1

New therapies in diabetes mellitus

(or how to keep your friendly diabetologist busy)

Melissa Meredith, M.D.Mar. 7, 2007

2

New Available Therapies

Incretin agents

Incretin agonists

– Exenatide (Byetta)

DPP-IV inhibitors

– Sitagliptin (Januvia)

– Vildagliptin (Galvus)

Insulin

Insulin detemir (Levemir)

Inhaled insulin- Exubera

Pramlintide (Amylin)

3

Patterns of Glucose, Insulin, and Glucagon in Type 2 Diabetes

400

Type 2 diabetes

Normal

0

120

240

360

-60 0 60 120 180 240 300

Delayed and reduced

Postprandial hyperglycemia

Minutes

300

200

100

Mitrakou A et al. Diabetes. 1990;39:1381-1390

pm

ol/

L m

g/d

L

Glucose

Insulin

-60 0 60 120 180 240 300

60

30

45

High and not suppressed

Minutes

fmo

l/L

Glucagon

4

Time, min

IR In

sulin

, mU

/L nm

ol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

The Incretin Effect in Subjects Without and With Type 2 Diabetes

Control Subjects (n=8)

Patients With Type 2 Diabetes (n=14)

Time, min

IR In

sulin

, mU

/L nm

ol / L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 120 0

Oral glucose load

Intravenous (IV) glucose infusion

Incretin Effect

The incretin effect is diminished

in type 2 diabetes.

Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.Permission pending.

5

GLP-1 Effects in HumansUnderstanding the Natural Role of Incretins

Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553Adapted from Drucker DJ. Diabetes. 1998;47:159-169

Stomach:Stomach: Helps regulate Helps regulate

gastric emptyinggastric emptying

Promotes satiety and Promotes satiety and reduces appetitereduces appetite

Liver:Liver: Glucagon reduces Glucagon reduces

hepatic glucose outputhepatic glucose outputBeta cells:Beta cells:Enhances glucose-Enhances glucose-

dependent insulin secretiondependent insulin secretionDecreased apoptosisDecreased apoptosisBeta cell regenerationBeta cell regeneration

Alpha cells:Alpha cells: PostprandialPostprandial

glucagon secretionglucagon secretion

GLP-1 secreted upon the ingestion of food

Beta-cellworkload

Beta-cellworkload

Beta-cellresponse

Beta-cellresponse

GLP-1 levels are decreased in DM 2

6

Glucose-Dependent Effects of GLP-1 Infusion on Insulin and Glucagon Levels in Patients With Type 2 Diabetes

Glucose

Glucagon When glucose levels approach normal values, glucagon levels rebound.

When glucose levels approach normal values,insulin levels decrease.

*P <0.05Patients with type 2 diabetes (N=10)

mm

ol/

L

15.012.510.0

7.55.0

25020015010050

mg

/dL*

* * * * * *p

mo

l/L 250

200150100

50

40

30

20

10

0

mU

/L

* ** ** * * *

Infusion

Minutes

pm

ol/

L 20

15

10

5

0 60 120 180 240

* * * *

pm

ol/L

20

15

10

5

Placebo

GLP-1

Insulin

2.50

0

0 0

0

Adapted from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag.Permission pending

–30

7

Effect of Exenatide on A1C

SFU

See Important Safety Information included in this presentationMean (SE); *P<0.005Data from DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100Data from Buse JB, et al. Diabetes Care. 2004;27:2628-2635Data from Kendall DM, et al. Diabetes Care. 2005;28:1083-1091

Placebo BID Exenatide 5 mcg BID Exenatide 10 mcg BID

MET + SFU

0.2

-0.6*

*-0.8

247 245 241

8.5 8.5 8.5

0.1

-0.5*

*-0.9

123 125 129

8.7 8.5 8.6

MET

-0.4*

- 0.8*-1

-0.5

0

0.5

Baseline

n 113 110 113

8.2 8.3 8.2

A1C (%) 0.1

8N = 283; Mean (± SE); P<0.05.Henry R, et al. Diabetes 2006; 55:A116.

