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

Click for larger picture

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

Click for larger picture

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.

Click for larger picture