1. MK-0431 P051 PDT APPROVED 4/10/09 11/13/2018 2:49 PM
Protocol PN051, p9B
Multinational, placebo-controlled, randomized, double-blind, parallel-group, 24-week study
Involved patients who were receiving insulin (not routine pre-meal short- or rapid-acting insulin, except as pre-mixed insulin) administered alone or in combination with metformin (1500 mg per day) and who had inadequate glycemic control (A1C 7.5% and ≤11%)
Eligible patients continued on their current insulin regimen (with/without metformin) and entered a 2-week single-blind placebo run-in period, followed by randomization (1:1) to treatment with sitagliptin 100 mg once daily or placebo for a 24-week stable-insulin dose, double-blind treatment period.
Patients stratified by 1) use of metformin at Visit 1 2) the patient’s use of pre-mixed insulin at Visit 1, and 3) participation in the 10-point, frequently sampled, meal tolerance test.[PN051 p21A]
Proportion of patients using pre-mixed insulin or metformin capped at ≤25% and ≤75% of the entire cohort, respectively. [Protocol P051, p21B]
MK-0431 P051 CSR PDT ppt

2. MK-0431 P051 PDT APPROVED 4/10/09 11/13/2018 2:49 PM
CSR P051 p86 Table 10-5
This slide summarizes the baseline efficacy endpoints and diabetes history of all randomized patients by treatment group.
Baseline efficacy endpoints and diabetes history at baseline were generally balanced across treatment groups. [CSR P051 p84A]
MK-0431 P051 CSR PDT ppt

3. MK-0431 P051 PDT APPROVED 4/10/09 11/13/2018 2:49 PM
CSR P051 p87 Table 10-6
This slide summarizes the baseline insulin use of all randomized patients by treatment group.
Baseline anti-hyperglycemic medication use was generally balanced across treatment groups. [CSR P051 p84A]
MK-0431 P051 CSR PDT ppt

4. A1c Change over Time MK-0431 P051 PDT APPROVED 4/10/09
11/13/2018 2:49 PM
A1c Change over Time
MK-0431 P051
MK-0431 P051 CSR PDT ppt

5. Change from Baseline in A1C by Pre-mixed Insulin Stratum
MK-0431 P051 PDT APPROVED 4/10/09
11/13/2018 2:49 PM
Change from Baseline in A1C by Pre-mixed Insulin Stratum
FAS, LOCF (Week 24) Excluding Data After Initiation of Rescue Therapy
On Pre-mixed Insulin
On Long-acting or Intermediate-acting Insulin
CSR P051 p93 Table 11-2
N=80
N=80
N=225
N=232
Sitagliptin
Placebo
-0.04
-0.02
A1C (%) LS Mean Change from Baseline
This slide shows the A1C results for the FAS population at Week 24 by insulin strata (ie, subpopulations of patients receiving pre-mixed insulin or receiving long-acting or intermediate-acting insulin).
For patients on a long-acting or intermediate-acting insulin, the LS Mean decrease from baseline in A1C was significantly greater in the sitagliptin 100 mg group compared with the placebo group (p<0.001), resulting in success for the test of this secondary hypothesis (after 24 weeks, treatment with sitagliptin vs. placebo will provide a greater reduction in A1C in the sub-population of patients on a long-acting or intermediate-acting insulin (but not on pre-mixed combinations of intermediate and short-acting insulins) alone or in combination with metformin) [Protocol P051 p14D]. There was no significant treatment by stratum interaction (P=0.949). [CSR P051 p93A]
For patients on pre-mixed insulin, change from baseline in A1C at Week 24 was also significantly greater in the sitagliptin 100 mg group vs. the placebo group (p<0.001). [CSR P051 Table 11-2 p93D]
Footnote
P-values based on ANCOVA model with terms for treatment, metformin stratum, pre-mixed insulin stratum, treatment by pre-mixed insulin stratum interaction, and baseline A1C as a covariate. [CSR P051 p93B]
p-Value for Treatment by Subgroup Interaction =0.949
-0.61
-0.58
p<0.001
p<0.001
MK-0431 P051
CSR P051 (01/30/09)
MK-0431 P051 CSR PDT ppt

