ukpds
-
Upload
beny-rilianto -
Category
Documents
-
view
35 -
download
2
Transcript of ukpds
![Page 1: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/1.jpg)
ukpds
The UKThe UKProspectiveProspective
DiabetesDiabetesStudyStudy
![Page 2: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/2.jpg)
ukpds
UK Prospective Diabetes StudyUK Prospective Diabetes Study
multi-centre
randomised controlled trial
of different therapies
of Type 2 diabetes
![Page 3: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/3.jpg)
ukpds
complications of Type 2 diabetes develop over decades
Protocol written 1976
Recruitment 1977-1991
End of study Sept. 1997
Clinical Centres 23
Type 2 diabetic patients 5102
Person years follow-up 53,000
Funding £23 million
UKPDS : need for a long-term studyUKPDS : need for a long-term study
![Page 4: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/4.jpg)
ukpds
UK Prospective Diabetes Study CentresUK Prospective Diabetes Study Centres
Aberdeen Lilian Murchison Manchester Andrew Boulton
Belfast City Randal Hayes Northampton Charles Fox
Belfast Royal David Hadden Norwich Richard Greenwood
Birmingham David Wright Oxford Robert Turner
Carshalton Steve Hyer Rury Holman
Memo Spathis Peterborough Jonathan Roland
Derby Ian Peacock Salford Tim Dornan
Dundee Ray Newton Scarborough Phil Brown
Roland Jung St George’s Nigel Oakley
Exeter Kenneth McLeod Stevenage Les Borthwick
John Tooke Stoke on Trent John Scarpello
Hammersmith Anne Dornhorst Lionel Alexander
Eva Kohner Torbay Richard Paisey
Ipswich John Day Whittington John Yudkin
Leicester Felix Burden
![Page 5: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/5.jpg)
ukpds
Co-ordinating StaffCo-ordinating Staff
Chief Investigators : Robert Turner, Rury HolmanStatisticians : Irene Stratton, Carole Cull
Ziyah Mehta, Heather McElroyModeller : Richard StevensEpidemiologists : Andrew Neil, Amanda AdlerDiabetologists : David Matthews, Valeria FrighiBiochemists : Susan Manley, Iain RossAdministrators : Philip Bassett, Suzy OakesRetinopathy Grading Centre : Eva Kohner, Steve AldingtonHealth Economics : Alastair Gray, Maria RaikouGrant Applications : Ivy Samuel, Caroline WoodComputing Support : Ian Kennedy, John Veness
And many others
![Page 6: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/6.jpg)
ukpds
Acknowledgements Acknowledgements
• patients • physicians• nurses• dietitians• retinal photographers
• Retinopathy Grading : Hammersmith Hospital• Biochemistry : Diabetes Research Laboratories• ECG Grading : Guy’s Hospital
![Page 7: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/7.jpg)
ukpds
Major Funding BodiesMajor Funding Bodies
UK Medical Research Council
British Diabetic Association
UK Department of Health USA National Institutes of Health (NEI, NIDDK)
British Heart Foundation Wellcome Trust
Novo Nordisk Bayer Lilly
Bristol Myers Squibb Lipha Hoechst
Farmitalia Carlo Erba
![Page 8: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/8.jpg)
ukpds
Glucose Control StudyGlucose Control Study
UK Prospective Diabetes StudyUK Prospective Diabetes Study
![Page 9: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/9.jpg)
ukpds
Blood Glucose Control Study : AimsBlood Glucose Control Study : Aims
to determine whether • improved glucose control of Type 2 diabetes
will prevent clinical complications
• therapy with sulphonylurea - first or second generation insulin metformin
has any specific advantage or disadvantage
![Page 10: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/10.jpg)
ukpds
Patient CharacteristicsPatient Characteristics
5102 newly diagnosed Type 2 diabetic patients
age 25 - 65 years mean 53 y
gender male : female 59 : 41%
ethnic group Caucasian 82%Asian 10%
Afro-caribbean 8%
Body Mass Index mean 28 kg/m2
fasting plasma glucose (fpg) median 11.5 mmol/L
HbA1c median 9.1 %
hypertensive 39%
![Page 11: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/11.jpg)
ukpds
UK Prospective Diabetes StudyUK Prospective Diabetes Study
• follow-up of patients to major fatal and non-fatal clinical endpoints
• recording of surrogate endpoints : clinical and biochemical markers
e.g. urine albuminretinal photographsvisual acuity
• intention to treat analysis
![Page 12: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/12.jpg)
ukpds
RandomisationRandomisation
fpg : fasting plasma glucose (mmol/L)
5102 newly diagnosed Type 2 diabetic patients
Diet Alone3%
fpg < 6asymptomatic
17%
Main Randomisation82%
fpg 6.1 - 15.0asymptomatic
68%
Diet Failure15%
fpg > 15or symptomatic
15%
Diet therapy
14%
![Page 13: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/13.jpg)
ukpds
Does an intensive glucose Does an intensive glucose control policy reduce the risk control policy reduce the risk of complications of diabetes?of complications of diabetes?
