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DIABETES THE NEW EPIDEMIC 3rd June 2014 Professor Paolo Pozzilli In collaboration with Rocky Strollo and Valentina Greto

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Number of people with diabetes (20-79 years), 2013 IDF Diabetes Atlas, 6th Edition, 2013 Tot: 382,000,000 in 2013 Tot: 471,000,000 in 2035

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Trends in age-standardized diabetes prevalence by regions in MALES (1980-2008) Danaei et al. Lancet 2011 High income regions Europe/North America Central/Eastern EuropeSub-Saharan AfricaOceania Central Asia, North Africa, Middle-East South AsiaEast Asia and SE Asia World Southern America Central/Andean America High income Asia Diabetes Prevalence (%) 20 16 12 8 4 20 16 12 8 4 20 16 12 8 4 1985 1995 2005

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Trends in age-standardized diabetes prevalence by regions in FEMALES (1980-2008) Danaei et al. Lancet 2011 High income regions Europe/North America Central/Eastern EuropeSub-Saharan Africa Oceania Central Asia, North Africa, Middle-East South Asia East Asia and SE Asia World Southern America Central/Andean America High income Asia Diabetes Prevalence (%) 20 16 12 8 4 20 16 12 8 4 20 16 12 8 4 1985 1995 2005

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Overall prevalence of antidiabetic drug use in children and adolescents by age on IMS, 1998-2005 inclusive girls boys and overall Hsia Y et al., British Journal of Clinical Pharmacology, 2008 Increased prevalence of diabetes in children and adolescents Results from prescription data from a UK general practice database

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Prevalence of insulin, oral antidiabetic and oral antidiabetic drugs with a diabetes indication amongst children and adolescents aged 0-18 (with 95% CIs), insulin oral antidiabetic drugs oral antidiabetic drugs with diabetes indication ; * a significant trend for increasing use (p< 0.001). * * * Increasing use of antidiabetic drugs among children and adolescents Hsia Y et al., British Journal of Clinical Pharmacology, 2008

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Type 1 diabetes (15%) It is caused by an autoimmune reaction, where the bodys defence system attacks the insulin- producing beta cells in the pancreas. The body can no longer produce the insulin that it needs. Type 2 diabetes (85%) It is the most common type of diabetes. It usually occurs in adults, but it is increasingly seen in children and adolescents. The body is able to produce insulin but either this is not sufficient or the body is unable to respond to its effects.

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Projections of the number of individuals aged

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Projections of the number of individuals aged

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Prevalence of type 2 diabetes in urban and rural areas in the Arabic-speaking countries, 2011 Badran M and Laher I, International Journal of Endocrinology, 2012

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Type 2 diabetes prevalence in South Africa, 2009 Betram MY et al., Global Health Action 2013

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Prevalence of type 2 diabetes in Asian countries in 2013 data source: http://www.idf.org/diabetesatlas/data-visualisations Abdullah N et al., International Journal of Endocrinology, 2014

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Worldwide prevalence of obesity Source: World Health Organization (WHO), 2012

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Obesity prevalence is high in developing countries Prevalence of obesity in Arabian countries in adult males and females aged between 15 and 100 years, WHO estimates, 2010. Badran M et al., Journal of Obesity, 2011

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Obesity prevalence in adults (Italy), 2011 Valle dAosta 8,3% Piemonte 9.1% Umbria 11.2% Liguria 8.3% Toscana 8.7% Lazio 9.2% Calabria 11.4% Lombardia 8.9% Trentino 7.5% Friuli-V.G. 11.8% Basilicata 13.1% Puglia 12.6% Abruzzo 8.7% E.Romagna 12.0% Molise 13.5% Campania 10.9% Sardegna 10.2% Marche 9.6% Veneto 9.9% Sicilia 9.8% Source: ISTAT 2013

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Percentage of US adults who were obese or diagnosed with diabetes Centre for Disease Control and Prevention: National Diabetes Surveillance System http://apps.nccf.cdc.gov/DDTSTRS/default.aspx. Accessed March 2013 Diabetes Obesity (BMI 30 KG/m 2 )

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Obesity prevalence remains high altough no significant changes between 2003-2012 9120 participants in the 2011-2012 nationally representative National Health and Nutrition Examination Survey Ogden et al. JAMA 2014 Childhood obesity (2-19 years) Adult obesity (>20 years)

