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Update on Lipids and what’s new with CV risk in Type 2 Diabetes

Daniel Weiss MD CDE FACP Endocrinology/Metabolism Your Diabetes Endocrine Nutrition Group, LLC Mentor Clinical Assistant Professor of Medicine, CWRU. Update on Lipids and what’s new with CV risk in Type 2 Diabetes. A new study to assess cardiovascular outcomes in Type 2 Diabetes: ACCORD

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Update on Lipids and what’s new with CV risk in Type 2 Diabetes

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  1. Daniel Weiss MD CDE FACP Endocrinology/Metabolism Your Diabetes Endocrine Nutrition Group, LLC Mentor Clinical Assistant Professor of Medicine, CWRU Update on Lipids andwhat’s new with CV risk in Type 2 Diabetes

  2. A new study to assess cardiovascular outcomes in Type 2 Diabetes: ACCORD The Heart Protection Study A new look at statin treatment How effective is our current therapy Crestor the most studied statin prior to FDA approval Outline

  3. Increased thrombogenicity Abnormal platelet function and abnormal coagulation Dyslipidemia Hypertension Impaired endothelial and vascular smooth muscle function Increased reactive oxygen species H2O2, O2-, OH- Tobacco use Hyperglycemia Beckman et al JAMA ( May) 2002; 287: 2570- 81. Factors that may promote macrovascular disease in diabetes

  4. ACCORD trial: Glycemia Hypothesis In middle-aged or older people with type 2 diabetes at high risk for a CVD event: Does a therapeutic strategy that targets HbA1c < 6.0% reduce the rate of CV events more than a strategy that targets HbA1c 7.0% to 7.9% (with expectation of a median of 7.5%)?

  5. ACCORD: Action to Control Cardiovascular Risk in Type 2 Diabetes • ACCORD: HbA1c < 6% vs. 7.0 to 7.9% • Systolic blood pressure of < 140 vs <120 • Simvastatin with or without fenofibrate • Patients age 40 or older if have event; others 55 or older • Study Medications provided free • Planned minimum 5 years • Multicenter (US and Canada) with multiple sites in the greater Cleveland area

  6. Potential patients can call 800-320-2833 ACCORD trial

  7. Increased thrombogenicity Abnormal platelet function and abnormal coagulation Dyslipidemia Hypertension Impaired endothelial and vascular smooth muscle function Increased reactive oxygen species H2O2, O2-, OH- Tobacco use Hyperglycemia Beckman et al JAMA ( May) 2002; 287: 2570- 81. Factors that may promote macrovascular disease in diabetes

  8. 318 men patients with CAD and LDL-C > 130 randomized to open label, treat-to-target study over 54 weeks Titrated every 12 weeks until LDL goal of 105 mg/dl reached. Mean LDL-C of 173 at baseline Conducted in 1997 when maximum fluvastatin and simvastatin doses were 40 mg Brown AS et al J Am Coll Cardiol 1998; 32: 665 Do Patients with CAD Easily Reach LDL Goals with Statin Therapy Alone?

  9. CHD Patients Often Do Not Achieve NCEP Goal with Monotherapy Brown et al. (1998) J Am Coll Cardiol32:665-672

  10. Clinical Pharmacology of Rosuvastatin

  11. Molecular Structure of Rosuvastatin Statin Pharmacophore Methane-Sulfonamide Group O (3R, 5S) H O O O H F CH3 CH3 N N H3C N CH3 S O O Adapted with permission from McTaggart F, et al. Am J Cardiol. 2001;87(suppl):28B-32B. [illus. Page 29B]

  12. Pharmacokinetics of Rosuvastatin • Absorption/Distribution • Hepatoselective and relatively hydrophilic • The absolute bioavailability of rosuvastatin is approximately 20% • Rapidly absorbed (peak plasma concentration reached in 3-5 hours) • Cmax and AUC increase in proportion to dose • Significant LDL-C reduction is seen with or without food, regardless of the time of day • Highly protein bound (88% - mostly albumin; reversible, independent of plasma levels) CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.

  13. Pharmacokinetics of Rosuvastatin • Metabolism • >90% of HMG-CoA reductase inhibitory activity occurs via the parent compound, rosuvastatin1 • The major metabolite, N-desmethyl rosuvastatin is formed primarily by cytochrome P450 (CYP450) isoenzyme 2C92 • N-desmethyl rosuvastatin has ~1/6 to ½ the HMG-CoA reductase inhibitory activity of rosuvastatin1 • Rosuvastatin is not extensively metabolized1 • Rosuvastatin had no significant inhibitory effect on CYP450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 in human hepatic tissue in vitro studies2 1. CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003. 2. McCormick AD, et al. J Clin Pharmacol. 2000;40:1055. Abstract 46.

