1. A1C: Is the Target Moving ? Pamela L. Stamm, PharmD, CDE, BCPS Associate Professor of Pharmacy Practice, Auburn University Harrison School of Pharmacy, July 23, 2011

2. Objectives Discuss A1C as a treatment targetDiscuss A1C as a treatment target Identify benefits and risks of tight glucose controlIdentify benefits and risks of tight glucose control Recognize when evidence supports tight vs relaxed A1C goalsRecognize when evidence supports tight vs relaxed A1C goals Select A1C targets for individual patientsSelect A1C targets for individual patients

3. Case 1: Ms. Taylor 67 year old female in nursing home67 year old female in nursing home Recently diagnosed w/ DM on lifestyle aloneRecently diagnosed w/ DM on lifestyle alone PMH: HTN, OA, and now DMPMH: HTN, OA, and now DM FSBG: 150-160FSBG: 150-160 A1C: 8.0%A1C: 8.0%

4. Case 2: Mr. Samuels 70 yo African American male70 yo African American male FH: mom and brother required dialysisFH: mom and brother required dialysis PMH: Type 2 DM, HTN, CKD stage 3, OAPMH: Type 2 DM, HTN, CKD stage 3, OA A1C: 7.5A1C: 7.5 Current medications:Current medications: Glargine 30 units dailyGlargine 30 units daily Aspart 10 units with mealsAspart 10 units with meals

5. Case 3: Ms. Lopez 74 year old Hispanic Female in nursing home w/ DM74 year old Hispanic Female in nursing home w/ DM Takes metformin and glipizideTakes metformin and glipizide No hypoglycemic symptomsNo hypoglycemic symptoms FSBG: 72-90FSBG: 72-90 A1C: 6.8%A1C: 6.8% 1-2 falls per month1-2 falls per month

6. Case 4: Mr. Kopeski 80 year old male in assisted living80 year old male in assisted living Takes maximum metformin and glipizideTakes maximum metformin and glipizide No hypoglycemiaNo hypoglycemia FSBG: 160-180FSBG: 160-180 PMH: HTN, MI (5 years ago), COPD on O 2PMH: HTN, MI (5 years ago), COPD on O 2 Recent A1C: 8.5Recent A1C: 8.5

7. Guidelines ADAAACE < 6.5%< 6.5% Should individualizeShould individualize Below or around 7%Below or around 7% Can go lowerCan go lower Less stringent goals may be appropriateLess stringent goals may be appropriate Endocrine Practice 2011;17(Suppl 2): 3-53. Diabetes Care 2011; 34 (Suppl) 1S11-S61.

8. Why relax the A1C goal? Reduced life expectancy,Reduced life expectancy, Extended duration of DMExtended duration of DM Presence or absence of microvascular or macrovascular complicationsPresence or absence of microvascular or macrovascular complications Presence of Co-morbiditiesPresence of Co-morbidities Risk of hypoglycemia, especially severe hypoglycemiaRisk of hypoglycemia, especially severe hypoglycemia Endocrine Practice 2011;17(Suppl 2): 3-53. Diabetes Care 2011; 34 (Suppl) 1S11-S61.

9. History that established A1C DCCT (Type 1)DCCT (Type 1) Kumomato Study (Type 2)Kumomato Study (Type 2) UKPDS (Type 2)UKPDS (Type 2)

10. Goal A1C: History KumomatoUKPDS Populations<6.5% vs standard 7% vs 7.9% Duration Microvascular events ↓↓ Macrovascular events Not assessed ↔ Diabetes Res Clin Pract 1995; 28: 103–117 Lancet 1998; 352: 837–853

11. Many Questions Unanswered Could macrovascular benefits be see after long term therapy?Could macrovascular benefits be see after long term therapy? Are there incremental benefits in A1C reduction?Are there incremental benefits in A1C reduction? What about persons w/ established DM?What about persons w/ established DM? Are benefits the same in the elderly?Are benefits the same in the elderly? Are benefits the same in those w/ significant co-morbidities?Are benefits the same in those w/ significant co-morbidities?

