Insulin resistance is associated with increased cholesterol synthesis, decreased cholesterol absorption and enhanced lipid response to statin therapy

Objective: Increasing insulin resistance is associated with a shift in cholesterol metabolism to increased synthesis and decreased absorption. Since statins inhibit cholesterol synthesis, we hypothesized that insulin-resistant patients will have greater LDL cholesterol (LDL-C) response to statins than insulin-sensitive patients.

Methods: High-risk vascular patients not on lipid-lowering therapy were recruited and treated with Atorvastatin 80 mg for 6 weeks. Percent LDL-C response to Atorvastatin was related to insulin sensitivity using the quantitative insulin sensitivity check index (QUICKI). Comparisons: (1) correlation between %LDL-C response and QUICKI. (2) Differences in cholesterol metabolism markers in insulin-resistant (lowest tertile QUICKI) vs insulin-sensitive patients (highest tertile of QUICKI). (3) Correlation of QUICKI with percent LDL-C response after correction for cholesterol metabolism markers.

Results: 154 patients were enrolled of which 66 were suitable for this sub-study. Average LDL-C reduction was 57+/-12% (mean+/-SD). QUICKI correlated negatively with percent LDL-C reduction (Pearson's r=-0.258, p=0.037) and on regression analysis explained approximately 7% (R2=0.067) of the variation in percent LDL-C response which approximates that reported by pharmacogenomics. Insulin-resistant patients had higher levels of cholesterol synthesis markers (desmosterol, lathosterol) and lower levels of absorption markers (cholestanol, sitosterol) and the correlation between QUICKI and percent LDL-C response ceased to be significant when these factors were controlled for.

Conclusions: Insulin-resistant patients have superior LDL-C responses to statin therapy and that this may be related to increased cholesterol synthesis.

Background: Patients with features of the metabolic syndrome, e.g. high triglycerides (TG) and low high density lipoprotein cholesterol (HDL-C) may have an enhanced benefit from statin therapy. A retrospective analysis from the 4S investigators where the study population was stratified by HDL-C and TG quartiles revealed variations in statin efficacy. Patients who fell into both the lowest quartile of HDL-C (<39 mg/dl) and highest quartile of TG (>159 mg/dl) had a greater frequency of features of the metabolic syndrome (high BMI, hypertension, diabetes) than the patients in the highest quartile of HDL-C (>52 mg/dl) and lowest quartile of TG (<98 mg/dl). The 4S investigators suggested that patients with low HDL-C and high TG achieved an enhanced clinical benefit from statins compared to patients with high HDL-C and low TG with hazard ratios of 0.48 and 0.86 respectively and a treatment-by-subgroup interaction p value of 0.03 [1]. Since the clinical benefit of statin therapy is directly proportional to achieved percent reduction in low density lipoprotein cholesterol (LDL-C) [2], we hypothesized that insulin-resistant patients would have greater percent decreases in LDL-C with statin therapy.