BEYOND DIGAMI: GLYCEMIC MANAGEMENT IN ACUTE MYOCARDIAL INFARCTION JULIA CREIDER, PGY5 ENDOCRINE &...

BEYOND DIGAMI: GLYCEMIC MANAGEMENT IN ACUTE MYOCARDIAL INFARCTION

JULIA CREIDER, PGY5

ENDOCRINE & METABOLISM

OBJECTIVESUnderstand myocardial energy metabolism

Examine the effects of hyperglycemia in post-MI state

Understand the “glucose hypothesis” and the role for insulin

Assess some of the major trials in glycemic management during ACS and their results

Examine the DIGAMI trials

METABOLISM BASICS

Two major forms of cellular energy production

• Glycolysis = anaerobic process• By-products are pyruvate and lactic acid

• Oxidative phyosphorylation = aerobic process• Occurs in the mitochondria• Involves the Krebs cycle and electron transport chain• By-producs are ATP, CO2 and H2O

METABOLISM BASICS

CARDIAC METABOLISM

Primarily oxidative physophorylation

Estimate of daily cardiac metabolic energy requirement:

• 300g heart – utilizes 5000g of ATP per day• Requires +++ rapid turnover of ATP pool

Myocardium uses two major substrates for energy production:

• Free fatty acids (50-80%)• Glucose (10-25%)• Other – lactate (10-25%), ketones

CARDIAC METABOLISM

FATTY ACID METABOLISM GLUCOSE METABOLISM

ENERGY METABOLISM DURING ISCHEMIA

Switches from aerobic metabolism to glycolysis

• Anaerobic process• Substrate is glucose from blood or glycogen stores• By-products include pyruvate and lactic acid• Requires less O2 than oxidation of FFAs• Reduced intracellular pH

GLYCOLYSIS IS PROTECTIVE

Studies in myocytes have shown glycolysis to prevent opening of potassium channels

Maintains mitochondrial function during ischemia and reperfusion

Prevents myocardial contracture

Improved membrane phospholipid synthesis


Increased plasma free fatty acids (FFAs)

• Due to increased lipolytic action of catecholamines +/- therapeutically administered heparin

• Causes increased myocyte FFA uptake• Decreased contractility• Increased oxygen demands• Accumulation of toxic FFA derivatives

ISCHEMIC EFFECTS ON POTASSIUM

Onset of ischemia associated with very rapid loss of intracellular potassium

Shift believed to be mediated by ATP-sensitive potassium channels

ISCHEMIC EFFECTS ON MYOCARDIUM

Ischemia is initially reversible

If persistent can become irreversible cell death

Prior to cell death, period of time where cell is viable, but is vulnerable to further injury if blood flow is restored

• Ischemia-reperfusion injury• Myocardial, vascular or electrophysiological dysfunction

induced by restoration of blood flow to previously ischemic tissue


Ischemia-Reperfusion Injury Mechanisms:

• Cell/organelle membrane damage• Myocyte hypercontracture• Free radical toxicity• Aggregation of leukocytes/inflammatory mediators• Platelet and complement activation• Pro-apoptotic signaling• Endothelial damage


Ischemia-Reperfusion Injury Clinical Manifestations:

• Reperfusion arrhythmias• Endothelial cell damage microvascular dysfunction• Myocardial stunning• Myocyte death and infarction

GLUCOSE EFFECTS ON THE HEART

Hyperglycemia:

• Causes an osmotic diuresis reduces intravascular volume

• Promotes inflammation activates transcription factors that promote expression of pro-inflammatory cytokines

• Promotes coagulation prolongs fibrinogen half-life, increased pro-thrombin fragments, factor VII

• Independent predictor of abnormal coronary vasodilation

• Promotes oxidative stress

• Shifted to polyol pathway which generates superoxide radicals

• Radicals inactivate ATP production & promote more radical production

HYPERGLYCEMIA AND ACS

US registry of 141, 680 patients ≥ 65 years presenting with ACS

<6.1 6.1-7.8

7.9-9.5

9.6-13.3

>13.30.00%

5.00%

10.00%

15.00%

20.00%

25.00%

30.00%Blood Glucose at Admission (m-mol/L)

**74% previously diagnosed with DM, but DM diagnosed in minority of cases in other groups

Kosiborod et al. Circulation 2005; 111:3078-86


Associated with increased in-hospital mortality

• Relationship stronger in non-diabetics than diabetics• Non-diabetics BG 6.1-8mmol/L = 3.9 fold higher risk of

mortality• An increase in BG by 1mmol/L associated with 4%

increase in mortality over 50 months after MI

In non-diabetics admission BG also associated with increased morbidity

• Reinfarction• Hospitalization with heart failure• Adverse ventricular remodelling

Stranders et al. Arch Int Med 2004; 164:982-8


1720 subjects post AMI, 72% received PCI

Ishihara et al. Am Heart J., 2005; 150:814-20

Death MACE0%

5%

10%

15%

20%

25%

Acute HyperglycemiaNormoglycemia

IS IT JUST OCCULT DIABETES?

