St

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Fall 2007Symposia Series

• St

• Sheraton Buckhead Hotel AtlantaAtlanta,
  GeorgiaNovember 10, 2007

2
Optimizing Therapy for Type 2 Diabetes Tipping
Toward Earlier Insulin Use

• Charles F. Shaefer, Jr, MD
• Assistant Clinical Professor of Medicine
• Medical College of Georgia
• Augusta, Georgia

3
Key Question

• At what point in therapy are you most comfortable
  with initiating insulin in your patient
  population?

• As the first agent
• As the second agent
• As the third agent
• As the last resort after all oral agents have
  been tried
• Use your keypad to vote now!

4
At what point in therapy are you most comfortable
with initiating insulin in your patient
population?

• As the first agent
• As the second agent
• As the third agent
• As the last resort after all oral agents have
  been tried

Use your keypad to vote now!
5
Faculty Disclosure

• Dr Shaefer speakers bureau Daiichi-Sankyo,
  Pfizer Inc, sanofi-aventis, Takeda.

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Learning Objectives

• State current management goals for diabetes
• Identify barriers to optimal use of insulin, and
  how to overcome them
• Discuss the roles of short-, intermediate-, and
  long-acting insulins in the management of
  diabetes

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A1C Targets Suggested by Different Organizations

Optimal target A1C lt6 (normal range)
As close to normal (lt6) without significant
hypoglycemia. Prospective data on A1C and
macrovascular disease are less conclusive than on
AIC and microvascular disease. AACE American
Association of Clinical Endocrinologists ADA
American Diabetes Association EASD European
Association for the Study of Diabetes.
8
Diabetes Demographics in the United States
Population Aged 20 Years
Adapted from National Center for Health
Statistics. Health, United States, 2006. With
Chartbook on Trends in the Health of Americans.
Hyattsville, Md 2006.
9
Insights from NHANES How Are We Doing?

• A1Cs in 1999-2000 not as well controlled as in
  1988-1994
• 7.7 vs 7.9 average A1C
• Wide selection of treatments may cause clinical
  inertia
• Choice of treatment has changed between old and
  new study
• Diet only 27 vs. 20
• OADs only 45.4 vs 52.5
• Insulin OADs 3.1 vs 11
• Insulin only 24.2 vs 16.4

Koro C et al. Diabetes Care. 20042717-20, 2004.
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Risk Factor Control in Adults With Diabetes
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n 1204
NHANES 1999-2000, n 370
48.2
50
P lt.001
44.3
40
37.0
35.8
33.9
29.0
30
Patients ()
20
10
7.3
5.2
0
A1C lt7
BP lt130/80 mm Hg
TC lt200 mg/dL
Good control
Achieved all 3 indicated goals. BP blood
pressure NHANES National Health and Nutrition
Examination Survey TC total cholesterol.
Saydah SH et al. JAMA. 2004291335-342.
11
Steno-2 Study Intensive Risk Factor Control
Reduces Cardiovascular Events
P .007
60
50
Conventional therapy
40
30
Primary Composite End Point ()
20
Intensive therapy
10
0
0
12
24
36
48
60
72
84
96
Follow-up (months)
Patients had type 2 diabetes. N 160. Intensive
therapy included low-fat diet, exercise, smoking
cessation, angiotensin-converting enzyme
inhibitor or angiotensin receptor blocker,
multivitamin, and if necessary an oral
hypoglycemic agent. The primary end point was a
composite of death from cardiovascular causes,
nonfatal myocardial infarction, nonfatal stroke,
revascularization, and amputation. Gaede P et
al. N Engl J Med. 2003348383-393.
12
Stages of Type 2 Diabetes Criteria for
Advancing to Next Stage?
A1C not at target ?7.0
100
Monotherapy
75
Combination oral therapy
ß-Cell Function ( ß)
50
Insulin
25
Type 2 Diabetes Phase I
Type 2 Diabetes Phase II
Phase III
0
-12
-10
-6
-2
2
0
6
10
14
Years From Diagnosis
Based on data of UKPDS 16. UKPDS Group.
Diabetes. 1995441249-1258.
13
Key Question

• What is the approximate amount that A1C
• can be lowered through use of oral agents?
• 1
• 2
• 3
• 4
• Use your keypad to vote now!

