Lead Investigator: João Sérgio Neves, Faculty of Medicine of University of Porto
Title of Proposal Research: Albiglutide and Cardiovascular Outcomes in Type 2 Diabetes With and Without Concomitant Sodium-Glucose Cotransporter-2 Inhibition Use
Vivli Data Request: 8542
Funding Source: None
Potential Conflicts of Interest: None
Summary of the Proposed Research:
Cardiovascular disease is the main cause of death in people with type 2 diabetes (T2D). SGLT2 inhibitors (SGLT2i) and GLP1 receptor agonists (GLP1-RA) are medications used to treat T2D. SGLT2i are daily oral medications that contribute to the elimination of glucose (sugar) in the urine, and GLP1-RA are injectable or oral medications (may be given daily or weekly) that decrease emptying of the stomach, decrease food intake and improve insulin secretion. Both SGLT2 inhibitors (SGLT2i) and GLP1 receptor agonists (GLP1-RA) have shown protection from cardiovascular events in T2D. Whether the protection from adverse outcomes in people with T2D at risk is greater with combined SGLT2i and GLP1-RA treatment (vs the use of SGLT2i or GLP1RA alone) is still uncertain.
Several lines of evidence suggest that the benefits of SGLT2i and GLP1-RA may be additive. First, SGLT2i and GLP1-RA act trough different mechanisms. While the protection from cardiovascular events with SGLT2i may be predominantly related to effects on the kidney and on the function of the heart, the protection with GLP1-RA appears to be mediated by anti-atherosclerotic effects (i.e. protect against build up of fats in the arteries). Second, the effects of SGLT2i and GLP1-RA on cardiovascular risk factors is additive: combination of SGLT2i with GLP1-RA is associated with a significantly greater decrease of blood glucose (sugar), body weight and blood pressure than each drug alone. Finally, a post-hoc analysis of the Effect of Efpeglenatide on Cardiovascular Outcomes (AMPLITUDE-O) trial suggests that the benefits of using GLP1-RA are similar among patients treated with SGLT2i and those not treated with SGLT2i. However, this is the only data available on the effect of the combination of SGLT2i with GLP1-RA on cardiovascular outcomes and confirmation of these findings is needed.
The cardiovascular safety and efficacy of albiglutide (a GLP1-RA) was tested in the Harmony Outcomes trial, that enrolled patients with type 2 diabetes and cardiovascular disease. In this trial, 575 (6%) participants were treated with SGLT2i and the effects of effect of albiglutide on cardiovascular outcomes according to baseline SGLT2i use has not been explored.
The present proposal aims to study the impact of albiglutide on cardiovascular outcomes among patients with type 2 diabetes, with and without treatment with SGLT2i at baseline (i.e., prior to randomization). Given the significant residual risk among patients with T2D and cardiovascular disease, even after treatment with SGLT2i, it is important to evaluate if additional protection from cardiovascular adverse outcomes can be obtained with treatment with GLP1-RA. This proposal aims to fill this gap in knowledge by studying the effects of albiglutide on cardiovascular outcomes in patients with type 2 diabetes according to treatment with SGLT2i at baseline in the Harmony Outcomes trial.
Statistical Analysis Plan:
Participants of the Harmony Outcomes will be divided into two subgroups according to treatment with SGLT2i at baseline (with vs. without SGLT2i at baseline). Their clinical characteristics will be described as mean (standard deviation) or medians (percentile25-75) for continuous variables and number (%) for categorical variables and compared through Student’s t-test, Mann-Whitney and Chi2 tests, as appropriate. The effect of albiglutide vs. placebo will be tested using Cox models for time-to-first event analyses with treatment group as explanatory variable and SGLT2i at baseline as stratification variable, with treatment-by-SGLT2i interaction term in the model. The results will be presented separately for patients with and without SGLT2i at baseline, along with the respective interaction P-value. Analyses will be performed according to the intention-to-treat principle. The Kaplan-Meier method will be used to estimate event rates. The effect of treatment on body weight, blood pressure and HbA1c over time, will be studied using mixed random effects models with treatment, time, SGLT2i at baseline, baseline value of the variable of interest, treatment-by-time, and treatment-by-SGLT2i at baseline interaction terms in the model; random effects will be set at the patient id level using an unstructured covariance matrix. Adverse events will be studied among patients who received at least one dose of the study drug using logistic regression models with treatment group as explanatory variable and SGLT2i at baseline as stratification variable, with treatment-by-SGLT2i at baseline interaction term in the model. No adjustment for multiplicity will be performed given the exploratory nature of this analysis. Patients with missing data will be excluded from analysis for that specific variable but included in the analysis of other variables. A two-sided P-value <0.05 will be considered statistically significant for main effects, and a two-sided P-value <0.10 will be considered statistically significant for interaction tests, which have less statistical power. Analyses will be performed using Stata® (StataCorp. 2021. Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC).
Requested Studies:
A Long Term, Randomised, Double Blind, Placebo-controlled Study to Determine the Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Patients With Type 2 Diabetes Mellitus
Data Contributor: GlaxoSmithKline
Study ID: NCT02465515
Sponsor ID: GLP116174
Public Disclosures:
Neves, J.S., Borges-Canha, M., Vasques-Nóvoa, F., Green, J.B., Leiter, L.A., Granger, C.B., Carvalho, D., Leite-Moreira, A., Hernandez, A.F., Del Prato, S. and McMurray, J.J., 2023. GLP-1 receptor agonist therapy with and without SGLT2 inhibitors in patients with Type 2 diabetes. Journal of the American College of Cardiology, 82(6), pp.517-525. Doi: 10.1016/j.jacc.2023.05.048