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Discussion. Why is glucose control (intensive Rx) not more Closely related to CAD risk?.

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discussion
Discussion

Why is glucose control (intensive Rx) not more

Closely related to CAD risk?

  • 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.
possible basis for hypothesis that glycemia may lead to more stable plaques
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 plaques1
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
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.

slide5

Figure 2

Incidence density of coronary artery disease and overt nephropathy by estimated Glucose Disposal Rate

at baseline

n/1000 person years

eGDR tertiles

screening for diabetes
SCREENING FOR DIABETES

Screening

Patient has CHD

Diabetes status?

Patient has diabetes

? CAD status

Annual

• ECG

• Clinical history

• Ankle-brachial

index measurement

• Review the need for

cardiac testing

Yes

Known diabetic?

• Check risk factors

• Check who is

controlling the

diabetes

No diabetes

determined in

past 3 years?

No

Check fasting

plasma glucose

level (HbA1c) or

order oral glucose

tolerance test

Yes

Advise a recheck

every 1-3 years

prevention checklist for all diabetic patients who have coronary heart disease
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 referral

Is blood pressure less than 130/80mg?

If not, instigate or modify treatment or contact the primary care provider

Is LDL cholesterol less than 100mg/dl?

If not, instigate or modify treatment or contact the primary care provider

Is HbA1c over 8.0%?

If yes, instigate or modify treatment or contact the primary care provider or diabetologist

Is patient a current smoker?

If yes, instigate or modify cessation strategy or contact the primary care provider

screening of diabetic patients for coronary artery disease
SCREENING OF DIABETIC PATIENTS FOR CORONARY ARTERY DISEASE

Benefits Implementation of prevention programs

Early initiation of anti-ischemic medications

Identification of patients for whom

revascularization is appropriate

Method Clinical history

Annual resting ECG

Annual ABI

EBT (?)

indications for cardiac testing in diabetic patients joint acc ada recommendations
INDICATIONS FOR CARDIAC TESTING IN DIABETIC PATIENTSJOINT ACC/ADA RECOMMENDATIONS

Typical or atypical cardiac symptoms

Resting ECG suggestive of ischemia or infarction

Peripheral or carotid occlusive arterial disease

Sedentary lifestyle, age  35 years and plans to begin a vigorous exercise program

Two 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
METHODS OF CARDIAC TESTING IN DIABETIC PATIENTSJOINT ADA/ACC RECOMMENDATIONS

High probability of

ischemia (e.g. Q

wave on ECG)

Lower probability of

ischemia (e.g. two

risk factors only)

Stress perfusion

imaging or stress

echocardiography

Regular stress test

(EBT not currently

recommended)

lipid lowering 1 o prevention diabetes
Lipid Lowering 1o Prevention Diabetes

Study Intervention Outcome

HelsinkiGemfibrozil 68%  CHD death/MI

(p=0.19)

SendCapBezafibrateCarotid ultrasound-NS

MI/ischemia-68% (p<0.01)

AFCaps/Lovastatin21% CHD death/MI

TexCapsor unstable angina

lipid lowering 2 o prevention diabetes
Lipid Lowering 2o Prevention Diabetes

Study Intervention Outcome

4SSimvastatin43%  mortality, p=0.09

55% MI/CHD death, p=0.002

CARE Pravastatin13%  CHD death/MI, p=NS

25%  “Expanded”, p=0.05

LIPID Pravastatin19%  CHD death, p=NS

VAHIT Gemfibrozil24%  CHD death/MI, p=NS

BIP Bezafibrate9.4%  CHD death/MI, p=NS

DAIS Fenofibrate40%  Lumen diameter, p=0.03

42%  stenosis, p=0.02

bp lowering diabetes
BP Lowering Diabetes

Study Intervention Outcome (% reduction)

HDFP “stepped care”Mortality

Fasting > 140mg/dl  3.2

1 hr PG > 205mg/dl  17.9

h/o diabetes  4.9

SHEP chlorthalidone stroke  22*

Atenolol/Reserpine CHD death/MI  54*

CVD  34*

ABCDNisoldipineMI  700*

v

Enalapril

FACET Fosinopril CVD events  51*

v

Amlodipine

bp lowering diabetes cont
BP Lowering Diabetes (cont.)

Study Intervention Outcome (% reduction)

UKPDS Captropil, Atenolol Diabetes events  24%**

150/85 v 180/105 Diabetes death  32%*

Mortality  18%

HOTFelodipine <90, <85, <80 90 v 80 mortality  43%

CVD  51%*

SystEurNitrendipine 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
BLOOD PRESSURE TREATMENT IN DIABETES

The goal is 130/85mmHg (or 130/80mmHg).

management of type 2 diabetes from a cardiologic viewpoint
MANAGEMENT OF TYPE 2 DIABETES FROM A CARDIOLOGIC VIEWPOINT

HbA1c  8.0 percent (upper limit

of normal is 6.0%) despite diet

and exercise

TZD

Non-obese

patients

Sulfonylurea

Obese patients

Metformin

BARI 2D addressing

the issue, as to how

best to treat the diabetes

to benefit the heart.

Insulin sensitization or

provision?

Combination sulfonylurea

± metformin± TZD

? Insulin therapy ± TZD

summary reduction of cvd risk in diabetes
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
4S: Diabetic Patients

P(n-96) S(n=105) RR p-value

# K-M # K-M

Total24 0.69 15 0.84 0.56 0.08

Mortality

CHD 17 0.75 12 0.87 0.64 0.23

Mortality

CHD Death or 43 0.52 24 0.75 0.46 0.002

MI

Diabetes, May 1995; 125

conclusions
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.
whitehall study niddm and cvd risk
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 CHD

BS > 95th pc 1.2 (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
Aggregate endpoints by treatments and relative risk

EndpointIntensive 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

in hospital mi case fatality rate by sex year and diabetes status minnesota heart survey
In-hospital MI case fatality rate by sex, year, and diabetes statusMinnesota Heart Survey
  • Men Women
  • DiabeticNondiabetic DiabeticNondiabetic
  • Year Rate/100 Rate/100 Rate/100 Rate/100
  • 1970 21.4 (42) 21.6 (521) 38.8 (38) 25.7 (195)
  • 17.6 (81) 13.7 (552) 36.6 (51) 16.6 (179)
  • 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
The Survival Curve for CAD by IR Status

Percent

free of

event

Follow-up (years)

slide29

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 plasma

American Diabetes Assoc. Medical Management of

Non-insulin-Dependent (Type II) Diabetes; 1994; 1-99.

angiographic changes in placebo and fenofibrate groups
Angiographic Changes in Placebo and Fenofibrate Groups

DAIS. Lancet 2001; 357: 905-910.

Click for larger picture