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What is the approximate amount that A1C can be
lowered through use of oral agents?

• 1
• 2
• 3
• 4

Use your keypad to vote now!
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Antihyperglycemic MonotherapyMaximum Therapeutic
Effect on A1C
Acarbose
Nateglinide
Sitagliptin
Rosiglitazone
Pioglitazone
Repaglinide
Glimepiride
Glipizide GITS
Metformin
Insulin
-0.5
0
-1.0
-1.5
-2.0
Reduction in A1C ()
Precose PI. West Haven, Conn Bayer 2003
Aronoff S et al. Diabetes Care.
2000231605-1611 Garber AJ et al. Am J Med.
1997102491-497 Goldberg RB et al. Diabetes
Care. 199619849-856 Hanefeld Met al. Diabetes
Care. 200023202-207 Lebovitz HE et al. J Clin
Endocrinol Metab. 200186280-288 Simonson DC
et al. Diabetes Care. 199720597-606
Wolfenbuttel BH, van Haeften TW. Drugs.
199550263-288.
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UKPDS Early Initiation of Insulin Therapy
Improves A1C Control
Conventional therapy Insulin therapy Sulfonylurea
insulin therapy
ULN upper limit of A1C nondiabetic
range. Wright A et al. Diabetes Care.
200225330-336.
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Clinical Inertia Failure to Advance Therapy
When Required
Last A1C Value Before Abandoning Treatment
10
9.6
9.1
Mean A1C at Last Visit ()
9
8.6
8.8
8
ADA Goal
7
Sulfonylurea
Combination
Diet/Exercise
Metformin
2.5 Years
2.9 Years
2.2 Years
2.8 Years
Brown JB et al. Diabetes Care. 2004271535-1540.
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ADA/EASD Consensus Algorithm for Type 2 Diabetes
Diagnosis
Lifestyle Intervention Metformin
Add Glitazone (no hypoglycemia)
Add Sulfonylurea (least expensive)
Add Basal Insulin (most effective)
Intensify Insulin
Add Glitazone
Add Basal Insulin
Add Sulfonylurea
Add Basal or Intensify Insulin
Intensive Insulin Metformin /- Glitazone
Check A1C every 3 months until lt7 and then at
least every 6 months. Although 3 oral agents
can be used, initiation and intensification of
insulin therapy is preferred based on
effectiveness and expense.Nathan DM et al.
Diabetes Care. 2006291963-1972.
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Key Question

• What are the barriers for your patients with
• type 2 diabetes regarding initiation of
• insulin therapy?
• Concern that insulin use is forever
• Fear of injection
• Equating insulin use with worsening diabetes and
  complications
• Fear of weight gain
• Use your keypad to vote now!

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What are the barriers for your patients with
type 2 diabetes regarding initiation of insulin
therapy?

• Concern that insulin use is forever
• Fear of injection
• Equating insulin use with worsening diabetes and
  complications
• Fear of weight gain

Use your keypad to vote now!
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Patient Barriers to Insulin Use Perception vs
Reality
OAD oral antidiabetic drug. Meese J. Diabetes
Educ. 2006329S-18S Peyrot M et al. Diabet Med.
2005221379-1385.
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Clinician Barriers to Insulin Use Perception vs
Reality
Douek IF et al. Diabet Med. 200522634-640
Malmberg K et al. J Am Coll Cardiol.
19952657-65 Malmberg K et al. BMJ.
19973141512-1515 Romano G et al. Diabetes.
1997461601-1606 UKPDS Group. Lancet.
1998352837-853.
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Information and Patient Education Links for
Healthcare Professionals

• American Association of Diabetes Educators
  (www.diabeteseducator.org)
• American Association of Clinical Endocrinologists
  (www.aace.com)
• American Diabetes Association (www.diabetes.org)
• International Diabetes Federation (www.idf.org)
• National Diabetes Education Initiative
  (www.ndei.org)
• National Diabetes Education Program
  (ndep.nih.gov)
• National Institute of Diabetes and Digestive and
  Kidney Diseases (www2.niddk.nih.gov)

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Next Steps

• What do we do for the patient who has failed on 1
  or 2 oral agents?

