Macrovascular disease in diabetes

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Macrovascular disease in diabetes

  1. 1. Macrovascular Disease in Diabetes Jamie Smith
  2. 2. •         CVD  related  mortality  increases  in  pa3ents  with  type  2   diabetes   People  with  type  2  diabetes:   •  48% 52% •  •  CVD deaths will  die  5-­‐10  years  before  people   without  diabetes   are  twice  as  likely  to  have  a  heart  a;ack   or  stroke  as  people  who  do  not  have   diabetes   are  15-­‐40  3mes  more  likely  to  have  a   lower  limb  amputa3on   Other deaths 1AHA  in  h;p://www.americanheart.org/downloadable/heart/1236204012112INTL.pdf     2Morish  et  al.  Diabetologia  2001;44(Suppl  2):S14-­‐S21.  Lancet  1997;350(Suppl.  1):SI23–8  
  3. 3. Excess  risk  for  coronary  heart  disease  in  pa3ents  with   type  2  diabetes   Age  adjusted   Rela-ve  risk   Women   3.69   Men   2.16   Mul-ple  adjusted*   Women   3.12   Men   1.99   1   1.5   2   3   4   8   Rela3ve  risk  (95%  CI)   *All  studies  adjusted  for  systolic  blood  pressure  and  total  cholesterol.  All  but  two  studies  also  adjusted  for   smoking   CI,  confidence  interval   Huxley  et  al.  BMJ  2006;332:73–8  
  4. 4. Does  Primary  Preven3on  Exist  in  Type  2   Diabetes?   7-year incidence of MI (%) Diabetic patients without previous MI have as high a risk of MI as non-diabetic patients with previous MI 45 40 35 30 25 Without previous MI With previous MI 20 15 10 5 0 non-diabetic with diabetes Haffner SM, et al. New England Journal of Medicine 1998;339:229–234.
  5. 5. Kaplan-Meier survival curves for a coronary heart disease event by baseline diabetes and MI status; the ARIC study, 1987 to 1997.
  6. 6. Insulin Resistance Syndrome Insulin 
 Resistance! Genetic influences! Environmental influences! Hyperinsulinaemia " Glucose intolerance! Increased triglycerides! Hypertension! Endothelial dysfunction! Decreased HDL ! Small dense LDL! Procoagulant state! Cardiovascular disease! Modified  from  Reaven  G.  In:  Le  Roith  D,  et  al.  (eds).  Diabetes  Mellitus:  A  Fundamental  and  Clinical  Text.  2000;pp604-­‐614  
  7. 7. Risk  factors  for  cardiovascular  disease   LDL   Libby  and  Plutzky.  Circula0on  2002;106:2760–3  
  8. 8. The  Major  Suspects   HYPERGLYCAEMIA   DYSLIPIDAEMIA   HYPERTENSION  
  9. 9. A1C  Predicts  Myocardial  Infarc-on     in  Type  2  Diabetes   UKPDS   4585 Patients Followed for 10 Years* Relative 3 risk 2.5 2 2.4 9 to <10 ≥10 1.9 1.8 1.3 1 1 0 <6 6 to <7 7 to <8 8 to <9 A1C (%) *Adjusted for age, sex, and duration of diabetes Stratton IM et al. BMJ. 2000;321:405-412
  10. 10. Glycated  Hemoglobin,  Diabetes  and  Cardiovascular  Risk  in   Non  Diabe-c  Adults   Selvin  et  al.  New  Eng  J  Med  362:800-­‐811,  2010  
  11. 11. HbA1c  and  All  Cause  Mortality   Met  +  SU   Currie  et  al.  Lancet  375:2010   Insulin  based  regime  
  12. 12. CV benefits of tight glycaemic control 10 years after intensive treatment discontinuation: UKPDS SU/insulin vs. conventional Hazard ratio 1.2 1.4 MI HR=0.84 p=0.052 HR=0.85 p=0.014 1.2 Hazard ratio 1.4 Metformin vs. conventional 1.0 0.8 MI HR=0.61 p=0.010 HR=0.67 p=0.005 1.0 0.8 0.6 0.6 0.4 Percentage of events 0.4 Percentage of events Conventional: 21 SU/insulin: 18 21 1997 24 24 27 27 31 30 1999 2001 2003 34 32 36 2005 2007 Holman et al. N Engl J Med 2008;359:113 Conventional: 24 Metformin: 14 1997 27 30 34 38 41 16 20 23 24 29 1999 2001 2003 2005 2007
