Cardiovascular events & Hypoglycemia

Hypoglycemia and Cardiovascular Events

Choosing right therapies and targets, and the right patient

Mathew JohnEndocrinologist

Providence Endocrine & Diabetes Specialty Centre

Trivandrum, India www.endocrinologydiabetes.com

Plan

• Show evidence that CV disease is increased in type 2 diabetes

• Show evidence that multifactorial interventions including glycemic control will reduce risk of CV diseaseglycemic control will reduce risk of CV disease

• Evaluate hypoglycemia in recent trials

• How hypoglycemia is related to CV outcomes

• Fitting targets and drugs to the right patient

Improved Glycemic Control Has Been Shown to Reduce the Risk of Complications

According to the United Kingdom Prospective DiabetesStudy (UKPDS) 35, Every 1% Decrease in A1C Resulted in:

21%14% 12%

37%

Stratton IM et al. BMJ. 2000;321:405-412.

Decrease in risk of

microvascularcomplications

(P<.0001)

Decrease in risk of any

diabetes-related end point(P<.0001)

Decreasein risk of MI(P<.0001)

Decrease in risk of stroke(P=.04)

37%

Intervention Works...but at a Price: DCCT and UKPDS

Severe Hypoglycemia

Majo

r E

pis

od

es In

cid

en

ce (

%)

100

80

60

Rate

/100 P

ati

en

t Y

ears

5

4

DCCT (Type 1) UKPDS (Type 2)

Major Episodes

DCCT Research Group, Diabetes. 1997;46:271-286 UKPDS Group (33), Lancet. 352: 837-853, 1998

Majo

r E

pis

od

es In

cid

en

ce (

%)

HbA1c (%) During Study

60

40

20

0

5 6 7 8 9 10 11 12 13 14

Rate

/100 P

ati

en

t Y

ears

Conventional

Intensive 3

2

1

0

0 3 6 9 12 15

Intensive

Conventional

Years from Randomization

Asymptomatic Episodes of Hypoglycemia May Go Unreported

• In a cohort of patients with diabetes, more than 50% had asymptomatic (unrecognized) hypoglycemia, as identified by

50

75

100

Pati

en

ts, % 55.7

62.5

46.6

hypoglycemia, as identified by continuous glucose monitoring1

• Other researchers have reported similar findings2,3

1. Chico A et al. Diabetes Care. 2003;26(4):1153–1157. Permission pending.

2. Weber KK et al. Exp Clin Endocrinol Diabetes. 2007;115(8):491–494.

3. Zick R et al. Diab Technol Ther. 2007;9(6):483–492.

0

25

All patients with

diabetes

Type 1 diabetes

Pati

en

ts, %

Type 2diabetes

Patients With ≥1 Unrecognized Hypoglycemic Event, %

n=70 n=40 n=30

Reporting hypoglycemia

• Documented symptomatic hypoglycemia: plasma glucose < 70 + symptoms

• Severe hypoglycemia: requiring assistance of another person for resuscitation

• Asymptomatic hypoglycemia• Asymptomatic hypoglycemia

• Probable symptomatic hypoglycemia

• Relative hypoglycemia: symptoms of hypoglycemia+ plasma glucose > 70 mg/dl

ADA Working Group on Hypoglycemia Diabetes Care 2005: 28(5): 1245-1249.

Severe hypoglycemia : definition in ACCORD

Requiring medical or paramedical attention in which

there was either a documented capillary glucose level 50 mg/dL (2.8 mmol/L) or in which prompt recovery was achieved with oral carbohydrate, intravenous glucose, or glucagonsglucagons

Severe Hypoglycemia Monitoring and Risk Management Procedures in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial . Am J Cardiol 2007;99[suppl]:80i–89i)

Counter regulatory hormone response

82 mg/dl

70 mg/dl

Inhibition of endogenous insulin secretion

Counterregulatory hormone releaseGLUCAGON, CATECHOLAMINES

50-60 mg/dl

< 50 mg/dl

GLUCAGON, CATECHOLAMINES

Onset of autonomic and neuroglycopenic symptoms

< 30 mg/dl

Cognitive dysfunction

coma,convulsions

Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes Diabetes Care 2005: 28: 12: 2948-2961

