Award Title: What is the best second line therapy for people aged 65 years or over with type 2 diabetes?: systematic review and network meta-analysis
Funder: Department of Health and Social Care

Abstract: Research question   What is the most effective and safe second line therapy for people aged 65-years and over with type 2 diabetes(T2DM)?  Background   One-in-six people aged 65-years or over has T2DM and over half of prevalent T2DM cases are in this age group. Older adults have a higher risk of adverse cardiovascular and renal outcomes, and potentially more adverse-effects from drugs. Evidence suggests that the relationships between therapy and outcome may differ between older and younger people so the common approach of trial participant selection (recruiting people with a wide range of ages) may not allow a full description of the responses in this age group.  Aims and Objectives   To perform a systematic review and network meta-analysis (NMA) using either stratified summary data or individual patient data (IPD) of all relevant randomised controlled trials to determine the rankings of second line therapies for patients aged 65-years or over with T2DM.   Objective 1. Calculate the relative effectiveness of drugs and combinations of drugs in patients aged 65-years or over who are also receiving metformin.   Objective 2. Calculate the relative effectiveness of drugs and combinations of drugs in patients aged 65-years or over who are not receiving metformin  Methods   We will update the search in a recent NMA and perform risk of bias assessments on newly identified studies. We will obtain individual patient data (IPD) for all relevant studies using 5 different processes. Including data repositories, contacting data owners, and authors of papers. The statistical analysis will be a two-stage process. First, IPD will be analysed independently for each trial using appropriate regression models for each outcome. Models will adjust for variables that were stratified by in randomisation. We will also adjust for baseline values of HbA1c, sex, BMI, presence of cardio-vascular disease, presence of chronic kidney disease in all models. Second, these summary treatment effect estimates and their standard errors will be used in a NMA to synthesise the evidence in a single mathematically coherent model. This will allow us to rank treatments by efficacy and safety, and then estimate the relative effectiveness of all treatments with confidence intervals.  Timelines for delivery   Pre-grant phase(12/19-05/20): Update literature search, apply to trial portals and request data from study teams, develop protocol.   05/20-01/21: Finalise protocol, continue data acquisition and develop computer code for evidence synthesis.   11/20-06/21: Clean data, quality assess newer studies and analyse data   07/21-10/21: Update database and perform NMA. Write-up study and disseminate.   Many processes overlap during these phases. PPI will be throughout the project.  Anticipated Impact and Dissemination   We will identify the best second line treatments for patients with T2DM who are 65-years or older. Findings will be disseminated to patients in collaboration with (e.g. Foundation for Diabetes Research in Older People); to clinicians via diabetes, older people and general practice conferences, networks and publications; policy makers through the NICE diabetes management guidelines committees. We envisage the results will change practice by impacting on evidence-based prescribing for older people, reduce adverse effects, and potentially improved cardiovascular health, and quality of life.

Lay Abstract: Background   Almost half of people with type 2 diabetes are aged above 65 years. One in six people aged above 65 years have type-2-diabetes. This is expected to increase as people live longer.  Currently experts recommend metformin as the first drug of choice for people with type-2-diabetes to control their blood sugar. When metformin alone does not control blood sugar, we need to give an additional drug or replace metformin. This is known as second-line treatment. There are many drugs to choose from at this stage, but doctors do not know which is the best for people aged over 65 years. Most research studies only include a small number of older people which does not allow us to identify the best choice of drug for them. This is unfortunate, because older people are more likely than younger people to have other health problems like heart disease and kidney disease, which could affect the choice of which drug to use as a second-line treatment; particularly that we now have newer drugs that improve glucose levels and at the same time prevent heart and kidney disease. On the other hand, we need to be careful with our choice of drugs because older people are also more likely to experience side effects.  Aims   We will identify then combine all evidence regarding older people from different research studies comparing different treatments. Then we will do a new analysis using these data to identify the best second-line treatments for older patients with type 2 diabetes, in terms of their ability to improve the blood sugar control, prevent diabetes complications and reduce side effects.  Methods   We will identify all of the scientific evidence by searching all published studies. For each study, we will attempt to obtain data specific for patients age 65 and over. We will do this by searching data storage sites which hold anonymised patient data and by contacting authors of published studies. We will use established analytical methods to combine this information and achieve the above mentioned aims.  Patient and public involvement (PPI)   We have discussed this research with patients who are aged 65 or over with type 2 diabetes. They were enthusiastic about the project and its potential benefits. Many of them reported issues with side effects from their current treatments such as low blood sugar. They were unaware about potential benefits towards the health of their heart and kidneys.  Dissemination   We will make these results available freely to as many people as possible by publishing papers in journals and on websites, and by talking to doctors, researchers, and patients. We will also work with the Diabetes UK charity, Diabetes Frail organisation and will involve Clinical Commissioning Groups and NICE guidelines committee.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: METABOLIC AND ENDOCRINE