Mechanisms of Glucose Lowering Effects of Sitagliptin and Metformin Alone and in Combination in Patients With T2DM

NCT ID: NCT00820573

Last Updated: 2013-12-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 16 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-10-31
• Study Completion Date: 2012-10-31

Brief Summary

In patients with type 2 diabetes with inadequate glycemic control on diet and exercise after 6 weeks of treatment:

Objective: To assess the effects of co-administration of sitagliptin and metformin compared to placebo on hepatic glucose production (HGP).

Hypothesis: After 6 weeks of treatment, the co-administration of sitagliptin and metformin provides greater reduction in hepatic glucose production (HGP) compared to placebo.

Detailed Description

PRIMARY:

In patients with type 2 diabetes with inadequate glycemic control on diet and exercise after 6 weeks of treatment:

Objective: To assess the effects of co-administration of sitagliptin and metformin compared to placebo on hepatic glucose production (HGP).

Hypothesis: After 6 weeks of treatment, the co-administration of sitagliptin and metformin provides greater reduction in hepatic glucose production (HGP) compared to placebo.

SECONDARY:

In patients with type 2 diabetes with inadequate glycemic control on diet and exercise after 6 weeks of treatment:

1. Objective: To assess the effects of co-administration of sitagliptin and metformin compared to placebo on post-meal glucose during meal tolerance test (MTT).

Hypothesis: After 6 weeks of treatment the co-administration of sitagliptin and metformin provides greater reduction in the total glucose AUC (0-6 hr) during MTT compared to placebo.

2. Objective: To assess the effects of co-administration of sitagliptin and metformin compared to placebo on fasting plasma glucose (FPG).

Hypothesis: After 6 weeks of treatment the co-administration of sitagliptin and metformin provides greater reduction in FPG compared to placebo.

3. Objective: To assess the effects sitagliptin alone compared to placebo on HGP. Hypothesis: After 6 weeks of treatment, sitagliptin alone provides greater reduction in HGP compared to placebo

EXPLORATORY OBJECTIVES:

(i) Objective: after 6 weeks of treatment, to assess the effects co-administration of sitagliptin and metformin compared to placebo on:

1. active and inactive incretin concentrations (fasting and post-meal GLP-1 and fasting and post-meal GIP).

2. glucagon concentration (fasting and post-meal).

3. parameters of insulin secretion and insulin sensitivity.

4. splanchnic glucose uptake.

(ii) Objective: after 6 weeks of treatment, to assess the effects co-administration of sitagliptin and metformin compared to treatment with sitagliptin alone and metformin alone on:

5. glucose concentration (fasting and total glucose AUC [0-6 hr]).

6. active and inactive incretin concentrations (fasting and post-meal GLP-1 and fasting and post-meal GIP).

7. glucagon concentration (fasting and post-meal).

8. parameters of insulin secretion and insulin sensitivity.

9. HGP.

10. splanchnic glucose uptake. (iii) Objective: after 6 weeks of treatment, to assess the effects of sitagliptin alone and metformin alone compared to placebo on:

11. glucose concentration (fasting and total glucose AUC [0-6 hr]).

12. active and inactive incretin concentrations (fasting and post-meal GLP-1 and fasting and post-meal GIP).

13. glucagon concentration (fasting and post-meal).

14. parameters of insulin secretion and insulin sensitivity.

15. HGP.

16. splanchnic glucose uptake.

