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 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


• 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


• 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


• 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


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


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


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


2.29%/yr

2.11%/yr

HR = 0.90(0.78-1.04)P = 0.16

Primary Outcome


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


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


OverallNever

Experienced a Hypoglycemic Event

ExperiencedHypoglycemic Event

Intensive Glycemia

1.4% / year(257 Deaths)



Standard Glycemia




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


• 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 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


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: Primary Outcomes


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


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


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%


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


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


~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)


~18% ↑in HDL-C

60

100

140

180

220

260

STDINT

VADT: On-Study TG (Median/IQR mg/dL)


~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


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


*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


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


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








UKPDS: “Legacy Effect” of Earlier Glucose Control with Metformin in Overweight Patients


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








0%

10%

20%

30%

35%

0 3 6 9 12 15

Proportion of patients with events


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


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


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


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)

Documents

Glucose Lowering in Diabetes Mellitus: