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

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

• Dr. Anita Chekuri
• CVA Ltd

2
Background

• Epidemiologic analyses suggest that the risk for
  CVD in patients with diabetes increases in a
  graded fashion with increases HbA1c, BP, LDL, and
  TG and with a decrease in HDL.
• Diabetics without Hx of MI have same risk of a
  coronary event as do non-diabetics with previous
  MI
• To determine whether CVD event rates can be
  reduced in patients with T2DM who are at high
  risk for CVD events by intensively targeting 3
  important CVD risk factors hyperglycemia,
  dyslipidemia, and elevated blood pressure.

Buse J. Action to Control Cardiovascular Risk in
Diabetes (ACCORD) Trial Design and MethodsThe
American Journal of Cardiology 20079921-33. Haff
ner 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 1998339229-234
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2 X 2 Factorial Design
BP trial BP trial Lipid trial Lipid trial
Glycaemic trial SBPlt110mmHg SBPlt140mmHg Group A Group B Total
HbAIC lt 6 1178 1193 1383 1374 5128
HbAIC 7.0-7.9 1184 1178 1370 1391 5123
2362 2371 2753 2765
Total 4733 4733 5518 5518 10251
Buse J. Action to Control Cardiovascular Risk in
Diabetes (ACCORD) Trial Design and MethodsThe
American Journal of Cardiology 20079921-33.
4
Eligibility

• Stable Type 2 Diabetes for 3 months
• A1C gt7.5 AND lt9 (more meds) OR lt11 (fewer
  meds)
• Age 40-79 previous CVD events OR
• Age 55-79 with
• anatomical ASCVD, albuminuria, LVH OR
• gt 2 CVD risk factors (dyslipidemia, hypertension,
  smoking, obesity)
• BMI lt 45 Cr lt 1.5 (133 uM)
• No frequent/recent serious hypoglycemia
• Able/willing to take insulin, do glucose
  monitoring
• Eligible for BP or Lipid Trial
• LDL 60-180 mg/dl
• HDL lt 55 mg/dl (women, blacks), lt 50 (all others)
• TG lt750 (not on lipid therapy) or lt400 (on lipid
  therapy)

The ACCORD study group. Effects of intensive
glucose lowering in type 2 diabetes. N Engl J Med
20083582545-2559. The ACCORD Study Group.
Effects of combination lipid therapy in type 2
diabetes mellitus. N Engl J Med 2010. DOI
10.1056/NEJMoa1001282
5
ACCORD Glycaemic Control Arm

• Dr. Anita Chekuri
• CVA Ltd

6
Background

• An increase of 1 in the HbAIC is associated with
  an increase of 18 in the risk of cardiovascular
  events1
• Determine whether therapeutically targeting
  normal HbAIC levels (lt 6.0) would reduce the
  rate of cardiovascular events, as compared to
  targeting HbAIC from 7.0 to 7.92
• The finding of higher mortality in the
  intensive-therapy group led to termination of the
  intensive regimen 17 months before the scheduled
  end of the study2

1Selvin E, Marinopoulos S, Berkenblit G, et al.
Meta-analysis glycosylated hemoglobin and
cardiovascular disease in diabetes mellitus. Ann
Intern Med 2004141421-431 2The ACCORD study
group. Effects of intensive glucose lowering in
type 2 diabetes. N Engl J Med 20083582545-2559.
7
Randomization
BP trial BP trial Lipid trial Lipid trial
Glycaemic trial SBPlt110mmHg SBPlt140mmHg Group A Group B Total
HbAIC lt 6 1178 1193 1383 1374 5128
HbAIC 7.0-7.9 1184 1178 1370 1391 5123
2362 2371 2753 2765
Total 4733 4733 5518 5518 10251
The ACCORD study group. Effects of intensive
glucose lowering in type 2 diabetes. N Engl J Med
20083582545-2559.
8
Outcomes