UK Prospective Diabetes StudyUK Prospective Diabetes Study
![Page 14: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/14.jpg)
ukpds
Randomisation of Treatment PoliciesRandomisation of Treatment Policies
342 allocated to metformin
Conventional Policy30% (n=1138)
Intensive Policy70% (n=2729)
Sulphonylurean=1573
Insulinn=1156
Main Randomisationn=4209 (82%)
3867
![Page 15: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/15.jpg)
ukpds
Treatment Policies in 3867 patientsTreatment Policies in 3867 patients
Conventional Policy
n = 1138• initially with diet alone• aim for
near normal weightbest fasting plasma glucose < 15 mmol/Lasymptomatic
• when marked hyperglycaemia developsallocate to non-intensive pharmacological therapy
![Page 16: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/16.jpg)
ukpds
Treatment Policies in 3867 patientsTreatment Policies in 3867 patients
Intensive Policy with sulphonylurea or insulin
n = 2729 • aim for
fasting plasma glucose < 6 mmol/Lasymptomatic
• when marked hyperglycaemia developson sulphonylurea
add metforminmove to insulin therapy
on insulin, transfer to complex regimens
![Page 17: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/17.jpg)
ukpds
Actual TherapyActual Therapy
Years from randomisation
1 2 3 4 5 6 7 8 9 10 11 120
20
40
60
80
100
pro
po
rtio
n o
f p
ati
en
ts
diet alone
1 2 3 4 5 6 7 8 9 10 11 12
intensivepharmacologicaltherapy
diet aloneadditional non-intensivepharmacological therapy
Intensive Policyaim for < 6 mmol/L
Conventional Policyaccept < 15 mmol/L
![Page 18: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/18.jpg)
ukpds
HbAHbA1c1c cross-sectional, median values
06
7
8
9
0 3 6 9 12 15
HbA 1
c (%
)
Years from randomisation
Conventional
Intensive
6.2% upper limit of normal range
![Page 19: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/19.jpg)
ukpds
Change in Body WeightChange in Body Weightcross-sectional, mean values
-2.5
0.0
2.5
5.0
7.5
0 3 6 9 12 15
kg
Years from randomisation
Conventional
Intensive
![Page 20: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/20.jpg)
ukpds
Hypoglycaemic EpisodesHypoglycaemic Episodes
• self-reported at each clinic visit• assessed by clinician to determine severity• graded as
minor : treated by patient alone major : requiring third party assistance
• grade of most severe episode recorded• all major episodes audited from clinical records
![Page 21: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/21.jpg)
ukpds
Hypoglycaemic episodes per annumHypoglycaemic episodes per annum
Actual Therapy analysis
0
10
20
30
40
50
0 3 6 9 12 15
Pro
port
ion
of
pati
en
ts (
%)
Years from randomisation
0
1
2
3
4
5
0 3 6 9 12 15
any episode major episodes
![Page 22: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/22.jpg)
ukpds
Any Diabetes Related EndpointAny Diabetes Related Endpoint
1401 of 3867 patients (36%)
First occurrence of any one of:
• diabetes related death
• non fatal myocardial infarction, heart failure or angina
• non fatal stroke
• amputation
• renal failure
• retinal photocoagulation or vitreous haemorrhage
• cataract extraction or blind in one eye
![Page 23: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/23.jpg)
ukpds
Any Diabetes Related Endpoint (cumulative )Any Diabetes Related Endpoint (cumulative )
0%
20%
40%
60%
0 3 6 9 12 15
% o
f pa
tient
s w
ith a
n ev
ent
Years from randomisation
Intensive (2729)
Conventional (1138)
Risk reduction 12%(95% CI: 1% to 21%)
p=0.029
1401 of 3867 patients (36%)
![Page 24: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/24.jpg)
ukpds
Diabetes Related DeathsDiabetes Related Deaths
414 of 3867 patients (11%)
Any of:
• fatal myocardial infarction or sudden death
• fatal stroke
• death from peripheral vascular disease
• death from renal disease
• death from hyper/hypoglycaemia
![Page 25: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/25.jpg)
ukpds
Diabetes Related Deaths (cumulative)Diabetes Related Deaths (cumulative)
0%
10%
20%
30%
0 3 6 9 12 15
% o
f pa
tient
s w
ith a
n ev
ent
Years from randomisation
Intensive (2729)
Conventional (1138)
p=0.34
414 of 3867 patients (11%)
![Page 26: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/26.jpg)
ukpds
Microvascular Endpoints (cumulative)Microvascular Endpoints (cumulative)
p=0.0099
0%
10%
20%
30%
0 3 6 9 12 15
% o
f pa
tient
s w
ith a
n ev
ent
Years from randomisation
Intensive
Conventional
Risk reduction 25%(95% CI: 7% to 40%)
renal failure or death, vitreous haemorrhage or photocoagulation346 of 3867 patients (9%)
