Pathophysiology in the
Treatment of Type 2
Diabetes
Newer Agents
Part 3 of 5
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”
2
1Drucker
DJ. Diabetes Educator. 2006;32(Suppl 2):65S-71S.
T, Holst JJ. Diabetologia. 2004;47:357-366.
2Vilsbøll
Glucagon-like Peptide-1 (GLP-1)
Most well-characterized incretin
Secreted from L cells of the intestines
Very short half-life
Possibly deficient and GLP-1 resistance in type
2 diabetes
3
Adapted
from Aronoff SL, et al. Diabetes Spectrum. 2004;17:183-190.
Summary of Incretin Actions on Different Target Tissues
Neuroprotection
Appetite
Brain
Stomach
Heart
Gastric emptying
Cardioprotection
Cardiac output
GLP-1
Liver
GI tract
Insulin sensitivity
Muscle
Insulin biosynthesis
b cell proliferation
b cell apoptosis
Insulin secretionovercomes decreased
insulin secretion of
steroids and tacrolimus
Glucagon secretion
Glucose production
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 D. J. Cell Metabolism 2006
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
Hyperglycemia in Type 2 Diabetes Results from
Abnormal Meal-Related Insulin and Glucagon Dynamics
Normal (n=11)
T2DM (n=12)
Insulin
(µU/mL)
120
90
60
30
0
Glucagon
(pg/mL)
140
130
120
110
100
90
Glucose
(mg %)
Meal
360
330
300
270
240
110
80
-60
0
60
120
Time (min)
Müller WA, et al. N Engl J Med. 1970;283:109-115.
180
240
Premeal
Postmeal
 Insulin
 Insulin
 Glucagon
 Glucagon
 HGP
 HGP
 FPG
 PPG
Glucose-dependent Effects of GLP-1
Placebo
GLP-1
Type 2 Diabetes (n = 10)
Glucose (mg/dL)
270
300
*
180
*
20
200
*
*
90
*
* * 100
*
-30 0
60
120
Time (min)
180 240
0
-30 0
60
*
120
* *
* *
10
* *
* *
0
Glucagon (pmol/L)
Insulin (pmol/L)
*
*
180 240
0
-30 0
Time (min)
Mean (SE); *P < 0.05 GLP-1 = glucagon-like peptide-1
Adapted from Nauck MA, et al. Diabetologia. 1993;36:741–744.
60
120
180 240
Time (min)
CV effects of GLP-1, GLP-1 RA, DPP-4 Inh.
Added by Dr S
Glp1 in major
Surgery in DMBenefit in
Stress/ Steroid
DM
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
GLP-1 like effect
GLP agonists 7-10 x
DPP4-I 2-3 x
Glucose
dependent
GLP-1 receptor agonists
Ingestion of
food
Resists degradation by DPP-4
 Insulin
 Glucose
uptake by
peripheral tissue
Pancreas
GI tract
Release of
active incretins
GLP-1 and GIP
Sitagliptin
Saxagliptin
(DPP-4
inhibitors)
X
Beta cells
Alpha cells
 Blood glucose in
fasting and
postprandial states
DPP-4
Glucosedependent
enzyme
 Glucagon
Inactive
GLP-1
GLP-1 Receptor Agonists= parenteral, weight loss,
nausea risk
DPP-4 Inhibitor = oral , weight neutral, no nausea
Inactive
GIP
 Hepatic
glucose
production
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
DPP-4 Inhibitors
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:
interaction
cost
hypersensitivity reactions, ?pancreatitis (sitagliptin);
with CYP3A 4/5 strong inhibitors
(saxagliptin);
HgA1c Drop with DPP-4 Inhibitors
Weight Changes With Sitagliptin:
Mono and Combination Therapy
Monotherapy Monotherapy Add-on to
24 Weeks1
24 Weeks2 Pioglitazone
24 Weeks3
N
741
PBO
Sit
Glip
353
Sit
Pio
Sit +
Pio
Add-on to
Insulin
24 Weeks5
Add-on to
Pio vs
Met+Pio
12 Months6
441
641
151
Glim
Sit +
Glim
Ins
Sit +
Ins
Met +
Pio
Sit +
Pio
 Weight (kg)
Treatment
793
Add-on to
Glimepiride
24 Weeks4
*
*
*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 Saxagliptin:
Mono and Combination Therapy
Monotherapy Initial Combo
24 Weeks1 w/ Metformin
24 Weeks2
N
401
PBO
Weight (kg)
Treatment
Add-on to
Metformin
24 Weeks3
Add-on to
Metformin
18 Weeks4
Add-on to
Glyburide vs
Uptitration
24 Weeks5
Add-on to
TZD
24 Weeks6
743
801
768
565
1306
Sax
Met
Sax +
Met
Met
Sax +
Met
Sit +
Met
Sax +
Met
Gly
Sax +
Gly
TZD
*
*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.
Sax +
TZD
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
16