Comparative effectiveness of gliclazide MR and sitagliptin as second line treatment after metformin monotherapy in uncontrolled type 2 diabetes patients using the UK Clinical Practice Research Datalink (CPRD) database

Date of ISAC Approval: 
Lay Summary: 
Type 2 Diabetes (T2D) is an important public health issue. After lifestyle changes, patients are prescribed oral antidiabetic treatment to reduce blood glucose level. HbA1c (glycosylated haemoglobin) blood test should be performed regularly to assess the control of diabetes over time. For the majority of patients, the treatment goal is to target an HbA1c <7%. Usually, patients are prescribed with a first drug called metformin as first line treatment. Then, when HbA1c control becomes not sufficient, they are prescribed with an additional antidiabetic drug while continuing metformin (second line treatment). In this study, we aim to evaluate and compare the effect on HbA1c of two antidiabetic drugs often prescribed in the UK as second line treatment: gliclazide modified release (MR) and sitagliptin. Using routinely collected health information from the Clinical Practice Research Datalink (CPRD), the main objective is to determine and compare the proportions of patients treated who reach first HbA1c control (HbA1c<7%). The risk of hypoglycaemia reported to the GP after initiating one of the two treatments will be also described. Indeed, in rare cases, an excessive reduction of blood glucose level with these medications can cause hypoglycaemia (very low blood glucose level) which is a safety issue. This research is considered relevant since such evidence does not exist. The findings of this study should help clinicians and ultimately patients considering second-line therapies for the treatment of T2D.
Technical Summary: 
The study design is a matched cohort of new users of gliclazide MR or sitagliptin for T2D in second line treatment after metformin monotherapy. High-dimensional propensity score will be used to match patients (ratio 1:1) between those initiated on gliclazide MR and those initiated on sitagliptin. The analysis will include adult T2D patients using the UK Clinical Practice Research Datalink (CPRD) database. The study population consists of patients initiating a treatment with gliclazide MR or sitagliptin between 1st January 2010 and the latest available data capture. Initiation of treatment is defined as having at least 2 consecutive prescriptions of gliclazide MR or sitagliptin without a gap >/=90 days, the first prescription defining the cohort entry date. Only patients having received metformin as first-line therapy will be included. Patients with continuous enrolment in the database one year prior to the cohort entry and having an HbA1c lab value >/=7% in the 6 months before cohort entry will be included. Patients will be excluded if they had Type 1 Diabetes, other forms of secondary diabetes or gestational diabetes mellitus. Study period will be until the latest available data capture using GP/ONS/HES linked data. HbA1c assessment window starts at day 60 after cohort entry and ends 30 days after end of durability (defined as index treatment duration until switch/add-on/stop). Outcomes will be defined using UK primary care data (CPRD GOLD and HES). Primary outcome is achieving a target of HbA1C level <7.0%. Proportional hazard models will be used to estimate hazard ratios (HRs) with 95% confidence intervals of the HbA1c outcome with the use of gliclazide MR versus sitagliptin. Secondary outcomes are as follows: reduction of HbA1c level >/= 1% compared to baseline value, achieving a target of HbA1c level </= 6.5%, incidence rate of hypoglycaemia, durability and persistence of index treatments.
Health Outcomes to be Measured: 
HbA1c; hypoglycaemia; durability; persistence.

Dr Cortese Viviana - Chief Investigator - IRIS - Institut de Recherches Internationales Servier
Dr Alice Rouleau - Collaborator - IRIS - Institut de Recherches Internationales Servier
Ms Briana Coles - Collaborator - University of Leicester
Emmanuelle Jacquot - Collaborator - IRIS - Institut de Recherches Internationales Servier
Dr Francesco Zaccardi - Corresponding Applicant - University of Leicester
Professor Kamlesh Khunti - Collaborator - University of Leicester
Pauline Macouillard - Collaborator - IT&M Stats
Ms Siham Eltaief - Collaborator - IT&M Stats
Valerie Lehner-Martin - Collaborator - IRIS - Institut de Recherches Internationales Servier

HES Admitted;ONS;Practice IMD (Standard)