Preventive care in type 2 diabetes: improving risk prediction among older and multimorbid adults and assessing the effects of novel anti-diabetic drugs
Description: BackgroundType 2 diabetes (T2D) is highly prevalent among older adults and a major cause of cardiovascular disease (CVD) and chronic kidney disease (CKD). Preventive care of CVD and CKD is therefore critical in T2D. Until recently, reaching a relatively low level of hemoglobin A1c (HbA1c) was a standard goal in T2D. Among multimorbid older adults, new diabetes guidelines recommend less stringent Hb1Ac targets because harms of intensive strategies might outweigh benefits on clinical outcomes such as CVD. However, little is known on how levels of Hb1Ac relate with CVD-risk in this multimorbid older population, as most randomized controlled trials (RCTs) have excluded multimorbid older adults. Furthermore, while T2D patients are at high risk of CVD, the strength of T2D as a risk factor for CVD is unclear and whether T2D is a coronary risk equivalent among multimorbid older adults, because of very limited data among this population. Current CVD risk-estimation tools for T2D patients have also not been validated in multimorbid older adults and building a CVD risk score in this fast-growing population is therefore needed. Novel anti-diabetic drugs seem to provide benefits on CVD and CKD, but their effect on retinopathy leads to conflicting results. However, the effects of these drugs on such outcomes and harms (adverse events) may differ between drugs, between younger versus older, for different HbA1c levels reached after treatment, and these drugs have not been compared head-to head in RCTs. In the absence of head-to-head RCTs, network meta-analysis (NMA) is the most powerful method for comparing the benefits and harms of multiple drugs and it allows ranking of the drugs according to benefit/harm profile. However, among the few NMAs conducted on novel anti-diabetics, harms were not always assessed, none examined CVD and CKD among older adults and by different HbA1c levels and little is known on their effects on retinopathy. It is therefore timely to conduct an up-to-date, comprehensive, and high quality NMA to assess the benefit/harm profile of novel anti-diabetic drugs, accounting for different HbA1c levels, especially among older adults.Goal and specific aimsOur overarching goal is to improve risk prediction among multimorbid older adults with T2D and to compare the benefit/harm of novel anti-diabetic drugs. Our specific aims are: 1) To assess the predictive values of T2D and different HbA1c levels on the risk of CVD and mortality outcomes and if T2D is a coronary risk equivalent in multimorbid older adults from multiple large cohort studies,2) To derive a novel risk score for CVD and mortality in multimorbid older adults with T2D from multiple cohort studies,3) To use NMA to compare, overall and according to age and HbA1c levels, the benefits and harms of novel anti-diabetic drugs in reducing the risk of CVD and CKD in adults with T2D and clarify the controversial impact on retinopathy. MethodsThe data for Aims 1 and 2 will be from participants =65years from OPERAM Study (n=2008), CoLaus Study (n=798), Health and Retirement Study (n=10032), and Survey of Health, Ageing and Retirement in Europe (n=5850). The data for Aim 2 will be from the subgroup of participants with T2D from the same sources (n=3601). For the OPERAM study, we will collect data over 5 years by extending the follow-up for the study participants in Bern (Switzerland) and Louvain (Belgium). For Aim 1 we will analyze individual participant data using a flexible parametric survival model to assess in multimorbid older adults 1) the predictive values of T2D, 2) of different HbA1c levels, and 3) if T2D is a coronary risk equivalent on the composite outcome of CV events and all-cause mortality, accounting for multiple confounding factors. The analysis for Aim 2 will first identify predictors of our composite outcome using the same model and then derive a score system among older adults with T2D. The model’s performance and internal-external cross validation will be assessed. For Aim 3, we will conduct a systematic review and NMA of RCTs that compared novel anti-diabetics drugs to each other, to metformin or to placebo in patients with T2D. The benefits on CVD, CKD and retinopathy, as well as adverse events such as hypoglycemia, will be assessed overall, according to HbA1c levels after treatment and age. We will use the novel Confidence in Network Meta-Analysis (CINeMA) tool to assess the extent to which NMA results are trustable. Expected value and impactOur novel research project will immediately advance personalized management of T2D by improving risk prediction and tailoring treatment strategies for multimorbid older adults. We will clarify how T2D and HbA1c impact on the risk of CVD and mortality, as well as if T2D is a coronary risk equivalent, among older multimorbid adults. We will develop a new CVD and mortality risk score in multimorbid older adults with T2D. We will provide the best evidence on the benefits on CVD and CKD outcomes and harms of different novel anti-diabetes drugs, and asses their benefits/harms among older adults. The strengths and novelty of our study are: 1) the large sample size from multiple prospective cohort studies of older and multimorbid adults, 2) the unique opportunity to acquire long follow-up data on these risks in an existing unique international cohort of 2000 multimorbid older adults insuring the originality and high feasibility of our project, 3) the development of a novel, clinically relevant score system specifically for diabetic multimorbid older adults, and 4) assessing the effects of novel drugs (no head to head RCTs) on CVD and CKD as well as retinopathy among older adults, accounting for HbA1c levels after treatment, using NMA, a powerful method to generate high-quality evidence on comparing the benefit/harm profile of multiple drugs, and the new CINeMA tool to strengthen the confidence in results. Our results will help physicians to personalize management of T2D and guideline developers to better tailor recommendations.
Amount: CHF 337,100
Funding type: research
Funder scheme: Project funding
Start date: 2021-10-01
End date: 2025-02-28
Investigator: Gencer, Baris
Institution: University of Berne – BE
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Funded outputs count: 21
Funder award ID: 204361
OpenAlex ID: G4580751607