Conditions

Diabetes

Keywords

Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Placebo

Placebo to be provided for 6 weeks

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo 6 weeks

Sitagliptin

Sitagliptin to be provided for 6 weeks

Group Type: EXPERIMENTAL

Sitagliptin

Intervention Type: DRUG

tablet, 100 mg/day, 6 weeks

Metformin

Metformin to be provided for 6 weeks

Group Type: EXPERIMENTAL

Metformin

Intervention Type: DRUG

tablet, 1000 mg/ bid, 6 weeks

Sitagliptin+Metfromin

Sitagliptin + Metformin combined will be provided for 6 weeks

Group Type: EXPERIMENTAL

Sitagliptin + Metformin

Intervention Type: DRUG

tablet, Sitagliptin (100mg/day) + tablet, Metformin (1000 mg/bid), 6 weeks

Interventions

Sitagliptin

tablet, 100 mg/day, 6 weeks

Intervention Type: DRUG

Metformin

tablet, 1000 mg/ bid, 6 weeks

Intervention Type: DRUG

Sitagliptin + Metformin

tablet, Sitagliptin (100mg/day) + tablet, Metformin (1000 mg/bid), 6 weeks

Intervention Type: DRUG

Placebo

Placebo 6 weeks

Intervention Type: DRUG

Other Intervention Names

Januvia; Glucophage; Januvia and glucophage; Placebo tablet

Eligibility Criteria

Inclusion Criteria

• Patients with screening values/findings outside ranges described in the protocol may have one repeat determination performed and if the repeat value satisfies the criterion, they may continue in the screening process.
• If the repeat value does not satisfy the criterion, the principal investigator will review the abnormal laboratory value and decide whether the subject may continue in the screening process.
• All screening laboratory measurements are to be performed after an overnight fast ≥10 hours in duration.
• Patients must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent.
• Patients can be either male or female.
• Patients are ≥18 and ≤70 years of age on the day of signing informed consent.
• Patients must meet the current American Diabetes Association criteria for the diagnosis of type 2 diabetes mellitus
• Patients must be on diet or diet plus exercise therapy.
• Patients must have a HbA1c ≥ 7.5% and ≤ 9.5%
• Patients must have a BMI of 23-40 kg/m2
• Patients must have the following laboratory values:

• Hematocrit Males ≥ 34 vol%
• Females ≥ 33vol%
• Serum creatinine ≤ 1.5 mg/dL in males and ≤ 1.4 mg/dL in females
• AST (SGOT): ≤ 2.5 times upper limit of normal
• ALT (SGPT): ≤ 2.5 times upper limit of normal
• Alkaline phosphatase ≤ 2.5 times upper limit of normal
• If serum creatinine is > 1.5 mg/dl in males and > 1.4 mg/dl in females, the Principal Investigator can include the patient if the measured GFR is >70 ml/min (24 hour creatinine clearance)
• Patients must have been on a stable dose of allowed chronic medications for ≥30 days prior to entering the study.
• Only patients whose body weight has been stable (±4 pounds) over the three months prior to the study will be included.

Exclusion Criteria

• Patients are excluded from participation in the study if they meet any of the following criteria:

• Patient has type 1 diabetes.
• Patient has received insulin for more than one week within the previous year prior to entry.
• Patient has been treated with exenatide or a non-TZD, oral antihyperglycemic agent within the last 2 months or with a TZD (pioglitazone or rosiglitazone) within the last 4 months.
• Patient is receiving any medications with known adverse effects on glucose tolerance (e.g., systemic glucocorticoids, psychotropic drugs like clozapine, olanzapine, haloperidol, risperidone). Note: Patients may be taking stable doses of estrogens, other hormonal replacement therapy, or lipid and blood pressure lowering agents if the patient has been on these agents for the prior three months.
• Patient has evidence of a significant cardiovascular disorder within 6 months of signing informed consent (e.g. acute coronary syndrome, coronary artery intervention, stroke or transient ischemic neurological disorder) or has New York Heart Association Classification greater than Class 2; or has significant findings on ECG (other than non-specific ST-T wave changes); or peripheral vascular disease (history of claudication); or has dyspnea on exertion of one flight or less, or abnormal breath sounds on auscultation.
• Patient has a history of intolerance or hypersensitivity to a DPP-4 inhibitor or to metformin.
• Patient is pregnant or plans to become pregnant within the projected duration of the study.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

The University of Texas Health Science Center at San Antonio

OTHER

Sponsor Role: lead

Responsible Party

Eugenio Cersosimo

Associate Professor Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Eugenio Cersosimo, MD

Role: PRINCIPAL_INVESTIGATOR

University of TX Health Science Center

Locations

Texas Diabetes Institute

San Antonio, Texas, United States

Countries

United States

References

Solis-Herrera C, Triplitt C, Garduno-Garcia Jde J, Adams J, DeFronzo RA, Cersosimo E. Mechanisms of glucose lowering of dipeptidyl peptidase-4 inhibitor sitagliptin when used alone or with metformin in type 2 diabetes: a double-tracer study. Diabetes Care. 2013 Sep;36(9):2756-62. doi: 10.2337/dc12-2072. Epub 2013 Apr 11.

Reference Type: DERIVED

PMID: 23579178 (View on PubMed)

Other Identifiers

35464

Identifier Type: -

Identifier Source: org_study_id