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

Worldwide rates of diabetes mellitus: predictions Prevalence (millions) North America EuropeSoutheas t Asia Year World Health Organization 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 Harris. Diabetes Care 1993;16:

Haffner Am J Cardiol 1999;84:11J-4J. Framingham study: diabetes and CAD mortality at 20-year follow-up Cardiovascular Disease Risk is Increased 2 to 4 Times

UK Prospective Diabetes Study multi-centre randomised controlled trial of different therapies of Type 2 diabetes

Does an intensive glucose control policy reduce the risk of complications of diabetes? UK 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 Characteristics 5102 newly diagnosed Type 2 diabetic patients age years mean 53 y gendermale : female59 : 41% ethnic group Caucasian82% Asian 10% Afro-caribbean8% Body Mass Index mean 28 kg/m 2 fasting plasma glucose (fpg) median 11.5 mmol/L HbA 1c median 9.1 % hypertensive39%

Randomisation of Treatment Policies 342 allocated to metformin Conventional Policy 30% (n=1138) Intensive Policy 70% (n=2729) Sulphonylurea n=1573 Insulin n=1156 Main Randomisation n=4209 (82%) 3867

Actual Therapy

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

Microvascular Endpoints (cumulative) renal failure or death, vitreous haemorrhage or photocoagulation 346 of 3867 patients (9%)

HbA 1c cross-sectional, median values

Beta cell function in the UKPDS Years from diagnosis Beta cell function (%) –12–10–8–6–4–20246 Holman RR et al. Diabetes Res Clin Pract 1998;40(suppl):S21–S25

WHAT’S THE PROBLEM It used to be easy diet+DiaBeta/glyburide metformin do as you’re told We must reach glucose targets -CDA guidelines; UKPDS; Kumamoto see you later It doesn’t work poor control vascular complications

A BIG ISSUE glyburide works-then fails metformin works-then fails insulin, using standard regimens, works-then fails

UKPDS TREATMENT FAILURE On SU treatment: 5%/year HbA1c increased 0.3%/year

UKPDS monotherapy failure A1c<0.07 at 9 years % UKPDS JAMA

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 2 diabetes Opara JU, Levine JH, South Med J. 1997;90:

Type 2 Diabetes: Underlying Defects Type 2 diabetes  Beta-cell function Insulin resistance Other defects:  lipolysis release of NEFA  hepatic glucose production Adapted from Matthaei et al. Endocrine Reviews 2000;21: 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: Liver Pancreas Peripheral Tissues (Muscle and Adipose) Increased glucose production Glucose Impaired insulin secretion Receptor + postreceptor defects Insulin resistance Pathophysiology

Metabolic syndrome Obesity Atherosclerosis risk Insulin resistance Diabetes Dyslipidaemia 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 2 diabetes Opara JU, Levine JH, South Med J. 1997;90:

Treatment: stepwise approach Combination of oral medicines Oral plus insulin Insulin One oral medicine Diet & exercise + + +

% of Patients Uncontrolled (HbA1c  115% N) Diet Only (n=506) Oral Monotherapy (n=740) Dual Oral Therapy(n=98)Insulin(n=903) 0 50% 100% General Population (non-Aboriginal; n=2015) Aboriginal (n=232) NS p = p < 0.05 NS 60.9% 54.5% 44.1% 59.2% 56.9% 68.2% 24.8% 20.0% Prevalence of Uncontrolled Glucose Levels in an Alberta Aboriginal and Non-Aboriginal Population (N=2,247)

Table 3: UNCONTROLLED DIABETES DURATION on THERAPY years * * p<0.001 MONO DUAL INSULIN ** ** p=0.009 age

Thiazolidinediones: Rosiglitazone-Avandia Pioglitazone-Actos

Peroxisome Proliferator Activated Receptors (PPAR) are Ligand-Activated Nuclear Receptors Thyroid Hormones Steroid Hormones ThyroidSteroid 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 HbA 1c

Fasting Plasma Glucose Conway,R; Rosiglitazone in Family Practice, CDA Oct 2002

HbA1c over 40 months Conway,R; Rosiglitazone in Family Practice, CDA, Oct 2002

Mean Change from Baseline in HbA 1C (%) BMI < 25BMI 25–30BMI > 30 Months BMI > 30 kg/m 2 : Extension study (18 months) Glycemic parameters by body mass index (BMI): Rosiglitazone added to metformin MET + placebo MET + RSG 4 mg/day MET + RSG 8 mg/day HbA 1c (%) Effect of BMI: Double-blind studies (26 weeks) 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

Results Effect Avandia Montherapy on HbA 1c 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

Results Effect of Avandia+ Metformin on HbA 1c 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

Results Effect of Avandia + SU on HbA 1c 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

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 Beta cell function (%) –12–10–8–6–4–20246 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 TZD rosiglitazone/pioglitazone Statin ACE/ARB Insulin

Insulin Secretion Evidence Impaired beta-cell function in 1 st 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

Insulin Resistance Evidence Population-based study (N=888) Prevalence of insulin resistance in subjects with: – Impaired glucose tolerance65.9% – Type 2 diabetes83.9% – Plurimetabolic syndrome95.2% – Subjects with no metabolic disorder 9.6% Bonora E et al, Diabetes 1998;47: