Difficulties in Achieving
Target A1c Values
John B. Buse, MD, PhD
Associate Professor of Medicine
Chief, Division of General Medicine and Clinical Epidemiology
Director, Diabetes Care Center
University of North Carolina
Chapel Hill, NC
jbuse@med.unc.edu
63% of Patients With Diabetes
are Not At ADA A1C Goal <7%
Adults aged 20-74 years with previously diagnosed diabetes who participated in the interview
and examination components of the National Health Examination Survey (NHANES), 1999-2000.
100
80
% of
Subjects
n = 404
60
12.4%
7.8%
63%
7%
17.0%
25.8%
>10%
>9%
>8%
7-8%
40
20
37.2%
>8%
A1C
37.0%
<7%
0
Only 7% of adults with diabetes in NHANES 1999-2000 attained:
• A1C level <7%
• Blood pressure <130/80 mm Hg
• Total cholesterol <200 mg/dL
Saydah SH et al. JAMA. 2004;291:335-342.
Case
DATE
FPG AVG
A1c
3/28
150
9.8
4/11
4/25
8.4
5/11
162
5/22
132
6.9
6/20
89
5.6
7/18
8/15
9/19
REGIMEN
70/30 - 36 BID
ADD MTF 500 BID
INCREASE 70/30 - 40 BID
INCREASE MTF 1000 BID
INCREASE 70/30 50 BID
ADD ROSIGLITAZONE 4 QD
CHANGE 70/30 - 45 Q AM, 50 Q PM
5.8
73
5.2
SUMMARY
MONITOR
I
2/d
I+M
2/d
I+M+R
2/d
I+M+R
2/d
SWITCH INSULINS: GLARGINE 75 QHS
+ ASPART 10 ac TID
CHANGE ASPART 1 unit/5 grams CHO
CHANGE GLARGINE 70 QHS
INCREASE ROSIGLITAZONE 4 BID
INCREASE ASPART 1 unit/3 grams
CHO
I+M+R
4/d
MDI+M+R
4/d
MDI+M+R
4/d
CHANGE GLARGINE 65 QHS
MDI+M+R
4/d
CHANGE GLARGINE 62 QHS
MDI+M+R
4/d
Difficulties in Achieving
Target A1C Values

What is the appropriate A1C target

Challenges
– Late diagnosis and initiation of therapy
– Therapeutic inertia
– Lack of effective lifestyle intervention
– Secondary failure
– Adverse events associated with antihyperglycemic
therapies
– Complexity of care
– Role of postprandial glucose in failure
Difficulties in Achieving
Target A1C Values

What is the appropriate A1C target

Challenges
– Late diagnosis and initiation of therapy
– Therapeutic inertia
– Lack of effective lifestyle intervention
– Secondary failure
– Adverse events associated with antihyperglycemic
therapies
– Complexity of care
– Role of postprandial glucose in failure
Intensive Diabetes Therapy:
Reduced Incidence of Complications
HbA1c
Retinopathy
Nephropathy
Neuropathy
Cardiovascular
disease
DCCT
9  7.2%
63%
54%
60%
Kumamoto
9  7%
69%
70%
Improved
UKPDS
8  7%
17-21%
24-33%
-
41% (NS)
-
16% (NS)
DCCT Research Group. N Engl J Med. 1993;329:977-986.
Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117.
UKPDS 33: Lancet 1998; 352, 837-853.
Slide modified from D. Kendall - International Diabetes Center, Minneapolis.
Potential Adverse Effects Related to
Pursuit of Stringent Glycemic Goals

Hypoglycemia

Cost

Long-term exposure to poorly studied
combinations of medications

Lessened attention to other difficult to manage
health care risks (e.g. BP, HDL, immunization,
cancer screening)

