Type 2 Diabetes
Conditions
Keywords
Type 2 Diabetes, DPP-4 inhibitors, renal sodium excretion
Brief summary
Background: Dedicated renal hemodynamic and renal function studies are lacking for DPP-4 inhibitors in patients with Type 2 diabetes; accordingly little is known regarding the mechanisms mediating the renal effects of DPP-4 inhibitors in humans. Objectives: To evaluate the effect of DPP-4 inhibition acutely (single dose) and following short-term therapy (28 days) on renal sodium handling and renal hemodynamics and function in patients with type 2 diabetes and systolic hypertension. Design: double-blind, randomized, placebo-controlled trial, Phase IV. Patient population: 32 patients with Type 2 diabetes, HbA1c (6.5%-9%), with systolic blood pressure ranging from 120-160 mmHg. Intervention: subjects will be randomized (1:1) to either sitagliptin (100 mg daily) or to placebo (1 tablet daily) for 28 days. Endpoints: Fractional excretion of sodium, renal function, and renal hemodynamics.
Detailed description
Background: DPP-4 inhibition improves glycemic control, modestly reduces blood pressure and may also reduce albuminuria in patients with Type 2 diabetes; effects which occur without significantly modifying heart rate or body weight. While preclinical studies have demonstrated that DPP-4 inhibition acutely increases urinary sodium excretion in addition to other favorable renal effects (anti-inflammatory, anti-proteinuric), few studies have examined the renal effects of DPP-4 inhibition either acutely or following short-term therapy in humans with type 2 diabetes. Considering the world-wide prevalence of Type 2 diabetes and the increasing use of DPP-4 inhibitors amongst patients, it is important to ascertain potential non-glycemic effects of DPP-4 inhibitors including those within the kidney. Study Objectives: To determine effect(s) of DPP-4 inhibition on tubular sodium handling, renal hemodynamics, and renal function. Study Design: double-blind, randomized, placebo-controlled trial, Phase IV. Study Patients: 32 patients with Type 2 Diabetes and Systolic Hypertension (SBP 120-160 mmHg). Endpoints: Fractional excretion of sodium, renal function (measured GFR), renal hemodynamics (effective renal plasma flow, filtration fraction, renal blood flow, renal vascular resistance), systemic hemodynamics (non-invasive cardiac monitoring), plasma neurohormones, urinary vasoactive mediators, markers of free radical stress.
Interventions
DRUGSitaglitpin
Oral DPP-4 inhibitor, 100 mg tablet administered once daily for 28 days
OTHERPlacebo
Oral tablet (no medicinal ingredients) administered once daily for 28 days
Sponsors
Merck Sharp & Dohme LLC
University Health Network, Toronto
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Individuals of 18-70 years of age, * with Type 2 Diabetes, * with an HbA1c (6.5%-9%), * and with a systolic blood pressure (120-160 mmHg).
