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 ]

The aim of the study is to investigate the longterm impact on cardiovascular morbidity and mortality, relevant efficacy parameters (e.g., glycaemic parameters) and safety (e.g., weight and hypoglycaemia) of treatment with linagliptin in patients with type 2 diabetes at elevated cardiovascular risk receiving usual care, and compare outcome against glimepiride.

• 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 heamoglobin (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

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. Inappropriateness of glimepiride treatment for renal safety issues according to local prescribing information