Attaining Glycemic Goals in Type 2 Diabetes:Diet & Exercise

Turner RC et al. JAMA. 1999;281:2005-2012.

0

10

20

30

40

50

60

3 Years 6 Years 9 Years

Pro

port

ion

of P

atie

nts

With

HbA

1c <

7% (

%)

Blood glucose

Intestine: glucose absorption

Thiazolidinediones -glucosidase inhibitors

Treatment of Type 2 Diabetes

SulfonylureasMeglitinidesBiguanides

Pancreas: insulin secretionLiver: hepatic glucose production

Muscle and adipose tissue:glucose uptake

GLP-1 analogs DPP4 inhibitors

Biguanides:Basic Characteristics of Metformin (Glucophage, Glucomin)

Mechanism of action Decreases hepatic glucoseproduction

Depends upon Presence of insulin

Power Decreases HbA1c 1% to 2%

Dosing One to three times daily

Side effects Diarrhea, nausea

Main risk Lactic acidosis

Insulin Secretagogues:Basic Characteristics of Sulfonylureas and Meglitinides

Mechanism of action Increase basal and postprandialinsulin secretion

Depends upon Functioning -cells

Power Decreases HbA1c 1% to 2%

Dosing Once or twice daily (sulfonylureas);three times daily (meglitinides)

Side effects Weight gain

Main risk Hypoglycemia

4-18

Mechanism of Sulfonylurea Induced Insulin Secretion

Glucose

K+

DepolarizationCa++

INSULIN & C-PEPTIDE

Sulfonylureas

ATP/ADP

Ca++

Carbachol

PKC

DAG

IP3

AC+ -

cAMP

PKA

GlucagonGLP-1

SomatostatinCatecholamines

GLUT 2

Glucose

Glucose-6-P GK(sensor)

Krebs

Thiazolidinedione Chemical Structures

Rosiglitazone (Avandia)

Pioglitazone

Troglitazone

O

CH3

O

NS

N N O

O

NS

N O

Et

O

CH3

O

NSO

O

HO

H3C

CH3

CH3 O

Activation of PPARgamma Alters Expression of Specific Genes

Gene encoding GLUT-4, lipoprotein lipase,

PEPCK, aP2 etc.

PPRE (DR-1)

PPAR RXR

AGGTCA X AGGTCA

Regulates gene transcription

RSG retinoic

Sites of action of Glitazones

Oakes ND, et al. Diabetes 1994; 43:1203–1210.Young PW, et al. Diabetes 1995; 44:1087–1092.

Digestiveenzymes

AdiposetissueAdiposetissue

Blood glucoseBlood

glucose

GutGut

MuscleMuscleLiverLiver

InsulinInsulin

Carbohydrates

Glitazones reduces insulin resistance in the liver, muscle and adipose tissue

PancreasPancreas

Rosilitazone Increases Islet Area and Density in Pancreatic Islets of db/db Mice

Pancreatic sections were immunohistochemically stained for insulin

Control Rosiglitazone

Scale 100 m (enlarged view)

Lister et al, Diabetologia 1998; 41 (Supplement 1):A660.

Thiazolidinediones (Glitazones):Basic Characteristics

Mechanism of action Enhances muscle and adiposetissue response to insulin

Depends upon Presence of insulin and resistanceto its action

Power Decreases HbA1c 0.5% to 1.3%

Dosing Once or twice daily

Side effects Edema, weight gain, anemia

Main risk Liver failure (only troglitazone?)

Data from Henry. Endocrinol Metab Clin. 1997;26:553-573; Gitlin, et al. Ann Intern Med. 1998;129:36-38; Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41; Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139; Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176.