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Basal Insulin Therapy

• Usual first step when beginning insulin therapy
• Continue OAD and add basal insulin to optimize
  FPG
• A1C of up to 9.0 often brought to goal by
  addition of basal insulin therapy to OADs
• Easy and safe patient-directed treatment
  algorithms with small risk of serious
  hypoglycemia
• ADA and EASD recommended Although 3 OADs can be
  used, initiation and intensification of insulin
  therapy is preferred based on effectiveness and
  expense

FPG fasting plasma glucose. ADA. Diabetes Care.
200629(suppl 1)S4-S42 AACE position statement.
Available at http//www.aace.com/pub/pdf/guideli
nes/OutpatientImplementationPositionStatement.pdf.
Nathan DM et al. Diabetes Care.
2006291963-1972.
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Rationale for Basal Insulin TherapyInsulin and
Glucose Patterns
Basal insulin
Normal
T2DM
Glucose
Insulin
400
120
100
300
80
µU/mL
mg/dL
200
60
40
100
20
600
1000
1800
1400
200
2200
600
600
1000
1800
1400
200
2200
600
B
L
D
B
L
D
Time
Time
B breakfast D dinner L lunch T2DM type
2 diabetes mellitus. Polonsky KS et al. N Engl J
Med. 19883181231-1239.
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Options for Initiating Insulin Therapy

• Basal insulin
• NPH insulin (at bedtime)
• Insulin detemir (once or twice daily)
• Insulin glargine (once daily)
• Premixed insulin preparations
• 70/30 NPH insulin/regular insulin
• 50/50 NPL insulin/insulin lispro
• 70/30 NPA insulin/insulin aspart
• 75/25 NPL insulin/insulin lispro
• Premixed insulins are not recommended during
  adjustment on doses 1

Analog premixes
NPA neutral protamine aspart NPL neutral
protamine lispro. 1. Nathan DM et al. Diabetes
Care. 2006291963-1972.
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Idealized Profiles of Human Insulinand Basal
Insulin Analogs
NPH
Plasma Insulin Levels
Detemir
Glargine
200
400
600
800
1200
1400
1600
1800
2000
2200
2400
000
1000
Time
Plank J et al. Diabetes Care. 2005281107-1112
Rave K et al. Diabetes Care. 2005281077-1082
Rosenstock J, Goldstein BJ, et al, eds. Textbook
of Type 2 Diabetes. London, UK, and New York, NY
Martin Dunitz 2003131-154.
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ADA/EASD Algorithm Avoid Pre-Mixed Insulin in
Dose Adjustment Phase
Glucose levelsInsulin levels
Adapted with permission from Leahy J. In Leahy
J, Cefalu W, eds. Insulin Therapy. New York
Marcel Dekker 200287 Nathan DM. N Engl J Med.
20023471342-1349.
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Steps in Transition From Basal to Basal-Bolus
Insulin Therapy in T2DM
Above target A1C gt7.0 FPG gt110 mg/dL
A1C lt7.0, FPG lt110 mg/dL
HS at bedtime. Adapted with permission from
Karl DM. Curr Diab Rep. 20045352-357.
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Case Study
32
Case Study Initiating Insulin Therapy

• 60-year-old man 10-year history of T2DM and
  hypertension
• Current T2DM medications metformin 1000 mg bid,
  and glimepiride 8 mg qd
• Hypertension medications 40 mg lisinopril, 10 mg
  amlodipine, 12.5 mg HCTZ
• Dyslipidemia medication 10 mg atorvastatin
• Physical exam weight 245 lb height 60
  BMI 34.2 kg/m2 waist circumference 44 in
  BP 130/80 mm Hg
• Laboratory TC 167 mg/dL TG 206 mg/dL HDL
  35 mg/dL LDL 90 mg/dL
• A1C 8.9 plasma glucose in the office 198
  mg/dL
• Creatinine 1.1 mg/dL, normal LFTs

