CAROLINA: Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes

• Time to first occurrence of any of the following adjudicated components of the composite endpoint: CV death (including fatal stroke and fatal MI), non-fatal stroke, non-fatal MI (excluding silent MI) [ Time Frame: 400 weeks ] [ Designated as safety issue: No ]
• Proportion of patients on study treatment at study end, that at Final Visit maintain glycemic control (HbA1c <= 7.0%) without need for rescue medication, without any moderate/severe hypoglycaemic episodes and without > 2% weight gain (from V6 on) [ Time Frame: 400 weeks ] [ Designated as safety issue: No ]
• Occurence of any of the adjudicated components of the composite primary and composite first key secondary endpoint. [ Time Frame: 400 weeks ] [ Designated as safety issue: No ]
• Transitions in albuminuria classes between baseline and Final visit. [ Time Frame: 400 weeks ] [ Designated as safety issue: No ]
• Proportion of patients on study treatment at study end, that at Final Visit maintain glycaemic control (HbA1c <= 7.0%) without need for rescue medication and without > 2% weight gain (from V6 on) [ Time Frame: 400 weeks ] [ Designated as safety issue: No ]
• Occurence of and time to composite endpoint of all CEC confirmed adjudicated events [ Time Frame: 400 weeks ] [ Designated as safety issue: No ]
• Change from baseline to Final Visit in diabetes related laboratory parameters: HbA1c, fasting plasma glucose, Total cholesterol, LDL cholesterol, HDL cholesterol, Triglycerides, Creatinine, eGFR (MDRD formula), Albumin [ Time Frame: 400 weeks ] [ Designated as safety issue: No ]

• Composite endpoint of (proportion of patients on study treatment at study end, maintain glycemic control (HbA1c =< 7%) without need of rescue medication and without moderate/severe hypoglycemic episodes and without => 2% weight gain at final visit [ Designated as safety issue: No ]
• Composite endpoint of (proportion of patients on study treatment at study end, maintain glycemic control (HbA1c =< 7%) without need of rescue medication and without => 2% weight gain at final visit [ Designated as safety issue: No ]

• Drug: linagliptin
  linagliptin tablets 5mg QD
• Drug: glimepiride
  glimepiride over-encapsulated tablet 1-4 mg QD
• Drug: linagliptin placebo
  linagliptin placebo
• Drug: glimepride placebo
  glimepiride placebo

• Experimental: linagliptin
  patient to receive linagliptin or glimepiride placebo overencapsulated tablet QD
  Interventions:

  • Drug: linagliptin
  • Drug: glimepride placebo
• Active Comparator: glimepiride 1-4 mg QD
  patient to receive glimepiride 1-4 mg or linagliptin placebo tablet QD
  Interventions:

  • Drug: glimepiride
  • Drug: linagliptin placebo

Inclusion criteria:

1. Type 2 diabetes
2. Elevated glycosylated haemoglobin (HbA1c): 6.5 - 8.5%, inclusive, if treatment naïve or mono-/dual therapy with metformin and/or an alpha-glucosidase inhibitor; 6.5 - 7.5%, inclusive, if treatment with sulphonylurea/glinide in mono- or dual (with metformin OR an alpha-glucosidase inhibitor) therapy)
3. Pre-existing cardiovascular disease OR specified diabetes end-organ damage OR age => 70 years OR two or more specified cardiovascular risk factor
4. BMI =< 45kg/m²
5. age between >= 40 and =< 85 years
6. signed and dated written ICF
7. stable anti-diabetic background for at least 8 wks before study start

Exclusion criteria:

1. Type 1 diabetes
2. Treatment with other antidiabetic drugs (e.g. rosiglitazone, pioglitazone, Glucagon-like peptide 1 (GLP-1) analogue/agonists, Dipeptidyl-peptidase IV (DPP-IV) inhibitors or any insulin) prior to informed consent (previous short term use of insulin (up to two weeks) is allowed if taken at least 8 weeks prior informed consent)
3. treatment with any anti-obesity drug less than 3 months before ICF
4. uncontrolled hyperglycemia
5. previous or planned bariatric surgery or intervention
6. current or planned system corticoid treatment
7. change in thyroid hormones treatment
8. acute liver disease or impaired hepatic function
9. pre-planned coronary artery revascularization within 6 months of ICF
10. known hypersensitivity to any of the components
11. Inappropriateness of glimepiride treatment for renal safety issues according to local prescribing information
12. congestive heart failure class III or IV
13. acute or chronic metabolic acidosis
14. hereditary galactose intolerance
15. alcohol or drug abuse
16. participation in another trail with IMP given 2 months before IMP start
17. pre-menopausal women who are nursing or pregnant or of child-bearing potential and not willing to use acceptable method of birth control
18. patients considered reliable by the investigator
19. acute coronary syndrome =< 6 wks before ICF
20. stroke or TIA =< 3 months prior to ICF