![Page 27: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/27.jpg)
ukpds
Myocardial Infarction (cumulative)Myocardial Infarction (cumulative)
0%
10%
20%
30%
0 3 6 9 12 15
% o
f pa
tient
s w
ith a
n ev
ent
Years from randomisation
Intensive
Conventional
p=0.052
Risk reduction 16%(95% CI: 0% to 29%)
fatal or non fatal myocardial infarction, sudden death573 of 3867 patients (15%)
![Page 28: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/28.jpg)
ukpds
Aggregate Clinical EndpointsAggregate Clinical Endpoints
Favoursconventional
0.5 1 2
0.88
0.90
0.94
0.84
1.11
0.75
0.029
0.34
0.44
0.052
0.52
0.0099
Any diabetes related endpoint
Diabetes related deaths
All cause mortality
Myocardial infarction
Stroke
Microvascular
RR p
Favoursintensive
Relative Risk& 95% CI
![Page 29: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/29.jpg)
ukpds
Progression of RetinopathyProgression of RetinopathyTwo step change in Early Treatment Diabetic Retinopathy Study (ETDRS) scale
1.03
0.83
0.83
0.79
0.78
0.017
0.012
0.015
0 - 3 years
0 - 6 years
0 - 9 years
0 - 12 years
RR p 0.5 1 2
Relative Risk& 99% CI
Favoursconventional
Favoursintensive
![Page 30: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/30.jpg)
ukpds
MicroalbuminuriaMicroalbuminuriaUrine albumin >50 mg/L
0.89
0.83
0.88
0.76
0.67
0.70
0.24
0.043
0.13
0.00062
0.000054
0.033
Baseline
Three years
Six years
Nine years
Twelve years
Fifteen years
RR p 0.5 1 2
Relative Risk& 99% CI
Favoursconventional
Favoursintensive
<
![Page 31: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/31.jpg)
ukpds
Glucose Control Study SummaryGlucose Control Study Summary
The intensive glucose control policy maintained a lower HbA1c by mean 0.9 % over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in risk of:
12% for any diabetes related endpoint p=0.02925% for microvascular endpoints p=0.0099
16% for myocardial infarction p=0.05224% for cataract extraction p=0.046
21% for retinopathy at twelve years p=0.01533% for albuminuria at twelve yearsp=0.000054
![Page 32: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/32.jpg)
ukpds
ConclusionConclusion
The UKPDS has shown that intensive blood
glucose control reduces the risk of diabetic
complications, the greatest effect being on
microvascular complications
![Page 33: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/33.jpg)
ukpds
Does insulin or Does insulin or sulphonylurea therapy have sulphonylurea therapy have
specific advantages or specific advantages or disadvantages?disadvantages?
UK Prospective Diabetes Study
![Page 34: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/34.jpg)
ukpds
Sulphonylurea TherapySulphonylurea Therapy
advantages• known to improve glycaemic control• stimulates endogenous insulin production
disadvantages• in the heart sulphonylurea mimics ATP
and may prevent vasodilation in ischaemia • 1st generation agents may increase arrhythmia
![Page 35: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/35.jpg)
ukpds
Insulin TherapyInsulin Therapy
advantages• well-used therapy to improve glycaemic control• may be essential for many patients
disadvantages• need for injections• risk of weight gain and hypoglycaemia• raised insulin levels may promote
atherosclerosis
![Page 36: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/36.jpg)
ukpds
RandomisationRandomisation
Diet alonen = 896
Conventional Policy
Chlorpropamiden = 619
Glibenclamiden = 615
Insulinn = 911
Intensive Policy
3041 patientsin 15 centres
comparison between three intensive therapies
compare each with conventional policy
![Page 37: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/37.jpg)
ukpds
HbAHbA1c1c
cohort, median data
06
7
8
9
0 2 4 6 8 10
%
Years from randomisation
GlibenclamideChlorpropamideConventional Insulin
![Page 38: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/38.jpg)
ukpds
change in weightchange in weightcohort, mean data
-2.5
0.0
2.5
5.0
7.5
10.0
0 2 4 6 8 10
kg
Years from randomisation
ChlorpropamideConventional Insulin Glibenclamide
![Page 39: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/39.jpg)
ukpds
Hypoglycaemic episodes per annumHypoglycaemic episodes per annum
Actual Therapy analysis
0
10
20
30
40
50
0 3 6 9 12 15
Pro
port
ion o
f pati
ents
(%
)
Years from randomisation
0
2
4
6
8
10
0 3 6 9 12 15
any episode major episodes
![Page 40: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/40.jpg)
ukpds
Blood PressureBlood Pressure
70
75
80
