Triglycerides, plasma

A 35-year-old male with markedly elevated plasma triglyceride and LDL levels, and low plasma HDL levels, is treated with gemfibrozil. What is the mechanism of action of gemfibrozil ... 

Familial lipoprotein lipase deficiency is characterized by a massive accumulation of chylomicrons and a corresponding increase in plasma triglycerides or a type I lipoprotein pattern. Presenting manifestations include repeated attacks of pancreatitis and abdominal pain, eruptive cutaneous xanthomatosis, and hepatosplenomegaly beginning in childhood. Symptom severity is proportional to dietary fat intake, and consequently to the elevation of chylomicrons. Accelerated atherosclerosis is not associated with this disease. 

Treatment of type I hyperlipoproteinemia is directed toward reduction of chylomicrons derived from dietary fat with the subsequent reduction in plasma triglycerides. Total daily fat intake should be no more than 10 to 25 g/day, or approximately 15% of total calories. Secondary causes of hypertriglyceridemia should be excluded, and, if present, the underlying disorder should be treated appropriately. 

Metformin is the only biguanide available in the United States. It enhances insulin sensitivity of both hepatic and peripheral (muscle) tissues. This allows for increased uptake of glucose into these insulin-sensitive tissues. Metformin consistently reduces A1C levels by 1.5% to 2%, FPG levels by 60 to 80 mg/dL, and retains the ability to reduce FPG levels when they are very high (>300 mg/dL). It reduces plasma triglycerides and low-density lipoprotein (LDL) cholesterol by 8% to 15% and modestly increases high-density lipoprotein (HDL) cholesterol (2%). It does not induce hypoglycemia when used alone. 

Pioglitazone decreases plasma triglycerides by 10% to 20%, whereas rosiglitazone tends to have no effect. Pioglitazone does not cause significant increases in LDL cholesterol, whereas LDL cholesterol may increase by 5% to 15% with rosiglitazone. 

Observations in different types of primary hyperlipidemia revealed in general an inverse correlation between Lp(a) concentrations and plasma triglyceride and triglyceride-rich lipoprotein concentrations in hypertriglyceridemic subjects (A 10, B22, H30, W11). As far as this observation is not troubled by technical problems in the analysis (E8), the possibility exists that Lp(a) catabolism is partly related to the catabolism of triglyceride-rich and/or cholesterol-rich particles (P10, R16). 

Similar problems occur for the nephelometric and turbidimetric methods, where the sizes of the IgG-Lp(a) complexes depend upon that of apo(a) itself (L2, W4). Furthermore, problems due to interferences from elevated plasma triglyceride are commonly encountered in the precipitation techniques (C3). As Lp(a) can be redistributed among the Lp(a) fraction and the triglyceride-rich lipoproteins, especially in patients after a fatty meal (B11), these methods are not appropriate for monitoring Lp(a) levels and distribution in plasma. 

Wll. Werba, S. P., Safa, O., Gianfranceschi, G., Michelagnoli, S., Sirtori, C. R., and Franceschini, G., Plasma triglycerides and lipoprotein(a) Inverse relationship in a hyper-lipidemic Italian population. Atherosclerosis (Shannon, Irel.) 101, 203-211 (1993). 

Mr Patel came to the UK from his native India in 1969 when he was 22 years old. For almost 30 years he has run, very successfully with the help of his family, a small business which now employs 30 people in the suburbs of Leicester. At the age of 38 years, Mr Patel was diagnosed with diabetes mellitus (Type 1 diabetes) and now has trouble controlling his weight and is on medication to regulate his plasma triglyceride and cholesterol concentrations. 

A patient with a history of recurring attacks of pancieathis, eruptive xanthomas, and increased plasma triglyceride levels (2000 mg/dL) associated with chylomicrons, most likely has a deficiency in... 

Lipoproteins are an important class of serum proteins in which a spherical hydrophobic core of triglycerides or cholesterol esters is surrounded by an amphipathic monolayer of phospholipids, cholesterol and apolipoproteins (fatbinding proteins). Lipoproteins transport lipid in the circulation and vary in size and density, depending on their proteindipid ratio (Figure 7.3). Lipoprotein metabolism is adversely affected by obesity low-density lipoprotein (LDL)-cholesterol and plasma triglyceride are increased, together with decreased high-density lipoprotein (HDL)-cholesterol concentrations. 

Familial hyperlipoproteinemia Estrogen therapy may be associated with massive elevations of plasma triglycerides leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism. 

D. Pancreatitis. Extremely high plasma triglycerides, as in this patient, present a serious risk of acute pancreatitis. 

D. Lipoprotein lipase. Fenohbrate is a hypotriglyc-eridemic drug that lowers plasma triglycerides by increasing the activity of hpoprotein lipase, the enzyme responsible for disassembly of triglycerides in serum lipoproteins (VLDL, IDL and chylomicrons). 

Mechanism of Action An antihyperlipidemic that inhibits hydroxymethylglutaryl-CoA (HMG CoA) reductase, the enzyme that catalyzes the early step in cholesterol synthesis. Therapeutic Effect Decreases LDL and VLDL cholesterol, and plasma triglyceride levels increases HDL cholesterol concentration. 

Mechanism of Action An antihyperlipidemic that enhances synthesis of lipoprotein lipase and reduces triglyceride-rich lipoproteins and VLDLs. Therapeutic Effect Increases VLDL catabolism and reduces total plasma triglyceride levels. Pharmacokinetics Well absorbed from the GI tract. Absorption increased when given with food. Protein binding 99%. Rapidly metabolized in the liver to active metabolite. Excreted primarily in urine lesser amount in feces. Not removed by hemodialysis. Half-life 20 hr. 

Mechanism of Action An HMG-CoA reductase inhibitor that interferes with cholesterol biosynthesis by preventing the conversion of HMG-CoA reductase to meva-lonate, a precursor to cholesteroh Therapeutic Effect Lowers serum LDL and VLDL cholesterol and plasma triglyceride levels increases serum HDL concentration. Pharmacokinetics Poorly absorbed from the G1 tract. Protein binding 50%. Metabolized in the liver (minimal active metabolites). Primarily excreted in feces via the biliary system. Not removed by hemodialysis. Half-life 2.7 hr. 

Mechanism of Action An antihyperlipidemicthat interferes with cholesterol biosynthesis by inhibiting the conversion of the enzyme hydroxymethylglutaryl-CoA (HMG-CoA) to mevalonate, a precursor to cholesterol. Therapeutic Effect Decreases LDL cholesterol, VLDL, and plasma triglyceride levels, increases HDL concentration. Pharmacokinetics Protein binding 88%. Minimal hepatic metabolism. Primarily eliminated in the feces. Half-life 19 hr (increased in patients with severe renal dysfunction). 

Simvastatin has been shown to reduce both normal and elevated low-density lipoprotein (LDL) cholesterol concentrations. Apolipoprotein B, VLDL cholesterol and plasma triglycerides also reduce and can produce increase in HDL cholesterol. 

Gemfibrozil reduces plasma triglycerides by 40 to 55% by decreasing the concentration of VLDL. Its effectiveness is less in lowering LDL. 

---