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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