Not necessarily!

Admission BG is NOT an independent predictor of an abnormal OGTT

In those with BG >11.1mmol/L, DM only diagnosed in 50% and IGT in only 69%

EFFECT OF DM ON MORTALITY AND CARDIOVASCULAR EVENTS

Ishihara et al. Am Heart J., 2005; 150:814-20

1720 subjects post AMI, 72% received PCI

Death MACE0%

2%

4%

6%

8%

10%

12%

14%

16%

DiabeticNon-diabetic

P = NS

P = NS

IS IT A STRESS RESPONSE?

Post MI catecholamine response occurs during first 5 days after event

Catecholamine response proportional to size of infarct

• Faster heart rate• Poorer Killip class• Lower EF on discharge

Hyperglycemia may be an epiphenomenon

• Associated with larger infarction• Associated with HF on admission

SINGLE ADMISSION VS PERSISTENT HYPERGLYCEMIA

Persistent hyperglycemia more accurate predictor of death

Mean glucose concentration the most practical tool

Relationship between mean BG and mortality demonstrated by “J-shaped” curve

Kosiborod et al. Circulation; 2008: 1018-27

“GLUCOSE HYPOTHESIS”

Glucose-Insulin-Potassium (GIK) Therapy

• First postulated in 1960s• Concept that insulin may be beneficial during ACS• Rationale for GIK:

• GLUCOSE – substrate for glycolysis• INSULIN – shifts primary metabolic substrate from FFA to

glucose• POTASSIUM – prevents insulin-mediated hypokalemia

while optimizing intracellular [K+]


Proposed Beneficial Mechanisms:

• Reduces myocardial O2 demand• Reduces glycolytic generation of radicals• Increases efficiency of ATP production

• Protect cell membrane• Drives transport of Ca2+

• Improves Na+ homeostasis

• Promotes cell survival• Anti-apoptotic effects• Limits effects of reperfusion injury

• Anti-inflammatory effects• CRP increase post MI blunted ~50% by insulin

• Inhibits platelet aggregation • Promote vasodilation improves myocardial perfusion


Potential Drawbacks:

• Increased glycolysis could be harmful• Increased acidosis from lactate accumulation• Requires residual blood flow for lactate washout

• Risk of hyperglycemia or hypoglycemia• Volume overload

INTERVENTION TRIALS

PRE-REPERFUSION ERA

Meta-analysis – Fath-Ordoubadi F & Beatt KJ 1997 Circulation 96:1152-1156

• 9 RCTs 1965-1987, 1932 patients• Large variability in design and GIK solution

• Oral glucose, subcutaneous insulin• IV GIK (high dose vs other)

• 1 trial gave thrombolytics• Most studies excluded patients with DM• Evaluated in-hospital mortality

STUDY YEAR DELAY BETWEEN

ONSET OF MI AND RX

EXCLUSION CRITERIA

GIK REGIMEN

DURATION OF

TREATMENT

Mittra 1965 < 48 h IDDM, RF Oral GK, sc insulin

14 days

Pilcher 1967 (not available) DM Oral GK, sc insulin

14 days

Pentecost 1968 < 48 h IDDM, severe LVF

IV 48 hours

MRC 1968 < 48 h DM, RF Oral GK, sc insulin

14 days

Hjermann 1971 < 48 h Age >75, IDDM, RF

Oral GK, sc insulin

10 days

Heng 1977 < 12 h cardiogenic shock, RF

High-dose IV 6-12 hours

Stanley 1978 < 12 h (not available) High-dose IV 48 hours

Rogers 1979 <12 h Age>75, IDDM, RF

High-dose IV 48 hours

Satler 1987 < 24 h Age>75, IDDM High-dose IV 48 hours

High dose IV – 30% glucose, 50 U insulin, 80 mmol K at >1.5 ml/kg/hr

COMPARISON OF MORTALITY OUTCOME IN PATIENTS TREATED WITH GIK THERAPY COMPARED WITH PLACEBO

PRE-REPERFUSION ERA

Meta-analysis – Fath-Ordoubadi F & Beatt KJ 1997 Circulation 96:1152-1156

• In-hospital mortality:• 21% placebo group vs 16.5% GIK group• P=0.004, OR 0.72, 95% CI 0.57-0.90

“…GIK therapy may have an important role in reducing in-hospital mortality after acute MI.”

