contribution to clinicians of the last revision of the
TRANSCRIPT
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Contribution to clinicians of the last revision of the UKPDS study
The Oxford Centrefor Diabetes, Endocrinology and Metabolism
Prof. David R. MatthewsSalamanca 29th January 2010. IV congress on
Diabetes and obesity
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
• Title: Contribution to clinicians of the last revision of the UKPDS study Given where: Salamanca, Spain
• Based on: Florence , Teneriffe• Keywords: Glycaemia, trials, Advance, Record, Adopt,UKPDS,Proactive
• Date: 29/01/2010• Occasion: IV congress on Diabetes and Obesity• Sponsor: • Contact: academic• Feedback:• Duration: 45mins• Timing: • Notes:• Discussion:• Thoughts:• Revisions necessary
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
Risks of complications in type 2 diabetes
• Glycaemia• Hypertension• Dyslipidaemia• Smoking• Obesity
• Age• Sex• Race• Genes (within
race)• Competing risks
**
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
The problem
• We utilise glucose as our main metabolic fuel
• Glucose can be stored and mobilised in seconds
• A fit person can run on glucose energy for about 15miles
BUTGlucose is very osmotically
activeEven 8mmol/l will damage
vesselsIf we could survive with glucose
at just 12mmol/l most diabetes would be irrelevant
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
How do we know that high glucose is dangerous?
• Rats and mice run a higher blood glucose than man –typically 8mmol/l– Evolutionary pressure is
not about 70-year survival but 3 year survival
– Fuel more important than glucose risk
• In man we have trial evidence of the risk
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
• UGDP• UKPDS• PROactive• (ADOPT)• (Nissen et al meta-analysis)• RECORD• ACCORD• ADVANCE• UKDPS PTM• VADT
Trials relating to glycaemia and outcomes
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
1970
1980
1990
2000
2010
UGDP UKPDS
Advance
VADT
Accord
ProActive
Glycaemic outcome trials
RECORD
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
1970
1980
1990
2000
2010
UGDP UKPDS
Advance
VADT
Accord
ProActive
Glycaemic outcome trialsEach of these trials was controversial in
some respects
RECORD
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
Randomised controlled trials
Define the population
Treatment A
Treatment B
Randomise
How long?
What difference is going to be measured?
How many? = power
Is it safe?
?
What complexity?
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
Problems in trials
Define the population
Treatment A
Treatment B
Randomise
How long?
What difference is going to be measured?
How many? = power
Is it safe?
?
UGDPVADT
ACCORD
ProActiveRECORD
ADVANCE
UKPDS
What complexity?
VADT
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
UGDP – perhaps tolbutamide was dangerous?
More people died in the tolbutamide group
Leibel B. An analysis of the UGDP. Can Med Assoc J. 1971 Aug 7;105(3):292-4.
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
UGDP
Define the population
Comparator groupsRandomise
there were 30% more baseline ECG abnormalities in the tolbutamide group
there was 40% more angina in the tolbutamide group
Tolbutamide group More deaths
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UKPDS
• Primary intervention randomised controlled outcome trial
• Used sulphonylureas– mainly glibenclamide and chlorpropamide– small number of patients used gliclazide and
acarbose (not formally part of the trial)• Used metformin in the overweight (120% Ideal body
weight)• Used insulin as primary intervention• Recruited patients with fasting glucose greater than
6mmol/l
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20 years 5years
5012
Num
bers
in th
e st
udy
Randomised trial Post-study monitoring
(non-randomised)
UKPDS assessment designUKPDS assessment design(end(end--point counting)point counting)
1997
: en
d19
98 :
pub
lish
Deaths
†
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20 years 10 years
5012
Num
bers
in th
e st
udy
Randomised trial Post-study monitoring
(non-randomised)
UKPDS designUKPDS design
1997
: en
d19
98 :
pub
lish
Deaths
50% mortality ~30years
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Mortality in the UKPDS (1997)
Cardiac41%
Sudden6%
Stroke9%
Unknown2%
Cancer25%
Accident2%
Other15%
End of the trial (1997): 1/7 of all the patients had died (20y)By 2000: 1/4 of all the patients had diedEnd of Post Study Monitoring:
1/2 of all the patients had died (30y)
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HbAHbA1c1ccohort, median data
ukpds
06
7
8
9
0 2 4 6 8 10
%
Years from randomisation
GlibenclamideChlorpropamideConventional Insulin
HbA1c
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
UKPDS: Any Diabetes Related endpointsab
solu
te ri
sk
Glucose control trial
Conventional Policy
Intensive Policy
Blood pressure control trial
Less tight control
Tight control
80
60
40
20
0
80
60
40
20
0
…but myocardial infarction reduction in the main trial was not significantly (p=0.052)
reduced
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
Epidemiology vs trial
• Trials randomise patients and examine the outcome on the basis of the randomised intervention.
