1. Improving Patient Outcomes: Insights From Recent Clinical Trials in Diabetes

2. Diabetes and CVD: Time To Act! “With the rising tide of diabetes around the globe, the double jeopardy of diabetes and cardiovascular disease is set to result in an explosion of these and other complications— unless preventive action is taken.” Prof Sir George Alberti, IDF President International Diabetes Federation 2001 International Diabetes Federation 2001 http://www.idf.org/webdata/docs/CVD_ExecSum.pdf. Accessed May 25, 2004.

3. Impact of Type 2 Diabetes on Macrovascular Disease Largest cause of morbidity and mortality Risk of CVD increased 2- to 4-fold Higher case fatality vs. non diabetic individuals Reduced survival post–MI, post–CABG, and particularly post–PTCA Risk of stroke and peripheral vascular disease substantially increased Betteridge DJ. Acta Diabetol. 1999;36:S25-S29. Nesto R. Acta Diabetol. 2001;38:S3-S8.

4. Atherosclerosis in Type 2 Diabetes The Black Box Diabetic dyslipidemia Procoagulant state Insulin resistance/ hyperinsulinemia Glycation and advanced glycation of proteins “Glycoxidation” and oxidation Hormone-, growth factor-, and cytokine-enhanced SMC proliferation and foam cell formation Bierman E. Arterioscler Thromb.1992;12:647-656.

5. Type 2 Diabetes Is a Vascular Disease Hyperglycemia is just 1 risk factor among many for CVD Intensive blood glucose control can reduce microvascular, but not macrovascular, complications of diabetes CVD risk reduction should involve appropriate management of all major modifiable risk factors De Backer G, et al. Eur Heart J. 2003;24:1601-1610. Holman R. Acta Diabetol. 2001;38:S9-S14.

6. UKPDS: Benefits of Tight BP Control in Type 2 Diabetes Population: 1148 patients, mean age 56 y; mean BP at entry, 160/94 mm Hg Treatment: Tight control (aim < 150/85) vs less tight (aim < 180/105); captopril vs atenolol regimen; mean BP during follow-up 144/82 vs 154/87 mm Hg (P < 0.0001) RRR: 24% diabetes-related end points 32% diabetes-related deaths 37% microvascular end points Stroke P = 0.013 Years from randomization Patients with events (%) 0912475 0 10 20 863 Less tight control Tight control RRR = 44% (95% CI,11-65%) Adapted from UKPDS Group. BMJ. 1998;317:703-713.

7. UKPDS: Strong Association Between SBP and Microvascular End Points and MI Incidence of microvascular end points and MI by updated mean SBP Adjusted for age, sex, and ethnic group Expressed for white men, 50-54 y at baseline and with mean diabetes duration of 10 y MI Microvascular end points Updated mean SBP (mm Hg) Adjusted incidence per 1000 patient-years (%) 110170120130150160140 0 50 40 30 20 10 Adapted from Adler AI, et al. BMJ. 2000;321:412-419.

8. Diabetic Dyslipidemia Compared with nondiabetic individuals, patients with diabetic dyslipidemia may have: Elevated plasma triglyceride levels Decreased plasma HDL-C levels Relatively normal plasma LDL-C levels Relatively high proportion of small, dense LDL-C American Diabetes Association. Diabetes Care. 2004;27:S68-S71.

9. UKPDS: Risk Factors for CAD in Type 2 Diabetes  LDL-C  HDL-C  TGs  HbA 1c  SBP  Fasting plasma glucose Smoking status Turner RC, et al. BMJ. 1998;316:823-828.

