effective use of insulin in diabetes: update for 2007 kenneth s. hershon, md director of research...

Effective Use of Insulin in Diabetes: Update for 2007

Kenneth S. Hershon, MDDirector of Research

North Shore Diabetes and Endocrine AssociatesNew Hyde Park, New York

Assistant Clinical Professor of MedicineAlbert Einstein College of Medicine

Bronx, New York

Key Question

1. Completely comfortable

2. Somewhat comfortable

3. Slightly comfortable

4. Not comfortable at all

Use your keypad to vote now!

?How comfortable are you with initiating insulin therapy in your patient population?

Faculty Disclosure

Dr Hershon: honorarium, research support, speakers bureau: Eli Lilly and Company, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Pharmaceuticals Inc, Pfizer Inc, sanofi-aventis Group.

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

A1C Targets Suggested by Different Organizations

Optimal target: A1C <6% (normal range)

*As close to normal (<6%) without significant hypoglycemia.

AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association; EASD = European Association for the Study of Diabetes.

Organization A1C Target (%)

AACE <6.5

EASD <6.5

ADA <7 (general)

<6* (individual patient)

VT = 26.7NH = 20.4MA = 29.5CT = 28.4RI = 29.5NJ = 67.3DE = 66.4MD= 68.1

WA 68.4 MT

55.2OR64.2 ID

63.3 WY63.0

ND29.7

SD24.6

NE56.5

CO67.1

UT72.4

NV67.3

CA34.5

AZ67.3

NM68.6

TX67.7

OK65.6

KS67.0

MN59.3

IA58.9

MO66.2

AR69.6

LA71.3

MS72.8

AL71.3 GA

69.3

FL63.9

SC66.3

NC65.7

VA67.7

WV69.5KY

66.8TN65.6

IL72.6

W24.2I MI

65.4

IN66.4

OH71.7

PA70.9

NY71.1

VTNH

ME27.2

MARI

NJ

DEMD

CT

Top 10 Highest

AACE. State of Diabetes in America. May 2005. Available at: http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf

National average = 67% above goal (A1C 6.5%)

N >157,000

State of Diabetes in America: Blood Sugar Control Across the United States as Measured by A1C

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.

0

2

4

6

8

10

12

14

Male Female White Black Mexican TOTAL

1988-1994

2001-2004

0

2

4

6

8

10

12

14

Male Female White Black Mexican TOTAL

1988-1994

2001-2004

Ph

ysic

ian

-Dia

gn

ose

d D

iab

etes

(%

)

Un

dia

gn

ose

d D

iab

etes

(%

)

Ad

just

ed I

nci

den

ce p

er 1

000

Per

son

-Yea

rs (

%)

UKPDS = United Kingdom Prospective Diabetes Study.Stratton IM et al. BMJ. 2000;321:405-412.

Epidemiologic Data From the UKPDS

Updated Mean A1C (%)

Myocardial infarctionMicrovascular end points

40

60

80

20

05 6 7 8 9 10 11

?

AACE Goal

No A1C Threshold in Type 2 Diabetes

*Achieved all 3 indicated goals.BP = blood pressure; NHANES = National Health and Nutrition Examination Survey; TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.

Pat

ien

ts (

%)

A1C <7%

44.3%

NHANES III, n = 1204

0

10

20

30

40

50

BP <130/80 mm Hg

TC <200 mg/dL

29.0%

Good control*

7.3%5.2%

33.9%35.8%

37.0%P <.001

48.2%

Risk Factor Control in Adults With Diabetes: NHANES III (1988-1994)/NHANES 1999-2000

NHANES 1999-2000, n = 370

Stages of Type 2 Diabetes: Criteria for Advancing to Next Stage?

100

75

50

25

0

-10 -6 -2 20 6 10 14-12

Years From Diagnosis

β-C

ell

Fu

nct

ion

(%

β)

Type 2DiabetesPhase I

Monotherapy

Type 2DiabetesPhase II

Combination oral therapy

Phase III

Insulin

A1C not at target: 7.0%

Based on data of UKPDS 16. UKPDS Group. Diabetes. 1995;44:1249-1258.

Adapted from Williams G. Lancet. 1994;343:95-100.

