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.