IMPLICATIONS OF UKPDS GSK Advisory Board 24 May 2003 Dr. J. R. Conway.

IMPLICATIONS OF UKPDS

GSK Advisory Board

24 May 2003

Dr. J. R. Conway

Worldwide rates of diabetes mellitus: predictions

Worldwide rates of diabetes mellitus: predictions80

70

60

50

40

30

20

10

0

Prevalence (millions)

North America

Europe Southeast

Asia

Year199520002025

World Health Organization. 1997.Canadian Diabetes Association, 1998 website.

Frequency of diagnosed and undiagnosed diabetes and IGT, by age (U.S. data - Harris)

2.2 Million Canadians Have Diabetes Mellitus

0

5

10

15

20

25

30

35

40

20-34 35-44 45-54 55-64 65-74

% ofpopulation

IGTUndiagnosed diabetesDiagnosed diabetes

Harris. Diabetes Care 1993;16:642-52.

Haffner Am J Cardiol 1999;84:11J-4J.

Framingham study: diabetes and CAD mortalityat 20-year follow-up

Cardiovascular Disease Risk is Increased 2 to 4 Times

17.4

8.5

17.0

3.602468

101214161820

Annual CAD Deaths per 1,000

Persons

Men Women

Diabetics Nondiabetics

UK Prospective Diabetes Study

multi-centre

randomised controlled trial

of different therapies

of Type 2 diabetes

Does an intensive glucose Does an intensive glucose control policy reduce the risk of control policy reduce the risk of

complications of diabetes?complications of diabetes?

UK Prospective Diabetes StudyUK Prospective Diabetes Study

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

Patient Characteristics5102 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%

Randomisation of Treatment Policies

342 allocated to

metformin

Conventional Policy30% (n=1138)

Intensive Policy70% (n=2729)

Sulphonylurean=1573

Insulinn=1156

Main Randomisationn=4209 (82%)

3867

Actual 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

atie

nts

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

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

Microvascular Endpoints (cumulative)Microvascular Endpoints (cumulative)

p=0.0099

0%

10%

20%

30%

0 3 6 9 12 15

% o

f pat

ient

s w

ith a

n ev

ent


Intensive

Conventional

Risk reduction 25%(95% CI: 7 % to 40%)

renal failure or death, vitreous haemorrhage or photocoagulation346 of 3867 patients (9%)

HbA1c cross-sectional, median values

06

7

8

9

0 3 6 9 12 15

HbA

1c (%

)


Conventional

Intensive

6.2% upper limit of normal range

Beta cell function in the UKPDS

Years from diagnosis

Bet

a ce

ll f

un

ctio

n (

%)

100

90

80

70

60

50

40

30

20

10

0–12 –10 –8 –6 –4 –2 0 2 4 6

Holman RR et al. Diabetes Res Clin Pract 1998;40(suppl):S21–S25

WHAT’S THE PROBLEM

• It used to be easydiet+DiaBeta/glyburidemetformin

do as you’re told• We must reach glucose targets

-CDA guidelines; UKPDS; Kumamotosee you later

•It doesn’t workpoor controlvascular complications

A BIG ISSUE

•glyburide works-then fails

•metformin works-then fails

•insulin, using standard regimens, works-then fails

UKPDSTREATMENT FAILURE

• On SU treatment: 5%/year

• HbA1c increased 0.3%/year

UKPDS monotherapy failureA1c<0.07 at 9 years

0

5

10

15

20

25

30

35

40

45

50

dietSUmetformininsulin

%

UKPDS JAMA 1999 281 2005

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 2000;108(6A) 15S-22S

Insulin resistance: an underlying problem

Insulin resistance

Insulin production

Glucose level

Time

Non-diabetes

Pre-diabetes

Type 2diabete

sOpara JU, Levine JH, South Med J. 1997;90:1162-1168.

Type 2 Diabetes: Underlying Defects

Type 2 diabetes

Beta-cell functionInsulin resistance

Other defects:

lipolysisrelease of NEFA

hepatic glucose production

Adapted from Matthaei et al. Endocrine Reviews 2000;21:585-618.Adapted from Frayn. Br J Nutr 2000;83(suppl 1): S71-S77.

Pathophysiology

Pathophysiology of Type 2 Diabetes

Adapted from Saltiel et al. Diabetes 1996; 45:1661-1669.

Liver

PancreasPeripheral Tissues

(Muscle and Adipose)

Increased glucoseproduction

Glucose

Impaired insulinsecretion

Receptor + postreceptor defects

Insulinresistance

Pathophysiology

Metabolic syndrome

Obesity

Atherosclerosisrisk

Insulinresistance

Diabetes

DyslipidaemiaDyslipidaemia

Hyper-tension

THE ARGUMENT

• Insulin insufficiency

• Insulin resistance

Insulin resistance: an underlying problem

Insulin resistance

Insulin production

Glucose level

Time

Non-diabetes

Pre-diabetes

Type 2diabete

sOpara JU, Levine JH, South Med J. 1997;90:1162-1168.

