THE ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES STUDY (ACCORD) Dr. Anita Chekuri CVA Ltd.

THE THE ACTION TO ACTION TO CONTROL CONTROL CARDIOVASCULAR CARDIOVASCULAR RISK IN DIABETESRISK IN DIABETES STUDY (ACCORD)STUDY (ACCORD)

Dr. Anita ChekuriDr. Anita Chekuri

CVA LtdCVA Ltd

BackgroundBackground

Epidemiologic analyses suggest that the risk for CVD Epidemiologic analyses suggest that the risk for CVD in patients with diabetes increases in a graded fashion in patients with diabetes increases in a graded fashion with increases HbA1c, BP, LDL, and TG and with a with increases HbA1c, BP, LDL, and TG and with a decrease in HDL.decrease in HDL.

Diabetics without Hx of MI have same risk of a Diabetics without Hx of MI have same risk of a coronary event as do non-diabetics with previous MIcoronary event as do non-diabetics with previous MI

To determine whether CVD event rates can be reduced To determine whether CVD event rates can be reduced in patients with T2DM who are at high risk for CVD in patients with T2DM who are at high risk for CVD events by intensively targeting 3 important CVD risk events by intensively targeting 3 important CVD risk factors: hyperglycemia, dyslipidemia, and elevated factors: hyperglycemia, dyslipidemia, and elevated blood pressure.blood pressure.

Buse J. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial: Design and MethodsThe American Journal of Cardiology 2007;99:21-33.

Haffner SM, Lehto S, Ronnemaa T, Pyöräla K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-234

2 X 2 Factorial Design2 X 2 Factorial DesignBP trialBP trial Lipid trialLipid trial

Glycaemic trialGlycaemic trial SBP<110SBP<110mmHgmmHg

SBP<140SBP<140mmHgmmHg

Group Group AA

Group Group BB

TotalTotal

HbAIC < 6%HbAIC < 6% 11781178 11931193 13831383 13741374 51285128

HbAIC 7.0-HbAIC 7.0-7.9%7.9%

11841184 11781178 13701370 13911391 51235123

23622362 23712371 27532753 27652765

TotalTotal 47334733 55185518 1025110251

Buse J. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial: Design and MethodsThe American Journal of Cardiology 2007;99:21-33.

EligibilityEligibility Stable Type 2 Diabetes for 3+ monthsStable Type 2 Diabetes for 3+ months A1C A1C >>7.5% 7.5% AND AND <<9% 9% (more meds)(more meds) OR OR <<11% 11% (fewer meds)(fewer meds) Age 40-79 + previous CVD events Age 40-79 + previous CVD events OROR Age 55-79 with:Age 55-79 with:

anatomical ASCVD, albuminuria, LVH anatomical ASCVD, albuminuria, LVH OROR >> 2 CVD risk factors 2 CVD risk factors (dyslipidemia, hypertension, smoking, obesity)(dyslipidemia, hypertension, smoking, obesity)

BMI BMI << 45; Cr 45; Cr << 1.5 (133 uM) 1.5 (133 uM) No frequent/recent serious hypoglycemiaNo frequent/recent serious hypoglycemia Able/willing to take insulin, do glucose monitoring Able/willing to take insulin, do glucose monitoring Eligible for BP or Lipid TrialEligible for BP or Lipid Trial

LDL 60-180 mg/dlLDL 60-180 mg/dl HDL < 55 mg/dl (women, blacks), < 50 (all others)HDL < 55 mg/dl (women, blacks), < 50 (all others) TG <750 (not on lipid therapy) or <400 (on lipid therapy)TG <750 (not on lipid therapy) or <400 (on lipid therapy)

The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559.

The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010. DOI: 10.1056/NEJMoa1001282

ACCORD Glycaemic ACCORD Glycaemic Control ArmControl Arm


CVA LtdCVA Ltd


An increase of 1% in the HbAIC is associated An increase of 1% in the HbAIC is associated with an increase of 18% in the risk of with an increase of 18% in the risk of cardiovascular eventscardiovascular events11

Determine whether therapeutically targeting Determine whether therapeutically targeting normal HbAIC levels (< 6.0%) would reduce normal HbAIC levels (< 6.0%) would reduce the rate of cardiovascular events, as compared the rate of cardiovascular events, as compared to targeting HbAIC from 7.0 to 7.9%to targeting HbAIC from 7.0 to 7.9%22

The finding of higher mortality in the intensive-The finding of higher mortality in the intensive-therapy group led to termination of the therapy group led to termination of the intensive regimen 17 months before the intensive regimen 17 months before the scheduled end of the studyscheduled end of the study22

1Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004;141:421-431

2The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559.

