Lowering of Hemoglobin A1C and Risk of Cardiovascular Outcomes
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This study examined the association between the magnitude of reduction in HbA1c in type 2 diabetes (T2D) patients and cardiovascular outcomes for sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1(GLP1) agonists, and dipeptidyl peptidase-4 (DPP4) inhibitors. Within individual medication classes, each additional 0.5% reduction in HbA1c in the active drug arm, relative to placebo, was associated with a lower incidence of cardiovascular events for GLP1 agonists but not for SGLT2 inhibitors or DPP4 inhibitors.
- The results of this study further support the idea that reducing cardiovascular risk in T2D is partly explained by a reduction in HbA1c, although this was seen with only one class of antidiabetic medication in this study.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBackground
The management of type 2 diabetes predominantly focuses on reducing hemoglobin A1C (HbA1c). We examined the association between the magnitude of reduction in HbA1c and cardiovascular outcomes for new diabetes medications: sodium-glucose cotransporter-2 [SGLT2] inhibitors, glucagon-like peptide-1 [GLP1] agonists, and dipeptidyl peptidase-4 [DPP4] inhibitors.
Methods
We reviewed all published, placebo-controlled, randomized cardiovascular outcome trials. Meta-regression was performed to evaluate the association between HbA1c reduction (i.e., [post-intervention HbA1c for active drug – pre-intervention HbA1c for active drug] – [post-intervention HbA1c for placebo – pre-intervention HbA1c for placebo]) and the composite cardiovascular outcome (i.e., stroke, myocardial infarction, or cardiovascular death).
Results
We identified 14 cardiovascular outcome clinical trials, the median sample size was 9401, the median age was 64 years, the median time since diagnosis of diabetes was 12 years, and the median duration of trial follow-up was 120 weeks. Within individual medication classes, each additional 0.5% reduction in HbA1c in the active drug arm, relative to placebo, was associated with a lower incidence of cardiovascular events for GLP1 agonists (0.82, 0.68-0.98) but not for SGLT2 (0.97, 0.69-1.36) or DPP4 (1.03, 0.39-2.74) inhibitors.
Discussion
Our study provides further support that reducing the risk of cardiovascular events for adults with diabetes is partly explained by a reduction in HbA1c.
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Additional Info
Disclosure statements are available on the authors' profiles:
Lowering of Hemoglobin A1C and Risk of Cardiovascular Outcomes and All-Cause Mortality, A Meta-Regression Analysis
J Diabetes Complicat 2020 Jul 31;[EPub Ahead of Print], M Fralick, M Colacci, A Odutayo, R Siemieniuk, RJ GlynneFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The controversy as to whether glucose-lowering medications reduce the elevated cardiovascular (CV) risk seen in people with type 2 diabetes appeared to have been settled by the landmark United Kingdom Prospective Diabetes Study (UKPDS) published in 1998. This trial showed that tight glycemic control from diagnosis significantly reduced the risk of diabetes-specific, microvascular complications but had a lesser impact on large-vessel disease, such as myocardial infarction and stroke.
Then, in 2007, a meta-analysis suggested that a thiazolidinedione glucose-lowering therapy actually increased CV risk. This led the FDA to mandate that novel antidiabetes drugs demonstrate CV safety and heralded an era of diabetes CV outcomes trials (CVOTs). Cue the EMPA-REG OUTCOME trial in 2015, which to general surprise showed CV superiority for a sodium-glucose transporter 2 inhibitor over placebo; this was followed by positive CVOTs for three glucagon-like peptide receptor agonists (GLP-1RAs). The presumption was that the CV benefit from these medicines was due to pleiotropic effects on pathologies such as heart failure and atherosclerosis.
The publication by Fralick et al in this journal brings us full circle. The authors’ meta-regression analysis suggests that, for newer classes of glucose-lowering drugs at least, reduction in CV events is partly explained by reduction in HbA1c. Furthermore, this effect was most pronounced for the GLP-1RAs, which have generally had the largest reductions in HbA1c versus placebo in CVOTs. The relationship between glucose-lowering and CV events has yet to be fully explained—expect more twists and turns.