Vildagliptin vs Sitagliptin add-on to Insulin - Impact on Glycemic Profile and Correlation of Hypoglycemic Episodes and Heart Function
Condition: Diabetes Mellitus Type 2
MeSH terms: Diabetes Mellitus, Type 2
Intervention: Vildagliptin; Sitagliptin
Intervention description: vildagliptin 50mg BID for 8 weeks; sitagliptin 100mg QD for 8 weeks
Intervention MeSH terms: Sitagliptin Phosphate; Vildagliptin
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 51.0
Sex: All
Minimum age: 40 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: vildagliptin; sitagliptin; 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

Summary:

      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.
    

Eligibility criteria:

        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:

               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

               2. use of any oral antidiabetic medication or GLP-1 analogues within the last 12
                  weeks, except metformin

               3. use of weight control products including weight-loss medications in the last 12
                  weeks.

               4. 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.

               5. treatment with growth hormone within the previous 6 months.

               6. 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:

               1. acute metabolic conditions such a ketoacidosis, lactic acidosis or hyperosmolar
                  state (including precoma and coma) within the past 6 months.

               2. current diagnosis of congestive heart failure (NYHA III or IV).

               3. myocardial infarction within the past 6 months.

               4. coronary artery bypass surgery or percutaneous coronary intervention within the
                  past 6 months.

               5. Stroke, transient ischemic attack, or reversible ischemic neurologic deficit
                  within the past 6 months.

               6. unstable angina within the past 6 months.

               7. sustained and clinically relevant ventricular arrhythmia (patients with premature
                  ventricular contractions if deemed not clinically significant may be enrolled).

               8. Patients with permanent atrial fibrillation or pacemaker.

               9. active substance abuse, alcohol abuse and history of alcohol-related diseases
                  within the past 2 years.

              10. type 1 diabetes, monogenic diabetes, diabetes resulting from pancreatic injury,
                  or secondary forms of diabetes (e.g. Cushing's syndrome or acromegaly-associated
                  diabetes).

              11. 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.

              12. 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.

              13. 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:

               1. clinically significant increase or reduction in thyroid stimulating hormone (TSH)
                  outside of the normal range.

               2. clinically significant renal dysfunction: glomerular filtration rate (GFR) <50
                  mL/min/1.73m2 (via MDRD formula).

               3. Patients on metformin with a GFR <60 mL/min/1.73m2 (via MDRD formula).

               4. 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.

               5. total bilirubin > 2 x ULN and/or direct bilirubin > 1 x ULN confirmed by repeated
                  measurements within 3 working days.

               6. positive Hepatitis B surface antigen (HBsAg).

               7. positive Hepatitis C virus (HCV) antibody test (anti-HCV).

               8. elevated fasting triglycerides (TGs) > 500mg/dL (5.65mmol/L), confirmed by a
                  repeated measurements within 3 working days.

               9. 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:

               1. second or third degree atrio-ventricular block.

               2. A QTc of > 440 ms.

               3. 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.