HCTZ hydrochlorothiazide TG triglycerides
HDL high-density lipoprotein LFTs liver
function tests BMI body mass index.
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Case Study (contd)

• Patient agrees to basal insulin therapy, however
• Expresses feelings of failure at inability to
  control glycemia with OADs
• Displays anxiety about injections
• You explain the progressive nature of diabetes
• Convey that insulin injections are the best way
  to achieve glycemic control
• Describe injection options (painless needles,
  injector pens, etc)
• Indicate that you and the patient will be a
  team in getting to the A1C goal

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Decision Point

• Which insulin would you use?
• NPH at bedtime
• Glargine once daily
• Twice-daily premixed
• Detemir at bedtime
• Use your keypad to vote now!

35
Which insulin would you use?

• NPH at bedtime
• Glargine once daily
• Twice-daily premixed
• Detemir at bedtime

Use your keypad to vote now!
36
Treat-to-Target Trial Oral Agents Glargine or
NPH at Bedtime (n756) Efficacy Results
In both groups, FPG decreased from 194 or 198
mg/dL to 117 or 130 mg/dL, respectively, by study
end, and A1C decreased from 8.6 to 6.9 by 18
weeks.
Riddle MC et al. Diabetes Care. 2003263080-3086.
37
Treat-to-Target Trial Timing and Frequency of
Hypoglycemia
Hypoglycemia by Time of Day
Basal insulin
Insulin glargine
350


NPH insulin
300

250

Hypoglycemia Episodes (PG ?72 mg/dL)
200



150
100
50
B L D
0
2000
2200
2400
200
400
600
800
1000
1200
1400
1600
1800
2000
Time
P lt.05 (between treatment).
Riddle MC et al. Diabetes Care. 2003263080-3086.
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Detemir vs NPH Insulin in T2DM (n 476)
Detemir NPH
400 350 300 250 200 150 100 50 0
A1C ()
10.0 9.0 8.0 7.0 6.0
Detemir NPH
Hypoglycemia Events
2
0
4
8
12
16
20
24
-2
0
4
8
12
16
20
24
Study Week
Study Week
All reported events, including symptoms only.
Hermansen K et al. Diabetes Care.
2006291269-1274.
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Strategy Increase Basal Insulin by 1 Unit/Day
to FPG ?100 mg/dL
INSIGHT Study Oral Agents Insulin Glargine
Estimates of the likelihood of achieving and
maintaining the indicated outcome based on Cox
regression before and after adjustment for
baseline A1C, baseline oral agent use, and site.
Gerstein HC et al. Diabet Med. 200623736-742.
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Case Study (contd)

• Patient is seen 1 month later
• FPG still above 200 mg/dL, using up to 30 U
  daily
• Patient is frustrated and feels the insulin does
  not work

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Decision Point

• What do you do now?
• Keep increasing the insulin dose
• Go to twice-daily premixed
• Switch to exenatide
• Send patient for gastric bypass consult
• Use your keypad to vote now!

42
What do you do now?

• Keep increasing the insulin dose
• Go to twice-daily premixed
• Switch to exenatide
• Send patient for gastric bypass consult

Use your keypad to vote now!
43
Treat-to-Target Trial
50
45
Units
Total Daily Dose (U)
42
37
40
33
28
30
21
20
10
10
0
21
0
1
2
3
4
5
6
7
8
10
12
15
18
N 756. Riddle MC et al. Diabetes Care.
2003263080-3086.
Weeks in Study
44
Case Study (contd)

• Patient is taking 75 U with FPG controlled (lt100
  mg/dL to rarely gt110 mg/dL) since last visit 4
  months ago
• Patients last A1C 6.9, monitoring occasional
  postprandial blood sugars
• Patient finds insulin injections painless and
  after speaking with you, feels that he is now a
  partner in his therapy program

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Case Study (contd)

• Over the next 3 years, patient seen for routine
  follow-up every 3 to 4 months
• Remains medically stable, with A1C values 6.5
  to 7.2
• 3.25 years after adding basal insulin glargine,
  A1C has increased to 8.2, however, FPG checks
  remain lt120 mg/dL

