1. Glucagon-Like Peptide-1 Receptor (GLP-1R) Agonists and Dipeptidyl Peptidase-4 (DPP-4) Inhibitors: How Do They Exert Their Metabolic Actions? Part 4

2. Clinical Adverse Events in Active-Comparator Add-on to Metformin Study
Patients With Adverse Events, n (%)
Sitagliptin 100 mg (n=588)
Glipizide
(n=584)
One or more AEs
419
(71.3)
444
(76.0)
Drug-related AEs 85
(14.5)
177
(30.3)
Serious AEs (SAEs) 43
( 7.3) 44
( 7.5)
Serious drug-related AEs
( 0.0) 2
( 0.3)
Died 1
( 0.2)
Discontinued due to AEs 16
( 2.7) 21
( 3.6)
Discontinued due to drug-related AEs 8
( 1.4)
Discontinued due to SAEs 6
( 1.0) 7
( 1.2)
Discontinued due to serious drug-related AEs
Sitagliptin has an excellent safety profile and is associated with significantly fewer drug-related adverse events than glipizide.
Stein P. Presented at: ADA 66th Scientific Sessions; June 9-14, 2006; Washington DC. Late-breaking abstracts.
Stein P. ADA 66th Scientific Sessions; June 9-14, 2006; Washington DC. Late-breaking abstracts.

3. Sitagliptin and Measures of -Cell Function
Compared to placebo, sitagliptin therapy for 24 weeks reduced the proinsulin/insulin ratio and increased HOMA-beta, suggesting a beneficial effect on beta-cell function.
Aschner P, Kipnes MS, Lunceford JK, et al; Sitagliptin Study 021 Group. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;2(12):

4. Sitagliptin: B-Cell Response to Glucose
During the frequently sampled meal tolerance test (MTT) performed before and after 18 weeks, sitagliptin significantly augmented insulin secretion compared to the placebo-treated group.
Adapted from Raz I, Hanefeld M, Xu L, et al; Sitagliptin Study 023 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006;9(11):

5. Vildagliptin Studies: Summary1
As monotherapy, vildagliptin was as effective in reducing A1C as sulfonylureas and metformin and was completely additive in decreasing A1C when added to metformin- and pioglitazone-treated patients with T2DM. Initial combination therapy with pioglitazone in drug-naive patients with T2DM produced an additive effect to decrease A1C.
1. Rosenstock J, Zinman B. Dipeptidyl peptidase-4 inhibitors and the management of type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2007;14(2):
2. Dejager S, Razac S, Foley JE, et al. Vildagliptin in drug-naïve patients with type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled, multiple-dose study. Horm Metab Res. 2007;39(3): Pi-Sunyer FX, Schweizer A, Mills D, et al. Efficacy and tolerability of vildagliptin monotherapy in drug-naïve patients with type 2 diabetes. Diabetes Res Clin Pract. 2007;76(1):
4. 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): Dejager S, Lebeaut A, Couturier A, et al. Sustained reduction in HbA1C during one-year treatment with vildagliptin in patients with type 2 diabetes (T2DM). Presented at: ADA 66th Scientific Sessions; June 9-14, 2006; Washington DC. Abstract 120-OR.]
6. 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): Garber AJ, Schweizer A, Baron MA, et al. Vildagliptin in combination with pioglitazone improves glycaemic-control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes Obes Metab. 2007;9(2):
8. Rosenstock J, Kim SW, Baron MA, et al. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab. 2007;9(2): Fonseca V, Dejager S, Albrecht D, et al. Vildagliptin as add-on to insulin in patients with type 2 diabetes (T2DM). Presented at: ADA 66th Scientific Sessions; June 9-14, 2006; Washington DC. Abstract 467-P.