Exclusion criteria
* Individuals with: 1. Type 1 Diabetes, 2. eGFR \<50mL/min/1.73m, 3. pregnancy or breast feeding, 4. significant cardiac, pulmonary or liver disease, 5. prior history of pancreatitis, medullary thyroid cancer, multiple endocrine neoplasia syndromes, 6. SBP \>161 mmHg, 7) DBP \>100 mmHg, 7. alcohol or substance abuse, 8. states of secondary hypertension.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Fractional Excretion of Sodium (FENA) | 3 Hrs post-administration after 1 month and after 1 dose | FENA at 3Hrs post-study drug administration after 1 month compared to FENA at 3Hrs post-study drug administration after 1 dose expressed as percent change, sitagliptin vs. placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fractional Excretion of Lithium (FELi) | 3 Hrs post-administration after 1 month and after 1 dose | FELi at 3 Hr post-study drug administration after 1 month compared to FELI at 3hrs post-study drug administration after 1 dose, sitagliptin vs. placebo |
| Change From Baseline in SDF-1alpha^1-67 (Intact) Measured by Immunoaffinity and Tandem Mass Spectrometry | 3 Hr vs. baseline after 1 dose | Plasma concentration of SDF-1alpha\^1-67 (intact) measured by quantitative mass spectrometry methods after antibody-based affinity enrichment, sitagliptin vs. placebo |
| Change in Glomerular Filtration Rate (GFR) | 3 Hrs post-administration after 1 month and after 1 dose | Measured GFR (Inulin Clearance) at 3Hrs post study-drug after 1 month compared to Measured GFR at 3Hrs post-study drug after 1 dose, sitagliptin vs. placebo |
| Change in Systolic Blood Pressure (SBP), Non-invasive Cardiac Output Monitoring | 3 Hrs post-administration after 1 month and after 1 dose | SBP by Non-Invasive cardiac output monitoring at 3Hrs post- study drug administration after 1 month compared to SBP by Non-invasive cardiac output monitoring at 3Hrs after 1 dose, sitagliptin vs placebo |
| Change in Effective Renal Plasma Flow (ERPF) | 3 Hrs post-administration after 1 month and after 1 dose | ERPF (para-aminohippurate clearance) 3Hrs post-study drug administration after 1 month compared to ERPF at 3Hhrs post-study drug administration after 1 dose, sitagliptin vs placebo |
| Change From Baseline in SDF-1alpha^3-67 (Truncated) Measured by Tandem Mass Spectrometry With Antibody-based Affinity Enrichment | 3Hrs vs baseline after 1 dose | Plasma concentration of SDF-1alpha\^3-67 (intact) measured by quantitative mass spectrometry methods after antibody-based affinity enrichment, sitagliptin vs. placebo |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental Arm sitagliptin (DPP-4 inhibitor) oral tablet (100 mg); Januvia; administered once daily for 28 days
Sitaglitpin: Oral DPP-4 inhibitor, 100 mg tablet administered once daily for 28 days | 16 |
| Placebo Arm placebo (no medicinal ingredients) oral tablet (100 mg); administered once daily for 28 days
Placebo: Oral tablet (no medicinal ingredients) administered once daily for 28 days | 16 |
| Total | 32 |
Baseline characteristics
| Characteristic | Placebo Arm | Total | Experimental Arm |
|---|---|---|---|
| Age, Continuous | 59.3 years STANDARD_DEVIATION 8.8 | 59.8 years STANDARD_DEVIATION 8.1 | 60.4 years STANDARD_DEVIATION 7.6 |
| Diabetes Duration | 8.5 years | 8.0 years | 6.0 years |
| HbA1c (%) | 7.31 Percentage STANDARD_DEVIATION 0.84 | 7.2 Percentage STANDARD_DEVIATION 0.8 | 7.18 Percentage STANDARD_DEVIATION 0.97 |
| Sex: Female, Male Female | 7 Participants | 12 Participants | 5 Participants |
| Sex: Female, Male Male | 9 Participants | 20 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 17 | 0 / 18 |
| serious Total, serious adverse events | 1 / 17 | 2 / 18 |
Outcome results
Primary
Percent Change in Fractional Excretion of Sodium (FENA)
FENA at 3Hrs post-study drug administration after 1 month compared to FENA at 3Hrs post-study drug administration after 1 dose expressed as percent change, sitagliptin vs. placebo
Time frame: 3 Hrs post-administration after 1 month and after 1 dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental Arm | Percent Change in Fractional Excretion of Sodium (FENA) | 41 percentage of change | Standard Deviation 43 |
