Transcript DRUG THERAPY OF OBESITY: METFORMIN (UKPDS)

TREATING LIPIDS FOR PREVENTION
OF CAD :
HOW AGGRESSIVE SHOULD WE BE?
Robert B. Baron MD MS
Professor and Associate Dean
UCSF School of Medicine
Declaration of full disclosure: No conflict of
interest
IN CLINICAL TRIALS
WE TRUST
A RISK-BASED APPROACH
Risk
reduction
$$
Harm
The magnitude of benefit from any given intervention is a function of:
1) The relative risk reduction conferred by the intervention, and
2) The native risk of the patient
STATIN MEGA TRIALS:
PRE-ATP III
Primary Prevention
Secondary Prevention
1994 - 4S (Scandinavian Simvastatin)
1995 - WOSCOP (West of Scotland)
1996 - CARE
1998 - LIPID Trial
1998 - AFCAPS / TexCAPS
NEWER STATIN TRIALS:
POST-ATP III
Primary Prevention
Secondary Prevention
2002 - Heart Protection Study (simva 40)
2002 - PROSPER (prava 40)
2003 - ALLHAT (prava 40)
2003 - ASCOT
(atorva 10)
2004 - PROVE IT (prava 40 vs atorva 80)
2004 - CARDS (atorva 10 in DM)
2005 - TNT (atorva 10 vs atorva 80)
63 yo woman; s/p MI
LDL 115
HDL 45
TG 160
LDL Goal and Cutpoints in Patients with CHD and CHD
Risk Equivalents (10-Year Risk >20%)
2001
LDL Goal
<100 mg/dL
LDL Level at Which to
Initiate Diet
100 mg/dL
LDL Level at Which to
Consider Drug Therapy
130 mg/dL
(100–129 mg/dL:
drug optional)
LDL Goal and Cutpoints in Patients with CHD and CHD
Risk Equivalents (10-Year Risk >20%)
2004
LDL Goal
<100 mg/dL
Optional : <70
LDL Level at Which to
Initiate Diet
100 mg/dL
LDL Level at Which to
Consider Drug Therapy
100 mg/dL
(<100mg/dL:
drug optional)
HEART PROTECTION STUDY
• RCT of 20,536 high-risk individuals; 40-80 yr
• Total cholesterol >135 mg/dl (>3.5 mmol/L)
• Confirms efficacy of statin in secondary
prevention:
All-cause mortality: 12.9% vs 14.7%
CAD mortality: 5.7% vs 6.9%
• Benefit seen in subgroups poorly represented in
other trials
HPS: Vascular Events
by Baseline LDL-C
No. Events
Baseline
Feature
Statin
(10,269)
Placebo
(10,267)
Risk Ratio and 95% Cl
Statin better
worse
Statin
LDL (mg/dL)
<100
285
360
≥100 <130
670
881
1087
1365
2042
(19.9%)
2606
(25.4%)
≥130
ALL PATIENTS
24% reduction
(p<0.00001)
0.4 0.6 0.8 1.0 1.2 1.4
TREATING TO NEW TARGETS (TNT)
• RCT of 10,001 patients with stable CHD; 35-75 yr
• LDL <130 mg/dl
• Atorvastatin 10 vs atorvastain 80
• Followed for 4.9 years
• Research question: safety and efficacy of
lowering LDL below 100 mg/dl
LaRosa, NEJM 2005
TREATING TO NEW TARGETS (TNT)
Atorv 10
LDL
101
Event %
10.9
Atorv 80
77
8.7
2.0
<0.001
0.09
p value
Death %
2.5
 LFTs %
0.2
1.2
LaRosa, NEJM 2005
“The Lower, the Better”
3.7
1
2.9
Relative
2.2
Risk
for CHD 1.7
(Log Scale)
1.3
1.0
0
40
70
100
130
160
LDL-C (mg/dL)
Grundy SM et al. Circulation 2004;110:227–239.
190
63 yo woman; diabetes
LDL 115
HDL 45
TG 160
HPS: Vascular Events
by Prior Disease
No. Events
Baseline
Feature
Statin
(10,269)
Risk Ratio and 95% Cl
Placebo
(10,267)
Previous MI
1007
1255
Other CHD
452
597
CVD
182
215
PVD
332
427
Diabetes
279
369
Statin better
Statin worse
No prior CHD
ALL PATIENTS
2042
(19.9%)
24%
reduction
(p<0.00001)
2606
(25.4%)
0.4
0.6
0.8
1.0
1.2
1.4
COLLABORATIVE ATORVASTATIN
DIABETES STUDY (CARDS)
• RCT of 2838 patients, 40-70, with DM2 + HTN,
cigs, or diabetic complication
• LDL 117 mg/dl
• Atorvastatin 10 vs placebo
• Followed for 4 years
• Research question: is statin better than placebo
for primary prevention in patients with diabetes?