Stepwise Management of Type 2 Diabetes

+ +

Diet andexercise

+ Oral monotherapy

+ Oral combination

+ Oral combo + insulin

+ Insulin

+

Biggest Clinical Hurdle?

Key Question

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

1. 1%

2. 2%

3. 3%

4. 4%


?

Antihyperglycemic MonotherapyMaximum Therapeutic Effect on A1C

Insulin

Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld Met al. Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288; Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW. Drugs. 1995;50:263-288.

-0.50 -1.0 -1.5 -2.0

Nateglinide

Reduction in A1C (%)

Glipizide GITS

GlimepirideRepaglinidePioglitazone

Acarbose

Metformin

Rosiglitazone

Sitagliptin

UKPDS: Early Initiation of Insulin Therapy Improves A1C Control

ULN = upper limit of A1C nondiabetic range.Wright A et al. Diabetes Care. 2002;25:330-336.

Conventional therapyInsulin therapySulfonylurea ± insulin therapy

9

8

7

6

50

A1C

(%

)

ULN = 6.2%

41 2 3 650

Years From Randomization

Clinical Inertia: “Failure to Advance Therapy When Required”

Brown JB et al. Diabetes Care. 2004;27:1535-1540.

Diet/Exercise

2.5 Years

Mea

n A

1C a

t L

ast

Vis

it (

%)

8

9

10

7

8.6%

Last A1C Value Before Abandoning Treatment

2.9 Years

Sulfonylurea

2.2 Years

Metformin

2.8 Years

Combination

9.1%

8.8%

9.6%

ADA Goal

Key Question

What are the barriers for your patients with type 2 diabetes regarding initiation of insulin therapy?1. Concern that insulin use is “forever”2. Fear of injection3. Equating insulin use with worsening diabetes

and complications4. Fear of weight gain


?

Perception Reality

Failing oral therapy

58% of patients believe using insulin means they have failed OAD therapy

OAD failure is due to progressive nature of type 2 diabetes; insulin is best agent to control disease

Needle phobia

Fear associated with early experiences

Current needles considered painless; easy-to-use injection systems are available

Fear of complications

Common association of insulin with diabetic complications

Complications are due to uncontrolled, progressive disease; insulin actually results in reduction of vascular damage

Patient Barriers to Insulin Use: Perception vs Reality

OAD = oral antidiabetic drug. Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.

Perception RealityHypoglycemia is prevalent with insulin use

Severe hypoglycemia is very uncommon in patients with type 2 diabetes, occurring at 10% the rate in patients with type 1 diabetes

Insulin use increases atherosclerosis

Studies indicate no exacerbation of cardiovascular disease

There is weight gain with insulin use

Weight gain is modest and can be controlled with diet and exercise

Patients have a negative attitude regarding insulin use

Insulin is a “positive” approach to achieving glycemic control

Clinician Barriers to Insulin Use: Perception vs Reality

Douek IF et al. Diabet Med. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65; Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606; UKPDS Group. Lancet. 1998;352:837-853.

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)

Information and Patient Education Links for Healthcare Professionals

Next Steps…

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

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. 2006:29(suppl 1):S4-S42; AACE position statement. Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.

B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus.Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.

100

200

300

400Glucose Insulin

6:00 10:00 18:0014:00 2:0022:00 6:00

Time

6:00 10:00 18:0014:00 2:0022:00 6:00

Time

20

40

60

80

100

120

B L DB L D

Normal T2DM

mg

/dL

μU

/mL

Basal insulin

Rationale for Basal Insulin Therapy:Insulin and Glucose Patterns

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

NPA = neutral protamine aspart; NPL = neutral protamine lispro.1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.

Analog premixes

Plank J et al. Diabetes Care. 2005;28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082; Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY: Martin Dunitz; 2003:131-154.

Idealized Profiles of Human Insulinand Basal Insulin Analogs

0:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00

Pla

sma

Insu

lin

Lev

els

Time

NPH

GlargineDetemir

Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.