6. MK-0431 P051 PDT APPROVED 4/10/09 11/13/2018 2:49 PM
CSR P051 p199 Table 12-16
This slide shows the effect of sitagliptin 100 mg on the incidence of hypoglycemic endpoints (the only pre-specified Tier 1 clinical AE) over the 24-week treatment period in the APaT population. [CSR P051 p147A; p196A]
The results show that improved glycemic control observed with sitagliptin 100 mg (when added to insulin administered alone or in combination with metformin) was associated with an increase in events of hypoglycemia compared with placebo (p= 0.003), but these were mostly mild to moderate, and generally did not lead to discontinuation. [CSR P051 p222A; p196B] Two episodes in 2 patients receiving sitagliptin 100 mg and 1 episode in a patient receiving placebo group met the protocol-specified criteria of marked severity. [CSR P051 p221B - 222B]
Initiation of rescue therapy or a sustained >10% insulin dose increase had no impact on the analysis of hypoglycemia in the entire cohort or in the stratum of patients on metformin. [CSR P051 p196E]
In studies of sitagliptin treatment in patients with T2DM, the incidence of hypoglycemia has generally been similar to placebo, including studies of sitagliptin used as monotherapy or in combination with metformin or a PPAR agonist [Aschner 2006; raz 2006; Rosenstock 2006; Goldstein 2007]. The low rate of hypoglycemia with sitagliptin used as monotherapy or in combination with metformin or a PPAR agonist similar to the rate observed with placebo is consistent with the glucose-dependency of insulin secretion and glucagon suppression observed with incretin-targeted therapies.
In contrast, sitagliptin added to patients inadequately controlled on a sulfonylurea alone or in combination with metformin had an incidence of hypoglycemia higher in the sitagliptin group compared with the placebo group [Hermansen 2007]. Unlike sitagliptin, sulfonylureas are associated with hypoglycemia whether used as monotherapy or in combination therapy. This observation is likely due to the non-glucose-dependent mechanism of action of sulfonylurea -stimulation of insulin secretion [Inzucchi 2002] resulting in a higher incidence of hypoglycemia when sitagliptin is added to a sulfonylurea.
Similarly, since levels of exogenously-administered insulin are not regulated by either ambient glucose or incretin concentrations, the finding that the addition of sitagliptin to an insulin regimen (with or without metformin) led to a higher incidence of hypoglycemia compared with placebo in the current study was, therefore, not unexpected. In patients with T2DM, the frequency of hypoglycemia in patients taking insulin has similarly been shown to be related to glycemic control [Yki-Järvinen 1999].
PPAR agonists when added to the regimen of patients on insulin, an increased incidence of hypoglycemia–comparable to the incidence observed in this study–has also been reported and is reflective of the hypoglycemic effect of insulin [Rosenstock 2002; Raskin 2001; Sheffield 2008] [CSR P051 p220B - 221B]
MK-0431 P051 CSR PDT ppt

8. GLP-1 RAs Added to Multiple Oral Agents: Comparisons With Basal Insulin

9. A: A1C over time for the study population.
Lira Triple therapy
A: A1C over time for the study population.
A: A1C over time for the study population. B: Percentage of subjects achieving ADA and AACE/IDF A1C goals at the end of the study. C: FPG values over time. D: Change in body weight over time. E: SBP over time. F: Percentage of subjects with nausea by week. Data are intent to treat, last observation carried forward for all postbaseline values, with the exception of F, which is data from the safety analysis set. Error bars shown in A, C, D, and E are 2 × SE. **P = ; ***P <
Zinman B et al. Dia Care 2009;32:
Copyright © 2011 American Diabetes Association, Inc.

10. Baseline Endpoint Insulin Dose (Units)30 40 50 60 70 80 90
100
110
120
130
140
150
Insulin Dose (Units)
Balena R, Hensley IE, Miller S, Barnett AH. Combination therapy with GLP-1 receptor agonists and basal insulin: a systematic review of the literature. Diabetes Obes Metab Oct 15. doi: /dom [Epub ahead of print] PubMed PMID:
Permission needed
FXCX:
Balena 2012: graphs: fig p6
Footnote: p3 c1 under literature identified

12. Incretin-Based Therapy in Combination With Basal Insulin

13. Twice-daily Exenatide as Add-on to Basal Insulin (Glargine)

14. Exenatide Twice Daily Added to Insulin Glargine

15. Twice-daily Exenatide as Add-on to Basal Insulin (Glargine): Results

16. Exenatide Twice Daily Added to Insulin Glargine