Time-dependent effect of GLP-1 receptor agonists on cardiovascular benefits: a real-world study

Abstract

Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown cardiovascular benefits in cardiovascular outcome trials in type 2 diabetes mellitus. However, the most convincing evidence was obtained in subjects with established cardiovascular (CV) disease. We analyzed the determinants of GLP-1 RA-mediated CV protection in a real-world population of persons with type 2 diabetes with and without a history of CV events with long-term follow-up. Methods Retrospective cohort study of 550 individuals with type 2 diabetes (395 in primary CV prevention, 155 in secondary CV prevention), followed at a single center after the first prescription of a GLP-1 RA between 2009 and 2019. CV and metabolic outcomes were assessed. Results Median duration of follow-up was 5.0 years (0.25–10.8) in primary prevention and 3.6 years (0–10.3) in secondary prevention, with a median duration of treatment of 3.2 years (0–10.8) and 2.5 years (0–10.3) respectively. In the multivariable Cox regression model considering GLP-1 RA treatment as a time-dependent covariate, in the primary prevention group, changes in BMI and glycated hemoglobin did not have an impact on MACE risk, while age at the time of GLP-1 initiation (HR 1.08, 95% CI 1.03–1.14, p = 0.001) and GLP-1 RA cessation by time (HR 3.40, 95% CI 1.82–6.32, p < 0.001) increased the risk of MACE. Regarding the secondary prevention group, only GLP-1 RA cessation by time (HR 2.71, 95% CI 1.46–5.01, p = 0.002) increased the risk of MACE. With respect to those who withdrew treatment, subjects who continued the GLP-1 RA had significantly greater weight loss and lower glycated hemoglobin levels during follow-up. Conclusions In this real-world type 2 diabetes population, discontinuation of GLP-1 RA treatment was associated to a higher risk of major cardiovascular events, in both subjects with and without a history of CV events.

GLP-1 receptor agonists for weight reduction in people living with obesity but without diabetes: a living benefit–harm modelling study

“… 49 , 50 This was supported by an observational study, albeit in people living with diabetes, that reported an increased risk of CVD events in those who withdrew GLP-1 RAs. 51 …”

The Current and Future Role of Insulin Therapy in the Management of Type 2 Diabetes: A Narrative Review

“…In addition to losing the cardiorenal protection benefits, individuals who discontinue GLP-1 RA medications typically gain back much of the weight they had lost during therapy [ 55 ]. In a retrospective cohort study of adults with T2D, investigators assessed changes in cardiovascular risk and other outcomes in 395 individuals with no history of CVD (primary prevention group) and 155 individuals with a known history of CVD (secondary prevention) [ 55 ]. In the primary prevention arm of the trial ( n = 395), 40.25% of patients discontinued therapy after mean of 3.2 years.…”

“…At year 4, weight loss was significantly greater among patients who continued therapy than among those who discontinued therapy (− 4.14 vs. − 1.19 kg; respectively; p < 0.001), and even greater differences were observed in the secondary prevention group (− 4.46 vs. − 0.75 kg, respectively; p = 0.006). The investigators reported that discontinuation of therapy was independently associated with a significant increase in the risk of developing a major adverse cardiovascular event (MACE) [ 55 ].…”

Insulin resistance/hyperinsulinemia: an important cardiovascular risk factor that has long been underestimated

“…However, although GLP-Ras have actually been shown to improve cardiovascular risk factors such as body weight, blood pressure, LDL cholesterol and triglycerides, and glycemic control, they have been shown to reduce all-cause mortality in patients with type 2 diabetes at high risk of cardiovascular events, but have not reduced cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke and hospitalizations for HF ( 71 , 72 ). Another recent meta-analysis carried out on 54,092 pts from 7 randomized controlled trials on the use of GLP-1 Ras in subjects with type 2 diabetes, of whom 16% also had a history of HF, demonstrated that these drugs appear to protect the diabetic population from the development of HF, but, in subjects with pre-existing HF, they do not reduce the onset of episodes of HF exacerbation with consequent hospitalization, nor mortality ( 73 ).…”