1. GLP-1 Agonists and DPP-4 Inhibitors How do they work?
Part 2

2. Incretin Physiology in Type 2 Diabetes Mellitus
GLP-1 & GIP Secretion in Type 2 Diabetes Mellitus

3. Postprandial GLP-1 Levels Are Decreased in Patients With IGT and Type 2 Diabetes
During a meal tolerance test, GLP-1 levels are reduced in participants with IGT and further decreased in participants with T2DM.
Toft-Nielsen MB, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86(8):

4. Glucose-Dependent Insulinotropic Polypeptide (GIP) Response During OGTT
In contrast to GLP-1 levels, plasma GIP is increased in patients with T2DM during an OGTT, while the plasma insulin response is diminished. This suggests resistance to the stimulator effect of GIP on insulin secretion and, in fact, this has been demon-strated by Holst et al. (Holst citation is included below for reference. Data does not appear on this slide.)
Jones IR, Owens DR, Luzio S, et al. The glucose dependent insulinotropic polypeptide response to oral glucose and mixed meals is increased in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1989;32(9):
Holst JJ, et al. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab 2004;287:

5. What Is DPP-4?
A serine protease widely distributed throughout the body
Cleaves N-terminal amino acids of a number of biologically active peptides, including the incretins GLP-1 and gastric inhibitory peptide (GIP), resulting in inactivation
Its effects on GLP-1 and GIP have been shown to affect incretin activity
Inactivates GLP-1 >50% in ~1 to 2 minutes
Ahrën B. Curr Enzyme Inhib. 2005;1:65-73.

6. DPP-4
Rasmussen HB, Branner S, Wiberg FC, et al. Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat Struct Biol. 2003;10(1):19-25

7. DPP-4 Action/Inhibition
DPP-4 is present ubiquitously in plasma and on cell membranes and rapidly cleaves two amino acids off of GIP and GLP-1, rendering them inactive. Inhibition of DPP-4 activity blocks the degradation of GLP-1 and GIP, and prolongs their half-life in the plasma.

8. Overview Discuss normal GLP-1 physiology
Examine the actions of DPP-4 inhibitors and GLP-1R agonists
Review the tissue-specific differences in the mechanisms of action of GLP-1 analogs, DPP-4 inhibitors, and GLP-1R agonists

9. Inhibition of DPP-4 Increases Active GLP-1
The half-life of GLP-1 is very short, 1 to 2 minutes, but can be prolonged markedly with a DPP-4 inhibitor.
Adapted from Rothenberg P, Kalbag J, Smith M, et al. Treatment with a DPP-IV inhibitor, NVP-DPP728, increases prandial intact GLP-1 levels and reduces glucose exposure in humans. Diabetes. 2000;49(suppl 1):A39.

10. Normalization of Diurnal Plasma Glucose Concentrations by Continuous IV GLP-1
Rachman et al demonstrated that continuous infusion of GLP-1 maintained a constant level of hormone in plasma-augmented insulin secretion, inhibited glucagon secretion, and normalized fasting and postprandial glucose levels in study participants with type 2 diabetes mellitus (T2DM).
Rachman J, Barrow BA, Levy JC, et al. Diabetologia. Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM. 1997;40(2):

11. Levels of Intact GLP-1 (7-36 amide) Postmeal Are Increased Within the Normal Range After Vildagliptin
DPP-4 inhibition with vildagliptin raises the GLP-1 levels of participants with T2DM into the normal range (10-12 pmol/L), but these GLP-1 levels are much lower than those observed following a subcutaneous injection of exenatide or GLP-1.
Balas B, Baig MR, Watson C, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007;92(4):

12. Effect of Vilagliptin on Plasma Glucagon Levels During Mixed Meal
Patients with T2DM manifest a paradoxical rise or lack of suppression of glucagon in response to a mixed meal. Vildagliptin, 100 mg orally, markedly inhibits the plasma glucagon response to a meal.
Balas B, Baig MR, Watson C, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007;92(4):

