No, Severe Hypoglycemia is Rather an Indicator of a Frail Patient Phenotype at Risk of Cardiovascular Events

Eberhard Standl MD, PhD, FESC
Forschergruppe Diabetes eV at Munich Helmholtz Centre

Post hoc analyses of several large-scale, long-term randomized cardiovascular (CV) outcome trials evaluating glucose lowering drugs or strategies have identified an association between hypoglycemia and a subsequent increased risk of all-cause mortality or CV mortality in people with type 2 diabetes. This is particularly the case for patients experiencing severe hypoglycemic events (SHEs), with typically close to twice the risk of CV death in those who have experienced an SHE compared with those who have not. As a result, many diabetes management guidelines have been modified to advocate less aggressive glycemic targets to reduce the incidence of SHEs in the belief that this will minimize mortality risk, although less strict glycemic targets have not been shown to reduce the risk of SHEs. However, it remains unclear whether SHEs have a causal role in increasing CV mortality rates and whether more cautious glycemic targets, which may increase the risk of microvascular disease in the longer term, are warranted. Against this background, we conducted post hoc analysis of TECOS data and found not only there was an increased rate of SHEs preceding major CV events such as CV death and non-fatal myocardial infarction or stroke, but also, conversely, a very robust association between SHEs and previous non-fatal major CV events, with a near doubling in the risk of an SHE following a nonfatal CV or hospitalization for heart failure (hHF) event, even after full statistical adjustment. The bidirectional relationship between SHEs and CV outcomes suggests that there may be a common “frail” type 2 diabetes phenotype of patients who are susceptible to both of these events. Thus SHEs, rather than being causative of MACE, hHF, or all-cause death events, may simply be indicative of patients with a frail type 2 diabetes phenotype who are at high risk of both outcomes likely due to a multitude of coexisting risk factors. Thus, while it remains important to seek to minimize the risk of SHEs in people with type 2 diabetes, the focus on attaining good glycemic control to minimize the risk of diabetes complications should not be unduly compromised. A precision medicine approach is required to delineate those with a frail phenotype who need special consideration from those likely to benefit from more aggressive glycemic targets.