1. אתגר הטיפול בסוכרת מסוג 2 מעל 50% מהחולים אינם מגיעים ליעדי האיזון HbA1c>7% Ford et al (NHANES). Diabetes Care. 2008; 31: 102–4 Slide No 1

2. UKPDS 34. Lancet 1998:352:854–65. n=at baseline; Kahn et al (ADOPT). NEJM 2006;355(23):2427–43 רוב הטיפולים הקיימים גורמים לעלייה במשקל לאורך זמן רוב הטיפולים הקיימים גורמים לעלייה במשקל לאורך זמן Glibenclamide (n=277) Years from randomisation Insulin (n=409) Metformin (n=342) Conventional treatment (n=411); diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/L UKPDS: up to 8 kg in 12 yearsADOPT: up to 4.8 kg in 5 years Weight (kg) Annualised slope (95% CI) Rosiglitazone, 0.7 (0.6 to 0.8) Metformin, -0.3 (-0.4 to -0.2)** Glibenclamide, -0.2 (-0.3 to 0.0)** Change in weight (kg) 0 1 5 036912 8 7 6 4 3 2 Years 012345 96 92 88 0 100 Treatment difference (95% CI) Rosiglitazone vs. metformin 6.9 (6.3 tp 7.4); p<0.001 Rosiglitazone vs. glibenclamide, 2.5 (2.0 to 3.1); p<0.001 Slide No 2

3. Current treatments increase risk of hypoglycaemia p<0.05 glibenclamide vs. rosiglitazone Patients with hypoglycaemia** (%) 10 39 0 5 10 15 20 25 30 35 40 45 RosiglitazoneMetformin Glibenclamide 12 Hypoglycaemia, events/patient/year* 0 5 10 20 GlargineNPH *All symptomatic hypoglycaemic events 15 ** Patients self-reporting (unconfirmed) hypoglycaemia Riddle et al. Diabetes Care 2003;26:3080; Kahn et al (ADOPT). NEJM 2006;355:2427–43

4. 6.2% – upper limit of normal range Median HbA 1c (%) Conventional* Glibenclamide Metformin Insulin UKPDS 6 7 8 9 Years from randomisation 2468100 7.5 8.5 6.5 Recommended treatment target <7.0% † הטיפול הקיים אינו מצליח לעצור את הידרדרות הסוכרת UKPDS 34. Lancet 1998:352:854–65; Kahn et al (ADOPT). NEJM 2006;355(23):2427–43 Slide No 4 *Diet initially then sulphonylureas, insulin and/or metformin if FPG>15 mmol/L †ADA clinical practice recommendations. UKPDS 34, n=1704

5. Control (no diabetes) Patient numbers % mortality (CHD) 10-year age-adjusted mortality from CHD according to blood glucose at baseline Borderline diabetes Diabetes 10 20 Males Females AC IA Δ systolic blood pressure (mmHg) 243721961962257239220246238221 Years of diabetes 369369369 WC 12 10 8 6 4 2 0 -2 -4 הטיפול הקיים אינו מצליח לעצור את העלייה בלחץ דם והתמותה ממחלות הלב Davis et al. Diabetes Care 2001;24:1167–74; Jarrett et al. Diabetologia 1982;22(2):79–84. Slide No 5 Mean (bars) and 99% CIs (vertical lines) for cross-sectional changes; WC, white Caucasian; AC, Afro-Caribbean; IA, Asian of Indian origin

6. ההורמון הטבעי 1 GLP – בעל השפעה ישירה על מנגנונים פיזיולוגיים רבים בגוף האדם Brain Insulin secretion (glucose-dependent) and beta-cell sensitivity Glucagon secretion (glucose-dependent) Insulin synthesis Beta-cell mass* Pancreas Liver Hepatic glucose output Energy intake* GI tract Decreased motility *in animal studies

7. Liraglutide is a once-daily, human GLP-1 analogue 7 36 9 Lys HisAlaThr Ser PheGluGly Asp Val Ser TyrLeuGluGlyAla GlnLys Phe Glu IleAlaTrp LeuGly ValGlyArg Native human GLP-1 T ½ =1.5–2.1 min Enzymatic degradation by DPP-4 Slow absorption from subcutis Resistant to DPP-4 Long plasma half-life (T ½ =13 h) 97% amino acid homology to human GLP-1; Improved PK: albumin binding through acylation; heptamer formation C-16 fatty acid (palmitoyl) HisAlaThr Ser PheGluGly Asp Val Ser TyrLeuGluGlyAla GlnLys Phe Glu IleAlaTrp LeuGly ValGlyArg Glu Arg 7 9 36 Liraglutide Knudsen et al. J Med Chem 2000;43:1664–9; Degn et al. Diabetes 2004;53:1187–94

8. GLP1 בעל השפעה מובהקת ומשמעותית בהורדת משקל Glimepiride + metformin Liraglutide 1.8 mg + metformin* 2 1 0 -2 -3 -4 Change in body weight (kg) Liraglutide 1.2 mg + metformin* *p≤0.01 vs glimepiride + metformin Waist circumference was reduced from baseline by 2.7 cm (1.06 inches) with liraglutide (p<0.0001) Waist circumference increased by 0.3 cm (0.12 inches) with glimepiride Slide No 8 Nauck et al. Diabetes 2008; 57 (Suppl. 1): Abstract 504-P