Exenatide Sustained A1C Reduction2-Year Completers

0 10 20 30 40 50 60 70 80 90 100 1106.5

7.0

7.5

8.0

8.5

Time (wk)

Placebo-Controlled Open-Label Extensions

Baseline A1C8.3%

-1.1 0.1%

A

1C (

%)

9

No diet and exercise regimen was provided.N = 283; Mean (± SE); P<0.05.Henry R, et al. Diabetes 2006; 55:A116.

Exenatide Continued to Reduce Weight 2-Year Completers

0 10 20 30 40 50 60 70 80 90 100 110-7

-6

-5

-4

-3

-2

-1

0

1Placebo-Controlled Open-Label Extensions

Baseline Weight100 kg

-4.7 0.3 kg

Time (wk)

W

eig

ht

(kg

)

10

GLP-1 and GIP Are Degraded by the DPP-4 Enzyme

Meal

Intestinal GIP and GLP-1 release

GIP and GLP-1 Actions

DPP-4Enzyme

GIP-(1–42)GLP-1(7–36)

Intact

GIP-(3–42)GLP-1(9–36)Metabolites

Rapid Inactivation

Half-life*GLP-1 ~ 2 minutes

GIP ~ 5 minutes

Deacon CF et al. Diabetes. 1995;44:1126–1131.*Meier JJ et al. Diabetes. 2004;53:654–662.

11

Mean Baseline: 8.0% P <0.001*

–0.8-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Ch

an

ge

in

A1

C,

%

†

‡

A1C

(95% CI: –1.0, –0.6)

A1C, FPG, and 2-Hour PPG Placebo-Adjusted Resultsin a 24-Week Study of Sitagliptin Phosphate(Januvia)

*Compared with placebo.†Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.

‡Difference from placebo.

• Sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared with placebo.

• A1C lowering appears to be related to the degree of A1C baseline level.

Section

14.1

n=229

Mean Baseline: 170 mg/dL P <0.001*

–17

-25

-20

-15

-10

-5

0

Ch

ang

e in

FP

G, m

g/d

L

†

‡

FPG

(95% CI: –24, –10)

n=234

Mean Baseline: 257 mg/dL P<0.001*

–47-60

-50

-40

-30

-20

-10

0

Ch

ang

e in

2-h

r P

PG

, m

g/d

L

†

‡

2-hr PPG

(95% CI: –59, –34)

n=201

12

Pooled Analysis*

–1.4

–0.7–0.6

–0.7

-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Reduction of A1C Overall and Stratified by Baseline A1C in aPrespecified Pooled Analysis of 2 Monotherapy Studies of sitagliptin

Reductions are placebo-subtracted. * P<0.001 overall and for treatment by subgroup interactions.+ Combined number of patients on sitagliptin or placebo

Inclusion Criteria: 7%–10%

Monotherapy Studies: Mean Response of A1c to Sitagliptin Appears to Be Related to the Degree of A1C Elevation at Baseline

Overall <8 ≥8–<9 ≥9

Baseline A1C

(%)

Ch

an

ge in

A1

C,

%

n=411+

n=239+

n=119+

n=769+

The magnitude of A1C lowering by strata varied by study.

Section

14.1

13

Comparison of incretin agents

Exenatide DPP-IV inhibitor

FDA indications Combo with SU, metformin or TZD

Mono; combo with metformin or TZD

Mode of administration

Injected BID Oral; once daily

Weight effects Average loss 10# Weight neutral

Side effects 30% nausea Virtually none

Renal insufficiency Not recommended Dose adjustment necessary

14

Summary- incretin agents

Incretin agonists and DPP-4 inhibitors appear to have similar ability to lower blood glucose and A1c

Both agents are most suitable for patients with diabetes for <10 years duration (need to be able to secrete adequate insulin)

Consider when patient has reasonable FPG, but post-prandial hyperglycemia

Both agents are costly ($130-179/month range)

ADA recommends metformin as first-line agent for virtually all patients with DM 2 (unless contraindicated or not tolerated) and these agents currently are best suited for second or third line therapy

.

