Download SCREENING FOR DIABETES

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
• 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 2
Incidence density of coronary artery disease and overt
nephropathy by estimated Glucose Disposal Rate
at baseline
45
40
35
30
CAD
25
ON
20
15
10
5
0
low
middle
eGDR tertiles
high
SCREENING FOR DIABETES
Screening
Patient has CHD
Diabetes status?
No diabetes
determined in
past 3 years?
No
Check fasting
plasma glucose
level (HbA1c) or
order oral glucose
tolerance test
Yes
Known diabetic?
• Check risk factors
• Check who is
controlling the
diabetes
Yes
Advise a
recheck
every 1-3
years
Patient has diabetes
? CAD status
Annual
• ECG
• Clinical history
• Ankle-brachial
index measurement
• Review the need for
cardiac testing
PREVENTION CHECKLIST FOR ALL DIABETIC PATIENTS
WHO 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
Benefits of Beta Blockers
Post-MI in Diabetes
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
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
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 1o Prevention Diabetes
Study
Intervention
Outcome
Helsinki
Gemfibrozil
68%  CHD death/MI
(p=0.19)
SendCap
Bezafibrate
Carotid ultrasound-NS
MI/ischemia-68% (p<0.01)
AFCaps/
TexCaps
Lovastatin
21% CHD death/MI
or unstable angina
Lipid Lowering 2o Prevention Diabetes
Study
Intervention
Outcome
4S
Simvastatin
43%  mortality, p=0.09
55% MI/CHD death, p=0.002
CARE
Pravastatin
13%  CHD death/MI, p=NS
25%  “Expanded”, p=0.05
LIPID
Pravastatin
19%  CHD death, p=NS
VAHIT
Gemfibrozil24%  CHD death/MI, p=NS
BIP
Bezafibrate
9.4%  CHD death/MI, p=NS
DAIS
Fenofibrate
40%  Lumen diameter, p=0.03
42%  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 tolerance
Avoid in those bordering on the need for oral
hypoglycemic therapy. Also lowers lipoprotein (a) and
raises HDL cholesterol
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
Atenolol/Reserpine CHD death/MI
CVD
 22*
 54*
 34*
ABCD
 700*
Nisoldipine
MI
v
Enalapril
FACET
Fosinopril
v
Amlodipine
CVD events
 51*
BP Lowering Diabetes (cont.)
Study
Intervention
UKPDS
Captropil, Atenolol
150/85 v 180/105
HOT
Outcome
(% reduction)
Diabetes events
Diabetes death
Mortality
Felodipine <90, <85, <80 90 v 80 mortality
CVD
SystEur
Nitrendipine plus
Total mortality
enalpril/hydrochlorthazide CBVD
v placebo
CAD
CAPP Captopril v Diuretic/Bblocker Fatal CVD
Nonfatal MI/CVA
All Stroke
All MI
 24%**
 32%*
 18%
 43%
 51%*
 55%*
 73%
 63%
 40%*
 24%
 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
Calcium channel blockers
May have additional renal protective
effect if mean blood pressure > 100
mmHg
Some evidence of increased
cardiovascular events
The goal is 130/85mmHg (or 130/80mmHg).
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
Combination sulfonylurea
± metformin± TZD
? Insulin therapy ± TZD
BARI 2D addressing
the issue, as to how
best to treat the diabetes
to benefit the heart.
Insulin sensitization or
provision?
SUMMARY
REDUCTION 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)
#
K-M #
K-M
RR
p-value
Total
Mortality
24
0.69
15
0.84
0.56
0.08
CHD
17
0.75
12
0.87
0.64
0.23
CHD Death or 43
MI
0.52
24
0.75
0.46
0.002
Mortality
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 CHD
BS > 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
(N=2729)
(N=1138)
RR for Intensive Treatment
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
Year
1970
1980
1985
Diabetic
Rate/100
21.4 (42)
17.6 (81)
18.0 (105)
Women
Nondiabetic
Rate/100
Diabetic
Rate/100
Nondiabetic
Rate/100
21.6 (521)
13.7 (552)
10.1 (555)
38.8 (38)
36.6 (51)
16.2 (67)
25.7 (195)
16.6 (179)
16.6 (194)
Sprafka JM, et al. Diabetes Care 1991; 14(7): 537-43.
The Survival Curve for CAD by IR Status
100.0
80.0
Percent
free of
event
60.0
40.0
Insulin Sensitive Q 2-5
20.0
Insulin Resistant Q 1
0.0
2
4
6
Follow-up (years)
8
10
Diagnosis of Diabetes Mellitus and Impaired
Glucose Tolerance by Oral Glucose Tolerance Test
ADA and WHO criteria
Diabetes mellitus
 140 mg/dL
Fasting
or
OGTT
(2-h glucose)
 200 mg/dL
IGT
< 140 mg/dL*
or
140-199 mg/dL
*Venous plasma
American Diabetes Assoc. Medical Management of
Non-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