Vildagliptin vs Sitagliptin add-on to Insulin - Impact on Glycemic Profile and Correlation of Hypoglycemic Episodes and Heart Function

Study Overview
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Brief Summary
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Vildagliptin and Sitagliptin both belong to the class of DPP-4 inhibitors, but differ in their pharmacokinetic profile as well as in their approved application (Vildagliptin, 2x 50 mg daily, Sitagliptin, 1x 100 mg daily). This leads to distinct results regarding postprandial blood-glucose normalization as well as protective properties regarding hypoglycemic episodes - especially during the night. Additionally, in type 1 diabetic patients a correlation has been described between hypoglycemia and abnormal heart function (QTc-elongation), which can have severe consequences for the patients. This study aims for the evaluation of the potency of both drugs to prevent and/or reduce hypoglycemic events in insulin-dependent type-2 diabetics and furthermore to evaluate the correlation of hypoglycemic episodes with changes in heart-function measured by Holter-ECG. The hypothesis is tested, if vildagliptin leads to a more favourable glycemic profile than sitagliptin and is more potent in protecting from nocturnal abnormalities in heart-function caused by undetected hypoglycemic episodes.

Official Title
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Multicentric Cross-over Trial to Assess the Glycemic Profiles on 8 Weeks of Vildagliptin and Sitagliptin Treatment, Each, in Type-2 Diabetic Patients With a Pre-existing Cardiovascular Disease Pre-treated With Insulin, Using a PROBE-design

Conditions
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Diabetes Mellitus Type 2

Intervention / Treatment
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* Drug: Vildagliptin
* Drug: Sitagliptin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Written informed consent must be obtained before any assessment is performed. 2. Ability to comply with all study requirements. 3. Patients with Type 2 diabetes treated with stable, once or twice daily doses (minimal dose of 0.3 unit/kg/day) of basal long-acting or intermediate-acting insulin alone or in pre-mixed combination with rapid-acting or short-acting insulin for at least 12 weeks prior to Visit 1. Stable is defined as ±10% of the Visit 1 dose during the previous 12 weeks. 4. Patients receiving metformin must be on a stable dose of metformin (at least 1500 mg daily or a maximally tolerated dose) for at least 12 weeks prior to Visit 1. 5. HbA1c ≥7.5 to ≤ 9,0% at Visit 1 6. Known CV disease based on a documented history of one or more of pre-defined criteria 7. Age: ≥40 to ≤80 years at Visit 1 Exclusion Criteria: 1. FPG ≥ 270 mg/dL (15 mmol/L) at Visit 1. 2. Use of any of the following medications as assessed at Visit 1: rapid or short acting insulin except in pre-mixed formulations with intermediate or long-acting insulin; insulin administration more frequently than twice-daily, or total insulin dose < 0.3 unit/kg/day for the past 12 weeks use of any oral antidiabetic medication or GLP-1 analogues within the last 12 weeks, except metformin use of weight control products including weight-loss medications in the last 12 weeks. use of oral (≥7 consecutive days) or chronic parenteral or intra-articular corticosteroid treatment within the last 8 weeks. Inhaled or topical steroids without systemic effects will be allowed. treatment with growth hormone within the previous 6 months. treatment with any drug of known and frequent toxicity to a major organ, or that may interfere with the interpretation of the efficacy and safety data during the study. 