Comparative effects of different antidiabetic treatments on COVID-19 mortality and vascular outcomes

Date of Approval: 
2021-05-26 00:00:00
Lay Summary: 
Type 2 Diabetes Mellitus (T2DM) is a common, chronic health condition in which a person’s glucose levels are too high. This can cause a range of complications, including damage to the eyes and kidneys, heart disease, stroke and heart attacks. The UK National Institute for Health and Care Excellence, which issues treatment guidelines for a range of medical conditions, specify that all T2DM patients should be offered drug treatment to reduce glucose levels, if lifestyle changes such as exercise and dieting are not effective. Metformin, an oral anti-diabetic, is the first line drug. If glucose control remains poor or worsens after treatment with metformin, treatment is intensified by adding another oral anti-diabetic agent: either DPP-4 inhibitors (DPP4-i, gliptins), pioglitazone, sulphonylurea or Sodium/glucose cotransporter-2 inhibitors (SGLT2i). Although the efficacy and safety of oral anti-diabetic agents have been determined in clinical trials, evidence of the long-term effects (+5 years) of the newer treatment classes, including gliptins and SGLT2-is, is limited. Recently, there has also been interest in whether some of these newer treatment classes could offer some protection against poor outcomes in COVID-19. This project will describe and compare the long-term risk of diabetic complications among people receiving gliptins or SGLT2-I. We will also investigate whether either drug might offer protection against COVID-19. Finally, given that the risk of diabetic complications is known to vary according to ethnicity, we will investigate whether there is any evidence that the treatment effects vary according to self-reported ethnicity or levels of social deprivation.
Technical Summary: 
Type 2 Diabetes Mellitus (T2DM) affects approximately ~5% of individuals in the UK, and can cause both microvascular complications, such as retinopathy, kidney disease and neuropathy, as well as macrovascular complications, such as coronary heart disease, stroke, myocardial infarction and heart failure. More recently, individuals with T2DM have also been found to be at increased risk of COVID-19 mortality, a risk which is particularly marked for those with poorly controlled diabetes (HbA1c levels > 58 mmol/mol). The management of T2DM is complex, but drug treatment is commonly offered together with advice on lifestyle modification. Metformin, an oral antidiabetic agent, is the first-line drug treatment of T2DM in the UK, unless contraindicated or not tolerated. However, if glucose control remains poor or worsens despite initiation of metformin and lifestyle interventions, treatment is intensified by adding another oral antidiabetic agent: including pioglitazone, sulphonylurea, or one of the newer diabetic drugs DPP-4 inhibitors (DPP4-i, gliptins) or Sodium/glucose cotransporter-2 inhibitors (SGLT2i). The efficacy and safety of oral antidiabetic agents have been determined in randomised controlled trials. However, there is limited data available on long-term microvascular and macrovascular outcomes following the first treatment intensification. Existing data indicate that SGLT2-i may provide greater reductions in HbA1c compared to gliptins over the medium term; although whether this will translate into a long-term benefit when considering clinical endpoints is not yet known. There have also been few studies looking at the impact of diabetic treatment choice and COVID-19 risk. This study will use data from CPRD to describe and compare microvascular, macrovascular and COVID-19 outcomes among patients with T2DM receiving either a gliptin or SGLT2i in the UK. Multivariable regression modelling will be used to account for potentially confounding factors, and effect modification by ethnicity and social deprivation will be investigated.
Health Outcomes to be Measured: 
This is a comparative study of two antidiabetic treatments, looking at a range of outcomes: both traditional microvascular and macrovascular outcomes, as well as outcomes specific to COVID-19. The latter has increased in clinical importance during the past year despite not being outcomes typically included in studies of anti-diabetic treatment outcomes. The specific drugs of interest in this study - gliptins and SGLT2i - have both been hypothesised to potentially impact COVID-19 outcomes (Sainsbury et al., 2021), therefore providing a specific rationale for this being included in the current project. We believe it is suitable to include this range of outcomes in a single project, as the population and exposure definitions will be identical despite different outcomes being studies. In response to reviewer comments raised during the ISAC review, the study team notes that this could be submitted as two different ISACs, if required. The outcomes of interest are: Microvascular disease (retinopathy, kidney disease, neuropathy), defined using Read codes Macrovascular disease (coronary heart disease, stroke, myocardial infarction and heart failure), defined using Read codes and ICD-10 codes (in the ONS data). COVID-19 (diagnoses and/or mortality, defined using primary care codes and ONS death records) All-cause mortality, defined using date of death as given in the ONS. Codelists available as supplementary materials (appendix I). It should be noted that microvascular and macrovascular disease will be defined as the first occurrence of either event listed. Although individual events may be described in sensitivity analyses, the primary outcome definitions will use combined end-points to ensure sufficient power.
Application Number: 

Anna Schultze - Chief Investigator - London School of Hygiene & Tropical Medicine ( LSHTM )

Anna Schultze - Corresponding Applicant - London School of Hygiene & Tropical Medicine ( LSHTM )

Owen Taylor - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )

Rohini Mathur - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )

Selina Kim - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )

ONS, Patient IMD, Practice IMD