| Placebo Arm | Percent Change in Fractional Excretion of Sodium (FENA) | -5.0 percentage of change | Standard Deviation 31 |
p-value: =0.012Regression, Linear
Secondary
Change From Baseline in SDF-1alpha^1-67 (Intact) Measured by Immunoaffinity and Tandem Mass Spectrometry
Plasma concentration of SDF-1alpha\^1-67 (intact) measured by quantitative mass spectrometry methods after antibody-based affinity enrichment, sitagliptin vs. placebo
Time frame: 3 Hr vs. baseline after 1 dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental Arm | Change From Baseline in SDF-1alpha^1-67 (Intact) Measured by Immunoaffinity and Tandem Mass Spectrometry | 0.5 ng per mL | Standard Deviation 0.2 |
| Placebo Arm | Change From Baseline in SDF-1alpha^1-67 (Intact) Measured by Immunoaffinity and Tandem Mass Spectrometry | 0 ng per mL | Standard Deviation 0 |
p-value: <0.001Regression, Linear
Secondary
Change From Baseline in SDF-1alpha^3-67 (Truncated) Measured by Tandem Mass Spectrometry With Antibody-based Affinity Enrichment
Plasma concentration of SDF-1alpha\^3-67 (intact) measured by quantitative mass spectrometry methods after antibody-based affinity enrichment, sitagliptin vs. placebo
Time frame: 3Hrs vs baseline after 1 dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental Arm | Change From Baseline in SDF-1alpha^3-67 (Truncated) Measured by Tandem Mass Spectrometry With Antibody-based Affinity Enrichment | -2.0 ng per mL | Standard Deviation 0.4 |
| Placebo Arm | Change From Baseline in SDF-1alpha^3-67 (Truncated) Measured by Tandem Mass Spectrometry With Antibody-based Affinity Enrichment | 0.4 ng per mL | Standard Deviation 0.3 |
p-value: <0.001Regression, Linear
Secondary
Change in Effective Renal Plasma Flow (ERPF)
ERPF (para-aminohippurate clearance) 3Hrs post-study drug administration after 1 month compared to ERPF at 3Hhrs post-study drug administration after 1 dose, sitagliptin vs placebo
Time frame: 3 Hrs post-administration after 1 month and after 1 dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental Arm | Change in Effective Renal Plasma Flow (ERPF) | 31.1 ml per min per 1.73 m2 | Standard Deviation 152.1 |
| Placebo Arm | Change in Effective Renal Plasma Flow (ERPF) | -24.7 ml per min per 1.73 m2 | Standard Deviation 142.8 |
Secondary
Change in Fractional Excretion of Lithium (FELi)
FELi at 3 Hr post-study drug administration after 1 month compared to FELI at 3hrs post-study drug administration after 1 dose, sitagliptin vs. placebo
Time frame: 3 Hrs post-administration after 1 month and after 1 dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental Arm | Change in Fractional Excretion of Lithium (FELi) | 29 percentage of change | Standard Deviation 55 |
| Placebo Arm | Change in Fractional Excretion of Lithium (FELi) | 7 percentage of change | Standard Deviation 44 |
p-value: 0.15Regression, Linear
Secondary
Change in Glomerular Filtration Rate (GFR)
Measured GFR (Inulin Clearance) at 3Hrs post study-drug after 1 month compared to Measured GFR at 3Hrs post-study drug after 1 dose, sitagliptin vs. placebo
Time frame: 3 Hrs post-administration after 1 month and after 1 dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental Arm | Change in Glomerular Filtration Rate (GFR) | 3.9 ml per min per 1.73 m2 | Standard Deviation 20.4 |
| Placebo Arm | Change in Glomerular Filtration Rate (GFR) | -1.8 ml per min per 1.73 m2 | Standard Deviation 17.8 |
p-value: 0.4Regression, Linear
Secondary
Change in Systolic Blood Pressure (SBP), Non-invasive Cardiac Output Monitoring
SBP by Non-Invasive cardiac output monitoring at 3Hrs post- study drug administration after 1 month compared to SBP by Non-invasive cardiac output monitoring at 3Hrs after 1 dose, sitagliptin vs placebo
Time frame: 3 Hrs post-administration after 1 month and after 1 dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental Arm | Change in Systolic Blood Pressure (SBP), Non-invasive Cardiac Output Monitoring | 5.7 mmHg | Standard Deviation 9.9 |
| Placebo Arm | Change in Systolic Blood Pressure (SBP), Non-invasive Cardiac Output Monitoring | 0.0 mmHg | Standard Deviation 14 |
p-value: 0.42Regression, Linear