Combination Therapy for

Type 2 Diabetes

Paul Davidson, MD, FACE

Atlanta Diabetes Associates

Atlanta, Georgia

Presented in Dalton, GA on Aug 14, 2003

ACE / AACE Targets for Glycemic Control

HbA1c < 6.5 %

Fasting/preprandial glucose < 110 mg/dL

Postprandial glucose < 140 mg/dL

ACE / AACE Consensus Conference, Washington DC August 2001

Goals of Intensive Diabetes Management

A Normal HbA1c Is Not Everything.

It Is the Only Thing!

TYPE 2 DIABETES . . . A PROGRESSIVE DISEASE

Natural History and Treatment

0

Years of Diabetes

Relative -Cell Function

PlasmaGlucose

Insulin resistance

Insulin secretion

126 mg/dL Fasting glucose

Post-meal glucose

Wt Loss

Sensitizes

Adapted from International Diabetes Center (IDC). Minneapolis, Minnesota

Secretors

Insulin

Exercise

-10-20 10 20 30

TYPE 2 DIABETES . . . A PROGRESSIVE DISEASE

Progressive Decline of -Cell Function in the UKPDS

0

20

40

60

80

100

10 9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6Years

-C

ell F

un

ctio

n (

%

)

Adapted from UK Prospective Diabetes Study (UKPDS) Group. Diabetes. 1995; 44:1249-1258.

6-4

Basal vs Mealtime Hyperglycemia in Diabetes

Riddle. Diabetes Care. 1990;13:676-686.

Pla

sma

Glu

cose

(m

g/d

L)

200

100

00600 1200

Time of Day1800 2400

Type 2 Diabetes

0600

150

250

50

Basal hyperglycemia Mealtime hyperglycemia

6-18

Normal

AUC from normal basal >1875 mgm/dL.hr; Est HbA1c >8.7%

When Basal Corrected

Pla

sma

Glu

cose

(m

g/d

L)

200

100

00600 1200

Time of Day1800 2400 0600

150

250

50

Basal hyperglycemia Mealtime hyperglycemia

6-18

Normal

Basal vs Mealtime Hyperglycemia in Diabetes

AUC from normal basal 900 mgm/dL.hr; Est HbA1c 7.2%

When Mealtime Hyperglycemia Corrected

Pla

sma

Glu

cose

(m

g/d

L)

200

100

00600 1200

Time of Day1800 2400 0600

150

250

50

Basal hyperglycemia Mealtime hyperglycemia

6-18

Normal

Basal vs Mealtime Hyperglycemia in Diabetes

AUC from normal basal 1425 mgm/dL.hr; Est HbA1c 7.9

When Both Basal & Mealtime Hyperglycemia Corrected

Pla

sma

Glu

cose

(m

g/d

L)

200

100

00600 1200

Time of Day1800 2400 0600

150

250

50

Basal hyperglycemia Mealtime hyperglycemia

6-18

Normal

Basal vs Mealtime Hyperglycemia in Diabetes

AUC from normal basal 225 mgm/dL.hr; Est HbA1c 6.4%

Step Therapy

Diet

Exercise

Sulfonylurea or Metformin

Add Alternate Agent

Add hs NPH

Switch to Mixed Insulin bid

Switch to Multiple Dose Insulin

Utilitarian, Common Sense, RecommendedProne to Failure fromMisscheduling and Mismanagement

Stumble Therapy

YAG Diet

Golf Cart Exercise

Sample of the Week Medication

– Interupted,

– Not Combined

Poor Understanding of Goals

Poor Monitoring

HbA1c >8% (If Seen)

Informed Patient Refers Self Elsewhere

PETS TherapyStep--Spelled Backwards

All at once, nothing first, Just like bubbles, when they burst.

Start with Fast to Glucose <126 mg/dL

– IV Insulin Feed PSMF Diet Add SU, MF, TZD, Repaglanide + prn Lispro for BG <150 “Normal” BG from Day 1 Monitor BG qid See Patient Monthly, HFP HbA1c Bimonthly

GI Problems: Cut MFHypoglycemia: Cut SUHypoglycemia Again: Cut RepaglinideAllow 2 Month to See TZD Effect