Counter regulatory hormone response

Counter regulation: physiological mechanisms

that normally prevent or rapidly correct hypoglycemia

• Glucagon : predominant hormone

• Catecholamines

• Cortisol

• Growth hormone

Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes Diabetes Care 2005: 28: 12: 2948-2961

Complications and Sequelaeof Hypoglycemia

Release of

Increased risk ofcardiac arrhythmia•Abnormal prolonged cardiac repolarization—

Plasma glucose level

90

100

110

5

6

Release of epinephrine and norepinephrine

•Abnormal prolonged cardiac repolarization—↑in QTc and QTd—associated with ↑ levels of

epinephrine and hypokalemia•Cardiac death

Neuroglycopenia

• Reduced attention span

• Inability to focus

• Personality change

• Confusion

• Seizure

• Coma

• Brain death

Cryer PE. J Clin Invest. 2006:116:1470–1473.

10

20

30

40

50

60

70

80

1

2

3

4

mg/dl

mmol/l

Cardiovascular benefits of glycemic control and Multifactorial

Interventions Interventions

UKPDS legacy effect ACCORD study : subgroupsVADT : subgroups

ACCORD : Kaplan–Meier Curves for the Primary Outcome and Death from any cause

Composite primary outcome

Nonfatal MI + nonfatal stroke +

death from CV causes(6.9% in Intensive vs. 7.2% in std therapy group

HR 0.90 CI 0.78-1.04, p: 0.16)

Not significant

Death from any cause

Intensive vs. Std 257 vs. 2035 % vs. 4 % , HR 1.22 95 %CI : 1.01-1.46, p=0.04)

Why was mortality increased ?

• Not certain

• Speed of HbA1c reduction ( 1.4 % vs. 0.6% in 4 months)

• Drug combinations

• Unidentified hypoglycemia

• Weight gain • Weight gain

• Hypoglycemia unawareness (associated cardiac autonomic neuropathy)

Analysis proves that the increased mortality rates are not related to

1. Specific OAD ( Rosiiglitazone, SU , Insulin etc)

2. Changes in other medications( Statins,Aspirin etc)

Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD,ADVANCE, and VA Diabetes Trials Diabetes Care January 2009 vol. 32 no. 1 187-192

Increased Mortality, Myocardial Infarction, and Hypoglycemia With Intensive Therapy:

ACCORD Trial

Mortality (% per year)1

≥1 severe hypoglycemia

(n = 705)3.1

1 Bloomgarden ZT. Diabetes Care. 2008;31(9):1913–1919. 2. Dluhy RG, McMahon GT. N Engl J Med. 2008;358:2630–2633.

(n = 705)

No hypoglycemia

(n = 9,546)1.2

a Defined by requirement for medical or paramedical intervention, with

documented glucose <50 mg/dL and relief by parenteral or oral glucose or by glucagon.

ACCORD

• Rate of 1-year change in A1c showed that a greater decline in A1c was associated with a lower risk of death

• 20% higher risk of death for every 1% higher A1c level above 6%, suggesting that lower blood glucose levels above 6%, suggesting that lower blood glucose levels may be a worthy target in some patients

• Patients with the [consistently] lowest A1c levels had the lowest risk. The excess mortality risk was in those patients who failed to achieve and sustain A1c levels between 6% and 7%.

Update on ACCORD. International Diabetes Federation 2009 World DiabetesCongress. October 22, 2009; Montreal, QC. American Diabetes Association (ADA) 69th Scientific Sessions:

Abstract 468-P. Presented June 9, 2009

ACCORD: Adjusted mortality rates by treatment strategy

Riddle MC, Ambrosius WT Epidemiologic relationships between A1C and all cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care 2010;33: 983–990

ACCORD : Adjusted log HR by treatment strategy

The excess risk associated with intensive

glycemic treatment occurred among

those participants whose average A1C,

contrary to the intent of the strategy, was

>7%.