Colhoun, Lancet, 2004
COLLABORATIVE ATORVASTATIN
DIABETES STUDY (CARDS)
• Trial terminated two years early
• Placebo 127 events vs. atorvastain 83
• Reduction 37% all events
• Reduction in CHD (36%), revascularisations
(31%), stroke (48%), death (27%)
Colhoun, Lancet, 2004
FENOFIBRATE INTERVENTION AND
EVENT LOWERING IN DIABETES
(FIELD) STUDY
• RCT of 9795 patients, 50-75, with DM2
• Fenofibrate 200 vs placebo
• Followed for 5 years
• Outcome: coronary events
Lancet, 2005
FENOFIBRATE INTERVENTION AND
EVENT LOWERING IN DIABETES
(FIELD) STUDY
• Coronary events:
– 5.9% on placebo vs. 5.2% on
fenofibrate
• 11% reduction, not statistically significant
• HR 0.89 (95% CI 0.75 - 1.05) p=0.16
Lancet, 2005
CHD Risk Equivalents
Risk for major coronary events equal to that in
established CHD e.g. >20%risk of MI or CHD
death in 10 years
•
•
•
•
•
Peripheral artery disease
Abdominal aortic aneurysm
Symptomatic CVD
Diabetes
Multiple risk factors with >20% risk in 10 years
Other Potential CHD Risk Equivalents
Risk for major coronary events equal to that in
established CHD e.g. >20%risk of MI or CHD
death in 10 years
• Renal insufficiency: yes
• Congestive heart failure: yes
• Metabolic syndrome: probably not (calculate
Framingham risk)
LDL Goal and Cutpoints in Patients with CHD and CHD
Risk Equivalents (10-Year Risk >20%)
2004
LDL Goal
<100 mg/dL
Optional : <70
LDL Level at Which to
Initiate Diet
100 mg/dL
LDL Level at Which to
Consider Drug Therapy
100 mg/dL
(<100mg/dL:
drug optional)
63 yo man; s/p MI
LDL 70
HDL 25
TG 400
63 yo man; s/p MI
{LDL 70, HDL 25, TG 400, Total 175}
Total - HDL = Non-HDL
175 - 25 = 150
NCEP non-HDL goal:
LDL goal + 30 = 100
Low HDL-C is an Independent Predictor of CHD Risk
Even When LDL-C is Low
25
100
160
220
LDL-C (mg/dL)
Gordon T et al. Am J Med 1977;62:707-714.
85
45 HDL-C
65
(mg/dL)
Management of Low HDL-C
Therapeutic lifestyle changes
– Smoking cessation
– Regular aerobic exercise
– Weight loss
– Alcohol use?
Cumulative Incidence
(%)
VA-HIT: Major Coronary Events in
Gemfibrozil vs. Placebo Groups
Placebo
–22%
reduction
P = 0.006
0
1
2
Gemfibrozil
3
Year
4
Rubins HB et al. N Engl J Med 1999;341:410-418.
