Long-term Safety of Alogliptin in Patients With Type 2 Diabetes Mellitus

• Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
  Safety was assessed by physical examinations, clinical laboratory parameters, electrocardiogram (ECG) readings, vital sign measurements, oral temperature, and hypoglycemic events. Changes in laboratory values or ECG parameters were considered to be adverse events if they were judged to be clinically significant. A TEAE was any event that started on or after the first dose of open-label study drug and within 14 days after the last dose.
  
  

• Change From Baseline Over Time in Glycosylated Hemoglobin [ Time Frame: Baseline and Month 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42 and 45. ] [ Designated as safety issue: No ]
  The change from Baseline in glycosylated hemoglobin (HbA1c; the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) during the study. Endpoint was defined as the last postbaseline observation collected within 7 days after the last dose of open-label study drug.
  
  
• Change From Baseline in Fasting Plasma Glucose [ Time Frame: Baseline and Year 4 ] [ Designated as safety issue: No ]
  The change from Baseline in fasting plasma glucose (FPG) at the last post-baseline observation, collected within 7 days after the last dose of open-label study drug.
  
  
• Percentage of Participants With Marked Hyperglycemia [ Time Frame: Randomization up to 4 years. ] [ Designated as safety issue: No ]

  Marked Hyperglycemia is defined as fasting plasma glucose greater than or equal to 200 mg/dL (≥11.10 mmol/L).

  The Month 42 to Month 45 interval includes all marked hyperglycemic episodes occurring on or after Day 1247 (a 203-day visit window).

  
  
• Change From Baseline in Proinsulin Level [ Time Frame: Baseline and Year 4 ] [ Designated as safety issue: No ]

  Proinsulin is a precursor to insulin, and was measured as an indicator of pancreatic function. The change from Baseline in fasting proinsulin to the last post-baseline observation, collected within 7 days after the last dose of open-label study drug.

  Note: A transcription error occurred in the reporting of 1 proinsulin value for a patient in the alogliptin 25 mg completed group, for whom a partial patient ID number was mistakenly entered as an end-of-treatment proinsulin level.

  
  
• Change From Baseline in Insulin Level [ Time Frame: Baseline and Year 4 ] [ Designated as safety issue: No ]
  The change from Baseline in fasting insulin at the last post-baseline observation, collected within 7 days after the last dose of open-label study drug.
  
  
• Change From Baseline in C-peptide Level [ Time Frame: Baseline and Year 4 ] [ Designated as safety issue: No ]
  C-peptide is a byproduct created when the hormone insulin is produced and is measured by a blood test. Change from Baseline to the last post-baseline observation, collected within 7 days after the last dose of open-label study drug.
  
  
• Change From Baseline in Body Weight [ Time Frame: Baseline and Year 4 ] [ Designated as safety issue: No ]
  Change from Baseline in body weight to the last post-baseline observation collected within 7 days after the last dose of open-label study drug.
  
  
• Percentage of Participants With a Clinical Response [ Time Frame: Weeks 2, 4, 8, 12, every 3 months up to 4 years, and 1 Day after final dose. ] [ Designated as safety issue: No ]

  Clinical response was defined based on the absolute value of HbA1c meeting one of two clinical targets at any post-baseline visit:

  • HbA1c ≤6.5%;
  • HbA1c ≤7.0%.
  
  

SYR-322 (alogliptin) is an inhibitor of the dipeptidyl peptidase IV enzyme. Dipeptidyl peptidase IV is thought to be primarily responsible for the degradation of 2 peptide hormones released in response to nutrient ingestion, namely glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. It is expected that inhibition of dipeptidyl peptidase IV will improve glycemic (glucose) control in patients with type 2 diabetes mellitus by prolonging the beneficial effects of glucagon-like peptide-1.

The rising incidence of type 2 diabetes mellitus and the limitations of the currently available treatments suggest the need for new therapies for glycemic control. Studies have been undertaken in humans that evaluated the effects of directly augmenting glucagon-like peptide-1 and glucose-dependent insulinotropic peptide levels and of inhibiting the activity of dipeptidyl peptidase IV.

This study is an extension of 7 controlled phase 3 studies of alogliptin. These phase 3 studies included 1 monotherapy study of alogliptin (SYR-322-PLC-010; NCT00286455); 4 placebo-controlled add-on studies of alogliptin, namely in combination with a sulfonylurea (SYR-322-SULF-007; NCT00286468), metformin (SYR-322-MET-008; NCT00286442), a thiazolidinedione (pioglitazone; SYR-322-TZD-009; NCT00286494), and insulin (SYR-322-INS-011; NCT00286429); 1 coadministration study with pioglitazone in combination with metformin (01-05-TL-322OPI-001; NCT00328627), and 1 coadministration study with pioglitazone (01-06-TL-322OPI-002; NCT00395512).

The end of treatment or early withdrawal visit from the preceding study will be the screening visit for this study, after which enrolled patients will be required to commit to approximately 22 additional visits at the study center.