Secondary Outcomes

Secondary Outcomes

Main Results

ADVANCE

All-cause mortality

Relative risk reduction 7%: 95% CI -6 to 17%

P=0.28

Follow-up (months)

Cum

ulat

i ve

i nci

denc

e (%

)25

20

10

5

0

Standard

Intensive

0 6 12 18 24 30 36 42 48 54 60 66

15

Death

Cardiovascular death 253 289 12% (-4 to 26)

All deaths 498 533 7% (-6 to 17)

Non-cardiovascular death 245 244 0% (-20 to 16)

Number of patients with event

Intensive Standard

(n=5,571) (n=5,569)

Relative risk

reduction (95%CI)

Favors

Intensive

Favors

Standard

Hazard ratio

0.5 1.0 2.0

Coronary and cerebrovascular events

Major cerebrovascular events‡ 238 246 3% (-16 to 19)

Total cerebrovascular events 352 327 -8% (-26 to 7)

Major coronary events† 310 337 8% (-7 to 21)

Total coronary events 560 572 2% (-10 to 13)

Number of patients with eventIntensive Standard(n=5,571) (n=5,569)

Relative riskreduction (95% CI)

FavorsIntensive

FavorsStandard

Hazard ratio

0.5 1.0 2.0

†Non-fatal MI or death from coronary heart disease

‡Non-fatal stroke or death from cerebrovascular disease

Renal events

New or worsening nephropathy 230 292 21% (7 to 34)

New microalbuminuria 1318 1434 9% (2 to 15) ‡

Total renal events 1498 1669 11% (5 to 17)



FavorsIntensive

FavorsStandard

Hazard ratio

0.5 1.0 2.0

†P<0.001

‡P=0.02

***P=0.006

†

***

Nephropathy

New or worsening nephropathy 230 292 21% (7 to 34)†

Macroalbuminuria 162 231 30% (15 to 43)‡

End-stage renal disease 23 36 36% (-8 to 62)

Doubling of serum creatinine* 69 60 -15% (-63 to 18)



FavorsIntensive

FavorsStandard

Hazard ratio

0.5 1.0 2.0

*to at least 200 μmol/L (2.3 mg/dL)†P=0.006

‡P<0.001

Eye events

New or worsening retinopathy 332 349 5% (-10 to 18)

Visual deterioration 3033 3015 0% (-5 to 5)

Total eye events 3105 3094 0% (-5 to 5)



FavorsIntensive

FavorsStandard

Hazard ratio

0.5 1.0 2.0

Heart failure, PVD and neuropathy

All heart failure 220 231 5% (-14 to 21)

All peripheral vascular disease 343 366 6% (-9 to 19)

New or worsening neuropathy 2353 2311 -4% (-10 to 2)

Number (%) of patients with eventIntensive Standard(n=5,571) (n=5,569)


FavorsIntensive

FavorsStandard

Hazard ratio

0.5 1.0 2.0

Cognitive function and dementia

Cognitive decline 895 911 2% (-7 to 11)

Dementia 61 48 -27% (-86 to 13)


Intensive Standard

(n=5,571) (n=5,569)

Relative risk

reduction (95% CI)

Favors

Intensive

Favors

Standard

Hazard ratio

0.5 1.0 2.0

Effects in Patient Subgroups

ADVANCE

Effects by age, sex, SBP & glucose controlCombined primary end point

Age (years)

< 65 367 421 14% (1 to 25)

65 642 695 8% (-3 to 17)

Sex

Male 635 705 10% (0 to 19)

Female 374 411 10% (-3 to 22)

SBP (mmHg)

< 140 368 404 9% (-4 to 21)

140 641 712 11% (1 to 20)

HbA1c (%)

< 7.2 387 430 10% (-3 to 22)

7.2 620 682 10% (0 to 20)

Fasting blood glucose (mmol/L)

< 7.9 (142 mg/dL) 414 472 13% (0 to 23)

7.9 (142 mg/dL) 595 643 8% (-2 to 18)

All participants 1009 1116 10% (2 to 18)



FavorsIntensive

FavorsStandard

Hazard ratio

0.5 1.0 2.0

Phomogeneity all >0.1

Effects by disease history & ancillary treatmentCombined primary end point


History of macrovascular disease

No 591 678 14% (4 to 23)

Yes 418 438 4% (-10 to 16)

History of microvascular disease

No 799 892 11% (2 to 19)

Yes 210 224 4% (-16 to 21)

Treatment with any BP lowering drugs

No 199 222 11% (-7 to 27)

Yes 810 894 10% (1 to 18)

Treatment with ACE inhibitors

No 495 537 14% (3 to 24)