3. a history or evidence of any of the following at Visit 1: acute metabolic conditions such a ketoacidosis, lactic acidosis or hyperosmolar state (including precoma and coma) within the past 6 months. current diagnosis of congestive heart failure (NYHA III or IV). myocardial infarction within the past 6 months. coronary artery bypass surgery or percutaneous coronary intervention within the past 6 months. Stroke, transient ischemic attack, or reversible ischemic neurologic deficit within the past 6 months. unstable angina within the past 6 months. sustained and clinically relevant ventricular arrhythmia (patients with premature ventricular contractions if deemed not clinically significant may be enrolled). Patients with permanent atrial fibrillation or pacemaker. active substance abuse, alcohol abuse and history of alcohol-related diseases within the past 2 years. type 1 diabetes, monogenic diabetes, diabetes resulting from pancreatic injury, or secondary forms of diabetes (e.g. Cushing's syndrome or acromegaly-associated diabetes). malignancy of an organ system (other than localized basal cell carcinoma of the skin) treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. hepatic disorder defined as: acute or chronic liver disease, evidence of hepatitis, cirrhosis or portal hypertension. history of imaging abnormalities that suggest liver disease (except hepatic steatosis), such as portal hypertension, capsule scalloping, cirrhosis. acute infections which may affect blood glucose control within the past 4 weeks. 4. any of the following significant laboratory abnormalities as assessed at Visit 1: clinically significant increase or reduction in thyroid stimulating hormone (TSH) outside of the normal range. clinically significant renal dysfunction: glomerular filtration rate (GFR) <50 mL/min/1.73m2 (via MDRD formula). Patients on metformin with a GFR <60 mL/min/1.73m2 (via MDRD formula). alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2 x upper limit of normal (ULN) at Visit 1, confirmed by repeated measurements within 3 working days. total bilirubin > 2 x ULN and/or direct bilirubin > 1 x ULN confirmed by repeated measurements within 3 working days. positive Hepatitis B surface antigen (HBsAg). positive Hepatitis C virus (HCV) antibody test (anti-HCV). elevated fasting triglycerides (TGs) > 500mg/dL (5.65mmol/L), confirmed by a repeated measurements within 3 working days. clinically significant laboratory abnormalities which, in the opinion of the investigator, cause the patient to be considered inappropriate for inclusion in the study. 5. any of the following electrocardiographic abnormalities at Visit 1: second or third degree atrio-ventricular block. A QTc of > 440 ms. clinically significant electrocardiogram (ECG) abnormalities which, in the opinion of the investigator, may cause the patient to be considered inappropriate for inclusion in the study Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vildagliptin followed by Sitagliptin<br>Period 1: vildagliptin 50mg BID for 8 weeks; followed by Washout then Period 2: sitagliptin 100mg QD for 8 weeks | Drug: Vildagliptin<br>* vildagliptin 50mg BID for 8 weeks<br>* Other names: Vildagliptin (Galvus) LAF237;Drug: Sitagliptin<br>* sitagliptin 100mg QD for 8 weeks<br>* Other names: sitagliptin, Januvia;|
| Experimental: Sitagliptin followed by Vildagliptin<br>Period 1: sitagliptin 100mg QD for 8 weeks; followed by Washout then Period 2: vildagliptin 50mg BID for 8 weeks | Drug: Vildagliptin<br>* vildagliptin 50mg BID for 8 weeks<br>* Other names: Vildagliptin (Galvus) LAF237;Drug: Sitagliptin<br>* sitagliptin 100mg QD for 8 weeks<br>* Other names: sitagliptin, Januvia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hypoglycemic Profile of Vildagliptin Compared to Sitagliptin Over 4 Days After 8 Weeks of Treatment in Period 1 & 2 | The hypoglycemic profile is defined as the area under the curve glucose-time profile obtained by continuous glucose monitoring Interstitial glucose values below 3.9 mmol/L (averaged over 5 minutes) were considered relevant for the estimation of the interstitial glucose AUC in the hypoglycemic range These AUC<3.9mmol/L/5min. values were summed up over 4 days (unit: mmol/L/4d) or over 24 hours at measurement Days 2, 3, 4, and 5 (unit: mmol/L/24h). Lower values for AUC reflect less intense hypoglycemia. | baseline and 0-24 hours post-dose on Days 2 to 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Hypoglycemic Events During Vildagliptin Treatment Compared to Sitagliptin Treatment. | Hypoglycemic events are defined as blood glucose values <70 mg/dL measured by a self-monitored blood glucose (SMBG) or continuous glucose monitoring (CGM) measurement regardless of any symptoms suggestive of low blood glucose. | after 8 weeks period 1 and Period 2 | 
