8.2. APOE-related blood lipid response to Sardilipin (E-SAR-94010)
Basal cholesterol levels were significantly different in patients with the APOE-2/3 genotype vs. APOE-3/3 (p < 0.007), vs. APOE-3/4 (p < 0.001), vs. APOE-4/4 (p < 0.00002); APOE-2/4 vs. APOE-4/4 (p < 0.01); APOE-3/3 vs. APOE-4/4 (p < 0.005); and APOE-3/4 vs. APOE-4/4 (p < 0.01). 
The highest cholesterol levels were seen in APOE-4/4 > APOE-3/4 > APOE-3/3. All patients showed a clear reduction in cholesterol levels after treatment with Sardilipin. This was particularly significant in APOE-3/3 (p < 0.0000000001) > APOE-3/4 (p < 0.00000008) > APOE-4/4 (p < 0.002) > APOE-2/3 (p < 0.02) > APOE-2/4 carriers (p: 0.26) (Figure 1). The response rate by genotype was as follows: APOE-2/3: 63.93% RRs, 29.51% NRs, 6.56% SRs; APOE-2/4: 44.44% RRs, 22.22% NRs, 33.34% SRs; APOE-3/3: 54.32% RRs, 28.16% NRs, 17.52% SRs; APOE-3/4: 53.59% RRs, 31.58% NRs, 14.83% SRs; APOE-4/4: 65.71% RRs, 20.00% NRs, 14.29% SRs. 
HDL-cholesterol levels significantly decreased in APOE-3/3 (p < 0.001) > APOE-3/4 (p < 0.05), with no significant changes in patients with other genotypes. In contrast, LDL-cholesterol levels showed identical changes to those observed in total cholesterol, with similar differences among genotypes at baseline and almost identical decreased levels after treatment (APOE-3/3, p > 0.0000000001; > APOE-3/4, p < 0.00001; > APOE-2/3, p < 0.0004; > APOE-4/4, p < 0.001; > APOE-2/4, p:0.31).
Paradoxically, triglyceride levels tended to increase in all APOE genotypes (APOE-3/3, p < 0.01; > APOE-4/4, p < 0.03; > APOE-2/3, p:0.12; > APOE-3/4, p:0.17), except in APOE-2/4 carriers, who showed a tendency to decrease. Basal triglyceride levels were significantly lower in APOE-4/4 carriers than in APOE-2/3 (p < 0.03) and APOE-3/4 carriers (p < 0.04).
Sardilipin (E-SAR-94010, LipoEsar®, LipoSea®) is a natural product extracted from the marine species Sardina pilchardus, by means of non-denaturing biotechnological procedures [193]. The main chemical compounds of LipoEsar® are lipoproteins (60–80%) whose micelle structure probably mimics that of physiological lipoproteins involved in lipid metabolism. In preclinical studies, sardilipin has shown to be effective in (i) reducing blood cholesterol (CHO), triglyceride (TG), uric acid (UA), and glucose (Glu) levels, as well as liver alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity; (ii) enhancing immunological function by regulating both lymphocyte and microglia activity; (iii) inducing antioxidant effects mediated by superoxide dismutase activity; and (iv) improving cognitive function [16,193,194]. 
According to these results, it appears that the therapeutic response of patients with dyslipidemia to sardilipin is APOE-related. The best responders were patients with APOE-3/3 > APOE-3/4 > APOE-4/4. Patients with the other APOE genotypes (2/2,  2/3, 2/4) did not show any hypolipemic response to this novel compound [16,194]. In patients with dementia, the effects of sardilipin were very similar to those observed in patients with chronic dyslipidemia, suggesting that the lipid-lowering properties of sardilipin are APOE-dependent (Figure 1).
Clinical studies have revealed that sardilipin reduces blood total cholesterol (T-CHO) (20–30%), Glu (5–10%), UA (10–15%), TG (30–50%), ALT and AST, after 1–3 months of treatment at a daily dose of 250-500 mg (t.i.d). The effect on T-CHO is the result of decreasing LDL-CHO levels and increasing HDL-CHO levels in parallel with an improvement in hepatic protection reflected by reduction in ALT, AST, and GGT activity, as the result of reducing liver steatosis. Both LDL and HDL levels are modulated by dietary, behavioral and genetic factors [16]. Most of these therapeutic effects on the regulation of lipid metabolism tend to show an age-dependent pattern and are also associated with specific genomic profiles in the population. In addition, sardilipin diminishes the size of xanthelasma plaques by 30–60% after 6–9 months of treatment, and specifically protects against the hepatotoxicity induced by statins. Similar effects can be observed on atheromatous plaques on the aortic wall of patients with familial and sporadic dyslipidemia/hyperlipidemia. The daily administration of 1000–1500 mg/day of E-SAR p.o. for three months tends to reduce the average size of atherosclerotic plaques on the aortic wall by 10%. This effect is more significant in patients harboring the APOE-3/3 than in APOE-3/4 carriers in whom the size of the plaque is approximately 30–40% larger than in APOE-3/3 carriers [16,195].