15

Modification of isoelectric point - precipitation at pH 7.4

Insulin glargine

Strengthening of hexamer association, e.g., Co(III)-hexamer (substituting Zn ions with Cobalt at high

insulin concentration)

Acylation with hydrophobic residues, e.g.,

Insulin detemir

Strategies for engineering basal insulins

16

Insulin detemir: Mode of protraction

Self-association (hexameric)

Fatty acid side chains bind to albumin in injection depot

Albumin binding in circulation

Protracted absorption

‘Buffering’ effect and minor contribution to protraction

17

PD profiles in patients with type 1 DM

Plank et al. Diabetes Car.e. 2005;28(5):1107-12

GIR

(m

g/k

g/m

in)

Levemir 0.4 U/kgLevemir 0.2 U/kg

3.0

0

1.0

2.0

Time since Injection (hrs)0 4 8 12 16 20 24

4.0

5.0

6.0

Pharmacodynamic Parameters for LEVEMIR and NPH

LEVEMIR NPH

0.2 U/kg 0.4 U/kg 0.3 U/kg

AUCGIR (mg/kg) 419 1184 743

GIRmax (mg/kg/min) 1.1 1.7 1.6

NPH 0.3U/kg

GIR: Glucose infusion rate

18

PD profiles in patients with type 2 DM

0.4 U/kg 0.8 U/kgLevemir

glargine

0 2 4 6 8 10 12 14 16 18 20 22 240

0.5

1.0

1.5

2.0

2.5

3.0

Glu

cose

infu

sion r

ate

(mg/k

g/m

in)

Time (h)

Mean GIR profiles (smoothed with a local regression technique)for 0.4 and 0.8 U/kg Levemir and glargine*

*An additional dose of 1.4 U/kg was tested. No significant difference in pharmacodynamics was observed.

Klein et al. Diabetes. 2006;55(suppl 1):A76, 325-OR

19

Individual GIR profiles

GIR

(m

g/k

g/m

in)

GIR

(m

g/k

g/m

in)

GIR

(m

g/k

g/m

in)

6

0

3

6

0

3

8 16 240 8 16 240 8 16 240

8 16 240248 160

6

0

3

6

3

00 8 16 24

8 16 240248 160

6

0

3

6

3

00 8 16 24

Elapsed Time (hours)

Levemir

NPH-insulin

Insulin glargine

Heise et al. Diabetes. 2004;53:1614-1620

Each panel = 4 injections of the indicated formulation in an individual study subject.

20

Protracted time-action profile similar to insulin glargine

Comparable glycemic results as NPH insulin and insulin glargine

Lower risk of nocturnal hypoglycemia as compared with NPH-insulin

Less weight gain than NPH insulin and insulin glargine

Best results with BID (AM and HS)

Cost similar to glargine

Summary- insulin detemir

21

Pfizer / Aventis / Nektar Exubera® Pulmonary Insulin Delivery System

22

0

20

40

60

80

100

0 60 120 180 240 300 360 420 480 540 600

Me

an

Glu

cos

e In

fus

ion

Ra

te

(% o

f M

ax

imu

m)

Time (min)

INH 6 mgInsulin lispro 18 URegular insulin 18 U

INH Absorbed More Rapidly than SC Regular; as Rapidly as SC Lispro - Study 017

Diabetologia 2000;43(Suppl 1):A46.

23

Summary of INH therapy in Type 1DM

Similar level of glycemic control over 12-24 week time periods as SC NPH/regular insulin regimens

Short-term decreases in DLCO and increases in insulin antibody binding noted without apparent clinical consequences

Studies comparing to insulin analogs and real efficacy studies are on-going

Pts on INH therapy still require at least 1 SC injection/day of basal insulin

24

Summary of INH Therapy in DM2

Achieves similar glycemic control compared to SC NPH/regular insulin regimens over 12-24 weeks

Achieves better glycemic control than failing OHA regimens over 12-24 weeks

Patient satisfaction scores and quality of life scores higher with inhaled insulin

Patients report higher likelihood of using insulin if able to use inhaled insulin