Riddle MC, Ambrosius WT Epidemiologic relationships between A1C and all cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care 2010;33: 983–990

Higher risk of hypoglycemia

• Age > 65 years

• Longer duration of insulin use

• Higher HbA1c

• Use of insulin

• Use of SU • Use of SU

• Older age

• Renal dysfunction,

• Mental health issues,( e.g. dementia)

–10

–5

0

Re

lati

ve

ris

k r

ed

uc

tio

n (

%)

9%

UKPDS: long-term follow-up and legacy effect

10

9

UKPDS

Active

Conventional

Intervention ends UKPDS

Follow-up

1c (%

)

–30

–25

–20

–15

–10

Re

lati

ve

ris

k r

ed

uc

tio

n (

%)

24%

15%

13%P = 0.040

P = 0.001

P = 0.014 P = 0.007

8

7

6

0 5 10 15 5 10 1977 1997 2007

Years from randomization

Intensive

Me

dia

n H

bA

1c

Biochemical data no longer collected

Bailey CJ & Day C. Br J Diabetes Vasc Dis 2008; 8:242–247. Holman RR, et al. N Engl J Med 2008; 359:1577–1589.

After median 8.5 years post-trial follow-up

Aggregate Endpoint 1997 2007

Any diabetes related endpoint RRR: 12% 9%

P: 0.029 0.040

Microvascular disease RRR: 25% 24%

P: 0.0099 0.001

Legacy Effect of Earlier Glucose Control

P: 0.0099 0.001

Myocardial infarction RRR: 16% 15%

P: 0.052 0.014

All-cause mortality RRR: 6% 13%

P: 0.44 0.007

RRR = Relative Risk Reduction, P = Log Rank

Diabetes-related deaths

All –Cause Mortality

Lessons from UKPDS:Legacy Effect of Earlier Metformin Therapy

POST-Trial Monitoring

1997 - 2007

-30%-42%

UKPDS Trial Intervention

1977 - 1997

All –Cause Mortality

Myocardial Infarction

UKPDS 80. NEJM 2008; 359: 1577-89

CV Complicationsreduced and Survival

increased versus other therapies

UKPDS 34. Lancet 1998; 352: 854-65

-27%

-33%

-36%

-39%

CV Complicationsreduced and Survival increase maintained

Legacy Effect

A treatment has a legacy effect if the intervention, when discontinued, leads to long term decreased risk of outcome.

http://www.ganfyd.org/index.php?title=Legacy_effect

VADT

• Older patients > 60 yrs

• 12% reduction in risk of cardiovascular events with intensive control, but that did not nearly reach statistical significance,"

• The risk of having a primary cardiovascular event • The risk of having a primary cardiovascular event among patients with diabetes of 10 to 15 years' duration was reduced 40% with intensive glucose control

• Increased incidence of severe hypoglycemia in the intensive treatment group.

Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Glucose control and vascular complications in veterans with

type 2 diabetes. N Engl J Med 2009;360:129–139

Predictions from VADT: impact of bad glycemic legacy

9.0

8.5

9.5 Drives risk ofcomplications

Before entering VADT intensive treatment arm After entering VADT intensive

treatment arm

Generation of a‘bad glycemiclegacy’

Time since diagnosis (years)

Hb

A1

c(%

)

1 2 3 8 9 12 1364 5 10 11 14 157 16 17

8.5

8.0

7.5

7.0

6.5

6.0

Del Prato S. Diabetologia 2009; 52:1219–1226.

VADT: relationship between coronary calcification and outcome

* Significant event reduction with CAC score <100, not >100

**

VADT: Diabetes duration vs. intensive treatment CVD benefit

Diabetes duration, years

Copyrighted art

deleted from here

http://connect.in.com/nadodikattu/photos-390645-4018893.html

“ There is a time for everything”

Multifactorial intervention and CV event reduction : The Steno Trial

Intensive therapy was associated with a lower risk of death from cardiovascular causes(hazard ratio, 0.43; 95% CI, 0.19 to 0.94; P=0.04) and of cardiovascular events(hazard ratio, 0.41; 95% CI, 0.25 to 0.67; P<0.001).

