New Therapies for Diabetes

Abe DeSantis, MDClinical Asst. Professor

Division of Metabolism, Endocrinology and Nutrition

University of Washington Medical Center

Prevalence of Diabetes in United States

16.1 19.3

23.6

0

5

10

15

20

25

1988-94 1999-2002 2008

20%

http://www.cdc.gov/media/pressrel/2008/r080624.htm

Mil

lion

22%

Therapeutic Options forType 2 DM

• 1995• Sulfonylurea• INSULIN

– NPH– Regular– Ultralente

• 2008• Sulfonylurea• INSULIN

– NPH– Regular– Insulin analogues– Inhaled

• Metformin• TZDs• Alpha glucosidase inhibitors• Meglitinides• Endocannabinoid receptor -• Incretin mimetics• Amylin analogues• DPP IV inhibitors

Therapeutic Options forType 2 DM

• 1995• Sulfonylurea• INSULIN

– NPH– Regular– Ultralente

• 2008• Sulfonylurea• INSULIN

– NPH– Regular– Insulin analogues– Inhaled

• Metformin• TZDs• Alpha glucosidase inhibitors• Meglitinides• Endocannabinoid receptor-• Incretin mimetics• Amylin analogues• DPP IV Inhibitors

Sites of Action by Therapeutic Options Presently Available to Treat Type 2 Diabetes

GLUCOSE ABSORPTION

GLUCOSE PRODUCTIONBiguanidesBiguanides

(Thiazolidinediones)

MUSCLEMUSCLE

PERIPHERAL GLUCOSE UPTAKE

Thiazolidenediones(Biguanides)(Biguanides)

PANCREAS

INSULIN Secretion/replacementSulfonylureasSulfonylureasMeglitinidesMeglitinidesExenatideExenatide

DPP4 InhibitorsDPP4 InhibitorsInsulinInsulin

ADIPOSE ADIPOSE TISSUETISSUE

LIVERLIVER

alpha-glucosidase inhibitors

INTESTINE

Adapted from Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5

STOMACHDELAYED EMPTYING Exenatide, Pramlintide

BRAINEndocannabinoidReceptor BlockersExenatidePramlinitide

0 3 6 9 12

0

100000

200000

300000

400000

Time After Meal (h)

Pla

sma

Exe

nd

in-4

Co

nce

ntr

atio

n (

pg

/mL

)

Exendin-4 in the Gila Monster

♦Exendin-4 was originallyisolated from thesalivary secretions ofthe Gila monster

♦Exendin-4 wassubsequently found tocirculate as a meal-related peptide in this animal

Data from Young AA. Insulin Resistance and Insulin Resistance Syndrome 2002, 235-262

Reduced Incretin Effect in Type 2 Diabetic Patients

00

2020

4040

6060

8080

INS

UL

IN (

INS

UL

IN (

mU

/Lm

U/L ))

00 3030 6060 9090 120120 150150 180180TIME (min)TIME (min)

Control SubjectsControl Subjects

Intravenous GlucoseIntravenous Glucose

Oral GlucoseOral Glucose

**** **

**** ** **

00

2020

4040

6060

8080

INS

UL

IN (

INS

UL

IN (

mU

/Lm

U/L ))

00 3030 6060 9090 120120 150150 180180TIME (min)TIME (min)

Type 2 Diabetic PatientsType 2 Diabetic Patients

****

**

Nauck M, et al. Diabetologia. 1986;29:46-52.

Incretin effect

GLP-1 Modes of Action in Man

GLP-1 Modes of Action in Man

GLP-1 is secretedfrom the L-cells

in the jejunumand ileum

GLP-1 is secretedfrom the L-cells

in the jejunumand ileum

• Stimulates insulin secretion• Stimulates insulin secretion

• Suppresses glucagon secretion• Suppresses glucagon secretion

• Slows gastric emptying• Slows gastric emptying

Long term effectsdemonstrated in animals…Long term effectsdemonstrated in animals…• Increases beta-cell cell mass and maintains beta-cell efficiency• Increases beta-cell cell mass and maintains beta-cell efficiency

• Reduces food intake• Reduces food intake

Upon ingestion of food…Upon ingestion of food…

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412Drucker DJ. Mol Endocrinol 2003; 17:161-171

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412Drucker DJ. Mol Endocrinol 2003; 17:161-171

Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.

