The Montefiore Clinical Diabetes CenterDiabetes Disease Management Program

Joel Zonszein, MD

More diabetes in New York City

0

1

2

3

4

5

6

7

8

9

1995 2002

%

3.7

7.9

www.nyc.gov/health/survey NYC Vital Signs January 2003

0

2

4

6

8

10

12

Bro

nx

Bro

oklyn

Man

hattan

Qu

eens

Staten

Island

More diabetes in the Bronx

11.59.0

6.07.0

4.6

www.nyc.gov/health/survey NYC Vital Signs January 2003

%

LOW

SEVERE

GUARDED

ELEVATED

HIGH

HEALTHLAND SECURITY ADVISORY SYSTEM

Average preprandial glucose‡(mg/dL) 90–130Average bedtime glucose‡ (mg/dL) 110–150HbA1c (%) <7

Total Cholesterol (mg/dL) <200LDL-Cholesterol (mg/dL) <70 to 100Triglycerides (mg/dL) <150-200HDL-Cholesterol (mg/dL) >50Non-HDL Cholesterol (mg/dL) <100 to130Blood pressure (mm Hg) 130/80

Goal

Modified Goal Recommendations in Diabetes

Harris MI et al. Diabetes Care. 1999;22:403-408.

62% of patients on oral therapy are not at ADA goal of HbA1c <7%

62%

% o

f S

ub

ject

s

38%0

20

40

60

80

100

>7%

<7%

HbA1c

Glycemic Control in Type 2 DiabetesNHANES III (1988-1994)

Treatment of the abnormal metabolic milieu

• TLC and weight reduction• Hypertension• Dyslipidemia• Hyperinsulinemia• Hypercoagulable state

Diabetes Self-Management Education(DSME)

Michele and Joanne:What to do with difficult to control patients ? –multiple medications

DSME

DSME

DSME

TEST

FREQUENCY

TARGET DATE

RESULT

DATE

RESULT

Weight

Each visit

Blood Pressure

Each visit

Below 130/80

HbA1c

Every 3 months

Below 7.0%

Total Cholesterol

Yearly *

Below 200

HDL(good) cholesterol

Yearly *

Above 45 - male

Above 55 - female

LDL(bad) cholesterol

Yearly *

Below 70 to 100

Triglycerides

Yearly *

Below 150

Microalbumin

Annual

Negative

Eye Examination

Annual

Foot Examination

Yearly *

Sites of Action of Oral Antidiabetic Agents

Sonnenberg GE, Kotchen TA. Curr Opin Nephrol Hypertens. 1998;7(5):551-555.

Muscle and adipose tissue:Peripheral glucose uptakeTHIAZOLIDINEDIONES

Liver: GlucoseproductionBIGUANIDES

Pancreas: InsulinsecretionSULFONYLUREASMEGLITINIDES

Intestine: Digestion and absorption of carbohydrates-GLUCOSIDASE INHIBITORS

Michele and Joanne:When to prescribe different medications such as Actos

Treatment should be tailored according to pathophysiology of the disease

Combination often necessary

Dose titration…..

Kahn SE, et al. Diabetes. 1993;42:1663-1672.

Si (x10-5 min-1/pmol/L)

AIRmax

(pmol/L)

0 5 10 15 200

1,000

2,000

3,000

4,000

95th

50th

5th

Males

Females

Relationship Between Insulin Sensitivity and b-Cell Secretory Capacity

25th

Relationship Between Insulin Sensitivity and-Cell Secretory Capacity: ‘Climbing the Curve’

Normal curve

Insu

lin s

ecre

tion

Resistant Insulin sensitivity Sensitive

Relationship Between Insulin Sensitivity and-Cell Secretory Capacity: ‘Falling off the Curve’

Bergman RN. Diabetes. 1989;38:1512-1527.

Resistant Insulin sensitivity Sensitive

Insu

lin s

ecre

tion

Type 2diabetes

Normal curve

0

100

200

300

400

500

0 1 2 3 4 5

Insulin Sensitivity

Insu

lin S

ecre

tion

NGT NGTNGT

Non-progressors

n=23

Progressors

n=11

NGT

IGT

DIA

Adapted from: Weyer C, et al. Journal of Clinical Investigation. 1999; 104(6): 787-94.

