glucose and cv disease and glucose • how common is diabetes? • diabetes as a risk for cvd •...

Glucose and CV disease

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Diabetes and glucose

• How common is diabetes?

• Diabetes as a risk for CVD

• Does improving glucose control prevent complications?

• Does too tight glucose control cause death?

• Glucose vs glycation

– Hemoglobin Glycation Index

• What should our A1c target be?

Diabetes-related complications in the USA, 1990-2010Acute myocardial infarction

Adapted from Gregg EW, et al. N Engl J Med 2014;370:1514–1523. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.



• Diabetes as a risk for CVD.




• Hemoglobin Glycation Index




• Diabetes as a risk for CVD. Does A1c make a difference?






DCCT, Diabetes Control and Complications Trial.

1. Adapted from Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254.

2. DCCT. N Engl J Med. 1993;329:977-986.

3. DCCT. Diabetes. 1995;44:968-983.

Re

lati

ve

Ris

k

A1C (%)

15

13

11

9

7

5

3

1

6 7 8 9 10 11 12

A1C and Relative Risk of Microvascular

Complications: DCCT

Retinopathy

Nephropathy

Neuropathy

Microalbuminuria

20

17

HbA1c predicts Coronary Heart

Disease in Type 2 Diabetics

ukpdsSlide Source:

Lipids Onlinewww.lipidsonline.org

0

20

40

60

80

Incidence Rates of MI and Microvascular

Endpoints by Mean Hemoglobin A1c: UKPDS

5 6 7 8 9 10 11

Incid

ence p

er

1000 P

ers

on

Years

(%

)

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

Updated Mean Hemoglobin A1c Concentration (%)

Adjusted for age, sex, and ethnic group

Myocardial Infarction

Microvascular Endpoints

Rate of CVD, MI, or Ischemic Stroke Increases as Baseline HbA1c Increases*

*Adjusted for age, gender, duration of DM, glomular filtration rate (GFR), established atherosclerosis vs primary prevention, and microalbumin:creatinine ratio (mAlb:Cr)

Cavender, MA, et al. American Heart Association Scientific Sessions. November 2013, data from SAVOR

6 12 18 24

<7%

7%-<8%

8%-<9%

≥9%

Months

Adj HR (95% CI)

1.76 (1.48, 2.11)

1.37 (1.14, 1.65)

1.14 (0.96, 1.35)

Reference

2

4

6

8

10

12

CV

De

ath

, MI,

or

Isch

em

ic S

tro

ke

21

NEJM Volume 329: Number 14; 977-986

DCCT: Reduction in Retinopathy

ukpds

Solid line = risk of developing microalbuminuriaDashed line = risk of developing macroalbuminuria

DCCT: Reduction in Albuminuria

The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.

34% RRR (p<0.04)

43% RRR(p=0.001)

56% RRR(p=0.01)

Primary Prevention Secondary Intervention

guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca

Copyright © 2013 Canadian Diabetes Association

RRR = relative risk reductionCI = confidence interval

ukpdsThe Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.

DCCT: Reduction in neuropathy

Does tighter glycemic

control offer CV benefits?

57% risk reduction

in non-fatal MI, stroke or CVD death*

(P = 0.02; 95% CI: 12–79%)

Cu

mu

lati

ve

in

cid

en

ce

of

no

n-f

ata

l M

I, s

tro

ke

or

de

ath

fro

m C

VD Conventional

treatment

Intensive

treatment

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Years

0.06

0.04

0.02

0.00

Adapted from DCCT. N Engl J Med 1993; 329:977–986. DCCT/EDIC. JAMA 2002; 287:2563–2569.

DCCT/EDIC. N Engl J Med 2005; 353:2643–2653.

DCCT/EDIC: glycaemic control reduces the risk of

non-fatal MI, stroke or death from CVD in type 1

diabetes

0

7

1 6

Hb

A1C

(%)

9

8

2 3 4 5 7 8 9

Conventional treatment

Intensive treatment

11 12 13 14 15 16 1710

*Intensive vs conventional treatment

DCCT (intervention period EDIC (observational follow-up)

DCCT (intervention period) EDIC (observational follow-up)

Years

3 major studies that are referred to,

ADVANCE, ACCORD, VADT to provide

answers• All studies of “Intensive glucose control” vs “looser

glucose control”

• All were in very high risk patients who had their diabetes

for 8-11 years

– Either had documented vascular disease or

– Very high risk based on risk factors

ACCORD

10,251 pts with T2DM + CV risk

Average diabetes duration 10 yrs

Median baseline A1c = 8.1%

Intensive target <6.0% (actual 6.4%)

Standard target 7-7.9% (actual 7.5%)

Mean A1c 7.5%

Mean A1c 6.4%

Non-fatal MI, non-fatal CVA, death from CV causes

ACCORD:

Mean A1c 7.5%

Mean A1c 6.4%

HR 1.22, p = .04

We’ll discuss at much greater length

9.4% to 8.4%

9.4% to 6.9%

Mean A1c’s

VADT

And

VADT

hazard ratio in the intensive-therapy group of 0.88

(95% confidence interval [CI], 0.74 to 1.05).

8.4%

6.9%

Does VADT tell us anything?

Benefits of early vs late glycaemic intervention

Adapted from Del Prato S. Diabetologia 2009;52:1219–26.

Metabolic Memory = Glycaemic legacy

UKPDS: United Kingdom Prospective Diabetes Study

VADT: Veterans Affairs Diabetes Trial

Enters VADT intensive treatment

arm

1614121086420

0

6

7

9

8

10

Time since diagnosis (years)

Hb

A1c

(%)

‘Bad glycaemic legacy’

– drives risk of

complications

Estimated HbA1c time-

course based on

UKPDS data

Ideal time-course of

glycaemic control

HbA1c time course

in VADT

P = .o3

VADT

NEJM Vol 358, No 24, June12, 2008: ACCORD

heterogeneity

VADT

Early intervention!

