tight glycemic control in the prevention of cardiovascular disease

Glucose lowering for the prevention of CVD: Positive, Negative or NeutralIris Thiele Isip Tan MD, FPCP, FPSEMClinical Associate Professor, University of the Philippines College of MedicineSection of Endocrinology, Diabetes & MetabolismDepartment of Medicine, Philippine General Hospital

Who will benefit from tight

glycemic control?

What should be the target

HbA1c?

How do current therapies for

diabetes compare?

Cardiovascular Disease Prevention

UKPDSWho will benefit

from tight glycemic control?

Newly diagnosed type 2 diabetes

(n=3867) Median age 54 y

Objective

To determine whether improved glucose control would prevent complications

UKPDS Group, Lancet 1998;352: 837-53

UKPDS Design

Figure adapted from King et al. Br J Clin Pharmacol, 48:643-48

Therapeutic implications of the UKPDS

Newly diagnosed diabetes

Fasting plasma glucose >6mmol l–1

‘Prudent diet’for 3–4 months

>6mmol l–1

>6 and !15mmol l–1 >15mmol l–1

!6mmol l–1

Main randomization Primary diet failurerandomization

if becomes>6mmol l–1

Intensive policytarget <6mmol l–1

Conventional policytarget <15mmol l–1

Diet only Sulphonylurea Insulin Metformin(obese patients only)

Diet satisfactory

Figure 3 Design of UKPDS.

An unexpected finding was that the addition of metfor-min to sulphonylureas (in both obese and nonobesepatients) was associated with increased mortality. Thenumbers involved in this subgroup analysis were very small,with few deaths (26 vs 14 in the group treated withsulphonylureas alone) and no di!erence in the incidence ofheart attacks or strokes between the groups, only in theproportion who died. Furthermore, the mortality in thegroup treated by sulphonylureas alone was unexpectedlylow. The authors therefore concluded that this anomalousresult was likely to be have been due to chance.

• intensive glucose control, using existing treatments,

improved microvascular morbidity, but not mortality

• insulin and sulphonylureas were similarly effective

• metformin was advantageous in the obese

• intensive blood pressure control was more

beneficial, improving morbidity (both micro- and

macrovascular), and mortality

• ideal targets: HbAlc < 7%, BP < 140/80 mmHg

• any reduction was beneficial

Figure 4 Key points.Hypertension in Diabetes Study [18, 19]

One thousand one hundred and forty-eight patients tookin obese patients. However the number of patientsallocated to metformin was less than 10% of all those part. Half the participants were allocated to ‘tight control’

(target blood pressure less than 150/85 mm Hg) andrandomised. The findings could also be interpreted asindicating that insulin and sulphonylureas are equally were randomised to either atenolol or captopril, with

other agents added as necessary. The remainder wereharmful in the obese, possibly as a consequence ofhyperinsulinaemia. allocated to ‘less tight control’ (target blood pressure less

© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 643–648 645

Newly diagnosed diabetesFasting plasma glucose >6 mmol/L

‘Prudent diet’ for 3-4 mos

>6 mmol/L<6 mmol/L

Diet satisfactory >6 and <15 mmol/L >15 mmol/L

Main randomization

Primary diet failure randomization

Intensive policy target <6 mmol/L

Conventional policy target <15 mmol/L

If becomes >6 mmol/L

Diet only Sulphonylurea Insulin Metformin (obese patients only)

any diabetes-related endpoint

diabetes-related death

all-cause mortality

UKPDS Endpoints

UKPDS Group, Lancet 1998;352: 837-53

-50

-40

-30

-20

-10

0-16-21-33-25-12

% R

elat

ive

Ris

k R

educ

tion

p=0.03

p<0.01

p<0.01

p=0.052

p=0.02

Any DM endpoint Microvascular complicationsMicroalbuminuria at 12 yrs RetinopathyMyocardial Infarction

UKPDS Results

10-year follow-up median HbA1cIntensive 7.0% (6.2-8.2%)

Conventional 7.9% (6.9-8.8%)

remained after adjustment for other known riskfactors, including age at diagnosis, sex, ethnic group,systolic blood pressure, lipid concentrations, smoking,and albuminuria. Each 1% reduction in haemoglobinA1c was associated with a 37% decrease in risk formicrovascular complications and a 21% decrease in therisk of any end point or death related to diabetes. Theassociation with glycaemia was less steep for stroke andheart failure, for which blood pressure is a major con-tributing factor.32 34 35 In patients within the lowestcategory of updated mean haemoglobin A1c theincidence of myocardial infarction was higher thanthat of microvascular disease.5 These results suggestthat, in these people, the effect of hyperglycaemia itselfmay account for at least part of the excesscardiovascular risk observed in diabetic compared withnon-diabetic people beyond that explained by the con-ventional risk factors of dyslipidaemia, hypertension,and smoking.36 The rate of increase of relative risk formicrovascular disease with hyperglycaemia was greaterthan that for myocardial infarction, which emphasisesthe crucial role of hyperglycaemia in the aetiology ofsmall vessel disease and may explain the greater rate of

microvascular complications seen in populations withless satisfactory control of glycaemia.

