discussion glycemia may not be all bad! – while it may promote atherosclerosis generally, plaques...
TRANSCRIPT
Discussion
• Glycemia may not be all bad!– While it may promote atherosclerosis generally, plaques so formed may be more stable (less vulnerable).– Result a weaker than anticipated association with clinical events and a lower benefit for glycemic
improvement than anticipated.
Why is glucose control (intensive Rx) not moreClosely related to CAD risk?
Possible Basis for Hypothesis That Glycemia May Lead to
More Stable Plaques
• Glycemia strongly related to LEAD (stable stenosis) and weakly related to CAD events (plaque rupture)
• Diabetes complications are often sclerotic, e.g. connective tissue, kidney, fibrous proliferative retinopathy
Possible Basis for Hypothesis That Glycemia May Lead to
More Stable Plaques
• Concentric v eccentric morphology• “Negative remodelling”• Enhanced cross linking AGE formation• Enhanced SMC proliferation• Decreased lipid content
Atherogenesis in Diabetes:The “Black Box”
• Abnormalities of apoprotein and lipoprotein particle distribution (“diabetic dyslipidemia”)
• Procoagulant state• Insulin resistance and hyperinsulinemia• Glycation and advanced glycation of proteins in
plasma and arterial wall• “Glycoxidation” and oxidation• Hormone, growth factor, and cytokine enhanced
smooth muscle cell proliferation and foam cell formation
Blerman EL. Arterioscler Thromb. 1992; 12(6): 647-656.
Figure 2Incidence density of coronary artery disease and overt nephropathy by estimated Glucose Disposal Rate at baseline
eGDR tertiles
0
5
10
15
20
25
30
35
40
45
low middle high
CAD
ON
n/10
00 p
erso
n ye
ars
SCREENING FOR DIABETESScreening
Patient has CHDDiabetes status?
No diabetesdetermined inpast 3 years?
YesKnown diabetic?• Check risk factors• Check who is controlling the diabetes
Patient has diabetes? CAD status
Annual• ECG• Clinical history• Ankle-brachial index measurement• Review the need for cardiac testing
No
Check fastingplasma glucoselevel (HbA1c) ororder oral glucosetolerance test
Yes
Advise a recheckevery 1-3 years
PREVENTION CHECKLIST FOR ALL DIABETIC PATIENTSWHO HAVE CORONARY HEART DISEASE
Who is looking after the diabetes?If no one is, assume responsibility personally or make referralIs blood pressure less than 130/80mg?If not, instigate or modify treatment or contact the primary care providerIs LDL cholesterol less than 100mg/dl?If not, instigate or modify treatment or contact the primary care providerIs HbA1c over 8.0%?If yes, instigate or modify treatment or contact the primary care provider or diabetologistIs patient a current smoker?If yes, instigate or modify cessation strategy or contact the primary care provider
Benefits of Beta BlockersPost-MI in Diabetes
SCREENING OF DIABETIC PATIENTS FOR CORONARY ARTERY DISEASE
Benefits Implementation of prevention programsEarly initiation of anti-ischemic medicationsIdentification of patients for whom
revascularization is appropriate
Method Clinical historyAnnual resting ECGAnnual ABI EBT (?)