Getting Back on the Curve:Combination Therapy – the Short Cut

Sulfonylurea“Glinides”

Insulin

Diet, Exercise, Glitazones, Metformin

6

7

8

9

10

11

A1C Levels Attained by Oral Agents as Initial Therapy for Type 2 Diabetes

Pioglitazone

RosiglitazoneMetformin

IR XR Glipizide Repag. Nateg.

Me

an

A1C

(%

)

Efficacy of Oral Antidiabetes Drugs from Approved U.S. Prescribing Information

EBM

Baseline

Final

ADA Goal

0

10

20

30

40

50

60

UKPDS. JAMA. June 2, 1999.

6 Years 9 Years

Diet Insulin Sulfonylurea Metformin

Fraction of Monotherapy Patients Achieving 7% HbA1c (overweight cohort)

Percent

3 Years

Sites of Action of Oral Antidiabetic AgentsCOMBINATION THERAPY

Sonnenberg GE, Kotchen TA. Curr Opin Nephrol Hypertens. 1998;7(5):551-555.

Muscle and adipose tissue:Peripheral glucose uptakeTHIAZOLIDINEDIONES

Liver: GlucoseproductionBIGUANIDES

Pancreas: InsulinsecretionSULFONYLUREASMEGLITINIDES

Intestine: Digestion and absorption of carbohydrates-GLUCOSIDASE INHIBITORS

Metformin Monotherapy or combination Therapy With Glyburide

DeFronzo RA et al. N Engl J Med. 1995;333:541-549.

P<0.001 P<0.001 glyburide-metformin vs glyburideP<0.001 metformin vs glyburideP<0.01 metformin vs glyburide

*†

‡

§

Change infasting plasma

glucose (mg/dL)

Metformin

Metformin + glyburide

Glyburide

Week

4020

0-20-40

-800 5 9 13 17 21 25 29

† † †

‡‡

‡

§§‡

‡

‡ ‡‡ † † †

Diet + placebo

Diet + metformin

Week0 5 9 13 17 21 25 29

20

0

-20

-40

-60 ********

*

6

7

8

9

10

A1C Levels Attained by Oral Agents as 2nd-Line Therapy for Type 2 Diabetes

Pio +Metformin

Rosi +Metformin

Repaglinide +Metformin

Me

an

A1C

(%

)

Patients with Inadequate Glycemic Control on Metformin Therapy

Head-to-HeadComparison

Rosi +Metformin

Efficacy of Oral Antidiabetes Drugs From Approved U.S. Prescribing Information

Gly/MetTablets

ADA Goal

Baseline

Final

A1C Levels Attained by Oral Agents as2nd-Line Therapy for Type 2 Diabetes

6

7

8

9

10

Pio + SU

Rosi+ SU Metformin

+ SU

Gly/MetTablets

Glip/MetTablets

Me

an

A1C

(%

)

Patients with Inadequate Glycemic Control on Sulfonylurea Therapy

Efficacy of Oral Antidiabetes Drugs From Approved U.S. Prescribing Information

ADA Goal

Baseline

Final

Michele and Joanne:Common algorithms

Head to head studies for monotherapy

Combination, adding a second medication when one fails

Treatments are individual and sometimes capricious

MONTEFIORE DIABETES DISEASE MANAGEMENT APPROACH TO TREATMENT OF HYPERGLYCEMIA

EVERYONE GETS: EDUCATION/NUTRITION/EXERCISE

Metabolic Syndrome No Metabolic Syndrome

OBESE

TZD + METF

Older Non-Obese (>60 years)

SU

GOALS MET

Continue therapyFollow-up with A1c every 3-6 months

GOALS NOT MET

Change to

SU + INSULIN

GOALS NOT MET

INTENSIVE INSULIN THERAPY

Basal-Bolus

GOALS NOT MET

Add SU

(Triple Therapy)

GOALS NOT MET Change to

INSULIN + METF

GOALS NOT MET

Change to

INSULIN + METF

NON-OBESE

SU + METF

TZD + METF Young <60yrs

Insulins Peak (duration) hrs

• RAPID-ACTING– Humalog lispro 1-2 (2-6)– Novolog aspart 1-2 (2-6)