Relation to trial dataThis observational analysis provides an estimate of thereduction in risk that might be achieved by thetherapeutic lowering of haemoglobin A1c by 1.0%, but itis important to realise that epidemiological associa-tions cannot necessarily be transferred to clinical prac-tice. Tissue damage from previous hyperglycaemiamay not promptly be overcome, but the results are notinconsistent with those achieved by the policy of inten-sive glucose control in the clinical trial.1 This suggeststhat the reduction in glycaemia obtained over amedian 10 years of follow up of the trial, comparingmedian haemoglobin A1c 7.0% with 7.9%, providedmuch of the benefit that could be expected from thatdegree of improved glycaemic control. Our resultssuggest that intensive treatment with sulphonylurea orinsulin does not have an effect beyond that of loweringblood glucose concentration with respect to alteringrisk. The 16% risk reduction (P = 0.052) in myocardialinfarction in the clinical trial in the group allocated toa policy of intensive blood glucose control (associated

4

1

0.5

Haza

rd ra

tio

Any end point related to diabetes

Death related to diabetes

All cause mortality

P<0.0001

21% decrease per 1%reduction in HbA1c

4

1

0.5

Haza

rd ra

tio

P<0.0001


4

1

0.55 6 7 8 9 10

Haza

rd ra

tio

P<0.0001


Updated mean haemoglobin A1c concentration (%)

Fig 3 Hazard ratios, with 95% confidence intervals as floatingabsolute risks, as estimate of association between category ofupdated mean haemoglobin A1c concentration and any end point ordeaths related to diabetes and all cause mortality. Reference category(hazard ratio 1.0) is haemoglobin A1c <6% with log linear scales.P value reflects contribution of glycaemia to multivariate model. Dataadjusted for age at diagnosis of diabetes, sex, ethnic group,smoking, presence of albuminuria, systolic blood pressure, high andlow density lipoprotein cholesterol, and triglycerides


10

1

0.5

Haza

rd ra

tioHa

zard

ratio

Haza

rd ra

tioFatal and non-fatal myocardial infarction

P<0.0001

Fatal and non-fatal stroke

Microvascular end points Cataract extraction

Amputation or death fromperipheral vascular disease Heart failure


P=0.035


10

1

0.5

P<0.0001


P<0.0001


10

1

0.55 6 7 8 9 10 5 6 7 8 9 10

P<0.0001


P=0.021


Fig 4 Hazard ratios, with 95% confidence intervals as floating absolute risks, as estimate ofassociation between category of updated mean haemoglobin A1c concentration and myocardialinfarction, stroke, microvascular end points, cataract extraction, lower extremity amputation orfatal peripheral vascular disease, and heart failure. Reference category (hazard ratio 1.0) ishaemoglobin A1c <6% with log linear scales. P value reflects contribution of glycaemia tomultivariate model. Data adjusted for age at diagnosis of diabetes, sex, ethnic group,smoking, presence of albuminuria, systolic blood pressure, high and low density lipoproteincholesterol, and triglycerides

Papers

409BMJ VOLUME 321 12 AUGUST 2000 bmj.com

5 6 7 8 9 10Updated mean HbA1c (%)

Stratton et al, BMJ 2000; 321:405-12

dietary treatment, and systolic blood pressure repre-sented by the mean of measures at two and ninemonths after diagnosis. The hazard ratio was used toestimate the relative risk. At each event time, theupdated mean haemoglobin A1c value for individualswith an event was compared with the updated value ofthose who had not had an event by that time. Theupdated mean value was included as a time dependentcovariate to evaluate glucose exposure during followup.20 29 30 It was included as a categorical variable in thecategories of glycaemia listed above, with the lowestcategory ( < 6%) as the reference category assigned ahazard ratio of 1.0 and with the highest category >9%.(This is reflected in the point estimates as shown in fig-ures 3 and 4.) Separate models, with updated meanhaemoglobin A1c as a continuous variable, were used todetermine reduction in risk associated with a 1%reduction in haemoglobin A1c (see regression lines infigures 3 and 4). We evaluated the presence ofthresholds by visual inspection. The 95% confidenceintervals were calculated on the basis of the floatingabsolute risk.31 Log linear relations are reported byconvention.1 32 The risk reduction associated with areduction of 1% updated mean haemoglobin A1c wascalculated as 100% minus the reciprocal of the hazardratio expressed as a percentage. The risk reductionfrom the continuous variable model associated with a1% reduction in observed haemoglobin A1c wascompared with the risk reduction seen in the UKPDSintervention trial of an intensive versus a conventionalpolicy of blood glucose control, for which noadjustment for potential confounders was required asthey were balanced by randomisation.1

To assess whether the association between meanupdated haemoglobin A1c and complications was

independent of randomisation, separate modelsincluded mean updated haemoglobin A1c and randomi-sation to either intensive or conventional policy, as wellas all potential confounders listed above. The model forall end points related to diabetes included 3005individuals.