Glucose Dependent Actions of GLP-1in Patients With Type 2 Diabetes

Nauck MA, et al. Diabetologia 1993; 36:741-744

Data are mean ± SE.* P <0.05

25

20

15

10

5

0

Glucagon (pmol/L)

Time (min)

-30 0 60 120 180 240

**

* *

17.5

15.0

12.5

10.0

7.5

5.0

2.5

0.0

*

Glucose (mmol/L)

GLP-1/PBO infusion

***

**

*

-30 0 60 120 180 240

350

300

250

200

150

100

50

0

Insulin (pmol/L)

GLP-1/PBO infusion

Time (min)

* **

* ** * *

GLP-1/PBO infusion

Time (min)

-30 0 60 120 180 240

PlaceboGLP-1

Rationale for incretin-based therapy of Rationale for incretin-based therapy of diabetesdiabetes

"... - גילה" נ הבה

Eng J, et al. J Biol Chem 1992; 267:7402-7405 Chen YQE and Drucker DJ, J Biol Chem 1997; 272: 4108-4115

לטאת גילהGila Monster

GLP-1 analog

Exendin-4

(Exenatide)

Exenatide + Met Study: Effect on A1C

PlaceboLead-in

5 10 15 20 25 30Screen 0

6.5

7.0

7.5

8.0

8.5

9.0M

ean

(±S

E)

A1C

(%

)

Time (wk)

+0.1%

-0.4%

-0.8%

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

ITT, N = 336 (Placebo, n = 113; 5 µg exenatide, n = 110; 10 µg exenatide, n = 113) * P <0.0005 reductions from baseline (pairwise comparison to placebo) in both exenatide arms for Weeks 6 to 30

Met + PlaceboMet + 5 µg exenatide

Met + 10 µg exenatide

*

*

Dipeptidyl Peptidase 4 (DPP-4)Dipeptidyl Peptidase 4 (DPP-4)

Adapted from Evans DM IDrugs 2002;5:577–585; Drucker DJ Expert Opin Investig Drugs 2003;12:87–100; Rasmussen HB et al Nat Struct Biol 2003;10:19–25.

• DPP-4 is a serine protease of the prolyl oligopeptidase enzyme family that exists in two forms– Membrane-bound (widely expressed)– Soluble

Cell membraneCytosol

N N

C C

DPP-4 inhibition Increases Active Incretin Level

↑GLP-1 (7-36)

↑GIP (1-42)

DPP-4

DPP -4 Inhibitor

Incretinrelease GLP-1 (9-36)

GIP (3-42)

X

Adapted from Deacon CF et al Diabetes 1995;44:1126–1131; Ahrén B Curr Diab Rep 2003;3:365–372; Deacon CF et al J Clin Endocrinol Metab 1995; 80:952–957; Weber AE J Med Chem 2004;47:4135–4141.

24-week, Monotherapy, Placebo-controlled Study

Proportion of Patients Achieving HbA1c <7.0% at Week 24

Mean baseline values: sitagliptin, 8.01%; placebo, 8.03%All-patients-as-treated populationAdapted from Aschner et al. Diabetes Care. 2006;29:2632–2637.

P<0.001

0

10

20

30

40

50

60

Placebo (n=244) Sitagliptin 100 mg/day(n=229)

Pati

en

ts (

% t

o g

oal)

The miracle of insulin

Patient J.L., 15 December, 1922 15 February, 1923

1923: Nobel Prize to Banting and Macleod

FG Banting JJR Macleod CH Best JB Collip

Pharmacodynamics of Human Insulins

Insulin Onset Peak Duration Preparation

Regular 30-60 min 2-4 h 6-10 h

NPH/Lente 1-2 h 4-8 h 10-20 h

NB: Time-course of action of any insulin may greatly vary between individuals, or at different times in the same individual

6-22

INSULIN TACTICS

Once-daily Mixed Insulin

Regular

NPH

B SL HS

Insu

lin

Eff

ect

B

6-23

INSULIN TACTICS

Twice-daily Mixed Insulin

Regular

NPH

B SL HS

Insu

lin

Eff

ect

B

6-23

INSULIN THERAPY

The Basal/Bolus Insulin Concept

• Basal Insulin– Suppresses glucose production between meals and overnight

– ~50% of daily needs

• Bolus Insulin (Mealtime or Prandial)– Limits hyperglycemia after meals

– 10% to 20% of total daily insulin requirement at each meal

6-20

INSULIN TACTICS

Multiple Daily InjectionsNPH + Regular

Insu

lin

Eff

ect

B SL HS B

Regular NPH

6-24

INSULIN TACTICSINSULIN TACTICSChronic Multiple Daily InjectionsChronic Multiple Daily Injections

Bedtime NPH + Mealtime RegularBedtime NPH + Mealtime Regular

Lindström, et al. Diabetes Care. 1992;15:27-34.