INDICATIONS FOR CARDIAC TESTING IN DIABETIC PATIENTS
JOINT ACC/ADA RECOMMENDATIONSTypical or atypical cardiac symptomsResting ECG suggestive of ischemia or infarctionPeripheral or carotid occlusive arterial diseaseSedentary lifestyle, age 35 years and plans to begin a vigorous exercise programTwo or more of the following risk factors in addition to diabetes: Total cholesterol 240 mg/dl, LDL cholesterol 160 mg/dl, or HDL cholesterol <35mg/dl Blood pressure over 140/90mmHg Smoking Family history of premature coronary artery disease Positive microalbuminuria or macroalbuminuria test
METHODS OF CARDIAC TESTING IN DIABETIC PATIENTS
JOINT ADA/ACC RECOMMENDATIONS
High probability ofischemia (e.g. Qwave on ECG)
Stress perfusionimaging or stressechocardiography
Lower probability ofischemia (e.g. tworisk factors only)
Regular stress test(EBT not currentlyrecommended)
Lipid Lowering 1o Prevention Diabetes
Study Intervention Outcome
Helsinki Gemfibrozil 68% CHD death/MI (p=0.19)
SendCap Bezafibrate Carotid ultrasound-NSMI/ischemia-68% (p<0.01)
AFCaps/ Lovastatin 21% CHD death/MITexCaps or unstable angina
Lipid Lowering 2o Prevention Diabetes
Study Intervention Outcome
4S Simvastatin 43% mortality, p=0.0955% MI/CHD death, p=0.002
CARE Pravastatin 13% CHD death/MI, p=NS25% “Expanded”, p=0.05
LIPID Pravastatin 19% CHD death, p=NS
VAHIT Gemfibrozil 24% CHD death/MI, p=NS
BIP Bezafibrate 9.4% CHD death/MI, p=NS
DAIS Fenofibrate 40% Lumen diameter, p=0.0342% stenosis, p=0.02
LIPID-MODULATING AGENTS AND DIABETES
DRUG CLASS COMMENTS
Bile acid resins Effective but constipating side effects
May be excerbated by GI autonomic neuropathy
Statins Effective and well tolerated
Indicated for LDLc and mild combined (LDL and VLDL) lipidemia. Clinical endpoint evidence positive.
Fibric acids Effective and generally well tolerated indicated for elevated VLDL cholesterol and triglycerides
Angiographic progression evidence positive.
Niacin Effective but may worsen glucose toleranceAvoid in those bordering on the need for oral hypoglycemic therapy. Also lowers lipoprotein (a) and raises HDL cholesterol
BP Lowering DiabetesStudy Intervention Outcome (% reduction)HDFP “stepped care” Mortality
Fasting > 140mg/dl 3.21 hr PG > 205mg/dl 17.9h/o diabetes 4.9
SHEP chlorthalidone stroke 22*Atenolol/Reserpine CHD death/MI 54*
CVD 34*
ABCD Nisoldipine MI 700* v
Enalapril
FACET Fosinopril CVD events 51* v
Amlodipine
BP Lowering Diabetes (cont.) Study Intervention Outcome (% reduction)UKPDS Captropil, Atenolol Diabetes events 24%**
150/85 v 180/105 Diabetes death 32%* Mortality 18%
HOT Felodipine <90, <85, <80 90 v 80 mortality 43%CVD 51%*
SystEur Nitrendipine plus Total mortality 55%*
enalpril/hydrochlorthazide CBVD 73%
v placebo CAD 63%
CAPP Captopril v Diuretic/Bblocker Fatal CVD 40%* Nonfatal MI/CVA
All Stroke 24%All MI 76%**
BLOOD PRESSURE TREATMENT IN DIABETES
DRUG CLASS COMMENTS
Diuretics Blood sugar increases, but no contraindication
Beta blockers Masking of hypoglycemia (less marked with cardioselective beta blockers)
Angiotensin converting
enzyme inhibitors
May have additional renal protective effect if mean blood pressure > 100 mmHg
Calcium channel blockers Some evidence of increased cardiovascular events
The goal is 130/85mmHg (or 130/80mmHg).
MANAGEMENT OF TYPE 2 DIABETES FROM A CARDIOLOGIC VIEWPOINTHbA1c 8.0 percent (upper limitof normal is 6.0%) despite dietand exercise
TZD
Non-obesepatientsSulfonylurea
Obese patientsMetformin
Combination sulfonylurea ± metformin± TZD
? Insulin therapy ± TZD
BARI 2D addressingthe issue, as to howbest to treat the diabetesto benefit the heart.Insulin sensitization orprovision?