Statistical analyses were performed with SASversion 6.12.33

ResultsThe risk of each of the microvascular and macrovascu-lar complications of type 2 diabetes and cataractextraction was strongly associated with hyperglycaemiaas measured by updated mean haemoglobin A1c. Theincidence rates for any end point related to diabetes,adjusted for age, sex, ethnic group, and duration ofdiabetes, increased with each higher category ofupdated mean haemoglobin A1c, with no evidence of athreshold and with a threefold increase over the rangeof updated mean haemoglobin A1c of < 6% (median5.6%) to >10% (median 10.6%) (figs 1 and 2). Theunadjusted and adjusted incidence rates are shown intable 2. Figure 2 shows the adjusted incidence rates formyocardial infarction and microvascular end points.The increase in the incidence rate for microvascularend points was greater over the range of increasingglycaemia than was the increase in the incidence ratefor myocardial infarction. Thus at near normalconcentrations of updated mean haemoglobin A1c therisk of myocardial infarction was twice to three timesthat of a microvascular end point, whereas in the high-est category of haemoglobin A1c concentration (>10%)the risks were of the same order.

120

100

160

140

80

60

40

20

05 6 7 8 9 10 11

Adju

sted

inci

denc

e pe

r 100

0 pe

rson

yea

rs (%

)


Fig 1 Incidence rate and 95% confidence intervals for any end pointrelated to diabetes by category of updated mean haemoglobin A1c

concentration, adjusted for age, sex, and ethnic group, expressed forwhite men aged 50-54 years at diagnosis and with mean duration ofdiabetes of 10 years

80

60

40

20

05 6 7 8 9 10 11

Adju

sted

inci

denc

e pe

r 100

0 pe

rson

yea

rs (%

)

Myocardial infarctionMicrovascular end points


Fig 2 Incidence rates and 95% confidence intervals for myocardialinfarction and microvascular complications by category of updatedmean haemoglobin A1c concentration, adjusted for age, sex, andethnic group, expressed for white men aged 50-54 years at diagnosisand with mean duration of diabetes of 10 years

Papers


Adjusted for age, sex and ethnic group, expressed for white men

aged 50-54 years at diagnosis and with mean duration of

diabetes at 10 years

Myocardial infarction Microvascular end points

Stratton et al, BMJ 2000; 321:405-12

At near normal A1cRisk of MI 2-3x that of micro-vascular endpoint

No benefit in UKPDS?


glycemic control?

Underpowered to detect reduction in CVD



glycemic control?

Too late to reverse macrovascular complications

Vascular disease begins early ...

LaSalle JR. Hosp Physician 2005

Insulin resistance precedes overt hyperglycemia or diabetes

Plante & Nadler, Seminars Cardiothoracic Vascular Anes 2003; 7(3):295-310




2-fold increased risk of CVD in IGT





2-fold increased risk of CVD in IGT

Newly-diagnosed diabetics have vascular disease at presentation


remained after adjustment for other known riskfactors, including age at diagnosis, sex, ethnic group,systolic blood pressure, lipid concentrations, smoking,and albuminuria. Each 1% reduction in haemoglobinA1c was associated with a 37% decrease in risk formicrovascular complications and a 21% decrease in therisk of any end point or death related to diabetes. Theassociation with glycaemia was less steep for stroke andheart failure, for which blood pressure is a major con-tributing factor.32 34 35 In patients within the lowestcategory of updated mean haemoglobin A1c theincidence of myocardial infarction was higher thanthat of microvascular disease.5 These results suggestthat, in these people, the effect of hyperglycaemia itselfmay account for at least part of the excesscardiovascular risk observed in diabetic compared withnon-diabetic people beyond that explained by the con-ventional risk factors of dyslipidaemia, hypertension,and smoking.36 The rate of increase of relative risk formicrovascular disease with hyperglycaemia was greaterthan that for myocardial infarction, which emphasisesthe crucial role of hyperglycaemia in the aetiology ofsmall vessel disease and may explain the greater rate of

microvascular complications seen in populations withless satisfactory control of glycaemia.

Relation to trial dataThis observational analysis provides an estimate of thereduction in risk that might be achieved by thetherapeutic lowering of haemoglobin A1c by 1.0%, but itis important to realise that epidemiological associa-tions cannot necessarily be transferred to clinical prac-tice. Tissue damage from previous hyperglycaemiamay not promptly be overcome, but the results are notinconsistent with those achieved by the policy of inten-sive glucose control in the clinical trial.1 This suggeststhat the reduction in glycaemia obtained over amedian 10 years of follow up of the trial, comparingmedian haemoglobin A1c 7.0% with 7.9%, providedmuch of the benefit that could be expected from thatdegree of improved glycaemic control. Our resultssuggest that intensive treatment with sulphonylurea orinsulin does not have an effect beyond that of loweringblood glucose concentration with respect to alteringrisk. The 16% risk reduction (P = 0.052) in myocardialinfarction in the clinical trial in the group allocated toa policy of intensive blood glucose control (associated

4

1

0.5

Haza

rd ra

tio

Any end point related to diabetes

Death related to diabetes

All cause mortality

P<0.0001


4

1

0.5

Haza

rd ra

tio

P<0.0001


4

1

0.55 6 7 8 9 10

Haza

rd ra

tio

P<0.0001



Fig 3 Hazard ratios, with 95% confidence intervals as floatingabsolute risks, as estimate of association between category ofupdated mean haemoglobin A1c concentration and any end point ordeaths related to diabetes and all cause mortality. Reference category(hazard ratio 1.0) is haemoglobin A1c <6% with log linear scales.P value reflects contribution of glycaemia to multivariate model. Dataadjusted for age at diagnosis of diabetes, sex, ethnic group,smoking, presence of albuminuria, systolic blood pressure, high andlow density lipoprotein cholesterol, and triglycerides


10

1

0.5

Haza

rd ra

tioHa

zard

ratio

Haza

rd ra

tioFatal and non-fatal myocardial infarction

P<0.0001

Fatal and non-fatal stroke

Microvascular end points Cataract extraction

Amputation or death fromperipheral vascular disease Heart failure


P=0.035


10

1

0.5

P<0.0001


P<0.0001


10

1

0.55 6 7 8 9 10 5 6 7 8 9 10

P<0.0001


P=0.021


Fig 4 Hazard ratios, with 95% confidence intervals as floating absolute risks, as estimate ofassociation between category of updated mean haemoglobin A1c concentration and myocardialinfarction, stroke, microvascular end points, cataract extraction, lower extremity amputation orfatal peripheral vascular disease, and heart failure. Reference category (hazard ratio 1.0) ishaemoglobin A1c <6% with log linear scales. P value reflects contribution of glycaemia tomultivariate model. Data adjusted for age at diagnosis of diabetes, sex, ethnic group,smoking, presence of albuminuria, systolic blood pressure, high and low density lipoproteincholesterol, and triglycerides

Papers


5 6 7 8 9 10

Microvascular but not macrovascular disease clearly associated with

hyperglycemia

Macrovascular disease occurs at a lower

glucose threshold; influenced by

components of MetSyn




glycemic control?

Cardiovascular disease in diabetes is multifactorial in origin

ATHEROSCLEROSIS

Statins

Fibric Acid Derivatives

Thiazolidinediones?

Insulin

Sulfonylureas

Metformin

Thiazolidinediones

NonsulfonylureaSecretagogues

Dyslipidemia

ACE Inhibitors

Calcium Channel Blockers

Angiotensin Receptor Blockers

!-Blockers

Diuretics

Aspirin

Clopidogrel

Ticlopidine

Insulin Resistance

Hyperglycemia

Hypertension

Platelet Activationand Aggregation

Beckman et al, JAMA 2002;287:2570-81

Steno-2

Gaede et al, NEJM 2003;348:383-93

Type 2 diabetes with microalbuminuriaMean age 55.1 yMean ff-up 7.8 y (n=160)

Objective

To compare the effect of a targeted, intensified, multifactorial intervention vs conventional treatment of modifiable CV risk factors

Multifactorial intervention and cardiovascular disease

Composite of CV death, nonfatal MI, nonfatal stroke, revascularization and amputation

Steno-2 Endpoint

Gaede et al, NEJM 2003;348:383-93

GlycosylatedHemoglobin

<6.5%

Cholesterol<175 mg/dl

Triglycerides<150 mg/dl

Systolic BP<130 mm Hg

Diastolic BP<80 mm Hg

Patie

nts

(%)

80

60

70

50

30

20

10

40

0

P=0.06

P=0.19

P<0.001

P=0.001

P=0.21

Intensive

Conventional

Gaede et al, NEJM 2003;348:383-93

Percentage of patients who reached intensive treatment goals at a mean of 7.8 years

A

No. at RiskConventional

therapyIntensive

therapy

13

19

41

59

44

61

50

63

59

66

63

71

70

74

72

78

80

80

Prim

ary

Com

posi

te E

nd P

oint

(%)

Months of Follow-up

P=0.007

Conventional therapy

Intensive therapy

60

50

40

30

20

10

00 12 24 36 9648 60 72 84

Gaede et al, NEJM 2003;348:383-93

Lower risk of CVDHR 0.47 (95%CI 0.24,0.73)

Conventional therapy

Intensive therapy



glycemic control?

