medwireNews: An umbrella review of meta-analyses has demonstrated mixed associations between different glucose-lowering agents and cardiovascular (CV) outcomes in people with type 2 diabetes, with the results favoring sodium-glucose cotransporter (SGLT)2 inhibitors and glucagon-like peptide (GLP)-1 receptor agonists as cardioprotective agents.
Junyan Wu (Sun Yat-sen University, Guangzhou, China) and team analyzed data from 36 published systematic reviews and 31 CV outcomes trials, comprising a total of 232 meta-analyses providing unique estimates of CV risks associated with diabetes drugs from 10 different classes. Comparator treatments included placebo, other glucose-lowering medications, or lifestyle interventions.
They report in The Lancet Diabetes & Endocrinology that SGLT2 inhibitors as a class were associated with a significant 13% lower risk for the composite outcome of major adverse cardiovascular events (MACE) relative to comparator treatments, as well as a significant reduction in the risk for the individual endpoints of death from CV disease, myocardial infarction, and heart failure.
When the SGLT2 inhibitors were analyzed separately, canagliflozin and empagliflozin significantly reduced MACE risk, but dapagliflozin did not, which the researchers say “might be related to differences in baseline cardiovascular disease risk among populations.”
Similar to the SGLT2 inhibitors, GLP-1 receptor agonists reduced the risk for MACE by a significant 12%, and patients treated with this class also had a significantly decreased risk for the individual eventpoints. CV benefits were also seen when albiglutide, dulaglutide, exenatide, liraglutide, and semaglutide were assessed separately.
Discussing these results in an accompanying comment, Srikanth Bellary (Aston University, Birmingham, UK) and colleagues say that “the argument favouring the use of SGLT2 inhibitors and GLP-1 receptor agonists earlier in the disease pathway, specifically in individuals at high cardiovascular risk, is increasingly persuasive.”
On the other hand, dipeptidyl peptidase (DPP)-4 inhibitors did not significantly reduce the risk for MACE, CV death, myocardial infarction, stroke, heart failure, or unstable angina. There was also no significant association between the individual DPP-4 inhibitors and CV outcomes, with the exception of saxagliptin, which increased heart failure risk by 22%.
Therefore, Wu and co-researchers say that “in patients with or at risk of heart failure, the appropriate choice as an alternative to a DPP-4 inhibitor, based on our results, should now be a SGLT2 inhibitor or GLP-1 receptor agonist.”
The team found mostly neutral results with sulfonylureas, acarbose and voglibose, nateglinide, bromocriptine, insulin, and metformin, although metformin was associated with numerically lower rates of MACE than comparator treatments.
Despite the lack of significant cardioprotective effects, “[m]etformin is cheap, widely available, safe, and appears to be more likely to reduce the risk of cardiovascular disease than to increase it, so its use as a first-line drug in patients with type 2 diabetes with a low cardiovascular disease risk appears to be justified,” comment the researchers.
The commentators agree, noting that “[p]erhaps the time has not yet come for us to lose metformin as the preferred first-line agent,” but they highlight that “the continued use of sulfonylureas as a second-line treatment is clearly questionable, especially in people with established cardiovascular disease.”
Wu and colleagues identified “substantial differences in cardiovascular safety” between the two currently available agents in the thiazolidinedione class, with rosiglitazone conferring a significant 28% increased risk for myocardial infarction and 72% increased risk for heart failure, while pioglitazone was associated with a 16% reduction in MACE risk and a 20% reduction in myocardial infarction risk, but increased the risk for heart failure by 40%.
The researchers say that the results of their umbrella review “could inform clinical guidelines and therapeutic choices,” but they note that “most populations studied were at high risk of developing cardiovascular disease,” highlighting the need for additional studies to determine “whether these results are translatable to low-risk populations.”
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Lancet Diabetes Endocrinol 2020; doi:10.1016/S2213-8587(19)30422-X
Lancet Diabetes Endocrinol 2020; doi:10.1016/S2213-8587(20)30020-6