2011 Annual Diabetes Practice Update
Session:
Update on Cardiovascular Disease & Diabetes:
Prevention of CVD in Patients with Diabetes
September 30th, 2011
Craig Williams, Pharm.D., FNLA
Associate Professor; OSU School of Pharmacy and OHSU School of Medicine
williacr@ohsu.edu
2011 Annual Diabetes Practice Update
Session:
Prevention of CVD Atherothrombosis in Patients with Diabetes
September 30th, 2011
Craig Williams, Pharm.D., FNLA
Associate Professor; OSU School of Pharmacy and OHSU School of Medicine
williacr@ohsu.edu
Presenter Disclosure Information
In compliance with the accrediting board policies, the
American Diabetes Association requires the following
disclosure to the participants:
Name of Presenter: Craig Williams, Pharm.D., FNLA
Research Support: Merck & Co., Inc.
Speakers Bureau: Merck & Co., Inc.
VI. Prevention and management of
complications
A. Cardiovascular disease
1. HTN control
2. Dyslipidemia management
3. Anti-platelet
4. Smoking cessastion
5. Hyperglycemia?
There is a clear epidemiologic association between glycemic control and CVD
NEW ENGLAND JOURNAL OF MEDICINE
March 4, 2010
Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Nondiabetic Adults
Elizabeth Selvin, Michael Steffes, Hong Zhu, Kunihiro Matusushita, et al.
Data from 11,092 black and white
subjects in the ARIC trial
(Atherosclerosis Risk in
Communities)
Median follow approximately 14
years.
Despite clear epidemiology, controversy continues regarding the role of glucose
lowering to prevent coronary events
ADA position on glycemia
and macrovascular disease in
2010 Standards of Care
guideline
ADA Standards of Care. Diabetes Care
2010;33:S11-62
Three large trials of glycemic control published in 2008 failed to find CVD
benefit
Non-fatal MI significantly reduced 24% (p=0.001)
So hyperglycemia doesn’t matter to the heart?
Sklyer JS, et al. Intentive glycemic control and the prevention of cardiovascular events. A position statement of the
ADA/ACC/AHA. Diabetes Care 2009;32:187-92.
Hyperglycemia is toxic at several steps in the atherosclerosis process
Retnakaran R, Zinman B. Lancet 2008;371:1790-99.
Failure to find benefit may have related to the A1C levels tested:
6.4% vs. 7.5%
6.3% vs. 7.0%
6.9% vs. 8.5%
So hyperglycemia matters to the heart but intense control (A1C < 7%) provides little
additional benefit over moderate control (A1C 7-8%)
Sklyer JS, et al. Intentive glycemic control and the prevention of cardiovascular events. A position statement of the ADA/ACC/AHA. Diabetes
Care 2009;32:187-92.
2011 ADA guideline appropriately
discusses microvascular benefits of A1C
< 7% while acknowledging lack of
proven macrovascular benefits at the
A1C values that were studied.
VI. Prevention and management of
complications
A. Cardiovascular disease
1. HTN control
2. Dyslipidemia management
3. Anti-platelet
4. Smoking cessastion
2. Dyslipidemia/ lipid management
ADA Standards of Care; Diabetes Care, January 2011
“Alternative goals…..”
Three points critical to understanding the evidence base of the ADA
guidelines for lipid management:
1.
The etiologic role of lipoproteins in atherosclerosis
2.
The etiology of dyslipidemia as seen in patients with diabetes
3.
The clinical outcomes literature in patients with diabetes
1.
