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MANAGEMENT OF DIABETES IN CARDIAC PATIENTS
NEW ADA GUIDE LINES 2011DR GOPI KRISHNA
Age-Adjusted CVD Mortality According
to Number of CVD Risk Factors: MRFIT
Probability of Death From CHD in Patients With Type 2 Diabetes With or Without Previous MI
Diabetes Doubles Risk for MI Mortality Despite Advances in Cardiac Care
Diabetes and Heart Failure:Current Knowledge
Relation of Glucose Tolerance Status to LVM
• In the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-2 (GISSI-2) study of thrombolytic therapy in patients with myocardial infarction, diabetes increased the rate of death in men by 40 percent and women by 90 percent.
• In the Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) trial,[which evaluated a strategy of early revascularization in patients with myocardial infarction complicated by cardiogenic shock, 31.1 percent of the patients had diabetes, a much higher percentage than in the population in general.
PATHOPHYSIOLOGY OF DIABETIC VASCULAR DISEASE
Adipocyte Biology and Inflammation
Diabetic Metabolic and Vascular Dysfunction
The vascular effects of advanced glycation end products (AGEs)
• Management of diabetes in cardiovascular patients
Diabetes Control and Complications Trial (DCCT)
Compared effects of two diabetes treatment regimens – standard therapy and intensive control – on the complications of diabetes
DCCT. New England Journal of Medicine, 329(14), September 30, 1993.
Glucose control is key to preventing or delaying complications of diabetes
Any sustained lowering of blood glucose helps, even if the person has a history of poor control
DCCT Findings
DCCT. New England Journal of Medicine, 329(14), September 30, 1993.
DCCT Findings
Lowering blood glucose reduced risk of:
• Eye disease by 76%
• Kidney disease by 50%
• Nerve disease by 60%
DCCT. New England Journal of Medicine, 329(14), September 30, 1993.
Epidemiology of Diabetes Interventions and Complications Study (EDIC)
• Observational study
• DCCT participants
• Looked at risk factors for long-term complications
DCCT/EDIC N Engl J Med 2005: 353:2643-2653.
DCCT/EDICDCCT/EDICMetabolic Results
DCCT InterventionDCCT Intervention
S t u d y Y e a rS t u d y Y e a rDCCT DCCT
1 2 3 4 5 6 7 8 9
EDIC ObservationEDIC ObservationTrainingTraining
EDIC EDIC
ConventionalConventionalEDIC mean 8.2%EDIC mean 8.2%
IntensiveIntensiveEDIC mean 8.0%EDIC mean 8.0%
Participants continue to benefit from metabolic memory of intense glucose control
Intensive therapy aimed at achieving near normoglycemia:
• Reduces CVD events by more than half• Should be implemented as early as possible
EDIC Findings: Intensive Therapy and Diabetes Complications
DCCT/EDIC N Engl J Med 2005: 353:2643-2653.
ConventionalConventional
IntensiveIntensive
Non-Fatal MI, Stroke or CVD DeathNon-Fatal MI, Stroke or CVD Death
Cardiovascular EventsCardiovascular Events
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 210 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Number at Risk Intensive: 705 686 640 118 Conventional: 721 694 637 96
Years from Study EntryYears from Study Entry
0.000.00
0.020.02
0.040.04
0.060.06
0.080.08
0.100.10
0.120.12
Cu
mu
lati
ve I
nci
den
ce
Cu
mu
lati
ve I
nci
den
ce
Risk reduction 57% Risk reduction 57% 95% CI: 12, 7995% CI: 12, 79Log-rank P = 0.018Log-rank P = 0.018
United Kingdom Prospective Diabetes Study (UKPDS)
Clinical Trial
Looked at intensive management of blood glucose levels and long term risk-factors for diabetes complications
UKPDS. BMJ. 2000; 321:405-412. ukpds
HbA1c cross-sectional, median values
06
7
8
9
0 3 6 9 12 15
HbA
1c (
%)
Years from randomisation
Conventional
Intensive
6.2% upper limit of normal range
ukpds
Mirrored the findings of DCCT in people with type 2 diabetes—better glucose control reduced development of microvascular complications
Demonstrated the need for management of high blood pressure and cholesterol as well as blood glucose levels .
UKPDS Findings
UKPDS. BMJ. 2000; 321:405-412. ukpds
Any Diabetes Related Endpoint (cumulative )Any Diabetes Related Endpoint (cumulative )
0%
20%
40%
60%
0 3 6 9 12 15
% o
f pat
ient
s w
ith a
n ev
ent
Years from randomisation
Intensive (2729)
Conventional (1138)
Risk reduction 12%(95% CI: 1% to 21%)
p=0.029
1401 of 3867 patients (36%)
ukpds
UKPDS Findings
Stratton IM, et al. BMJ. 2000;321:405-412.
