Antidiabetic drugs and hypoglycaemia risk in patients with atrial fibrillation treated with non-vitamin K antagonist oral anticoagulants

In the landmark action to control cardiovascular risk in diabetes (ACCORD) study, it became evident that the diabetes treatment has to be individualized in respect to glycemic control.¹ In ACCORD, the use of intensive blood glucose lowering therapy to reach near normal blood glucose values increased mortality and showed that this approach is harmful for patients with type 2 diabetes who are at high cardiovascular (CV) risk. Since then, a ‘gluco-centric’ approach per se has been criticized, and it is no more advised to treat diabetes intensively in every person with diabetes, hence avoiding the rule the lower glycemic value the better for everyone.

Hypoglycaemia itself, previously thought to be only an unpleasant adverse event of diabetes treatment, nowadays is a recognized risk factor for micro- and macro-vascular complications especially when it is related to glycaemia variability.² Hence, there is much effort put on avoidance of hypoglycaemia risk when choosing antihyperglycemic treatment of diabetes, especially in patients with high CV risk.³ Unfortunately, the issue of avoiding hypoglycaemia is not simple and may be complicated by concomitant drugs, which may interfere with antidiabetic drugs (i.e. glucose-lowering drugs) and augments the risk of hypoglycaemia. Hence, it is especially important to look at drugs used to treat concomitant diseases in patients with diabetes as their concomitant administration may be associated with drug–drug interactions and potentially higher hypoglycaemia risk.

Diabetes affects 1 out of every 10 adults aged 20–79 and the commonest heart rhythm disorder, atrial fibrillation (AF), has at least two-fold higher prevalence in these patients.⁴ Both diabetes and AF share several risk factors and diabetes itself is an independent risk factor for AF occurrence and AF-related complications.⁴

One of the most threating complication of patients with AF are stroke and systemic embolism and avoiding stroke with oral anticoagulation (OAC) is one of the pillars of AF management, as well as patient-centered symptom directed, decisions on rate or rhythm control, and comorbidity and lifestyle factor management. Such a holistic or integrated care approach has been advocated in international guidelines,^5,6 given its associations with better clinical outcomes.⁷

OAC for stroke prevention in AF has traditionally been the vitamin K antagonists (VKAs, e.g. warfarin) but in latter years, the non-vitamin K antagonist oral anticoagulants (NOACs, i.e. apixaban, dabigatran, edoxaban, and rivaroxaban) are the preferred option.⁶ In patients with diabetes, the safety and efficacy of NOACs for stroke prevention^8,9 as well as lower risks of vascular mortality^10,11 and diabetes complications as compared with warfarin have been confirmed.¹¹

However, the evidence related to hypoglycaemia risk associated with the concomitant treatment with OACs and antidiabetic drugs is limited. To date, there are only two observational studies published, which assessed the risk of hypoglycaemia in patients with diabetes and AF treated with warfarin but not NOACs, which reported higher risks of hypoglycaemia events in patients treated with sulfonylureas.^12,13

The first study, which assessed the influence of NOACs on hypoglycaemia risk by Huang et al. suggested that NOACs use may lead to a lowered severe hypoglycaemia risk than warfarin in the on-treatment analysis.¹¹ However, different classes of antidiabetic or glucose-lowering drugs possess various hypoglycaemia risks.

In this issue of the journal, Huang et al. assessed different classes of antidiabetic drugs, looking at the risks of severe hypoglycaemia associated with concurrent use of NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) or warfarin in 30 219 patients with diabetes and AF.¹⁴ They found that there was a significantly lower risk of severe hypoglycaemia in patients treated with antidiabetic drugs and concurrent NOACs comparing to warfarin. The significantly lower severe hypoglycaemia risk associated with NOACs use was observed in patients treated with metformin, dipeptyl peptidase-4 inhibitors, or sulfonylurea, but not other antidiabetic drugs.

However, several limitations must be highlighted, among others the lack of data related to patients’ lifestyle, laboratory measurements, medical compliance, clinical complexity as well as small sample size of patients treated with new antidiabetic drugs such as sodium-glucose cotransporter 2 inhibitors (SGLT2 i) and glucagon-like peptide 1 receptor agonist (GLP-1 RA).

Moreover, it is important to stress that the outcomes show an associations, not causality, mainly due to observational nature of the study, and the outcomes could not be necessarily generalized to other populations than that studied. Residual confounding also has to be taken into account when analyzing the observed difference in severe hypoglycaemia risk because these could attenuate the effect and an increased risk could be a result of bias.

Even though the precise mechanistic pathways linking severe hypoglycaemia risk and concomitant use of NOACs and antidiabetic drugs in this very vulnerable group of patients with diabetes and AF are speculative, the study by Huang et al. does suggest that the risk of severe hypoglycaemia may be lower with NOACs comparing to warfarin. Indeed, there is some biological plausibility for drug–drug interactions between warfarin and antidiabetic drugs, especially those metabolized throughout cytochrome P450 2C9 hepatic pathway like sulphonylureas.¹⁴ On the other hand, the NOACs (unlike warfarin) do not block the activity of vitamin K—dependent proteins necessary for B cell insulin secretion, which is suggested to provide better glycemic control than warfarin.¹⁵ This is important as poor diabetes control increases the need for intensive diabetes treatment and potentially greater hypoglycaemia risk especially in the high cardiovascular risk patients.¹

What are the clinical implications? Severe hypoglycaemia risk reduction is important for patients with diabetes such that those who are to be treated with both antidiabetic drugs and anticoagulant medications may need to be offered an OAC drug class with better safety in relation to severe hypoglycaemia risk. Also, further studies including new antihyperglycemic drugs such as SGLT-2 i and GLP-1 RA are clearly needed to give us a more complete picture.

Conflict of interest: G. Y. H. L.—consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Anthos. No fees are received personally. G.Y.H.L. is co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 899 871.

K. N.—in the past 36 months, I received remunerations/fees for activities on behalf of Sanofi-Aventis, Eli Lilly, Novo Nordisk, Astra Zeneca, Boehringer Ingelheim, and

Hanna Kwiendacz—in the past 36 months, I received remunerations/fees for activities on behalf of Sanofi-Aventis, Eli Lilly, and Novo Nordisk.

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