| Mean Duration of Hypoglycemic Events (Min.) Measured With Continuous Glucose Monitoring (CGM) Over 4 Days After 8 Weeks of Treatment for Period 1 & Period 2 | the mean duration of hypoglycemic events is detected by continuous glucose monitoring (CGM)measurement. | after 8 weeks for Period 1 & Period 2 | 
| Mean Amplitudes of Hypoglycemic Events (mmol/L) Measured With Continuous Glucose Monitoring (CGM) Over 4 Days After 8 Weeks of Treatment for Period 1 & Period 2 | To evaluate by CGM measurement the grade of severity of hypoglycemia measured as the mean amplitude over 4 days after 8 weeks of treatment in Period 1 & Period 2 | after 8 weeks Period 1 & Period 2 | 
| Number of Severe Hypoglycemic Events During Vildagliptin Treatment Compared to Sitagliptin Treatment After 8 Weeks of Treatment in Period 1 and Period 2 | Severe hypoglycemic events are defined as any episode requiring the assistance of another party or measured plasma glucose levels of <40 mg /dL. Assessed by self-monitored blood glucose (SMBG)After 8 weeks of treatment in Period 1 and Period 2 | after 8 weeks Period 1 & Period 2 | 
| Glucose Fluctuations During the Day Under Vildagliptin Treatment Compared to Sitagliptin Treatment on Day 2 After 8 Weeks of Treatment Period 1 & Period 2 | Glucose fluctuations are assessed by the mean amplitude of glycemic excursions (MAGE) and standard deviations (SD) (Service et al., 1970). on day 2 after 8 weeks of treatment Period 1 & Period 2 | Day 2 after 8 weeks of treatment Period 1 & Period 2 | 
| Number of Participants With ECG Abnormalities Depending on Hypoglycemic Events After 8 Weeks of Treatment Period 1 & Period 2 | ECG abnormalities are defined as either: • Occurrence of >30 ventricular extrasystoles (VES) per hour or • Occurrence of ≥2 consecutive VES (Couplets) or • Occurrence of ≥3 consecutive VES (Triplets) or • QT-time corrected for heart rate (QTc) >440 ms. after 8 weeks of treatment Period 1 & Period 2 | after 8 weeks of treatment Period 1 & Period 2 | 
| Change From Baseline of Inflammatory Biomarkers High Sensitivity C-reactive Protein (hsCRP) After 8 Weeks of Treatment in Period 1 & Period 2 | The inflammatory biomarkers hsCRP was assessed at baseline and after 8 weeks of treatment Period 1 & Period 2 | Baseline, after 8 weeks Period 1 & Period 2 | 
| Change From Baseline of Inflammatory Biomarkers Interleukin 6 (IL-6) After 8 Weeks of Treatment in Period 1 & Period 2 | The inflammatory biomarkers IL-6 was assessed at baseline and after 8 weeks of treatment Period 1 & Period 2 | Baseline, after 8 weeks Period 1 & Period 2 | 
| Percentage Change From Baseline of Pro-insulin/C-peptide Ratios After 8 Weeks of Treatment Period 1 & Period 2 | Percentage Change from baseline of pro-insulin/C-peptide ratios after 8 weeks of treatment Period 1 & Period 2 Higher pro-insulin / C-peptide ratios (expressing disproportional hyperproinsulinemia) may be associated with increasing beta cell dysfunction and more inefficient pro-insulin processing | Baseline, after 8 weeks Period 1 & Period 2 | 
| Number of Occurrence of Pre-defined ECG Findings During 4 Days of Continuous ECG Monitoring at Baseline and in the 8th Week of Periods 1 and 2 | Number of Occurrence of pre-defined ECG findings during 4 days of continuous ECG monitoring at baseline and in the 8th week of Periods 1 and 2. ECG data were continuously recorded and analyzed over a period of 4 days simultaneously with continuous glucose monitoring. It assessed number of any Vertical Electric(al) Sounding (VES), number of 2 consecutive VES [couplets], and number of >3 consecutive VES [salves] | after 8 weeks Period 1 & Period 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sitagliptin, vildagliptin, continuous glucose monitoring (CGM), glycemic fluctuations, MAGE, impact of hypoglycemia on heart function (cardiac dysfuction measured via ECG), difference in glycemic profile of vildagliptin compared to sitagliptin