85
135
140
145
150
0 2 4 6 8 10
mm
Hg
Years from randomisation
ChlorpropamideConventional Insulin Glibenclamide
cohort, mean data
![Page 41: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/41.jpg)
ukpds
Any diabetes-related endpointsAny diabetes-related endpoints
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0 3 6 9 12 15
Pro
port
ion
of p
atie
nts
with
eve
nts
Years from randomisation
Conventional (896)
Chlorpropamide (619)
Glibenclamide (615)
Insulin (911)
C v G v Ip = 0.36
![Page 42: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/42.jpg)
ukpds
0.0
0.1
0.2
0.3
0.4
0 3 6 9 12 15
Pro
port
ion
of p
atie
nts
with
eve
nt
Years from randomisation
Conventional (896)
Chlorpropamide (619)
Glibenclamide (615)
Insulin (911)
Myocardial InfarctionMyocardial Infarction
C v G v Ip = 0.66
![Page 43: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/43.jpg)
ukpds
Progression of Retinopathy : 2 step changeProgression of Retinopathy : 2 step change
RR p
0-3 yearsChlorpropamideGlibenclamideInsulin
p=0.991.021.041.01
0.920.810.92
0-6 yearsChlorpropamideGlibenclamideInsulin
p=0.580.920.940.84
0.470.590.096
0-9 yearsChlorpropamideGlibenclamideInsulin
p=0.650.910.830.83
0.330.0680.048
0-12 yearsChlorpropamideGlibenclamideInsulin
p=0.00591.000.680.72
0.990.00440.0041
favours intensive
favours conventional
0.2 1 5
![Page 44: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/44.jpg)
ukpds
Sulphonylurea or Insulin : Summary 1Sulphonylurea or Insulin : Summary 1
• all three therapies were similarly effective in reducing HbA1c
• all three therapies had equivalent risk reductionfor major clinical outcomes compared with conventional policy
• in those allocated to chlorpropamide there was equivalent reduction of risk of microalbuminuria but no reduction of risk of progression of retinopathy
![Page 45: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/45.jpg)
ukpds
Sulphonylurea or insulin : Summary 2Sulphonylurea or insulin : Summary 2
Sulphonylurea therapy• no evidence of deleterious effect on myocardial
infarction, sudden death or diabetes related deaths
Insulin therapy• no evidence for more atheroma-related disease
![Page 46: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/46.jpg)
ukpds
Does metformin in Does metformin in overweight diabetic patients overweight diabetic patients
have any advantages or have any advantages or disadvantages?disadvantages?
UK Prospective Diabetes StudyUK Prospective Diabetes Study
![Page 47: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/47.jpg)
ukpds
IntroductionIntroduction
• the UKPDS has shown that an intensive glucose control policy using sulphonylurea or insulin therapy is effective in reducing the risk of complications in both overweight and normal weight patients
• overweight (>120% Ideal Body Weight) UKPDS patients could be randomised to an intensive glucose control policy with metformin instead of diet, sulphonylurea or insulin
![Page 48: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/48.jpg)
ukpds
RandomisationRandomisation
Main Randomisation4209
Overweight1704
Non overweight2505
Conventional Policy411
Intensive Policy1293
Metformin342
Insulin or Sulphonylurea951
![Page 49: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/49.jpg)
ukpds
Patient CharacteristicsPatient Characteristics
overweight patients > 120% ideal body weightafter three months’ diet therapy
age mean 53 years
gender male / female 46% / 54%
ethnic groups Caucasian 86%
Asian 6%
Afro-caribbean 8%
Body Mass Index mean 31 kg/m2
fasting plasma glucose median 8.1 mmol/L
HbA1c mean 7.2 %
![Page 50: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/50.jpg)
ukpds
HbAHbA1c1c
cohort, median values
06
7
8
9
0 2 4 6 8 10
HbA
1c (
%)
Years from randomisation
ChlorpropamideConventional GlibenclamideInsulin Metformin
overweight patients
![Page 51: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/51.jpg)
ukpds
Change in WeightChange in Weight
cohort, mean values
-5
0
5
10
0 2 4 6 8 10
wei
ght
chan
ge (
kg)
Years from randomisation
ChlorpropamideConventional GlibenclamideInsulin Metformin
overweight patients
![Page 52: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/52.jpg)
ukpds
Hypoglycaemic episodes per annumHypoglycaemic episodes per annum
Actual Therapy analysis
0
10
20
30
40
50
0 2 4 6 8 10
Pro
port
ion o
f pati
ents
(%
)
Years from randomisation
any episode major episodes
0
2
4
6
8
0 2 4 6 8 10
overweight patients
![Page 53: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/53.jpg)