Mean Hemoglobin A1CPETS Rx

Mean Hemoglobin A1C29 Total Patients

6.06.57.07.58.08.5

9.09.5

10.010.511.0

Baseline 2 mo 4 mo 6 mo

He

mo

glo

bin

A

1C

-2.0

Insulin

The agent we have

to control glucose

only

most powerfulpowerful

Comparison of Human Insulins / Analogues

Insulin Onset of Duration ofpreparations action Peak action

Regular 30–60 min 2–4 h 6–10 h

Lispro/aspart 5–15 min 1–2 h 4–6 h

NPH/Lente 1–2 h 4–8 h 10–20 h

Ultralente 2–4 h Unpredictable 16–20 h

Glargine 1–2 h Flat ~24 h

400

350

300

250

200

150

100

MealSC injection

50

00 30 60

Time (min)90 120 180 210150 240

Regular Lispro

500450400350300250

150

50

200

100

00 50 100

Time (min)150 200 300250

Pla

sm

a i

ns

uli

n (

pm

ol/

L)

Pla

sm

a i

ns

uli

n (

pm

ol/

L)

MealSC injection

Heinemann, et al. Diabet Med. 1996;13:625–629; Mudaliar, et al. Diabetes Care. 1999;22:1501–1506.

Short-Acting Insulin AnalogsLispro and Aspart Plasma Insulin Profiles

Regular Aspart

Short-Acting Analogs Lispro and Aspart

Convenient administration immediately prior to meals

Faster onset of action

Limit postprandial hyperglycemic peaks

Shorter duration of activity

– Reduce late postprandial hypoglycemia

– Frequent late postprandial hyperglycemia

Need for basal insulin replacement revealed

Limitations of NPH, Lente,and Ultralente

Do not mimic basal insulin profile

– Variable absorption

– Pronounced peaks

– Less than 24-hour duration of action

Cause unpredictable hypoglycemia

– Major factor limiting insulin adjustments

– More weight gain

1 5 10 15 20 25 30

1 5 10 15 20 Asp

Gly

ArgExtension

Substitution

Arg

Insulin GlargineA New Long-Acting Insulin Analog

Modifications to human insulin chain

– Substitution of glycine at position A21

– Addition of 2 arginines at position B30

Gradual release from injection site

Peakless, long-lasting insulin profile

Lepore, et al. Diabetes. 1999;48(suppl 1):A97.

6

5

4

3

2

1

00 10

Time (h) after SC injection

End of observation period

20 30

GlargineNPH

Glu

cose

uti

lizat

ion

rat

e(m

g/k

g/h

)

Glargine vs NPH Insulin in Type 1 DiabetesAction Profiles by Glucose Clamp

Glucose Infusion Raten = 20 T1DMMean ± SEM

SC insulin

4.0

3.0

2.0

1.0

0

24

20

16

12

8

4

0

0 4 8 12 16 20 24Time (hours)

mg

/kg

/min

µm

ol/k

g/m

in

Lepore M, et al. Diabetes. 2000;49:2142–2148.

NPH

Ultralente

Glargine

CSII

Treat to Target Study: NPH vs Glargine in DM2 patients on OHA

Add 10 units Basal insulin at bedtime (NPH or Glargine)

Continue current oral agents

Titrate insulin weekly to fasting BG < 100 mg/dL

- if 100-120 mg/dL, increase 2 units

- if 120-140 mg/dL, increase 4 units

- if 140-160 mg/dL, increase 6 units

- if 160-180 mg/dL, increase 8 units

Treat to Target Study; A1C Decrease

8.6

7.5

7.16.9 6.9

6.5

7

7.5

8

8.5

9

0 5 10 15 20 25 30

Weeks in Study (N=691)

Mea

n H

bA

1c%

Patients in Target (A1C < 7%)

2.5

32.3

48.8

66.2

58

0

10

20

30

40

50

60

70

Percentage of Patients

Week 0 Week 8 Week 12 Week 18 Week 24

Bedtime Glargine vs NPH, With Mealtime Regular

4

3

2

1

0

48

36

24

12

0Nocturnal

HypoglycemiaWeight Gain

*

**

Wei

ght

(kg)

NPH Glargine

Patien

ts (%)

*P < .0007**P < .02 (compared to NPH)

Rosenstock, et al. Diabetes. 1999;48(suppl 1):A100.