GLP-1 Secretion and Inactivation

IntestinalGLP-1

release

GLP-1 (7-36)active

Mixed meal

GLP-1 (9-36)inactive

(>80% of pool)

DPP-4

T1/2 = 1 to 2 min

Exenatide (Byetta)

♦ Synthetic exendin-4♦ In clinical studies, exenatide exhibited actions

that are similar to those of GLP-1:♦ Stimulation of insulin secretion only when

blood glucose concentrations are elevated♦ Suppression of postprandial glucagon

secretion♦ Slowing of gastric emptying

Acute Meal Challenge Study:Postprandial

Glucose and Glucagon Concentrations

Pla

sma

Glu

cag

on

(p

g/m

L)

Pla

sma

Glu

cose

(m

mo

l/L

)

0

5

10

15

20Exenatide or Placebo

Standardized Breakfast

0 60 120 180 240 300

Time (min)

0 120 18030 9060 150

Time (min)

50

100

150

200

250Exenatide or Placebo

Standardized Breakfast

PlaceboExenatide 0.1 µg/kg

PlaceboExenatide 0.1 µg/kg

Data from Kolterman OG, et al. J Clin Endocrinol Metab 2003; 88:3082-3089

n=20Mean ± SE

Proportion of Subjects Achieving A1C 7% at Week 30

Evaluable Population with Baseline A1C >7%Placebo

5 µg exenatide10 µg exenatide

DeFronzo R, et al. ADA 64th Annual Scientific Sessions, June 2004

Evaluable with baseline A1C >7%, N = 234 (Placebo, n =77; 5 µg exenatide, n =79; 10 µg exenatide, n = 84)*P <0.01, **P <0.0001

0

10

20

30

40

50

13%

32%

46%

*

**

Per

cen

t o

f S

ub

jec

ts

Ach

ievi

ng

A1C

≤7%

Date on file, Amylin Pharmaceuticals, Inc.

% Incidence of Nausea

0-4 >12-16 >16-20 >20-24 >24-28 >28 >4-8

>8-12

Placebo (N = 483)Exenatide 5 mcg BID (N = 480)Exenatide 10 mcg BID (N = 483)

Large Phase 3 Clinical Studies – Combined (ITT)

Large Phase 3 Clinical Studies – Combined (ITT)

Dose increased from 5 mcg to 10 mcg at wk 4

100

0

15

30

45

60

75

Time (wk)

Open-Label Study: Body Weight Over 24 Weeks

-4.0

-3.0

-2.0

-1.0

0.0

0 4 8 12 16 20 24

Evaluable population (N=105)

Mean (SE) Body Weight

(kg)

1.0

Time (wk)

Baseline = 89 ± 2 kg

-3.4 kg

Data from Poon T, et al. Diabetic Med 2004; 21(suppl 2):A45

Exenatide (Byetta)

♦ Pen prefill- one month’s supply♦ Given bid, 30-60 minutes prior to meal (250 cal)♦ Nausea experienced by almost all initially, typically

remits within days♦ Start at 5 mcg BID, then increase to 10 mcg BID after 1

month♦ Current indication: failing SFU, metformin, or both♦ Not FDA approved with insulin or monotherapy♦ Pancreatitis warning

Typical Results?

♦ Not magic wand for everyone-

15% no effect

evidence for loss of treatment response♦ Fullness sensation- Gastric or CNS?♦ Relearning to eat- satiety sense♦ Data support 20% fewer calories ingested♦ Expense and insurance coverage

TrendsTrends

• A1c and weight loss do not correlate• Prandial insulin dose decreases dramatically• Minimal basal insulin dose change• For women, weight loss persists in physically

active, in men not associated• Liraglutide- daily administration Phase 3 Trials

Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.

GLP-1 Secretion and Inactivation

IntestinalGLP-1

release

GLP-1 (7-36)active

Mixed meal

GLP-1 (9-36)inactive

(>80% of pool)

DPP-4

T1/2= 1 to 2 min

Inhibition of DPP-4 Increases Active GLP-1

GLP-1 (9-36)inactive

IntestinalGLP-1

release

Mixed meal

GLP-1 (7-36)active

DPP-4

Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.

