Delayed treatment intensification and risk of micro- and macrovascular complications in insulin-treated patients with type 2 diabetes; a United Kingdom Clinical Practice Research Datalink Retrospective Cohort Study

Date of ISAC Approval: 
Lay Summary: 
Researches have reported that the use of insulin in type 2 diabetes is often delayed well beyond recommended guidelines particularly in primary care. This delay can lead to patients not achieving good control of diabetes over prolonged periods and this in turn increases the risk of adverse effects on the heart, brain, feet, kidneys and eyes. Thus, it is essential to effectively and timely manage patients with poor glucose control. However, the consequences of a delay in treatment and subsequent poor diabetes control in patients with type 2 diabetes who are treated with long-acting insulin in real-world setting have not been previously studied in research. In addition, the length of time in which patients continue on long-acting insulin therapy following treatment start is not well known. Thus, accordingly, this study aims to investigate the effects of a delay in long-acting insulin treatment on the heart, brain, feet, kidneys and eyes in people with type 2 diabetes. We will also assess how long patients continue using long-acting insulin and what drugs they move onto following discontinuation of long acting insulin and the change in glucose control.
Technical Summary: 
A number of observational studies in type 2 diabetes patients (T2DM) have reported that insulin initiation is delayed until after multiple oral antidiabetic drug (OAD) failure and deterioration of glycaemic control well beyond recommended guidelines. Such delay in treatment intensification is even more evident after basal insulin (BI) initiation. In a retrospective cohort study of UK Clinical Practice Research Datalink (CPRD), only 30.9% of T2DM patients clinically eligible for intensification received additional treatment, with a median time to intensification of 3.7 years (95% CI 3.4 to 4.0). The delay in treatment intensification in patients with poor glycaemic control (clinical inertia) has long-lasting effects on micro- and macrovascular complications of T2DM and has been referred to as "negative metabolic memory" also known as dysglycaemic legacy. In line with this notion, a 1 year delay in treatment intensification in patients with suboptimal glycaemic control on OADs is associated with increased risk of major adverse cardiovascular outcomes including myocardial infarction, heart failure and stroke. However, the consequence of delayed treatment intensification and suboptimal glycaemic control in BI treated T2DM patients in a real world setting have not been previously investigated. It is unclear what proportions of patients who do not persist on their basal insulin therapies move onto the various classes of antidiabetic drugs and what the trajectory of HbA1c control is thereof. Thus, we aimed to investigate the associations of delayed treatment intensification and long-lasting hyperglycaemia with micro- and macro-vascular outcomes after BI initiation in T2DM patients using UK CPRD. This will be determined using time-to-event survival analysis using cox-proportional regression model (adjusting for time-dependent and time-independent covariates). Additionally, we will assess the duration of persistence for basal insulin therapies in people with type 2 diabetes, taking into consideration the various predictors of persistence and the type of insulin. We will also asses what drugs they move onto following non-persistence to basal insulin, and the mean change in HbA1c after 6 months.
Health Outcomes to be Measured: 
- Macrovascular endpoints: The occurrence of the first (new onset) major CV event (MI, stroke, CABG, PTCA , amputation, new or worsening HF, death from CV events) - Microvascular endpoints (Retinopathy): New onset retinopathy or progression entered onto Patient record after BI initiation - Microvascular endpoints (Nephropathy): Decline in renal function (doubling of serum creatinine , eGFR decline more than 5% yearly, ESRD ; eGFR </=15 ml/min/1.73 m2 or renal replacement therapy) - Composite Microvascular endpoints : occurrence of the first retinopathy or nephropathy event - First occurrence of composite of microvascular or macrovascular endpoint For those patients in home persistence to insulin did not occur - Mean duration of basal insulin persistence - HbA1c after 6 months post initiation of new antidiabetic therapy when the basal insulin regime stopped. - Weight after 6 months post initiation of new antidiabetic therapy when the basal insulin regime stopped.

Dr Samuel Seidu - Chief Investigator - Leicester Diabetes Centre
Dr David Webb - Collaborator - Leicester Diabetes Centre
Dr Francesco Zaccardi - Collaborator - University of Leicester
Professor Kamlesh Khunti - Collaborator - University of Leicester
Professor Melanie Davies - Collaborator - University of Leicester
Dr Muna Adan Hag Hersi - Corresponding Applicant - University of Leicester

HES Admitted;ONS;Patient IMD