ukpds
0.0
0.2
0.4
0.6
0 3 6 9 12 15
Pro
port
ion
of p
atie
nts
with
eve
nts
Years from randomisation
Conventional (411)
Intensive (951)
Metformin (342)
Any diabetes related endpointAny diabetes related endpoint
M v Ip=0.0034
overweight patients
M v C p=0.0023
![Page 54: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/54.jpg)
ukpds
0.0
0.1
0.2
0.3
0.4
0 3 6 9 12 15
Pro
port
ion
of p
atie
nts
with
eve
nts
Years from randomisation
Conventional (411)
Intensive (951)
Metformin (342)
Diabetes related deathsDiabetes related deaths
M v Ip=0.11
overweight patients
M v C p=0.017
![Page 55: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/55.jpg)
ukpds
Myocardial InfarctionMyocardial Infarction
M v Ip=0.12
overweight patients
0.0
0.1
0.2
0.3
0.4
0 3 6 9 12 15
Pro
port
ion
of p
atie
nts
with
eve
nts
Years from randomisation
Conventional (411)
Intensive (951)
Metformin (342)
M v Cp=0.010
![Page 56: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/56.jpg)
ukpds
0.0
0.1
0.2
0.3
0 3 6 9 12 15
Pro
port
ion
of p
atie
nts
with
eve
nts
Years from randomisation
Conventional (411)
Intensive (951)
Metformin (342)
Microvascular endpointsMicrovascular endpoints
M v Ip=0.39
overweight patients
M v Cp=0.19
![Page 57: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/57.jpg)
ukpds
Metformin ComparisonsMetformin Comparisons
favours metformin
favours conventional
overweight patientsRR p
Any diabetes related endpointMetformin 0.68 0.0023
Diabetes related deathsMetformin 0.58 0.017
All cause mortalityMetformin 0.64 0.011
Myocardial infarctionMetformin 0.61 0.01
RR (95% CI)
0.2 1 5
![Page 58: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/58.jpg)
ukpds
Metformin ComparisonsMetformin Comparisons
favours metformin or
intensive
favours conventional
overweight patientsM v Int RR p
Any diabetes related endpointMetforminIntensive
p=0.00340.680.93
0.00230.46
Diabetes related deathsMetforminIntensive
p=0.110.580.80
0.0170.19
All cause mortalityMetforminIntensive
p=0.0210.640.92
0.0110.49
Myocardial infarctionMetforminIntensive
p=0.120.610.79
0.010.11
RR (95% CI)
0.2 1 5
![Page 59: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/59.jpg)
ukpds
Sulphonylurea plus MetforminSulphonylurea plus Metformin
• patients primarily randomised to intensive therapy with sulphonylurea were not given additional metformin until their fpg was >15 mmol/L or they developed hyperglycaemic symptoms
• in view of the progressive hyperglycaemia in these patients, a protocol modification was made to secondarily randomise the subset of patients who were on maximum sulphonylurea therapy and had fpg >6 mmol/L to earlier addition of metformin
![Page 60: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/60.jpg)
ukpds
AimAim
• the aim of this secondary randomisation was to assess the degree to which glycaemic control might be improved by early combination therapy with metformin
• in view of the interesting results in the primary metformin study a secondary analysis was undertaken to examine any endpoints that had occurred
![Page 61: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/61.jpg)
ukpds
Aggregate EndpointsAggregate Endpoints
1.04
1.96
1.60
1.09
1.21
0.84
0.78
0.039
0.041
0.73
0.61
0.62
Any diabetes related endpoint
Diabetes related deaths
All cause mortality
Myocardial infarction
Stroke
Microvascular
RR pMedian follow up 6.6 years 0.1 1 10
Favourssulphonylureaalone
Favoursadded
metformin
Relative Risk& 95% CI
*
* interpret with caution in view of small numbers : 26 deaths on sulphonylurea plus metformin versus 14 deaths on sulphonylurea alone
![Page 62: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/62.jpg)
ukpds
Metformin in Overweight PatientsMetformin in Overweight Patients
• compared with conventional policy
32% risk reduction in any diabetes-related endpoints p=0.002342% risk reduction in diabetes-related deaths p=0.01736% risk reduction in all cause mortalityp=0.01139% risk reduction in myocardial infarction p=0.01
![Page 63: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/63.jpg)
ukpds
Metformin : SummaryMetformin : Summary
• the addition of metformin in patients already treated with sulphonylurea requires further study
• on balance, metformin treatment would appear to be advantageous as primary pharmacological therapy in diet-treated overweight patients
![Page 64: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/64.jpg)
ukpds
Blood Pressure Blood Pressure Control StudyControl Study
