Does Tight Glycemic ControlImprove CV Diabetic Complications?                    No              Khalifa Abdallah         ...
UKPDS: elevated blood glucose levels  increase the risk of diabetic complications                               80        ...
UKPDS                   Intensive vs. conventional management                   9                                         ...
Intensive Glucose Control Significantly         Reduced Microvascular Disease                                             ...
DCCT/EDIC: glycaemic control reduces the risk of non-  fatal MI, stroke or death from CVD in type 1 diabetes              ...
A1c Reduction With Intensive &                    Conventional Management                  10                             ...
UKPDS: Post-Trial Changes in HbA1c                                      Mean (95%CI)                      UKPDS results   ...
UKPDS: Legacy Effect of Earlier Glucose                  Control            After median 8.5 years post-trial follow-up  A...
UKPDS: Post-Trial Monitoring: Patients       1997                     2002                       2007# in survivor cohort ...
UKPDS                   Intensive vs. conventional management                   9                                         ...
Key insights from the latest     randomised trials
ACCORD ADVANCE and VADT- No Significant Effect     on Macro or Micro Vascular Outcomes                          ACCORD   A...
Summary of ACCORD, ADVANCE and VADT                           ACCORD         ADVANCE           VADTNo. of participants    ...
Summary of ACCORD, ADVANCE and VADT                           ACCORD         ADVANCE           VADTNo. of participants    ...
Summary of ACCORD, ADVANCE and VADT     Incidence of Severe Hypoglycemia (%)                ACCORD   ADVANCE   VADTIntensi...
A1c & Hypoglycemia                          Increase incidence of Hypoglycemia                                         Com...
Asymptomatic Episodes of Hypoglycemia May Go                   Unreported                   100                           ...
Severe Hypoglycemia Causes QTc Prolongation                               450                                P=0.0003     ...
Conclusions  • Although observational trials demonstrated    that the relationship between glycemic control    and CV diab...
Conclusions-Cont.  • Older patients with long standing    diabetes and existing co-morbidities do    not benefit from inte...
Thank you
Khalifa abdallah.glycemic control
Khalifa abdallah.glycemic control
Khalifa abdallah.glycemic control
Khalifa abdallah.glycemic control
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Khalifa abdallah.glycemic control

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Khalifa abdallah.glycemic control