Weight gain
Risk of Progression of Complications:
DCCT Study
Severe hypoglycemia
15
Diabetic retinopathy
Nephropathy
Neuropathy
Microalbuminuria
120
Rate of 100
Severe
80
Hypo.
(per 100
patient- 60
years)
40
13
11
9
7
5
3
20
0
1
6
7
8
9
10
HbA1c, %
Skyler JF. Endocrinol Metab Clin North Am. 1996;25:243-254.
11
12
Relative
Risk
EDIC 12-year Follow-Up of DCCT Study
Relative risk reduction (%)
(95% CI)
p
Cardiovascular
events
42 (19-63)
0.016
Nonfatal MI, stroke,
and cardiovascular
death
57 (12-79)
0.018
End point
Nathan D. American Diabetes Association 2005 Scientific Sessions; June 10-14, 2005; San Diego, CA.
Incidence Rate for Complications in UKPDS:
Epidemiological Analysis*
Adjusted incidence
per 1000 patient years (%)
160
90
140
120
100
60
Any diabetes
related endpoint
80
40
Myocardial
infarction
60
40
20
Microvascular
endpoints
20
5
6
7
8
9
10
11
5
6
7
8
9
10
11
Updated mean hemoglobin A1c
* Expressed for white men aged 50-54 years at diagnosis and with mean
duration of diabetes of 10 years
Stratton, et al. BMJ. 321:405-412, 2000
Glycemic Goals of Therapy
Goal
ADA
Premeal plasma glucose (mg/dl) 90-130
2-h postprandial plasma glucose <180*
HbA1c
<7%**
ACE
<110
<140
<6.5%
Verbal Target
~100
<<200
As low as
possible w/o
unacceptable AE
• Evaluation and treatment of postprandial glucose may be useful in the
setting of suspected postprandial hyperglycemia, with the use of agents
targeting postprandial hyperglycemia and for suspected hypoglycemia.
• More stringent glycemic goals (i.e. a normal A1C, <6%) may further
reduce complications at the cost of increased risk of hypoglycemia
Diabetes Care 28:s4-36, 2005
http://www.aace.com/pub/press/releases/diabetesconsensuswhitepaper.php
Difficulties in Achieving
Target A1C Values

What is the appropriate A1C target

Challenges
– Late diagnosis and initiation of therapy
– Therapeutic inertia
– Lack of effective lifestyle intervention
– Secondary failure
– Adverse events associated with antihyperglycemic
therapies
– Complexity of care
– Role of postprandial glucose in failure
Screening for Diabetes
– Fasting plasma glucose at least every 3 years
starting at age 30-45
– Earlier and more frequent screening in people with
risk factors:
-
Family history
- Dyslipidemia (TG >150 or HDL <40/50)
Overweight
- History gestational DM or child >9#
High-risk ethnicity - Hypertension (> 140/90)
Prior FPG >99 mg/dl - Known vascular disease
Characteristics of insulin resistance
American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2004; 27 Suppl 1:S15-35.
Diabetes Guidelines Task Force. AACE guidelines for the management of diabetes mellitus. Endocr Pract. 1995; 1:149157.
Glucose Tolerance Categories
Fasting Plasma
Glucose
Must have two
measures to make a
diagnosis*
Diabetes Mellitus
126 mg/dL
Impaired Fasting
Fasting
Impaired
Glucose
Glucose
110 mg/dL
100 mg/dL
2-Hour Plasma
Glucose on OGTT
Diabetes Mellitus
7.0 mmol/L
6.1 mmol/L
5.6 mmol/L
200 mg/dL
11.1mmol/L
Impaired Glucose
Tolerance
140 mg/dL
Normal
7.8mmol/L
Normal
“Pre-Diabetes”
* One can also make the diagnosis of diabetes based on unequivocal symptoms and
a random glucose > 200 mg/dl
Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.
Diabetes Care. Supplement 1, January 2004.
Effect of Early TZD Use on A1C
6.8 -
Rosiglitazone (n=39)
6.6 -
Pioglitazone (n=62)
6.4 -
Control (n=71)
†
*
†
6.2 -
A1C (%)
6.0 -
*
5.8 -
*
5.6 -
*
5.4 5.2 -
*
*
*
* P<0.001 vs. baseline; † P<0.001 vs. rosiglitazone and pioglitazone
5.0 -
Baseline
Switch
Durbin RJ Diabetes, Obesity & Metabolism 6:280-285, 2004
2-yr check
3-yr final
Difficulties in Achieving
Target A1C Values

