Betatrophin (ANGPTL8), also known as “Lipasin” (lipoprotein lipase inhibitor), has been reported as a dual-regulator of glucose and lipid metabolism. Functional variant R59W in betatrophin gene is common in Japanese (minor allele 25%) compared with Caucasian (5%). Little is known about long-term impact of this gene variant, and also about the effect of lipid-lowering drugs on this hormone. Methods: A total of 205 cases with dyslipidemia evaluated with baseline 75gOGTT, and post-heparin lipoprotein lipase activities were registered as a long-term cohort. As lipid-lowering trial, a total of 44 patients (Male 21, Age 65±11 ys) with primary dyslipidemia, and 18 genetically confirmed heterozygous familial hypercholesterolemia (FH) (Male 12, Age 65±10 ys,) were analyzed. Non-FH dyslipidemia was treated with 10mg Atorvastatin, and FH was treated with 20mg Rosuvastatin for 8 weeks. Plasma TG and betatrophin levels were log-transformed for statistical analysis. Results: In long-term cohort, 57 cases already showed diabetic pattern at baseline, 148 cases (Male 82, age 56±15 ys, hetero-FH 48 cases, mean follow-up period 10±3 ys) without diabetes at baseline were finally analyzed. Sixty-two cases (42%) developed newly diabetes mellitus during the follow-up, significantly fewer in FH than non-FH (25% vs. 50%, p <0.005). No differences in BMI, fasting glucose, HbA1c in baseline with R59W genotype. In low LPL activity group (n=31), W carriers showed significant increase in HbA1c compared with RR (2.1±0.5 vs. 0.9±0.4 %, p <0.05), but no differences in normal LPL group. In lipid lowering trial, baseline betatrophin levels were lower in FH group (19±13 vs. 13±6 ng/mL, p <0.05), but no difference with/without R59W variant. Statin treatment slightly decreased betatrophin in dyslipidemia group (-4%, p <0.01) and in FH group (-5%, p <0.01). Changes in betatrophin were positively correlated with changes in LDL-C with statins in both groups. Conclusion: Betatrophin R59W variant was a susceptibility factor of future diabetes mellitus with low LPL activity. Baseline betatrophin levels were lower in FH group than other primary dyslipidemia in lipid-lowering trial. Strong statin treatments slightly decreased betatrophin levels, but effect sizes were minimal.