SUMMARYREDUCTION OF CVD RISK IN DIABETES
Constant surveillance of all CHD patients for diabetes and the repeated screening of all diabetic patients for CHD. Vigorous risk factor management (blood pressure goal of 130/80mmHg, LDL cholesterol levels of less than 100 mg/dl) is indicated for the majority of diabetic subjects, as is adequate glycemic control (HbA1c < 7.0-8.0%). Beta-blockers, ACE inhibitors and aspirin should also be used as vigorously as they are in the general population. Of fundamental importance, however, is the assumption of responsibility for these aspects of care.
4S: Diabetic Patients
P(n-96) S(n=105) RR p-value # K-M # K-M
Total 24 0.69 15 0.84 0.56 0.08
Mortality
CHD 17 0.75 12 0.87 0.64 0.23Mortality
CHD Death or 43 0.52 24 0.75 0.46 0.002MI
Diabetes, May 1995; 125
CONCLUSIONS• The link between diabetes and atherosclerosis
is multifactorial and varies by diabetes type. Nonetheless, insulin resistance (and ? hyperinsulinemia) is a frequent finding.
• Future prevention of CVD in diabetic subjects may depend more on control of lipids and blood pressure than on glycemic control.
Proportion of Subjects Without Diabetes During the Trial
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WHITEHALL STUDY;NIDDM AND CVD RISK
• 17,051 NGT; 999 > 95 pc; 56 – New NIDDM, and 121 Previously dx NIDDM Men Only
• 15 yr Mortality, Relative Risk
CHD All CHDBS > 95th pc1.2 (1.0-1.5) 1.2 (1.0-1.5)New dx 2.6 (1.6-4.2) 2.2 (1.4-3.5)Known 2 yrs 2.3 (0.9-6.1) 2.5 (1.1-5.6)Known 3-6 yrs 2.2 (1.1-4.7) 2.4 (1.3-4.4)Known 7 yrs 2.5 (1.2-5.4) 1.9 (0.9-3.9)
Diabetologia, 1998; 31: 737-740.
Aggregate endpoints by treatments and relative risk
Endpoint Intensive Conventional RR for Intensive Treatment(N=2729) (N=1138)
Any diabetes endpoint 963 438 0.88 (0.79-0.99)Diabetes-related death 285 129 0.90 (0.73-1.11) All-cause mortality 489 213 0.94 (0.8-1.10) MI 387 186 0.84 (0.71-1.00) Stroke 148 55 1.11 (0.81-1.51)Amputation/ PVD death 29 18 0.65 (0.36-1.18)Microvascular 225 121 0.75 (0.60-0.93)
Lancet; Vol 352: Sept. 12, 1998; 837-53
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In-hospital MI case fatality rate by sex, year, and diabetes status
Minnesota Heart Survey
Men Women
Diabetic Nondiabetic Diabetic Nondiabetic
Year Rate/100 Rate/100 Rate/100 Rate/100
1970 21.4 (42) 21.6 (521) 38.8 (38) 25.7 (195)
1985 17.6 (81) 13.7 (552) 36.6 (51) 16.6 (179)
1986 18.0 (105) 10.1 (555) 16.2 (67) 16.6 (194)
Sprafka JM, et al. Diabetes Care 1991; 14(7): 537-43.
The Survival Curve for CAD by IR Status
0.0
20.0
40.0
60.0
80.0
100.0
2 4 6 8 10
Insulin Sensitive Q 2-5
Insulin Resistant Q 1
Follow-up (years)
Percentfree ofevent
Diagnosis of Diabetes Mellitus and Impaired Glucose Tolerance by Oral Glucose Tolerance Test
ADA and WHO criteria
Diabetes mellitus IGT
Fasting 140 mg/dL < 140 mg/dL* or or
OGTT 200 mg/dL 140-199 mg/dL (2-h glucose)
*Venous plasmaAmerican Diabetes Assoc. Medical Management ofNon-insulin-Dependent (Type II) Diabetes; 1994; 1-99.
Angiographic Changes in Placebo and Fenofibrate Groups
DAIS. Lancet 2001; 357: 905-910.
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