DPP-4inhibitor

GLP-1 (7-36)active

DPP 4 Inhibitors

♦ Once daily ingestion♦ Reduce fasting and postprandial glucose,

reduce HbA1c♦ Decrease glucagon response to ingested

meal♦ Initial studies in combination with metformin♦ 2 drugs

Vildagliptin Galvus® ( Novartis)

Sidagliptin Januvia ™ (Merck)

Effects of DPP-4 Inhibition

• ß-cell function

• Glucagon secretion

• Insulin sensitivity

• ß-cell mass

Adapted from Ahrén B, et al. J Clin Endocrinol Metab. 2004;89:2078–2084.

Glycemic, Incretin, and Islet Cell Response to a Meal After 4 Weeks of Treatment With Vildagliptin

GlucagonGlucose

0

25

50

75

–30 0 30 60 90 120 150 180 210 240

Time (min)

0

5

10

15

20

25

–30 0 30 60 90 120

Time (min)

5.0

8.0

11.0

14.0

50

75

100

125

GL

P-1

[7-

36a

mid

e]

(pm

ol/

L)

Glu

cag

on

(n

g/L

)Active GLP-1Insulin

Glu

cose

(m

mo

l/L

)IR

I (µ

U/m

L)

PlaceboVildagliptin (100 mg qd)

GLP-1 = glucagon-like peptide–1

Vildagliptin and -Cell Preservation and Regeneration (neonatal rat model)

Vehicle Vildagliptin

Brd

U-p

os

itiv

e c

ell

s (

%)

Ap

ota

g-p

os

itiv

e c

ell

s (

%)

Vehicle Vildagliptin Vehicle Vildagliptin

P<.001

P<.05

P<.05

-c

ell

ma

ss

(m

g)

Replication ß-cell mass

Vildagliptin

60 mg/kg, po x 21 days

Day 7 Day 21

Vehicle Vildagliptin

• Insulin

Adapted from Duttaroy A, et al. Diabetes 2005. 54 (suppl 1): A141.Abstract 572-P.

Apoptosis

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.0

0.5

1.0

1.5

2.0

2.5

0

20

40

60

80

100

120

6.8

7.2

7.6

8.0

8.4

–4 0 4 8 12 16 20 24 28 32 36 40 44 48 52

Weeks

Vildagliptin/Metformin (extension, n = 42)Placebo/Metformin (extension, n = 29)

Placebo/Metformin (initial study, n = 51)

HbA

1c

(%)

Vildagliptin/Metformin (initial study, n = 56)

Ahrén et al, Diabetes Care 27:2874-2880 (2004)

Combination of Vildagliptin and Metformin

P < .0001

–1.1 ± 0.2%

Summary of DPP-4 Inhibition

• Increases fasting and postprandial GLP-1 levels• Reduces fasting and postprandial glycemia• Improves ß-cell function

– Increases insulin secretion, reduces proinsulin/insulin ratio– Increases beta-cell mass

• Inhibits glucagon secretion– Reduces hepatic glucose production

• Increases insulin sensitivity• Reduces postprandial lipemia• No effect on gastric emptying or body weight• Reduces HbA1c by ~1%• Is safe and tolerable in short term• In renal impairment, dose decreased by 50%

Amylin

• Discovered in 1987• Co-secreted with insulin

– Absent in type 1 DM, deficient in type 2 DM

• Slows gastric emptying and digestion

• Decreases post-prandial glucagon

• Satiety effect CNS

Amylin Is Deficient in Diabetes

Without diabetes (n = 27)Late-stage type 2 (n = 12)Type 1 (n = 190)

Data from Kruger D, et al. Diabetes Educ 1999; 25:389-398

Time After Sustacal® Meal (min)

0

5

10

15

20

-30 0 30 60 90 120 150 180

Meal

Late Stage Type 2

Type 1

Without Diabetes

Pla

sma

Am

ylin

(p

M)

Pramlintide Improves Postprandial GlucoseTYPE 1 DIABETES

100

150

200

250

300

0 60 120 180 240

Time Relative to Meal and Pramlintide (min)

Mean (SE) Plasma Glucose

(mg/dL)

100

150

200

250

300

0 60 120 180 240

Mean (SE) Plasma Glucose

(mg/dL)