• Epidemiological analyses examine a surrogate marker within the trial (e.g. the glucose or the blood pressure) and examine the outcome based on what was achieved rather than what was administered.
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Microvascular diseaseMicrovascular disease
0.5
1
1015
0 5 6 7 8 9 10 11
updated mean HbA1c
haza
rd ra
tio
37% decrease per 1% decrement in HbA1c
p<0.0001
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Myocardial infarctionMyocardial infarction
updated mean HbA1c
haza
rd ra
tio
14% decrease per 1% decrement in HbA1c
p<0.0001
0.5
1
5
0 5 6 7 8 9 10 11
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0.5
1
5
0 5 6 7 8 9 10 11
Diabetes related deathsDiabetes related deaths
updated mean HbA1c
haza
rd ra
tio
21% decrease per 1% decrement in HbA1c
p<0.0001
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
Any Diabetes Related endpoints
HbA1c (%) systolic blood pressure
>87-8
6-7<6 <130
130-140140-150
>150
haza
rd ra
tio
012345
012345
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
Microvascular endpoints
HbA1c(%)
systolic blood pressure
>87-8
6-7<6 <13
0
130-140
140-150
>150
haza
rd ra
tio
0
5
10
15
20
25
0
5
10
15
20
25
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
PROactive
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PROactive
• Pioglitazone• Secondary prevention in type 2 diabetes and
macrovascular disease• N=5238 Duration 34.5 months• Primary outcome: composite of all-cause mortality,
non-fatal MI (including silent MI), non-fatal stroke, major leg amputation, ACS, cardiac intervention (bypass graft or percutaneous coronary intervention), and leg revascularization
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
Betteridge, D. J. et al. Eur Heart J 2008 29:969-983
Proactive composite outcome
Pio514 events
Placebo572 events
P=0.095
Primary composite event rate
Main secondary composite event rate
Placebo358 events
P=0.027 Pio301 events
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Pio
Placebo
P=0.045
Fatal and non-fatal MI
Fatal and non-fatal stroke
Placebo
P=0.009Pio
Betteridge, D. J. et al. Eur Heart J 2008 29:969-983
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
ProActive
Pioglitazone
Comparator
What difference is going to be measured?
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
Betteridge, D. J. et al. Eur Heart J 2008 29:969-983
Pioglitazone meta-anlyses
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
Rosiglitazone Meta-analysis42 trialsstudy duration of more than 24 weeksmean age 56 years; baseline HbA1c 8.2%
1 1.2 1.4 1.6 1.80.80.6 2.0
MI
Death
comparisons were randomized control
groups not receiving rosiglitazone
1.64 (95% CI, 0.98 to 2.74; P=0.06).
1.43 (95% CI, 1.03 to 1.98; P=0.03)
odds ratios:
Nissen N Engl J Med. 2007 Jun 14;356(24):2457-71.
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
EDIC(DCCT post trial monitoring)
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Distribution of HbA1c Concentration by Randomized Treatment Group at the End of the DCCT and in Each Year of the EDIC Study
JAMA 2003;290:2159-2167.
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism JAMA 2003;290:2159-2167.
Prevalence and Cumulative Incidence of Microalbuminuria
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
RECORD
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RECORD• An outcome trial of Rosiglitazone: interim results• The interim results for the primary end point were
inconclusive• a hazard ratio of 1.08 (95% CI, 0.89 to 1.31) on the
basis of events adjudicated by the committee reviewing clinical end points.