25

Safety of inhaled insulin

Adverse events: increased cough; no increased SAEs or deaths

Hypoglycemia- similar rates of hypoglycemia (vs. Regular); no difference in severe hypoglycemia

Pulmonary safety• Small decreases in FEV1 and DLCO were observed• Changes were not progressive or apparently clinically

significant, but did resolve with discontinuation

Insulin antibodies• Increased production of IgG antibodies, esp in DM 1

(30%)• Clinical significance unknown

26

Using Exubera

Available in 1 mg (approx. 3 units) and 3 mg (approx. 8 units) blisters

Initial pre-meal dosing determined by weight

Take no more than 10 minutes before the meal

Take in one breath and hold for 5 seconds

Clean the inhaler weekly

Replace release unit every 2 weeks

Store insulin at room temperature

27

Using Exubera

Get baseline spirometry (FEV1) and recheck in 6 months and then yearly

Do not use in smokers (need to have quit for 6 months prior to using)

Not recommended for people with COPD or asthma

Probably safe to use with upper respiratory illness; unclear with pneumonia

28

Conclusions- inhaled insulin

Inhaled insulin generally well-tolerated and as efficacious as Regular insulin in controlling blood glucose

Best use will probably be in adding to oral agents in type 2 patients

Studies comparing to insulin analogs are underway

Need longer duration studies for safety

Cost is about 30% higher than current insulins

29

Pramlintide (Symlin)

Analog of a beta-cell protein named amylin (islet-associated polypeptide)

Physiologic actions• Delayed gastric emptying• Reduced post-prandial glucose excursion• Neuroendocrine effects on appetite and satiety

FDA approved for use in type 1 and type 2 diabetes who are not controlled on insulin therapy

Injected with each meal

Trend to weight loss (or no gain with improved A1c)

30

36

Effect of Pramlintide on PostprandialGlucose Excursions When Added to Regular

Insulin or Insulin Lispro

Type 1 Diabetes, Insulin Lispro Type 1 Diabetes, Regular Insulin

Inc

rem

en

tal

Pla

sm

a

Glu

co

se

(m

g/d

L)

-50

-25

0

25

50

75

100

0 30 60 90 120 150 180 210 240

Time Relative to Meal (min)

-30-50

-25

0

25

50

75

100

0 30 60 90 120 150 180 210 240

Time Relative to Meal (min)

Inc

rem

en

tal

Pla

sm

a

Glu

co

se

(m

g/d

L)

-30

Weyer C, et al. Diabetes Care 2003; 26:3074-3079

Mean ±SEInsulin Lispro (n=21)Regular Insulin (n=19)

Placebo (-15 min)60 µg Pramlintide (0 min)

Placebo (-15 min)60 µg Pramlintide (0 min)

Mixed Meal, Lispro Mixed Meal

Insulin

31

Change in A1C in Type 1 and Type 2 Pivotal Phase 3 Trials (ITT Population)

-0.8

-0.6

-0.4

-0.2

0

**

** **

* *

** **

A

1C

(%

)

Time (wk)

0 13 26 39 52

-0.6

-0.4

-0.2

0

Time (wk)

0 13 26 39 52

-0.8 **

Type 1 Type 2Placebo + Insulin

120 µg Pramlintide + InsulinPlacebo + Insulin

30 µg/60 µg Pramlintide + Insulin

Data from Whitehouse F, et al. Diabetes Care 2002; 25:724-730Data from Hollander PA, et al. Diabetes Care 2003; 26:784-790

Type1: Placebo (n=237), Pramlintide (n=243)Type 2: Placebo (n=161), Pramlintide (n=166)*P <0.05, **P <0.001; Mean ± SE (change from baseline)

A

1C

(%

)

32

Pramlintide (Symlin)

Is injected with each meal containing at least 30 gms of carbohydrate

Cannot mix with insulin

Should not be used in patients who are non-compliant, have an A1c>9.0%, gastroparesis, severe hypoglycemia, children

Start with low dose to minimize GI effects

Need to decrease bolus insulin dose

Strongly encourage using this medication with a diabetes educator who is experienced in insulin dose adjustment