P <.0001 P = .035 P = .021 P = .0001
Risk reduction with 1% decline in annual mean A1C
Micro-vascular Disease
37%
PVD
43%
StrokeMI
14% 12%
Heart Failure
Cataract Extraction
16%19%
0%
15%
30%
45%
ukpds
Largest study in type 2 diabetes
ADVANCE
11,140 patients
20 countries
215 centers
Standard glucose control
Placebo
Intensive glucose control
Placebo
Standard glucose control
Routine
BP lowering therapy
Intensive glucose control
Routine
BP lowering therapy
2 x 2 factorial design
Randomized study treatments
• Glucose lowering
Sulfonylurea (gliclazide MR) based
intensive therapy targeting HbA1c of
6.5% versus usual guideline-based
care
Randomized glucose lowering strategies
• Intensive control arm Gliclazide MR (sulfonylurea) in all participants Unrestricted additional therapy to achieve target
HbA1c 6.5%
• Standard control arm Sulfonylurea other than Gliclazide MR Unrestricted additional therapy according to
standard local guidelines
• All other treatment At discretion of treating physician
Primary study outcomes Macrovascular
– Non-fatal stroke, non-fatal myocardial infarction or death from any cardiovascular cause (including sudden death)
Microvascular– New or worsening nephropathy or diabetic eye disease
Composite of macrovascular and microvascular outcomes
Hemoglobin A1c
Ä 0.67% (95% CI 0.64 - 0.70); p<0.001
Mea
n H
bA
1c (
%)
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
10.0
Follow-up (Months)
0 6 12 18 24 30 36 42 48 54 60 66
7.3 %
Mean HbA1c at final visit
6.5%
Standard
Intensive
Fasting blood glucose
Ä 1.22mmol/L [21.9 mg/dL] (95%CI 1.15 - 1.28); p<0.001
90
100
110
120
130
140
150
160
170
180
Follow-up (Months)
0 6 12 18 24 30 36 42 48 54 60 66
7.7 mmol/L
Mean FBG at final visit
6.2 mmol/L
139 mg/dL
112 mg/dL
Mea
n f
asti
ng
blo
od
glu
cose
5.5
6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
10.0
mmol/L mg/dL
5.0
Standard
Intensive
Combined primary outcomesMajor macro or microvascular event
Follow-up (months)
Cu
mu
lati
ve i
nci
de
nce
(%
)
25
20
15
10
5
0
0 6 12 18 24 30 36 42 48 54 60 66
Standard
Intensive
Relative risk reduction10%: 95% CI: 2 to 18%
p=0.013
10%
ACCORD TRIAL Rate of death from any cause and from cardiovascular
causes were significantly higher in the intensive-
therapy group than in the standard-therapy group
Nonfatal myocardial infarction was significantly lower in the intensive-therapy group
Nonfatal stroke and either fatal or nonfatal congestive heart failure did not differ significantly between the two groups
The benefits of intensive therapy appear after prolonged treatment (3 yrs)
ACCORD TRIAL
• 19 of the 41 excess deaths from CV causes in this study could be due to or related to hypoglycemia
• Few patients in the ACCORD trial met the treatment goal of below 6% of HbA1C
ACCORD TRIAL
Hypoglycemic episodes (requiring medical treatment) 3.1% (intensive group) 1.0% (standard group)
ACCORD demonstrated increase in MORTALITY with intensive treatment
N Engl J Med 2008;358:2560-72
Increase all cause mortality (events)
with Intensive therapy of ACCORD
Results…. Increased mortality in ACCORD study
22
35
-21
-12-7
-30
-20
-10
0
10
20
30
40
Any death CV death Nephropathy
Haz
ard r
atio
(%
)
ACCORD ADVANCE
N Engl J Med 2008;358:2545-59.; N Engl J Med 2008;358:2560-72.
**=significant
*
Increased deaths seen in ACCORD study
Intensive Glycemic Control and Intensive Glycemic Control and Cardiovascular Outcomes: VADTCardiovascular Outcomes: VADT
Duckworth W, et al., for the VADT Investigators. N Engl J Med 2009;360:129-139.
Primary Outcome: Nonfatal MI, nonfatal stroke, CVD death, hospitalization for heart failure, revascularization
HR=0.88 (0.74-1.05)
©2009 New England Journal of Medicine. Used with permission.
ACCORD, ADVANCE, and VADT Lessons Learned
• Intensive glucose control does not reduce CVD mortality in T2DM, and may increase risk, especially in patients with pre-existing CHD
• Aggressive A1c targets (<6.5%) were associated with a 3-fold increased risk hypoglycemia
• No excess CVD Mortality was seen with Rosigliatazone
ACCORD, ADVANCE, and VADT Lessons Learned- Continued
• Intensive control associated with reduced risk for nephropathy in ADVANCE.
• To reach and maintain A1c targets of <6.5 required frequent adjustments of multiple anti-diabetic medications
• Aggressive Targets (<6.5) are probably reasonable for healthy patients to reduce risk micro-vascular complications
Steno-2: Study Design
Steno-2: Treatment Goals
Steno-2: Multifactorial Intervention and CV Events in
Type 2 Diabetes
Management of diabetes in A.C.S
AFFECTS OF HYPERGLYCEMIA IN A.C.S
Management of diabetes in A.C.S.
• DIGAMI 1• DIGAMI 2• NICE.
STANDARDS OF MEDICAL CARESTANDARDS OF MEDICAL CAREIN DIABETES—2011IN DIABETES—2011
ADA Evidence Grading System for ADA Evidence Grading System for Clinical RecommendationsClinical Recommendations
Level of Level of EvidenceEvidence DescriptionDescription
A Clear or supportive evidence from adequately powered well-conducted, generalizable, randomized controlled trials
B Supportive evidence from well-conducted cohort studies or case-control study
C Supportive evidence from poorly controlled or uncontrolled studies
Conflicting evidence with the weight of evidence supporting the recommendation
E Expert consensus or clinical experience
ADA. Diabetes Care 2011;34(suppl 1):S12. Table 1.
Criteria for the Diagnosis of DiabetesCriteria for the Diagnosis of Diabetes
A1C ≥6.5%OR
Fasting plasma glucose (FPG)≥126 mg/dl (7.0 mmol/l)
OR
Two-hour plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT
OR
A random plasma glucose ≥200 mg/dl (11.1 mmol/l)
ADA. I. Classification and Diagnosis. Diabetes Care 2011;34(suppl 1):S13. Table 2.
DECODE STUDY