Lispro InsulinPramlintide 60 g + Lispro Insulin

Regular InsulinPramlintide 60 g + Regular Insulin

Pramlintide + Lispro insulin (n = 20)Pramlintide + Regular insulin (n = 18) Weyer C, et al. Diabetes Care 2003; 26:3074-3079

Pramlintide Improves Postprandial Glucose

TYPE 2 DIABETES

100

120

140

160

180

200

220

240

260

0 60 120 180 240

Time Relative to Meal and Pramlintide (min)

Pla

sma

Glu

cose

(m

g/d

L)

0

50

100

150

200

Time Relative to Meal and Pramlintide (min)

Pla

sma

Pra

mli

nti

de*

(p

mo

l/L

)

Placebo + Lispro InsulinPramlintide 120 g + Lispro Insulin

Pramlintide 120 g + Lispro Insulin

0 60 120 180 240

Data from Maggs DG, et al. Diabetes Metab Res Rev 2004; 20:55-60Pramlintide Acetate Prescribing Information, 2005Data on file, Amylin Pharmaceutical, Inc.

Pramlintide Clinical EffectsTYPE 2 DIABETES COMBINED PIVOTALS

-2

-1

0

1

***

**

**

**

**

****-4

-2

0

2

4

6

8

-0.8

-0.6

-0.4

-0.2

0

Insulin Use (%) A1C (%) Weight (kg)

Week 4 Week 13Week 26Week 4 Week 13Week 26Week 4 Week 13 Week 26

Placebo + Insulin 120 g Pramlintide BID + Insulin

Placebo + insulin (n = 284), Baseline A1C = 9.3%Pramlintide + insulin (n = 292), Baseline A1C = 9.1%*P <0.01, **P <0.0001; ITT population; Mean (SE) change from baseline

Pramlintide specifics:

♦ Injectable- insulin syringe♦ Starting dose Type 1 DM 15 mcg (2.5 units)♦ Starting dose Type 2 DM 60 mcg (10 units)♦ Titrate as tolerated every 3 days

♦ Symlin® pens (60 and 120 mcg)♦ Use at the time of a meal (250 cal)♦ Separate injection from insulin♦ Decrease dose of prandial insulin by 50%♦ Potentially less nausea than with exenatide

Severe Hypoglycemia

0-3 months 3-6 months

Type 1 Diabetes 5.7% (N=265) 3.8% (n=213)

Type 2 Diabetes 0.6% (N=265) 0.7% (n=213)

“Open-label, clinical practice study”

Symlin Package Insert

Case #1• Mrs LH, 82 yo F with known valvular

Heart disease, CAD, HTN, T2DM for 22 yrs

• Cardiac Meds

• 70/30 Humulin insulin – 23 u AM and 18u PM– A1c = 6.4%

• Issues with hypoglycemia lately

Meter DownloadCase #1

TIME 1-6AM 6AM-9AM 9AM-11A 11AM-2PM 2-4PM 4-8PM 8-10P 10-1AM ALL # 4 30 4 23 5 28 8 30 132AVG 84 154 186 138 88 113 98 192 131.625SD 72 86 104 98 100 64 82 96 87.75RANGE 55-103 82-286 44-388 92-204 54-102 54-212 38-242 114-335 38-388

Meter DownloadCase #1

TIME 1-6AM 6AM-9AM 9AM-11A 11AM-2PM 2-4PM 4-8PM 8-10P 10-1AM ALL # 4 30 4 23 5 28 8 30 132AVG 84 154 186 138 88 113 98 192 131.625SD 72 86 104 98 100 64 82 96 87.75RANGE 55-103 82-286 44-388 92-204 54-102 54-212 38-242 114-335 38-388

Meter Download Case #1

TIME 1-6AM 6AM-9AM 9AM-11A 11AM-2PM 2-4PM 4-8PM 8-10P 10-1AM ALL # 4 30 4 23 5 28 8 30 132AVG 84 154 186 138 88 113 98 192 131.625SD 72 86 104 98 100 64 82 96 87.75RANGE 55-103 82-286 44-388 92-204 54-102 54-212 38-242 114-335 38-388

