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

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

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.

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.