• In any interim trial report, there are inevitably some potential primary events pending adjudication. Adding in these pending events increased the hazard ratio to 1.11 (95% CI, 0.93 to 1.32).
Home, P.D. et al
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
RECORD
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RECORD
Comparator
How long?
What difference is going to be measured?
How many? = power
Is it safe?
?Rosiglitazone
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
ACCORD
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ACCORD (Action to Control Cardiovascular Risk in Diabetes)
Design
• to determine whether intensively lowering blood sugar would reduce the risk of cardiovascular events such as heart attack, stroke, or death from cardiovascular disease, specifically in people with type 2 diabetes who are at particularly high risk for a cardiovascular event
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Accord Study design
• 77 sites USA and Canada, • includes adults• ages of 40 – 82y at enrolment • type 2 diabetes, • PLUS:
–two or more other risk factors for heart disease –or had been diagnosed with heart disease before
entering the study.
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Enrolment
• average diabetes duration of 10 years at enrolment, • randomly assigned to either standard (n=5,123
participants) or intensive (n=5,128) blood sugar treatment goals.
• also enrolled in one of two other ACCORD randomized clinical trials examining effects of treatments for blood pressure or blood lipids.
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ACCORD: Patient Characteristics
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Glucose control in ACCORD
N Engl J Med 2008;358:2545-59
Treatments in intensive
control group
Insulin 77%
TZD 92%
SU 78%
Metformin 95%
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UKPDS and ACCORDUKPDS and ACCORDcohort, median data
ukpds
06
7
8
9
0 2 4 6 8 10
%
Years from randomisation
GlibenclamideChlorpropamideConventionalInsulin
ACCORDHbA1c
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Primary outcome
The first occurrence of nonfatal myocardial infarction or nonfatal stroke or death from cardiovascular causes.
The latter included death from myocardial infarction, heart failure, arrhythmia, invasive cardiovascular interventions, cardiovascular causes after noncardiovascular surgery, stroke, unexpected death presumed to be from ischaemic cardiovascular disease occurring within 24 hours after the onset of symptoms, and death from other vascular diseases.
ACCORD
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ACCORD
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ACCORD
54 excess deaths in the intensive
group257
deaths
203 deaths
Discontinued 2008 on advice from Data
Monitoring and Ethics Group
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Risk profile high
• Participants were included in the ACCORD trial because they were at especially high risk—more risk than is associated with diabetes alone—for having a heart attack, stroke, or of dying from cardiovascular disease.
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HbA1c
• intensive treatment group participants achieved, on average, A1C values lower than standard treatment group participants.
• half of the participants in the intensive treatment group achieved an A1C of less than 6.4 percent
• half of the participants in the standard treatment group achieved an A1C of less than 7.5 percent.
• The average blood sugar levels for both groups were lower than when they entered the study
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ACCORD Primary outcome
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ACCORD death from any cause
Younger
Higher A1c
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ACCORD
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The problem
• enrolled 10,251 participants. • Of these, 257 in the intensive treatment group died,
compared with 203 within the standard treatment group.
• This is a difference of 54 deaths, or 3 per 1,000 participants each year, over an average of almost four years of treatment.
• Participants had been followed for 2 years to 7 years at the time the intensive blood sugar control treatment was stopped
• The death rates in both groups were lower than seen in similar populations in other studies.
(14 deaths per 1000 patients per year versus 11 per 1000
patients per year in the standard treatment program; a difference of 0.3 deaths per 100 patients
per year).
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ACCORD
Define the population
Non-aggressive
Is it safe?
