The management of type 2 diabetes usually involves medication, initially with metformin, but as the condition progresses additional medications may be required. After metformin, treatment decisions about other medications are generally based on the physician's choice. However, considerations may be based on the potential of risk of side effects from medication use. Newer medications (GLP-1 receptor agonists, SGLT-2 inhibitors) have entered the market and their potential, particularly in combination with each other, has not be extensively explored but could offer greater benefits in terms of diabetes management and lower risk of serious diabetes-related complications including heart disease.
In recent clinical trials, the combination of an SGLT-2 inhibitor and GLP-1 receptor agonist was shown to have additive effects on lowering blood glucose levels, blood pressure and body weight in patients with type 2 diabetes. The effect of the combination of these two medication classes on adverse effects in routine health care settings is not currently known. We will study the effects of an SGLT-2 inhibitor antidiabetic medication regimen, GLP-1 receptor agonist antidiabetic medication regimen and combination regimen of a SGLT-2 inhibitor and GLP-1 receptor agonist, compared to other combination regimens on the adverse event risk in people with type 2 diabetes.
Maintaining glycaemic control is an integral part of managing type 2 diabetes and often requires pharmacological agents to achieve this. With newer drugs entering the market it is important to assess the safety and efficacy of these drugs used alone and in combination and to establish their place in the treatment algorithm for guiding clinical decision making. The proposed study will examine the effect of SGLT-2 inhibitor regimens, GLP-1 receptor agonist regimens and combined SGLT-2 inhibitor/GLP-1 receptor agonist regimens on risk of major cardiovascular events, osteoporotic fractures, all-cause and cardiovascular mortality.
Data will be obtained from three databases; CPRD GOLD, CPRD Aurum and the SAIL Databank (routinely-collected health care records from Wales), with a common protocol applied across the databases for cohort construction and analysis. The study populations will consist of any individual initiating a non-insulin antidiabetic drug up to 31 January 2018, with follow-up until 31 July 2018. In a nested case-control design, those who experience the outcome of interest will be matched to those who have not experienced the outcome at the time of the case event. Up to 20 controls will be randomly selected for each case and matched on the basis of sex, age, date of study cohort entry, and duration of treated diabetes. Cohorts will be built separately for each outcome. Odds ratios for the outcomes of interest among patients receiving SGLT-2 inhibitors and/or GLP-1 receptor agonists, as compared with those receiving other antidiabetic combination regimens, will be estimated from conditional logistic regression models and pooled across the three databases with the use of random-effects models. To investigate risks associated with SGLT-2 inhibitors compared with GLP-1 receptor agonists, a new-user cohort design will be implemented. Weighted Cox regression models will be used to estimate study-specific hazard ratios and pooled across the three databases.
Study 1
? Fatal and non-fatal major cardiovascular events (myocardial infarction/acute coronary syndrome, stroke/transient ischaemic attack, unstable angina).
? Heart failure
Study 2
? Osteoporotic fractures (fractures at any of the six anatomic locations: hip, vertebra, forearm, humerus, ribs and pelvis)
Study 3
? All-cause mortality
? Cardiovascular mortality
Darren Ashcroft - Chief Investigator - University of Manchester
Alison Wright - Corresponding Applicant - University of Manchester
Evangelos Kontopantelis - Collaborator - University of Manchester
Iain Buchan - Collaborator - University of Manchester
Martin Rutter - Collaborator - University of Manchester
Matthew Carr - Collaborator - University of Manchester
Naveed Sattar - Collaborator - University of Glasgow
Richard Emsley - Collaborator - King's College London (KCL)
HES Accident and Emergency;HES Admitted Patient Care;HES Outpatient;ONS Death Registration Data;Patient Level Index of Multiple Deprivation;Practice Level Index of Multiple Deprivation