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TZD’s in the management of diabetes & CV disease: All about benefits and safety

Cardio Diabetes Master Class Asian chapter January 28-30 2011, Shanghai. Presentation topic. TZD’s in the management of diabetes & CV disease: All about benefits and safety. Slide lecture prepared and held by:. Prof. John Betteridge, MD University College London London, United Kingdom.

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TZD’s in the management of diabetes & CV disease: All about benefits and safety

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  1. Cardio Diabetes MasterClass Asianchapter January 28-30 2011, Shanghai Presentation topic TZD’s in the management of diabetes & CV disease: All about benefits and safety Slide lecture prepared and held by: Prof. John Betteridge, MD University College London London, United Kingdom

  2. Diabetes and Cardiovascular Disease: 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

  3. Glucose Toxicity Retinopathy Nephropathy CH OH 2 H H O Neuropathy H H OH OH OH OH H  - cell damage Cardiovascular disease Hepatic and skeletal muscle insulin resistance

  4. MI Microvascular endpoints UKPDS:MicrovascularComplications, MI, and HbA1c 80 • Incidence rates by updated HbA1c • Adjusted for age, sex, and ethnic group • Expressed for white men, 50–54 years old at diagnosis; mean diabetes duration 10 years 60 Adjusted incidence per 1000 patient years (%) 40 20 0 5 6 7 8 9 10 11 Updated mean HbA1cconcentration (%) Adapted from Stratton IM et al BMJ 2000;321:405-412.

  5. UKPDS:Endpoints by Glucose Treatment Group Intensive Conventional rate/1000 rate/1000 % riskCause patient-years patient-yearsP reduction Any diabetes-related* 40.9 46.0 0.029 12 MI 14.7 17.4 0.052 16 Stroke 5.6 5.0 0.52 – PVD† 1.1 1.6 0 0.15 – Microvascular 8.6 11.4 0.0099 25 *Combined microvascular and macrovascular events. †Amputation or death from PVD. . UKPDS Group. Lancet 1998;352:837-53

  6. Haemoglobin A1c: Cardiovascular Disease and Mortality -The EPIC Study • Design: Prospective population study. 4662 men and 5570 women aged 45-79yrs, Norfolk England • Analysis: HbA1c and CVD risk factors assessed 1995-1997. CVD events and mortality assessed during follow-up period to 2003 • Events: 806 CVD, 521 deaths Age Adjusted RR by HbA1c CHD CVD Death MEN RR Khaw et al Ann Intern Med 2004; 141: 413

  7. Conclusions: RCTs of intensive versus standard glycaemic therapy have not shown a significant reduction in CVD outcomes during the randomized period of the trials. NB Long-term follow-up of DCCT and UKPDS suggests that HbA1c around 7% in years soon after diagnosis is associated with long-term risk reduction. Less stringent HbA1c goals may be appropriate for patients with history of severe hypoglycaemia, advanced CVD complications or extensive co-morbid conditions or those with long-standing diabetes in whom the general goal is difficult to maintain. Evidence-based recommendations should be followed for blood pressure management, statins smoking cessation, aspirin and healthy lifestyles Skyler et al Diabetes Care 2009, 33: 187

  8. Patho-physiology of Type 2 diabetes Site of Action of Available Drugs Decreased incretin effect Decreased glucose uptake • GLP1-agonists • DPP4-inhibitors Increased lipolysis • TZDs • TZDs • Metformin Increased glucagon secretion Increased HGP Hyperglycemia • GLP1-agonists • DPP4-inhibitors • GLP1-agonists • DPP4-inhibitors • Sulfonylureas • TZDs • Metformin Decreased insulin secretion β and -cell dysfunction

  9. Free Fatty Acids:Insulin Resistance, IGT and Type 2 NIDDM  Lipolysis Muscle  FFA mobilization Liver  FFA oxidation  FFA oxidation Adiponectin  Glucose utilization  Gluconeogenesis Insulin  Hyperglycaemia,Hyperinsulinaemia,IGT and Diabetes

