Several classes of new drugs for type 2 diabetes have been introduced in recent years. While there is a lot of data available on the benefits and side effects of these medications in the form of clinical trials, there is much less ‘real world’ data available, which is important as strict inclusion and exclusion criteria are often required for clinical trials, which means that this group of people can differ from population prescribed these medications in the community. Furthermore, follow up times in clinical trials are generally short and so do not allow assessment of longer term outcomes. We plan to quantify the effectiveness and safety of these newer diabetes medications in real-world usage in several large databases; this data is already being collected in Scotland, Wales, Denmark, Sweden and Finland. We would like to add data from England to these other data sets. Data from different countries will be analysed together to produce extremely large patients numbers needed to look at some of the smaller effects of these medications. We will include people over 18 with a label of type 2 diabetes in the CPRD database. We will use linked databases to examine the following outcomes for people with diabetes taking these medications compared to those who are not: weight, blood pressure, diabetes control, cholesterol levels, kidney function, development of heart failure, stroke, heart attacks, kidney disease, fatty liver disease, deaths, complications of diabetes, and known side effect of the medications.
Several classes of new diabetes drugs have been recently introduced; dipeptidyl peptidase IV (DPP-IV) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists and sodium glucose cotransporter 2 (SGLT2) inhibitors
Aims/Objectives: Quantify the effectiveness and safety of DPP-IV inhibitors, GLP-1 receptor agonists and SGLT2 inhibitors in real-world usage. Data will be combined with that from other large registries of people with diabetes from Scotland, Wales, Denmark, Sweden. Finland.
Study population of interest: People with type 2 diabetes
Primary exposure: DPP-IV inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors
Outcomes:
(1) Effectiveness of newer diabetic agents
• Metabolic end points: HbA1c, blood pressure, weight, BMI, total cholesterol, triglycerides, HDL & LDL cholesterol
• Microvascular complications diabetes: eGFR, albuminuria, renal composite outcome, retinopathy, neuropathy
• Macrovascular complications diabetes: Stroke, myocardial infarction, cardiovascular death, heart failure, peripheral vascular disease
• All-cause mortality
(2) Adverse events: list below
Study design/methods: Each centre will run analyses of the agreed set of exposures and outcomes and will provide summary statistics of drug effects for inclusion in meta-analyses. The coordinating centre (University of Edinburgh) will provide each centre with detailed database formatting specifications to create OMOP-like tables: 1) person, 2) observation period, 3) measurements 4) drug era 5) condition occurrence (events). Code to convert these centre-specific tables into a ‘survival table’ and undertake the analyses and generate centre-specific summary results will be sent to the coordinating centre where they will be combined to perform a meta-analysis. Only aggregated results will be shared. To preserve confidentiality, we will perform secondary suppression of small cell counts.
Main statistical tests: Within-person absolute and percentage changes in the clinical measures following drug initiation at regular intervals, mixed effects regression models, regression to the mean, event-based outcomes, poisson-likelihood regression models, parametric multistate survival models
Linked data sources: ONS death registration and HES APC
CPRD: Aurum
(1) Benefits of newer diabetic agents
• Metabolic end points: HbA1c (mmol/mol), systolic/diastolic blood pressure (mmHg), weight (kg), body mass index (kg/m2), total cholesterol (mmol/l), triglycerides (mmol/l), HDL cholesterol (mmol/l), LDL cholesterol (mmol/l),
• Microvascular complications of diabetes: eGFR (ml/min/1.73m2), albuminuria, renal composite outcome (sustained 40% reduction in eGFR / ESRD), retinopathy, neuropathy
• Macrovascular complications of diabetes: Stroke, myocardial infarction, cardiovascular disease death, heart failure, peripheral vascular disease
• All-cause mortality
(2) Adverse events – all of these adverse events have been previously reported from one of the 3 new diabetes drug classes
• Acute pancreatitis, pancreatic cancer, heart failure, inflammatory bowel disease, interstitial lung disease, hypoglycaemia, death, thyroid cancer, progression of retinopathy, gallbladder disease, bladder cancer, diabetic ketoacidosis, genitourinary infections, urinary tract infections, hospitalised hip fracture, lower limb amputation, fournier’s gangrene/necrotising fasciitis, NASH +/- abnormal liver chemistry, breast cancer
THERESA HYDES - Chief Investigator - University of Liverpool
THERESA HYDES - Corresponding Applicant - University of Liverpool
Deirdre Lane - Collaborator - University of Liverpool
Helen Colhoun - Collaborator - University of Edinburgh
Mike Merriman - Collaborator - NHS England
Pieta Schofield - Collaborator - University of Liverpool
Stephanie Harrison - Collaborator - University of Liverpool
Stuart McGurnaghan - Collaborator - University of Edinburgh
Thomas Caparrotta - Collaborator - University of Edinburgh
David Stevens - Collaborator - University of Liverpool
Emily Shipley - Collaborator - University of Liverpool
HES Admitted Patient Care;ONS Death Registration Data;Patient Level Index of Multiple Deprivation