12. More Recent Trials DCCT / EDICDCCT / EDIC UKPDS Follow-upUKPDS Follow-up ADVANCEADVANCE ACCORDACCORD VADTVADT Meta-analyses of trialsMeta-analyses of trials Co-morbidity trialCo-morbidity trial

13. UKPDS 10 year follow-up 5102 newly diagnosed persons with type 2 diabetes5102 newly diagnosed persons with type 2 diabetes Interventions: diet, sulfonylurea or insulin, or metformin (if >120% or IBW)Interventions: diet, sulfonylurea or insulin, or metformin (if >120% or IBW) Median follow-up approx. 17 yrsMedian follow-up approx. 17 yrs Post-trial follow-up in all 3 groups was approximately 50%Post-trial follow-up in all 3 groups was approximately 50% N Engl J Med 2008; 359:1577–1589.

14. UKPDS 10 year follow-up N Engl J Med 2008; 359:1577–1589.

15. UKPDS follow-up: SFU-Ins Cohort Outcome Intensive Therapy Conventional Therapy RR (95% CI) Any diabetes end point 48.1%52.2% 0.91 (0.83-0.99) Diabetes-related death 14.5%17.0% 0.83 (0.73-0.96) Death any cause 26.8%30.3% 0.87 (0.79-0.97) MI16.8%19.6% 0.85 (0.74-0.97) Microvascular disease 11.0%14.2% 0.76 (0.64-0.89) N Engl J Med 2008; 359:1577–1589.

16. UKPDS follow-up: Metformin Cohort Outcome Intensive Therapy Conventional Therapy RR (95% CI) Any diabetes end point 45.7%53.9% 0.79 (0.66-0.95) Diabetes- related death 14.0%18.7% 0.70 (0.53-0.92) Death any cause 25.9%33.1% 0.73 (0.59-0.89) MI14.8%21.1% 0.67 (0.51-0.89) Microvascular disease 12.4%13.4% 0.84 (0.60-1.17) N Engl J Med 2008; 359:1577–1589.

17. ADVANCE 11,140 persons mean age 66 with type 2 DM plus CV risk factors11,140 persons mean age 66 with type 2 DM plus CV risk factors 1/3 had CVD1/3 had CVD Baseline Glyc Hgb 7.48%Baseline Glyc Hgb 7.48% Mean duration of DM of 8 yrsMean duration of DM of 8 yrs Used mostly SFU & insulin, low TZD useUsed mostly SFU & insulin, low TZD use Lowered over 3 yearsLowered over 3 years Intensive (6.5%) vs standard (7.3%) controlIntensive (6.5%) vs standard (7.3%) control Study duration of 5-yearsStudy duration of 5-years N Engl J Med. 2008;358:2560–72.

18. ADVANCE Outcome Intensive (n = 4828) Standard (n = 4721) RRR (CI) Combined CV or micro event 18.1%20% 10% (2 to 18) Major CV event10%10.6%6% (-6 to 16) Major micro event9.4%10.9%14% (3 to 23) Severe hypoglycemia 2.7%1.5%P<0.01 N Engl J Med. 2008;358:2560–72.

19. ACCORD 10,251 with type 2 DM who were mean age of 62 and had CV risk factors10,251 with type 2 DM who were mean age of 62 and had CV risk factors 1/3 had previous CV event1/3 had previous CV event Baseline Glyc Hgb 8.3%Baseline Glyc Hgb 8.3% Median duration of DM of 10 yrsMedian duration of DM of 10 yrs Median intensive (6.4%) vs standard (7.5%) controlMedian intensive (6.4%) vs standard (7.5%) control High (91.2 vs 57.5%) use of TZDs (rosiglitazone)High (91.2 vs 57.5%) use of TZDs (rosiglitazone) Lowered over 1 yearLowered over 1 year Stopped early at mean of 3.5 yrsStopped early at mean of 3.5 yrs N Engl J Med. 2008; 358: 2545–59.