6-52

Treatment to Target Study: NPH vs Glargine in DM2 patients on OHA

57% had HbA1c <7%

Nocturnal Hypoglycemia reduced by 42% in the Glargine group

33% had HbA1c <7% without any nighttime hypoglycemia in glargine group

Results significantly better than with NPH

Overall Summary: Glargine

Insulin glargine has the following clinical benefits

– Once-daily dosing because of its prolonged duration of action and smooth, peakless time-action profile

– Comparable or better glycemic control (FBG)

– Lower risk of nocturnal hypoglycemic events

– Safety profile similar to that of human insulin

Goals of Intensive Diabetes Management

Near-normal glycemia– HbA1c less than 6.5%

Avoid short-term crisis– Hypoglycemia– Hyperglycemia– DKA

Minimize long-term complications Improve QOL

Type 2 Diabetes … A Progressive Disease

Over time, all patients will need insulin

to control glucose

Insulin Therapy in Type 2 Diabetes Indications

Significant hyperglycemia at presentation Hyperglycemia on maximal doses of oral agents Decompensation

– Acute injury, stress, infection, myocardial ischemia– Severe hyperglycemia with ketonemia and/or ketonuria– Uncontrolled weight loss– Use of diabetogenic medications (eg, corticosteroids)

Surgery Pregnancy Renal or hepatic disease

MIMICKING NATURE WITH INSULIN THERAPY

All persons need

both basal and mealtime insulin

(endogenous or exogenous)

to controlcontrol glucose

6-19

Starting Basal Insulin

Continue oral agent(s) at same dosage– May later reduce

Add single insulin glargine dose (Wt# x 0.1 units)– Usually at bedtime

Adjust dose to normalize fasting SMBG Increase insulin dose q 3 d as needed

– Increase 4 U if FBG > 140 mg/dL– Increase 2 U if FBG = 110 to 140 mg/dL

Treat to target (usually < 110 mg/dL)

Advancing to Multiple Dose Insulin

Indicated when FBG acceptable but

– HbA1c > 6.5%

Insulin options

– Add mealtime lispro/aspart

Oral agent options

– Stop sulfonylurea

– Continue metformin for weight control

– Continue glitazone for insulin sensativity

Goals in Management of Type 2 Diabetes

Fasting BG <126 mg/dl

– Less Than 4 Months

HbA1c <7.0%

– Less Than 8 Months

i.e. 6%

Managing Type 2 Diabetes

Four Months or Lessto Goal 1

B G < 1 2 6

G O A L

< 1 2 6

G O A L

< 1 2 6

G O A L

< 1 2 6

G O A L

M D I

> 1 2 6

h s G

> 1 2 6

P E TS

> 1 2 6

W N D

< 1 2 6

G O A L

< 1 2 6

G O A L

< 1 2 6

G O A L

M D I

> 1 2 6

h s G

> 1 2 6

W N D

< 1 2 6

G O A L

< 1 2 6

G O A L

M D I

> 1 2 6

h s G /W N D

> 1 2 6

P E TS

> 1 2 6

P S M F

IV In su lin

B G > 1 2 6

F as t

B G > 2 0 0

Managing Type 2 DiabetesGoal 2 (HbA1c <7.0%)

G OAL 2

<7.0%

G OAL 2

<7.0%

G OAL 2

CSII

>7.0%

PET S->hs G ->M DI

>7.0%

HbA1c

G OAL 1FPG <126 m g/dL

Cost of Therapy per Dayper 1% Improvement in HbA1c*

$0

$2

$4

$6

$8

PETS TZD+MF TZD Repeg TZD+SU CSII MF SU MD I (G+LP)

* Based on US costs, FDA efficacy data, and current study data

GEMS--Glargine Evening Mealtime Secretagogue

Basal Dosing

– (Weight in #`s x 0.1)

• Glargine hs Prior to Meals

– Short Acting Secretagogue

• Rapaglinide 2 mg

• Nateglinide 120 mg

– Glimepiride 2 mg

Routine Hospital Care for Type 2 Diabetes The Case for GEMS

Usually metformin contra-indicated

Glargine insulin required for normal am glucose

– Stress or steroids

Interrupted and/or unreliable food intake

Nursing routine problems

– Lispro insulin at time of tray

– Reluctance to give lispro with normoglycemia

Supplemental lispro with elevated glucose

Short-acting secretagogue in half hour before tray

– Little risk of hypoglycemia if limited intake

Infections in Diabetes

One BG >220 mg/dl results in 5.8 times increase in nosocomial infection rate

Two hours hyperglycemia results in impaired WBC function for weeks

Pomposelli, New England Deaconess,

J Parenteral and Enteral Nutrition 22:77-81,1998

DIGAMI StudyDiabetes, Insulin Glucose Infusion in Acute Myocardial Infarction(1997)

Acute MI With BG >200 mg/dl Intensive Insulin Treatment IV Insulin For >24 Hours Four Insulin Injections/Day For >3 Months Reduced Risk of Mortality By 28% Over 3.4 Years

51% in Those Not Previous Diagnosed

Malmberg BMJ 1997;314:1512Malmberg BMJ 1997;314:1512

Cardiovascular RiskMortality After MI Reduced by Insulin Therapy in the DIGAMI Study

Malmberg, et al. BMJ. 1997;314:1512-1515.

