensive: 6.9%Standard: 8.4%
Abraira, C, et al, J Diab. Complic, 2003; 17: 314
VADT: Primary Endpoint
Non-significant trend towards 12% decrease in CVD (composite) with intensive glycemic control
TreatmentStandard Intensive
N Incidence % N Incidence % P-value
899 263 29.3 892 231 25.9 0.11
Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
VADT: Antiplatelet/Anticoagulant, Statins and Cigarette Use (%)
0102030405060708090
100
STDINTSTDINTSTDINTCigarette Smoking
Antiplatelet/Anticoagulant
Statins
Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
VADT: On-Study LDL-C (Median/IQR mg/dL)
50
70
90
110
130
Baselin
e1 Y
ear
2 Yea
r
3 Yea
r
4 Yea
r
5 Yea
r
6 Yea
r
STD INT
Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
~30% ↓in LDL-C
25
30
35
40
45
50
Baselin
e1 Y
ear
2 Yea
r
3 Yea
r
4 Yea
r
5 Yea
r
6 Yea
r
STDINT
VADT: On-Study HDL-C (Median/IQR mg/dL)
Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
~18% ↑in HDL-C
60
100
140
180
220
260
STDINT
VADT: On-Study TG (Median/IQR mg/dL)
Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
~21% ↓in TG
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 1.33 1.19 1.49 <.0001HDL 0.83 0.76 0.91 <.0001
HbA1c 1.09 1.02 1.16 0.01Hypoglycemia 2.07 1.14 3.77 0.02DM Duration-
Std. Rx 1.01 0.99 1.02 0.5
DM Duration- Intens. Rx 1.03 1.02 1.05 <.0001
Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
VADT: Intensive Glycemia Rx Beneficial if Started Early
(DM Duration <15 years)
p<0.0001
Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy. http://www.diabetes.org/diabetesconnect/brousethe2008webcastcollection. Accessed July 2008
CVD
Haz
ard
Rat
io In
tens
ive/
Stan
dard
Rx
DM Duration (years)
No correlation in Std. Rx group
N Incidence % pImpaired ConsciousnessStd. Rx 899 79 8.8 <0.01Intens. Rx 892 178 20.0Loss of ConsciousnessStd. Rx 899 39 4.3 <0.01Intens. Rx 892 91 10.2Severe Hypoglycemia*Std. Rx 899 87 9.7 <0.01Intens. Rx 892 188 21.1
VADT: Severe Hypoglycemia
Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.
*Either impaired or total loss of consciousness. Some subjects had both.
Predictors of All-Cause Mortality
Variable HR Lower CI Upper CI p-value
Prior event 1.90 1.40 2.58 <.0001Age 2. 41 2.00 2.91 <.0001
Smoker 1.70 1.16 2.48 0.006Baseline
HbA1c1.17 1.06 1.29 0.002
Hypoglycemia* (Std Rx) 5.9 2.1 16.1 0.001
Hypoglycemia (Intens. Rx) 1.28 0.40 4.05 0.7
*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 TrialEffect of Rosiglitazone on Time to CVD Death
(Non-randomized Rx)
*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.
Unadjusted
Adjusted: baseline*
Adjusted: baseline and time covariates**
8 mg
Hazard Ratio: 0.5 1.0 1.5
4 mg
8 mg4 mg
8 mg4 mg
Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy. http://www.diabetes.org/diabetesconnect/brousethe2008webcastcollection. Accessed July 2008
In the VADT, it was better to be on Rosiglitazone than not.
Unadjusted
Adjusted: baseline*
Adjusted: baseline and time covariates**
8 mg
Hazard Ratio: 0.5 1.0 1.5
4 mg
8 mg4 mg
8 mg4 mg
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 TrialEffect of Rosiglitazone on Time to MI
(Non-randomized Rx)
*Baseline covariates: age, baseline insulin use, prior event, smoker, baseline SBP**Baseline and time-dependent covariates: age, baseline insulin Rx, prior CVD, smoker
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, FACEPrivate Solo Practice
Endocrinology, Diabetes and Metabolism, andClinical Professor of Medicine
Univ. of California, Irvine School of Medicine
DCCT Study yr0 1 2 3 4 5 6 7 8 9 10
5
6
7
8
9
10
11
Normal
ConventionalIntensive
A1c (%)
8.9%
7.1%
ConventionalIntensive
6
8
10
1 2 3 4 5 6 7 8
Normal 6.05
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
EDIC yr
DCCT/EDIC: Lower Glycemia in DM-1Diabetes Control & Complications Trial (Randomized Intervention) /
Epidemiology of Diabetes Interventions & Complications (Observational F/U)
7.8% 7.9%
mean 8.2%
mean 8.0%
Between group A1c difference 1.8%
0.00
0.02
0.04
0.06
0.08
0.10
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21Years since entry
MACE (NF MI, CVA, or CVD death)
Conventional treatment
Intensive treatment
DCCT/EDIC Study Research Group, N Engl J Med 2005; 353:2643-53.