• Primary
• First occurrence of nonfatal MI, nonfatal Stroke,
  or death from CV disease.
• Secondary
• Death from any cause.
• Also measured the effect of the intervention on
  microvascular disease, hypoglycemia, cognition,
  and quality of life.
• Intensive glycaemic control arm terminated in 3.5
  years (instead of 5.6 years as planned for)

The ACCORD study group. Effects of intensive
glucose lowering in type 2 diabetes. N Engl J Med
20083582545-2559.
9
Baseline Characteristics
Intensive (N 5128) Standard (N 5123)
Age 62.2 62.2
Women 38.7 38.4
Median DM Duration 10 10
Previous CVD Event 35.6 34.8
White/Black 64.4/19.7 64.5/18.9
Current Smoker 14.3 13.7
Mean BMI 32.2 32.2
Mean SBP/DBP 136.2/74.8 136.5/75.0
Mean/Median A1C 8.3 / 8.1 8.3 / 8.1
Mean FG 175 176
Mean LDL / HDL 105 / 47 105 / 47
The ACCORD study group. Effects of intensive
glucose lowering in type 2 diabetes. N Engl J Med
20083582545-2559.
10
Median Glycated Hemoglobin Levels at Each Study
Visit
The Action to Control Cardiovascular Risk in
Diabetes Study Group. N Engl J Med
20083582545-2559
11
(No Transcript)
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Adverse Events, Clinical Measures, Tobacco Use,
and Use of Nonglycemic Medication after
Randomization
The Action to Control Cardiovascular Risk in
Diabetes Study Group. N Engl J Med
20083582545-2559
13
Primary and Secondary Outcomes
The Action to Control Cardiovascular Risk in
Diabetes Study Group. N Engl J Med
20083582545-2559
14
Kaplan-Meier Curves for the Primary Outcome and
Death from Any Cause
The Action to Control Cardiovascular Risk in
Diabetes Study Group. N Engl J Med
20083582545-2559
15
Hazard Ratios for the Primary Outcome and Death
from Any Cause in Prespecified Subgroups
The Action to Control Cardiovascular Risk in
Diabetes Study Group. N Engl J Med
20083582545-2559
16
Observations

• Targeting HbAIC levels below 6.0 increased the
  rate of death from any cause after a mean of 3.5
  years
• Magnitude of reduction
• Speed of reduction
• Adverse drug interactions at high doses
• Rate of hypoglycaemia

The ACCORD study group. Effects of intensive
glucose lowering in type 2 diabetes. N Engl J Med
20083582545-2559.
17
Number of Participants With One or More Severe
Hypoglycemia Events Requiring Medical Assistance
(n and )
Intensive Group Intensive Group Standard Group Standard Group
Events n n
1 400 7.8 130 2.5
2 82 1.6 34 0.7
3 to 5 43 0.8 10 0.2
gt5 6 0.1 0 0
Cumulative number of events
The ACCORD study group. Effects of intensive
glucose lowering in type 2 diabetes. N Engl J Med
20083582545-2559.
18
Mortality By Treatment Group andSevere
Hypoglycemia
Overall Never Experienced a Hypoglycemic Event Experienced Hypoglycemic 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)
Hazard Ratio (95 CI) 1.22 (1.01, 1.46) 1.24 (1.02, 1.50) 0.54 (030, 0.96)
Mortality Higher in Intensive Group
Mortality Higher in Standard Group
Interaction P lt 0.01
The ACCORD study group. Effects of intensive
glucose lowering in type 2 diabetes. N Engl J Med
20083582545-2559.
19
Can we blame it all on hypoglycaemia?
Intensive Strategy
Higher Rates of Hypoglycemia
Higher Mortality
And can ACCORDdistinguish these?
No!
The ACCORD study group. Effects of intensive
glucose lowering in type 2 diabetes. N Engl J Med
20083582545-2559.
20
Observations

• Targeting HbAIC levels below 6.0 increased the
  rate of death from any cause after a mean of 3.5
  years
• Magnitude of reduction
• Speed of reduction
• Rate of hypoglycaemia
• Adverse drug interactions at high doses
• Longer time duration increases benefits of
  mortality from non-fatal MI, but also increases
  risk of death