POST-REPERFUSION ERA

Insulin Focused Trials

• Objective to correct relative insulin deficiency• Provide fixed dosed GIK infusions• Glucose acting to prevent hypoglycemia and acting as an

alternative energy substrate• Achieving a target BG not a priority• Goal to improve myocardial metabolism

Euglycemia Focused Trials

• Insulin administered to reduce elevated BG levels to normal• Goal to reverse any direct adverse effects of hyperglycemia

INSULIN FOCUSED TRIALS• Many trials 1998-2007

• Variable design, variable outcomes measured

• Clinical (in-hospital events, CHF, re-infarct)• Biochemical (cardiac enzymes, markers of oxidative stress)• Electrocardiographic (STE resolution)• Surrogate markers (variability index, LVEF, TIMI flow)

• Variable results

Kloner RA & Nesto RWCirculation 2008; 117:2523-2533

DIGAMI – DIABETES INSULIN-GLUCOSE IN ACUTE MYOCARDIAL INFARCTION

Malmberg K et al. 1995 J Am Coll Cardiol 26:57-65

• First study of GIK in reperfusion era with euglycemia focus

• Examined effect of insulin-glucose infusion followed by multidose insulin injections on mortality in diabetic patients with acute MI

• Multicentre, randomized, blinded

• Inclusion:

• Suspected acute MI in past 24h• Known hx DM and BG >11 or BG >11 (even without known hx

DM)• Exclusion:

• Inability/refusal to participate • Outside catchment area• In other studies (or already in DIGAMI)

DIAGAMI

Stratified into 1 of 4 groups:

• No insulin, low risk• No insulin, high risk• Insulin, low risk• Insulin, high risk

High risk = 2 or more of:

• Age > 70• Previous Hx MI• Previous Hx CHF• Current Rx with digitalis

Randomized to insulin-glucose (≥ 24h) or control

Goal BG on infusion 7-10

DIGAMI

At Hospital Discharge

• 87% insulin-glucose group on insulin• 43% control group• P<0.0001• This difference maintained at 3 months and 1 year

Three Month HbA1c

• 7.0 +/- 1.6% insulin-glucose group• 7.5 +/- 1.8% control group• P<0.01• HbA1c decreased in both groups over 1 year, but

significantly more in insulin-glucose group

DIGAMI

No difference between insulin-glucose and control groups in:

• In-hospital or follow-up treatment

• Except anti-diabetic meds/insulin

• In-hospital morbidity

26%

19%


P=0.0273

DIGAMI CONCLUSIONS

Long-term mortality in diabetic patients with acute MI could be reduced with insulin-glucose infusion followed by MDI insulin

Low risk, no prior insulin group benefited most

Follow-up – mortality benefit persisted at 3 years

DIGAMI-2

Malmberg K et al. 2005 Eur Heart J 26:650-661

• Compared 3 treatment strategies in DM2 with acute MI:

• 24hr insulin-glucose infusion (goal BG 7-10) then SC MDI insulin (FBG 5-7, random <10)

• 24hr insulin-glucose infusion then standard glucose control

• Routine metabolic management as per local practice

DIGAMI-2

Multicentre, randomized, open trial with blinded evaluation

Inclusion:

• Patients with type 2 DM or admission BG > 11• Suspected acute MI

Exclusion:

• Inability to cope with insulin or to receive info on study• Outside catchment area• In other studies• Already in DIGAMI 2

Primary objective– compare total mortality between groups 1 & 2

Secondary objective – compare total mortality between groups 2 & 3

Tertiary objective – compare morbidity between all groups

1253 Subjects

Group 1 (474-38%)

24h insulin-glucose infusion then long term MDI insulin

Group 2 (473-38%)

24h insulin-glucose infusion then routine metabolic management

Group 3 (306-24%)

Routine metabolic management

Malmberg K et al. Eur Heart J 2005;26:650-661

RESULTS - GLYCEMIA


RESULTS - MORTALITY23.4% grp 121.2% grp 2

17.9% grp 3


DIGAMI-2 - SUMMARY

No difference in mortality or morbidity found

Limitations:

• Inadequate recruitment under powered• Glycemic control similar in all 3 groups (did not achieve

target in group 1)• During follow-up, <50% group 1 used SC MDI insulin vs

15% group 2, 20% group 3• Overall event rate lower than expected in all groups

HI-5 – HYPERGLYCEMIA: INTENSIVE INSULIN INFUSION IN INFARCTION

Chung NW et al. Diabetes Care 2006. 29:765-770

Examined effect of tight glycemic control using insulin/dextrose infusion in diabetic patients with acute MI

