craig williams, pharm.d., fnla associate professor; osu school of pharmacy and ohsu school of...
TRANSCRIPT
Craig Williams, Pharm.D., FNLAAssociate Professor; OSU School of Pharmacy and OHSU School of Medicine
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., FNLAAssociate Professor; OSU School of Pharmacy and OHSU School of Medicine
Presenter Disclosure InformationIn compliance with the accrediting board policies, theAmerican 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?
NEW ENGLAND JOURNAL OF MEDICINE March 4, 2010
Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Non-diabetic AdultsElizabeth Selvin, Michael Steffes, Hong Zhu, Kunihiro Matusushita, et al.
There is a clear epidemiologic association between glycemic control and CVD
Data from 11,092 black and white subjects in the ARIC trial (Atherosclerosis Risk in Communities)
Median follow approximately 14 years.
ADA position on glycemia and macrovascular disease in 2010 Standards of Care guideline
ADA Standards of Care. Diabetes Care 2010;33:S11-62
Despite clear epidemiology, controversy continues regarding the role of glucose lowering to prevent coronary events
Three large trials of glycemic control published in 2008 failed to find CVD benefit
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.
So hyperglycemia doesn’t matter to the heart?
Non-fatal MI significantly reduced 24% (p=0.001)
Retnakaran R, Zinman B. Lancet 2008;371:1790-99.
Hyperglycemia is toxic at several steps in the atherosclerosis process
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%
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.
So hyperglycemia matters to the heart but intense control (A1C < 7%) provides little additional benefit over moderate control (A1C 7-8%)
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 processBasic Science for Clinicians
Subendothelial Lipoprotein Retention as the Initiating Process in AtherosclerosisUpdate 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
Liver
VLDL
TG
IDL
LDL
Lipase enzymes
Lipase enzymes
LDLc
Type (%)
Appearance of serum
Elevated particles
Associated clinical disorders TC TG
I (~1%) 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
+ ++
V (5%) Creamy top, turbid bottom
Chylomicrons, VLDL (remnants)
Diabetes + ++
Fredrickson Classification of DyslipidemiaWe look at this
Artery wall sees these
LDLLDL
LDLLDLEndotheliumEndothelium
Vessel LumenVessel LumenMonocyteMonocyte
MacrophageMacrophage
MCP-1MCP-1
AdhesionAdhesionMoleculesMolecules
Steinberg D et al. N Engl J Med 1989;320:915-924.
The primary atherogenic lipoprotein is LDLipoprotein is LDLlipoproteins of > 70 nm have limited transcytosis past the endotheliumlipoproteins of > 70 nm have limited transcytosis past the endothelium
The primary atherogenic lipoprotein is LDLipoprotein is LDLlipoproteins of > 70 nm have limited transcytosis past the endotheliumlipoproteins of > 70 nm have limited transcytosis past the endothelium
Foam CellFoam Cell
Modified LDL Modified LDL Taken up by Taken up by MacrophageMacrophage
IntimaIntima
Nascentchylomicron
Nascet VLDL
ΧΧ
Artery wall
Am Heart J 2008;156:112-119
2. Dyslipidemia vs. hyperlipdemia: Prevalence in NHANES 2008 data: High TG or low HDLc more
common than high LDLc
Prevalence of Dyslipidemia is high in Type 2 Diabetes
Jacobs MJ, et al. Diabetes Res Clin Pract. 2005;70:263-269.
Control of Lipids 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
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.
Hepatic lipase
Fat Cells Liver
Kidney
Insulin
CETPCETPCETPCETP
CE
VLDL HDL
Lipoprotein lipaseor hepatic lipase
Small, denseSmall, denseLDLLDLLDLLDL
TGApoA-I
TGTGCE
FFA
‘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
CE, cholesteryl esters; FFA, free fatty acids; TG, triglycerides.Ginsberg HN. J Clin Invest. 2000;106:453–458.