?Aggressive
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ADVANCE
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ADVANCE Inclusion criteriaType 2 diabetes mellitusAge 55 years or olderAdditional risk of vascular event Age ≥ 65 yearsHistory of major macrovascular diseaseHistory of major microvascular diseaseFirst diagnosis of diabetes >10 years prior to entryOther major risk factor
Any level of blood pressureAny level of glucose control but no definite indication for long-term insulin
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ADVANCE: Patient Characteristics
8 Years
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ADVANCE Intensive glucose control strategy
More frequent visits
Emphasis on lifestyle management
Drug titration at physician’s discretion based on HbA1c and FBG levels:
Maximize gliclazide MR dose
Add other oral agents
Add long-acting insulin
Use multiple insulin injection therapy
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
ADVANCE Hemoglobin A1c
∆ 0.67% (95% CI 0.64 - 0.70); p<0.001
Mea
n H
bA1c
(%)
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
10.0
Follow-up (Months)
0 6 12 18 24 30 36 42 48 54 60 66
7.3 %
Mean HbA1cat final visit
6.5%
StandardIntensive
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
ADVANCE Major macrovascular events
Follow-up (months)
Cum
ula t
ive
i nci
den c
e (%
)25
20
15
10
5
0
StandardIntensive
0 6 12 18 24 30 36 42 48 54 60 66
Relative risk reduction6%: 95% CI: -6 to 16%
p=0.32
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
ADVANCE Major microvascular events
Follow-up (months)
Cum
ula t
ive
i nci
den c
e (%
)25
20
15
10
5
0
StandardIntensive
0 6 12 18 24 30 36 42 48 54 60 66
Relative risk reduction14%: 95% CI: 3 to 23%
p=0.015
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
ADVANCE Major microvascular events
Microvascular 526 605 14% (3 to 23)
New or worsening nephropathy 230 292 21% (7 to 34)
New or worsening retinopathy 332 349 5% (-10 to 18)
Number of patients with eventIntensive Standard(n=5,571) (n=5,569)
Relative riskreduction (95% CI)
FavorsIntensive
FavorsStandard
Hazard ratio0.5 1.0 2.0
†P=0.01
‡P=0.006
†
‡
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
ADVANCE
Sulphonylurea
Comparators
How long?
What difference is going to be measured?
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
VADT
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
VADT
• 20 centres• 1791 patients• Major CVD events• 97% male• Duration 7.5 years• median f-up 6 years• Median 7% vs 8.4% HbA1c in groups• No difference in cardiovascular outcome
Underpowered trial
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
VADT
Treatment A
Treatment B
How long?
How many? = power
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
Trial
At the end of a trial all subjects are
treated with the best option
Group A
Group BPost trial
monitoring
Did being in Group A or B years ago make a difference to what is happening now?
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
UKPDS Post Trial Monitoring
![Page 71: Contribution to clinicians of the last revision of the](https://reader034.vdocuments.mx/reader034/viewer/2022043002/626af791ca6e83601940d3de/html5/thumbnails/71.jpg)
UK Prospective Diabetes Study
20-year Interventional Trial from 1977 to 19975,102 patients with newly-diagnosed type 2 diabetes recruited between 1977 and 1991
Median follow-up 10.0 years, range 6 to 20 years
Results presented at the 1998 EASD Barcelona meeting
10-year Post-Trial Monitoring from 1997 to 2007Annual follow-up of the survivor cohort
Clinic-based for first five years
Questionnaire-based for last five years
Median overall follow-up 17.0 years, range 16 to 30 years
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Post-Trial Monitoring: Aims
To observe HbA1c levels after cessation of theintervention trial
To observe glucose therapy regimens aftercessation of the intervention trial
To determine the longer-term impact of earlier improved glucose control on microvascularand on macrovascular outcomes
To evaluate the health economic implications with a projected 50% mortality at ten years post trial
