Abstract 13615: High-Dose Simvastatin Induce Insulin Resistance During Acute Myocardial Infarction by Inhibiting Intracellular Insulin Signaling, Without Attenuating Its Clinical Benefit

Abstract

Background: Hyperglycemia during the acute phase of myocardial infarction (MI) is a strong marker of mortality, but statin use in this set can potentially induce dysglycemia. We aimed to identify whether statins also induce hyperglycemia during MI and the related mechanisms as well as to evaluate its clinical relevance. Methods: We prospectively studied 550 patients with ST-elevation MI treated without (WS) or with simvastatin (S) at 20, 40 or 80 mg/day. Of these, 27 non-diabetics were randomized to S10 or S80mg/day and performed euglycemic hyperinsulinemic clamp (EHC) associated with abdominal adipose tissue biopsy after 40 minutes of insulin infusion in the second (D2) and sixth (D6) days after MI. Measurements of plasma glucose, insulin, C-peptide on admission (D1) and fifth (D5) day were performed in all patients. Results: Between D2 and D6, insulin sensitivity index (ISi) measured by EHC increased (20±60%) in the S10 group and reduced (-6±28%) in S80 (p=0.025). Analysis of the biopsies by Western-blot showed a reduction in phosphorylation/activation of Akt and IRS-1 in patients treated with S80 compared to those treated with S10. Among the 550 patients, ISi was estimated by HOMA2S (plasma glucose and insulin) and varied in 40±145% (WS), 22±117% (S20), 16±61 % (S40) and -2%±88% (S80) between D1 and D5 (p=0.001). Insulin secretion at D1 estimated by HOMA2B (glucose and C-peptide) (p=0.001) and the dose of S (p=0.009) were the only independent markers of a fall in HOMA2S between D1 and D5. Among patients not treated with statins or taking 20mg/day (WS + S20), plasma glucose ≥140mg/dl at admission (stress hyperglycemia) increased by 2.25x (95% confidence interval [CI] 1.30-3.85, p=0.004) the risk of death or MI after mean 634±501 days; but not in those treated with S40 or S80 (p=0.727). Stress hyperglycemia also increased the incidence of death in 30 days after MI in the WS + S20 group (HR 3.15, 95%CI 1.41-7.01; p=0.003), but not in the S40 + S80 group (p=0.858) Conclusion: The use of high-dose simvastatin in MI reduces IS through the inhibition of intracellular insulin signaling pathways. IS impairment is dependent on the dose of statin and the reserve of insulin secretion. However, high-dose statins attenuate the short- and long-term clinical impact of hyperglycemia in MI.