13. Effect of Vildagliptin on Plasma Insulin and C-Peptide Concentrations During Mixed Meal
After a single dose of vildagliptin, 100 mg orally, meal-stimulated plasma insulin and C-peptide concentrations increased significantly. These changes in plasma insulin and glucagon concentrations, as depicted here and in the previous slide (Effect of Vilagliptin on Plasma Glucagon Levels During Mixed Meal), were associated with a significant reduction in postmeal plasma glucose concentration.
Balas B, Baig MR, Watson C, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007;92(4):

14. Effect of Vildagliptin on Endogenous (Hepatic) Glucose Production During Mixed Meal
The increase in plasma insulin response in concert with the decline in plasma glucagon response following vildagliptin leads to an enhanced suppression of HGP during the meal.
Balas B, Baig MR, Watson C, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007;92(4):

15. Vildagliptin Does Not Increase Tissue Glucose Uptake After Mixed Meal
Increased tissue (muscle) glucose uptake does not contribute to the reduced postprandial rise in plasma glucose concentration seen after a meal when vildagliptin is administered 30 minutes prior. This is explained by a reduced plasma glucose concentration (decreased mass action effect of hyperglycemia to augment tissue glucose uptake) that offsets the increased plasma insulin response, which otherwise would augment muscle glucose uptake.
Balas B, Baig MR, Watson C, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007;92(4):

16. Vildagliptin: Comparison With Metformin
In a 1-year study, the reduction in A1C with vildagliptin is comparable to that observed with metformin in drug-naive patients.
Rosenstock J, Baron MA, Dejager S, et al. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes Care. 2007;30(2):

17. Vildagliptin Compared to Rosiglitazone in Drug-Naive Patients
In a 1-year study, the reduction in A1C with vildagliptin is comparable to that observed with rosiglitazone, irrespective of the starting A1C, in drug-naïve patients with T2DM.
Rosenstock J, Baron MA, Dejager S, et al. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes Care. 2007;30(2):

18. Vildagliptin Added to Metfromin in Patients With Type 2 Diabetes
When added to metformin, vildagliptin produces a dose-response additive effect to reduce A1C.
Bosi E, Camisasca RP, Collober C, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care. 2007;30(4):

19. Vildagliptin Provides Sustained Improvement of -Cell Function
Vildagliptin treatment for 1 year in patients with T2DM treated with metformin enhanced insulin secretion (left), the OGIS index of insulin sensitivity (middle), and the adaptation index (equivalent to the insulin secretion/insulin resistance or disposition index). The latter provides an index of beta-cell function that relates the insulin secretory response during the oral glucose tolerance test (OGTT) to the severity of insulin resistance.
Adapted from Ahrén B, Pacini G, Foley JE, et al. Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year. Diabetes Care. 2005; 28(8):

20. Vildagliptin: Pooled Analysis of Clinical Data Adverse Event Profiles
Vildagliptin 100 mg Daily (n=1530)
Metformin ≤2g Daily (n=252)
Rosiglitazone 8 mg Daily (n=267)
Placebo (n=255)
Any
63.6
75.4
64.0
60.0
Nasopharyngitis
7.6
9.5
7.5
7.1
Headache
5.2
5.9
Dizziness
5.8
6.0
4.1
4.3
Upper respiratory tract infection
4.6
3.0
2.7
Diarrhea
3.1
26.2
2.6
Nausea
2.9
10.3
0.7
3.9
Abdominal Pain
1.2
Vildagliptin has an excellent safety profile.
1. Nathwani A. Reduction in blood pressure in patients treated with vildagliptin as monotherapy or in combination with metformin for type 2 diabetes. Diabetes. 2006;55(suppl 1):A474-P.
2. Ferrannini E, Fonseca V, Zinman B, Matthews D, Ahrén B, Byiers S, Shao Q, Dejager S. Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes Obes Metab Feb;11(2):
3. Ahrén B. Emerging dipeptidyl peptidase-4 inhibitors for the treatment of diabetes. Expert. Opin Emerg Drugs Dec;13(4):
1. Nathwani A. Diabetes. 2006;55(suppl1):A474-P. 2. Ferrannini E, et al. Diabetes Obes Metab Feb;11(2):
3. Ahrén B. Expert Opin Emerg Drugs Dec;13(4):