United Kingdom Prospective Diabetes Study (UKPDS)

1
United Kingdom Prospective Diabetes Study(UKPDS)
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United Kingdom Prospective Diabetes Study
(UKPDS) Index to slides

• 1. Goals
• 2. Overview
• 3. Design
• 4. Conventional management regimen
• 5. Intensive management regimen
• 6. Clinical endpoints
• 7. Therapy progression
• 8. Effects of management on HbA1c
• 9. Effects of management on FPG
• 10. Effects of management on body weight
• 11. Effects of management onmyocardial
  infarction
• 12. Effects of management on microvascular
  endpoints
• 13. Effects of management on hypoglycaemia

14. Risk reduction 15. Quality of life assessment
measures 16. Quality of life 17. Conclusion
s 18. Metformin study Risk reduction 19.
Sulphonylurea inadequacy Overview 20.
Sulphonylurea inadequacy HbA1c 21.
Sulphonylurea inadequacy Summary 22. BP control
study Goals 23. BP control study
Management 24. BP control study Results 25. BP
control study Risk reduction 26. Relationship
between endpoints and HbA1c or BP 27. Implications
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UKPDS Goals

• Primary goal to determine the effect of
  intensive blood glucose control (pharmacological
  management) versus conventional blood glucose
  control (lifestyle changes) on the development of
  macrovascular and microvascular complications in
  Type 2 diabetes
• Secondary goal to determine if a particular
  therapy for glycaemic control (insulin,
  sulphonylureas, or metformin) has any advantages
  or disadvantages

UKPDS Group. Lancet. 1998352837853.
4
UKPDS Overview

• 20-year, multicentre, prospective, randomised,
  intervention trial
• 5102 people with newly diagnosed Type 2 diabetes
• FPG gt6 mmol/l (108 mg/dl)
• Mean follow-up 11 years

UKPDS Group. Lancet. 1998352837853.
5
UKPDS Design
3 month run-in period Diet management
regimen (n5102)
Randomisation (n4209)
Metformin treatment Overweight patients (n342)
Non-overweight and overweight patients (n3867)
Conventional management (n1138)
Intensive management (n2729)
Sulphonylurea treatment (n1573)
Insulin treatment (n1156)
UKPDS Group. Lancet. 1998352837853.
6
UKPDS Conventional management regimen (lifestyle
changes)

• Primary management diet
• Treatment goal
• near-normal body weight
• FPG lt15 mmol/l (270 mg/dl)
• premeal glucose 47 mmol/l (72126 mg/dl insulin
  only)
• Management if hyperglycaemia or hyperglycaemic
  symptoms develop
• nonintensive pharmacological therapy
  (sulphonylurea or insulin metformin if
  overweight)

UKPDS Group. Lancet. 1998352837853.
7
UKPDS Intensive management regimen
(pharmacological management)

• Primary management
• sulphonylurea (500 mg/day chlorpropamide) or 20
  mg/day glibenclamide
• insulin (daily injection with intermediate- or
  long-acting insulin)
• self-monitoring of blood glucose
• Treatment goal
• FPGlt6 mmol/l (108 mg/dl)
• premeal glucose 47 mmol/l (72126 mg/dl insulin
  only)
• Management if hyperglycaemia or hyperglycaemic
  symptoms develop
• sulphonyureas
• add metformin switch to insulin therapy if
  hyperglycaemia recurs
• insulin single bedtime injection
• initiate complex insulin regimen

UKPDS Group. Lancet. 1998352837853.
8
UKPDS Clinical endpoints

• Primary outcome measures 21 clinical endpoints
• Diabetes-related endpoints
• myocardial infarction, heart failure, angina,
  sudden death, stroke, amputation, retinal
  photocoagulation, renal failure, vitreous
  haemorrhage
• Non-diabetes-related endpoints
• death from accident, cancer

UKPDS Group. Lancet. 1998352837853.
9
UKPDS Therapy progression

Conventional Policy (accept lt15 mmol/l)
Intensive Policy (aim for lt6 mmol/l)
100
100
diet alone
additional non-intensive
80
80
pharmacological therapy
60
60
Percentage of patients
intensive
40
40
pharmacological
therapy
diet alone
20
20
0
0
1
2
3
4
5
6
7
8
9
10
11
12
1
2
3
4
5
6
7
8
9
10
11
12
Years from randomisation
UKPDS Group. Lancet. 1998352837853.
10
UKPDS Effects of management on HbA1c
9
Conventional
8
HbA1c ()
Intensive
7
6.2 upper limit of normal range
6
0
0
3
6
9
12
15
Years from randomisation
UKPDS Group. Lancet. 1998352837853.
11
UKPDS Effects of management on fasting plasma
glucose
11.1
Conventional
10.0
8.9
Median FPG (mmol/l)
Intensive
7.8
6.7
5.6
0
0
3
6
9
12
15
Years from randomisation
UKPDS Group. Lancet. 1998352837853.
12
UKPDS Effects of management onbody weight



7.5
Intensive
5.0
Change in body weight (kg)
2.5
Conventional
0.0
-2.5
0
3
6
9
12
15
Years from randomisation
UKPDS Group. Lancet. 1998352837853.
13
UKPDS Effects of management on myocardial
infarction
30
Conventional
20
p0.052
Percentage of patients with event
10
Intensive
0
0
3
6
9
12
15
Years from randomisation
UKPDS Group. Lancet. 1998352837853.
14
UKPDS Effects of management on microvascular
endpoints

30
20
plt0.01
Percentage of patients with event
Conventional
10
Intensive
Intensive
0
0
3
6
9
12
15
Years from randomisation
UKPDS Group. 1998352 Lancet. 837853.
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UKPDS Effects of management on hypoglycaemia
Any episode
Major episodes
50
5
40
4
Intensive
Intensive
30
3
Percentage of patients
20
2
10
1
Conventional
Conventional
0
0
0
3
6
9
12
15
0
3
6
9
12
15
Years from randomisation
UKPDS Group. Lancet. 1998352837853.
16
UKPDS Risk reduction

• Any diabetes-related endpoint 12
• Diabetes-related deaths 10
• Myocardial infarction 16
• Microvascular disease 25
• Retinopathy progression 21
• Cataract extraction 24
• Microalbuminuria 33

Risk reduction ()
At 12 years
UKPDS Group. Lancet. 1998352837853.
17
UKPDS Quality of life assessment measures

• Generic questionnaire (EQ5D)
• evaluates general health status
• Specific questionnaire
• evaluates relative burden of an intensive
  management regimen
• 46 core items
• 4 major dimensions
• work satisfaction
• mood disturbances (Profile of Mood State)
• cognitive failures (Cognitive Failure
  Questionnaire)
• symptoms experienced in the last week
• 5- or 7-point Likert scale
• 1 no impact, no worries, always satisfied
• 5 or 7 always affected, always worried, never
  satisfied

UKPDS Study Group. Diabetes Care
19992211251136.
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UKPDS Quality of life

• Diabetes complications associated with poorer
  quality of life
• Intensive insulin treatment regimen had no effect
  on quality of life

UKPDS Study Group. Diabetes Care
19992211251136.
19
UKPDS Conclusions

• Glycaemic control deteriorated with time
  regardlessof initial choice of therapy
• Pharmacological glycaemic control (intensive
  group) reduced HbA1c by 0.9 over 10 years, with
  a resulting decrease in clinical complications
• No significant reduction in macrovascular events
  with sulphonylureas or insulin therapy
• Pharmacological management was associated with
  significant increase in weight versus lifestyle
  changes

UKPDS Group. Lancet. 1998352837853.
20
UKPDS metformin study in overweight patients
Risk reduction
Risk reduction ()
Metformin intensive
Sulphonylurea/ insulin intensive
Any diabetes-related end-point 32 7 Diabetes-relat
ed deaths 42 20 Myocardial infarction
39 21 Microvascular disease 29 16
Compared with conventional therapy
UKPDS Group. Lancet. 1998352854865.
21
UKPDS sulphonyurea inadequacy Overview

