The Role of Hypoglycemia in Cardiovascular Outcomes in Diabetes

Abstract

Intensive glucose management, targeting lower glycated hemoglobin (A1C) levels, has been shown to reduce the microvascular complications of diabetes, but the effect on cardiovascular (CV) outcomes is less clear. Observational follow-up of intensive glucose management studies suggest possible long-term CV benefits, but no clear reduction in CV events has been seen over 3 to 5 years. Intensive glucose management also increases the risk for hypoglycemia, particularly in patients with longstanding diabetes, cognitive impairment and hypoglycemia unawareness. Severe hypoglycemia has been linked to adverse consequences, including cardiac dysrhythmias, CV events and death, but the precise role of hypoglycemia in CV outcomes is uncertain. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was terminated early because of a higher rate of CV events in the intensive arm. Post hoc analyses of ACCORD and other trials suggest that cardiac autonomic neuropathy may be a predisposing factor to CV events. The Analyses of the Action in Diabetes and Vascular Disease (ADVANCE) trial and the Veterans Affairs Diabetes Trial (VADT) showed that subjects with severe hypoglycemia had more frequent adverse outcomes. However, rather than causing adverse events, it appears that severe hypoglycemia may be a marker of vulnerability for such events. This review focuses on the current understanding of the association between hypoglycemia and CV risk.

Résumé

Il a été démontré que la prise en charge par un traitement intensif de la glycémie, qui cible des concentrations d'hémoglobine glyquée (A1c) plus faibles réduit les complications microvasculaires liées au diabète, mais l'effet sur les résultats cardiovasculaires (CV) s'avère moins évidente. Il est possible qu'il existe des avantages CV à long terme de la prise en charge par un traitement intensif de la glycémie, mais les études ne suggèrent aucune réduction évidente des événements CV sur une période de 3 à 5 ans. La prise en charge par un traitement intensif de la glycémie augmente également le risque d'hypoglycémie, particulièrement chez les patients ayant un diabète de longue date, des troubles cognitifs et une méconnaissance de l'hypoglycémie qui utilisent l'insuline. Une hypoglycémie grave a été associée à des conséquences défavorables, dont les dysrythmies cardiaques, les événements CV et la mort. Cependant, on ignore encore le rôle précis de l'hypoglycémie sur les résultats CV. L'essai ACCORD (Action to Control Cardiovascular Risk in Diabetes) a pris fin plus tôt en raison d'un taux plus élevé d'événements CV dans le volet de traitement intensif. Les analyses post-hoc de l'essai ACCORD et des autres essais suggèrent qu'il est possible que la neuropathie autonome cardiaque soit un facteur de prédisposition aux événements CV. Les analyses de l'essai ADVANCE (Action in Diabetes and Vascular Disease) et de l'essai VADT (Veterans Affairs Diabetes Trial) montraient que les sujets souffrant d'une hypoglycémie grave avaient une plus grande incidence de nombreux résultats indésirables. Cependant, il semble probable que l'hypoglycémie grave soit un marqueur de vulnérabilité plutôt que la cause d'événements indésirables. Cette revue porte sur la compréhension actuelle de l'association entre l'hypoglycémie et le risque CV.

Introduction

Cardiovascular (CV) disease, including myocardial infarction, unstable angina, heart failure, or stroke causes significant mortality and morbidity in patients with type 2 diabetes (1). Preventing CV events is among the primary goals of diabetes management. The benefits of improved glycemic control in microvascular complications, such as diabetic retinopathy and nephropathy, have been demonstrated in several large randomized studies 2, 3, 4. Intensive mutifactorial interventions, including targeting hyperglycemia, hypertension, dyslipidemia and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin, have been shown to reduce CV events in patients with type 2 diabetes (5). Long-term observational follow up of intensive glucose trials targeting lower glycated hemoglobin (A1C) levels, such as the United Kingdom Prospective Diabetes Study (UKPDS) and the Veterans Affairs Diabetes Trial (VADT), suggest a potential reduction in CV events 10 years after randomization, termed the legacy effect 6, 7. However, several clinical trials have demonstrated that intensive glucose management, in and of itself, does not improve CV outcomes over 3 to 5 years 4, 8, 9.

Because intensive glucose management is associated with an increased risk for hypoglycemia (low blood glucose), concerns surrounding the relationship between hypoglycemia and CV risk have emerged from the major glycemic trials, ACCORD, ADVANCE and VADT 4, 8, 9. In these trials, subjects who were randomized to intensive glucose management had higher incidences of hypoglycemia than those randomized to standard glucose control. In the ADVANCE and VADT studies, CV events were no different in intensively treated subjects than in those receiving standard treatment. In the ACCORD trial, the rate of CV mortality was greater in the intensive vs. the standard glycemic treatment groups. Post hoc analysis of the ACCORD data suggests that hypoglycemia was not the primary cause of increased CV mortality (10), but the relationship between hypoglycemia and the risk for CV events or death remains uncertain.