10. CHD Prevention Trials With Statins in Patients With Diabetes: Subgroup Analyses CHD risk reductionCHD risk reduction StudyDrugNondiabeticsDiabetics Primary Prevention HPS 1† Simvastatin 25%*26% Secondary Prevention CARE 2†† Pravastatin23%25% 4S 3‡ Simvastatin32%55% 4S reanalysis 4‡‡ Simvastatin32%42% HPS 1† Simvastatin 24%*12% NS CHD end points: † HPS = first major vascular event; †† CARE = absolute risk of coronary events; ‡ 4S = major CHD events; ‡‡ 4S reanalysis = major coronary events. Cohorts:*HPS = risk reduction for the entire cohort (nondiabetics and patients with diabetes). Footnote:NS = results not statistically significant. 1. HPS Collaborative Group. Lancet. 2002;360:7-22. 2. Goldberg RB, Mellies MJ, Sacks FM, et al. Circulation. 1998;98:2513-2519. 3. Pyörälä K, Pedersen TR, Kjekshus J, et al. Diabetes Care. 1997;20:614-620. 4. Haffner SM, Alexander CM, Cook TJ, et al. Arch Intern Med. 1999;159:2661-2667.

11. Greek Atorvastatin and CHD Evaluation (GREACE) Study Population: 1600 CHD patients (344 women) Design: Randomized, open, 3-year study, atorvastatin (10-80 mg) vs usual care Atorvastatin titrated to achieve NCEP goal of LDL <2.6 mmol/L (< 100 mg/dL); mean dose, 24 mg/d Usual care group 14% lipid-lowering drugs Lipid changes: LDL-C  46%; non–HDL-C  44%; TGs  31% HDL-C  7% (absolute LDL-C  2.1 mmol/L [81 mg/dL]) Primary end points: Death, nonfatal MI, unstable angina, CHF, stroke, and revascularization Athyros VG, et al. Curr Med Res Opin. 2002;18:220-228.

12. GREACE: Risk Reduction With Atorvastatin in Diabetic Cohort Risk reduction in composite primary end point: Atorvastatin Usual care All patients Diabetes 0.42 0.49 n = 313 (20%) n = 1297 P < 0.0001 0 Athyros VG, et al. Curr Med Res Opin. 2002;18:220-228.

13. Min 4 y Atorvastatin 10 mg 2838 Patients d/b PBO CARDS: Collaborative AtoRvastatin Diabetes Study Patient Population Type 2 diabetics Type 2 diabetics (40-75 y) No prior MI or CVD No prior MI or CVD Other risk factors + Other risk factors + Lipid profile: Lipid profile:  LDL-C  4.14 mmol/L (160 mg/dL)  TGs  6.78 mmol/L (600 mg/dL) Collaboration in the UK with Diabetes UK, NHS R&D, and Pfizer Collaboration in the UK with Diabetes UK, NHS R&D, and Pfizer Primary End Point Time to major CV event Time to major CV event (CHD death, nonfatal MI, (CHD death, nonfatal MI, revascularization, CABG, stroke) revascularization, CABG, stroke) Colhoun HM, et al. Diabet Med. 2002;19:201-211.

14. CARDS Inclusion Criteria Type 2 DM (WHO criteria) for at least 6 months prior to screening Age 40-75 y No history of CVD LDL-C  4.14 mmol/L (160 mg/dL) TGs  6.78 mmol/L (600 mg/dL) At least 1 other risk factor : –Hypertension (history of BP, or SBP  140 or DBP  90 mm Hg –Retinopathy –Micro-(albumin/creatinine ratio  2.5 mg/mmol/L) or macroalbuminuria (  25 mg/mmol/L) –Current smoker (all patients were counselled to quit) Colhoun HM, et al. Diabet Med. 2002;19:201-211.

15. CARDS Patient Baseline Characteristics 1350 (94.5%)1326 (94.0%)White ethnicity 28.7 (3.6)28.8 (3.5)BMI kg/m 2 (SD) 515 (36.1%)537 (38.1%)Obese (BMI > 30 kg/m 2 ) 456 (31.9%)453 (32.1%)Women 167 (11.7%)173 (12.3%) > 70 703 (49.2%)708 (50.2%) 60-70 558 (39.1%)529 (37.5%) < 60 Mean age (years) Atorvastatin n (%) Placebo n (%) 61.8 61.5 http://www.cardstrial.org/healthcare/slideresources.asp. Accessed June 8, 2004.

