A Target HbA1c Between 7 – 7.7% Reduces Macrovascular Events In ...

1. Introduction

In the recent past multiple cardiovascular outcome trials (CVOT) in type 2 diabetes (T2D) have demonstrated an improvement of macrovascular outcomes with the usage of molecules like glucagon-like peptide receptor agonist (GLP1-RA) and sodium glucose co-transporter 2 inhibitor (SGLT2i). All these studies have attempted “glycaemic equipoise” in order to display the positive effects of the molecules and dispel any uncertainty that the benefits may be due to an improvement in glycaemia, although a meta-regression analysis of 12 CVOTs documented an average HBA1c reduction of 0.86%.(1) Multiple studies of glycaemic efficacy have been unable to prove that a reduction of HbA1C is convincingly associated with a reduction in adverse macrovascular outcomes, though an increase in HbA1c is associated with worsening macrovascular outcomes. (2,3) The significantly higher HBA1c levels in the placebo arm of the CVOTs as well as the HBA1c differential achieved therefore poses a serious challenge to interpretation of the outcomes data. (4) In addition, results from the CONTROL meta-analysis suggest a statistically significant 9% reduction in MACE associated with a 0.9% difference in HBA1c between the intensive and conventional glycaemic control arms. (5)

To further complicate the issue, the standard of care in all the CVOTs had set a target HBA1c of less than 7% or as per local guidelines or as per individual requirements based on advanced disease and complication status. Though this is in keeping with the ADA and AACE guideline of 2020, it is in deep contrast with the ACP 2018 guideline which recommends a HbA1c between 7%-8% for most patients. (6,7,8) The patient population recruited in the CVOTs with established CVD or with high risk of CVD, mean duration of diabetes more than 10 years and mean age around 60 years, would necessitate the individualization of HbA1c strategy setting the target between 7-8% as per the strategy of individualization. (9)

Thus, though a large amount of the benefit seen in the CVOT may be attributed to the singular pharmacology of GLP1-RA and SGLT2i, the beneficial effect of glycaemic control cannot be discounted. This meta-analysis was therefore conducted on the glycaemic efficacy studies, including end of study HbA1c, duration of diabetes and its impact on the macrovascular endpoints in these studies in an attempt to finally provide the correct glycaemic target to reduce macrovascular outcomes, irrespective of the molecule in use.