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?