UK Prospective Diabetes StudyUK Prospective Diabetes Study
![Page 65: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/65.jpg)
ukpds
Blood Pressure Control Study : AimsBlood Pressure Control Study : Aims
to determine whether
• tight blood pressure control policy can reduce morbidity and mortality in Type 2 diabetic patients
• ACE inhibitor (captopril) or Beta blocker (atenolol) is advantageous in reducing the risk of development of clinical complications
![Page 66: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/66.jpg)
ukpds
Inclusion criteriaInclusion criteria
patients NOT on anti-hypertensive therapy
systolic >160 and/or diastolic > 90 mmHg
patients already ON anti-hypertensive therapy
systolic >150 and/or diastolic > 85 mmHg
excluded if:
required strict blood pressure control; severe illness;
contraindication to study medication or declined
informed consent
![Page 67: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/67.jpg)
ukpds
Patient CharacteristicsPatient Characteristics
1148 Type 2 diabetic patients
age 56 years
gender male / female 55% / 45%
ethnic groups Caucasian 87%
Asian 6%
Afro-caribbean 7%
Body Mass Index 29 kg/m2
HbA1c 6.8 %
systolic / diastolic blood pressure 160 / 94 mmHg
urine albumin > 50 mg/l 18%
![Page 68: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/68.jpg)
ukpds
RandomisationRandomisation
on antihypertensive therapyn = 421
not on antihypertensive therapyn = 727
avoid ACE inhibitor : Beta blockern = 390
34%
less tight blood pressure controlaim : BP < 180/105 mmHg
ACE inhibitorn = 400
35%
Beta blockern = 358
31%
tight blood pressure controlaim : BP < 150 / 85 mmHg
randomisation
1148 hypertensive patients
![Page 69: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/69.jpg)
ukpds
Blood Pressure : Tight vs Less Tight Control Blood Pressure : Tight vs Less Tight Control
60
80
100
140
160
180
0 2 4 6 8
mm
Hg
Years from randomisation
cohort, median values
Less tight control Tight control
![Page 70: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/70.jpg)
ukpds
mmHg baseline mean over 9 years
Less tight control 160 / 94 154 / 87
Tight control 161 / 94 144 / 82
difference 1 / 0 10 / 5
p n.s. <0.0001
ACE inhibitor 159 / 94 144 / 83
Beta blocker 159 / 93 143 / 81
difference 0 / 0 1 / 1
p n.s. n.s. / p=0.02
Mean Blood PressureMean Blood Pressure
![Page 71: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/71.jpg)
ukpds
Therapy requirementTherapy requirement
1 2 3 4 5 6 7 80
20
40
60
80
100
% o
f pa
tient
s
LessTight Control Policy
1 2 3 4 5 6 7 8
Years from randomisation
None one two > two
Tight Control Policy
number of antihypertensive agents
![Page 72: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/72.jpg)
ukpds
Any diabetes-related endpointsAny diabetes-related endpoints
0%
10%
20%
30%
40%
50%
0 3 6 9
% o
f pa
tient
s w
ith e
vent
s
Years from randomisation
Tight blood pressure control (758)
Less tight blood pressure control (390)
risk reduction24% p=0.0046
![Page 73: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/73.jpg)
ukpds
Diabetes-related deathsDiabetes-related deaths
0%
5%
10%
15%
20%
0 3 6 9
% o
f pa
tient
s w
ith e
vent
s
Years from randomisation
Tight blood pressure control (758)
Less tight blood pressure control (390)
risk reduction32% p=0.019
![Page 74: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/74.jpg)
ukpds
Myocardial InfarctionMyocardial Infarction
0%
5%
10%
15%
20%
25%
0 3 6 9
% o
f pa
tient
s w
ith e
vent
Years from randomisation
Tight Blood Pressure Control (758)
Less Tight Blood Pressure Control (390)
risk reduction21% p=0.13
![Page 75: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/75.jpg)
ukpds
StrokeStroke
0%
5%
10%
15%
20%
25%
0 3 6 9
% p
atie
nts
with
eve
nt
Years from randomisation
Tight Blood Pressure Control (758)
Less Tight Blood Pressure Control (390)
risk reduction44% p=0.013
![Page 76: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/76.jpg)
ukpds
Microvascular endpointsMicrovascular endpoints
0%
5%
10%
15%
20%
25%
0 3 6 9
% p
atie
nts
with
eve
nt
Years from randomisation
Tight Blood Pressure Control (758)
Less Tight Blood Pressure Control (390)
risk reduction37% p=0.0092
![Page 77: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/77.jpg)
ukpds
Heart FailureHeart Failure
0%
5%
10%
15%
20%
25%
0 3 6 9
% p
atie
nts
with
eve
nt
Years from randomisation
Tight Blood Pressure Control (758)
Less Tight Blood Pressure Control (390)
risk reduction 56% p=0.0043
![Page 78: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/78.jpg)
ukpds
Progression of Retinopathy : 2 step changeProgression of Retinopathy : 2 step change
Years from randomisationnumbers above bars are % affected
243 461 207 411 152 3000
20
40
60
% p
atie
nts
23 20
37
28
51
34
3 years 6 years 9 years
p=0.38 p=0.019 p=0.004
![Page 79: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/79.jpg)
ukpds
Deterioration of Vision : 3 lines on ETDRS chartDeterioration of Vision : 3 lines on ETDRS chart
Years from randomisationnumbers above bars are % affected
% p
atie
nts
293 575 257 523 180 3320
10
20
30
7 59
8
19
10
3 years 6 years 9 years
p=0.40 p=0.47 p=0.004
![Page 80: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/80.jpg)
ukpds
Urine Albumin >50 mg/LUrine Albumin >50 mg/L
Years from randomisationnumbers above bars are % affected
% p
atie
nts
317 618 274 543 166 2990
10
20
30
40
24
18
29
20
33
29
3 years 6 years 9 years
p=0.008p=0.052 p=0.33
![Page 81: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/81.jpg)
ukpds
in 1148 Type 2 diabetic patients a tight blood pressure control policy which achieved blood pressure of 144 / 82 mmHg gave reduced risk for
any diabetes-related endpoint 24% p=0.0046
diabetes-related deaths 32% p=0.019
stroke 44% p=0.013
microvascular disease 37% p=0.0092
heart failure 56% p=0.0043
retinopathy progression 34% p=0.0038
deterioration of vision 47% p=0.0036
Blood Pressure Control StudyBlood Pressure Control Study
![Page 82: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/82.jpg)
ukpds
Do ACE inhibitors or Do ACE inhibitors or Beta Blockers Beta Blockers
have any specific advantages have any specific advantages or disadvantages?or disadvantages?
UK Prospective Diabetes StudyUK Prospective Diabetes Study
![Page 83: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/83.jpg)
ukpds
Blood Pressure : ACE inhibitor vs Beta blockerBlood Pressure : ACE inhibitor vs Beta blocker
60
80
100
140
160
180
0 2 4 6 8
mm
Hg
Years from randomisation
cohort, median values
Less tight control ACE inhibitor Beta blocker
![Page 84: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/84.jpg)
ukpds
Reasons for non-complianceReasons for non-complianceCaptopril(n=400)
Atenolol(n=358) p
non-compliant 88 (22%) 125 (35%) <0.0001
cough 16 (4%) 0 <0.0001
increased creatinine 5 (1%) 0 0.064
claudication,cold fingers or toes
0 15 (4%) <0.0001
bronchospasm 0 22 (6%) <0.0001
impotence 1 (0%) 6 (2%) 0.057
![Page 85: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/85.jpg)
ukpds
Any Diabetes Related Endpoint (cumulative)Any Diabetes Related Endpoint (cumulative)429 of 1148 patients (37%)
0%
10%
20%
30%
40%
50%
0 3 6 9
% o
f pa
tient
s w
ith a
n ev
ent
Years from randomisation
ACE inhibitor (n=400)
Beta blocker (n=358)
Less tight BP control (n=390)
ACE vs Beta blocker p=0.43
Less tight vs Tightp=0.0046
![Page 86: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/86.jpg)
ukpds
Diabetes Related Deaths (cumulative)Diabetes Related Deaths (cumulative)144 of 1148 patients (13%)
0%
5%
10%
15%
20%
0 3 6 9
% o
f pa
tient
s w
ith a
n ev
ent
Years from randomisation
ACE inhibitor (n=400)
Beta blocker (n=358)
Less tight BP control (n=390)
ACE vs Beta blocker p=0.28
Less tight vs Tightp=0.019
![Page 87: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/87.jpg)
ukpds
Microvascular Endpoints (cumulative)Microvascular Endpoints (cumulative)renal failure or death, vitreous haemorrhage or photocoagulation
122 of 1148 patients (11%)
0%
5%
10%
15%
20%
0 3 6 9
% o
f pa
tient
s w
ith a
n ev
ent
Years from randomisation
ACE inhibitor
Beta blocker
Less tight BP control
ACE vs Beta blocker p=0.30
Less tight vs Tightp=0.0092
![Page 88: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/88.jpg)
ukpds
Aggregate Clinical EndpointsAggregate Clinical Endpoints
1.10
1.27
1.14
1.20
1.12
1.29
0.43
0.28
0.44
0.35
0.74
0.30
Any diabetes related endpoint
Diabetes related deaths
All cause mortality
Myocardial infarction
Stroke
Microvascular
RR p 0.5 1 2
Relative Risk& 95% CI
>
>
FavoursBeta blocker
FavoursACE inhibitor
![Page 89: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/89.jpg)
ukpds
Surrogate endpointsSurrogate endpoints
RR p
Retinopathy 2 step progressionmedian 1.5 years 0.99 0.75median 4.5 years 0.99 0.82median 7.5 years 0.91 0.28
Urine albumin > 50 mg/L3 years 1.11 0.556 years 0.93 0.659 years 1.20 0.31
Urine albumin >300 mg/L3 years 1.41 0.446 years 0.75 0.439 years 0.48 0.090
Relative Risk & 99% CI
favours ACE inhibitor