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P
Glucose Interventional Trial
Conventional
Intensive
Intensive
Trial end1997
P
UKPDS 8. Diabetologia 1991; 34: 877-89
5,102Newly-diagnosedtype 2 diabetes
744Diet failure
FPG >15 mmol/l
149Diet satisfactory
FPG <6 mmol/l
DietaryRun-in
4209
2,729Intensive
with sulfonylurea/insulin
1,138 (411 overweight)Conventional
with diet
342 (all overweight)Intensive
with metformin
Randomisation1977-1991
Mean age 54 years(IQR 48–60)
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Post-Trial Monitoring: Patients
880Conventional
2,118Sulfonylurea/Insulin
279Metformin
1997# in survivor cohort
Mortality 44% (1,852)Lost-to-follow-up 3.5% (146)
2002
Clinic
Clinic
Clinic
Questionnaire
Questionnaire
Questionnaire
2007# with final year data
379Conventional
1,010Sulfonylurea/Insulin
136Metformin
P
P
Mean age62±8 years
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Therapy for Glycaemia at 5 Years
0%
20%
40%
60%
80%
100%Conventional Intensive
Original randomisation
Pro
porti
on o
f pat
ient
s
Diet aloneOral monotherapy
Combined oral
Oral + insulin
Basal insulin
Basal + soluble
77%
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Post-Trial Changes in HbA1c
UKPDS resultspresented
Mean (95%CI)
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Any Diabetes-related Endpoint
Intervention TrialMedian follow-up 10.0 years
Intervention Trial + Post-trial monitoringMedian follow-up 16.8 years
RR=0.88 (0.79-0.99)P=0.029
Conventional
Sulfonylurea/Insulin
Conventional
Sulfonylurea/Insulin
1997-2007
1997-2007
1997-2007
A “legacy effect” ofprior improved glucose control
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Any Diabetes Related Endpoint Hazard Ratio
Intensive (SU/Ins) vs. Conventional glucose control
HR (95%CI)
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Microvascular Disease Hazard Ratio
Intensive (SU/Ins) vs. Conventional glucose control(photocoagulation, vitreous haemorrhage, renal failure)
HR (95%CI)
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Myocardial Infarction Hazard Ratio(fatal or non-fatal myocardial infarction or sudden death)
Intensive (SU/Ins) vs. Conventional glucose control
HR (95%CI)
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Post-Trial Monitoring: Protocol
At trial end, patients were returned to usual physician care for their diabetes management
No attempt was made to maintain them in randomised groups, or to influence their therapy
All endpoints were adjudicated in an identical mannerby the same Adjudication Committee as during the trial
From 1997 to 2002:
Patients were seen annually in UKPDS clinics for standardised collection of clinical and biochemical data
From 2002 to 2007:
Clinical outcomes were ascertained remotely by questionnaires sent to patients and GPs
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All-cause Mortality Hazard Ratio
Intensive (SU/Ins) vs. Conventional glucose control
HR (95%CI)
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Post-Trial Changes in HbA1c
UKPDS resultspresented Mean (95%CI)
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Any Diabetes Related Endpoint Hazard Ratio
Intensive (metformin) vs. Conventional glucose control
HR (95%CI)
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Microvascular Disease Hazard Ratio(photocoagulation, vitreous haemorrhage, renal failure)
Intensive (metformin) vs. Conventional glucose control
HR (95%CI)
![Page 86: Contribution to clinicians of the last revision of the](https://reader034.vdocuments.mx/reader034/viewer/2022043002/626af791ca6e83601940d3de/html5/thumbnails/86.jpg)
Myocardial Infarction Hazard Ratio (fatal or non-fatal myocardial infarction or sudden death)
Intensive (metformin) vs. Conventional glucose control
HR (95%CI)
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All-cause Mortality Hazard Ratio
Intensive (metformin) vs. Conventional glucose control
HR (95%CI)
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Are there Blood Pressure Are there Blood Pressure Therapy Legacy Effects?Therapy Legacy Effects?