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the prevention window

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Natural history of type 2 diabetes Progression of disease Impaired Glucose Tolerance Insulin level Insulin resistance Hepatic glucose production Diabetes Diagnosis Post-prandial glucose Fasting glucose -cell function Frank Diabetes 47 years

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Combined impaired fasting glucose (IFG) + impaired glucose tolerance (IGT) confers the highest risk of diabetes progression Metanalysis of total risk of pre-diabetes and diabetes progression, based on 21 cohort studies and 9 RCT (follow-up: 1-17 years) Gerstein HC et al. Diabetes Research and Clinical Practice 2007 Isolated IGT Isolated IFG Relative Risk (95% CI)

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Prediabetes increases the risk for cardiovascular events and death DECODE study group. Lancet 1999 Relative risk of death is linear by 2h-PG DECODE study

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Pathophysiological defects in type 2 diabetes -Cell dysfunction Insulin resistance Kahn CR et al. Joslins Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005 Increased glucose production by liver

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Loss of first phase insulin secretion in type 2 diabetes Polonsky KS et al. N Engl J Med, 1988 time 0 200 400 600 800 6.0010.0014.0018.0022.002.006.00 breakfastlunchdinner normal Type 2 diabetes Insulin secretion (pmol/min)

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- cell mass: decline over diabetes continuum Holman RR et al. Diabetes Res Clin Pract 1998 100 80 60 40 P < 0.0001 Timing to diagnosis (years) Beta cell function (%) 20 0 10987654321123456 0 1 2 Insulin resistance The United Kingdom Prospective Diabetes Study (UKPDS) -cell function Insulin resistance HOMA model, diet-treated n = 376

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Obese Lean -cell mass (%) -50% -63% - cell mass is already impaired at the diagnosis of type 2 diabetes Butler AE et al. Diabetes 2003; Leslie RD e Pozzilli P, J Clin Endocrinol Metab 2006 Type 2 diabetes

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Oral hypoglycemic agents targeting the pathophysiologic defects in type 2 diabetes Glucose absorption Hepatic glucose overproduction Impaired insulin secretion Insulin resistance Pancreas Glucose level Muscle and fat Liver Metformin TZDs DPP-4 inhibitors GLP1 analogues Sulfonylureas Meglitinides DPP-4 inhibitors GLP1 analogues TZDs Metformin -Glucosidase inhibitors Metformin Gut

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Lifestyle intervention can prevent type 2 diabetes development TrialnPopulation Follow-up (years) Interventions RR (95% CI) Da Qing 577 IGT (China) 6 1. Diet 2. Exercise 3. Diet & Exercise 0.66 (0.53-0.81) 0.56 (0.44-0.70) 0.49 (0.33-0.73) DPS 522 IGT overweight (Finland) 3.2 Diet & Exercise 0.42 (0.3-0.7) DPP3,234 IGT (USA) 2 1. Diet & Exercise 2. Metformin 0.42 (0.34-0.52) 0.69 (0.57-0.83) IDPP531 IGT (India) 2.5 1. Diet & Exercise 2. Metformin 3. Metformin + Diet & Exercise 0.72 (0.62-0.80) 0.74 (0.65-0.81) 0.72 (0.62-0.80) DPS, Finnish Diabetes Prevention Study; DPP, Diabetes Prevention Program; IDPP, Indian Diabetes Prevention Program

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Placebo (n=1082) Metformin (n=1073, p

The STOP-NIDDM: Acarbose Acarbose reduced risk of new Hypertension >140/90; 5.3% absolute risk reduction (P=0.006) Myocardial infarction (P=0.02) Any CVD event: CHD, CV death or stroke, CHF, PVD (P=0.03) Acarbose 100 mg TID n=682 Placebo n=686 25% Relative Risk Reduction P=0.0022 Chiasson JL, et al. Lancet. 2002;359(9323): 2072-2077; Chiasson JL, et al. JAMA. 2003;290(4):486-494.

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ACT NOW: Pioglitazone Pioglitazone reduced risk of type 2 diabetes by 72% vs. placebo (HR 0.28; 95% CI 0.160.49 P