Twice-Daily Split-Mixed Regimens or Lispro Mix (75/25)–Aspart Mix (70/30)

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

Insu

lin

Act

ion

8:0012:008:00Time

Glucose levelsInsulin levels

Open-Label, Twice-Daily Exenatide vs Once-Daily Insulin Glargine: Self-Monitoring Blood Glucose Profiles (n = 549)

Blo

od

glu

cose

(m

g/d

L)

3 AM

100

120

140

160

180

200

220

240

Baseline (week 0)Endpoint (week 26)

100

120

140

160

180

200

220

240

Baseline (week 0)Endpoint (week 26)

Exenatide5 μg bid 1st 4 weeks, then 10 μg bid

Insulin glargine10 U/d, titrated to target FPG <100 mg/dL

Prebreakfast Prelunch Predinner

Both medications lowered A1C from 8.2% to 7.1% from baselineWeight change: exenatide –2.3 kg, glargine +1.8 kg

Nausea: exenatide 57.1%, glargine 8.6%

Heine RJ et al. Ann Intern Med. 2005;143:559-569.

3 AMPrebreakfast Prelunch Predinner

HS = at bedtime.Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.

Steps in Transition From Basal to Basal-Bolus Insulin Therapy in T2DM

Above target:A1C >7.0%FPG >110 mg/dL

A1C <7.0%, FPG <110 mg/dL

Glargine, Detemir,

or NPH HS

• Weekly titration based on FPG

• All oral agents continued

STEP 1

Abovetarget

Add insulin

Main meal

STEP 2

Abovetarget

Add insulin

and exenatide or pramlintide

Next largestmeal

STEP 3

Abovetarget

Add insulin

Last meal

STEP 4

Case Study

Case Study: Initiating Insulin Therapy 60-year-old man: 10-year history of T2DM and hypertension Current T2DM medications: metformin 1000 mg bid, rosiglitazone

8 mg AM, 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 (10-lb increase); height = 6’0”;

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.

Case Study (cont’d)

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

Decision Point

Which insulin would you use?

1. NPH at bedtime

2. Glargine once daily

3. Twice-daily premixed

4. Detemir at bedtime


?

Treat-to-Target Trial: Oral Agents + Glargine or NPH at Bedtime

Patients (n = 756) with inadequate glycemic control (A1C >7.5%) taking 1 or 2 oral agents

Started with 10 U/d bedtime basal insulin and adjusted weekly to target FPG 100 mg/dL:

Riddle MC et al. Diabetes Care. 2003;26:3080-3086.

Mean self-monitored FPG values from preceding 2 days (mg/dL)

Increase of insulin dosage(U/d)

≥180 8

140 – 180 6

120 – 140 4

100 – 120 2

Treat-to-Target Trial: Oral Agents + Glargine or NPH at Bedtime (n=756): 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.


100

150

200

0 4 8 12 16 20 24

Weeks of Treatment

FP

G (

mg

/dL

)

Glargine NPH

6

6.5

7

7.5

8

8.5

9

0 4 8 12 16 20 24

Weeks of TreatmentA

1C

(%

)

Glargine NPH

Insulin glargine

NPH insulin

0

50

100

150

200

250

300

350

20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00

Time

B L D

Basal insulin

20:00

Hypoglycemia by Time of Day

Hyp

og

lyce

mia

Ep

iso

des

(P

G

72 m

g/d

L)


*P <.05 (between treatment).

*

**

**

**

Treat-to-Target Trial: Timing and Frequency of Hypoglycemia

Detemir vs NPH Insulin in T2DM (n = 476)

*All reported events, including symptoms only.

Hermansen K et al. Diabetes Care. 2006;29:1269-1274.

Hyp

og

lyce

mia

Eve

nts

*

10.0

9.0

8.0

7.0

6.0

-2 0 4 8 12 16 20 24

DetemirNPH

A1C (%)

Study Week20 4 8 12 16 20 24

Study Week

400

350

300

250

200

150

100

50

0

DetemirNPH


10 U glargine is added to OADs Patient is sent home with the “2, 4, 6, 8 algorithm” with a target

FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be used with detemir2

FPG (mg/dL) Insulin Dose (U/d) 120-140 2 140-160 4 160-180 6 >180 8

Alternative strategy: Increase basal insulin dose by 2 units every 3 days until FPG 100 mg/dL*3

*Certain populations (children, pregnant women, and the elderly) require special considerations.