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Hypertension in Diabetes Study (HDS)10-year Intervention Trial 1987-1997
1,148 patients with blood pressure ≥160/90 mm Hg,or ≥150/85 mm Hg if receiving antihypertensive treatment,enrolled over four years from 1987
Median follow-up 8.4 years, range 6 to 10 years
Results presented at the 1998 EASD Barcelona meeting
10-year Post-trial Monitoring 1997-2007Annual follow-up of the survivor cohort
Clinic-based for first five years
Questionnaire-based for last five years
Median overall follow-up 14.6 years, range 16 to 20 years
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Blood Pressure Interventional Trial
1,148BP >160/90 mm Hg
or >150/80 on Rx
Tight control
Less-tight control
Trial end1997
P
UKPDS 8. Diabetologia 1991; 34: 877-89
5,102UKPDS patients
759Tight control
ACEI or ß-blocker
390Less-tight control
No ACEI or ß-blocker
Randomisation1987-1991
Mean age56±8 years
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Post-Trial Monitoring: Patients
292Less-tight control
592Tight control
1997# in survivor cohort
Mortality 51% (584)Lost-to-follow-up 2.0% (23)
2002
Clinic
Clinic
2007# with final year data
Questionnaire
Questionnaire 126Less-tight control
250Tight control
P
Mean age63±8 years
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Antihypertensive Therapy at 5 years
Pro
porti
on o
f pat
ient
sLess Tight Tight
1
2
3
4
5
Number of agents
Original randomisation0
20%
40%
60%
80%
100%
0
74%
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Post-Trials Changes in Blood Pressure
UKPDSresults
presented Mean (95%CI)
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Any Diabetes Related Endpoint Hazard Ratio
Less-tight vs. Tight blood pressure control
HR (95%CI)
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Microvascular Disease Hazard Ratio
Less-tight vs. Tight blood pressure control(photocoagulation, vitreous haemorrhage, renal failure)
HR (95%CI)
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Myocardial Infarction Hazard Ratios
Less-tight vs. Tight blood pressure control(fatal or non-fatal myocardial infarction or sudden death)
HR (95%CI)
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All-cause Mortality Hazard Ratios
Less-tight vs. Tight blood pressure control
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After median 8.5 years post-trial follow-up
Aggregate Endpoint 1997 2007
Any diabetes related endpoint RRR: 12% 9%P: 0.029 0.040
Microvascular disease RRR: 25% 24%P: 0.0099 0.001
Myocardial infarction RRR: 16% 15%P: 0.052 0.014
All-cause mortality RRR: 6% 13%P: 0.44 0.007
RRR = Relative Risk Reduction, P = Log Rank
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After median 8.8 years post-trial follow-up
Aggregate Endpoint 1997 2007
Any diabetes related endpoint RRR: 32% 21%P: 0.0023 0.013
Microvascular disease RRR: 29% 16%P: 0.19 0.31
Myocardial infarction RRR: 39% 33%P: 0.010 0.005
All-cause mortality RRR: 36% 27%P: 0.011 0.002
RRR = Relative Risk Reduction, P = Log Rank
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The Benefits of Early Tight Control- UKPDS 10 year Post-Trial Follow-Up
1.Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008 Oct 9;359(15):1577-89.2. UKPDS 33. Lancet, 1998: 352; 837
2
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No Legacy Effect of Earlier BP Control
After median 8.0 years post-trial follow-up
Aggregate Endpoint 1997 2007
Any diabetes related endpoint RRR: 24% 7%P: 0.0046 0.31
Microvascular disease RRR: 37% 16%P: 0.0092 0.17
Myocardial infarction RRR: 21% 10%P: 0.13 0.35
All-cause mortality RRR: 18% 11%P: 0.17 0.18
RRR = Relative Risk Reduction, P = Log Rank
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Legacy effectsLegacy effects
• Legacy: “something handed on by or left unfinished by a predecessor or previous owner”*
• More likely to be gradually developing pathology than “metabolic memory”
*Chambers Dictionary 10th edition
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The performance of this machine may depend on its previous history as well as standards of care today.
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Accidents likely to happenAccidents likely to happenThe rust on
this machine today is the
result of what has
happened in the distant
past
Glycaemic control in the distant past
reduces the risks of events today
The air pressure in the
tyres of this machine is the result of what has happened in the recent
past
Blood pressure control in the recent past reduces the risks of events today
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What do we change in clinical practice?What do we change in clinical practice?
• Evidence is strongly in favour of intensive treatment for glycaemia early in T2DM
• Evidence suggests that in those with established CVD that a rapid lowering of glycaemia to aggressive targets may cause excess mortality.
