medwireNews: Glucose-lowering drugs or strategies reduce the risk for major adverse cardiovascular events (MACE) and death in people with or at risk for type 2 diabetes, but their impact on heart failure may depend on weight loss, shows an updated systematic review and meta-analysis.
Writing in The Lancet Diabetes & Endocrinology, Jacob Udell (Women’s College Hospital, Toronto, Canada) and co-authors say their findings “dispel perceptions that risk reduction for MACE is confined to GLP [glucagon-like peptide]-1 receptor agonists and that for heart failure is confined to SGLT [sodium-glucose cotransporter] 2 inhibitors.”
They add that the data “might reassure clinicians having difficulty implementing guidance that suggests prioritising one drug class over the other depending on which type of cardiovascular risk is most relevant to reduce in a patient with type 2 diabetes and established cardiovascular disease.”
The analysis included data from 30 large (≥1000 participants), randomized controlled trials, published between November 2013 and November 2019, that tested the effect of glucose-lowering drugs or strategies on MACE and heart failure in a total of 225,305 participants (mean age 63 years, mean diabetes duration 9.4 years).
After a mean follow-up of 3.8 years, 10.2% of participants had MACE – typically defined as cardiovascular death or all-cause mortality, myocardial infarction, and stroke – and 3.6% had a heart failure event. The rates of myocardial infarction, stroke, cardiovascular mortality and all-cause mortality were 4.9%, 2.9%, 4.5%, and 7.3%, respectively.
The investigators found that, overall, glucose-lowering drugs or strategies reduced the risk for MACE by a significant 8% compared with standard care or placebo. In addition, the risks for each of the individual MACE components were lowered by a significant 6–8%.
By contrast, the interventions had no significant effect on the risk for heart failure overall, but the researchers found that there was significant variation across drug classes and strategies as well as a potential effect modification according to the impact each had on bodyweight.
To investigate further, the team focused on glucose-lowering drugs or strategies that lead to effective weight reduction, namely SGLT2 inhibitors, GLP-1 receptor agonists, and intensive weight loss via lifestyle modification.
In this analysis they found these interventions reduced the risk for heart failure by a significant 19% overall relative to standard care or placebo. The risk reduction was greatest with SGLT2 inhibitors, at 32%, but was still a significant 9% lower with GLP-1 receptor agonists. Intensive lifestyle changes were associated with a nonsignificant reduction in heart failure risk.
The risk for MACE was also significantly lower with therapies or strategies that lower bodyweight than with standard care or placebo, at 12%, with the risk reduction ranging from 10% to 15% for each of the individual MACE components.
Udell and team also note that their findings were consistent among people with and without atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease at baseline.
And they conclude that the study shows “a potential broad cardiovascular benefit of using diabetes therapies that reduce bodyweight in routine clinical practice.”
In an accompanying comment, Angelo Avogaro and Gian Paolo Fadini, both from the University of Padova in Italy, say that although the analysis “establishes GLP-1 receptor agonists and SGLT2 inhibitors as disease-modifying drugs” in type 2 diabetes, “[t]rials with more focused endpoints would better guide clinicians in the choice of the best drug for each patient.”
This is because the efficacy on each MACE component varied between the trials, which “is an important shortcoming because, in the clinic, patients experience one event at a time, not a composite outcome,” they write.
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Lancet Diabetes Endocrinol 2020; 8: 418–435
Lancet Diabetes Endocrinol 2020; 8: 353–355