Treatment: stepwise approach

1

2

3

4

5

Combination oforal medicines

Oral plus insulin

Insulin

One oral medicine

Diet &exercise

+

++

% of Patients Uncontrolled (HbA1c % of Patients Uncontrolled (HbA1c 115% N) 115% N)

Diet OnlyDiet Only(n=506) (n=506)

Oral Monotherapy Oral Monotherapy (n=740)(n=740)

Dual OralDual OralTherapy(n=98)Therapy(n=98)

InsulinInsulin(n=903)(n=903)

00

50%50%

100%100%General Population (non-Aboriginal; n=2015)General Population (non-Aboriginal; n=2015)

Aboriginal (n=232)

NSNS

p = 0.017p = 0.017p < 0.05p < 0.05

NSNS60.9%

54.5%

44.1%

59.2% 56.9%

68.2%

24.8%20.0%

Prevalence of Uncontrolled Glucose Levels in an Alberta Prevalence of Uncontrolled Glucose Levels in an Alberta Aboriginal and Non-Aboriginal Population (N=2,247)Aboriginal and Non-Aboriginal Population (N=2,247)

Table 3:UNCONTROLLED DIABETES

DURATION on THERAPY

0

1

2

3

4

5

6

7

8

9

<65 >65 <65 >65 <65 >65

NON-ABORIGINALABORIGINAL

yearsyears*

* p<0.001* p<0.001

MONO DUAL INSULINMONO DUAL INSULIN

**

** p=0.009** p=0.009

age

Thiazolidinediones:

• Rosiglitazone -Avandia

• Pioglitazone -Actos

Peroxisome Proliferator Activated Receptors (PPAR) are

Ligand-Activated Nuclear Receptors

ThyroidHormones

SteroidHormones

Thyroid Steroid

RAR RXR

Receptors Orphans

retinoic acid

PPAR PPAR PPAR

peroxisome proliferator activated receptors (PPAR)

Murphy K et al. Endocrine Society Meeting 2000; Poster 450.

Long-term rosiglitazone monotherapy:Mean change in HbA1c

Long-term rosiglitazone monotherapy:Mean change in HbA1c

Fasting Plasma GlucoseAvandia - Fasting Blood Glucose

8.67.6 7.37.7 7.4 7.0 7.4 7.1

7.26.8

0

5

10

15

20

25

0 1 2 3 4 5 6 7 8 9

Quarter

mm

ol/L

Avg Of FBS Power (Avg Of FBS)

Conway,R; Rosiglitazone in Family Practice, CDA Oct 2002

HbA1c over 40 monthsRosiglitazone - Glycosylated Hemoglobin

0.0810.074 0.072 0.070 0.072 0.071 0.071 0.069

0.074 0.072

0

0.02

0.04

0.06

0.08

0.1

0.12

0.14

0.16

0 1 2 3 4 5 6 7 8 9

Quarter

Avg Of HGBA1C Power (Avg Of HGBA1C)

Conway,R; Rosiglitazone in Family Practice, CDA, Oct 2002

-1.5

-1

-0.5

0

0.5

1

Mea

n C

han

ge

fro

m B

asel

ine

in H

bA

1C (

%)

BMI < 25 BMI 25–30 BMI > 30

Months

BMI > 30 kg/m2: Extension study (18 months)BMI > 30 kg/m2: Extension study (18 months)

Glycemic parameters by body mass index (BMI):Rosiglitazone added to metformin

Glycemic parameters by body mass index (BMI):Rosiglitazone added to metformin

MET + placebo

MET + RSG 4 mg/day

MET + RSG 8 mg/day

Hb

A1c

(%

)

Effect of BMI: Double-blind studies (26 weeks)Effect of BMI: Double-blind studies (26 weeks)

0 3 6 9 12 15 180.0

7.0

7.5

8.0

8.5

9.0

9.5

Patients completing 18 months on metformin + RSG therapy (N = 124)

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

ResultsEffect 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

ResultsEffect of Avandia+ Metformin on HbA1c


*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

ResultsEffect of Avandia + SU on HbA1c


*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

WHAT HAS CHANGED

• We must treat the Metabolic Syndrome (insulin resistance)

-glucose levels-blood pressure

-lipids

ORAL AGENTS

Dose Response

Riddle M. Combining sulfonylureas and other oral agents. Am J of Med. 2000; 106(6A):16S-22S.

Beta cell function in the UKPDS

Years from diagnosis

Bet

a ce

ll f

un

ctio

n (

%)

100

90

80

70

60

50

40

30

20

10

0–12 –10 –8 –6 –4 –2 0 2 4 6

Holman RR et al. Diabetes Res Clin Pract 1998;40(suppl):S21–S25

NON-EVIDENCE-BASED THOUGHTS

• Use two agents early-on in treatment

• Consider a ‘glitazone’ +metformin, or

fast-acting insulin secretor

A Peek at the Future

• Fast-acting insulin secretors:gliclazide MR/repaglinide/nateglinide

• Metformin

• TZDrosiglitazone/pioglitazone

• Statin

• ACE/ARB

• Insulin

IMPLICATIONS OF UKPDS GSK Advisory Board 24 May 2003 Dr. J. R. Conway.

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