Pathophysiology in the Treatment of Type 2 Diabetes Newer Agents Part 3 of 5.
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Transcript of Pathophysiology in the Treatment of Type 2 Diabetes Newer Agents Part 3 of 5.
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