Targeting Glucose Metabolism to Stop Strokes IRIS: Insulin Resistance In Stroke study

Professor Gary Ford Chief Executive Officer, Oxford Academic Health Science Network Consultant Stroke Physician, Oxford University Hospitals Visiting Professor of Clinical Pharmacology, Oxford University UK Stroke Forum, Liverpool 29 November 2016

Insulin Resistance

Consequences: • Hyperinsulinemia • Hyperglycemia • Dyslipidemia • Inflammation • Vascular Smooth Muscle Cell Proliferation • Endothelial Dysfunction

A physiological state in which a normal amount of insulin produces a subnormal cellular response.

Insulin Resistance

• Associated with increased risk for Stroke Myocardial Infarction Diabetes

• Affects > 50% stroke patients without diabetes • Present in almost all patients with Type II

Diabetes

Excess Nutrient Intake Aging Diet Inactivity Genetics

Cellular Stress

Insulin Resistance

Increased Serum Glucose Metabolic Disease

CVD, Diabetes, Cancer

Tissue Inflammation Serum Free Fatty

Acids

JI Odegaard Science 2013;339:172

Insulin Resistance

Hyperglycaemia and Ischaemic Stroke Risk

T. Rundek Arch Neurol 2010;67:1195-1200. Emerg RF Collab Lancet 2010;375:2215. M Hyvarinen Stroke 2009;40:1633. AR Folsom Diab Care 1999;22:1077. EL Thacker Stroke 2011;42:3347

Adjusted RR for Stroke

Pioglitazone • Thiazolidinedione, ligand for

peroxisome proliferator-activated receptors (PPARs). Alters the transcription of genes

• Improves insulin sensitivity through its action at PPAR γ1 and PPAR γ2, and affects lipid metabolism through action at PPAR α

• ↑ glucose uptake and utilisation in peripheral organs, ↓ liver gluconeogenesis ↓ insulin resistance

IRIS – Insulin Resistance after Stroke Research Aims

IRIS – Insulin Resistance after Stroke Study Design

IRIS – Definition of Insulin Resistance

HOMA-IR = Fasting insulin (µU/ml) x Fasting glucose (mmol/L)

22.5

For IRIS, insulin resistance = HOMA-IR > 3.0

Homeostasis Model Assessment of Insulin Resistance

7634 Screened with HOMA Blood Test

3895 Randomized

1948 Pioglitazone 1947 Placebo

2796 (37%) Not Insulin Resistant

1939 Analyzed 1937 Analyzed

9 excluded 10 excluded

4865 (63%) Insulin Resistant

564 Retracted consent 379 Excluded other reasons

Randomisation by Country

USA Australia

Italy

Germany

Canada

UK

Israel

IRIS - Baseline Features

Pioglitazone (N=1939)

Placebo (N=1937)

Age, mean years 63.5 63.5 Male sex 67% 64% Black race 11% 12% Stroke at entry (vs. TIA) 87% 87% NIHSS ≥ 5 5% 4% Atrial Fibrillation 7% 7% Mean BMI, mean kg/m2 29.9 30.0 Event to rand, median d. 81 79

IRIS – Primary Outcome

Months in Trial

Cumulative Event-Free

Survival Probability

IRIS – Time to onset of Diabetes

Pioglitazone (N=1939)

Placebo (N=1937)

% (No.) % (No.) Hazard Ratio

(95% CI) P

Stroke or MI 9.0 (175) 11.8 (228) 0.76

(0.62, 0.93) 0.007 Cumulative

Incidence of Diabetes

Months in Trial

IRIS – Serious Adverse Events

Pioglitazone (N=1939)

Placebo (N=1937)

% (No.) % (No.) Hazard Ratio

(95% CI) P

Stroke or MI 9.0 (175) 11.8 (228) 0.76

(0.62, 0.93) 0.007

IRIS – Other Adverse Events

Pioglitazone (N=1939)

Placebo (N=1937)

% (No.) % (No.) Hazard Ratio

(95% CI) P

Stroke or MI 9.0 (175) 11.8 (228) 0.76

(0.62, 0.93) 0.007

IRIS – Summary of Results

• Among insulin resistant, non-diabetic patients with ischemic stroke or TIA, pioglitazone prevented:

Stroke or MI Absolute Risk Reduction = 2.9% Relative Risk Reduction = 24% Diabetes Absolute Risk Reduction = 3.9% Relative Risk Reduction = 52% • However, bone fracture requiring surgery or

hospitalization was more common with pioglitazone: 5.1% vs. 3.2% over 5 years

IRIS – Implications for Future Research

• Improving insulin resistance with thioglitazones reduced stroke risk

• Key proof of concept study • Trials of other therapies that reduce insulin resistance

should be considered - increased physical activity - obesity - other therapeutic agents

• Measure insulin resistance in future secondary prevention trials of other approaches to refine cardiovascular risk

IRIS – What the Guidelines say

• 2016 National Clinical Guidelines for Stroke • “People with stroke or TIA should not receive pioglitazone

for secondary vascular prevention.” • …..for every 100 patients treated with pioglitazone for about 5 years, 3 fewer

would suffer stroke or MI; 4 fewer would develop diabetes mellitus; 2 more would suffer bone fracture requiring hospitalisation; 18 more would gain >4.5 kg in weight, and 11 more would have new or worsening peripheral oedema. The study did not report quality of life outcomes and more evidence would be required before glitazone treatment can be recommended routinely for patients with insulin resistance. Targeting lifestyle modification, particularly exercise and diet, appears to be a safe and effective approach for reducing insulin resistance and progression to diabetes

IRIS – Implications for Clinical Practice • Consider introduction routine assessment insulin resistance

after TIA and ischaemic stroke • Promote interventions that reduce insulin resistance –

physical activity, weight loss, diet • Overall risk and benefit of pioglitazone therapy unclear. • In stroke survivors who remain insulin resistance – perhaps

pioglitazone should be an option available to informed patients, with registry follow up.

• 28 tab pack - Pioglitazone 30 mg £1.42 i.e. £17 / year

Increasing Physical Activity – Gym Members hip