Treatment was adjusted to FBG only (not PPBG)

1009080706050403020100

% c

on

trib

uti

on

7.1%-9.0% > 9.0%

HbA1C groups

p=0.004 p<0.001

< 7.0%–

45.750.4

30.2

69.8

49.654.3

Postprandial glucose exposure

Fasting hyperglycaemia

WHO criteria FPG < 6.0 mmol/L

COPYRIG

HT MED

INEW

S

(DIA

BETE

S) LIM

ITED

REPR

ODUCTION PR

OHIBITE

DPeter & Rees, Br J Diabetes Vasc Dis 2008;8:8-14

Relative contribution of postprandial and fasting glucose to HbA1c


Who will benefit from tight glycemic control?

Treatment was adjusted to FBG only (not PPBG)

Kumamoto study (n=110)Intensive insulin regimen vs conventional treatment x 8 yearsTitration based on FBG, HbA1c and PPBG Nonsignificant ~50% reduction in macrovascular complications

Peter & Rees, Br J Diabetes Vasc Dis 2008;8:8-14

ACCORDWho will benefit from tight glycemic control?

Type 2 diabetes Mean age 62.2 yMedian DM duration 10 y35% had previous CVD35% already on insulin(n=10,251)

Objective

To determine if 3 separate strategies can reduce CV events

Intensive therapy to target normal A1c levels (<6.0%) vs standard therapy to target A1c 7.0-7.9%

Therapy to target SBP <120 mm Hg vs <140 mm Hg

Addition of fenofibrate vs placebo in patients on statin therapy with optimal LDL-C

ACCORD Group, NEJM 2008;358: 2545-59

Composite of nonfatal MI,

nonfatal stroke or death from CV

causes

ACCORD Endpoint


25

15

20

10

5

00 1 2 3 4 5 6

Standard therapy

Intensive therapy

Intensive therapyStandard therapy

51285123

48434827

43904262

28392702

13371186

475440

448395


median HbA1c at 1 yStandard 7.5% Intensive 6.4%

n = 352

n = 371

HR 0.90 (95%CI 0.78,1.04) p=0.16

0.6 1.0 1.4

TotalPrevious cardiovascular event

NoYes

SexFemaleMale

Age at baseline<65 yr!65 yr

Glycated hemoglobin at baseline"8.0%>8.0%

RaceNonwhiteWhite

10,251

6,6433,608

3,9526,299

6,7793,472

4,8685,360

3,6476,604

723

330393

212511

383340

284438

222501

0.04

0.74

0.65

0.03

0.29


25

15

20

10

5

00 1 2 3 4 5 6

Standard therapy

Intensive therapy

Intensive therapyStandard therapy

51285123

49724971

48034700

32503180

17481642

523499

506480


n = 257

n = 203

HR 1.22 (95%CI 1.01,1.46) p=0.04

No benefit in ACCORD?


glycemic control?

Amount of HbA1c reduction achieved relative to baseline level

Rapidity with which HbA1c was achieved or actual HbA1c itself

Treatments used or sequence of treatments used

Presence of unrecognized hypoglycemia

Cheng & Leiter, Current Diabetes Reports 2009;9: 65-72

ADVANCEWho will benefit from tight glycemic control?

ADVANCE Collaborative Group, NEJM 2008;358:2560-72

Intensive glucose control

(Gliclazide MR-based)Target A1c <6.5%

Perindopril-Indapamide-based

Routine BP lowering

Standard glucose control

Target A1c based on local guidelines

Perindopril-Indapamide-based

Routine BP lowering

Intensive glucose control

(Gliclazide MR-based)Target A1c <6.5%

Usual BP lowering therapy

Standard glucose control

Target A1c based on local guidelines

Usual BP lowering therapy

Type 2 diabetes Mean age 66 yMean DM duration 8 y37% from Asia32% with history of macrovascular disease (n=11,140)

Composites of major macrovascular and microvascular events jointly and separately

ADVANCE Endpoints

Macrovascular events Death from CV causes, nonfatal MI or nonfatal stroke


Standardcontrol

Intensivecontrol

25

15

20

10

5

00 6 12 18 24 30 36 42 48 54 60 66

P=0.32

IntensiveStandard

55705569

54945486

54285413

53385330

52565237

51765163

50975084

50054995

49274922

43964385

20712108

486509


median HbA1c at 5 yStandard 7.3% Intensive 6.5%

HR 0.94 (95%CI 0.84,1.06)


HR 0.93 (95%CI 0.83,1.06)

No benefit in ADVANCE?


Inadequate statistical power to detect reduction in macrovascular events

Annual rate of 2.2% lower than anticipated rate of 3% (greater use of statins, BP-lowering drugs and anti-platelet agents)


VADTWho will benefit from tight glycemic control?