• Rosiglitazone needs further evidence for its safety in established T2DM
• Sulphonylureas may be appropriate for preventing microvascular disease (nephropathy)
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With thanks to…23 UKPDS Centres & Investi
Aberdeen John Stowers, LilianBelfast City Randal Hayes Belfast Royal David HaddenBirmingham David Wright Carshalton Steve Hyer, Memo SDerby Ian Peacock Dundee Ray Newton, Roland Exeter Kenneth McLeod, JoHammersmith Anne Dornhorst, EvaIpswich John Day Leicester Felix Burden Manchester Andrew BoultonNorthampton Charles FoxNorwich Richard GreenwoodOxford Robert Turner, Rury Peterborough Jonathan RolandSalford Tim Dornan, Martin GScarborough Phil BrownSt George’s Nigel Oakley, ArshiaStevenage Les BorthwickStoke on Trent John Scarpell, LionelTorbay Richard PaiseyWhittington John Yudkin
1998 EASD Investigator Meeting in Barcelona
…Robert Turnerdied August 1999
…Carole Culldied June 2007
…all 5,102 patients and UKPDS staff
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1997 to 2002
UK Medical Research Council
UK Department of Health
Diabetes UK
British Heart Foundation
National Institutes for Health
2002 to 2007Bristol-Myers Squibb
GlaxoSmithKline
Merck Serono
Novartis
Novo Nordisk
Pfizer
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
MEGA-trials(No cardiovascular outcomes assessable in diabetes without
mega-trials)
Defined (by me) as a randomised interventive trial with outcomes where greater than about 5,000,000 patient days are reported(e.g. 1,000 patients for 3 years…or greater)
AND they need to last longer than 5 yearsAND the glycaemic difference needs to be >0.5%
Hba1c.
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
What do we change in clinical practice (1)?
• Evidence is strongly in favour of intensive treatment for glycaemia early in T2DM
• Evidence suggests that in those with established CVD that a rapid lowering of glycaemia to aggressive targets may cause excess mortality.
• Rosiglitazone needs further evidence for its safety in established T2DM
• Gliclazide MR use may be appropriate for preventing microvascular disease (nephropathy)
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
What do we change in clinical practice (2)?
• Evidence suggests that recent blood pressure control is protective, while a past history of good control is less significant.
• Evidence suggests that MULTIPLE risk-factor intervention is important.– (Steno studies – not reviewed today, but suggest
that a well-delivered package of intervention has beneficial outcome)
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
“You might as well fall flat on your face, as lean over too far backwards”
James Thurber.
Fl. 1945
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
The roller-coaster:trials relating to glycaemia
Ent
husi
asm
Time
UGDP
UKPDS
PROactive(EASD)
PROactive(on reflection)
(NissenMeta analysis)
ADOPT
RECORD
ACCORD
ADVANCE
VADT?
![Page 113: Contribution to clinicians of the last revision of the](https://reader034.vdocuments.mx/reader034/viewer/2022043002/626af791ca6e83601940d3de/html5/thumbnails/113.jpg)
The Oxford Centrefor Diabetes, Endocrinology and Metabolism
The roller-coaster:trials relating to glycaemia
Ent
husi
asm
Time
UGDP
UKPDS
PROactive(EASD)
PROactive(on reflection)
(NissenMeta analysis)
ADOPT
RECORD
ACCORD
ADVANCE
VADT?
![Page 114: Contribution to clinicians of the last revision of the](https://reader034.vdocuments.mx/reader034/viewer/2022043002/626af791ca6e83601940d3de/html5/thumbnails/114.jpg)
The Oxford Centrefor Diabetes, Endocrinology and Metabolism
The roller-coaster:trials relating to glycaemia
Ent
husi
asm
Time
UGDP
UKPDS
PROactive(EASD)
PROactive(on reflection)
(NissenMeta analysis)
ADOPT
RECORD
ACCORD
ADVANCE
VADT?
![Page 115: Contribution to clinicians of the last revision of the](https://reader034.vdocuments.mx/reader034/viewer/2022043002/626af791ca6e83601940d3de/html5/thumbnails/115.jpg)
The Oxford Centrefor Diabetes, Endocrinology and Metabolism
The roller-coaster:trials relating to glycaemia
Ent
husi
asm
Time
UGDP
UKPDS
PROactive(EASD)
PROactive(on reflection)
(NissenMeta analysis)
ADOPT
RECORD
ACCORD
ADVANCE
VADT?
![Page 116: Contribution to clinicians of the last revision of the](https://reader034.vdocuments.mx/reader034/viewer/2022043002/626af791ca6e83601940d3de/html5/thumbnails/116.jpg)
The Oxford Centrefor Diabetes, Endocrinology and Metabolism
The roller-coaster:trials relating to glycaemia
Ent
husi
asm
Time
UGDP
UKPDS
PROactive(EASD)
PROactive(on reflection)
(NissenMeta analysis)
ADOPT
RECORD
ACCORD
ADVANCE
VADT?
