Cardiovascular Safety With Linagliptin in Patients With T2DM
Cardiovascular Safety With Linagliptin in Patients With T2DM
The current meta-analysis included all randomized, double-blind, placebo- or active-controlled Phase 3 trials of linagliptin of > 12 weeks duration for which the database lock for the interim or final analyses was completed on or before 16 February 2010. This included eight studies that assessed linagliptin 5 mg or 10 mg/day versus placebo, glimepiride 1–4 mg/day, or voglibose 0.6 mg/day over 18–52 weeks as monotherapy or in combination with various common background therapies (for further details see Additional file 1, or the individual study publications).
All patients from each study provided written informed consent. Local ethics committees/institutional review boards reviewed and approved all study protocols. All studies were conducted within ethical standards and in accordance with the Declaration of Helsinki and any applicable regulatory requirements.
Common criteria across the Phase 3 trials included a diagnosis of inadequately controlled T2DM, age ≥ 18 years and, in most studies, body mass index (BMI) ≤ 40 kg/m. Background medication with metformin was mandatory except where inclusion criteria required treatment-naïve patients, metformin-ineligible patients, or washout of pre-existing oral glucose-lowering drugs (including metformin). In all studies, rescue medication was provided with pioglitazone and/or insulin dose adjustment or supplementation for glycaemic deterioration, triggered by plasma glucose levels measurement on two separate occasions of > 13.3, > 11.1, or > 10.0 mmol/L after overnight fasts during the first 12, 12–24, or > 24 weeks, respectively.
Adverse events (AEs) were captured and collected on-site by the study investigators using electronic case report forms. AEs were then mapped to preferred terms according to the Medical Dictionary for Regulatory Activities (MedDRA). A pre-specified list of trigger events (the Standard MedDRA Queries for ischaemic heart disease and cerebrovascular disorders) and all fatal events were identified for adjudication. In patients with a trigger event, an individual patient data package (patient profile and all available cardiology or neurology tests, laboratory tests, and medical records) was prepared for the adjudication committee. A cardiology or neurology clinical event committee, based on the data package, without knowledge of the treatment allocation, adjudicated on the trigger event and recorded the type of event as appropriate. These adjudicated events were collected and included in the clinical trial database upon completion of database lock for the full or interim analyses.
The primary endpoint was a composite of CV death (including fatal stroke and fatal myocardial infarction [MI]), non-fatal stroke, non-fatal MI, and hospitalization for unstable angina pectoris (UAP). Secondary endpoints were composites of: (i) CV death, non-fatal stroke, and non-fatal MI; (ii) all adjudicated CV events which included CV death, non-fatal stroke, non-fatal MI, UAP with or without hospitalization, stable angina pectoris (SAP), and transient ischaemic attacks (TIA); and (iii) FDA-defined custom major adverse CV events (MACE) derived from 34 unadjudicated MedDRA preferred terms for stroke and MI. Tertiary endpoints were the individual adjudicated components (as listed above) and total mortality.
Analyses were based on individual patient data in the treated set, which was defined as all patients who were randomized and received at least one dose of study medication, in all Phase 3 studies. Descriptive statistics (incidence and incidence rates per 1000 patient-years) were determined for all endpoints in each of the pooled treatment groups within the treated set.
The primary analyses assessed the CV risk for all primary, secondary, and tertiary endpoints associated with linagliptin versus total comparators. Risk estimates were calculated using several common statistical methods that included: (i) the hazard ratio (HR) for time to first event calculated using the Cox proportional hazards model with adjustments for study and treatment group; (ii) the incidence-rate risk ratio (RR) for time to first event calculated using Poisson regression with adjustment for study and treatment group; (iii) the odds ratio (OR) for occurrence of events calculated using a stratified Exact test; and (iv) the RR for occurrence of events calculated using a stratified Cochran-Mantel-Haenszel (CMH) test with continuity correction for trials with zero events.
Sensitivity analyses included evaluation of the primary endpoint associated with linagliptin versus total comparators in pre-specified subgroups based on age, gender, race, and use of rescue medication, as well as further exploratory subgroups based on occurrence of hypoglycaemia and Framingham 10-year CV risk score. In addition, a post hoc analysis of the primary endpoint assessed events in linagliptin- and placebo-treated patients, taken only from placebo-controlled trials and placebo-controlled periods within trials. In addition, the influence on the primary endpoint of the factors: study, treatment, gender, race and time since diagnosis of diabetes, was investigated using Cox regression.
This combined study analysis was developed to fully adhere to the recent FDA guidance on assessment of CV safety for the development of oral glucose-lowering drugs.
