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

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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

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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