What is the appropriate A1C target

Challenges
– Late diagnosis and initiation of therapy
– Therapeutic inertia
– Lack of effective lifestyle intervention
– Secondary failure
– Adverse events associated with antihyperglycemic
therapies
– Complexity of care
– Role of postprandial glucose in failure
Stepwise Management of Type 2
Diabetes: Treat-to-Failure Approach
Diet, exercise, lifestyle…
wait for failure
Monotherapy… wait for failure
Combination therapy… wait for failure
Based on failure, consider:
Higher order combination therapy . . .
Slide provided by Steve Edelman, MD.
Patients Remain on Monotherapy
>1 Year After First A1c >8.0%*
Length of time that the patient’s A1c remained above 8.0%
before a switch/addition in therapy*
25
20 months
20
Months
15
14 months
10
5
0
Metformin Only
(n=354)
Sulfonylurea Only
(n=2517)
*May include up-titration. Length of time between first A1c >8.0% and switch/addition in therapy could include periods where patients
had subsequent A1c test values below 8%. Based on nonrandomized retrospective database analysis. Data from Kaiser Permanente
Northwest 1994-2002. Patients had to be continuously enrolled for 12 months with A1c lab values.
Brown et al. Diabetes. 2003;52(suppl 1):A61-A62. Abstract 264-OR.
Difficulties in Achieving
Target A1C Values

What is the appropriate A1C target

Challenges
– Late diagnosis and initiation of therapy
– Therapeutic inertia
– Lack of effective lifestyle intervention
– Secondary failure
– Adverse events associated with antihyperglycemic
therapies
– Complexity of care
– Role of postprandial glucose in failure
Patient Centered Team Diabetes
Management
Providers are coaches
Patients are clients
Role of the Provider
in Diabetes Management

Provide guidance in goal setting and evaluation
to manage the risk of complications

Suggest strategies to achieve goals and
techniques to overcome barriers

Provide skills training (self-management
techniques)

Screen for complications
Role of the Patient
in Diabetes Management

Commit to self-care

Participate in the development of a treatment
plan

Make ongoing decisions regarding self-care

Communicate frequently and honestly with
the rest of the team
Prioritizing Lifestyle Messages
Medical
Nutrition
Therapy

Emphasize blood glucose
control, not weight loss.

Focus on carbohydrate
foods, portions, and number
of servings per meal.

Encourage physical activity.

Use food records with blood
glucose monitoring data.
Compliance/Adherence

Comply: “to act in accordance with and fulfillment
of requests, demands, conditions or regulations”

Is “non-compliance” a patient or provider problem?
– Compliance model
- Greyhound motto: “Leave the driving to us”
– Informed choice/empowerment model
- Hertz motto: “We put you in the driver’s seat”
Difficulties in Achieving
Target A1C Values

What is the appropriate A1C target

Challenges
– Late diagnosis and initiation of therapy
– Therapeutic inertia
– Lack of effective lifestyle intervention
– Secondary failure
– Adverse events associated with antihyperglycemic
therapies
– Complexity of care
– Role of postprandial glucose in failure
Progressive Hyperglycemia Despite Insulin,
Sulfonylurea, or Metformin
Median HbA1c (%)
9
Conventional
Glibenclamide
Metformin
Chlorpropamide
Insulin
8
7
6
0
UKPDS 34, Lancet 1998.
2
4
6
8
Years from randomization
10
Impact on TZD Therapy on b-cell
Function in ZDF Rats

ZDF rat model
– Obese, insulin resistant
– Progressive decline in b cell
Lean control
Obese 6 weeks
Obese 12 weeks
TZD 12 weeks
Obese 16 weeks
TZD 16 weeks
function and mass

Effect of Glitazone
– Improve insulin resistance
and normalize glucose
– Rosiglitazone prevents
decline in b cell mass and
maintains normal glucose
Finegood D. Diabetes 50:1021–1029, 2001
Pioglitazone Comparator Studies – Europe
Durability
R. Urquhart. IDF 2003.
Pioglitazone Comparator Studies – Europe
Durability
R. Urquhart. IDF 2003.
Difficulties in Achieving
Target A1C Values