  1. 1. Does Tight Glycemic ControlImprove CV Diabetic Complications? No Khalifa Abdallah Prof. of Internal Medicine Diabetes, Metabolism & Lipidology Unit Alexandria Faculty of Medicine
  2. 2. UKPDS: elevated blood glucose levels increase the risk of diabetic complications 80 HbA1c 6.5% Microvascular 60 disease Incidence per Myocardial 40 1,000 patient-years infarction 20 0 0 5 6 7 8 9 10 11 Updated mean HbA1c (%)Study population: White, Asian Indian and Afro-Caribbean UKPDS patients (n = 4,585)Adjusted for age, sex and ethnic groupError bars = 95% CI Adapted from Stratton IM, et al. BMJ 2000; 321:405–412.
  3. 3. UKPDS Intensive vs. conventional management 9 Conventional Treatment (n=1138) } 0.9% 8 Intensive Treatment (n=2729) Median A1C (%) 7 6 0 0 3 6 9 12 15 Time from randomization (years)Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.
  4. 4. Intensive Glucose Control Significantly Reduced Microvascular Disease Rate* Conventional Intensive glucose glucose control control % Risk (n=2729) (n=1138) reduction p Macrovascular events • MI 17.4 14.7 16 0.052 • Stroke 5.0 5.6 –11 NS • PVD 1.6 1.1 35 NS • Diabetes-related death 11.5 10.4 10 NS • All-cause mortality 18.9 17.9 6 NS Microvascular events 11.4 8.6 25 0.0099 All events** 46.0 40.9 12 0.029NS = not significant; PVD = peripheral vascular disease.*Per 1000 patient-years.**Combined microvascular and macrovascular events.Adapted from United Kingdom Prospective Diabetes Study Group (UKPDS) Lancet 1998;352:837-853.
  5. 5. DCCT/EDIC: glycaemic control reduces the risk of non- fatal MI, stroke or death from CVD in type 1 diabetes 9 Conventional treatment HbA1C (%) 8 Intensive treatment 7 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Years DCCT (intervention period EDIC (observational follow-up) 0.06 Cumulative incidence of non-fatal MI, stroke or death from CVD 57% risk reduction 0.04 in non-fatal MI, stroke or CVD death* Conventional (P = 0.02; 95% CI: 12–79%) treatment 0.02 Intensive treatment 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 DCCT (intervention period) EDIC (observational follow-up) Years*Intensive vs conventional treatment Adapted from DCCT. N Engl J Med 1993; 329:977–986. DCCT/EDIC. JAMA 2002; 287:2563–2569. DCCT/EDIC. N Engl J Med 2005; 353:2643–2653.
  6. 6. A1c Reduction With Intensive & Conventional Management 10 Conventional 9.1% 9 HbA1c (%) 8 Intensive 7.2% 7 6 0 0 1 2 3 4 5 6 7 8 9 10 Years from randomizationDCCT Research Group. N.Eng.J.Med. 1993;329:977–986.
  7. 7. UKPDS: Post-Trial Changes in HbA1c Mean (95%CI) UKPDS results presentedUKPDS 80. N Eng J Med 2008; 359
  8. 8. UKPDS: Legacy Effect of Earlier Glucose Control After median 8.5 years post-trial follow-up Aggregate Endpoint 1997 2007 Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040 Microvascular disease RRR: 25% 24% P: 0.0099 0.001 Myocardial infarction RRR: 16% 15% P: 0.052 0.014 All-cause mortality RRR: 6% 13% P: 0.44 0.007 RRR = Relative Risk Reduction, P = Log RankN Eng J Med 2008
  9. 9. UKPDS: Post-Trial Monitoring: Patients 1997 2002 2007# in survivor cohort # with final year data 2,118 Clinic Questionnaire 1,010Sulfonylurea/Insulin Sulfonylurea/Insulin P 880 Clinic Questionnaire 379 Conventional Conventional P 279 Clinic Questionnaire 136 Metformin Metformin Mean age Mortality 44% (1,852) 62±8 years Lost-to-follow-up 3.5% (146) N Eng J Med 2008
  10. 10. UKPDS Intensive vs. conventional management 9 Conventional Treatment (n=1138) } 0.9% 8 Intensive Treatment (n=2729) Median A1C (%) 7 Median A1c 6 Conventional : 7.9 % Intensive : 7% 0 0 3 6 9 12 15 Time from randomization (years)Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.
  11. 11. Key insights from the latest randomised trials
  12. 12. ACCORD ADVANCE and VADT- No Significant Effect on Macro or Micro Vascular Outcomes ACCORD ADVANCE VADTNo. of participants 10,251 11,140 1791Participant age ,years 62 66 60Duration of diabetes at 10 8 11.5study entry, yearsHbA1C at Baseline, % 8.1 7.5 9.4Participants with prior 35 32 40cardiovascular event, %Duration of follow-up, 3.4 5.0 6years
  13. 13. Summary of ACCORD, ADVANCE and VADT ACCORD ADVANCE VADTNo. of participants 10,251 11,140 1791Participant age ,years 62 66 60HbA1C at Baseline, % 8.1 7.5 9.4Significant Effect on No No NoMacrovascularOutcomes?Significant Effect on NA Significant for NoMicrovascular nephropathy, notOutcomes? retinopathyRosiglitazone use, 90% vs. 58% 17% vs. 11% 85% vs.(intensive vs. standard) 78%Duration of follow-up, 3.4 5.0 6years
  14. 14. Summary of ACCORD, ADVANCE and VADT ACCORD ADVANCE VADTNo. of participants 10,251 11,140 1791Participant age ,years 62 66 60HbA1C at Baseline, % 8.1 7.5 9.4Significant Effect on NA Significant for NoMicrovascular nephropathy, notOutcomes? retinopathyRosiglitazone use, 90% vs. 58% 17% vs. 11% 85% vs.(intensive vs. standard) 78%Duration of follow-up, 3.4 5.0 6yearsSignificant Effect onMacrovascular No No NoOutcomes?
  15. 15. Summary of ACCORD, ADVANCE and VADT Incidence of Severe Hypoglycemia (%) ACCORD ADVANCE VADTIntensive arm 16.2 2.7 21.2Standard arm 5.1 1.5 9.9
  16. 16. A1c & Hypoglycemia Increase incidence of Hypoglycemia Complications Hypoglycaemia 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 HbA1c (%)DCCT Research Group. N.Eng.J.Med. 1993;329:977–986.
  17. 17. Asymptomatic Episodes of Hypoglycemia May Go Unreported 100 • In a cohort of patients with diabetes, more than 75 62.5 50% had asymptomatic Patients, % 55.7 46.6 (unrecognized) 50 hypoglycemia, as 25 identified by continuous glucose monitoring1 n=70 n=40 n=30 0 All patients Type 1 Type 2 • Other researchers have with diabetes diabetes diabetes reported similar Patients With ≥1 Unrecognized findings2,3 Hypoglycemic Event, %1. Copyright © 2003 American Diabetes Association. Chico A et al. Diabetes Care. 2003;26(4):1153–1157. Reprinted with permission from the American Diabetes Association.2. Weber KK et al. Exp Clin Endocrinol Diabetes. 2007;115(8):491–494.3. Zick R et al. Diab Technol Ther. 2007;9(6):483–492.
  18. 18. Severe Hypoglycemia Causes QTc Prolongation 450 P=0.0003 440 Mean QT interval, ms 430 420 P=NS 410 400 390 380 Significant QTc prolongation 370 during 360 hypoglycemia 0 Euglycemic clamp Hypoglycemic clamp (n=8) 2 weeks after glibenclamide withdrawal Baseline (t=0) (n=13) End of clamp (t=150 min) ACCORD?Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.
  19. 19. Conclusions • Although observational trials demonstrated that the relationship between glycemic control and CV diabetic complications was log-linear and extended down to the normal A1c with no threshold, yet randomized clinical trials failed to confirm this hypothesis • There is no solid evidence that tight glycemic control ( A1c <6.5 %) has clear benefit on reducing CV outcome in type 2 diabetic individuals but there is definite evidence that tight glycemic control increases the risk of severe hypoglycemia
  20. 20. Conclusions-Cont. • Older patients with long standing diabetes and existing co-morbidities do not benefit from intensive glycemic control • Controlling nonglycemic risk factors (hypertension, dyslipidemia, obesity, …) with standard glycemic control (A1c < 7%) is still the recommended strategy to prevent CV diabetic complications)
  21. 21. Thank you

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