Type 2 diabetes Mean age 60 yMean DM duration 11.5 yMean HbA1c 9.4%40% had a CV event(n=1,791)

Objective

To determine effects of intensive glycemic control (target HbA1c <6%) vs standard control (HbA1c 8% to 9%) on CV outcomes

Duckworth et al NEJM 2009;360:129-39

Time from randomization to first occurrence of major CV event*

VADT Primary Endpoint

* Composite of myocardial infarction, stroke, death from CV causes, CHF, surgery for vascular disease, inoperable coronary disease and amputation for ischemic gangrene



1.0

0.8

0.6

0.4

0.2

0.00 2 4 6 8

Intensive therapy

Standard therapy

P=0.14

Standard therapyIntensive therapy

899892

770774

693707

637639

570582

471510

240252

5562

00

median HbA1cStandard 8.4% Intensive 6.9%

Intensive groupHR 0.88 (95%CI 0.74-1.05)

n = 235

n = 264

VADT Results

No benefit in VADT?


glycemic control?

Suggests that tight glycemic control appears to be ineffective at later stages

Animal model of atherosclerosis

Glucose plays an important role in lesion initiation

Lipids play a more dominant role in lesion progression

UKPDS Follow-up


UKPDS participants(n=3277) Annual visits x 5 years Questionnaire x 5 more years assessing outcomes

Objectives

To determine whether the effects of improved glucose control on microvascular disease persisted 10 years after study completion

Whether such therapy had a long-term effect on macrovascular outcomes

Holman et al, NEJM 2008;359: 1577-89

UKPDS Follow-upClinical Outcomes

Any diabetes-

related endpoint *

* Sudden death, death from hyperglycemia or hypoglycemia, fatal or nonfatal MI, angina, heart failure, amputation, vitreous hemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction

Diabetes-related deathSudden death or death from MI, stroke, PVD,

renal disease, hyper- or hypoglycemia

Death from any cause

Myocardial infarction

Fatal or nonfatal MI

StrokeFatal or

nonfatal stroke

PVDAmputation of at

least 1 digit or death from PVD

Microvascular diseaseVitreous

hemorrhage, retinal photocoagulation or

renal failure

Glycemic control at MD’s

discretion Median ff-up

17 y (range 16-30 y)

Holman et al, NEJM 2008;359: 1577-89

1.4

1.2

1.0

0.8

0.4

0.6

P=0.01P=0.052

Conventional therapySulfonylurea–insulin

186387

212450

239513

271573

296636

319678

Post-trial risk reduction 15%

Holman et al, NEJM 2008;359: 1577-89

1.0

0.6

0.8

0.4

0.2

0.0

P=0.01


0 5 10 15 20 25

11382729

10132488

8572097

5781459

221577

2066

Conventionaltherapy

Sulfonylurea–insulin

Holman et al, NEJM 2008;359: 1577-89

Legacy Effect

Meta-analysisWho will benefit from tight glycemic control?

UKPDS 33, 1998 UKPDS 34, 1998 ACCORD, 2008 ADVANCE, 2008 VADT, 2009

Kelly et al, Ann Intern Med Jul 2009;151: 394-403

Objective

To summarize clinical benefits and harms of intensive vs conventional glucose control for adults with type 2 diabetesn = 27,802

fect, with a 2.5-fold increased risk for hypoglycemia, or anabsolute increase of 54 events per 1000 patients over 5years of treatment, associated with intensive glucose con-trol. ACCORD showed the largest relative risk for hypo-glycemia, followed closely by VADT. As with ACCORD,VADT had an increased number of sudden deaths in theintensive compared with the conventional glucose controlgroups, again calling attention to the possibility of incor-rect ascertainment of hypoglycemia-related deaths. Second-ary analyses examining the effect of lower HbA1c thresh-olds on mortality could provide important information onthis topic.

With more than 27 000 participants among the 5trials, we had excellent power to detect small but clinicallyimportant effects of intensive glucose control on major car-diovascular end points and all-cause mortality. In contrast,the power of subgroup analyses to detect small effects ofintensive glucose control was limited. A further limitationof the current study includes the use of summary datarather than individual-patient data from the 5 includedtrials. In addition, the recent clinical trials of intensivetherapy were of relatively shorter duration than the UKPDSand raise the issue of inadequate time for demonstrationof some cardiovascular and total mortality benefits.

Figure 3. Pooled relative risk and risk difference (per 1000 patients over 5 years of treatment) estimates of nonfatal MI, fatal MI,nonfatal stroke, fatal stroke, and PAD.

