IMPLICATIONS OF UKPDS

1
IMPLICATIONS OF UKPDS

• GSK Advisory Board
• 24 May 2003
• Dr. J. R. Conway

2
Worldwide rates of diabetes mellitus predictions
80 70 60 50 40 30 20 10 0
Prevalence (millions)
Year 1995 2000 2025
North America
Europe
Southeast Asia
World Health Organization. 1997. Canadian
Diabetes Association, 1998 website.
3
2.2 Million Canadians Have Diabetes Mellitus
Frequency of diagnosed and undiagnosed diabetes
and IGT, by age (U.S. data - Harris)
Harris. Diabetes Care 199316642-52.
4
Cardiovascular Disease Risk is Increased 2 to 4
Times
Framingham study diabetes and CAD mortalityat
20-year follow-up
Haffner Am J Cardiol 19998411J-4J.
5
UK Prospective Diabetes Study

• multi-centre
• randomised controlled trial
• of different therapies
• of Type 2 diabetes

6
UK Prospective Diabetes Study
Does an intensive glucose control policy reduce
the risk of complications of diabetes?
7
Blood 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

8
Patient 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

9
Randomisation of Treatment Policies
10
Actual Therapy
11
Any 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

12
Microvascular Endpoints (cumulative)
renal failure or death, vitreous haemorrhage or
photocoagulation 346 of 3867 patients (9)
13
HbA1c
cross-sectional, median values
14
Beta cell function in the UKPDS
100 90 80 70 60 50 40 30 20 10 0
Beta cell function ()
12 10 8 6 4 2 0 2 4 6
Years from diagnosis
Holman RR et al. Diabetes Res Clin Pract
199840(suppl)S21S25
15
WHATS THE PROBLEM

• It used to be easy dietDiaBeta/glyburide
  metformin do as youre told
• We must reach glucose targets -CDA guidelines
  UKPDS Kumamoto
• see you later
• It doesnt work poor control vascular
  complications

16
A BIG ISSUE

• glyburide works-then fails
• metformin works-then fails
• insulin, using standard regimens, works-then
  fails

17
UKPDSTREATMENT FAILURE

• On SU treatment 5/year
• HbA1c increased 0.3/year

18
UKPDS monotherapy failureA1clt0.07 at 9 years

UKPDS JAMA 1999 281 2005
19
COMBINATION THERAPY

• Achieves better blood glucose levels
• Less side-effects than high dose monotherapy
• Delays use of insulin
• Patients more prepared for aggressive therapies
• ? Protects beta-cell function
• M. Riddle Am J Med 2000108(6A) 15S-22S

20
Insulin resistance an underlying problem
Time
Insulin resistance Insulin production Glucose
level
Non- diabetes
Pre- diabetes
Type 2 diabetes
Opara JU, Levine JH, South Med J.
1997901162-1168.
21
Type 2 Diabetes Underlying Defects
Pathophysiology
? Beta-cell function
Insulin resistance
Type 2 diabetes
Other defects ? lipolysis release of NEFA ?
hepatic glucose production
Adapted from Matthaei et al. Endocrine Reviews
200021585-618. Adapted from Frayn. Br J Nutr
200083(suppl 1) S71-S77.
22
Pathophysiology of Type 2 Diabetes
Pathophysiology
Receptor postreceptor defects
Glucose
Insulin resistance
Liver
Increased glucose production
Peripheral Tissues (Muscle and Adipose)
Pancreas
Impaired insulin secretion
Adapted from Saltiel et al. Diabetes 1996
451661-1669.
23
Metabolic syndrome
Insulin resistance
Obesity
Diabetes
Hyper- tension
Dyslipidaemia
Atherosclerosis risk
24
THE ARGUMENT

• Insulin insufficiency
• Insulin resistance

25
Insulin resistance an underlying problem
Time
Insulin resistance Insulin production Glucose
level
Non- diabetes
Pre- diabetes
Type 2 diabetes
Opara JU, Levine JH, South Med J.
1997901162-1168.
26
Treatment stepwise approach

5

Insulin
4

Oral plus insulin
3
Combination oforal medicines
2
One oral medicine
1
Diet exercise

27
Prevalence of Uncontrolled Glucose Levels in an
Alberta Aboriginal and Non-Aboriginal Population
(N2,247)
100
General Population (non-Aboriginal n2015)
Aboriginal (n232)
p lt 0.05
NS
68.2
p 0.017
60.9
59.2
56.9
54.5
50
44.1
of Patients Uncontrolled (HbA1c ? 115 N)
NS
24.8
20.0
0
Diet Only (n506)
Oral Monotherapy (n740)
Dual Oral Therapy(n98)
Insulin (n903)
28
Table 3UNCONTROLLED DIABETES DURATION on
THERAPY