Yes 514 579 5% (-7 to 16)

Treatment with statins

No 746 815 10% (1 to 19)

Yes 263 301 10% (-6 to 24)

Treatment with anti-platelet drugs

No 485 541 9% (-2 to 20)

Yes 524 575 11% (0 to 21)

All participants 1009 1116 10% (2 to 18)



FavorsIntensive

FavorsStandard

Hazard ratio

0.5 1.0 2.0

Effects by age, sex, SBP and glucose controlCardiovascular death

Age (years) < 65 63 64 2% (-39 to 31) 65 190 225 15% (-3 to 30)Sex

Male 172 197 12% (-8 to 28) Female 81 92 12% (-18 to 35)

SBP (mmHg) < 140 82 112 27% (3 to 45) 140 171 177 3% (-19 to 22)HbA1c (%)

< 7.2 90 110 18% (-8 to 38) 7.2 161 178 10% (-12 to 27)Fasting blood glucose (mmol/L)

< 7.9 (142 mg/dL) 110 137 20% (-3 to 38) 7.9 (142 mg/dL) 143 152 6% (-18 to 25)

All participants 253 289 12% (-4 to 26)



FavorsIntensive

FavorsStandard

Hazard ratio0.5 1.0 2.0


Effects by age, sex, SBP and glucose controlAll cause mortality

Age (years) < 65 111 119 7% (-20 to 28) 65 387 414 6% (-8 to 18)

Sex Male 350 360 2% (-13 to 16) Female 148 173 15% (-6 to 32)

SBP (mmHg) < 140 168 203 17% (-1 to 33) 140 330 330 -0% (-17 to 14)

HbA1c (%) < 7.2 206 214 3% (-17 to 20) 7.2 289 317 9% (-7 to 22)Fasting blood glucose (mmol/L)

< 7.9 (142 mg/dL) 225 263 15% (-2 to 28) 7.9 (142 mg/dL) 272 270 0% (-19 to 15)

All participants 498 533 7% (-6 to 17)

Number (%) of patients with eventIntensive Standard(n=5,571) (n=5,569)


FavorsIntensive

FavorsStandard

Hazard ratio0.5 1.0 2.0


Subgroup effects

No evidence of different effects in patient subgroups for the combined primary outcome, cardiovascular death or total mortality

Other risk factors and concomitant treatments

Main Results

ADVANCE

Other risk factors levelsAt end of follow-up

Parameter Randomized treatment

Intensive (n=5571)

Standard (n=5569)

Systolic BP (mmHg) 135.5 137.9

Diastolic BP (mmHg) 73.5 74.3

Body mass index (kg/m2) 28 28

LDL chol. (mmol/L [mg/dL]) 2.64 [102] 2.65 [102]

HDL chol. (mmol/L [mg/dL]) 1.24 [48] 1.25 [48]

Triglycerides (mmol/L [mg/dL]) 1.70 [151] 1.82 [161]

Current smoking (%) 8 8

Ancillary drug therapyAt end of follow-up

Randomized treatment

Intensive (n=5571)

Standard (n=5569)

Any BP lowering drug 89% 88%

Statin 46% 48%

Other lipid modifying drug 7% 7%

Aspirin 57% 55%

Other antiplatelet drugs 7% 6%

Summary – effects on main efficacy outcomes

Intensive glucose control resulted in:

10% reduction in combined primary outcome 14% reduction in microvascular events 21% reduction in nephropathy No significant effects on macrovascular events No significant effects on all-cause or cardiovascular

mortality Consistent treatment effects in patient subgroups

Hypoglycemia

ADVANCE

Definition

A blood glucose level <2.8 mmol/L (50mg/dL) and/or an episode with typical symptoms and signs of hypoglycemia, without other apparent cause

SEVERE where an individual had transient central nervous system dysfunction and was unable to treat him/herself (required help from another person)

MINOR where the individual was able to treat him/herself

Occurrence of hypoglycemia

Number of patients

with event

Total number of

events

Rate per 100 patient

years

Severe hypoglycemia 231 298 0.56

Minor hypoglycemia 4432 56,239 105

Any hypoglycemia 4524 56,537 106

Any hypoglycemia 2654 1870 42% (36 to 49)

Severe hypoglycemia 150 81 85% (42 to 142)

Minor hypoglycemia 2598 1834 42% (35 to 48)


Intensive Standard(n=5,571) (n=5,569)

Relativeincrease (95% CI)

