Persons with type 2 diabetes (T2D) are at an increased risk of developing cardiovascular disease (CVD) such as myocardial infarction, stroke, end-stage-renal disease, and heart failure as well as an increased risk of cardiovascular death. Following the findings of large trials, CVD prevention is now an integrated part of T2D treatment. Both new oral glucose-lowering drugs (sodium-glucose co-transporter-2 inhibitors [SGLT2] and glucagon-like peptide-1 receptor agonists [GLP1] are available and prescribed to persons with T2D, however no current trials has investigated the potential combined preventive effect of both drugs. Using English nationwide health care registries and novel analysis, we aim to investigate the preventive effect of combined GLP1 and SGLT2 use compared to other combinations of glucose lowering drugs on CVD, heart failure hospitalization and end-stage-renal disease. Our main hypothesis is that prevention of CVD among persons with T2D is better achieved with combined use of SGLT2 and GLP1 compared to other common combinations of glucose lowering drugs. This research project aids with important knowledge on CVD disease prevention in persons with T2D and has the potential to challenge current clinical practices.
The cardiovascular and renal disease prevention potential of combined GLP1 and SGLT2 in persons with T2D is not well investigated.
We aim to investigate the preventive effect of combined GLP1 and SGLT2 use compared to other combinations of second line therapy (GLP1+DPP4/SU/TZD, SGLT2+DPP4/SU/TZD or a combination of DDP4/SU/TZD) on major cardiovascular adverse events, heart failure hospitalization, and end-stage-renal disease among persons with T2D.
The study design is an observational retrospective cohort study including persons with T2D in the time period between 2010-2022.
The main data source for the study will be the Clinical Practice Research Datalink (CRPD) Aurum Database, which holds information from general practitioners. CRPD Aurum will be used to define the T2D population, demographic details, ethnicity, all relevant clinical parameters including laboratory values, and concomitant medication. Information on CVD, renal outcomes, and date/cause of all-cause death will be extracted by linking to ONS Death Registration Data, and HES Admitted Patient Care.
The average treatment effect will be estimated using Longitudinal Targeted Maximum Likelihood Estimation. The target parameters of the primary analysis are the 5-year risks of first time heart failure hospitalization after the index date under the 4 treatment regimens and differences as well as ratios thereof. All nuisance parameter models needed for the initial estimator and for the targeting step are adjusted for additive effects of all covariates, suitably updated to the current time interval, such that we never confuse the causal time order of the variables. All nuisance models are fitted using penalized elastic net regression. The penalty parameters are selected based on 10-fold cross-validation. Reported are the LTMLE estimates with 95% confidence intervals.
This research project aids with important knowledge on CVD disease prevention in persons with T2D and has the potential to challenge current clinical practices.
Primary outcomes:
• First-time heart failure hospitalization following inclusion.
Secondary outcomes
• Incident chronic renal disease
• Composite outcome of persistent estimated glomerular filtration rate (eGFR) decline of greater than or equal to 50 percent from inclusion date, end-stage renal disease, or death from cardiovascular disease.
• Major adverse cardiovascular event defined as a composite outcome of: non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death.
• End-stage-renal disease
• eGFR decline of greater than or equal to 50 percent
• Non-fatal myocardial infarction
• Non-fatal stroke
• Cardiovascular death
• All-cause death
• Change in HbA1c (%) from index date to 1 year after index date among one-year survivors. This analysis will only be conducted if sufficient data is available.
• Change in eGFR (mL/min/1.73 m^2/year) from index date to 1 year after index date among one-year survivors. This analysis will only be conducted if sufficient data is available.
Trine Abrahamsen - Chief Investigator - Novo Nordisk A/S
Bochra Zareini - Corresponding Applicant - University of Copenhagen
Thomas Gerds - Collaborator - University of Copenhagen
HES Admitted Patient Care;ONS Death Registration Data;Patient Level Index of Multiple Deprivation