Abstract
Increased cardiovascular mortality has been reported in trials of intensive glycaemic control in patients with type 2 diabetes. Evidence that hypoglycaemia predicts subsequent mortality in the weeks after a cardiovascular event is strong. Altered fibrin structure characteristics and subclinical inflammation have been implicated in the predisposition to cardiovascular events. We hypothesised that hypoglycaemia creates a thrombotic–inflammatory environment, contributing to increased mortality after the event.
Ten patients with type 2 diabetes were recruited (mean age 50 years [SD 8], duration of diabetes 9·5 years [4·6], and HbA1c 8·7% [2·1]). They all completed paired hyperinsulinaemic clamp studies separated by at least 4 weeks. Glucose was maintained at hypoglycaemia (2·5 mmol/L) or euglycaemia (6 mmol/L) for two 60 min periods. Four timepoints were analysed: baseline, end of clamp, and days 1 and 7 post clamp in both arms. Fibrin network properties and fibrinolysis of plasma samples were assessed with a dynamic turbidimetric assay. Plasma fibrinogen concentrations were measured with the Clauss assay, and high sensitivity CRP (hsCRP) was measured with an immunoturbidimetric assay. We also analysed heart rate variability as an indicator of vagal activity.
Clot maximum absorbance, a measure of clot density, increased after hypoglycaemic clamp reaching a peak at day 7, whereas a decrease occurred after euglycaemic clamp (mean change from baseline [Δ] 0·040 [SD 0·093] and −0·035 [0·080], respectively; p=0·01). Clot lysis time, an indicator of fibrinolysis potential, increased after hypoglycaemic clamp up to day 7 but decreased after euclycaemic clamp (mean Δ 64 s [SD 119] vs −51 [64], p=0·02). hsCRP increased on day 7 after hypoglycaemic clamp whereas there was a reduction after euglycaemic clamp (0·80 mg/dL [0·98] vs −0·89 [0·80], p<0·0001). Similarly, fibrinogen concentrations were higher at day 7 after hypoglycaemic clamp than after euglycaemic clamp (1·09 mg/mL [2·58] vs 0·17 [1·25], p=0·05). There were similar decreases in vagal tone as shown by high frequency heart rate variability after hypoglycaemic clamp in contrast with an increase in vagal tone after euglycaemic clamp (p=0·02)
Hypoglycaemia induces prothrombotic changes in the fibrin network and aggravates subclinical inflammation, with effects that are sustained for at least 1 week. The mechanism of these changes is unclear but might involve depression of the cholinergic anti-inflammatory pathway. Hypoglycaemia might mitigate the benefits of intensive glucose control by creating a thrombotic and inflammatory milieu. Our data provide a possible explanation for the observed increase in cardiovascular mortality weeks after a hypoglycaemic event.
National Institute of Health Research.