Downstream thrombotic and inflammatory effects of increased glucose assessed as potential link to cardiovascular mortality.
The leading cause of death in patients with type 2 diabetes is cardiovascular disease. Many studies have sought to reduce the risk of cardiovascular disease in patients with type 2 diabetes via intensive glycemic management; however, the results of these trials indicate no change in risk or, on occasion, increased risk. These seemingly paradoxical findings are the result of increased incidence of hypoglycemia with intensive glycemic management, as hypoglycemia has been linked to increased cardiovascular risk. The mechanism by which this increased risk occurs is thought to deal with the prothrombotic effect that has been correlated with hypoglycemia in people with type 1 diabetes. Prior to this study, no trials had been conducted to determine if a similar response occurs in patients with type 2 diabetes. Consequently, the aim of this study is to assess the effects of hypoglycemia on inflammatory and thrombosis markers.
In order to determine the downstream thrombotic and inflammatory effects of hypoglycemia in people with type 2, a controlled crossover experimental trial was selected as the study design. Participants included BMI= and age-matched people with and without type 2 diabetes. Exclusion criteria included: any evidence of cardiovascular disease, pregnancy, epilepsy, untreated hyperthyroidism, and any other concurrent serious illness.
All participants underwent both a hypoglycemic and a hyperinsulinemic-euglycemic clamp (a study technique that allows the researcher to maintain a constant glycemic level in the participant), of which the serum glucose target was 2.5 and 6 mmol/L respectively. The participants received two 60-minute sessions of their assigned clamp (morning and evening). Four to eight weeks were allowed to pass before the other variety of clamp was administered in order to prevent any crossover effects of the previously administered clamp. Inflammatory markers, platelet reactivity, and fibrin clot properties were assessed at baseline, upon completion of the clamp, and 30 minutes, 1 day, and 7 days post procedure. Statistical significance was determined by two-way ANOVA (for comparison of euglycemic vs hypoglycemic clamp data), two-way repeated measures ANCOVA (for analysis of fibrin clot properties), and linear mixed model (for change in biomarker concentration over time).
In all, 12 patients with type 2 diabetes and 11 age- and BMI-matched patients without diabetes were included in the study to achieve a reported > 81% power for determining a 15% difference in clot lysis time. The results indicate that both the participants with and without diabetes demonstrated a decreased thrombotic activity (decreased fibrin clot density, reduced platelet reactivity, and improved fibrinolytic efficiency) after the euglycemic clamp.
Conversely, both groups demonstrated increased platelet activity (increased platelet reactivity and aggregation) during the hypoglycemic clamp but resolved shortly after. In the patients with type 2 diabetes only, analysis of post hypoglycemic clamp data revealed significantly elevated levels of fibrinogen and complement factor C3, as well as increased fibrin density and clot lysis times at the 7-day post procedure mark when compared to baseline. The data from the participants without diabetes indicated no prolonged thrombotic or inflammatory effects when compared to baseline.
The results of this study indicate that patients both with and without type 2 diabetes have increased thrombotic activity during hypoglycemia. While patients without diabetes return to baseline shortly after the hypoglycemic event, patients with type 2 diabetes exhibit prolonged prothrombotic changes after experiencing hypoglycemia. These findings provide a potential mechanism by which hypoglycemia increases the risk of developing cardiovascular complications, and why people with type 2 are at increased risk when compared to people without diabetes.
- Hypoglycemia is associated with increased risk of developing cardiovascular complications.
- The mechanism by which hypoglycemia increases cardiovascular risk may be the stimulation of increased thrombotic activity.
- While more research is required to validate the findings of this study, this study further illustrates the dangers of hypoglycemia and the care that must be taken to prevent hypoglycemia in patients with type 2 diabetes.
Chow, Elaine, et al. “Prolonged Prothrombotic Effects of Antecedent Hypoglycemia in Individuals With Type 2 Diabetes.” Diabetes Care, 2018, p. dc180050., doi:10.2337/dc18-0050.
Trovati M, Anfossi G, Cavalot F, et al. “Studies on mechanisms involved in hypoglycemia induced platelet activation.” Diabetes, vol. 35, 1986, pp. 818–825
Michael Zaccaro, Pharm. D. Candidate 2019, LECOM School of Pharmacy