favours Beta blocker
0.1 1 10
![Page 90: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/90.jpg)
ukpds
ConclusionConclusion
ACE inhibitors and Beta blockers were equally effective in lowering mean blood pressure in hypertensive patients with type 2 diabetes and in reducing the risk of:
• any diabetes related endpoint• diabetes related deaths• microvascular endpoints
![Page 91: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/91.jpg)
ukpds
Potential implications Potential implications for clinical care of for clinical care of diabetic patientsdiabetic patients
UK Prospective Diabetes StudyUK Prospective Diabetes Study
![Page 92: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/92.jpg)
ukpds
UK Prospective Diabetes StudyUK Prospective Diabetes Study
An intensive glucose control policy HbA1c 7.0 % vs 7.9 %
reduces risk of
any diabetes-related endpoints 12% p=0.030 microvascular endpoints 25% p=0.010 myocardial infarction 16% p=0.052
A tight blood pressure control policy 144 / 82 vs 154 / 87 mmHg
reduces risk of
any diabetes-related endpoint 24% p=0.005 microvascular endpoint 37% p=0.009 stroke 44% p=0.013
![Page 93: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/93.jpg)
ukpds
Choice of TherapiesChoice of Therapies
diabetes :• each of the available therapies studied can be used • in overweight, diet-treated patients, metformin may
be advantageous
hypertension :• Beta blockers and ACE inhibitors each provide
protection
![Page 94: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/94.jpg)
ukpds
Which goals of therapy?Which goals of therapy?
• current guidelines suggest HbA1c <7%
• the risk of diabetic complications was reduced in the UKPDS trial which achieved a median HbA1c 7.0%in the intensive glucose control group
• this HbA1c level is in accord with current guidelinesbut is difficult to accomplish in some patients
• epidemiological analysis suggests that any reduction of hyperglycaemia would be advantageous
![Page 95: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/95.jpg)
ukpds
Which goals of therapy?Which goals of therapy?
• current guidelines suggest blood pressure<140 / 85 mmHg or <130 / 85 mmHg
• the risk of diabetic complications was reducedin the UKPDS blood pressure control trialwhich achieved a mean blood pressure 144 / 82 mmHg in the tight control group
• this result is in accord with current guidelines,which are also supported by the epidemiological analysis
![Page 96: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/96.jpg)
ukpds
PolypharmacyPolypharmacy
• glycaemia combinations of agents with different actions
will be needed more patients will require insulin
• blood pressure many patients will need 3 or more different
types of agents
![Page 97: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/97.jpg)
ukpds
Differences between TherapiesDifferences between Therapies
• sulphonylurea, insulin and metformin are each effective in reducing the risk of any diabetes related endpoints and microvascular endpoints
• no evidence of increased risk of complications for any single therapy
• ACE inhibitors and Beta blockers are each effective in reducing the risk of macrovascular and microvascular endpoints
• no evidence that either is specifically advantageous
![Page 98: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/98.jpg)
ukpds
UK Prospective Diabetes StudyUK Prospective Diabetes Study
The UKPDS has shown conclusively that :
• intensive therapy to reduce glycaemia is worthwhile as it reduces risk of complications
• tight blood pressure control is worthwhile as it reduces risk of complications
• there are no major differences between the therapies tested
• reduction in risk of complications of diabetes is a realisable goal
![Page 99: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/99.jpg)
ukpds
Beneficial Effects of Intensive TherapyBeneficial Effects of Intensive Therapy
The UKPDS has shown that
more intensive monitoring
more intensive use of existing therapies
which improves
blood glucose control
blood pressure control
can reduce the risk of diabetic complications
![Page 100: ukpds](https://reader034.fdocuments.in/reader034/viewer/2022051820/552a6ef65503469d428b4661/html5/thumbnails/100.jpg)
ukpds
UK Prospective Diabetes StudyUK Prospective Diabetes Study
papers presenting major results of the study
UKPDS 33: Lancet (1998) 352, 837-853
UKPDS 34: Lancet (1998) 352, 854-865
UKPDS 38: BMJ (1998) 317, 703-713
UKPDS 39: BMJ (1998) 317, 713-720