Applying for EU FP7 research funding David J Stott David Cargill Professor of Geriatric Medicine

Summer 2010

Sabbatical, Leiden; Jan-March 2011

TRUST Multi-modal effects of Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism; a randomised placebo-controlled Trial THEME [HEALTH.2011.2.2.2-1] Investigator-driven clinical trials for therapeutic interventions in elderly populations

Definition – subclinical hypothyroidism Few / no symptoms or signs of thyroid dysfunction TSH > 4.5 IU/L Serum free thyroxine (fT4) within the reference range Excludes patients on T4 hormone treatment Consensus conference Surks, JAMA 2004;291:228

Prevalence of elevated TSH by age and gender Canaris et al , The Colorado Thyroid Disease Prevalence Study, Arch Intern Med 2000;160:526-534

Brain Heart Vascular system Bone Muscle Executive function Verbal memory Heart Cardiac output Atrial fibrillation Vascular system Cholesterol Bone Muscle

Subclinical Hypothyroidism and Coronary Heart Disease Mortality Systematic review and meta-analysis Prospective cohort studies 55,287 subjects, 6.2% subclinical hypothyroidism HRs for CHD mortality TSH 4.5-6.9 mIU/L, HR 1.09 (95% CI, 0.91-1.30) TSH 7.0-9.9 mIU/L, HR 1.42 (95% CI, 1.03-1.95) TSH 10.0-19.9 mIU/L, HR 1.58 (95% CI, 1.10-2.27) P=0.005 for trend Similar results for CHD events No association total mortality Rodondi et al, JAMA. 2010;304:1365-1374

Hypothyroidism in the Leiden 85+ study No association with poor health status disability, depression, cognitive impairment Increased TSH and lower fT4 associated with lower mortality HR 0.77 (95% CI 0.63-0.94; P=0.009) per SD increase of TSH HR 1.16 (95% CI, 1.04-1.30; P=0.009) per SD increase of fT4 Gussekloo et al, JAMA, 2004;292:2591

Thyroid hormone replacement for subclinical hypothyroidism Cochrane Database of Systematic Reviews 12 controlled trials, 6-14 months duration, 350 patients Levo-thyroxine replacement versus placebo / no treatment No data on (cardiovascular) mortality or morbidity No significant improvement in symptoms, mood, QOL Inconsistent effects on cognitive function Probable reduction in total cholesterol Improved LV diastolic function (echo) Only 4 studies reported adverse events with no statistically significant differences between groups Villar et al, CDSR, 2009

Balancing act – benefits and risks

Acknowledgements Funders EU FP7 Wellcome Trust CSO Scottish Executive Collaborators Ian Ford Naveed Sattar Gordon Lowe Michele Robertson Ann Rumley Paul Welsh Christopher J Packard James Shepherd Stuart Cobbe Stella Trompet Rudi Westendorp Anton de Craen J Wouter Jukema Brendan Buckley Patricia Kearney Nicolas Rodondi Funders EU FP7 Wellcome Trust CSO Scottish Executive Bristol-Myers Squibb Chest Heart and Stroke Scotland