Atherosclerosis is a lipoprotein driven process
Basic Science for Clinicians
Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis
Update and Therapeutic Implications
Ira Tabas, MD, PhD;
Kevin Jon Williams, MD;
Jan Borén, MD, PhD
Circulation, October 16th, 2007
Lipoproteins share structural homology
Chylomicrons, VLDL, IDL, LDL, HDL all share a basic biochemistry
TG
Liver
Lipase
enzymes
VLDL
Lipase
enzymes
LDL
IDL
LDLc
Fredrickson Classification of Dyslipidemia
We look at this
Artery wall sees these
Appearance of
serum
Elevated
particles
Type
(%)
I (~1%)
Associated clinical disorders
TC
TG
Creamy top layer
Chylomicrons,
VLDL
Lipoprotein lipase deficiency, apolipoprotein C-II
deficiency
+
+++
IIa (10%)
Clear
LDL
Familial hypercholesterolemia, polygenic
hypercholesterolemia, nephrosis, hypothyroidism,
familial combined hyperlipidemia
++
↔
IIb (40%)
Clear
LDL, VLDL
Familial combined hyperlipidemia
++
+
III (~1%)
Turbid
IDL
Dysbetalipoproteinemia
+
+
IV (45%)
Turbid
VLDL
Familial hypertriglyceridemia, familial combined
hyperlipidemia, sporadic hypertriglyceridemia,
diabetes
+
++
Creamy top, turbid
bottom
Chylomicrons,
VLDL (remnants)
Diabetes
+
++
V (5%)
The primary atherogenic lipoprotein is LDL
lipoproteins of > 70 nm have limited transcytosis past the endothelium
Nascent
chylomicron
Monocyte
Χ
Adhesion
Molecules
Nascet
VLDL
Χ
MCP-1
Artery wall
Vessel Lumen
LDL
Endothelium
LDL
Modified LDL
Taken up by
Macrophage
Foam Cell
Macrophage
Steinberg D et al. N Engl J Med 1989;320:915-924.
Intima
2. Dyslipidemia vs. hyperlipdemia:
Prevalence in NHANES 2008 data: High TG or low HDLc more
common than high LDLc
Am Heart J 2008;156:112-119
Prevalence of Dyslipidemia is high in Type 2 Diabetes
Patients With
Diabetes, %
Patients Without
Diabetes, %
P Value
LDL-C
> 100 mg/dL
74.7
75.7
NS
HDL-C
< 40 mg/dL (men)
< 50 mg/dL (women)
63.7
40.0
< .001
Triglycerides
> 150 mg/dL
61.6
25.5
< .001
Control of Lipids
N = 498 adults (projected to 13.4 million) aged > or = 18 years with diabetes representative of the US
population and surveyed within the cross-sectional National Health and Nutrition Examination Survey
1999-2000.
Jacobs MJ, et al. Diabetes Res Clin Pract. 2005;70:263-269.
‘Dyslipidemia’ is a state of relative insulin resistance resulting in a conversion of adipose
tissue to an exocrine state. Excessive production of free fatty acids (FFA) increases hepatic
VLDL production
Fat Cells
 FFA
↑ TG
↑ ApoB
↓ HDLc
↔ LDLc
Liver
 FFA
CE
HDL
VLDL
Kidney
CETP
X
Insulin
resistance
TG
ApoA-I
TG
CE
CETP
IDL
Small, dense
LDL
LDL
Insulin
Hepatic lipase
Lipoprotein lipase
or hepatic lipase
CE, cholesteryl esters; FFA, free fatty acids; TG, triglycerides.
Ginsberg HN. J Clin Invest. 2000;106:453–458.
Liver
While LDLc is similar,
particle burden is heavier
LDL particle count vs. cholesterol content
To carry the same amount of cholesterol, a larger number of particles are needed if they are
smaller
Large, buoyant: 30-35 nm
LDLc=115 mg/dl
apoB is a measure of number of atherogenic
lipoproteins (essentially VLDL, IDL, LDL).
Non-HDL is measure of cholesterol carried in
these same particles
Small, dense: 25-30 nm
LDLc=115 mg/dl
LDLc measures cholesterol carried
in LDL and IDL
Summary: Patients with diabetes have elevated TG
and lower HDLc but also a greater number of LDL
particles which confers greater risk at any measured
LDLc value
3.
What are the data for LDLc lowering?
ADA guidelines: Major statin trials or sub-studies in diabetic patients
Lancet 2004;364:685
Diabetes Care 2006;29:1220
Lancet 2003;361:2005
Diabetes Care 2006;7:1478
Diabetes Care 1997;20:614
*Num. needed to treat (NNT) for moderate-high risk DM to avoid one death or MI:
3-50
ADA Standards of Care; Diabetes Care, January 2011
Reduction in 10-year CVD events with statin therapy in patients with diabetes:
Event reduction correlates with relative risk – more risk, more benefit
Endpoint: 10-year Fatal CHD/Non-fatal MI and LDL lowering
2○
Relative Risk reduction
ARR
LDL reduction

4S-DM
85.7 to 43.2% (50%)
42.5%
186 to 119 mg/dL (36%)

ASPEN 20
35.1 to 23.2% (34%)
11.9%
112 to 79 mg/dL (29%)

HPS-DM 20
43.8 to 36.3% (17%)
7.5%
123 to 84 mg/dL (31%)

CARE-DM
40.8 to 35.4% (13%)
5.4%
136 to 99 mg/dL (27%)

TNT-DM
26.3 to 21.6% (18%)
4.7%
99 to 77 mg/dL (22%)
HPS-DM 10
17.5 to 11.5% (34%)
6.0%
124 to 86 mg/dL (31%)

CARDS
11.5 to 7.5% (35%)
4%
118 to 71 mg/dL (40%)

ASCOT-DM
11.1 to 10.2% (8%)
0.9%
125 to 82 mg/dL (34%)

ASPEN 10
9.8 to 7.9% (19%)
1.9%
114 to 80 mg/dL (30%)
1○ 
10: Primary prevention data
20: Secondary prevention
The differential benefit of LDLc lowering in patients with diabetes has been
evident from the earliest statin trials and is more evidence that higher
risk=greater benefit : 4S study: Major Coronary Events
Coronary Death and non-fatal MI
Percent of patients
without major CV event
100
90
80
Diabetic - simvastatin
70
55%
Diabetic – simvastatin
Diabetic – placebo
Nondiabetic – simvastatin
Nondiabetic - placebo
60
50
0
0
1
2
3
Risk reduction
Diabetic - placebo
4
5
p=0.002
6
Years since randomization
Pyörälä K, et al. Diabetes Care. 1997;20:614–620
Within a given population, lower goals do further reduce CVD
events: Risk Curve Concept
Higher risk patients have more to gain from aggressive therapy
Cardiovascular Event Rate (%)
80
CHD + Diabetes
70
60
50
CHD + MS or IFG
40
30
CHD - NoMS or IFG
20
Diabetes - No CVD
10
No CVD - No diabetes
0
0
20
40
60
80
100
120
140
LDL (mg/dL)
Robinson JG, Stone NJ. Am J Cardiol. 2006;98:1405-1408
160
180
200
What aggressive LDL lowering does: reduces atheroma volume in
arterial wall providing plaque ‘stabilization’
Treated: LDLc of 84 mg/dL (47%
reduction)
Untreated: LDLc of 163 mg/dL with
statin+resin
Brown et al. Arter Thromb Vasc Biol 2001;21:1623
LDLc lowering and residual risk – more is needed
The majority of CVD events still occur: CVD events occurring in the ontreatment groups in major statin trials
J Am Coll Card 2005;46:1225-8
%
CHD
events
on
statin
N
4,444
∆LDL -36%
TxLDL 119
9,014
-25%
154
secondary
4,159
-28%
98
20,536
-29%
90
high risk
6,595
-26%
113
6,605
-27%
112
primary
Despite the need beyond LDLc lowering, outcomes data
supporting combination therapy still limited
ADA Standards of Care; Diabetes Care, January 2011
The lipid arm of the ACCORD trial was relatively disappointing for
combination therapy (as was FIELD in 2005)– WHY?
April 29, 2010 N Engl J Med
Conclusion: “The combination of fenofibrate and simvatatin did not reduce the rate of
fatal cardiovascular events, non-fatal MI or non-fatal stroke, as compared with simvatatin
alone.”
