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

Transcription

1 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

2 Insulin Resistance A physiological state in which a normal amount of insulin produces a subnormal cellular response. Consequences: Hyperinsulinemia Hyperglycemia Dyslipidemia Inflammation Vascular Smooth Muscle Cell Proliferation Endothelial Dysfunction

3 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

4 Insulin Resistance Aging Diet Excess Nutrient Intake Inactivity Genetics Serum Free Fatty Acids Cellular Stress Insulin Resistance Increased Serum Glucose Metabolic Disease Tissue Inflammation CVD, Diabetes, Cancer JI Odegaard Science 2013;339:172

5 Hyperglycaemia and Ischaemic Stroke Risk Adjusted RR for Stroke T. Rundek Arch Neurol 2010;67: 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

6 Pioglitazone Thiazolidinedione, ligand for peroxisome proliferatoractivated 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

7 IRIS Insulin Resistance after Stroke Research Aims

8 IRIS Insulin Resistance after Stroke Study Design

9 IRIS Definition of Insulin Resistance Homeostasis Model Assessment of Insulin Resistance HOMA-IR = Fasting insulin (µu/ml) x Fasting glucose (mmol/l) 22.5 For IRIS, insulin resistance = HOMA-IR > 3.0

10 7634 Screened with HOMA Blood Test 4865 (63%) Insulin Resistant 3895 Randomized 2796 (37%) Not Insulin Resistant 564 Retracted consent 379 Excluded other reasons 1948 Pioglitazone 1947 Placebo 9 excluded 10 excluded 1939 Analyzed 1937 Analyzed

11 Randomisation by Country Canada UK Israel USA Germany Australia Italy

12 IRIS - Baseline Features Pioglitazone (N=1939) Placebo (N=1937) Age, mean years 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/m Event to rand, median d

13 IRIS Primary Outcome Cumulative Event-Free Survival Probability Months in Trial

14 IRIS Time to onset of Diabetes Cumulative Incidence of Diabetes Pioglitazone (N=1939) Placebo (N=1937) % (No.) % (No.) Stroke or MI 9.0 (175) 11.8 (228) Hazard Ratio (95% CI) P 0.76 (0.62, 0.93) Months in Trial

15 IRIS Serious Adverse Events Pioglitazone (N=1939) Placebo (N=1937) % (No.) % (No.) Stroke or MI 9.0 (175) 11.8 (228) Hazard Ratio (95% CI) P 0.76 (0.62, 0.93) 0.007

16 IRIS Other Adverse Events Pioglitazone (N=1939) Placebo (N=1937) % (No.) % (No.) Stroke or MI 9.0 (175) 11.8 (228) Hazard Ratio (95% CI) P 0.76 (0.62, 0.93) 0.007

17 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

18 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

19 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

20 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

21 Increasing Physical Activity Gym Members hip