years

plt0.001
p0.009
age
MONO DUAL INSULIN
29
Thiazolidinediones

• Rosiglitazone -Avandia
• Pioglitazone -Actos

30
Peroxisome Proliferator Activated Receptors
(PPAR) are Ligand-Activated Nuclear Receptors
Receptors
Thyroid
Steroid
Orphans
peroxisome proliferator activated receptors
(PPAR)
retinoic acid
ThyroidHormones
SteroidHormones
RAR RXR
?
PPAR?
PPAR?
PPAR?
31
Long-term rosiglitazone monotherapyMean change
in HbA1c
Murphy K et al. Endocrine Society Meeting 2000
Poster 450.
32
Fasting Plasma Glucose
Conway,R Rosiglitazone in Family Practice, CDA
Oct 2002
33
HbA1c over 40 months
Conway,R Rosiglitazone in Family Practice, CDA,
Oct 2002
34
Glycemic parameters by body mass index
(BMI)Rosiglitazone added to metformin
BMI gt 30 kg/m2 Extension study (18 months)
Effect of BMI Double-blind studies (26 weeks)
1
9.5
Patients completing 18 months on metformin RSG
therapy (N 124)
9.0
0.5
8.5
0
Mean Change from Baseline in HbA1C ()
HbA1c ()
8.0
-0.5
7.5
-1
7.0
0.0
-1.5
BMI lt 25
BMI 2530
BMI gt 30
0
3
6
9
12
15
18
Months
MET placebo
MET RSG 4 mg/day
MET RSG 8 mg/day
35
Long-Term Durability of Rosiglitazone as
Monotherapy or in Combination Therapy in Patients
with Type 2 Diabetes

• Gould E, Cobitz, A.
• Presented at 84th Annual
• Meeting of the Endocrine Society, San Francisco,
  CA, June 19-22, 2002
• P1-60

36
Results
Effect Avandia Montherapy on HbA1c Open-label
42-month Completer Analysis
Patients who received Avandia 8 mg qd and 4 mg
bid for at least 42 months during 2 double-blind,
26-week, placebo-controlled trials and their
open label extensions. Completer analysis
limited by potential bias towards responders to
treatment, and small numbers of patients at
various time points.
1. Gould E,et al. Presented at 84th Annual
Meeting of the Endocrine Society, San Francisco,
CA, June 19-22, 2002 P1-60
37
Results
Effect of Avandia Metformin on HbA1c Open-label
30-month Completer Analysis
Patients who received Avandia 4 mg bid plus 2.5
g/day of metformin for at least 30 months during
1 double-blind, 26-week, placebo-controlled
trial and its open label extension. Completer
analysis limited by potential bias towards
responders to treatment, and small numbers of
patients at various time points.
1. Gould E,et al. Presented at 84th Annual
Meeting of the Endocrine Society, San Francisco,
CA, June 19-22, 2002 P1-60
38
Results
Effect of Avandia SU on HbA1c Open-label
30-month Completer Analysis
Patients who received Avandia 2 mg bid plus
glyburide for at least 30 months during 1
double-blind, 26-week, placebo-controlled trial
and its open label extension. Completer analysis
limited by potential bias towards responders to
treatment, and small numbers of patients at
various time points.
1. Gould E,et al. Presented at 84th Annual
Meeting of the Endocrine Society, San Francisco,
CA, June 19-22, 2002 P1-60
39
WHAT HAS CHANGED

• We must treat the Metabolic Syndrome (insulin
  resistance) -glucose levels -blood
  pressure -lipids

40
ORAL AGENTS

• Dose Response

41
Riddle M. Combining sulfonylureas and other oral
agents. Am J of Med. 2000 106(6A)16S-22S.
42
Riddle M. Combining sulfonylureas and other oral
agents. Am J of Med. 2000 106(6A)16S-22S.
43
Beta cell function in the UKPDS
100 90 80 70 60 50 40 30 20 10 0
Beta cell function ()
12 10 8 6 4 2 0 2 4 6
Years from diagnosis
Holman RR et al. Diabetes Res Clin Pract
199840(suppl)S21S25
44
NON-EVIDENCE-BASED THOUGHTS

• Use two agents early-on in treatment
• Consider a glitazone metformin,
  or fast-acting insulin secretor

45
A Peek at the Future

• Fast-acting insulin secretors gliclazide
  MR/repaglinide/nateglinide
• Metformin
• TZD rosiglitazone/pioglitazone
• Statin
• ACE/ARB
• Insulin

46
Insulin Secretion Evidence

• Impaired beta-cell function in 1st degree
  relatives
• Type 2 diabetes can occur without insulin
  resistance but not without impaired insulin
  secretion
• Reduction of obesity normalizes insulin
  resistance but not not impaired insulin secretion

47
Insulin Resistance Evidence

• Population-based study (N888)
• Prevalence of insulin resistance in subjects
  with
• Impaired glucose tolerance 65.9
• Type 2 diabetes 83.9
• Plurimetabolic syndrome 95.2
• Subjects with no metabolic disorder 9.6

Bonora E et al, Diabetes 1998471643-1649