IS IT POSSIBLE TO PROVE THAT IMPROVED

GLYCEMIC CONTROL CAN DECREASE CVD?

• CVD event rate = 1.5% per year

• 25% risk reduction with intervention

• Alpha = 0.05

3 year study……………………….28,000

5 year study……………………….14,700

10 year study……………………….6,800

FOR 90% POWER Number

ASSUME

Are there any studies looking at

glucose control early in the course of

the diabetes?

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

Mean difference .9%

ukpds

Myocardial Infarction (cumulative)

0%

10%

20%

30%

0 3 6 9 12 15

% o

f pa

tien

ts w

ith a

n e

ven

t


Intensive

Conventional

p=0.052

Risk reduction 16%(95% CI: 0% to 29%)

fatal or non fatal myocardial infarction, sudden death

573 of 3867 patients (15%)

ukpds

Myocardial Infarction

M v I

p=0.12

overweight

patients

0.0

0.1

0.2

0.3

0.4

0 3 6 9 12 15

Pro

po

rtio

n o

f p

atie

nts

with e

ven

ts


Conventional (411)

Intensive (951)

Metformin (342)

M v C

p=0.010

RRR

31%

5

Abstract 1338

Delay in Treatment Intensification Increases the Risks of Cardiovascular Events in Patients with Type 2 Diabetes

Adapted from Paul SK et al. Cardiovasc Diabetol. 2015 Aug 7;14:100.

Compared to patients with HbA1c <7%, in patients with HbA1c ≥7%, a ≥ 12 month delay in receiving treatment intensification was associated with significantly increased risk:

MI 67%

HR 1.67 (CI: 1.39,

2.01)*

51%

HR 1.51 (CI: 1.25,

1.83)*

HF 64%

HR 1.64 (CI: 1.40,

1.91)*

CVE 62%

HR 1.62 (CI: 1.46,

1.80)*

MI= myocardial infarction, HF=Heart Failure, CVE= composite MI, Stroke & HFRetrospective cohort study (N = 105,477) from the United Kingdom Clinical Practice Research Datalink

Not Proof of Cause and Effect * P <0.01

STROKE

• The earlier you start while the blood vessels are clean, the more benefit you expect from tighter glucose control

Who died in ACCORD?

What does ACCORD really tell us?

• Tight glycemic control shows CV benefit after

5 years

• People who died had higher A1c’s

• People who died were people in whom it was

not possible to lower their A1c’s

• People who died had a high “Hemoglobin

Glycation Index”

• People who died tended not to be on beta

blockers

But when you adjust for glucose control….



5 years





Glycation Index”


blockers

What is it about this group of people that it wasn’t possible to

lower their A1c



5 years





Glycation Index”


blockers

A1c’s do not accurately describe glucose

profiles in ALL people

(Even excluding people with

hemoglobinopathy, hemolysis, anemia, etc

which are known to affect A1c)

Mr. R. R.

Mr. F. S.

• (Actual A1c) minus (Predicted A1c based on glucose

values)

• Someone has a high HGI, (i.e., rapid glycator) if their

glucoses are good but their A1c is high

• Someone has a low HGI, (i.e., slow glycator) if their

glucoses are high but their A1c is low

Hemoglobin Glycation Index (HGI)

High HGILow HGI

High HGI Low HGI

Survivors

Standard: dashed

Intensive: solid

High HGI

Moderate HGI

Low HGI

Mr. F. S



5 years





Glycation Index”


blockers

People on beta blockers had more events (not as surprise – they had more disease) but being on intensive therapy lowered the event rate

People not on beta blockers didn’t have as many events (less disease) but intensive therapy did not lower the event rate

People on beta blockers had more events (not as surprise – they had more disease) but being on intensive therapy did not increase the event rate

People not on beta blockers didn’t have as many events (less disease) but intensive therapy increased the event rate

Summary and Conclusions (1):

• Good glycemic control lowers risk of

microvascular disease

• Aggressive glucose control early in the course of

diabetes seems to be the best strategy

• Aggressive glucose control prior to the

development of a large atherosclerotic burden

seems to be best strategy

• This does not mean that if an individual has had

their diabetes for a long period or has had a CV

event that they won’t benefit – will take more time

Non-fatal MI, non-fatal CVA, death from CV causes

NEJM Vol 358, No 24, June12, 2008


• A1c does not always tell the whole story. Look at

the glucoses – Look at the Pt’s glucose meter!!!

– If A1c is high but glucoses are good, this

patient is a rapid glycator with a high HGI.

• This is a higher risk patient

• There seems no gain in pushing his

glucoses down further to lower his A1c

–It won’t happen

– It would increase risk of hypoglycemia

• Concentrate on other risk factors

• In people with vascular disease, beta blockers appear to

be synergistic with tightening glucose control to lessen

CV complications

– Protection for adrenergic stimulation from either

• Hypoglycemia?

• Further hyperinsulinemia????




• Why do we treat it?

• Does glycemic control predict complications?








Individualizing A1C Targets

which must be balanced against the risk of hypoglycemia

Consider 7.1-8.5% if:

2013

• Keep the above targets in mind, but …

• Try to achieve the lowest A1c possible with the best

balance of minimal highs and minimal lows

• The determination of “best balance of minimal lows”

depends on risk of hypoglycemia and other general

factors

– To do this, you must look at the meter and the

logbook

Hardin’s suggestion for A1c target:



Individualizing A1C Targets

which must be balanced against the risk of hypoglycemia

Consider 7.1-8.5% if:

2013

glucose and cv disease and glucose • how common is diabetes? • diabetes as a risk for cvd •...

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