  14. Pharmacokinetics of Rosuvastatin • Excretion • Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%) • Elimination half-life is approximately 19 hours • After IV dose, total body clearance 28% via renal and 72% via hepatic routes CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.

  15. Pharmacokinetic Profile of Selected Statins • Pravastatin Rosuvastatin Atorvastatin Simvastatin CYP450 3A4 Metabolism No Yes Yes No Clinically Significant Metabolites No Yes Yes No Dual renal / hepatic Primarily hepatic Duel renal / hepatic Duel renal / hepatic Plasma Clearance Relatively Hydrophilic Yes No No Yes Hepatoselective Yes Yes Yes Yes Bioavailability 20% 14% <5% 17% Elimination Half-life* (hours) 19 14 1.9 77 *Elimination T1/2 of drug and metabolites, if any. CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003. Atorvastatin Calcium Prescribing Information 2002,Pfizer Inc, NY, NY; Simvastatin Prescribing Information, Merck & Co., Inc., Whitehouse Station, NJ; Pravastatin Prescribing Information 2003, Bristol-Meyers Squibb Company, Princeton, NJ

  16. Rosuvastatin Drug Interaction Studies DigoxinNo change in digoxin level FenofibrateNo significant change in rosuvastatin or fenofibrate levels GemfibrozilClinically significant increase in rosuvastatin level;90 and 120% increase AUC and Cmax Antacid (aluminum/magnesium hydroxide combination)54% decrease in rosuvastatin level when coadministered; no clinically significant change when given 2 hours after rosuvastatin Oral contraceptivesEthinyl estradiol level increased 26%; norgestrel level increased 34% KetoconazoleNo change in rosuvastatin level ErythromycinSmall decrease in rosuvastatin level; not clinically significant Itraconazole39% increase in rosuvastatin AUC; not clinically significant Fluconazole14% increase in rosuvastatin AUC; not clinically significant CyclosporineNo significant change in cyclosporine concentration; clinically significant 11- and 7-fold increase in rosuvastatin Cmax and AUC WarfarinNo change in warfarin; clinically significant increase in INR CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.

  17. Clinical Pharmacology of RosuvastatinSpecial Populations • Race • A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic, and Black or Afro-Caribbean groups • Pharmacokinetic studies show an approximate 2-fold elevation in median exposure (AUC) in Japanese subjects residing in Japan and in Chinese subjects residing in Singapore when compared with Caucasians residing in North America and Europe • No studies directly examining Asian ethnic populations residing in the U.S. are available, so the contribution of environmental and genetic factors to the observed increases in rosuvastatin drug levels have not been determined CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.

  18. Clinical Pharmacology of RosuvastatinSpecial Populations • Gender • There were no differences in plasma concentrations of rosuvastatin between men and women • Geriatric • There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age 65 years) • Pediatric • In a pharmacokinetic study, 18 patients (9 boys and 9 girls) 10 to 17 years of age with homozygous FH received single and multiple oral doses of rosuvastatin. Both Cmax and AUC of rosuvastatin were similar to values observed in adult subjects administered the same doses CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.

  19. Clinical Pharmacology of RosuvastatinSpecial Populations • Renal Insufficiency • Mild to moderate renal impairment (creatinine clearance ≥30 mL/min/1.73m2) had no influence on plasma concentrations of rosuvastatin when oral doses of 20 mg rosuvastatin were administered for 14 days. However, plasma concentrations of rosuvastatin increased to a clinically significant extent (about 3-fold) in patients with severe renal impairment (CLcr <30 mL/min/1.73m2) compared with healthy subjects (CLcr >80 mL/min/1.73m2) • Hemodialysis • Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.

  20. Clinical Pharmacology of RosuvastatinSpecial Populations • Hepatic Insufficiency • In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased. In patients with Child-Pugh A disease, Cmax and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child Pugh B disease, Cmax and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.

  21. Rosuvastatin Clinical Trial Program

  22. Clinical Trial Program for Rosuvastatin: Overview2-7 • Worldwide comprehensive program of 10,2751 patients, more than any other statin at their time of FDA approval • Types of trials: • Efficacy across the dose range • Comparator • Combination therapy • Outcomes program under way 1. CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003 2. New Drug Application for Lipitor (four-month safety update) 3. New Drug Application for Baycol (conclusion with regards to safety) 4. New Drug Application for Lescol (exposure) 5. New Drug Application for Mevacor (safety report and analysis) 6. New Drug Application for Zocor (simvastatin safety update II) 7. New Drug Application for Pravachol (medical officer’s review and evaluation of NDA report

  23. Rosuvastatin Dose-Ranging Program A multicenter, double-blind, placebo-controlled dose-ranging study to assess the lipid-regulating effects of rosuvastatin in patients with primary hypercholesterolemia