Randomization Randomization

BP trialBP trial Lipid trialLipid trial



Group Group AA

Group Group BB

TotalTotal

HbAIC < 6%HbAIC < 6% 11781178 11931193 13831383 13741374 51285128

HbAIC 7.0-HbAIC 7.0-7.9%7.9%

11841184 11781178 13701370 13911391 51235123

23622362 23712371 27532753 27652765

TotalTotal 47334733 55185518 1025110251


Outcomes Outcomes

Primary Primary First occurrence of nonfatal MI, nonfatal Stroke, or First occurrence of nonfatal MI, nonfatal Stroke, or

death from CV disease.death from CV disease. SecondarySecondary

Death from any cause.Death from any cause. Also measured the effect of the intervention on Also measured the effect of the intervention on

microvascular disease, hypoglycemia, cognition, microvascular disease, hypoglycemia, cognition, and quality of life. and quality of life.

Intensive glycaemic control arm terminated in Intensive glycaemic control arm terminated in 3.5 years (instead of 5.6 years as planned for)3.5 years (instead of 5.6 years as planned for)


IntensiveIntensive(N = 5128)(N = 5128)

StandardStandard(N = 5123)(N = 5123)

AgeAge 62.2 62.2 62.2 62.2 WomenWomen 38.738.7 38.438.4Median DM Median DM DurationDuration 1010 1010

Previous CVD Previous CVD EventEvent 35.635.6 34.834.8

White/BlackWhite/Black 64.4/19.764.4/19.7 64.5/18.964.5/18.9Current SmokerCurrent Smoker 14.314.3 13.713.7Mean BMIMean BMI 32.2 32.2 32.2 32.2 Mean SBP/DBPMean SBP/DBP 136.2/74.8136.2/74.8 136.5/75.0136.5/75.0Mean/Median A1CMean/Median A1C 8.3 / 8.18.3 / 8.1 8.3 / 8.18.3 / 8.1Mean FGMean FG 175 175 176 176 Mean LDL / HDLMean LDL / HDL 105 / 47 105 / 47 105 / 47 105 / 47

Baseline Characteristics Baseline Characteristics


Median Glycated Hemoglobin Levels at Each Study Visit

The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559

ACCORD: Glucose-lowering drugs by treatment strategy

55.477.3Insulin

4.917.8Incretin

5.123.2α-Glucosidase inhibitor

58.391.7Thiazolidinedione

73.886.6Secretagogue

Patients (%)

86.994.7Metformin

Standard therapy(n = 5123)

Intensive therapy(n = 5128)

ACCORD Study Group. N Engl J Med. 2008;358:2545-59.

Adverse Events, Clinical Measures, Tobacco Use, and Use of Nonglycemic Medication after Randomization


Primary and Secondary Outcomes


Kaplan-Meier Curves for the Primary Outcome and Death from Any Cause


Hazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified Subgroups


Observations Observations

Targeting HbAIC levels below 6.0% increasedTargeting HbAIC levels below 6.0% increased the rate the rate of death from any cause after a mean of 3.5 yearsof death from any cause after a mean of 3.5 years Magnitude of reductionMagnitude of reduction Speed of reductionSpeed of reduction Adverse drug interactions at high dosesAdverse drug interactions at high doses Rate of hypoglycaemiaRate of hypoglycaemia


Intensive GroupIntensive Group Standard GroupStandard Group# Events # Events

**** nn %% nn %%

11 400400 7.87.8 130130 2.52.5

22 8282 1.61.6 3434 0.70.7

3 to 53 to 5 4343 0.80.8 1010 0.20.2

>5>5 66 0.10.1 00 00

**Cumulative number of events

Number of Participants With One or More Severe Hypoglycemia Events

Requiring Medical Assistance (n and %)


OverallOverallNeverNever

Experienced a Experienced a Hypoglycemic EventHypoglycemic Event

ExperiencedExperiencedHypoglycemic EventHypoglycemic Event

Intensive Intensive GlycemiaGlycemia

1.4% / year1.4% / year

(257 Deaths)(257 Deaths)

1.3% / year1.3% / year


2.8% / year2.8% / year


Standard Standard GlycemiaGlycemia

1.1% / year1.1% / year


1.1% / year1.1% / year


4.9% / year4.9% / year


HazardHazardRatioRatio(95% CI)(95% CI)

1.221.22 (1.01, 1.46)(1.01, 1.46) 1.241.24 (1.02, 1.50)(1.02, 1.50) 0.54 0.54 (030, 0.96)(030, 0.96)

Mortality By Treatment Group andSevere Hypoglycemia

Mortality Higher inIntensive Group

Mortality Higher inStandard Group

Interaction P < 0.01The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559.

