Multifactorial Intervention to Reduce Cardiovascular Disease in Type 1 Diabetes

Background: Individuals with type 1 diabetes (T1D) are at high risk for cardiovascular, disease (CVD). Even with optimal glycemic control, the risk is doubled compared to healthy, individuals. Treatment of type 2 diabetes (T2D) is based on multifactorial intervention, (MFI). The development of new drug classes has had profound impact on treatment guidelines, through a documented reduction in mortality and morbidity in individuals with T2D. MFI, acknowledges the need for control and interventions directed towards several risk factors for, CVD, and not focus merely on glucose levels. A fundamental change in risk management with a, strong focus on MFIs to lower CVD risk in individuals with T1D and comorbidity of CVD, CKD,, HF or obesity, has the potential to improve morbidity and survival in T1D., Objective: The aim of the Steno 1 study is to test MFI in individuals with T1D at high risk, of CVD with ambitious treatment targets. We hypothesize, that the MFI reduces major adverse, cardiovascular endpoints (MACE) hospitalization for heart failure (HHF), kidney failure and, mortality., Design: This study uses a PROBE design (prospective, cluster-randomized, open, blinded, endpoint evaluation), as it will not be possible to mask the MFI. The study is a superiority, trial., Patient population: High-risk individuals with T1D of >10 years duration (>40 years of age, with presence of either CKD, CVD, HF, obesity or a >10% 5-year CVD risk determined by the, Steno T1 Risk Engine). Participants are recruited from Steno Diabetes Centres or partner, clinics., Randomization: There will be formed three clusters (large patient pool, intermediate- and, small). Within each cluster, participating centers will be randomised to either group A or, group B. Group A will receive current guideline-recommended standard of care and group B will, receive the multifactorial risk based intensive therapy. Participants are allocated to, centers based on geography and not based on phenotype., Intervention: For the intensively treated group, the MFI will be determined by the risk, profile and risk markers of each individual and the participants will be allocated to, Semaglutide, sotagliflozin, finerenone, ezetimibe and/ or PCSK9-inhibitors. The intervention, will also comprise more ambitious treatment targets for blood pressure and lipid levels. In, addition, all participants will take aspirin 75 mg OD., Endpoints: The primary endpoint is to determine whether MFI is superior to standard care with, respect to MACE+HHF (composite of time to first non-fatal myocardial infarction, first, non-fatal stroke, cardiovascular death or first hospitalization for heart failure). Secondary, endpoints are to determine whether MFI is superior to standard care with respect to all-cause, mortality, a composite endpoint of renal function (end-stage kidney disease (ESKD) (dialysis,, renal death, transplantation) or >50% sustained decline in eGFR) compared to standard of care, and to determine whether MFI including the use of SGLT2i and GLP1RA leads to an increased, frequency of diabetic ketoacidosis compared to standard of care.