ACCORD
LIPID: Lipid
parameters
ADA guidelines changed text related to lipoprotein control in 2008:
ADA guidelines, 2007
ADA guidelines, 2008-2011
Statins are safe but nothing is without risk: Review of 35 statin
therapy trials
FDA-approved statin* monotherapy vs placebo (N = 74,102)
Outcome
Statin
(%)
Placebo
(%)
RD
P value
Statin better
Myalgias
15.4
18.7
2.7
0.37
CK elevations
0.9
0.4
0.2
0.64
Rhabdomyolysis
0.2
0.1
0.4
0.13
LFT elevation
1.4
1.1
4.2
<0.01
AE discontinuation
5.6
6.1
-0.5
0.80
-30
*Atorvastatin, fluvastatin, lovastatin, pravastatin,
rosuvastatin, simvastatin
CK = creatine kinase
AE = adverse events
Placebo better
-15
0
15
Risk difference per 1000 patients (RD)
(95% CI)
30
Kashani A et al. Circulation. 2006;114:2788-97.
Subjective myopathy incidence is high but myositis and
rhabdomyolysis is low
20,536 patients from HPS (40mg simvastatin vs. placebo): 8 cases of rhabdomyolysis,
3 on placebo
Lancet 2002;360:7-23
Rhabdomyolysis per 10,000 person-years of therapy with lipid lowering agents*
Drug
Monotherapy incidence
rates
+agent
Combo. Incidence
rates‡
Atorvastatin
0.54
fenofibrate
22.45
Cerivatatin
5.34
gemfibrozil
1035
Simvastatin
0.49
gemfibrozil
18.73
Gemfibrozil
3.70
*Data from 252,460 patients enrolled in 11 different health care plans in U.S. with at least 180 days enrolled in
respective health care plan
‡ Data based on 7300 patient-years of combination therapy
Data from: [CDER] Graham D. JAMA 2004;292:2585-2590.
Use of run-in phases in recent, large trials of statin drugs results in likely underestimation of myopathy incidence in practice
Waters DD et al. Am J Cardiol. 2004;93:154-8.
HPS investigators, Lancet 2002;360:7-22
Run-in
Control
Wash-out
Blinded Statin
Statin 40-80 mg
1-8 weeks
HPS:
TNT:
63,603 patients
18,469 patients
4-8 weeks
32,145
15,464
~ 5 years
20,536
10,003
Run-in: HPS, of 11,609 excluded after drug exposure, 1% for selfidentifed ADRs
TNT, of 5,461 excluded after drug exposure, 3.7% for selfidentified ADRs
Lipid summary:
Lipid management for cardiometabolic risk reduction:
• Use statin-based LDLc-lowering therapy to:
• Achieve LDLc < 100 mg/dL in patients with diabetes 40 years of age and older
with another risk factor
• Achieve LDLc < 70 mg/dL in patients with diabetes and CVD
VI. Prevention and management of
complications
A. Cardiovascular disease
1. HTN control
2. Dyslipidemia management
3. Anti-platelet
4. Smoking cessastion
Historic goal SBP of < 130 mmHg in diabetes is an extrapolation
of data regarding benefits in nephropathy
AJKD 2004;43(suppl 1):S120
July, 2009
Haven’t previous trials found a benefit from tighter BP control in diabetes?
…ended up comparing mean of 154/87 to 144/82
Four trials looked at major CVD outcomes based on randomized BP control;
Two trials (ABCD) were exclusively in patients with diabetes
Cochrane review 2009
April 29th, 2010
N Engl J Med
ACCORD BP: Using an average of 3 drugs, the authors achieved a SBP of 119
mmHg vs. 133 mmHg
ACCORD BP: Results
Conclusions: “In patients with type 2 diabetes at high risk for cardiovascular events,
targeting a systolic blood pressure of less than 120 mmHg, as compared with less
than 140 mmHg, did not reduce the rate of fatal and nonfatal major CVD events.”
Implications on practice
 Summary of the evidence:
 Lower BP goals
Trial
Goal (mmHg)
Achieved (mmHg)
ABCD (H)
DBP 75 vs 80-89
132/78 vs 138/86
ABCD (N)
DBP 10 < baseline vs 80-89
128/75 vs 137/81
ACCORD
SBP <120 vs <140
119/64 vs 133/70
 Lower BP goals:
 Do not change overall CV outcomes (all 3 trials).
 Do reduce rates of stroke (ABCD (H) and ACCORD, but how clinically sig?).