All Subjects

(N = 620)Risk reduction (28%)

P = .011

Standard treatment

0

.3

.2

.4

.7

.1

.5

.6

0 1Years of Follow-up

2 3 4 5

Low-risk and Not Previously on Insulin

(N = 272)Risk reduction (51%)

P = .0004

IV Insulin 48 hours, then 4 injections daily

0

.3

.2

.4

.7

.1

.5

.6

0 1Years of Follow-up

2 3 4 5

6-11

ICU Survival

1548 Patients

All with BG >200 mgm/dl

Randomized into two groups

– Maintained on IV insulin

– Conventional group (BG 180-200)

– Intensive group (BG 80-110)

1.74 X mortality in conventional group

Van den Berghe NEJM 2001;345:1359

Protocol for Insulin in Hospitalized Patient

Glucommander While NPO hs: Wt(#) x 0.1 Glargine Meals Eaten: 1.5 units per 15 Gm CHO eaten BG >150: (BG-100) / CF

CF = 7000 / Wt(#) Do Not Use Sliding Scale Only Any BG <80: D50 (100-BG) x 0.3 ml

Maintain INT Do Not Hold Insulin When BG Normal

If HbA1c is Not to Goal i.e. 6.5%

SMBG

– frequency

– recording

– memory meter

Diet

– accurate CHO counting

– appropriate CHO/insulin bolusing

Infusion site areas Overtreatment of low BG Delayed or undertreatment

of high BG

If HbA1c Not to Goal i.e. 6.5%

SMBG

– frequency

– recording

– memory meter

Infusion site areas Overtreatment of low BG Delayed or undertreatment

of high BG

More than 4/day

2.8 x Wt / TDD

1700 Rule

(100-BG) x 0.2

Diet

–accurate CHO counting

–appropriate CHO/insulin bolusing

Improvement in HbA1c with Increased BG Testing

4

6

8

10

12

14

16

0 2 4 6 8 10 12

Blood Glucose Tests / day

He

mo

glo

bin

A1

c.....

If HbA1c Not to Goal i.e. 6.5%

SMBG

– frequency

– recording

– memory meter

Infusion site areas Overtreatment of low BG Delayed or undertreatment

of high BG

More than 4/day

2.8 x Wt / TDD

1700 Rule

(100-BG) x 0.2

Diet

–accurate CHO counting

–appropriate CHO/insulin bolusing

0

5

10

15

20

25

0 2 4 6 8 10

BW# / TDD

CIR

Median slope = 2.82

Data: file: IPDC020510A1cCIRs2, 127 pts

CARBOHYDRATE TO INSULIN RATIOCIR = 2.8 * BW# / TDD

If HbA1c Not to Goal i.e. 6.5%

SMBG

– frequency

– recording

– memory meter

Infusion site areas Overtreatment of low BG Delayed or undertreatment

of high BG

More than 4/day

22.8 x Wt / TDD

1700 Rule

(100-BG) x 0.2

Diet

–accurate CHO counting

–appropriate CHO/insulin bolusing

20

40

60

80

100

120

140

160

Before / After

Glu

cose

Correction of Hypoglycemia with Glucose100-BG X 0.15 Grams

If HbA1c Not to Goal i.e. 6.5%

SMBG

– frequency

– recording

– memory meter

Infusion site areas Overtreatment of low BG Delayed or undertreatment

of high BG

More than 4/day

2.8 x Wt / TDD

1700 Rule

(100-BG) x 0.2

Diet

–accurate CHO counting

–appropriate CHO/insulin bolusing

0

20

40

60

80

100

120

140

0 0.02 0.04 0.06 0.08 0.1

1 / TotalDailyInsulin

Co

rrecti

on

Facto

rCorrection Factor

The 1700 Rule

CF = 1724 / TDD

n = 166

Future of Diabetes Management Improvements in Insulin & Delivery

Insulin analogs and inhaled insulin

External pumps

Internal pumps

Closed-loop systems

Conclusion

Intensive therapy to target is the

only way to treat patients

with diabetes

4. Insulin Pump

3. Glargine + Lispro/Aspart

2. Glargine + Glinide or Sulfonylurea

1. Metformin + Glinide or Sulfonylurea