A. Early Trials

Event

Intensive

Nonfatal MI

Fatal MI

Nonfatal stroke

Fatal stroke

PAD

221/3071

250/3071

120/3071

49/3071

35/3071

Conventional

Events/Total, n/n

141/1549

150/1549

60/1549

24/1549

27/1549

Relative Risk(95% CI)

0.80 (0.65 to 0.98)

0.74 (0.46 to 1.18)

0.78 (0.34 to 1.79)

1.08 (0.65 to 1.80)

0.70 (0.42 to 1.17)

Risk Difference(95% CI)

–9 (–13 to –5)

–13 (–29 to 3)

–4 (–15 to 7)

0 (–3 to 3)

–3 (–4 to –1)

Relative Risk (95% CI)

0.5 1.0 2.0

B. Recent Trials

Event

Intensive

Nonfatal MI

Fatal MI

Nonfatal stroke

Fatal stroke

PAD

390/11 591

290/11 591

303/11 591

39/11 591

374/6463

Conventional

Events/Total, n/n

457/11 591

287/11 591

302/11 591

52/11 591

406/6468


0.85 (0.74 to 0.99)

1.08 (0.80 to 1.46)

1.00 (0.85 to 1.19)

0.75 (0.49 to 1.14)

0.92 (0.81 to 1.06)


–9 (–20 to 1)

3 (–5 to 11)

–2 (–7 to 4)

–1 (–3 to 1)

–5 (–9 to –1)


0.5 1.0 2.0

C. All Trials

Event

Intensive

Nonfatal MI

Fatal MI

Nonfatal stroke

Fatal stroke

PAD

611/14 662

540/14 662

423/14 662

88/14 662

409/9534

Conventional

Events/Total, n/n

598/13 140

437/13 140

362/13 140

76/13 140

433/8017


0.84 (0.75 to 0.94)

0.94 (0.75 to 1.18)

0.98 (0.82 to 1.17)

0.87 (0.63 to 1.20)

0.91 (0.79 to 1.03)


–9 (–16 to 3)

–3 (–10 to 4)

–3 (–7 to 2)

0 (–2 to 1)

–3 (–5 to –1)


0.5 1.0 2.0

MI ! myocardial infarction; PAD ! peripheral artery disease.

ReviewGlucose Control and Cardiovascular Disease in Diabetes

www.annals.org 15 September 2009 Annals of Internal Medicine Volume 151 • Number 6 401

Kelly et al, Ann Intern Med Jul 2009;151: 394-403

Intensive glucose control reduced the risk for nonfatal MI

Intensive glucose control did not reduce the risk for CV death or all-cause mortality and increased the risk for severe hypoglycemia

↓ 0.9% HbA1c over 5 years from

baseline 7.8% NNT 87

↓ 4 mm Hg BP prevents 12.5 CV events

↓ 1 mmol/L LDL prevents 8.2 CV events

Benefit from glycemic control is modest compared to control of lipids and blood pressure

Ray et al, Lancet 2009;373:1765-72


glycemic control?

Glycemic control does play a role in reducing CV complications ...

Start early in the disease course

Summary

Individuals in the ACCORD, ADVANCE and VADT have had diabetes 8 to 11 years at start of trial



glycemic control?

Glycemic control does play a role in reducing CV complications ...

Benefit becomes evident only after a long period of time

Summary


Follow-up periods in the ACCORD, ADVANCE and VADT were between 3.5 to 5 years

Follow-up time required to demonstrate macrovascular benefit in UKPDS was median of 17.8 years


HbA1c?


glycemic control?


diabetes compare?


What should be the target HbA1c?

A1c goal for patients in general is <7%

A1c goal for the individual patients is an A1c as close to normal (<6%) as possible without causing hypoglycemia

Buse, Circulation 2007;115:114-26

Primary Prevention of CVD in People with Diabetes Mellitus

A Scientific Statement from AHA & ADA


Not enough basis for <7%

Kumamoto study is the only long-term study with clinical events as primary outcomes

HbA1c data from UKPDS, ACCORD, ADVANCE and VADT considered observational

Participants randomized to A1c target not to the level achieved

HbA1c <7% OR <6.5%?

Lund & Vaag, Diabetes Care Jul 2009;32(7):e90


HbA1c <7% OR <6.5%?

as HbA1c target decreases

Hypoglycemia increases


A1c target <6.5% might not increase hypoglycemia per se

ADVANCE intensive group had 2-3% higher hypoglycemia risk than conventional group

Lower than hypoglycemia risk in ACCORD/VADT intensive group (~15-20%)

Lower than hypoglycemia risk in ACCORD/VADT conventional group (~5-10%)

HbA1c <7% OR <6.5%?