Steno 2 trial: 13year follow up

Total mortality in the intensive arm was reduced by 46% (RRR) corresponding to an absolute risk reduction of 20%N Engl J Med. 358:580-591,2008

Hypoglycemia and CV events

• 14,670 patients with coronary artery disease, recruited

for the Bezafibrate Infarction Prevention study over an

8-year mean follow-up, hypoglycemia was a predictor

of increased all-cause mortality (with a HR of 1.84)

• Veterans Affairs Cooperative Study on Glycemic

Control and Complications in Type 2 Diabetes:

more cardiac events were documented in patients after

institution of intensive glycemic control versus standard

control (32 vs. 20%)

Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Glucose control and vascular complications in veterans with

type 2 diabetes. N Engl J Med 2009;360:129–139

CEREBRAL ISCHEMIA, STROKE, ANDDEMENTIA

• Severe hypoglycemia has been known to induce focal

neurological deficits and transient ischemic attacks,

which are reversible with the correction of blood glucose

• Recurrent or severe hypoglycemia may predispose to • Recurrent or severe hypoglycemia may predispose to

long-term cognitive dysfunction and dementia.

• Conversely, severe cognitive dysfunction has been

associated with increased risk of hypoglycemia

Totalepisodes

Episodes withchest pain/angina

Episodeswith ECG

abnormalities

Hypoglycemia 54 10* 6*

Cardiac Ischemia Associated With Hypoglycemia Episodes: More Episodes of Chest Pain and ECG

Abnormalities

CGMS and Holter monitoring abnormalities

Study included patients (n=19, mean age, 58±16 years) with type 2 diabetes, history of

frequent hypoglycemia, HbA1c of 8%, and coronary artery disease (defined as history of

myocardial infarction, coronary bypass surgery, or angioplasty).

Symptomatic 26 10* 4*

Asymptomatic 28 — 2

Normoglycemia without rapid changes N/A 0 0

Hyperglycemia 59 1 0

Rapid changes in glucose (>100 mg · dl-1 · h-1) 50 9* 2

*P<0.01 vs episodes during hyperglycemia and normoglycemia.

ECG=electrocardiographic; CGMS=continuous glucose monitoring system.

Desouza C et al. Diabetes Care. 2003;26:1485–1489.

Meta-analysis: impact of intensive glucose control on coronary heart disease* events

Intensive treatment/standard treatment

Odds ratio(95% CI)

Odds ratio

(95% CI)

Participants Events

UKPDS 3,071/1549 426/259 0.75 (0.54–1.04)

PROactive 2,605/2633 164/202 0.81 (0.65–1.00)

Reproduced from Ray KK, et al. Lancet 2009; 373:1765–1772.

ADVANCE 5,571/5,569 310/337 0.92 (0.78–1.07)

VADT 892/899 77/90 0.85 (0.62–1.17)

ACCORD 5,128/5123 205/248 0.82 (0.68–0.99)

Overall 17,267/15,773 1,182/1,136 0.85 (0.77–0.93)

0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

Intensive treatment better Standard treatment better

*Included non-fatal myocardial infarction and death from all cardiac mortality.

Mechanisms by which hypoglycemia may affect cardiovascular events

Souza CV . Hypoglycemia, Diabetes, and Cardiovascular Events DIABETES CARE, VOLUME 33, NUMBER 6, JUNE 2010

Which TARGET for WHOM?

WHOEVERWINS….WE LOSE.

Hypoglycemia vs. Hyperglycemia

Factors deciding the target HbA1c

Several factors can be taken into consideration when tailoring treatment including

• Duration of diabetes

• Stage of disease

• Life expectancy• Life expectancy

• Risk of hypoglycemia

• Risk factors for CV disease (CVD).