  10. Pioglitazone 30-45 mg/d Reduces Plasma Glucose,Insulin and FFA and Increase Adiponectin in Diabetes P=0.035 P=0.08 40 30 20 10 0 200 150 100 50 0 Glucose (mg/dL ) Insulin ( µU/mL ) P=0.035 P=0.0004 25 20 15 10 5 0 0.6 0.5 0.4 0.3 0.2 0.1 0.0 FAs ( mEq/L) Adiponectin ( µg/mL ) NAGASHIMA K et al. J Clin Invest 115:1323, 2005

  11. 0.25 N events: 3-year estimate: placebo 572 / 2633 23.5% 0.20 pioglitazone 514 / 2605 21.0% 0.15 0.10 0.05 0.0 Time to Primary Composite Endpoint* Kaplan-Meier event rate Risk reduction : 10 % HR 95% CI p value pioglitazone 0.904 0.802, 1.018 0.0951 vs placebo N at Risk: 5238 5018 4786 4619 4433 4268 693 (228) 0 6 12 18 24 30 36 Time from randomisation (months) *Death, non-fatal myocardial infarction (including silent MI), stroke, major leg amputation, acute coronary syndrome, coronary or leg revascularisation

  12. Death Non-fatal MI ACS Stroke PCI/CABG Major leg amputation Leg revascularisation Pioglitazone Placebo 177 186 131 157 65 78 92 119 195 240 28 28 115 92 803 900 PROactive Total Events

  13. N events: 3-year estimate: placebo 358 / 2633 14.4% pioglitazone 301 / 2605 12.3% Time to : Death, MI ( excluding silent ) or Stroke Secondary composite endpoint 0.15 0.10 Risk reduction : 16 % 0.05 HR 95% CI p value pioglitazone 0.841 0.722, 0.981 0.0273 vs placebo 0.0 N at Risk: 5238 5102 4991 4877 4752 4651 786 (256) 0 6 12 18 24 30 36 Time from randomisation (months)

  14. In high-risk patients with type 2 diabetes and previous MI, pioglitazonesignificantlyreduced the occurrence of recurrent fatal and nonfatal MI and ACS

  15. Time to Fatal/Non-fatal MI Patients with previous MI n=2445 Kaplan-Meier event rate 0.10 pioglitazone (65 / 1230) 0.08 placebo (88 / 1215) 0.06 0.04 Risk reduction : 28 % 0.02 0.0 N at Risk: 2445 2387 2337 2293 2245 2199 399 (139) 0 6 12 18 24 30 36 Time from Randomization (months)

  16. In high-risk patients with type 2 diabetes and previous stroke, pioglitazone significantly reduced the occurrence of recurrent fatal and nonfatal stroke. Stroke, 2007;38:865-873

  17. Kaplan-Meier event rate 0.12 pioglitazone (27 / 486) 0.10 placebo (51 / 498) 0.08 0.06 0.04 0.02 HR 95% CI p value pioglitazone vs placebo 0.53 0.34, 0.85 0.008 0.00 N at Risk: 984 952 926 903 877 849 132 0 6 12 18 24 30 36 Time from Randomization (months) Time to Fatal or Non-Fatal Stroke in Patients with Previous Stroke Patients with previous Stroke n=984 Risk reduction : 47 %

  18. Hazard Ratios for CardiovascularEvents with Glitazones Rosiglitazone Metaanalysis Nissen et al.1MyocardialInfarction (OR) Metaanalysis Nissen et al.1CardiovascularDeath (OR) Metaanalysis Krall2MyocardialInfarction (OR) Metaanalysis FDA3MyocardialIschemia (OR) Metaanalysis GSK4MyocardialIschemia (HR) Data from Nissen + RECORD5MyocardialInfarction (OR) Cardiovascular Death´(OR) Metaanalysis Singh6MyocardialInfarction (HR) 1.43 1.64 1.4 1.31 1.24 1.07 1.42 Pioglitazone PROactive7 Primary Endpoint (HR) PROactive7 MI, Strokeand Death (HR) PROactive MI-Subgroup8MyocardialInfarction (HR) Metaanalysis Lincoff et al9 MI, Strokeand Death (HR) 0.90 0.84 0.72 0.82 1 0 2 Hazard Ratio/Odds Ratio Glitazonesbetter Glitazonesworse ç 1Nissen SE and Wolski K. NEJM 2007; 356:2457-2471; 2Krall RL. Lancet 2007; 369:1995-1996; 3FDA-Homepage www.fda.gov; FDA-Hearing 30.07.2007;4 SPC Avandia®; 5Bracken MB N Engl J Med. 2007; 357:937; 6Singh S et al. JAMA 2007;298:1189-1195; 7Diamond G et al. Ann Int Med 2007; in press; 7Dormandy JA et al. Lancet 2005; 366:1279-1289; 8Erdmann E et al. JACC 2007; 49:1772-1780; 9Lincoff AM et al. JAMA 2007;298;1180–1188.

