Severe hypoglycaemia predicts CV outcomes, non-severe episodes do not

ORIGIN Trial Investigators
Eur Heart J. 2013 Oct;34(40):3137-44. doi: 10.1093/eurheartj/eht332

Background

Glucose-lowering therapy may induce hypoglycaemia. In addition to its acute clinical effects, evidence suggests that hypoglycaemia may also directly or indirectly induce abnormal myocardial repolarisation, QT-prolongation, ventricular arrhythmias, and myorcardial ischaemia [1-3]. These effects may cause cardiovascular (CV) events, as is supported by epidemiological studies [4,5]. It is, however, unclear whether this is related to hypoglycaemia itself, or to factors linked to the propensity for hypoglycaemia.
The Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) trial of insulin-mediated normoglycaemia vs. standard care with oral glucose-lowering agents in people with early type 2 diabetes and dysglycaemia at high risk for cardiovascular outcomes prospectively measured both non-severe and severe episodes of hypoglycaemia [6]. The trial data provide an opportunity to assess the relationship between hypoglycaemia and CV events in this population.

Main results

• 3518 out of 12537 participants had at least one episode of hypoglycaemia, during the median follow-up of 6.2 years, of which 2614 (74.3%) were in the glargine group.
• People with 1, 2, 3, 4, 5 or more non-severe hypoglycaemic episodes showed a lower crude incidence and a lower hazard of outcomes than people who did not have episodes, after adjustment for propensity score.
• People with 1, 2, 3, 4, 5 or more severe hypoglycaemic episodes showed a higher crude incidence of outcomes than people without severe hypoglycaemic episodes, but after adjustment for propensity scores, no increased hazards were observed.
• When all severe hypoglycaemic episodes were included in a model as a time-varying covariate (which takes into account the numbers of episodes and the moment of the episode relative to the outcome), severe hypoglycaemia increased the risk of all four outcomes by over 50%, even after adjusting for the severe hypoglycaemia propensity score. Outcomes were a primary composite of CV death, nonfatal MI and stroke,  mortality, CV mortality or arrhythmic death.
• Fewer outcomes were seen in people with hypoglycaemic episodes than without hypoglycaemia in the glargine group. In the standard care group, outcome incidence was lower for non-severe hypoglycaemia but higher for severe and severe nocturnal hypoglycaemia.
  Thus, more people in the glargine group had severe hypoglycaemia, but people with these episodes experienced fewer outcomes than people with severe hypoglycaemic episodes in the standard care group. Indeed, treatment allocation  influenced the relationship between severe hypoglycaemia and clinical outcome. No interaction was seen for treatment for the relation between non-severe hypoglycaemic episodes and clinical outcome.

Conclusion

In people with cardiovascular risk factors and early type 2 diabetes or dysglycaemia, severe hypoglycaemia and nocturnal severe hypoglycaemia independently predict cardiovascular events and mortality. Participants allocated to insulin glargine experienced a higher incidence of both severe and non-severe hypoglycaemia. Nevertheless, the relationship between severe hypoglycaemia and clinical outcomes was substantially stronger in individuals receiving standard glycaemic control vs. those who received insulin glargine. Thus, achieving normoglycaemia with insulin glargine had a neutral effect on clinical CV outcomes despite a higher number of hypoglycaemic episodes.

References

1. Desouza C, Salazar H, Cheong B, et al. Association of hypoglycemia and cardiac ischemia: a study based on continuous monitoring. Diabetes Care 2003; 26:1485–1489.
2. Heller SR. Cardiac arrhythmias in hypoglycaemia. Diabetes Nutr Metab 2002;15: 461–465.
3. Frier BM, Schernthaner G, Heller SR. Hypoglycemia and cardiovascular risks. Diabetes Care 2011;34:S132–S137.
4. Yakubovich N, Gerstein HC. Serious cardiovascular outcomes in diabetes: the role of hypoglycemia. Circulation 2011;123:342–348.
5. Zoungas S, Patel A, Chalmers J, de et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010; 363:1410–1418.
6. Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012;367:319–328.

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