• SHORT-ACTING– Regular 2-4 (3-6)

• INTERMEDIATE-ACTING– NPH 6-12 (10-24)– Lente 6-14 (12-24)

• LONG ACTING– Ultralente 18-20 (18-28)– Lantus glargine none (10-24)

Insulin analogues

-4

-3

-2

-1

0

1

2

3

4

Morning NPH (N=32)

Evening NPH (N=28)

Twice-daily injections (=29)

Multiple-Daily injections (N=30)

Control (N=30)

Comparison of Insulin RegimensAmong Oral Treatment Failures

Change in HbA1c (%) Weight Change (kg)

Yki-Jarvinen H, et al. N Engl J Med. 1992;327:1426-1433

-1.7* -1.9* -1.8* -1.6*-0.5

*P 0,001 vs. control group†P < 0.05 vs. other insulin treatment groups

2.2*1.2*†

1.8*2.9*

-0.9

Insulin Combination Therapies in T2DM

• Bedtime NPH insulin + daytime sulfonylurea (BIDS)

• Bedtime NPH insulin + sulfonylurea + metformin

• Bedtime NPH insulin + metformin

• Lantus (glargine) + metformin

Yki-Jarvinen,H. Diabetes Care April 2001;24:758-67

Treat-to-Target Study: Timingand Frequency of Nocturnal Hypoglycemia

*P<0.03; †P<0.02.Rosenstock J et al. HOE901/4002 Study Group. Diabetes. 2002;51(suppl 2):A482. Abstract 1482-PO.

Patients reaching HbA1c 7%

Pati

ents

(%

)

4748

55

58

40

45

50

55

60

*†

1 Episodenocturnal

hypoglycemia

Insulin glargine

NPH insulin

mg

% o

r

U/m

l

100

0

12 6 12 6 12

GLUCOSE

INSULIN

Breakfast Lunch Tea Dinner

Normal insulin secretion

GLUCOSE

INSULIN

Breakfast Lunch Tea Dinner

Glucose and insulin in T2DM

300 mg/dl

100 mg/dl

5-20 mcu/L

20-200 mcu/L

GLUCOSE

Breakfast Lunch Dinner

Insulin therapy in T2DM

300 mg/dl

100 mg/dl

BG mg/dl Insulin units

<250 0

251-300 4

301-350 6

351-400 8

>400 10

Regular Insulin30 units/D in 100 K

GLUCOSE

Breakfast Lunch Dinner bed-time

300 mg/dl

100 mg/dl NPH/Lente

Insulin therapy in T2DM

• T1DM Insulin replacement 0.3-0.5 U/Kg/D – 2/3 given in the AM, 1/3 in the PM

– 2/3 long acting, 1/3 short acting

• T2DM Insulin supplementation 0.5-1.0 U/K/D– Bedtime only (h.s.)– AM + h.s.– If elevated postprandials: change to “insulin replacement”

Insulin Dosage Schedules

Examples of “Pen” Insulin Delivery Devices

Michele and Joanne:Management of Steroid induced hyperglycemia

Sensitizers

Insulin therapy

Relationship between steroid doses and hyperglycemia

Michele and Joanne:Side effects and holding medications

All have side effects:

SUO

Insulin secretagogues

TZD’s

Metformin

Alpha glucosidase inhibitors

Insulin

Hospitalized patients

Contrast media

MICROVASCULOPATHY

INSULIN THERAPY

IGT T y p e 2 d I a b e t e s

ALPHA-GLUCOSIDASE INHIBITORS

M E T F O R M I N

SULFONYLUREAS & MEGLITINIDES

CO

MP

LIC

AT

ION

S

T H I A Z O L I D I N D I O N E S

HYPERGLYCEMIA

DYSLIPIDEMIAHYPERTENSIONHYPERINSULINEMIAOBESITYHEMOSTASISOTHER RISK FACTORS

MACROVASCULOPATHY

Zonszein J. in Hurst’s the Heart (Ch 78) 1998;2117-2142