 Do help to reduce the progression of nephropathy in terms of urinary albumin excretion and
progression of microalbuminuria to overt albuminuria (ABCD (H) and (N)).
VI. Prevention and management of
complications
A. Cardiovascular disease
1. HTN control
2. Dyslipidemia management
3. Anti-platelet
4. Smoking cessastion
We have known for decades that platelets are more “responsive” in
patients with diabetes. Reasons are still not fully understood nor the
impact on use of anti-platelet agents
NEJM 2007;357:2482-94
The promiscuous platelet: many pathways exist for platelet activation. So do
overactive platelets respond better or less well to standard anti-platelet therapy?
Pignone M, Williams CD. Nature Review Endo, November 2010
ASA: The benefit of anti-platelet therapy is greater in higher risk patients and
quite low in low risk patients
Carlo Patrono, Barry Coller, Garret A. FitzGerald, Jack Hirsh, and Gerald Roth
CHEST 2004;126: 234S-264S.
2 Events prevented per
1000 treated in healthy
population
Case for CVD prevention with ASA in moderate risk patients not so clear
FDA committee votes not to approve aspirin for the primary prevention of MI
Tue, 09 Dec 2003 21:00:00 Michael O'Riordan
Gaithersburg, MD - The evidence supporting the use of aspirin for the primary prevention of MI
failed to hold up to the scrutiny of the FDA's Cardiovascular and Renal Drugs Advisory
Committee at its most recent December 8, 2003 meeting.
The committee voted overwhelmingly 11 votes against and three votes for approval of the petition
sought by Bayer Corp to approve aspirin for the reduction of the risk of a first MI in moderate-risk
patients, those with a 10-year coronary heart disease risk >10%.
Despite the existing data, which consisted of five major clinical trials, the committee felt the
evidence supporting the extended label for aspirin was inconsistent at best or lacking at worst.
While the benefit
aspirininincreases
increases,
bleedingwith
staysASA
constant
Risk vs.ofbenefit
primary as
vs.risk
secondary
prevention
So the benefits of antiplatelet therapy in low-risk patients is offset by major bleeding
episodes:
NEJM 2005;353:2373-83
Diabetes Care, June 2010
2009 Update from Oxford group on clinical trials evidence
for aspirin
Meta-analysis in general population for primary prevention:
Conclusion: “For primary prevention, aspirin is of uncertain net value as reduction in
occlusive events is weighed against increase in major bleeds…….”
“There is the possibility that some category of individual will eventually be identified in
which primary prevention with aspirin is of definite net benefit. One particularly important
such category might be adults with diabetes…..”
ASA
placebo
Nine trial meta-analysis in
ADA/AHA/ACCF statement:
CHD: RR 0.91 (0.79-1.05)
Stroke: RR 0.85 (0.66-1.11)
What about bleeding in patients with diabetes?
Generic estimate ~ 1/1000 per year for non-stroke bleeding and ~ 1/10,000
for hemorrhagic stroke
In patient-level ATT meta-analysis, patients with diabetes examined
separately: 25 GI bleeds with ASA (0.23%) and 22 bleeds with placebo
(0.21%)
Hemorrhagic stroke: 6 events on ASA, 9 on placebo
The Bottom Line
At a 10% 10-year risk of MI and Stroke, aspirin would prevent 1 MI and 1 stroke
and maybe cause 1 major GI bleed. At a 20% 10-year risk, 2 MIs and 2 strokes
would be prevented with no change in bleed risk
ADA Standards of Care, Diabetes Care; January, 2011
Conclusions:
For cardiometabolic risk reduction:
• A lot of new clinical trial data has solidified current clinical goals:
• A1C ~ 7%
• SBP ~ 130 mmHg
• LDLc < 100mg with statin (ACCORD lipid achieved 80 mg/dL)
• Use of ASA in higher risk patients with diabetes
• Same data suggests that more aggressive targets not warranted for CVD reduction:
• A1C < 7%
• SBP < 130 (ACCORD achieved 119 mmHg SBP)
• Addition of fibrate or niacin to statin to target TG if LDLc already at goal
• ASA should not be used if CVD risk is low