Meter Download Case #1

TIME 1-6AM 6AM-9AM 9AM-11A 11AM-2PM 2-4PM 4-8PM 8-10P 10-1AM ALL # 4 30 4 23 5 28 8 30 132AVG 84 154 186 138 88 113 98 192 131.625SD 72 86 104 98 100 64 82 96 87.75RANGE 55-103 82-286 44-388 92-204 54-102 54-212 38-242 114-335 38-388

Regular Insulin

NPH Insulin

Meter Download Case #1

TIME 1-6AM 6AM-9AM 9AM-11A 11AM-2PM 2-4PM 4-8PM 8-10P 10-1AM ALL # 4 30 4 23 5 28 8 30 132AVG 84 154 186 138 88 113 98 192 131.625SD 72 86 104 98 100 64 82 96 87.75RANGE 55-103 82-286 44-388 92-204 54-102 54-212 38-242 114-335 38-388

Regular Insulin

NPH Insulin

Meter Download Case #1

TIME 1-6AM 6AM-9AM 9AM-11A 11AM-2PM 2-4PM 4-8PM 8-10P 10-1AM ALL # 4 30 4 23 5 28 8 30 132AVG 84 154 186 138 88 113 98 192 131.625SD 72 86 104 98 100 64 82 96 87.75RANGE 55-103 82-286 44-388 92-204 54-102 54-212 38-242 114-335 38-388

Rapid Insulin analogue

Glargine Insulin

Case #1• Decision to convert to basal bolus

therapy• TDD = 70/30 23uAM and 18uPM= 41• Due to hypoglycemia TDD = 36 units• 50% basal 18 units glargine• Breakfast 5u Lunch 4u Dinner 8u• Correction 1500/36 = 42

– ISF 1:40 day– ISF 1:80 night

target 80correction factor 1 units for every mg/dl over target

Premeal Novolog Humalog X Apidra Regularblood glucose < 80 80 to 150 to 190 to 230 to 270 to 310 to 350 to 391 to 431 to 471 to 511 to 551 to 591 to 631 to

(mg/dl) 149 189 229 269 309 349 390 430 470 510 550 590 630 670

Breakfast 5

Lunch 4

Dinner 8BED

Long Acting Insulin _Lantus _Detemir _ NPH _ 70/30 _ 75/25X

AM __18____units at bedtime

150

19 20 21

17 18

16 17

11 12 13 14 15 16 17 18

12 13 14 158 9 10 116

10

754

8

Dose if no BG check

40

54

7

3

9

13 14 15 1611 12106 7 8 9

12:00 AM 6:00 AM 12:00 6:00 PM 12:00 AM

Glu

co

se

(m

g/d

L)

400

300

200

100

0

Glucose measurement

Insulinbolus

TargetRange

Fingerstick Blood Glucoses

12:00 AM 6:00 AM 12:00 6:00 PM 12:00 AM

Glu

co

se

(m

g/d

L)

400

300

200

100

0

Glucose measurement

Insulinbolus

TargetRange

Continuous Glucose Monitoring Provides More Comprehensive Picture of Glycemic Patterns

Glucose Sensors

GuardControl StudyGuardControl Study162 subjects (half children/half adults) T1 DM randomized to: Guardian RT continuously Guardian RT 3 days every 2 weeks Continued SBGMInitial A1c >8.1%

P-value: Change from baseline between Continuous & Control groups

Control

Intermittent useContinuous use

Deiss D, et al. Diabetes Care. 2006;12:2730-2732.

MealCalibration

140 mg/dL

170 mg/dL

calibrate during steady-state conditions

Capillary blood

Interstitial fluid

Sensor “Lag”There is typically a 7 to 15 min lag between ISF glucose and blood glucose

Why the Sensor Lag Is So Important To Understand

• Calibration

• Upward trend: more insulin is needed

• Downward trend: beware of hypoglycemia!

• Because of these issues, rt-CGM does not replace SMBG yet!

Combined glucose sensing and insulin delivery

1 month CGM: ave 141/ SD64

6 months CGM: 123/49

Future Options• Inhaled insulin

– Tritiated compound Mannkind Afresa ® clinical trials

• DPP 4 inhibitors– Sitagliptin,

vildagliptin,saxagliptin,linagliptin,alogliptin

• Extended GLP-1 agonists– Exenatide LAR (once weekly)– Liraglutide once daily

• Newer CGMS

Thank You !