Hypoglycemia not significantly related to excess mortality in intensive group

Intensive control increased mortality irrespective of pre-existing CVD

In patients with preexisting CVD, intensive control had no effect on CVD (i.e. no harm)

Hypoglycemia did not explain the increased mortality

Mortality Analyses in ACCORD



In both arms, patients with severe hypoglycemia had higher mortality than those without

Higher mortality in standard arm among participants with at least one episode of severe hypoglycemia

Higher mortality in intensive arm among participants with no history of severe hypoglycemia

Mortality Analyses in ACCORD

Skyler et al, J Am Coll Cardiol 2009;53:298-304

What should be the target HbA1c?General A1c goal <7%

Lower A1c goal if can be achieved without significant hypoglycemia

Short duration of diabetes

Long life expectancy

No significant CVD

Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE and VA Diabetes Trials A Position Statement of the ADA and a Scientific Statement of the ACC & AHA


What should be the target HbA1c?General A1c goal <7%

Less stringent A1c goal History of severe hypoglycemia

Limited life expectancy

Advanced micro- or macrovascular complications or extensive comorbid conditions

Long-standing diabetes which is difficult to control

Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE and VA Diabetes Trials A Position Statement of the ADA and a Scientific Statement of the ACC & AHA



glycemic control?


HbA1c?


diabetes compare?


How do current therapies for diabetes compare?

UKPDS Overweight patients on Metformin

↓ MI by 39% (p=0.01)

↓ all-cause mortality by 36% (p=0.01)

Holman et al, NEJM 2008;359: 1577-89

1.0

0.6

0.8

0.4

0.2

0.0

P=0.005

Conventional therapyMetformin

0 5 10 15 20 25

411342

360317

311274

213214

95106

416

Metformin

Conventionaltherapy

Holman et al, NEJM 2008;359: 1577-89

Legacy Effect

1.0

0.6

0.8

0.4

0.2

0.0

P=0.01


0 5 10 15 20 25

11382729

10132488

8572097

5781459

221577

2066

Conventionaltherapy

Sulfonylurea–insulin

Holman et al, NEJM 2008;359: 1577-89

Legacy Effect


PROACTIVEPROspective PioglitAzone Clinical

Trial In macroVascular Events

Type 2 diabetesEvidence of CVDContinued on current treatmentRandomized to pioglitazone or placebo

Objective

To determine if treatment with pioglitazone will decrease CV events in high-risk patients with type 2 diabetes

Singaram & Pratley, Diabetes Vasc Dis Res 2007; 4:237-40

PROACTIVE Endpoints

Composite of all-cause mortality, non-fatal MI,

stroke, ACS, endovascular/surgical

intervention in coronary/leg arteries or amputation above the

ankle


Secondary endpoint: composite of all-cause mortality, non-fatal MI and stroke

PROACTIVE Primary Endpoint

Dormandy et al, Lancet 2005;366:1279-89

PROACTIVE Secondary Endpoint


PioglitazonePROACTIVE

Unclear whether the effect of pioglitazone on macrovascular endpoints is a unique property of the drug

Slight improvements in SBP, TG and HDL-C unlikely to get individual patients to goal

40% higher risk of CHF unsurprising



Objective

To systematically examine the peer-reviewed literature on the CV risk associated with oral agents

Meta-analysis

40 controlled trials that reported CV events (primarily MI and stroke)

Selvin et al, Arch Intern Med 2008;168(19):2070-80

How do current therapies for diabetes compare? Results

Metformin ↓ risk of CV mortality (OR 0.74; 95%CI 0.62-0.89)

Rosiglitazone ↑ risk of CV morbidity or mortality but not statistically significant (OR 1.68; 95%CI 0.92-3.06)

No other significant associations for other oral agents

Meta-analysis

40 controlled trials that reported CV events (primarily MI and stroke)

Selvin et al, Arch Intern Med 2008;168(19):2070-80


BARI 2D

BARI 2D Study Group, NEJM 2009;360:2503-15

Prompt coronary revascularization

Insulin sensitization therapy

(Metformin/RSG)

Medical TherapyInsulin sensitization

therapy(Metformin/RSG)

Prompt coronary revascularizationInsulin provision

therapy (SU/Insulin)

Medical TherapyInsulin provision

therapy(SU/Insulin)

Type 2 diabetes and heart disease (n=2,368)

Randomization stratified according to choice of PCI or CABG

BARI 2D Endpoints

Death rate

Composite of death, MI or stroke


P=0.89

Insulin sensitization

Insulin provision

100

80

90

70

60

40

30

10

50

20

00 1 2 3 4 5

88.2

87.9

2368 2296 2247 2197 1892 1196


P=0.13

Insulin sensitization

Insulin provision

100

80

90

70

60

40

30

10

50

20

00 1 2 3 4 5

77.7

75.4

2368 2094 1984 1807 1459 823


Insulin sensitization strategy Fewer severe hypoglycemia, less weight gain and higher HDL-C


glycemic control?



glycemic control?


HbA1c?



glycemic control?


HbA1c?


diabetes compare?


Thank Youhttp://www.endocrine-witch.info

http://www.endocrine-witch.info

http://www.endocrine-witch.info

tight glycemic control in the prevention of cardiovascular disease

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