  19. 0.2 ‡ † * 0 A1C change from baseline (least square means, %) -0.2 -0.4 -0.6 Baseline 16 24 32 40 48 60 72 Week Glimepiride Pioglitazone CHICAGO: GlycaemicControl Change in HbA1c *P = 0.04; †P = 0.01; ‡P = 0.002 (treatment-group difference) Mazzone T et al. JAMA. 2006.

  20. CHICAGO: Treatment effect on posterior wall mean CIMT 0.016 0.012 Mean change from baseline (least squares, mm) 0.008 P = 0.02 0.004 0 -0.004 -0.008 -0.012 Baseline Week 24 Week 48 Week 72 Glimepiride Pioglitazone CIMT = carotid intima-media thickness Mazzone T et al. JAMA. 2006.

  21. Objective: Will pioglitazone stabilize carotid artery vulnerable plaque in patients with acute coronary syndromes (ACS) and type 2 diabetes. Population: 61 patients with type 2 diabetes, age 63yrs, approx 70% male and echo lucent carotid plaques within 5 days of ACS. Random allocation to pioglitazone 15-30mg/day or matching placebo. Methods: Vulnerable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated back scatter (IBS) An increase in IBS reflects an increase in plaque echogenicity. Echolucent plaques with low IBS represent identify lipid and macrophage-rich lesions, unstable plaques

  22. PROactiveMetabolic Effects of Pioglitazone HbA1c - 0.5% HDL-cholesterol + 8.9% LDL-cholesterol + 2.3% Triglycerides - 13.2 Systolic BP - 3 mmHg Weight + 4 kg

  23. 25 Pioglitazone Rosiglitazone 20 15 10 5 0 -5 -10 Apo B LDL-C LDL particle size LDL particle concentration Change in LDL cholesterol, Particle size,Apoprotein B and Particle Concentration 23.3 Changefrom baselineat week 24 (%) 15.7* 12.0 11.5 2.4** 1.7 1.5* -7.8* n=363 n=356 n=333 n=325 n=333 n=325 n=346 n=334 *p<0.001 and **p=0.005between treatment groups Goldberg et al. Diabetes Care 2005; 28: 1547-1554Goldberg et al. Circulation 2005; 111: 1727–1728

  24. CHF CHF Death Lancet, 2007; 370: 1129-1136

  25. More pioglitazone (5.7%) than placebo patients (4.1%) had episode of serious heart failure, (requiring hospitalization or life threatening) but there was no difference in mortality p=0.639 P=0.007 Erdmann et al Diabetes Care 30:2773–2778, 2007

  26. The Development of Heartfailure on Pioglitazone in PROactivedid not affect subsequentprognosis Placebo Pioglitazone Kaplan Meier estimates of time from serious heart failure to all-cause mortality Erdmann et al Diabetes Care 30:2773–2778, 2007

  27. Whole body glucose disposal and Myocardial glucose utilization during hyperinsulinaemic clamp FDG uptake using Positron Emission Tomography Whole body glucose disposal p<0.05 between treatment differences Myocardial glucose utilization JACC, 2007; 50: 2051

  28. Hyperaemic Myocardial Blood FlowBefore and After Pioglitazone p<0.05 between treatment differences JACC, 2007; 50: 2051

  29. Setting: • UK general practice research dta Objective: To investigate risk of incident MI, congestive heart failure and all cause mortality associated with prescription of oral anti diabetes drugs Design: Retrospective cohort study Setting: UK general practice research data base 1990-2005 Participants: 91521 people with diabetes Methods: Person time intervals for drug treatment were categorised by drug class excluding non-drug intervals and intervals for insulin 3588 MIs, 6900 CCF, 18548 deaths

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