  13. 13. All  Cause  Mortality  in  ACCORD  Study   1.41%/yr   1.14%/yr   HR  =  1.22  (1.01-­‐1.46)   P  =  0.04  
  14. 14. Primary  &  Secondary  Outcomes:   ACCORD     Intensive   N  (%)   Standard   N  (%)   HR  (95%  CI)   P   352 (6.86) 371 (7.23) 0.90 (0.78-1.04) 0.16 Mortality   257 (5.01) 203 (3.96) 1.22 (1.01-1.46) 0.04 Nonfatal  MI   186 (3.63) 235 (4.59) 0.76 (0.62-0.92) 0.004 Nonfatal  Stroke   67 (1.31) 61 (1.19) 1.06 (0.75-1.50) 0.74 CVD  Death   135 (2.63) 94 (1.83) 1.35 (1.04-1.76) 0.02 CHF   152 (2.96) 124 (2.42) 1.18 (0.93-1.49) 0.17 Primary   Secondary  
  15. 15. Concern of cardiovascular risk with traditional oral anti-diabetic drugs “Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance.” Nissen et al. The New England Journal of Medicine 2007; 356:24 Rrosiglitazone now withdrawn from UK market
  16. 16. FDA guidance to industry on cardiovascular outcome trials FDA request Retrospectively compare incidence of Major Adverse Cardiovascular Events (MACE) between drug X and total comparator MACE liraglutide vs. total comparator Incidence rate ratio Upper limit of 95% confidence interval < 1.0 > 1.3 and < 1.8 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf
  17. 17. Lipids  
  18. 18. Why do Patients With Type 2 Diabetes Develop Cardiovascular Disease? Type 2 Diabetes Risk Obesity ♥ Hypertension Raised LDL cholesterol Cardiovascular Disease  ♥   Low HDL cholesterol Hypertriglyceridaemia Diabetes can be considered as ‘a state of premature cardiovascular death which is associated with chronic hyperglycaemia’.
  19. 19. Dyslipidaemia:  What’s  it  all  about?   “Bad  Cholesterol”     LDL   “Good  Cholesterol”     HDL     Apo  B   Apo  A1   Cholesterol   Carries  cholesterol   to  peripheral   -ssues   Atherosclero-c   plaque  forma-on   Carries  excess  cholesterol   from  peripheral  -ssues   back  to  the  liver  
  20. 20. Treatment  Effect  on  the  Primary  Endpoint  :  CARDS   Study   Event   Placebo*   Atorva*   Hazard  Ra-o                  Risk  Reduc-on  (CI)   Primary  endpoint   127  (9.0%)   83  (5.8%)   37%  (17-­‐  52)   p=0.001   Acute  coronary  events   77  (5.5%)   51  (3.6%)   36%  (9-­‐  55)   Coronary   revascularisa-on   34  (2.4%)   24  (1.7%)   31%  (-­‐16-­‐  59)   Stroke   39  (2.8%)   21  (1.5%)   48%  (11-­‐  69)   .2 .4 .6 .8 *  N  (%  randomised)   1 1.2 Favours  Atorvasta-n                              Favours  Placebo  
  21. 21. Numbers  Needed  to  Treat  to  Prevent  One  First   Major  Cardiovascular  Event     NNT  for  4  years     NNT  for  5    years     Atorvasta-n  10mg  daily                27    21.5  
  22. 22. Meta-analysis of Statin Trials in Diabetes
  23. 23. Event Rates Plotted Against LDL-C Levels (2o prevention trials) 4S Statin Placebo 30 Event (%) 25 4S 20 15 LIPID ? LIPID CARE 10 HPS 5 CARE HPS TNT (10 mg of atorvastatin) TNT (80 mg of atorvastatin) 0 0.3 0.8 1.3 1.8 2.3 2.9 3.4 3.9 4.4 4.9 5.4 LDL-C (mmol/L) after LaRosa et al. NEJM 2005
  24. 24. Question 3 What about HDL?   The Framingham Study
  25. 25. Uncertainty  over  future  of  HDL  Raising   Therapies……………………………………....  
