Prolonged Prothrombotic Effects of Antecedent Hypoglycemia in Individuals With Type 2 Diabetes

Abstract

Hypoglycemia has been linked to persistent increases in cardiovascular (CV) mortality in type 2 diabetes after the event. Our aim was to examine acute and downstream effects of hypoglycemia on markers of thrombosis risk and inflammation in type 2 diabetes. RESEARCH DESIGN AND METHODS Twelve individuals with type 2 diabetes with no history of CV disease and 11 age-and BMI-matched volunteers without diabetes underwent paired hyperinsulinemiceuglycemic (glucose 6 mmol/L for two 60-min periods) and hypoglycemic (glucose 2.5 mmol/L for two 60-min periods) clamps on separate occasions on day 0. Fibrin clot properties, platelet reactivity, and inflammatory markers were measured at baseline, end of and after recovery from the initial clamp, day 1, and day 7 using validated assays and electron microscopy. RESULTS Euglycemic hyperinsulinemia reduced platelet reactivity, decreased fibrin clot density, and improved fibrinolytic efficiency in both groups. Platelet reactivity and aggregation increased during acute hypoglycemia in both groups, resolving at recovery. In type 2 diabetes, clot lysis times and clot maximum absorbance increased up to day 7 (P = 0.002 and 0.001 vs. euglycemia, respectively), but clots from control subjects without diabetes showed limited changes. Fibrin network density increased D 1.15 6 0.28 fibers/mm 2 at day 7 after the hypoglycemic clamp (P < 0.01 for glycemic arm), whereas fibrinogen and complement C3 increased after hypoglycemia up to day 7 in type 2 diabetes only. CONCLUSIONS Antecedent hypoglycemia has acute and persistent prothrombotic effects, lasting at least 7 days, that were enhanced in individuals with type 2 diabetes. These findings identify mechanisms by which hypoglycemia might increase short-and medium-term risk of CV mortality. Cardiovascular (CV) disease is the leading cause of death in type 2 diabetes. A number of large clinical trials have attempted to address the role of intensive glucose control on vascular events and have shown either no reduction (1,2) or an increase in mortality (3). Hypoglycemia is associated with increased CV mortality (2,4), but evidence establishing cause and effect is lacking. In interventional trials, the increased mortality associated with hypoglycemia extended well beyond the acute event, with elevated risk months later (2). Mechanisms by which hypoglycemia might lead to increased CV mortality in the short to medium term are unclear.

Hypoglycaemia leads to a delayed increase in platelet and coagulation activation markers in people with type 2 diabetes treated with metformin only: Results from a stepwise hypoglycaemic clamp study

“…Our data support and extend the study findings by Chow et al demonstrating increased platelet reactivity after hypoglycaemia. However, the present study used different measurements to assess platelet reactivity.…”

“…Our finding again corresponds with the results reported by Chow et al showing delayed clot lysis after hypoglycaemia. Interestingly, we observed a drop in PAI‐1 in all clamps shortly after the initiation of the insulin infusion, a finding that was reported previously, suggesting a direct insulin mediated PAI‐1‐lowering effect …”

“…Interestingly, in the preset study, the increase in platelet reactivity was mainly observed the day after the hypoglycaemic clamp and was sustained over the next 6 days. While Chow et al included people who were on various glucose‐lowering agents including insulin, with two of them also taking aspirin, our study participants had a short duration of diabetes and were all on metformin only and none was taking any antiplatelet agents.…”

The effect of hypoglycaemia during hospital admission on health‐related outcomes for people with diabetes: a systematic review and meta‐analysis

“…Catecholamine release in response to hypoglycaemia is less well tolerated by older patients and those with cardiac morbidities. In addition, hypoglycaemia increases both platelet aggregation and prothrombotic factors, which could also contribute to increased harm . Although the association may not be causal, this review suggests it could be a marker for ill health or worse outcomes.…”

Glucose monitoring in diabetes: from clinical studies to real‐world practice

“…The drive for tighter glycaemic control has led to an increased prevalence of hypoglycaemia, which has shown an association with increased mortality . A number of mechanisms have been implicated including: cardiac dysrhythmias; increased production of vascular inflammatory molecules; and enhanced thrombotic environment (summarised in Figure ). Additionally, the problem with hypoglycaemia may have a greater prevalence than previously recognised, as SMBG fails to capture all episodes of low glucose levels due to individuals ‘treating’ these events without testing, or hypoglycaemia may simply go unnoticed in those with impaired awareness .…”