a1c: is the target moving ? pamela l. stamm, pharmd, cde, bcps associate professor of pharmacy...
TRANSCRIPT
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
Objectives
• Discuss A1C as a treatment target
• Identify benefits and risks of tight glucose control
• Recognize when evidence supports tight vs relaxed A1C goals
• Select A1C targets for individual patients
Case 1: Ms. Taylor
• 67 year old female in nursing home
• Recently diagnosed w/ DM on lifestyle alone
• PMH: HTN, OA, and now DM
• FSBG: 150-160
• A1C: 8.0%
Case 2: Mr. Samuels
• 70 yo African American male
• FH: mom and brother required dialysis
• PMH: Type 2 DM, HTN, CKD stage 3, OA
• A1C: 7.5
• Current medications:
• Glargine 30 units daily
• Aspart 10 units with meals
Case 3: Ms. Lopez
• 74 year old Hispanic Female in nursing home w/ DM
• Takes metformin and glipizide
• No hypoglycemic symptoms
• FSBG: 72-90
• A1C: 6.8%
• 1-2 falls per month
Case 4: Mr. Kopeski
• 80 year old male in assisted living
• Takes maximum metformin and glipizide
• No hypoglycemia
• FSBG: 160-180
• PMH: HTN, MI (5 years ago), COPD on O2
• Recent A1C: 8.5
Guidelines
ADA AACE
• < 6.5%
• Should individualize
• Below or around 7%
• Can go lower
• Less stringent goals may be appropriate
Endocrine Practice 2011;17(Suppl 2): 3-53.Diabetes Care 2011; 34 (Suppl) 1S11-S61.
Why relax the A1C goal?
• Reduced life expectancy,
• Extended duration of DM
• Presence or absence of microvascular or macrovascular complications
• Presence of Co-morbidities
• Risk of hypoglycemia, especially severe hypoglycemia
Endocrine Practice 2011;17(Suppl 2): 3-53.Diabetes Care 2011; 34 (Suppl) 1S11-S61.
History that established A1C
• DCCT (Type 1)
• Kumomato Study (Type 2)
• UKPDS (Type 2)
Goal A1C: History
Kumomato UKPDS
Populations <6.5% vs standard
7% vs 7.9%
Duration
Microvascular events
↓ ↓
Macrovascular events
Not assessed ↔
Diabetes Res Clin Pract 1995; 28: 103–117Lancet 1998; 352: 837–853
Many Questions Unanswered
• Could macrovascular benefits be see after long term therapy?
• Are there incremental benefits in A1C reduction?
• What about persons w/ established DM?
• Are benefits the same in the elderly?
• Are benefits the same in those w/ significant co-morbidities?
More Recent Trials
• DCCT / EDIC
• UKPDS Follow-up
• ADVANCE
• ACCORD
• VADT
• Meta-analyses of trials
• Co-morbidity trial
UKPDS 10 year follow-up
• 5102 newly diagnosed persons with type 2 diabetes
• Interventions: diet, sulfonylurea or insulin, or metformin (if >120% or IBW)
• Median follow-up approx. 17 yrs
• Post-trial follow-up in all 3 groups was approximately 50%
N Engl J Med 2008; 359:1577–1589.
UKPDS 10 year follow-up
N Engl J Med 2008; 359:1577–1589.
UKPDS follow-up: SFU-Ins Cohort
OutcomeIntensive 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)
MI 16.8% 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.
UKPDS follow-up: Metformin Cohort
OutcomeIntensive 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)
MI 14.8% 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.
ADVANCE
• 11,140 persons mean age 66 with type 2 DM plus CV risk factors
• 1/3 had CVD
• Baseline Glyc Hgb 7.48%
• Mean duration of DM of 8 yrs
• Used mostly SFU & insulin, low TZD use
• Lowered over 3 years
• Intensive (6.5%) vs standard (7.3%) control
• Study duration of 5-years
N Engl J Med. 2008;358:2560–72.
ADVANCE
Outcome
Intensive(n = 4828)
Standard(n = 4721)
RRR(CI)
Combined CV or micro event 18.1% 20% 10%
(2 to 18)
Major CV event 10% 10.6% 6%(-6 to 16)
Major micro event 9.4% 10.9% 14%(3 to 23)
Severe hypoglycemia 2.7% 1.5% P<0.01
N Engl J Med. 2008;358:2560–72.
ACCORD• 10,251 with type 2 DM who were mean age of 62
and had CV risk factors
• 1/3 had previous CV event
• Baseline Glyc Hgb 8.3%
• Median duration of DM of 10 yrs
• Median intensive (6.4%) vs standard (7.5%) control
• High (91.2 vs 57.5%) use of TZDs (rosiglitazone)
• Lowered over 1 year
• Stopped early at mean of 3.5 yrs
N Engl J Med. 2008; 358: 2545–59.