1. Riddle MC et al. Diabetes Care. 2003;26:3080-3086.2. Hermansen K et al. Diabetes Care. 2006;29:1269-1274.3. Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.


Patient is seen 1 month laterFPG still above 200 mg/dL, using up to

30 U dailyPatient is frustrated and feels the insulin

does not work

Decision Point

What do you do now?

1. Keep increasing the insulin dose

2. Go to twice-daily premixed

3. Switch to exenatide

4. Send patient for gastric bypass consult


?

42

10

21

28

3337

45

0

10

20

30

40

50

0 1 2 3 4 5 6 7 8 10 12 15 18 21

Units

Weeks in Study

To

tal

Dai

ly D

ose

(U

)

N = 756.


Treat-to-Target Trial


Patient is taking 75 U with FPG controlled (<100 mg/dL to rarely >110 mg/dL) since last visit 4 months ago

Patient’s 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

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 <120 mg/dL


Decision Point

What do you do now?

1. Increase glargine

2. Switch to twice-daily premixed

3. Switch to 4-shot basal-bolus program

4. Increase monitoring to AC and HS, and have patient report after 2 weeks


?

AC = before meals; HS = at bedtime.

PPG = postprandial glucose.Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.

Co

ntr

ibu

tio

n (

%)

A1C Quintile

At Lower A1C Levels, PPG Contributes More to Overall A1C Than FPG

1 2 3 4 5

Prandial Excursions Are Evident, Especially Around a Single Key Meal: Insulin Glargine vs Premixed (n = 209)

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. 2005;28:260-265.

*

Pla

sma

Glu

cose

(m

g/d

L)

Week 28

Baseline

GlarginePremixed†

Time of DayBB B90 BL L90 BD D90 Bed 3 AM

350

300

250

200

150

100

50

**

**

*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; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082.

Idealized Profiles: Rapid-Acting Insulin Analogs

0:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00

Pla

sma

Insu

lin

Lev

els

Time

GlargineDetemir

NPHRegular insulin

Rapid-acting

Inhaled insulin*

Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.

Twice-Daily Split-Mixed Regimens or Lispro Mix (75/25)–Aspart Mix (70/30)

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

Insu

lin

Act

ion

8:0012:008:00Time

Glucose levelsInsulin levels


Breakfast Lunch Dinner MSMiddle of NightDose Blood

Sugar Dose Blood Sugar Dose Blood

Sugar Dose Blood Sugar

Monday 107 126 133 185

Tuesday 116 123 120 164 118

Wednesday 102 121 105 205 112

Thursday 94 132 120 213

Friday

Saturday

Sunday

Daily Blood Glucose Diary July 24Week Ending

Meal Insulin: Rapid-Acting Analogs (Lispro, Aspart, Glulisine) vs Regular

Hours

RHI = regular human insulin.Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.

10

8

6

4

2

00 1 2 3 4 5 6 7 8 9 10 11 12

Insu

lin

Act

ivit

y

RHI

Timing offood

absorbed

Analog insulin

Advantages of Rapid-Acting Analogs

Short duration of action—fewer 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. 2005;352:174-183.Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443.*Heise T et al. Diabetes. 2005;54(suppl 1):A145.

Decision Point

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

1. Before a meal

2. After a meal

3. Either works well


?

Pre- and Postmeal Efficacy of Insulin Glulisine vs Regular Human Insulin

Garg SK et al. Endocr Pract. 2005;11:11-17; Garg SK et al. Poster presented at ADA 64th Annual Scientific Sessions, June 4-8, 2004, Diabetes. 7:529P.

Significant A1C reduction with premeal glulisine compared to premeal human insulin

Significant reduction in A1C with pre- and postmeal glulisine

Baseline

Endpoint

P <.05P <.05P <.05


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 byMeal carbohydrate contentActivity 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

PCE Takeaways

PCE Takeaways: Basal-Prandial Insulin Replacement

1. An effective insulin treatment strategy provides both basal and postprandial insulin coverage

2. 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

3. Rapid-acting insulin analogs closely match normal mealtime insulin patterns

Key Question

1. Much more comfortable

2. Somewhat comfortable

3. Slightly comfortable

4. Not comfortable at all


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

effective use of insulin in diabetes: update for 2007 kenneth s. hershon, md director of research...

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