This study demonstrates that empagliflozin reduced long-term HbA1c variability in the EMPA-REG OUTCOME trial, and furthermore that high HbA1c variability early (i.e. within first year of treatment) and during the trial is associated with increased risk of cardiovascular death. Empagliflozin reduces the risk of cardiovascular death, but this effect does not seem to be mediated by the reduction in HbA1c variability.
The association between HbA1c variability and cardiovascular outcomes
Mounting evidence demonstrates that glucose variability is associated with cardiovascular complications, particularly cardiovascular death (2-6), not only in diabetes but also in people without diabetes (12-14), and our study adds to this body of evidence. Interestingly, a small study in patients with type 2 diabetes undergoing percutaneous coronary intervention found that while HbA1c identified patients at higher thrombotic risk, the highest diagnostic accuracy for high platelet reactivity seemed to be achieved by combining glucose variability and HbA1c (15). Our analyses, adjusting for baseline HbA1c levels, support that using a combination of HbA1c and HbA1c variability may improve the risk assessment of patient with type 2 diabetes.
Moreover, our sensitivity analyses assessing HbA1c variability as a time-dependent co-variate and assessing the association of fasting blood glucose variability to cardiovascular death showed results in line with our main analyses, supporting our conclusions.
SGLT2 inhibitors’ impact on glucose variability
At the same time, SGLT-2 inhibitors, including empagliflozin, reduce glucose variability in both type 2 and type 1 diabetes (16-18). In our study, we found that empagliflozin significantly reduced HbA1c variability as compared to placebo, but this reduction did not seem to be a mediator of the reduction in cardiovascular death with empagliflozin. Published analyses demonstrate that the reduction in cardiovascular death with empagliflozin is independent of glucose control at baseline and during the trial (10), indicating that the reduction was not driven by control of glucose. In line with this, a mediation analysis found changes in markers of plasma volume (haematocrit) to be the strongest mediator of cardiovascular death reductions whereas measures of glycaemia seemed to have only modest mediating effects (19). Moreover, although the blood glucose lowering effect of empagliflozin diminishes with declining eGFR, (20) the cardiopreotective effects are consistent down to eGFR 30 ml/min/ 1.73 m2 (21).
On the other hand, intriguingly, it has been reported that in diabetic rats the reduction of glucose variability with dapagliflozin is associated with a reduction of early atherosclerosis of the vessel walls (22). The impact of glucose variability on diabetic complications has been linked to an increase of oxidative stress generation (23), produced by an increase of free radicals accompanied by an inadequate antioxidant response of the cells (24, 25). In diabetes, oxidative stress plays a key role in favouring the appearance of cardiovascular complications (26). In patients with type 2 diabetes, dapagliflozin reduced glucose variability as well as oxidative stress (27), while it has been reported in an animal model of diabetes that empagliflozin can reduce oxidative stress generation (28). Therefore, although not detected in our analyses, we believe that the role of reducing HbA1c variability in the beneficial effects of empagliflozin on cardiovascular death remains to be fully elucidated.
Glucose variability’s role in clinical practice
Our findings of an association between HbA1c variability and cardiovascular death in the EMPA-REG OUTCOME trial also supports the possible role for glucose variability in the complications of diabetes (2). The analyses exploring the association of quintiles of HbA1c variability and cardiovascular death suggested that the assumption of a continuous effect of increases in HbA1c variability (the higher the HbA1c variability, the higher the risk for cardiovascular death) underlying the previous analyses might not hold true, but rather indicate that there could be thresholds of HbA1c variability after which the risk of cardiovascular death increases (Supplemental figure S2). This also suggests that the overall effect as seen in these analyses might in part be driven by patients with a rather high HbA1c variability (fifth and forth quintile).
This is important since glucose variability is emerging as a new challenge in the management of diabetes and is quickly moving from being just a scientific topic to clinical practice (29). The increased availability of new type 2 diabetes treatments that impact glucose variability, and the increased availability of new tools to measure glucose variability, certainly favour the clinician to address this new aspect of diabetes management. Empagliflozin is on the list of drugs which potentially can reduce glucose variability, at the same time improving prognosis by reducing the risk of cardiovascular death as well as heart failure and renal outcomes (30, 31).
Our analyses have some limitations. These were post-hoc analyses from the EMPA-REG OUTCOME trial that was designed to explore the long-term cardiovascular safety and effects of empagliflozin. Thus, there were no daily measurements of glucose, and HbA1c was measured relatively infrequently (Supplemental Table S1). Moreover, HbA1c as a marker of glycaemic control has several limitations and new parameters such as time in range are emerging. Continuous blood glucose monitoring was not done in EMPA-REG OUTCOME and time in range therefore not captured. The study was powered to assess the effects of empagliflozin on the primary endpoint 3-point – major adverse cardiovascular events and was not powered to explore the effects on cardiovascular death alone. The strengths of our analyses are the long observation time with a high number of, and adjudication of, cardiovascular deaths. Furthermore, our analyses of three different definitions of HbA1c variability as well as fasting blood glucose variability confirms the robustness of our results.