1) Health economics model aim: People with kidney disease have more rapid decline in kidney function which means that they may require dialysis or a kidney transplant. They are also more likely than people without kidney disease to develop cardiovascular diseases such as heart disease and stroke and die earlier. Previous research has shown that statins to lower cholesterol and blood pressure medications can help people with kidney disease reduce their chances of developing cardiovascular disease. Recently new drugs have been found that also slow the decline in kidney function. Our research will focus on people with kidney disease, assess their disease progression and other complications, and evaluate these new drugs over longer term, while also looking at the impact of slowing kidney function decline on the chances of developing cardiovascular disease and other poor health. We will determine the groups of patients who are likely to benefit most from these new drugs to help better target limited NHS resources.
(2) Use of risk modifying treatment aim: Several treatments for kidney and cardiovascular disease have been found to work in clinical trials. Effective implementation of such treatment is crucial to ensure disease risks are safely reduced in the UK. We know that some patient groups are less likely to receive such treatments in a timely manner and therefore we wish to better understand the patterns of prescription and use over time in different types of people at risk. This will help highlight where there is underuse or inequitable use.
Aim 1: Health economic model
Background: SGLT2 inhibitors (SGLT2is) reduce heart failure admissions, mortality and kidney disease progression. However, there is no individual patient data-derived CKD model to evaluate the long-term effects of such treatments in different categories of patients.
Methods: Using a pre-specified CPRD CKD cohort, a long-term CKD decision-analytic policy model will be developed and validated as follows: 1) estimation of multivariable prediction models of time-to-event outcomes (myocardial infarction, stroke, heart failure hospitalisation and death) and longitudinal outcomes (estimated glomerular filtration rate); 2) estimation of multivariable generalised linear models for annual healthcare costs of CKD patients; 3) models from 1) and 2), together with data on quality of life in CKD informed from EMPA-KIDNEY trial data and/or published studies, will be integrated into a CKD model; 4) CKD cohort participants’ characteristics and effects of SGLTi informed from randomised trials will be used to assess the cost-effectiveness of SGLTi in categories of CKD patients. All aforementioned models will adjust simultaneously for a pre-specified set of covariates with no single covariate being the focus of interest.
Aim 2: Assessing UK prescription trends of proven risk modifying therapies in patients with an indication
Study population: Adult patients with CKD, type 2 diabetes and/or heart failure
Primary exposure: prescribed SGLT2i (yes/no)
Secondary exposures: prescribed renin-angiotensin-aldosterone pathway inhibitors, GLP-1 receptor antagonists, statin-based therapy and prescriptions for treatment of anaemia in CKD
Outcome: Proportion of indicated population who are prescribed SGLT2 inhibitor and,
separately, secondary exposures
Study design: Cohort study
Methods: Descriptive analyses will summarise patterns of use over time of the
aforementioned exposures by indication for use (using guidelines or trial-driven indications). Logistic regressions will then identify factors associated with underuse (including age, sex, level of deprivation, ethnicity, comorbidity [including CKD, heart failure and diabetes], and markers of kidney disease risk (eGFR/albuminuria/proteinuria).
Note to reviewer: For aim 1, use of SGLT2i is a covariate of interest alongside other pre-specified covariates associated with disease risks; it is not focus of the investigation. For aim 2, SGLT2i is an exposure. We have now distinguished between primary outcomes and key secondary outcomes.
A. Outcomes to be Measured
Aim 1
Primary outcomes (i.e. the longitudinal and time-to-event outcomes that will be modelled)
Longitudinal outcome:
• Estimated glomerular filtration rate (eGFR), including derivation from serum creatinine using the CKD-EPI 2009 equation(1) and, as a sensitivity analysis, the CKD-EPI 2021 equation without race(2).
Time to event outcomes:
• Myocardial infarction
• Stroke
• Transient ischaemic attack
• Hospitalisation for heart failure
• Cardiovascular death
• Non-cardiovascular death (includes death due to kidney failure, infection and cancer).
Key secondary outcomes:
Costs outcomes:
Primary care costs
• GP consultation
• Diagnostic and monitoring tests
• Prescription medication
Hospital care costs
• Inpatient admission
• Outpatient visits
• Accident and emergency visits
Potential adverse events from treatments:
SGLT2i:
• Ketoacidosis (in patients with diabetes)
• Lower limb amputation
• Urinary tract infections
• Mycotic genital infections
• Severe hypoglycaemia
• Bone fracture
• Fournier’s gangrene
Renin-angiotensin-aldosterone (RAAS) pathway inhibitors (ACE inhibitors, Angiotensin-II receptor blockers and mineralocorticoid receptor antagonists):
• Hypotension
• Hyperkalaemia (or serum potassium concentration >5.5 mmol/L)
GLP-1 receptor antagonists
• Gastrointestinal disorder (nausea, vomiting, diarrhoea)
• Severe hypoglycaemia
• Pancreatitis
• Malignancy and specifically pancreatic carcinoma, medullary thyroid carcinoma
Statin-based therapy
• Myopathy and rhabdomyolysis
• New onset diabetes”
Aim 2
Primary outcome
• proportion of the study population with an indication for the primary exposure SGLT2 inhibition (CKD, type 2 diabetes or heart failure) who are prescribed SGLT2 inhibitor
Secondary outcomes
• proportion of the study population (CKD, type 2 diabetes or heart failure) with an indication for a secondary exposure who are prescribed the respective secondary exposure. Secondary exposures are renin-angiotensin-aldosterone pathway inhibitors (ACE inhibitors, Angiotensin-II receptor blockers and mineralocorticoid receptor antagonists [steroidal and non-steroidal]), GLP-1 receptor antagonists, statin-based therapy and prescriptions for treatment of anaemia in CKD.
Borislava MIHAYLOVA - Chief Investigator - University of Oxford
Claire Williams - Corresponding Applicant - University of Oxford
Junwen Zhou - Collaborator - Nuffield Department of Population Health
Kaitlin Mayne - Collaborator - Nuffield Department of Population Health
Natalie Staplin - Collaborator - University of Oxford
Richard Haynes - Collaborator - University of Oxford
William Herrington - Collaborator - University of Oxford
Ryoki Arimoto - Collaborator - Nuffield Department of Population Health
HES Accident and Emergency;HES Admitted Patient Care;HES Outpatient;ONS Death Registration Data;Patient Level Index of Multiple Deprivation;CPRD Aurum Ethnicity Record