Pathophysiology in the Treatment of Type 2

Diabetes

Newer AgentsPart 3 of 5

2

Incretins• Nutrient stimulated gut hormones • Favorable effects on glucose metabolism• Major humans incretins1,2

– Glucagon-like peptide-1 (GLP-1)

– Glucose-dependent insulinotropic polypeptide (GIP)

• “Incretin effect”

1Drucker DJ. Diabetes Educator. 2006;32(Suppl 2):65S-71S.2Vilsbøll T, Holst JJ. Diabetologia. 2004;47:357-366.

3

Glucagon-like Peptide-1 (GLP-1)Most well-characterized incretinSecreted from L cells of the intestinesVery short half-lifePossibly deficient and GLP-1 resistance in type

2 diabetes

Adapted from Aronoff SL, et al. Diabetes Spectrum. 2004;17:183-190.

Drucker D. J. Cell Metabolism 2006

Summary of Incretin Actions on Different Target Tissues

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

Schwartz, Kohl, "Type 2 Diabetes Mellitus and the Cardiometabolic Syndrome:Impact of Incretin-based Therapies","Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy". 7/10

Müller WA, et al. N Engl J Med. 1970;283:109-115.

Hyperglycemia in Type 2 Diabetes Results from Abnormal Meal-Related Insulin and Glucagon Dynamics

Glucose (mg %)

Insulin (µU/mL)

Glucagon (pg/mL)

Time (min)

-60 0 60 120 180 240

Premeal Postmeal

Insulin Insulin

Glucagon

HGP

Glucagon

HGP

FPG PPG

Meal120

90

60

30

0

140

130

120

110

100

90

360

330

300

270

T2DM (n=12)

Normal (n=11)

240

110

80

Mean (SE); *P < 0.05 GLP-1 = glucagon-like peptide-1

Glucose-dependent Effects of GLP-1

Glucose (mg/dL) Insulin (pmol/L) Glucagon (pmol/L)

Type 2 Diabetes (n = 10)

Type 2 Diabetes (n = 10)

PlaceboPlaceboGLP-1GLP-1

270270

180180

9090

00-30-30 00 6060 120120 180180 240240

300300

200200

100100

00-30-30 00 6060 120120 180180 240240

2020

1010

00-30-30 00 6060 120120 180180 240240

Time (min)Time (min) Time (min)Time (min) Time (min)Time (min)

*

*

*

*

* * *

*** **

* *

*

** * *

Adapted from Nauck MA, et al. Diabetologia. 1993;36:741–744.

CV effects of GLP-1, GLP-1 RA, DPP-4 Inh.

Glp1 in major Surgery in DM-

Benefit in Stress/ Steroid

DM

Added by Dr S

Strategies for Enhancing GLP-1 Action

• GLP-1 receptor agonists (resistant to DPP-4)– Exenatide– Liraglutide

• DPP-4 inhibitors– Inhibit actions of DPP-4– Sitagliptin, saxagliptin

Pharmacologically achieving GLP-1 effects

Release ofactive incretinsGLP-1 and GIP

Blood glucose in fasting and

postprandial states

Ingestion of food

Glucagon

Hepatic glucose

production

GI tract

DPP-4 enzyme

InactiveGLP-1

XSitagliptinSaxagliptin

(DPP-4 inhibitors)

Insulin

Glucose-dependent

Glucose dependent

Pancreas

InactiveGIP

GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

Beta cells

Alpha cells

Glucose uptake by

peripheral tissue

GLP-1 receptor agonistsResists degradation by DPP-4

GLP-1 like effectGLP agonists 7-10 x DPP4-I 2-3 x

GLP-1 Receptor Agonists= parenteral, weight loss, nausea risk

DPP-4 Inhibitor = oral , weight neutral, no nausea

Sitagliptin, Saxagliptin

• Mechanism: Glucose-dependent insulin secretion and glucagon secretion

Lowers PPG more than FPG

• Efficacy: modest ( HbA1c 0.6-0.8%)

• Advantages: weight neutral, no hypoglycemia, may use in patients with any degree renal dysfunction (dose appropriately), infrequent dosing

• Disadvantages: hypersensitivity reactions, ?pancreatitis (sitagliptin); interaction with CYP3A 4/5 strong inhibitors (saxagliptin); cost

DPP-4 Inhibitors

HgA1c Drop with DPP-4 Inhibitors

*P<0.001 vs comparator.

1. Aschner P, et al. Diabetes Care. 2006;29:2632-2637. 2. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205.3. Rosenstock J, et al. Clin Ther. 2006;28:1556-1568. 4. Hermansen K, et al. Diabetes Obes Metab. 2007;9:733-745. 5. Vilsbøll T, et al. Diabetes Obes Metab. 2010;12:167-177. 6. Derosa G, et al. Metab Clin Exp. 2010;59:887-895.

Weight Changes With Sitagliptin:Mono and Combination Therapy

Monotherapy24 Weeks1

Monotherapy24 Weeks2

Add-on to Pioglitazone24 Weeks3

Add-on to Glimepiride24 Weeks4

Add-on toInsulin

24 Weeks5

Add-on to Pio vs

Met+Pio12 Months6

N 741 793 353 441 641 151

Treatment PBO Sit Glip Sit Pio Sit +Pio

Glim Sit + Glim

Ins Sit +Ins

Met + Pio

Sit +Pio

*

*

*P=0.01 vs glyburide uptitration.

1. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 2. Jadzinsky M, et al. Diabetes Obes Metab. 2009;11:611-622.3. DeFronzo RA, et al. Diabetes Care. 2009;32:1649-1655. 4. Scheen AJ, et al. Diabetes Metab Res Rev. 2010;26:540-549.5. Chacra AR, et al. Int J Clin Pract. 2009;63:1395-1406. 6. Hollander P, et al. J Clin Endocrinol Metab. 2009;94:4810-4819.

Weight Changes With Saxagliptin:Mono and Combination Therapy

Monotherapy24 Weeks1

Initial Combow/ Metformin

24 Weeks2

Add-on to Metformin24 Weeks3

Add-on to Metformin18 Weeks4

Add-on to Glyburide vs Uptitration24 Weeks5

Add-on toTZD

24 Weeks6

N 401 1306 743 801 768 565

Treatment PBO Sax Met Sax +Met

Met Sax +Met

Sit +Met

Sax +Met

Gly Sax +Gly

TZD Sax +TZD

*

16

DPP-4 Inhibitors: Summary

• Oral once-daily agents with glucose-lowering potential

• Can be used as monotherapy and as part of combination therapy strategies (sitagliptin approved for combination with Insulin)

• A1C reduction• Well tolerated• Weight neutral