5
6
Combination Drug Therapy
Adding Niacin or a Fibrate to a Statin
Pros
•Better  TG and  HDL-C
•May  LDL-C more
(niacin or fenofibrate)
• Lp(a) (niacin)
• LDL particle size
• Fibrinogen (fibrates)
•Angiographic data
Cons
• Increased cost and
complexity
• Increased myositis risk
• Increased hepatitis risk
(niacin)
• Potential for other drug
interactions
• Lack of outcome data
Management of Low HDL-C
Lifestyle changes and secondary causes
Pharmacologic therapy
– If LDL-C elevated: statin
– If TG elevated: fibrate or fish oil
– If isolated low HDL-C: niacin
Combination therapy
63 yo woman, no risk factors
LDL 175
HDL 45
TG 160
POSITIVE RISK FACTORS
• Age: Men >45: women >55
• Family history premature CHD
• Cigarette smoking
• Hypertension
• Low HDL-cholesterol (<40 mg/dl)
NEGATIVE RISK FACTOR
High HDL-cholesterol >
60 mg/dl
LDL Goal and Cutpoints
Patients with 0–1 Risk Factor
2001 and 2004
LDL Level at Which to
Initiate Diet
LDL Goal
<160 mg/dL
160 mg/dL
LDL Level at Which to
Consider Drug Therapy
190 mg/dL
(160–189 mg/dL:
LDL-lowering drug
optional)
63 year old woman, HTN
LDL 175
HDL 45
TG 160
SBP 120 on RX
Nonsmoker
POSITIVE RISK FACTORS
• Age: Men >45: women >55
• Family history premature CHD
• Cigarette smoking
• Hypertension
• Low HDL-cholesterol (<40 mg/dl)
LDL Goal and Cutpoints
Patients with Multiple Risk Factors (10-Year Risk  20%)
2001
LDL Level at Which to
Initiate Diet
LDL Goal
LDL Level at Which to
Consider Drug Therapy
10-year risk 10–20%:
130 mg/dL
<130 mg/dL
130 mg/dL
10-year risk <10%:
160 mg/dL
LDL Goal and Cutpoints
Patients with Multiple Risk Factors (10-Year Risk  20%)
2004
LDL Level at Which to
Initiate Diet
LDL Goal
<130 mg/dL
130 mg/dL
LDL Level at Which to
Consider Drug Therapy
10-year risk 10–20%:
≥130
Optional 100-129
10-year risk <10%:
160
On-line and PDA tools
 www.nhlbi.nih.gov/guidelines/cholesterol
 www.statcoder.com
 www.med-decisions.com
63 yo woman, HTN
LDL 175
HDL 45
TG 160
SBP 120 on RX
Nonsmoker
NCEP: yes
10 yr risk: 6%…maybe not
63 yo man, HTN
LDL 175
HDL 45
TG 160
SBP 120 on RX
Nonsmoker
NCEP: yes
10 yr risk: 18%…yes
63 yo woman, no risks
LDL 175
HDL 45
TG 160
SBP 120
Nonsmoker
NCEP: no treat
10 yr risk: 3%…no
63 yo man, no risk factors
LDL 175
HDL 45
TG 160
SBP 120
Nonsmoker
NCEP: no treat
10 yr risk: 13%…yes
EMERGING RISK FACTORS
• Lipoprotein (a)
• Small Dense LDL
• Homocysteine
• Fibrinogen
• Inflammatory factors
• Subclinical
atherosclerosis
EMERGING RISK FACTORS
• Evidence review of CRP, Lp(a),
fibrinogen, homocysteine
• All independently associated with CVD
• Little evidence of additional yield over
Framingham risk factors
• Less evidence on use in guiding
treatment
• Explanatory power of established risk
factors underestimated
Coronary Artery Calcium
“Heartscan™”
Does it just reflect what we already know?
Adjusted RR estimates from meta-analysis
CAC score
0
1-100
101-400
> 400
Pletcher et al; Arch Int Med 2004; 164:1285-68
RRadj (95% CI)
1 (ref)
2.1 (1.6-2.9)
5.4 (2.2-13)
10 (3.1-34)
C-reactive protein (CRP)
Meta-analysis of cohort studies
RR 1.7 for top third vs. bottom third
Mean CRP levels 2.4 in top third, 1.0
in bottom
C-reactive protein (CRP)
Hard to directly integrate into the Framingham risk….
Rough calculations:
CRP in top third increases risk by
factor of 1.2-1.3
Risk in top tertile = 1.3x
Average risk = x
Risk in middle tertile = x
Risk in middle tertile = 0.7x
CONCLUSIONS
 Patients with CHD or CHD equivalent:
• Treat aggressively with statin independent of
LDL level (to LDL <70 in most cases)
• Treat other risk factors aggressively as well,
especially easy ones (HTN, Aspirin use)
• Treat elevated non-HDL cholesterol and low
HDL
• Patients at high risk are undertreated
CONCLUSIONS
 Patients without CHD:
• Assess overall risk with Framingham risk score
LDL goal
High Risk (>20%)
<100 (<70 optional)
Mod high risk (10-20%) <130
Moderate risk (5-10%)
<130
Lower risk (<5%)
<160
LDL treatment threshold
≥100 (<100 optional)
≥130 (100-129 optional)
≥160
≥190 (160-189 optional)
• Engage patient in shared decision making, especially
if risk <10%