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אתגר הטיפול בסוכרת מסוג 2. מעל 50% מהחולים אינם מגיעים ליעדי האיזון HbA1c>7%. Ford et al (NHANES). Diabetes Care. 2008; 31: 102–4. רוב הטיפולים הקיימים גורמים לעלייה במשקל לאורך זמן. UKPDS: u p to 8 kg in 12 years. ADOPT: up to 4.8 kg in 5 years. 100. 8. Treatment difference (95% CI)
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אתגר הטיפול בסוכרת מסוג 2 מעל 50% מהחולים אינם מגיעים ליעדי האיזון HbA1c>7% Ford et al (NHANES). Diabetes Care. 2008; 31: 102–4
רוב הטיפולים הקיימים גורמים לעלייה במשקל לאורך זמן UKPDS: up to 8 kg in 12 years ADOPT: up to 4.8 kg in 5 years 100 8 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 Insulin (n=409) 7 6 96 5 Glibenclamide (n=277) Change in weight (kg) 4 Weight (kg) 92 3 2 88 1 Metformin (n=342) 0 0 3 6 9 12 0 0 1 2 3 4 5 Years from randomisation Years 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)** Conventional treatment (n=411); diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/L UKPDS 34. Lancet 1998:352:854–65. n=at baseline; Kahn et al (ADOPT). NEJM 2006;355(23):2427–43
Current treatments increase risk of hypoglycaemia 45 20 39 40 35 p<0.05 glibenclamide vs. rosiglitazone 30 25 Patients with hypoglycaemia** (%) 10 20 15 12 10 5 10 5 0 0 Rosiglitazone Metformin Glargine NPH Glibenclamide 15 Hypoglycaemia, events/patient/year* *All symptomatic hypoglycaemic events ** Patients self-reporting (unconfirmed) hypoglycaemia Riddle et al. Diabetes Care 2003;26:3080; Kahn et al (ADOPT). NEJM 2006;355:2427–43
הטיפול הקיים אינו מצליח לעצור את הידרדרות הסוכרת Conventional* Rosiglitazone Glibenclamide Metformin UKPDS ADOPT Metformin Glibenclamide Insulin 9 Rosiglitazone vs Metformin–0.13 (–0.22 to –0.05), p=0.002 Rosiglitazone vs Glibenclamide–0.42 (–0.50 to –0.33), p<0.001 8.0 8.5 8 7.5 7.5 Median HbA1c (%) 7.0 7 Recommended treatment target <7.0%† 6.5 6.5 6 6.0 6.2% – upper limit of normal range 0 1 2 3 4 5 0 2 4 6 8 10 Time (years) Years from randomisation *Diet initially then sulphonylureas, insulin and/or metformin if FPG>15 mmol/L †ADA clinical practice recommendations. UKPDS 34, n=1704 UKPDS 34. Lancet 1998:352:854–65; Kahn et al (ADOPT). NEJM 2006;355(23):2427–43
3 3 3 6 6 6 9 9 9 הטיפול הקיים אינו מצליח לעצור את העלייה בלחץ דם והתמותה ממחלות הלב 10-year age-adjusted mortality from CHD according to blood glucose at baseline 12 WC AC IA 10 Males 8 20 Females 6 Δ systolic blood pressure (mmHg) 4 2 % mortality (CHD) 10 0 -2 -4 Years of diabetes 2437 2196 1962 257 239 220 246 238 221 Control (no diabetes) Borderline diabetes Diabetes Patient numbers Mean (bars) and 99% CIs (vertical lines) for cross-sectional changes; WC, white Caucasian; AC, Afro-Caribbean; IA, Asian of Indian origin Davis et al. Diabetes Care 2001;24:1167–74; Jarrett et al. Diabetologia 1982;22(2):79–84.
ההורמון הטבעי 1 GLP – בעל השפעה ישירה על מנגנונים פיזיולוגיים רבים בגוף האדם Liver Hepatic glucose output Pancreas Brain Insulin secretion (glucose-dependent) and beta-cell sensitivity Energy intake* Insulin synthesis Glucagon secretion (glucose-dependent) GI tract Decreasedmotility Beta-cell mass* *in animal studies
Liraglutide is a once-daily, human GLP-1 analogue Liraglutide C-16 fatty acid(palmitoyl) 7 9 His Ala Glu Gly Thr Phe Thr Ser Asp Enzymatic degradation by DPP-4 Val Ser Glu Ser Lys Ala Ala Gln Gly Glu Leu Tyr 7 9 Glu 36 Phe His Ala Glu Gly Thr Phe Thr Ser Asp Arg Ile Ala Trp Val Gly Arg Leu Gly Val Ser 97% amino acid homology to human GLP-1; Improved PK: albumin binding through acylation; heptamer formation Ser Lys Ala Ala Gln Gly Glu Leu Tyr Glu 36 Phe Lys Ile Ala Trp Leu Val Gly Arg Gly • Slow absorption from subcutis • Resistant to DPP-4 • Long plasma half-life (T½=13 h) T½=1.5–2.1 min Native human GLP-1 Knudsen et al. J Med Chem 2000;43:1664–9; Degn et al. Diabetes 2004;53:1187–94
GLP1 בעל השפעה מובהקת ומשמעותית בהורדת משקל 2 • 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 1 0 Change in body weight (kg) -1 -2 -3 Liraglutide 1.2 mg + metformin* Liraglutide 1.8 mg + metformin* Glimepiride + metformin -4 *p≤0.01 vs glimepiride + metformin Nauck et al. Diabetes 2008; 57 (Suppl. 1): Abstract 504-P