6. Sitagliptin Studies: Summary1
As monotherapy, sitagliptin was as effective in reducing A1C as metformin and pioglitazone and was completely additive in decreasing A1C when given to metformin- treated patients with T2DM.
1. Rosenstock J, Zinman B. Dipeptidyl peptidase-4 inhibitors and the management of type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2007;14(2):
2. Aschner P, Kipnes MS, Lunceford JK, et al; Sitagliptin Study 021 Group. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;2(12):
3. Raz I, Hanefeld M, Xu L, et al; Sitagliptin Study 023 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006;49(11):
4. Charbonnel B, Karasik A, Liu J, et al; Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006;29(12):
5. Nauck MA, Meininger G, Sheng D, et al; Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9(2):
6. Williams-Herman D, Goldstein BJ, Feinglos MN, et al. Initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin provides substantial glycemic improvements and HgbA1c goal attainment in patients with type 2 diabetes mellitus (T2DM). Diabet Med. 2006;23(suppl 4):319.
7. Rosenstock J, Brazg R, Andryuk PJ, et al; Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28(10):

7. DPP-4 Inhibition and Plasma Levels of GLP-1
DPP-4 inhibition prevents the degradation of active GLP-1 but does not increase GLP-1 secretion nor prevent the kidney from rapidly clearing GLP-1
DPP-4 inhibition also acutely decreases L-cell secretion of GLP-1, most likely via negative feedback inhibition of the L-cell. During a meal, total GLP-1 decreases but active GLP-1 (7-36) increases

8. DPP-4 Inhibition and Plasma Levels of GLP-1
DPP-4 inhibition prevents the degradation of active GLP-1 but does not increase GLP-1 secretion nor prevent the kidney from rapidly clearing GLP-1

9. Exendin-4: A GLP-1R Agonist
Exendin-4 binds to the GLP-1 receptor with similar affinity to that of GLP-1. Exenatide, a GLP-1 receptor agonist, is a synthetic version of exendin-4.
Chen YE, Drucker DJ. Tissue-specific expression of unique mRNAs that encode proglucagon-derived peptides or exendin 4 in the lizard. J Biol Chem. 1997;272(7):

10. Exenatide Restores First-Phase Insulin Secretion in Type 2 Diabetes
In participants with T2DM, the acute (first) phase insulin response to an acute intravenous glucose challenge is absent. Infusion of exenatide for 4 hours restored the first phase insulin response to normal in individuals with T2DM.
Fehse F, Trautmann M, Holst JJ, et al. Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2005;90(11):

11. Effect of Exenatide Versus Glargine Insulin on Insulin Secretion in Type 2 Diabetes
Subjects: 55 type 2 diabetes Age=58 years; BMI=30.5 kg/m2
Diabetes duration=4.8 years
A1C=7.5%; FPG=9.1 mM
Study Design: Exenatide*(n=36) vs glargine (n=33)
Treatment goal = A1C ≤7.0%
Actual A1C=6.8±0.1%
∆ Body wt (kg)=+1.0 glargine vs exenatide
Study Duration: 1 Year
The effect of exenatide versus glargine insulin therapy on insulin secretion was examined following a similar reduction in A1C (to 6.8%) in study participants with T2DM. Because glucose toxicity can impair beta-cell function, a group of patients with T2DM were treated with glargine to similarly reduce A1C as in the exenatide group. Participants received a hyperglycemia clamp followed by an intravenous arginine (5 grams) bolus to evaluate insulin secretion.
*5-10 µg BID up to µg TID.

12. C-Peptide Secretion During Hyperglycemic Clamp After 1 Year of Exenatide (10 µg BID-15 µg TID) vs Glargine Insulin Therapy to Reduce A1C <7.0%
After 1 year of treatment with glargine, there were modest increases in both the first ( minutes) and second ( minutes) phases of insulin secretion. In contrast, both first- and second-phase insulin secretion were markedly increased with exenatide. The insert displays the ratio of plasma insulin response during the hyperglycemic clamp before and after exenatide and glargine. Glargine increased the insulin response by 31%, ie, reversal of glucotoxicity. In contrast, exenatide increased the insulin response 3.19-fold, indicating a potent stimulatory effect on insulin secretion.
Bunck MC, Diamant MA, Corner EB, et al. One year treatment with exenatide improves beta cell function and glycaemic control in metformin treated type 2 diabetes. Diabetologia. 2007;50(suppl 1):S111.

13. Effect of Exenatide vs Glargine on Postmeal Blood Glucose Excursion
In patients with T2DM treated with exenatide or glargine for 26 weeks, there was a similar decrease in A1C. However, the primary effect of exenatide was to reduce the postprandial plasma glucose excursion, whereas the primary effect of glargine was to reduce the FPG concentration without affecting the postprandial glucose excursion.
Heine RJ, Van Gaal LF, Johns D, et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005;143(8):