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.
ACCORD: What explains the results?
• Not Hypoglycemia
• Not rate of glucose fall
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))
Intensive 1.2 2.8 Unadj: 1.79 (1.32-2.44)Adj: 1.41 (1.03-1.93)
Standard 1.0 3.7 Unadj: 2.93 (1.86-4.63)Adj: 2.30 (1.46-3.65)
BMJ. 2009;339:b4909 doi10.1136/bmjb4909
Hypoglycemic events requiring medical assistance
No history
History HR (95%CI)
Intensive 1.3% 2.8% Unadj: 1.72 (1.19 to 2.47)Adj: 1.28 (0.88 to 1.85)
Standard 1.0% 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
Risk factors for hypoglycemia
• Gender (women > men)
• Age
• Ethnicity (African American)
• Lower education levels
BMJ. 2009; 339. doi:10.1136/bmj.b5444
VADT
• 1791 persons mean age 60.4 yrs w/ type 2 DM
• About 40% w/ CV event
• Baseline Glyc Hgb 9.4%
• Duration of DM of 11.5 yrs
• Median glyc hgb intensive (6.9%) vs standard (8.4%)
• Lowered in 6 months and sustained
• Median duration 5.6 yrs
N Engl J Med. 2009; 360: 129–39.
VADT
OutcomeIntensive(n = 899)
Standard(n = 892)
HR(CI)
Death (any cause) 102 95 1.07(0.81-1.42)
Death (CV cause) 38 29 1.32(0.81-2.14)
Cardiovascular event 29.5% 33.5%
0.88(0.74-1.05)
Severe hypoglycemia(patient-yrs)
11/100 4/100 P<0.01
N Engl J Med. 2009; 360: 129–39.
How to apply this data to patient care?
Meta-Analysis
Lancet 2009; 373: 1765–72.
Meta-Analysis
Lancet 2009; 373: 1765–72.
Systematic Review
Ann Intern Med 2009;151:394-403.
Systematic Review
Ann Intern Med 2009;151:394-403.
Both reviews
• Consistent benefit for CHD, although small reduction
• No benefit for stroke
• No benefit for heart failure
• No benefit for CV mortality
• No benefit for all-cause mortality
Ann Intern Med 2009;151:394-403.Lancet 2009; 373: 1765–72.
Comorbidity may impact benefit
• 2613 patients with type 2 DM mean age 62-64 observed over median 4.96 yrs
• Mean baseline A1C 7.2 - 7.4
• Objective: Does level of comorbidity associated with benefit or lack of benefit from tight control
Annals of Internal Medicine 2009;15 (12): 854-60.
Risk of CV event according to comorbidity level
TIBI score A1C < 6.5% A1C >6.5% HR
Low – mod comorbidity
2.2 3.8 0.6 (0.42-85)
High comorbidity 4.9 5.2 0.92 (0.68-1.25)
TIBI score A1C < 7.0% A1C >7.0% HR
Low – mod comorbidity
2.4 4.1 0.61 (0.44-0.83)
High comorbidity 4.8 5.4 0.86 (0.64-1.14)
Annals of Internal Medicine 2009;15 (12): 854-60.
Is there a J-Curve for A1C?
All cause mortality
Metformin and SFU Insulin
The Lancet. 2009; 375(9713): 481-489.
A1C Facts to Remember
• Rises naturally with aging (0.03%/yr)
• Inaccurate w/
• Hemoglobin variations
• Altered RBC lifespan (iron def, hemolytic anemia, renal failure)
Diabetes Care 2008; 31(10): 1991-1996.Clinical Chemistry 2011; 57 (2): 205-14.
Case 1: Ms. Taylor
• 67 year old female in nursing home
• Recently diagnosed w/ DM on lifestyle alone
• PMH: HTN, OA, and now DM
• FSBG: 150-160
• A1C: 8.0%
Case 2: Mr. Samuels
• 70 yo African American male
• FH: mom and brother required dialysis
• PMH: Type 2 DM, HTN, CKD stage 3, OA
• A1C: 7.5
• Current medications:
• Glargine 30 units daily
• Aspart 10 units with meals
Case 3: Ms. Lopez
• 74 year old Hispanic Female in nursing home w/ DM
• Takes metformin and glipizide
• No hypoglycemic symptoms
• FSBG: 72-90
• A1C: 6.8%
• 1-2 falls per month
Case 4: Mr. Kopeski
• 80 year old male in assisted living
• Takes maximum metformin and glipizide
• No hypoglycemia
• FSBG: 160-180
• PMH: HTN, MI (5 years ago), COPD on O2
• Recent A1C: 8.5
Summary
• Achieving 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 complications
• Those with lower comorbidity levels appear to have cardiovascular benefits from lower A1C
• Goal A1C should be individualized
Unanswered Question
• Does the rate of fall of glycemia impact benefit?