Intensive 705 686 640 118Conventional 721 694 637 96
No. at Risk
Intervention ----------------Follow-up------------------
↓57% RRR p=0.02)
Lower Glycemia in DM-1 Decreases CVD But Benefits are Delayed (DCCT-EDIC)
UKPDS: Lower Glycemia in DM-2 with Intensive Intervention
UKPDS Group. Lancet. 1998;352:837-853.
06
7
8
9
0 3 6 9 12 15
Median A1c (%)
Years from randomization
Conventional
Intensive (Sulfonylurea or Insulin)
Average between group A1c difference = 0.9%
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
UKPDS: Aggregate Clinical Endpoints in Glucose Control Study with Between Group HbA1c Difference of Only 0.9%
Favors FavorsIntensive Conventional
UKPDS Group. Lancet. 1998;352:837-853
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
Relative risk* (95% CI)Reduced Increased
0.5 risk 1 risk 2
*vs. conventional policy.
After Mean 10-Years’ Follow-Up
Microvascular, NOT Macrovascular, events were reduced in UKPDS trial
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)
Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:
*no attempts to maintain previously assigned therapies.
UKPDS Post-Trial Follow-Up A1c
UKPDS resultspresented
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 HbA1c diff. 0.9% end of trial
Interv. F/UAggregate Endpoint -1997 -2007
Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040
Microvascular disease RRR: 25% 24% P: 0.0099 0.001
Myocardial infarction RRR: 16% 15% P: 0.052 0.014
All-cause mortality RRR: 6% 13% P: 0.44 0.007
RRR = Relative Risk Reduction, P = Log Rank
UKPDS “Legacy Effect” of Earlier Glucose Control with Insulin or Sulfonylurea
Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:
Interv. F/UAggregate Endpoint -1997 -2007
Any diabetes related endpoint RRR: 32% 21% P: 0.0023 0.013
Microvascular disease RRR: 29% 16% P: 0.19 0.31
Myocardial infarction RRR: 39% 33% P: 0.010 0.005
All-cause mortality RRR: 36% 27% P: 0.011 0.002
RRR = Relative Risk Reduction, P = Log Rank
UKPDS: “Legacy Effect” of Earlier Glucose Control with Metformin in Overweight Patients
Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:
UKPDS Post-Trial Follow-up Blood PressureUKPDSresults
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
Interv. F/UAggregate Endpoint -1997 -2007
Any diabetes related endpoint RRR: 24% 7% P: 0.0046 0.31
Microvascular disease RRR: 37% 16% P: 0.0092 0.17
Myocardial infarction RRR: 21% 10% P: 0.13 0.35
All-cause mortality RRR: 18% 11% P: 0.17 0.18
RRR = Relative Risk Reduction, P = Log Rank
Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:
0%
10%
20%
30%
35%
0 3 6 9 12 15
Proportion of patients with events
Years from randomization
Conventional (n=411)Intensive (n=951)Metformin (n=342)
UKPDS CVD (Diabetes-Related Deaths) and Trial Duration at Curve Separation: What are your expectations for ACCORD, ADVANCE and VADT
M vs. IP=0.11
M vs. C P=0.017
UKPDS Group. Lancet. 1998;352:854-865.
TrialStandard A1c Between group A1c differenceIntensive A1c
7.9
7.00.9
I vs. CP=0.029
UKPDS 15 yrs, mean F/U 10 yrs
0%
10%
20%
30%
35%
0 3 6 9 12 15
Proportion of patients with events
Years from randomization
Conventional (n=411)Intensive (n=951)Metformin (n=342)
UKPDS CVD (Diabetes-Related Deaths) and Trial Duration at Curve Separation: What are your expectations for ACCORD, ADVANCE and VADT
M vs. IP=0.11
M vs. C P=0.017
UKPDS Group. Lancet. 1998;352:854-865.
VADT
ADVANCE
ACCORD
ACCORD, ADVANCE and VADT trials were much shorter than 10 years; likely far too short to show reduction in CVD with intensive glycemic control.
7.5
7.3
6.58.4
6.4
6.9
1.1
1.5
0.8TrialStandard A1c Between group A1c differenceIntensive A1c
7.9
7.00.9
I vs. CP=0.029
UKPDS 15 yrs, mean F/U 10 yrs
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 65%* 67%** • Photocoagulation 40%* 77%* Nephropathy• Progression of nephropathy 57%* 66%** Neuropathy• Clinical neuropathy 58-80%* 64%** Macrovascular Disease• Macrovascular complications 46%NS 54%* • Diabetes-related death --- 81%*
Wake N, Hisashige A, Katayama T et al. Diabetes Res Clin Pract 2000; 48: 201–210Ohkubo Y, Kishikawa H, Araki E, et al. Diabetes Res Clin Pract 1995;28:103-117
Mean RRR
*p<0.05 **p<0.03
6 years 10 years
Steno-2 Study Design
Conventional Rx
Intensive Rx
Endpoint examinations
Microvascular Macrovascular
4 years 8 years
80
80
Randomized
• 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)
Gæde P, et al, NEJM 2003;348:383-393
STENO-2: Total Mortality by Rx Arm Over Time
Gæde P, et al, NEJM. 2008;358:580-591
Intensive vs. Conventional HR: ~2 1.0 0.5 year 4 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)
Summary and Conclusions: Time-Course of CVD Prevention in DMGlycemic 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)