Categorize patients into different groups

• Newly diagnosed patients

Obese patients

Lean patients

• Patients with inadequate glycemic control, but

no co morbiditiesno co morbidities

• Patients with CVD

• Individuals at risk of hypoglycemia

S. Del Prato; J. LaSalle; S. Matthaei; C. J. Bailey Tailoring Treatment to the Individual in Type 2 Diabetes Practical Guidancefrom the Global Partnership for Effective Diabetes Management Int J Clin Pract. 2010;64(3):295-304

Newly diagnosed patients

•Aggressive glycemic control

•Use agents with minimum risk of

hypoglycemia

•Target HbA1c < 6.5-7 %

UKPDSLegacy

Effect

•Chose therapies with likely beta cell

preservation

•Address cardiovascular risk factors

•Consider insulin if HbA1c > 9 %

S. Del Prato; J. LaSalle; S. Matthaei; C. J. Bailey Tailoring Treatment to the Individual in Type 2 Diabetes Practical Guidancefrom the Global Partnership for Effective Diabetes Management Int J Clin Pract. 2010;64(3):295-304

Patients with inadequate glycemic control, but no co morbidities

• Bad glycemic legacy

•Likely to have one /more microvascular complication

UKPDSLegacy Effect

•Aggressive glycemic control

•Gradual reduction in HbA1c

•Diabetes education

•Assess risk of hypoglycemia

S. Del Prato; J. LaSalle; S. Matthaei; C. J. Bailey Tailoring Treatment to the Individual in Type 2 Diabetes Practical Guidancefrom the Global Partnership for Effective Diabetes Management Int J Clin Pract. 2010;64(3):295-304

Patients with CVD

•Long duration of DM

•Poor glycemic control•

•Large pill burden

ACCORD

VADT

ADVANCE

• Benefits of good glycemic control vs. risk of hypoglycemia

•Gradual reduction in HbA1c

• Consider contraindications of agents used

• Assess risk of hypoglycemia

S. Del Prato; J. LaSalle; S. Matthaei; C. J. Bailey Tailoring Treatment to the Individual in Type 2 Diabetes Practical Guidancefrom the Global Partnership for Effective Diabetes Management Int J Clin Pract. 2010;64(3):295-304

High risk group in ACCORD

Patients with a history of CVD who do not respond to aggressive glucose-lowering strategies may be more susceptible to CV events

Calles J, Banerji M, Bonds DE et al. Baseline characteristics and mortality in ACCORD. Diabetes 2009; 58 (Suppl. 1): A24.

Patients with risk of hypoglycemia

•Long duration of DM

•Previous history of hypoglycemia

•Reduced Creatinine clearance

•Irregular eating/lifestyle habits

ACCORD

VADT

ADVANCE

• Less stringent HbA1c targets

•Gradual reduction in HbA1c

• Consider agents with less hypoglycemia

• Assess risk of hypoglycemia

•Irregular eating/lifestyle habits

S. Del Prato; J. LaSalle; S. Matthaei; C. J. Bailey Tailoring Treatment to the Individual in Type 2 Diabetes Practical Guidancefrom the Global Partnership for Effective Diabetes Management Int J Clin Pract. 2010;64(3):295-304

Adverse event concerns of add on therapy

Insulin Sulphonylurea TZD GLP-1 / DPP4 inhibitors

Hypoglycemia

Weight gainWeight gain

CV safety Ischemic

Preconditioning

UKPDS/ UGDP

MI

Fluid retention

Other concerns Fractures

Macular edema

Pancreatitis

Nausea

Effective interventions

Messages

• Glycemic control reduces Cardiovascular events

• Benefits of intensive glycemic control on CV events is pronounced when it is achieved early in the course of diabetes diabetes

• Identify patients with high CV risk and high hypoglycemia risk

• Individualize treatment

Disclaimer

The material for these slides were derived from various sources

including pictures and cartoons from the world wide web. I havetried my best to acknowledge all possible sources and references.However, if I have overlooked any particular reference, it is notdone intentionally. Anyone reproducing materials from thispresentations should acknowledge the author of the original work.presentations should acknowledge the author of the original work.

Cartoons are made to simplify certain concepts. The presentershould attach explanations to all cartoons or else it will appear quiteamateurish.