Non-DM Insulin8 weeks

0800 1200 1600 2000 2400 0400 0800

Time of Day

Serum Insulin R NR R

0

300

200

100

pm

ol/L

6-50

Rapidly Acting Insulin AnaloguesRapidly Acting Insulin Analogues

INSULIN TACTICS

Shorter-acting Insulin Analogues: Lispro & Aspart

400

350

300

250

200

150

100

MealSC injection

50

00 30 60

Time (min)90 120 180 210150 240

Lispro

Regular Human

500450400350300250

150

50

200

100

00 50 100

Time (min)150 200 300250

Aspart

Regular HumanP

lasm

a In

suli

n (

pm

ol/L

)

Pla

sma

Insu

lin

(p

mol

/L)

MealSC injection

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

6-28

INSULIN TACTICS

Insulin Glargine:A New Long-acting Insulin Analogue

• 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

1 5 10 15 20 25 30

1 5 10 15 20 Asp

Gly

ArgExtension

Substitution

Arg

6-33

INSULIN TACTICS

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

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

Glargine

NPH

Glu

cose

Uti

liza

tion

Rat

e(m

g/k

g/h

)

6-34

Structure of Insulin Structure of Insulin DetemirDetemir

Pharmacodynamic action profiles for insulin detemir and NPH insulin in subjects with type 1 diabetes

Insulin detemir 0.1 U/kgInsulin detemir 0.2 U/kgInsulin detemir 0.4 U/kgNPH insulin 0.3 IU/kg

2.0

1.5

1.0

0.5

00 4 8 16 20 2412

Time since insulin injection (hours)

GIR

(m

g/k

g/m

in)

J Plank et al. Diabetes Care 2005;28(5):1107-12

Intention to Treat — Initiating Insulin and the 4-T StudyGraham T. McMahon, M.D., M.M.Sc., and Robert G. Dluhy, M.D.editorial , New England journal of med., 10.1056/nejme078196

Pharmacodynamics of Native & Engineered Human Insulin Preparations

Insulin Onset Peak Duration

Preparation

Lispro/Aspart 5-15 min 1-2 h 4-6 h

Human Regular 30-60 min 2-4 h 6-10 h

Human NPH/Lente 1-2 h 4-8 h 10-20 h

Glargine 1-2 h Flat ~24 h

NB: Time-course of action of any insulin may greatly vary between individuals, or at different times in the same individual

6-22

B SL HS B

Immediate acting analogs Glargine

Insu

lin E

ffec

t

INSULIN TACTICSINSULIN TACTICSGlargine at HS + Short Acting AnalogsGlargine at HS + Short Acting Analogs

Insulin Pump

HbA1c < 6.5%

Pati

ents

reach

ing inte

nsi

ve-

treatm

en

t goals

at

mean

7.8

year

(%)

Cholesterol< 175 mg/dl(4.5 mmol/l)

Triglycerides< 150 mg/dl(1.7 mmol/l)

Systolic BP< 130 mmHg

Diastolic BP< 80 mmHg

Intensive therapy; n = 67 Conventional therapy; n = 63

P = 0.06 P < 0.001 P = 0.19 P = 0.001

P = 0.21

0

10

20

30

40

50

60

70

80

90

Multifactorial Intervention and Cardiovascular Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 DiabetesDisease in Patients with Type 2 Diabetes

N Engl J Med 348:383-93, 2003

Islet Transplantation in Type 1 DiabetesIslet Transplantation in Type 1 Diabetes

Robertson RP, N Engl J Med, 2004