  26. 26. ACCORD  Double    2  x  2  Factorial  Design   Lipid   BP   Placebo            Fibrate   Intensive   Standard   Intensive   Glycemic   Control   1383   1374   1178   1193   5128   Standard   Glycemic   Control   1370   1391   1184   1178   5123   2765   2362   2371   10,251   2753   5518   4733*   *    94%  power  for  20%  reduc-on  in  event  rate,  assuming  standard   group  rate  of  4%  /  yr  and  5.6  yrs  follow-­‐up  
  27. 27. ACCORD  Study  Design     •  Overall  ACCORD  Glycemia  Trial:  10,251  par3cipants     •  Lipid  Trial:  5,518  par3cipants     •  2765  randomized  to  fenofibrate   •  2753  randomized  to  placebo     •  Primary  Outcome:  First  occurrence  of  a  major  cardiovascular  event   (nonfatal  MI,  nonfatal  stroke,  cardiovascular  death)   •  87%  power  to  detect  a  20%  reduc3on  in  event  rate,  assuming  placebo   rate  of  2.4%/yr  and  5.6  yrs  follow-­‐up  in  par3cipants    without  events.  
  28. 28. Plasma Lipid Levels During Trial
  29. 29. Adverse  Experiences  During  Follow-­‐up   Fenofibrate (N=2765) Placebo (N=2753) P value 1110 (40.1%) 7 (0.3%) 1 (0.04%) 1115 (40.5%) 8 (0.3%) 2 (0.07%) 0.79 0.79 0.62 Any nonhypoglycemic SAE 54 (2.0%) 43 (1.6%) 0.27 Any Myopathy/Myositis/ Rhabdomyolysis SAE 4 (0.1%) 3 (0.1%) 1.00 Any Hepatitis SAE 3 (0.1%) 0 (0.0%) 0.25 Any SAE attributed to lipid meds 27 (1.0%) 18 (0.7%) 0.18 Adverse events (no. (%)) Out of the ordinary severe muscle aches/pains: regardless of CPK plus CPK > 5 X ULN plus CPK > 10 X ULN Revised 06/16/10
  30. 30. Primary  Outcome   Fenofibrate   (N=2765)   Rate   N  of     Events   (%/yr)   Primary  Outcome:                           Major  Fatal  or  Nonfatal     Cardiovascular  Event   291   2.24   Placebo   (N=2753)   Rate   N  of     Events   (%/yr)   310   2.41   HR  (95%  CI)   P  Value              0.92     0.32   (0.79  -­‐  1.08)  
  31. 31. Primary  Outcome  By  Treatment  Group  and  Baseline  Subgroups  
  32. 32. Comparison of ACCORD subgroup results with those from prior fibrate studies Trial (Drug) HHS (Gemfibrozil) BIP (Bezafibrate) FIELD (Fenofibrate) ACCORD (Fenofibrate) Primary Endpoint: Entire Cohort (P-value) -34% (0.02) Lipid Subgroup Criterion TG > 200 mg/dl LDL-C/HDL-C > 5.0 Primary Endpoint: Subgroup -71% (0.005) TG > 200 mg/dl -7.3% -11% -8% (0.24) (0.16) (0.32) -39.5% (0.02) TG > 204 mg/dl HDL-C < 42 mg/dl -27% (0.005) TG > 204 mg/dl HDL-C < 34 mg/dl -31%
  33. 33. Lipid  Guidance  in  Diabetes  :  NICE  2008   High serum Triglyceride (fasting > 4.5mmol/L) •  Assess and treat secondary causes •  NB. Trigs > 10 mmol/L risk of pancreatitis •  If persists – offer fibrate •  Consider omega-3 fish oils if needed • If high CV risk and TG 2.3-4.5 mmol/L despite statin, consider adding fibrate
  34. 34. Lipid  Guidance  in  Diabetes  :  JBS  2   Statins recommended for: 1.  All those aged 40 or more with type 1 or type 2 diabetes 2.  Those aged 18-39yrs with type 1 or 2 who have the following: retinopathy (not BDR) nephropathy (inc. microalb +) poor glycaemic control (HbA1c>9%) hypertension cholesterol > 6mmol/L features of “metabolic syndrome” family history of premature CVD in 10 relative Joint British Societies’ Guidelines 2: Heart, vol 91; December 2005
  35. 35. Lipid  Guidance  in  Diabetes  :  JBS  2   Lipid targets: Total cholesterol 4mmol/L LDL cholesterol 2mmol/L “Other lipid-lowering drugs should be considered in addition to a statin if cholesterol (total / LDL) not achieved or if other lipid parameters such as HDL cholesterol or triglycerides need to be addressed.” Joint British Societies’ Guidelines 2: Heart, vol 91; December 2005