  24. Rosuvastatin Dose-Ranging Program RSV 1, 2.5, 5,10, 20, or 40 mg vs placebo (n=111) Study Design Randomized, double-blind, 6-week, phase II trial • Men (18–70 y) and women (50–70 y, postmenopausal) • Fasting: LDL-C >160 and <240 mg/dL; TG <300 mg/dL • Baseline mean LDL-C: 191 mg/dL 6-week dietary lead-in, then patients were randomized to 6 weeks of active treatment • Primary outcome: percentage change from baseline in LDL-C at 6 weeks End Points RSV, rosuvastatin; The dose range for rosuvastatin is 5 to 40 mg once daily Data on file, (Study 8, DA-CRS-05) AstraZeneca Pharmaceuticals LP, Wilmington, DE.

  25. Rosuvastatin Dose-Ranging ProgramDose-Response Relationship 0 –10 –20 –30 –40 –50 –60 –70 Percent Change in LDL-C at 6 Weeks n=13 n=17 n=17 n=17 n=18 –7 Mean Percent Change From Baseline in LDL-C –45* –52* –55* –63* 5 mg Placebo 10 mg 20 mg 40 mg Observed data in ITT population. *P<.001 vs placebo Data on file, (Study 8, DA-CRS-05) AstraZeneca Pharmaceuticals LP, Wilmington, DE.

  26. Rosuvastatin Dose-Ranging Program Dose-Response Relationship 2 4 6 8 –52 –63 Therapeutic Response Seen Within 1 Week Week 0 10 0 –7 –10 –20 Mean Percent Change From Baseline in LDL-C Placebo Rosuvastatin 10 mg Rosuvastatin 40 mg –30 –40 –50 –60 –70 Observed data in ITT population. Data on file, (Study 8, DA-CRS-05) AstraZeneca Pharmaceuticals LP, Wilmington, DE.

  27. Rosuvastatin Dose-Ranging Program • Conclusions • Rosuvastatin produced marked dose-related decreases in LDL-C, with reductions of 45% to 63% across the dose range of 5 to 40 mg • Rapid onset of action with a therapeutic response seen within 1 week 1. Data on file, (Study 8, DA-CRS-05) AstraZeneca Pharmaceuticals LP, Wilmington, DE. 2. CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003

  28. Rosuvastatin NDA Phase III Trials Overview

  29. Rosuvastatin NDA Phase III Trials:Overview • Types of trials: • Efficacy and safety across the dose range • Comparator: • Atorvastatin, simvastatin, pravastatin • Combination therapy: • Niacin, fenofibrate, cholestyramine, HRT HRT, hormone replacement therapy.

  30. Rosuvastatin NDA Phase III Trials:Inclusion Criteria • Inclusion Criteria: • No upper age limit defined • Creatinine cutoff of 2.5 mg/dL at entry in most trials* • Women of childbearing potential were included provided they were not pregnant and were using appropriate contraception • Adequately controlled hypertension; for diabetics, diabetes under adequate glycemic control (hemoglobin A1c <9%) • Patient Populations Included • Established atherosclerosis • Postmenopausal women • Homozygous FH† and Heterozygous FH • Hypertriglyceridemia • Diabetics *Except for those that evaluated combination therapy with extended-release niacin or fenofibrate †Familial hypercholesterolemia

  31. Tendon xanthomas

  32. STELLAR • 6 week randomized, 15-arm trial directly comparing efficacy of rosuvastatin vs select statins in more than 2240 patients with Type IIa/IIb dyslipidemia Rosuvastatin 10-40 mg Atorvastatin 10-80 mg Simvastatin 10-80 mg Pravastatin 10-40 mg Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:152-160.

  33. STELLAR  Dose-Range Comparison of Rosuvastatin vs. Other Statins Rosuvastatin (n=480) Atorvastatin (n=641) Simvastatin (n=655) 10 mg 10 mg 20 mg 20 mg 40 mg 40 mg 80 mg 80 mg 10 mg 20 mg 40 mg 10 mg 20 mg 40 mg Study Design After a 6-week dietary lead-in, 2240 patients were randomized to the following arms to receive 6 weeks active treatment: Pravastatin (n=492) Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:152-160.

  34. Demographics and Baseline Lipids Gender Male Mean Female 58 231 249 187-194 50-51 179-183 58 321 320 189-190 50-51 174-181 58 322 333 187-190 50-51 172-182 57 248 244 187-190 49-50 179-187 Age (years) Mean baseline lipids (mg/dL) LDL-C HDL-C TG Rosuvastatin Atorvastatin Simvastatin Pravastatin Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:152-160.