Methods
Study Selection
The current meta-analysis included all randomized, double-blind, placebo- or active-controlled Phase 3 trials of linagliptin of > 12 weeks duration for which the database lock for the interim or final analyses was completed on or before 16 February 2010. This included eight studies that assessed linagliptin 5 mg or 10 mg/day versus placebo, glimepiride 1–4 mg/day, or voglibose 0.6 mg/day over 18–52 weeks as monotherapy or in combination with various common background therapies (for further details see Additional file 1, or the individual study publications).
All patients from each study provided written informed consent. Local ethics committees/institutional review boards reviewed and approved all study protocols. All studies were conducted within ethical standards and in accordance with the Declaration of Helsinki and any applicable regulatory requirements.
Analysis Population
Common criteria across the Phase 3 trials included a diagnosis of inadequately controlled T2DM, age ≥ 18 years and, in most studies, body mass index (BMI) ≤ 40 kg/m. Background medication with metformin was mandatory except where inclusion criteria required treatment-naïve patients, metformin-ineligible patients, or washout of pre-existing oral glucose-lowering drugs (including metformin). In all studies, rescue medication was provided with pioglitazone and/or insulin dose adjustment or supplementation for glycaemic deterioration, triggered by plasma glucose levels measurement on two separate occasions of > 13.3, > 11.1, or > 10.0 mmol/L after overnight fasts during the first 12, 12–24, or > 24 weeks, respectively.
CV Event Data Collection and Adjudication
Adverse events (AEs) were captured and collected on-site by the study investigators using electronic case report forms. AEs were then mapped to preferred terms according to the Medical Dictionary for Regulatory Activities (MedDRA). A pre-specified list of trigger events (the Standard MedDRA Queries for ischaemic heart disease and cerebrovascular disorders) and all fatal events were identified for adjudication. In patients with a trigger event, an individual patient data package (patient profile and all available cardiology or neurology tests, laboratory tests, and medical records) was prepared for the adjudication committee. A cardiology or neurology clinical event committee, based on the data package, without knowledge of the treatment allocation, adjudicated on the trigger event and recorded the type of event as appropriate. These adjudicated events were collected and included in the clinical trial database upon completion of database lock for the full or interim analyses.
Study Endpoints
The primary endpoint was a composite of CV death (including fatal stroke and fatal myocardial infarction [MI]), non-fatal stroke, non-fatal MI, and hospitalization for unstable angina pectoris (UAP). Secondary endpoints were composites of: (i) CV death, non-fatal stroke, and non-fatal MI; (ii) all adjudicated CV events which included CV death, non-fatal stroke, non-fatal MI, UAP with or without hospitalization, stable angina pectoris (SAP), and transient ischaemic attacks (TIA); and (iii) FDA-defined custom major adverse CV events (MACE) derived from 34 unadjudicated MedDRA preferred terms for stroke and MI. Tertiary endpoints were the individual adjudicated components (as listed above) and total mortality.
Statistical Analysis
Analyses were based on individual patient data in the treated set, which was defined as all patients who were randomized and received at least one dose of study medication, in all Phase 3 studies. Descriptive statistics (incidence and incidence rates per 1000 patient-years) were determined for all endpoints in each of the pooled treatment groups within the treated set.
The primary analyses assessed the CV risk for all primary, secondary, and tertiary endpoints associated with linagliptin versus total comparators. Risk estimates were calculated using several common statistical methods that included: (i) the hazard ratio (HR) for time to first event calculated using the Cox proportional hazards model with adjustments for study and treatment group; (ii) the incidence-rate risk ratio (RR) for time to first event calculated using Poisson regression with adjustment for study and treatment group; (iii) the odds ratio (OR) for occurrence of events calculated using a stratified Exact test; and (iv) the RR for occurrence of events calculated using a stratified Cochran-Mantel-Haenszel (CMH) test with continuity correction for trials with zero events.
Sensitivity analyses included evaluation of the primary endpoint associated with linagliptin versus total comparators in pre-specified subgroups based on age, gender, race, and use of rescue medication, as well as further exploratory subgroups based on occurrence of hypoglycaemia and Framingham 10-year CV risk score. In addition, a post hoc analysis of the primary endpoint assessed events in linagliptin- and placebo-treated patients, taken only from placebo-controlled trials and placebo-controlled periods within trials. In addition, the influence on the primary endpoint of the factors: study, treatment, gender, race and time since diagnosis of diabetes, was investigated using Cox regression.
This combined study analysis was developed to fully adhere to the recent FDA guidance on assessment of CV safety for the development of oral glucose-lowering drugs.