What is the appropriate A1C target

Challenges
– Late diagnosis and initiation of therapy
– Therapeutic inertia
– Lack of effective lifestyle intervention
– Secondary failure
– Adverse events associated with antihyperglycemic
therapies
– Complexity of care
– Role of postprandial glucose in failure
Anti-Hyperglycemic Agents in Type 2 Diabetes
Class
Insulin
Sulfonylureas, particularly
glimepiride and glipizide GITS
Fast acting secretagogue
("glinides"):
Biguanides (metformin)
Thiazolidinediones
("glitazones")
Alpha-glucosidase inhibitors
Amylin-mimetics (pramlintide)
Incretins (exenatide)
Advantages
Efficacy
Titratability
Inexpensive
Titratability
Flexibility
Fast on - Fast off
No weight gain
?CVD reduction
?CVD reduction
Preserve β-cell
No hypoglycemia
No weight gain
Weight loss
No hypoglycemia
Weight loss
No hypoglycemia
?preserve β-cell
Disadvatages
Weight gain
Hypoglycemia
Min. hypoglycemia
Minimal wt gain
TID
Expense
BID - GI complaints
Contraindications
Expensive - Slow onset
Weight gain - Fluid retention
GI complaints
Expensive
Injected
Expensive
Injected
Expensive
Diabetes Therapy and Weight Gain:
Management

Inform the patient of the risk
– Greatest risk of weight gain
-




Young
Female
Shorter duration of DM
Higher A1C at baseline
Lifestyle intervention
Use metformin, α-glucosidase inhibitors, exenatide,
pramlintide
– Consider weight loss medications
Monitor weight
Dose reduction in response to excessive weight gain
Diabetes Therapy and Hypoglycemia:
Management





Inform the patient of the risk
– Longer duration of DM
– Lower A1C
– Sliding scale insulin
Lifestyle intervention, patient education
Use metformin, glitazones, α-glucosidase inhibitors,
exenatide, nateglinide, analog insulin
Monitor glucose, keep logs
Goal resetting and dose reduction in response to
severe or asymptomatic hypoglycemia
Difficulties in Achieving
Target A1C Values

What is the appropriate A1C target

Challenges
– Late diagnosis and initiation of therapy
– Therapeutic inertia
– Lack of effective lifestyle intervention
– Secondary failure
– Adverse events associated with antihyperglycemic
therapies
– Complexity of care
– Role of postprandial glucose in failure
Core Treatments to Prevent
Complications

Blood glucose control

Blood pressure control

Lipid management

Smoking cessation

Specific therapies
Difficulties in Achieving
Target A1C Values

What is the appropriate A1C target

Challenges
– Late diagnosis and initiation of therapy
– Therapeutic inertia
– Lack of effective lifestyle intervention
– Secondary failure
– Adverse events associated with antihyperglycemic
therapies
– Complexity of care
– Role of postprandial glucose in failure
As Patients Get Closer to A1c Goal, the
Need to Manage PPG Increases
100
30%
80
%
60
Contribution
40
20
70%
55%
60%
50%
FPG
PPG
70%
30%
40%
45%
50%
9.2-8.5
8.4-7.3
0
>10.2
10.2-9.3
A1C Range (%)
Monnier L, et al. Diabetes Care. 2003;26:881-885.
<7.3
Treatment Algorithm - Glucose
Diagnosis
by screening or with symptoms
Lifestyle Intervention
nutrition, exercise, education
Quarterly to
semi-annual
follow-up
Are A1c/FPG Targets Achieved?
Yes
Monthly to
quarterly
follow-up
No
FPG > 200 mg/dL
Target Insulin
Deficiency
*
Target Insulin
Resistance
FPG < 130 mg/dL
Target PPG
*Keep adding agents until target is reached. Self-titration at home when possible.
Metformin, glitazone
Exenatide, nateglinide, α-glucosidase inhibitors, rapid-acting insulin, pramlintide
SFUs/glinide, insulin, exenatide