16. CARDS Patient Baseline Characteristics Smoking 498 (34.9%)485 (34.4%) Current 622 (43.6%)601 (42.7%) Ex-smoker 308 (21.6%)323 (22.9%) Never 956 (67)940 (67) On BP drug BP 83 (8.5)83 (8.4) DBP (mm Hg) 144 (15.9)144 (16.1) SBP (mm Hg) Atorvastatin Mean (SD) or n (%) Placebo Mean (SD) or n (%) http://www.cardstrial.org/healthcare/slideresources.asp. Accessed June 8, 2004.

17. CARDS Patient Baseline Lipids* 1.3 (1.2-1.6) 52 (45-60) 1.4 (1.2-1.6) 53 (46-61) HDL-C (mmol/L) (mg/dL) 3.1 (2.6-3.6) 119 (100-138) 3.1 (2.6-3.6) 118 (100-137) LDL-C (mmol/L) (mg/dL) 5.4 (4.8-5.9) 207 (186-228) 5.4 (4.8-5.9) 207 (185-229) Total cholesterol (mmol/L) (mg/dL) Atorvastatin Median (IQR) Placebo Median (IQR) *Subject to final verification. http://www.cardstrial.org/healthcare/slideresources.asp. Accessed June 8, 2004.

18. CARDS: Stopped Early Due to Significant Benefit of Atorvastatin Treatment In June 2003, the independent Steering Committee stopped the trial after only 2 years because the magnitude of benefit for the primary end point exceeded the prespecified stopping rule Preliminary results of the CARDS trial showed a significant reduction in MI, stroke, and other coronary events in patients treated with atorvastatin CARDS became the second atorvastatin trial to end early because of observed treatment benefit (ASCOT- LLA was the first)

19. AHA Prevention Conference VI Diabetes and Vascular Disease Goals of Therapy GlycemiaHbA 1c < 7% (ADA) BP< 130/85 (JNC VI) < 130/80 (ADA) LDL-C< 2.6 mmol/L (100 mg/dL) (NCEP) HDL-C < 1 mmol/L (< 40 mg/dL)Raise HDL (no goal) TGs 2.2-5.6 mmol/L (200-499 mg/dL)Non–HDL-C < 3.4 mmol/L (130 mg/dL) BMI > 25 kg/m 2 Lose 10% body wt (OEI) Physical activityExercise (ADA) CigarettesStop Prothrombotic stateLow-dose aspirin (ADA) Grundy SM, et al. Circulation. 2002;105:2231-2239.

20. Trends in Risk Factor Control NHANESNHANES (1988-1994)(1999-2000) HbA 1c < 7%44%37% BP < 130/80 mm Hg29%35.8% TC < 2.3 mmol/L (200 mg/dL)33.9%48.2% HbA 1c < 7% and BP < 130/80 mm Hg and TC < 2.3 mmol/L (200 mg/dL)5.2%7.3% Saydah SH, et al. JAMA. 2004;291:335-342.

21. LIPITOR (atorvastatin calcium) is indicated as an adjunct to diet to reduce elevated total cholesterol, LDL-cholesterol, apo B, and TG levels and to increase HDL-cholesterol in patients with primary hypercholesterolemia (heterozygous familial) or combined hyperlipidemia. In clinical trials, the most common adverse events were constipation, flatulence, dyspepsia and abdominal pain, headache, nausea, myalgia, asthenia, diarrhea, insomnia. LIPITOR is contraindicated in patients with hypersensitivity to any component of this medication; in patients with active liver disease or unexplained persistent elevation of serum transaminases; myopathy; in women during pregnancy, in nursing mothers, and in women of child-bearing potential not using appropriate contraceptive measures. Liver function tests should be performed before the initiation of treatment, at 6 and 12 weeks after initiation of therapy or elevation in dose, and periodically thereafter. LIPITOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. LIPITOR therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.

22. 0 ניאופרם בע"מ בית ניאופרם, רח' השילוח 8, ת.ד. 7063 פתח תקוה 49170, טל-9373737 03, פקס.9373716 03, E- mail:Neopharm@Neopharmisrael.com LIPITOR is available in 10-mg, 20-mg, 40-mg, and 80-mg film- coated tablets, administered once daily. For further information please see prescribing information. Lip06FE05