The ACCORD study group. Effects of intensive
glucose lowering in type 2 diabetes. N Engl J Med
20083582545-2559.
21
Kaplan-Meier Curves for the Primary Outcome and
Death from Any Cause
The Action to Control Cardiovascular Risk in
Diabetes Study Group. N Engl J Med
20083582545-2559
22
Observations

• Targeting HbAIC levels below 6.0 increased the
  rate of death from any cause after a mean of 3.5
  years
• Magnitude of reduction
• Speed of reduction
• Rate of hypoglycaemia
• Adverse drug interactions at high doses
• Longer time duration increases benefits of
  mortality from non-fatal MI, but also increases
  risk of death

The ACCORD study group. Effects of intensive
glucose lowering in type 2 diabetes. N Engl J Med
20083582545-2559.
23
ACCORD Lipid Control Arm

• Dr. Anita Chekuri
• CVA Ltd

24
Background

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

The ACCORD Study Group. Effects of combination
lipid therapy in type 2 diabetes mellitus. N Engl
J Med 2010. DOI 10.1056/NEJMoa1001282
25
Method

• 5518 high risk for CV events on Simvastatin
  started at randomization
• Treatment group add fenofibrate at 1 month-
  2765
• Placebo group- 2753
• Follow-up- 4.7 years

The ACCORD Study Group. Effects of combination
lipid therapy in type 2 diabetes mellitus. N Engl
J Med 2010. DOI 10.1056/NEJMoa1001282
26
Randomization
BP trial BP trial Lipid trial Lipid trial
Glycaemic trial SBPlt110mmHg SBPlt140mmHg Group A Group B Total
HbAIC lt 6 1178 1193 1383 1374 5128
HbAIC 7.0-7.9 1184 1178 1370 1391 5123
2362 2371 2753 2765
Total 4733 4733 5518 5518 10251
The ACCORD Study Group. Effects of combination
lipid therapy in type 2 diabetes mellitus. N Engl
J Med 2010. DOI 10.1056/NEJMoa1001282
27
Outcomes

• Primary
• First occurrence of nonfatal MI, nonfatal Stroke,
  or death from CV disease
• Secondary
• Primary plus revascularization or hospitalization
  for CCF (expanded macrovascular outcome)
• Combination of fatal coronary event, nonfatal MI,
  or unstable angina (major coronary disease
  events)
• Death from any cause
• Hospitalization due to HF

The ACCORD Study Group. Effects of combination
lipid therapy in type 2 diabetes mellitus. N Engl
J Med 2010. DOI 10.1056/NEJMoa1001282
28
Results

• Mean LDL decrease of
• 100.0 to 81.1 in Fenofibrate group
• 101.1 to 80.0 in placebo group

The ACCORD Study Group. Effects of combination
lipid therapy in type 2 diabetes mellitus. N Engl
J Med 2010. DOI 10.1056/NEJMoa1001282
29
Lipid Values
The ACCORD Study Group. N Engl J Med
201010.1056/NEJMoa1001282
30
Prespecified Primary and Secondary Outcomes
The ACCORD Study Group. N Engl J Med
201010.1056/NEJMoa1001282
31
Kaplan-Meier Analyses of the Primary Outcome,
Expanded Macrovascular Outcome, and Death
The ACCORD Study Group. N Engl J Med
201010.1056/NEJMoa1001282
32
Hazard Ratios for the Primary Outcome in
Prespecified Subgroups
The ACCORD Study Group. N Engl J Med
201010.1056/NEJMoa1001282
33
Observations

• No significant difference in primary outcome
  between groups
• In subgroup analysis, sex difference was
  significant. Men seemed to benefit from
  Fenofibrate.
• Suggestion of heterogenisity with baseline TG and
  HDL levels.

The ACCORD Study Group. Effects of combination
lipid therapy in type 2 diabetes mellitus. N Engl
J Med 2010. DOI 10.1056/NEJMoa1001282
34
Thank You

• Any Questions?.........