• Primary goal to evaluate the efficacy of the
  addition of insulin when maximal sulphonylurea
  therapy is inadequate in people with Type 2
  diabetes
• People with Type 2 diabetes were randomised to
  receive conventional management or intensive
  management regimen
• Patients randomised to intensive management
  regimen received insulin if FPG lt6 mmol/l (108
  mg/dl)

UKPDS Group. Diabetes Care. 200225330336.
22
UKPDS sulphonyurea inadequacy HbA1c
Conventional
Intensive (insulin alone)
9
Intensive (sulphonylurea insulin)
8
HbA1c ()
7
6
6.2 upper limit of normal range
5
0
0
3
2
4
5
1
6
Years from randomisation
UKPDS Group. Diabetes Care. 200225330336.
23
UKPDS sulphonyurea inadequacy Summary

• HbA1c was significantly lower in the
  sulphonylurea insulin
  intensive management group compared with the
  insulin alone intensive management group
• Weight gain was similar in both intensive
  management groups
• Major hypoglycaemia occurred less frequently in
  the sulphonylurea insulin intensive management
  group compared with the insulin alone intensive
  management group
• Early addition of insulin when maximal
  sulphonylurea therapy is inadequate can
  significantly improve glycaemic control without
  promoting increased hypoglycaemia or weight gain

UKPDS Group. Diabetes Care. 200225330336.
24
UKPDS intensive blood pressure control study
Goals

• To determine if tight blood pressure control
  policy can reduce morbidity and mortality in
  patients with Type 2 diabetes
• To determine if an ACE inhibitor (captopril) or
  beta-blocker (atenolol) is advantageous in
  reducing the risk of development of clinical
  complications
  

UKPDS Group. BMJ. 1998317703713.
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UKPDS intensive blood pressure control study
Management regimens

• 1148 hypertensive patients randomised
• Tight blood pressure control with ACE inhibitor
  (n400) or beta-blocker (n358)
• treatment goal lt150/85 mm Hg
• Less tight blood pressure control without ACE
  inhibitor or beta-blocker (n390)
• treatment goal lt180/105 mm Hg
  

UKPDS Group. BMJ. 1998317703713.
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UKPDS intensive blood pressure control study
Results
Less tight control
160/94 154/87 Tight control
161/94 144/82 Average difference
10/5
Start (mm Hg)
Finish (mm Hg)
Non-compliance of antihyperytensive agents
was 43of total person years in less tight
control group and 6 of total person years in
tight control group
UKPDS Group. BMJ. 1998317703713.
27
UKPDS Risk reduction in the intensive blood
pressure control study
Any
diabetes-related endpoint 24 Diabetes-related
deaths 32 Myocardial infarction
21 Heart failure 56 Stroke 44 Microva
scular disease 37
Risk reduction ()
Tight vs less tight control
UKPDS Group. BMJ. 1998317703713.
28
UKPDS Relationship between endpoints and HbA1c
or BP
80
Rate 95 CI
Microvascular endpoints
Myocardial infarction
60
HbA
1c
Incidence (1000-pt-yr-1)
40
HbA
1c
BP
20
BP
0
5.0
7.0
9.0
11.0
5.0
7.0
9.0
11.0
110
130
150
170
110
130
150
170
HbA
() or systolic BP (mmHg)
HbA
() or systolic BP (mmHg)
1c
1c
Stratton et al. BMJ. 2000321405412.
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UKPDS Implications

• The UKPDS results support the mandate that
  intensive glycaemic control is required to reduce
  the risk of microvascular complications in people
  with Type 2 diabetes
• Macrovascular disease prevention requires
  management of cardiovascular risk factors in
  addition to hyperglycaemia
• No increase in cardiovascular events or death was
  observed and the risk of atherosclerotic events
  should not discourage intensive management
• The benefits of intensive glycaemic control
  outweigh the risk of hypoglycaemia
• Tight blood pressure control reduces
  diabetes-related mortality, heart failure and
  stroke
• The phrase intensive in this study is somewhat
  misleading as it corresponds to usual clinical
  management in many centres