1. Blood Pressure and Lipid Trials: Rationale, Importance and Design
Presented at the American Diabetes Association
68th Scientific Sessions on June 10, 2008.

2. DSMB Recommendation and NHLBI Decision
Discontinue intensive glycemia treatment
Transition all participants to the standard glycemia treatment
Continue the BP and Lipid trials
“These trials continue to address important questions”
NHLBI Press Release, February 6, 2008

3. ACCORD Background: Diabetes and CVD
Hypertension and dyslipidemia
Are more common in persons with diabetes
Disproportionately higher CVD risk with each risk factor (combination multiplicative)
Optimal treatments for these CVD risk factors in diabetes are unknown
Goff et al., Am J Cardiol 2007;99[suppl]:4i-20i

4. ACCORD Blood Pressure Trial4

5. Ischemic CHD Mortality VS. Usual BP Stratified by Age
120
140
160
180 1 2 4 8 16 32 64
128
256
Usual systolic BP (mm Hg)
Usual diastolic BP (mm Hg)
Ischemic Heart Disease mortality (floating absolute risk and 95% CI) 70 80 90
100
110
Age at risk:
80-89
years
70-79 years
60-69 years
50-59 years
40-49 years
Systolic Blood Pressure
Diastolic Blood Pressure
Systolic BP increases linearly with age whereas diastolic increases until about age 50, then declines
Prospective Studies Collaboration. Lancet. 2002;360:1903.

6. ACCORD BP Question
“In middle-aged or older men and women with type 2 diabetes who are at high risk for having a CVD event, in the context of good glycemic control, does a therapeutic strategy that targets a systolic blood pressure <120mmHg reduce the rate of CVD events more than a strategy that targets a systolic blood pressure of <140 mmHg?”

7. Rationale for BP Trial
SHEP DM Participants same RRR as others, but still at 2X AR.
HOT DM Sub-Group 51% RRR, others not.
UKPDS-Intensive Group (<150/85 vs <180/105)
Reduced DMRE 24%
Reduced Deaths DMR 32%
Reduced Strokes 44%
Reduced MVEP 37%
SystEUR-Similar to SHEP
ABCD-Microvascular Events Reduced
Evidence very modest for BPs <144/<82
Regimens: Used agents shown beneficial in DM
ACE-I or ARB: Strongly suggest use in those with previous events

8. Clinical Trials of BP Lowering in Diabetic Patients: Mean Achieved Systolic (SBP)
Mean SBP
< intense
> intense
CVD Risk
Reduction
SHEP
583
155
146
22-56%
Syst-EUR
492
162
153
62-69%
HOT
1,501
148
144
30-67%
UKPDS
1,148
154
32-44%
ABCD
470
138
132
No CVD ↓
ADVANCE
11,140
140
135
14% mortality ↓

9. Treatment Algorithm for Intensive BP (SBP Goal <120 mmHb)

10. Treatment Algorithm for Standard BP (SBP Goal >140 mmHg)

11. BP Agents Used: A Test of Strategy
Number single antihypertensive medications – 13
Number of combination medications – 7
Number of classes – 10
Diuretics – 2
ACE-inhibitors – 3
β-blockers – 1
Dihydropyridine CCB – 1
Non-dihydropyridine CCB – 1
ARBs – 2
α-blockers – 1
Sympatholytics – 1
α-β blockers – 1
Vasodialators – 1

12. ACCORD Lipid Trial 12

13. Mortal Events/mmol/L Reduction in LDL-C in those With or Without DM
CTT Collaborators, Lancet :

14. Major CVD Events/mmol/L Reduction in LDL-C in those With or Without DM
CTT Collaborators,The Lancet :

15. Serum cholesterol quintile
Cholesterol Predicts CHD Mortality Rate in Diabetic and Nondiabetic Men: MRFIT Study
Rate/1000
Serum cholesterol quintile 80 60 40 20
Diabetic
Nondiabetic
Bierman EL. Arterioscler Thromb. 1992;12:

16. ACCORD Lipid Question
“In the context good glycemic control, does a therapeutic strategy that uses a fibrate to increase HDL-C and lower triglyceride levels together with statin to lower LDL-C reduce the rate of CVD events compared with a strategy that uses a statin plus a placebo?”

17. Rational for Lipid Trial
Increasing importance of DM: ATP I to III
CHD event rates high in trials even with effective statin treatment
Dyslipidemia in DM:
HDL-C Decreased
TGs Increased
TC similar in men, slightly higher in women
Treatment beyond statins needed to address LDL-C and other aspects of dyslipidemia
Concern about niacin and ultimately gemfibrozil
Fenofibrate selected

18. BP
Lipid
Intensive
(SBP<120)
Standard
(SBP<140)
Statin + Masked Study Drug
Statin + Masked Study Drug
Intensive
Glycemia
(A1C<6%)
1178
1193
1383
1374
5128*
Standard
Glycemia
(A1C 7-7.9%)
1184
1178
1370
1391
5123*
2362*
2371*
2753*
2765*
10,251
*Primary analyses compare the marginals for main effects

19. Statistical Power for BP and Lipid
BP: 94% power to detect 20% effect
Lipid: 87% power to detect 20% effect
Composite CVD outcome
Nonfatal MI, nonfatal stroke, CVD death
ACCORD Study Group, Am J Cardiol 2007;99[suppl]:21i-33i

20. Decision to discontinue intensive glycemia treatment
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
RFP &
Funding
Main Trial
Starts
Recruitment
ends Tx
continues FU
ends
Results
Published
Vanguard
Phase (1,174 pts)
starts