Intensive Strategy

Higher Mortality

Higher Rates ofHypoglycemia

Intensive Strategy

Higher Rates ofHypoglycemia

Higher Mortality

Can we blame it all on hypoglycaemia?

No!And can ACCORD

distinguish these?The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559.


Targeting HbAIC levels below 6.0% increasedTargeting HbAIC levels below 6.0% increased the rate the rate of death from any cause after a mean of 3.5 yearsof death from any cause after a mean of 3.5 years Magnitude of reductionMagnitude of reduction Speed of reductionSpeed of reduction Rate of hypoglycaemiaRate of hypoglycaemia Adverse drug interactions at high dosesAdverse drug interactions at high doses

Longer time duration increases benefits of mortality Longer time duration increases benefits of mortality from non-fatal MI, but also increases risk of deathfrom non-fatal MI, but also increases risk of death


Kaplan-Meier Curves for the Primary Outcome and Death from Any Cause



Targeting HbAIC levels below 6.0% increasedTargeting HbAIC levels below 6.0% increased the rate the rate of death from any cause after a mean of 3.5 yearsof death from any cause after a mean of 3.5 years Magnitude of reductionMagnitude of reduction Speed of reductionSpeed of reduction Rate of hypoglycaemiaRate of hypoglycaemia Adverse drug interactions at high dosesAdverse drug interactions at high doses

Longer time duration increases benefits of mortality Longer time duration increases benefits of mortality from non-fatal MI, but also increases risk of death from non-fatal MI, but also increases risk of death


ACCORD Lipid Control ACCORD Lipid Control ArmArm


CVA LtdCVA Ltd


To investigate whether combination To investigate whether combination therapy of statin (lower LDL) + fibrate therapy of statin (lower LDL) + fibrate (raise HDL, lower TG), as compared to (raise HDL, lower TG), as compared to statin monotherapy was superior in statin monotherapy was superior in reducing rate of CV events in high risk reducing rate of CV events in high risk Type 2 diabeticsType 2 diabetics


MethodMethod

5518 high risk for CV events on 5518 high risk for CV events on Simvastatin started at randomizationSimvastatin started at randomization Treatment group – add fenofibrate at 1 Treatment group – add fenofibrate at 1

month- 2765month- 2765 Placebo group- 2753Placebo group- 2753

Follow-up- 4.7 yearsFollow-up- 4.7 years


Randomization Randomization

BP trialBP trial Lipid trialLipid trial



Group Group AA

Group Group BB

TotalTotal

HbAIC < 6%HbAIC < 6% 11781178 11931193 13831383 13741374 51285128

HbAIC 7.0-HbAIC 7.0-7.9%7.9%

11841184 11781178 13701370 13911391 51235123

23622362 23712371 27532753 27652765

TotalTotal 47334733 55185518 1025110251


Outcomes Outcomes

Primary: Primary: First occurrence of nonfatal MI, nonfatal Stroke, or First occurrence of nonfatal MI, nonfatal Stroke, or

death from CV diseasedeath from CV disease

Secondary:Secondary: Primary plus revascularization or hospitalization for Primary plus revascularization or hospitalization for

CCF (expanded macrovascular outcome)CCF (expanded macrovascular outcome) Combination of fatal coronary event, nonfatal MI, or Combination of fatal coronary event, nonfatal MI, or

unstable angina (major coronary disease events)unstable angina (major coronary disease events) Death from any causeDeath from any cause Hospitalization due to HFHospitalization due to HF


Results Results

Mean LDL decrease ofMean LDL decrease of

100.0 to 81.1 in Fenofibrate group100.0 to 81.1 in Fenofibrate group

101.1 to 80.0 in placebo group101.1 to 80.0 in placebo group


The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001282

Lipid Values


Prespecified Primary and Secondary Outcomes


Kaplan-Meier Analyses of the Primary Outcome, Expanded Macrovascular Outcome, and Death


Hazard Ratios for the Primary Outcome in Prespecified Subgroups


No significant difference in primary No significant difference in primary outcome between groupsoutcome between groups

In subgroup analysis, sex difference was In subgroup analysis, sex difference was significant. Men seemed to benefit from significant. Men seemed to benefit from Fenofibrate.Fenofibrate.

Suggestion of heterogenisity with Suggestion of heterogenisity with baseline TG and HDL levels.baseline TG and HDL levels.


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THE ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES STUDY (ACCORD) Dr. Anita Chekuri CVA Ltd.

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