Multicenter, randomized, open-label

Inclusion:

• Known DM or no prior hx DM with BG >7.8• Evidence of acute MI

Exclusion:

• Pregnancy• DKA• Admission BG > 20

HI-5

Stratified into 2 groups

• Known DM or admission BG > 11.1 without prior hx DM• Admission BG 7.8-11 without prior hx DM

Randomized to insulin infusion or conventional Rx

Insulin infusion group = target BG 4-10 for at least 24hr, then managed as per usual care

Primary outcome = mortality during hospital admission and at 3 and 6 months

Cheung NW et al. Diabetes Care 2006. 29:765-770

RESULTS

No difference in mortality between groups

• Inpatient, 3 or 6 months

No difference in blood glucose at 24hr

• Mean duration prior to commencement of infusion 13hr, after reperfusion therapy

Subset analysis – BG ≤ 8 in first 24hr associated with lower mortality at 3, 6 months

IMPORTANT TRIALS OF INSULIN THERAPY IN ACS PATIENTS

Treat with insulin to a BG target

GIK Infusion

SYSTEMATIC REVIEW

Anantharaman, R. et al. Heart 2009; 95:697-703

Trials with an insulin focus do not show any significant benefit

Trials with a glycemic focus are inconclusive

STUDY LIMITATIONS

Paucity of non-diabetics in the euglycemia focus studies

• DIGAMI, DIGAMI2• HI-5 50% non-DM

Early, substantial decreases in BG compared to control not achieved in some studies

• CREATE-ECLA treatment arm BG actually rose, higher at 24hr compared to treatment

• CARDINAL study showed hyperglycemia in first 24hr after AMI predicts higher mortality in non-DM

All euglycemia focus trials treatment started > 12hr from time of symptom onset

STUDY LIMITATIONS

Adverse effects of hypoglycemia may be overshadowing possible benefits

• More patients in the insulin therapy or GIK infusion arms affected by low BGs

Both DIGAMI2 and HI-5 both failed to recruit sufficient number of patients

In the era of reperfusion and use of ASA, statins and beta blockers, any benefit achieved may be overshadowed

Selker H. et al. JAMA 2012. 301:1925-33

Selker H. et al. Am J Cardiol 2014. 113:1599-1605

Immediate administration of GIK at the first signs of a heart attack (pre-hospital) by EMS vs placebo

Double-blinded, randomized, placebo controlled

All-cause mortality at 30 days and 1 year

Inclusion: all patients aged >30 for whom had chest pain or other possible ACS symptoms (prediction tool)

Exclusion: CHF, on dialysis or unable to give consent

Study Population

• Average age was 63• 71% men, 86% presented with chest pain• Demographics similar between groups• 47% of participants received PCI• Median time from symptom onset to study drug was 90min• DM

• GIK 29.4%• Placebo 26.3%


Total Population – Results 30 days

x

Selker H. et al. JAMA 2012. 301:1925-33

Total Population – Results 1year


Subgroup Analysis – STEMI patients


Summary

• 30 day results• No reduction in primary end point of progression to AMI• Significant reductions in the composite end point of cardiac

arrest or mortality

• 1 year follow up• Serous end points were generally lower with GIK than

placebo but no statistically significant• In STEMI subgroup, had significant reduction in the

composites endpoints:• cardiac arrest or 1 year mortality• cardiac arrest, mortality or CHF hospitalization within

1 year

CURRENT PRACTICE

2011 Clinical Practice Guidelines

• All patients with AMI should have their BG checked regardless of history of DM

• When BG >11 mmol/L on admission, should receive glycemic control in the range of 7-10

• Patients should be maintained on strategies to achieve recommended glucose targets long term

SUMMARY

Cardiac metabolism is primarily oxidative phosphorylation with FFAs as primary energy substrates

In ischemia, glycolysis becomes primary mode of energy metabolism

• Conserves oxygen use• May have cardiac protective effects

Admission hyperglycemia following AMI associated with higher mortality and major cardiac events

• More pronounced in non-diabetic patients• Persistent hyperglycemia better predictor of death

SUMMARY

Interventions either have insulin or euglycemia focus

In the pre-reperfusion era GIK infusion may have had mortality benefit

In the reperfusion era

• Insulin focus trials do not show mortality benefit• Euglycemia focus trials may suggest possible benefit

BEYOND DIGAMI: GLYCEMIC MANAGEMENT IN ACUTE MYOCARDIAL INFARCTION JULIA CREIDER, PGY5 ENDOCRINE &...

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