46
At Lower A1C Levels, PPG Contributes More to
Overall A1C Than FPG
Contribution ()
1
2
3
4
5
A1C Quintile
PPG postprandial glucose. Reprinted with
permission from Monnier L et al. Diabetes Care.
200326881-885.
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Prandial Excursions Are Evident, Especially
Around a Single Key Meal Insulin Glargine vs
Premixed (n 209)
Plasma Glucose (mg/dL)
Time of Day
Total units 51.3 26.7 with glargine plus OADs
vs 78.5 39.5 with premixed insulin (BIAsp
70/30) Denotes statistically significant
difference between treatment groups at specific
times. Premixed BIAsp 70/30.
Raskin P et al. Diabetes Care. 200528260-265.
48
Idealized Profiles Rapid-Acting Insulin Analogs
Regular insulin
NPH
Plasma Insulin Levels
Detemir
Glargine
200
400
600
800
1200
1400
1600
1800
2000
2200
2400
000
1000
Time
Inhaled dry human insulin (Exubera) powder
Rosenstock J, Goldstein BJ, et al, eds. Textbook
of Type 2 Diabetes. London, UK, and New York, NY
Martin Dunitz 2003131-154 Plank J et al.
Diabetes Care. 2005 281107-1112 Rave K et al.
Diabetes Care. 2005281077-1082.
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Meal Insulin Rapid-Acting Analogs (Lispro,
Aspart, Glulisine) vs Regular
10
8
6
Insulin Activity
4
2
0
1
2
3
4
5
6
7
8
9
10
11
12
0
Hours
RHI regular human insulin. Adapted with
permission from Howey DC et al. Diabetes.
199443396-402.
50
Decision Point

• The best time to use a rapid-acting insulin
• analog is
• Before a meal
• After a meal
• Either works well
• Use your keypad to vote now!

51
The best time to use a rapid-acting insulin
analog is

• Before a meal
• After a meal
• Either works well

Use your keypad to vote now!
52
Advantages of Rapid-Acting Analogs

• Short duration of actionfewer between-meal
  hypos than regular insulin
• Flexible mealtime dosing
• More consistent kinetics
• Day to day
• Across anatomical sites
• With large doses
• Slightly faster onset of glulisine action
  (compared to lispro) in obese and morbidly obese
  subjects (independent of BMI)

Adapted from Hirsch IB. N Engl J Med.
2005352174-183. Becker RHA et al. Exp Clin
Endocrinol Diabetes. 2005113435-443. Heise T
et al. Diabetes. 200554(suppl 1)A145.
53
Case Study (contd)

• At 6-month follow-up patient is doing well with
  70 U glargine and 10 U to 17 U glulisine at
  supper
• Actual dose adjusted by
• Meal carbohydrate content
• Activity
• Insulin supplement of additional 1 U for every
  25 mg/dL above 130 mg/dL (prandial glucose)
• A1C 6.3
• He feels well, has infrequent hypos, and is
  pleased with his blood glucose control

54
Q A
55
PCE Takeaways
56
PCE Takeaways Basal-Prandial Insulin Replacement

• An effective insulin treatment strategy provides
  both basal and postprandial insulin coverage
• Initially, prandial insulin may be needed only at
  the largest meal of the day, with coverage at
  other meals added based on prandial glucose
  levels
• Rapid-acting insulin analogs closely match normal
  mealtime insulin patterns

57
Key Question

• How much more comfortable do you now feel you
  will be initiating insulin therapy in your
  patient population?

• Much more comfortable
• Somewhat comfortable
• Slightly comfortable
• Not comfortable at all
• Use your keypad to vote now!

58
How much more comfortable do you now feel you
will be initiating insulin therapy in your
patient population?

• Much more comfortable
• Somewhat comfortable
• Slightly comfortable
• Not comfortable at all

Use your keypad to vote now!
59
Fall 2007Symposia Series

• St

• Sheraton Buckhead Hotel AtlantaAtlanta,
  GeorgiaNovember 10, 2007