20. ACCORD Intensive (n = 4828) Standard (n = 4721) HR (CI) Primary outcome (MI, stroke, or CV death) 6.9%7.2% 0.90 (0.78-1.04) Death (any cause)5%4%1.22 (1.01-1.46) Death (CV cause)2.6%1.8%1.35 (1.04-1.76) Severe hypoglycemia 16.2%5.1%P<0.01 N Engl J Med. 2008; 358: 2545–59.

21. ACCORD: What explains the results? Not HypoglycemiaNot Hypoglycemia Not rate of glucose fallNot rate of glucose fall

22. Mortality rates by group Any hypoglycemic event requiring medical or nonmedical assistance No previous events (% per yr) At least one previous event (% per year) Hazard ratio (HR (95% CI)) Intensive1.22.8Unadj: 1.79 (1.32-2.44) Adj: 1.41 (1.03-1.93) Standard1.03.7Unadj: 2.93 (1.86-4.63) Adj: 2.30 (1.46-3.65) BMJ. 2009;339:b4909 doi10.1136/bmjb4909

23. Hypoglycemic events requiring medical assistance No history HistoryHR (95%CI) Intensive1.3%2.8%Unadj: 1.72 (1.19 to 2.47) Adj: 1.28 (0.88 to 1.85) Standard1.0%4.9%Unadj: 3.88 (2.35 to 6.40) Adj: 2.87 (1.73 to 4.76) ACCORD: mortality rates BMJ. 2009;339:b4909 doi10.1136/bmjb4909

24. Risk factors for hypoglycemia Gender (women > men)Gender (women > men) AgeAge Ethnicity (African American)Ethnicity (African American) Lower education levelsLower education levels BMJ. 2009; 339. doi:10.1136/bmj.b5444

25. VADT 1791 persons mean age 60.4 yrs w/ type 2 DM1791 persons mean age 60.4 yrs w/ type 2 DM About 40% w/ CV eventAbout 40% w/ CV event Baseline Glyc Hgb 9.4%Baseline Glyc Hgb 9.4% Duration of DM of 11.5 yrsDuration of DM of 11.5 yrs Median glyc hgb intensive (6.9%) vs standard (8.4%)Median glyc hgb intensive (6.9%) vs standard (8.4%) Lowered in 6 months and sustainedLowered in 6 months and sustained Median duration 5.6 yrsMedian duration 5.6 yrs N Engl J Med. 2009; 360: 129–39.

26. VADT Outcome Intensive (n = 899) Standard (n = 892) HR (CI) Death (any cause)102951.07 (0.81-1.42) Death (CV cause)38291.32 (0.81-2.14) Cardiovascular event 29.5%33.5% 0.88 (0.74-1.05) Severe hypoglycemia (patient-yrs) 11/1004/100P<0.01 N Engl J Med. 2009; 360: 129–39.

27. How to apply this data to patient care?

28. Meta-Analysis Lancet 2009; 373: 1765–72.

29. Meta-Analysis

30. Systematic Review Ann Intern Med 2009;151:394-403.

31. Systematic Review Ann Intern Med 2009;151:394-403.

32. Both reviews Consistent benefit for CHD, although small reductionConsistent benefit for CHD, although small reduction No benefit for strokeNo benefit for stroke No benefit for heart failureNo benefit for heart failure No benefit for CV mortalityNo benefit for CV mortality No benefit for all-cause mortalityNo benefit for all-cause mortality Ann Intern Med 2009;151:394-403. Lancet 2009; 373: 1765–72.