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
The roller-coaster:trials relating to glycaemia
Ent
husi
asm
Time
UGDP
UKPDS
PROactive(EASD)
PROactive(on reflection)
(NissenMeta analysis)
ADOPT
RECORD
ACCORD
ADVANCE
VADT?
![Page 118: Contribution to clinicians of the last revision of the](https://reader034.vdocuments.mx/reader034/viewer/2022043002/626af791ca6e83601940d3de/html5/thumbnails/118.jpg)
The Oxford Centrefor Diabetes, Endocrinology and Metabolism
The roller-coaster:trials relating to glycaemia
Ent
husi
asm
Time
UGDP
UKPDS
PROactive(EASD)
PROactive(on reflection)
(NissenMeta analysis)
ADOPT
RECORD
ACCORD
ADVANCE
VADT?
![Page 119: Contribution to clinicians of the last revision of the](https://reader034.vdocuments.mx/reader034/viewer/2022043002/626af791ca6e83601940d3de/html5/thumbnails/119.jpg)
The Oxford Centrefor Diabetes, Endocrinology and Metabolism
The roller-coaster:trials relating to glycaemia
Ent
husi
asm
Time
UGDP
UKPDS
PROactive(EASD)
PROactive(on reflection)
(NissenMeta analysis)
ADOPT
RECORD
ACCORD
ADVANCE
VADT?
![Page 120: Contribution to clinicians of the last revision of the](https://reader034.vdocuments.mx/reader034/viewer/2022043002/626af791ca6e83601940d3de/html5/thumbnails/120.jpg)
The Oxford Centrefor Diabetes, Endocrinology and Metabolism
The roller-coaster:trials relating to glycaemia
Ent
husi
asm
Time
UGDP
UKPDS
PROactive(EASD)
PROactive(on reflection)
(NissenMeta analysis)
ADOPT
RECORD
ACCORD
ADVANCE
VADT?
![Page 121: Contribution to clinicians of the last revision of the](https://reader034.vdocuments.mx/reader034/viewer/2022043002/626af791ca6e83601940d3de/html5/thumbnails/121.jpg)
The Oxford Centrefor Diabetes, Endocrinology and Metabolism
The roller-coaster:trials relating to glycaemia
Ent
husi
asm
Time
UGDP
UKPDS
PROactive(EASD)
PROactive(on reflection)
(NissenMeta analysis)
ADOPT
RECORD
ACCORD
ADVANCE
VADT?
![Page 122: Contribution to clinicians of the last revision of the](https://reader034.vdocuments.mx/reader034/viewer/2022043002/626af791ca6e83601940d3de/html5/thumbnails/122.jpg)
The Oxford Centrefor Diabetes, Endocrinology and Metabolism
The roller-coaster:trials relating to glycaemia
Ent
husi
asm
Time
UGDP
UKPDS
PROactive(EASD)
PROactive(on reflection)
(NissenMeta analysis)
ADOPT
RECORD
ACCORD
ADVANCE
VADT?
UKPDS PTM
![Page 123: Contribution to clinicians of the last revision of the](https://reader034.vdocuments.mx/reader034/viewer/2022043002/626af791ca6e83601940d3de/html5/thumbnails/123.jpg)
The Oxford Centrefor Diabetes, Endocrinology and Metabolism
Some cautions• There will be those who say that
glucose lowering is not cost effective
• There will be those who say that the target of 7.5% is adequate, without saying for whom
• There will be those who say that we should just lower cholesterol and blood pressure
• There will be those who will become famous for saying almost anything, but loudly
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
HbA
1c
Good evidence that glycaemic control is beneficial – UKPDS
and UKPDS-PTM
Fair evidence that aggressive late
glycaemic control is harmful–ACCORD
Fair evidence that slow late
glycaemic control is beneficial–
ADVANCE
•Good evidence for metformin (UKPDS)•Fair evidence for gliclazide and pioglitazone (ADVANCE and ProACTIVE)•Poor evidence for rosiglitazone (ACCORD and RECORD)
Time (years)0 10
6.5%
7.5%
Summary of evidence
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The Oxford Centrefor Diabetes, Endocrinology and Metabolism
If you have been…
…thank you for listening