  35. STELLAR Atorvastatin (mg) 10 20 40 10 20 40 Simvastatin (mg) Pravastatin (mg) 10 20 40 Comparisons of interest: • Rosuvastatin 10 mg vs: • Rosuvastatin 20 mg vs: Atorvastatin (mg) 20 40 80 Simvastatin (mg) 20 40 80 Pravastatin (mg) 20 40 - • Rosuvastatin 40 mg vs: Atorvastatin (mg) 40 80 - Simvastatin (mg) 40 80 - Pravastatin (mg) 40 - - Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:152-160.

  36. STELLAR Efficacy Results

  37. Percentage Change From Baseline in LDL-C at Week 6 by Dose (ITT)1,2 0 –10 Pravastatin –20 Simvastatin –30 –40 –50 –60 Dose 10 mg 20 mg 40 mg 80 mg Rosuvastatin Atorvastatin Mean Percent Change From Baseline in LDL-C (SE) * ** † • *P<.002 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg • **P<.002 vs atorvastatin 20 mg, 40 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg • † P<.002 vs atorvastatin 40 mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg • Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93: 152-160. • Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE.

  38. Percentage Change in LDL-C: Pairwise Comparisons with Rosuvastatin 10 mg 20 40 0 –10 –20 –30 –40 –50 –60 Rosuvastatin (mg) Atorvastatin (mg) Simvastatin (mg) Pravastatin (mg) 20 40 20 40 10 10 10 10 Mean Percent Change From Baseline in LDL-C (SE) -20.1 -24.4 -28.3 -29.7 -35.0 -36.8 -38.8 -42.6 -45.8 * -47.8 *P<.002 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg 1. Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:152-160. 2. Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE.

  39. Percentage Change in LDL-C: Pairwise Comparison of Rosuvastatin 20 mg and 40 mg 20 40 20 40 80 20 40 0 20 40 80 –10 –20 –30 –40 –50 –60 –52.4 * –55.0 ** Rosuvastatin (mg) Atorvastatin (mg) Simvastatin (mg) Pravastatin (mg) Mean Percent Change From Baseline in LDL-C (SE) -24.4 -29.7 -35.0 -38.8 -42.6 –45.8 -47.8 –51.1 *P<.002 vs atorvastatin 20 mg, 40 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg ** P<.002 vs atorvastatin 40 mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg 1. Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93: 152-160. 2. Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE.

  40. Percentage Change From Baseline in HDL-C at Week 6 by Dose (ITT) † 9.6 ** 9.5 * 7.7 12 6.8 10 6.0 5.7 5.6 5.3 5.2 4.8 4.4 4.4 8 3.2 6 2.1 4 2 0 Mean Percent Change From Baseline in HDL-C 10 20 40 10 20 40 80 10 20 40 80 10 20 40 Atorvastatin (mg) Simvastatin (mg) Pravastatin (mg) Rosuvastatin (mg) *P<.002 vs pravastatin 10 mg **P<.002 vs atorvastatin 20 mg, 40 mg, 80 mg; simvastatin 40 mg; pravastatin 20 mg, 40 mg † P<.002 vs atorvastatin 40 mg, 80 mg; simvastatin 40 mg; pravastatin 40 mg Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:152-160.

  41. Percentage Change From Baseline in Triglycerides at Week 6 by Dose (ITT) 10 20 40 10 20 40 80 10 20 40 0 10 20 40 80 -5 -10 -11.9 -14.8 -15 -17.6 -18.2 -19.8 * -20 -20 -22.6 -23.7 ** -25 -26.1 † -26.8 -28.2 -30 Rosuvastatin (mg) Atorvastatin (mg) Simvastatin (mg) Pravastatin (mg) -7.7 -8.2 Mean Percent Change From Baseline in TG Levels -13.2 *P<.002 vs pravastatin 10 mg, 20 mg **P<.002 vs simvastatin 40 mg; pravastatin 20 mg, 40 mg † P<.002 vs simvastatin 40 mg; pravastatin 40 mg Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:152-160.

  42. STELLAR Overall Conclusions • STELLAR was a very large statistically powerful statin comparative trial • Rosuvastatin demonstrated statistically significant improvements in the atherogenic lipid profile compared to atorvastatin, simvastatin, and pravastatin Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:155-160.

  43. Safety and Prescribing Information for Rosuvastatin

  44. Safety of Rosuvastatin • Adverse Reactions Summary • Rosuvastatin is generally well tolerated; adverse reactions have usually been mild and transient • The most frequent adverse events thought to be related to rosuvastatin were myalgia (3.3%), constipation (1.4%), asthenia (1.3%), abdominal pain (1.3%) and nausea (1.3%)1,2 • Discontinuations due to adverse events in placebo controlled clinical studies of up to 12 weeks duration occurred in 3% of patients taking rosuvastatin and 5% of patients taking placebo 1. CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003. 2. Data on file, (DA-CRS-01) AstraZeneca Pharmaceuticals LP, Wilmington, DE.

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