CETPCETPCETPCETP
↑ TG↑ ApoB↓ HDLc↔ LDLc
XInsulinInsulinresistanceresistance
Liver
IDLIDL
FFA
While LDLc is similar, particle burden is heavier
LDL particle count vs. cholesterol contentTo carry the same amount of cholesterol, a larger number of particles are needed if
they are smaller
apoB is a measure of number of atherogenic lipoproteins (essentially VLDL, IDL, LDL). Non-HDL is measure of cholesterol carried in these same particles
LDLc measures cholesterol carried in LDL and IDL
Small, dense: 25-30 nmLarge, buoyant: 30-35 nm
LDLc=115 mg/dl LDLc=115 mg/dl
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;364:685Diabetes Care 2006;29:1220Lancet 2003;361:2005Diabetes Care 2006;7:1478Diabetes 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 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%)
10: Primary prevention data 20: Secondary prevention
2○
1○
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
1111 2222 3333 4444 5555 6666000050505050
80808080
90909090
100100100100
55%55%
0000
Diabetic – simvastatinDiabetic – placeboNondiabetic – simvastatinNondiabetic - placebo
Diabetic - simvastatin
Diabetic - placebop=0.002
Risk reduction
Coronary Death and non-fatal MI
Years since randomizationPyörälä K, et al. Pyörälä K, et al. Diabetes CareDiabetes Care. 1997;20:614–620. 1997;20:614–620
Per
cent
of
patie
nts
with
out m
ajor
CV
eve
nt
70707070
Within a given population, lower goals do further reduce CVD events: Risk Curve ConceptHigher risk patients have more to gain from aggressive therapy
Robinson JG, Stone NJ. Am J Cardiol. 2006;98:1405-1408
0
Car
diov
ascu
lar
Eve
nt R
ate
(%)
0 20 40 60 80 100 120 140 160 180 200
LDL (mg/dL)
No CVD - No diabetes
Diabetes - No CVD
CHD - NoMS or IFG
CHD + MS or IFG
CHD + Diabetes
80
70
60
50
40
30
20
10
What aggressive LDL lowering does: reduces atheroma volume in arterial wall providing plaque ‘stabilization’
Brown et al. Arter Thromb Vasc Biol 2001;21:1623
Treated: LDLc of 84 mg/dL (47% reduction)Untreated: LDLc of 163 mg/dL with statin+resin
N 4,444 9,014 4,159 20,536 6,595 6,605∆LDL -36% -25% -28% -29% -26% -27%TxLDL 119 154 98 90 113 112
secondary high risk primary
% CHD
events on
statin
J Am Coll Card 2005;46:1225-8
LDLc lowering and residual risk – more is neededThe majority of CVD events still occur: CVD events occurring in the on-treatment groups in major statin trials
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, 2007
ADA guidelines, 2008-2011
ADA guidelines changed text related to lipoprotein control in 2008:
Statins are safe but nothing is without risk: Review of 35 statin therapy trials
Kashani A et al. Circulation. 2006;114:2788-97.
FDA-approved statin* monotherapy vs placebo (N = 74,102)
*Atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatinCK = creatine kinaseAE = adverse events
OutcomeStatin(%)
Placebo (%) RD P value
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
Statin better Placebo better
-30 -15 0 15 30Risk difference per 1000 patients (RD)
(95% CI)
20,536 patients from HPS (40mg simvastatin vs. placebo): 8 cases of rhabdomyolysis, 3 on placebo
Lancet 2002;360:7-23
Subjective myopathy incidence is high but myositis and rhabdomyolysis is low
Rhabdomyolysis per 10,000 person-years of therapy with lipid lowering agents*
Drug Monotherapy incidence +agent Combo. Incidence rates 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 under-estimation of myopathy incidence in practice
Control
Statin 40-80 mg
~ 5 years
Blinded Statin
4-8 weeks
Waters DD et al. Am J Cardiol. 2004;93:154-8.HPS investigators, Lancet 2002;360:7-22
1-8 weeks
Wash-out
Run-in
HPS: 63,603 patients 32,145 20,536TNT: 18,469 patients 15,464 10,003
Run-in: HPS, of 11,609 excluded after drug exposure, 1% for self-identifed ADRs
TNT, of 5,461 excluded after drug exposure, 3.7% for self- identified 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
AJKD 2004;43(suppl 1):S120
Historic goal SBP of < 130 mmHg in diabetes is an extrapolation of data regarding benefits in nephropathy
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
Cochrane review 2009
Four trials looked at major CVD outcomes based on randomized BP control;Two trials (ABCD) were exclusively in patients with diabetes
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
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)).
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
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
Pignone M, Williams CD. Nature Review Endo, November 2010
The promiscuous platelet: many pathways exist for platelet activation. So do overactive platelets respond better or less well to standard anti-platelet therapy?
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.
Risk vs. benefit in primary vs. secondary prevention with ASAWhile the benefit of aspirin increases as risk increases, bleeding stays constant
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
Meta-analysis in general population for primary prevention:
2009 Update from Oxford group on clinical trials evidence for aspirin
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