33. Comorbidity may impact benefit 2613 patients with type 2 DM mean age 62-64 observed over median 4.96 yrs2613 patients with type 2 DM mean age 62-64 observed over median 4.96 yrs Mean baseline A1C 7.2 - 7.4Mean baseline A1C 7.2 - 7.4 Objective: Does level of comorbidity associated with benefit or lack of benefit from tight controlObjective: Does level of comorbidity associated with benefit or lack of benefit from tight control Annals of Internal Medicine 2009;15 (12): 854-60.

34. Risk of CV event according to comorbidity level TIBI score A1C < 6.5% A1C >6.5% HR Low – mod comorbidity 2.23.80.6 (0.42-85) High comorbidity4.95.20.92 (0.68-1.25) TIBI score A1C < 7.0% A1C >7.0% HR Low – mod comorbidity 2.44.10.61 (0.44-0.83) High comorbidity4.85.40.86 (0.64-1.14) Annals of Internal Medicine 2009;15 (12): 854-60.

35. Is there a J-Curve for A1C? All cause mortality Metformin and SFUInsulin The Lancet. 2009; 375(9713): 481-489.

36. Time to first large vessel disease by A1C The Lancet. 2009; 375(9713): 481-489.

37. A1C Facts to Remember Rises naturally with aging (0.03%/yr)Rises naturally with aging (0.03%/yr) Inaccurate w/Inaccurate w/ Hemoglobin variationsHemoglobin variations Altered RBC lifespan (iron def, hemolytic anemia, renal failure)Altered RBC lifespan (iron def, hemolytic anemia, renal failure) Diabetes Care 2008; 31(10): 1991-1996. Clinical Chemistry 2011; 57 (2): 205-14.

38. Case 1: Ms. Taylor 67 year old female in nursing home67 year old female in nursing home Recently diagnosed w/ DM on lifestyle aloneRecently diagnosed w/ DM on lifestyle alone PMH: HTN, OA, and now DMPMH: HTN, OA, and now DM FSBG: 150-160FSBG: 150-160 A1C: 8.0%A1C: 8.0%

39. Case 2: Mr. Samuels 70 yo African American male70 yo African American male FH: mom and brother required dialysisFH: mom and brother required dialysis PMH: Type 2 DM, HTN, CKD stage 3, OAPMH: Type 2 DM, HTN, CKD stage 3, OA A1C: 7.5A1C: 7.5 Current medications:Current medications: Glargine 30 units dailyGlargine 30 units daily Aspart 10 units with mealsAspart 10 units with meals

40. Case 3: Ms. Lopez 74 year old Hispanic Female in nursing home w/ DM74 year old Hispanic Female in nursing home w/ DM Takes metformin and glipizideTakes metformin and glipizide No hypoglycemic symptomsNo hypoglycemic symptoms FSBG: 72-90FSBG: 72-90 A1C: 6.8%A1C: 6.8% 1-2 falls per month1-2 falls per month

41. Case 4: Mr. Kopeski 80 year old male in assisted living80 year old male in assisted living Takes maximum metformin and glipizideTakes maximum metformin and glipizide No hypoglycemiaNo hypoglycemia FSBG: 160-180FSBG: 160-180 PMH: HTN, MI (5 years ago), COPD on O 2PMH: HTN, MI (5 years ago), COPD on O 2 Recent A1C: 8.5Recent A1C: 8.5

42. Summary Achieving lower A1C reduces microvascular and macrovascular complications early after diagnosisAchieving lower A1C reduces microvascular and macrovascular complications early after diagnosis Achieving lower A1C reduces even after a diabetes duration of 8-10 yrs reduces microvascular complicationsAchieving lower A1C reduces even after a diabetes duration of 8-10 yrs reduces microvascular complications Those with lower comorbidity levels appear to have cardiovascular benefits from lower A1CThose with lower comorbidity levels appear to have cardiovascular benefits from lower A1C Goal A1C should be individualizedGoal A1C should be individualized

43. Unanswered Question Does the rate of fall of glycemia impact benefit?Does the rate of fall of glycemia impact benefit?