Effects of treatment on hypoglycemiaHazard ratios

All P<0.001

Standardworse

Intensiveworse

Risk ratio

0.5 1.0 2.0

Rates of hypoglycemiaMinor and severe

*P<0.001

0.7 0.40

20

40

60

80

100

120

140

Minor hypoglycemia Severe hypoglycemia

Eve

nts

per

100

patie

nt y

ears Intensive control

Standard control

+87%*

+40%*

Comparative rates of severe hypoglycemia

Pro

port

ion

of p

atie

nts

with

at l

eas

t o

ne e

ven

t eac

h y

ear

0.0%

0.4%

0.8%

1.2%

1.6%

2.0%

UKPDS ADVANCE

Intensive control

Standard control

Fatal or disabling sequelae of severe hypoglycemia

One fatal episode in the standard control group

One episode leading to permanent disability in each of the standard and intensive groups

Effects of severe hypoglycemia on cognitive function (MMSE)

0

10

20

30

None One or more

Number of severe hypoglycemic events

Mea

n M

MS

E s

core

At baseline

At final visit

Change in MMSE during follow-up0.11 (0.06-0.15)

Change in MMSE during follow-up0.67 (0.27-1.06)

Baseline to follow-up difference

0.56 (0.26-0.87)

Summary - hypoglycemia

Intensive glucose control increased the risk of severe hypoglycemia

Rates of severe hypoglycemia were low No significant long-term sequelae were identified More than half of patients reported neither minor or

severe hypoglycemia

Body Weight

ADVANCE

Difference in body weight

Difference 0.75kg (0.56, 0.94) 1.65lbs (1.23, 2.07), P<0.0001

Standard

Intensive

Wei

ght

(kg)

75

76

77

78

79

80

Follow-up (months)

0 6 12 18 24 30 36 42 48 54 60

Impact of ethnicity

Asian

Mean baseline weight = 67kg (145lbs) Mean weight difference = 0.44kg (0.97lbs) 0.7% of baseline weight

Non-Asian Mean baseline weight = 85kg (187lbs) Mean weight difference = 0.96kg (2.1lbs) 1.1% of baseline weight

Impact of follow-up duration

UKPDS Weight gain about 3.1kg (6.8lbs) Mostly in first few years after diagnosis Follow-up 10 years

ADVANCE No weight gain Weight difference 0.75kg (1.65lbs) Follow-up 5 years Weight difference projected to 10 years = 1.8kg

(4.0lbs)

Summary - weight

No weight gain in ADVANCE

Weight difference between randomized groups less in ADVANCE than UKPDS

Difference likely explained in part at least by ethnicity, stage of disease and duration of follow-up

Balance of risk and benefits

Five years treatment

Prevents one vascular event among every 52 patients (mostly renal events)

Causes one severe hypoglycemic event among every 81 patients

ADVANCE in the context of other studies

ADVANCE

Baseline characteristics

Characteristic UKPDS glucose study

ADVANCE ACCORD

Age, years

Female

Diabetes duration, years

History of CVD

Systolic BP, mmHg

HbA1c, %

Cholesterol, mmol/L

BMI, kg/m2

Current smoking

53

39%

0

135

7.1*

5.4

28

31%

66

42%

7

32%

145

7.5

5.1

28

14%

62

39%

10

35%

136

8.3

4.7

32

14%

* Calculated HbA1c

Treatments at baseline

Characteristic UKPDS glucose study

ADVANCE ACCORD

Sulfonylureas

Metformin

Insulin

Aspirin

Statins

BP lowering drug

0%

0%

0%

2%

0%

13%

72%

61%

1%

44%

28%

75%

50%

60%

35%

54%

59%

85%

UKPDS

ACCORD

Event rates – all cause mortality

0.0

0.5

1.0

1.5

2.0

UKPDS ADVANCE ACCORD

An

nua

l inc

ide

nce

(%

)

Risk ratio (95% CI)

0.5 1 2

Combined

ADVANCE

UKPDS 0.94 (0.80, 1.10)

0.93(0.83, 1.06)

Favors intensive glucose control Favors standard glucose control

Hazard ratio (95% CI)

Mortality (meta-analysis)

0.93(0.85, 1.02)

1.22 (1.01, 1.46)ACCORD

P heterogeneity = 0.016

Baseline characteristics

Characteristic UKPDS ADVANCE ACCORD

Age, years

Female

Diabetes duration, years

History of CVD

Systolic BP, mmHg

HbA1c, %

Cholesterol, mmol/L

BMI, kg/m2

Current smoking

53

39%

0

135

7.1

5.4

28

31%

66

42%

7

32%

145

7.5

5.1

28

14%

62

39%

10

35%

136

8.3

4.7

32

14%

Secondary Outcomes

Documents

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