  36. 36. Blood  Pressure  
  37. 37. Published  online  March  14,  2010  
  38. 38. Systolic  Pressures  (mean  +  95%  CI)   Mean  #  Meds                  Intensive:          3.2                                                        3.4                                                    3.5                                                        3.4                  Standard:          1.9                                                        2.1                                                    2.2                                                        2.3   Average  aner  1st  year:  133.5  Standard  vs.  119.3  Intensive,  Delta  =  14.2  
  39. 39. Medica3ons  Prescribed  (12  Month  Visit)  
  40. 40. Adverse  Events   Intensive   N  (%)   77  (3.3)   Standard   N  (%)   30  (1.3)   <0.0001   Hypotension   17  (0.7)   1  (0.04)   <0.0001   Syncope   12  (0.5)   5  (0.2)   0.10   Bradycardia  or  Arrhythmia   12  (0.5)   3  (0.1)   0.02   Hyperkalemia   9  (0.4)   1  (0.04)   0.01   Renal  Failure   5  (0.2)   1  (0.04)   0.12   eGFR  ever  <30  mL/min/1.73m2   99  (4.2)   52  (2.2)   <0.001   Any  Dialysis  or  ESRD   59  (2.5)   58  (2.4)   0.93   Dizziness  on  Standing†   217  (44)   188  (40)   0.36   Serious  AE   P   †    Symptom  experienced  over  past  30  days  from  HRQL  sample  of     N=969  par3cipants  assessed  at  12,  36,  and  48  months  post-­‐randomiza3on  
  41. 41. Primary  &  Secondary  Outcomes     Intensive     Events  (%/yr)   Standard   Events  (%/yr)   HR  (95%  CI)   P   208 (1.87) 237 (2.09) 0.88 (0.73-1.06) 0.20 Total  Mortality   150 (1.28) 144 (1.19) 1.07 (0.85-1.35) 0.55 Cardiovascular   Deaths   60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74 Nonfatal  MI   126 (1.13) 146 (1.28) 0.87 (0.68-1.10) 0.25 Nonfatal  Stroke   34 (0.30) 55 (0.47) 0.63 (0.41-0.96) 0.03 Total  Stroke   36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 0.01 Primary   Also  examined  Fatal/Nonfatal  HF  (HR=0.94,  p=0.67),  a  composite  of  fatal  coronary   events,  nonfatal  MI  and  unstable  angina  (HR=0.94,  p=0.50)  and  a  composite  of  the   primary  outcome,  revasculariza0on  and  unstable  angina                                                                      (HR=0.95,  p=0.40)  
  42. 42. Blood Pressure Targets 140/80 mmHg for those without complications 130/80 mmHg if kidney, eye or cerebrovascular damage
  43. 43. Effects  of  Cardiac  Autonomic  Dysfunc-on  on  Mortality  Risk  in  the  Ac-on  to  Control   Cardiovascular  Risk  in  Diabetes  (ACCORD)  Trial     Diabetes  Care.  2010  Jul;33(7):1578-­‐84.  Epub   2010  Mar  9.  
  44. 44. Platelet  Dysfunc-on   The  following  seem  to  be  specific  to  Type  2  diabetes:   –  –  –  increased  sensi-vity  to  aggrega-on   increased  glycosyla-on   decreased  concentra-on  of  Cyclic  AMP   These  result  in  increased  platelet  s-ckiness     Therefore  ALL  pa-ents  with  Type  2  diabetes  should  be   on    aspirin  therapy  (75-­‐150mg  per  day)  from  -me  of   diagnosis     Unless  Contraindicated!  
  45. 45. % risk reduction UKPDS found that metformin reduces risk of macrovascular complications 50 45 40 35 30 25 20 15 10 5 0 P=0.017 P=0.010 P=0.011 P=0.0023 Any diabetes related P=0.02 Macrovascular Myocardial infarction Diabetes related death Metformin in overweight patients. UKPDS 34. Lancet 1998;352:854–865 All cause mortality

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