The effect of high-dose simvastatin on triglyceride-rich lipoprotein metabolism in patients with type 2 diabetes mellitus

Abstract

Statins decrease triglycerides (TGs) in addition to decreasing low density lipoprotein-cholesterol. Although the mechanism for the latter effect is well understood, it is still unclear how TG decrease is achieved with statin therapy. Because hypertriglyceridemia is common in obese patients with type 2 diabetes mellitus, we studied triglyceride-rich lipoprotein triglyceride (TRL-TG) turnover in 12 such subjects using stable isotopically labeled glycerol. The diabetic subjects were studied after 12 weeks of placebo and after a similar course of therapy with simvastatin (80 mg daily) in a single-blind design. The results were compared with those from six nonobese nondiabetic control subjects. Simvastatin therapy reduced serum TGs by 35% in the diabetic subjects. Compared with the control subjects, TRL-TG secretion was almost 2-fold higher in the diabetic subjects (45.4 6 4.9 vs. 24.4 6 1.9 mmol/min; P , 0.002) and was unaffected by simvastatin therapy. However, TRL-TG clearance was significantly increased in the diabetic subjects during simvastatin treatment compared with placebo (0.25 6 0.03 vs. 0.16 6 0.02 pools/h; P , 0.002). This change was accompanied by a 49% increase in preheparin plasma lipase activity (P , 0.03) and a 21% increase in postheparin LPL activity (P , 0.01). Together, these findings provide strong evidence that the effect of statins on serum TGs is related to an increase in LPL activity, resulting in accelerated delipidation of TRL particles. HMG-CoA reductase inhibitors, or statins, are widely used in diabetic patients and have been shown to decrease cardiovascular morbidity in individuals with type 2 diabetes (5, 6). The major effect of statins is a reduction in low density lipoprotein-cholesterol (LDL-C) concentrations, primarily mediated by inhibition of the rate-limiting step in cholesterol biosynthesis, resulting in an increase in LDL receptors in the liver (7). In addition, statins can reduce TGs and increase HDL-C (8, 9), all of which lead to a reduced risk for coronary heart disease (CHD) in patients with type 2 diabetes mellitus (5, 6, 10).The mechanism responsible for the TG-lowering effect of statins is poorly defined. In theory, it could be related to decreased VLDL production (presumably secondary to decreased availability of hepatic free cholesterol for particle assembly), increased clearance of VLDL through the LDL receptor (or other lipoprotein receptors), increased delipidation of VLDL particles via LPL, or a combination of these mechanisms. To address these questions, we determined triglyceride-rich lipoprotein triglyceride (TRL-TG, which is predominantly VLDL) production and clearance in subjects with type 2 diabetes mellitus and hypertriglyceridemia on placebo and high-dose simvastatin therapy (80 mg daily) for 12 weeks and in nondiabetic controls. RESEARCH DESIGN AND METHODS Study subjects

Effect of AGTR1 and BDKRB2 gene polymorphisms on atorvastatin metabolism in a Mexican population

“…However, there was no association between the A/A or C/C genotypes with the fast metabolizer phenotype. To the best of our knowledge, this is the first report on the influence of rs5186 on ATV pharmacokinetics, though the rs5186 polymorphism has previously been associated with lipid levels (37), and ATV, as a statin, has lipid-lowering effects (38). Consistent with the present results, the C/C genotype has been related to higher levels of triglycerides in a healthy Malayan population (37).…”

Erratum: Statin-induced expression change of INSIG1 in lymphoblastoid cell lines correlates with plasma triglyceride statin response in a sex-specific manner

“…Though TG lowering is not the primary goal of statin treatment, recent studies demonstrating that high TG levels can cause CVD 3,4 and that TG levels may be responsible for some of the residual CVD risk in statin-treated individuals 5,6 highlight the value of understanding how statin treatment changes plasma TG levels [42][43][44][45][46][47][48] and increasing both preheparin plasma lipase activity and postheparin LPL activity, 43 while other studies have indicated that statins reduce VLDL-TG secretion and VLDL particle size. [49][50][51] It is possible that the mechanism by which statins reduce plasma TG levels could depend on an individual's baseline fractional catabolic rates and production rates.…”

Оценка Эффективности Гиполипидемической Терапии Розувастатином У Больных Ишемической Болезнью Сердца В Зависимости От Генотипов Липопротеинлипазы

“…Òðàíçèöèÿ íóêëåîòèäîâ + 495T>G â 8 èíòðîíå ãåíà LPL, áîëåå èçâåñòíàÿ êàê Hind III ïîëèìîðôèçì, îïðå-äåëÿåò íàëè÷èå (àëëåëü H+) èëè îòñóòñòâèå (àëëåëü Í-) ó÷àñòêà óçíàâàíèÿ äëÿ ýíäîíóêëåàçû HindIII [6]. Íîñèòåëüñòâî àëëåëüíîãî âàðèàíòà + 495G (Í-) àññî-öèèðîâàíî ñ ïîâûøåííîé àêòèâíîñòüþ è/èëè ýêñïðåñ-ñèåé ôåðìåíòà è ñâÿçàííûì ñ ýòèì ïîâûøåííûì ãèä-ðîëèçîì ÒÃ, óâåëè÷åíèåì óðîâíÿ ÕÑ ËÂÏ [15] è ïîíè-aeåííûì ðèñêîì ðàçâèòèÿ êîðîíàðíîãî àòåðîñêëåðîçà [10,14].…”