Type 2 diabetes is a serious long-term condition that causes a persons blood sugar level to become too high. There are many medications to help with type 2 diabetes. They all work by lowering blood sugar. However, they all have different side effects, so it is difficult for doctors to know which to prescribe.
We want to look at a relatively new class of drugs indicated for diabetes called sodium-glucose co-transporter 2 (SGLT2) inhibitors. Research suggests that they may be better at reducing heart and kidney problems than other treatments for type 2 diabetes. In particular, research has suggested that empagliflozin, which is a drug belonging to the SGL2-inhibitor drug class, may have a direct beneficial effect on the heart. People with type 2 diabetes tend to have a greater chance of having heart and kidney problems than other people.
To do our study, we will compare SGLT2 inhibitors with another class of drug that has been around for a longer called dipeptidyl peptidase-4 (DPP-4) inhibitors. We will compare effectiveness and safety outcomes between the groups and we will also carry out a sub-analysis focusing on comparing empagliflozin-drug with DPP-4 inhibitors.
We will make use of four large primary care databases in England and Wales to better understanding of the findings. Results from the primary care databases will be combined to provide a more precise result of the effectiveness and safety of SGLT2-inhibitor treatment. This will provide important information to help with primary care clinical decision making.
UK guidance recommends that sodium-glucose co-transporter 2 (SGLT2) inhibitors be considered as an option alongside other glucose-lowering agents at the first intensification of treatment for type 2 diabetes, where the patient has failed to achieve glucose control or cannot tolerate metformin. Growing evidence suggests that SGLT2 inhibitors have a favourable cardiometabolic safety profile but much of this evidence is based on randomised controlled trials which limits generalizability to the real-world clinical setting.
This part of a 5-site collaboration of different databases in the UK (SAIL, Discover, THIN, CPRD, RCGP). For the proposed analysis, Data from the Clinical Practice Research Datalink (CPRD) Gold database with linkage to Hospital Episode Statistics (HES) and Office for National Statistics (ONS) will be used to investigate:
1. risk of hospitalisation for heart failure in people with type 2 diabetes prescribed SGLT2 inhibitors compared with DPP-4 inhibitors;
2. risk of all-cause mortality in people with type 2 diabetes prescribed SGLT2 inhibitors compared with DPP-4 inhibitors;
3. risk of a composite outcome of all-cause mortality and hospitalisation for heart failure in people with type 2 diabetes prescribed SGLT2 inhibitors compared with DPP-4 inhibitors;
4. risk of cardiovascular mortality;
5. risk of composite outcomes of hospitalisation for heart failure and cardiovascular mortality;
6. risk of 3-point major adverse cardiovascular events (MACE), defined as a composite outcome including myocardial infarction, stroke and cardiovascular mortality in people with type 2 diabetes prescribed SGLT2 inhibitors compared with DPP-4 inhibitors;
7. risk of percutaneous coronary intervention;
8. risk of end-stage renal disease in people with type 2 diabetes prescribed SGLT2 inhibitors compared with DPP-4 inhibitors.
9. risk of hospitalisation, all-cause mortality, composite outcomes for empagliflozin vs DPP-4 inhibitors.
Results from the 5-sites will be combined using meta-analysis. We will take account of any overlap between CPRD and THIN using established methods.
Effectiveness outcomes
Primary outcomes:
Hospitalisation for heart failure (HHF)
All-cause mortality
Cardiovascular mortality
MACE outcomes (myocardial infarction, stroke and cardiovascular mortality)
Secondary outcomes:
End-stage renal disease
Percutaneous coronary intervention
Safety outcomes
Bone fracture
Diabetic ketoacidosis
Severe hypoglycaemia
Urinary tract cancers: bladder cancers, renal cancers, other urinary tract cancer (Appendix
Urinary tract infections or genitourinary infections
Lower limb amputation
Acute kidney injury requiring dialysis
Healthcare utilisation
Secondary care: time to hospitalisation, number of in-patient admissions per person-year and length of hospital stay
Primary care: number of GP consultations (in-practice, home-visits, telephone) per person-year
Kamlesh Khunti - Chief Investigator - University of Leicester
Muna Adan - Corresponding Applicant - Leicester Diabetes Centre
Francesco Zaccardi - Collaborator - University of Leicester
Freya Tyrer - Collaborator - University of Leicester
Sharmin Shabnam - Collaborator - University of Leicester
HES Admitted Patient Care;ONS Death Registration Data;Patient Level Index of Multiple Deprivation