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How to have your cake and still reduce LDL cholesterol
SCIENCE AND MEDICINE
How to have your cake and still reduce LDL cholesterol n Sept 5, the US FDA ruled that manufacturers of foods containing plant stanol and sterol esters can say that their products reduce the risk of heart disease. Previously, manufacturers could only claim that their products promote healthy cholesterol values. Just a week later, the publication of two papers provided additional data on the effects of stanol and sterol esters. Plant sterol and stanol esters are structurally similar to cholesterol and are thought to reduce serum LDL cholesterol values by interfering with cholesterol absorption in the gut. Work on plant sterols and stanols started in the 1950s, but the study done by Maarit Hallikainen (University of Kuopio, Finland) and colleagues is the first well-designed study to compare the ester formulations of stanols and sterols, says nutrition expert Nilo Cater (Southwestern Medical Center at Dallas, TX, USA). In this study, 34 hypercholesterolaemic patients were given margarines containing stanol, sterol, or no added plant ester as part of a low-fat diet for 4 weeks each (Eur J Clin Nutr 2000; 54: 715–25).
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similar 10% reduction in serum Both supplemented margarines LDL cholesterol values (Eur J Clin reduced serum LDL cholesterol Nutr 2000; 54: 671–77). “This is of values by more than 10% compared practical relevance”, notes Mensink, with the control margarine, and, “because it is easier notes Cater, “there for patients to were no significant consume their daily changes in serum Rights were not dose at one go by concentrations of granted to include using several prodcarotenoids and this image in ucts than to include fat-soluble vitamins a stanol source in when the margarines electronic media. every meal”. were consumed as Please refer to the As with all other part of a low-fat printed journal. studies on these diet with plenty of esters, neither trial vegetables”. By was of sufficient contrast, some previlength to be able to ous studies have assess effects on carfound that serum Spread it on thick! diovascular events, concentrations of but, says Cater, “this endpoint is not carotenoids are reduced when needed because we know that any the margarines are added to a intervention to reduce LDL choleshigh-fat diet. terol reduces risk”. The interim final In the second study, Ronald FDA rule (www.fda.gov/bbs/topics/ Mensink (Maastricht University, ANSWERS/ANS01033.html) recogNetherlands) and co-workers asked nises this, he says, and is important whether stanol esters need to be “because it will help the public to included in every meal or whether a understand that products containing single daily dose is effective. 39 plant stanol esters are more than just healthy volunteers ate no stanol foods low in saturated fat”. esters, 2·5 g at lunch, or 2·5 g spread over three meals for 4 weeks each. Both dosing strategies produced a Jane Bradbury
Scientists gain better understanding of heparin pharmacology
N
ew and rapidly developing mass spectrometric and electrophoretic technologies can now determine the precise sequence of biologically active saccharides. One of the first compounds to be subjected to scrutiny is heparin. This week, Ram Sasisekharan (Massachusetts Institute of Technology, Cambridge, MA, USA) and colleagues describe how they determined the exact sequence of a heparin oligosaccharide fragment (Proc Natl Acad Sci 2000; 97: 10359–64). A sister paper reveals the precise molecular mechanism that mediates the fragment’s anticoagulant activity (Proc Natl Acad Sci 2000; 97: 10365-70). “Although heparins have been used effectively for more than 60 years, poor understanding of the exact mechanism of their anticoagulation and antithrombotic activity has seriously limited quality control of these drugs”, says Sasisekharan. Currently used heparin preparations, even those of low-molecular weight, are a collection of oligosaccharides. The pharmaceutical grade
1006
products contain only a small percentage of the clinically active component. No current assay is able to reflect accurately heparin’s antithrombotic effect in the body. “Clinicians rely on laboratory anticoagulant activity assays for indirect measurement of drug levels, but these do not correlate directly with clinical activity”, explains Sasisekharan. Mike Greaves of Aberdeen University, UK, and Chair of a UK Taskforce on Haemostasis and Thrombosis agrees. “Heparin monitoring systems that are quantitative and that correlate accurately with clinical activity would be a big step forward”, he says. When large efficacy studies were carried out for the low molecular weight heparins, they were done on the basis of no monitoring, explains Greaves. This was possible, he adds, because a standard population was used; unfortunately extrapolating the data to non-standard patients such as obese people, pregnant women, and patients with kidney disease is not possible. “With a more
effective monitoring system, these subgroups of patients could receive heparin treatment much more safely”, says Greaves. In the future, this new technology should enable the development of better monitoring systems for blood concentrations and also more effective heparins. “We have already begun to develop strategies that have the potential to generate tailormade products that could have less adverse effects such as heparin induced thrombocytopenia (HIT) and osteoporosis”, says Sasisekharan. The groups involved are also poised to embark on detailed structure–activity studies of the heparan sulphates, which are emerging as a related family of multifunctional polysaccharides responsible for cell regulation. “Here, we have only just begun to scratch the surface, but the advent of new sequencing technologies is accelerating advances in this field”, concludes co-author Jeremy Turnbull (University of Birmingham, UK). Kathryn Senior
THE LANCET • Vol 356 • September 16, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
How to have your cake and still reduce LDL cholesterol n Sept 5, the US FDA ruled that manufacturers of foods containing plant stanol and sterol esters can say that their products reduce the risk of heart disease. Previously, manufacturers could only claim that their products promote healthy cholesterol values. Just a week later, the publication of two papers provided additional data on the effects of stanol and sterol esters. Plant sterol and stanol esters are structurally similar to cholesterol and are thought to reduce serum LDL cholesterol values by interfering with cholesterol absorption in the gut. Work on plant sterols and stanols started in the 1950s, but the study done by Maarit Hallikainen (University of Kuopio, Finland) and colleagues is the first well-designed study to compare the ester formulations of stanols and sterols, says nutrition expert Nilo Cater (Southwestern Medical Center at Dallas, TX, USA). In this study, 34 hypercholesterolaemic patients were given margarines containing stanol, sterol, or no added plant ester as part of a low-fat diet for 4 weeks each (Eur J Clin Nutr 2000; 54: 715–25).
O
similar 10% reduction in serum Both supplemented margarines LDL cholesterol values (Eur J Clin reduced serum LDL cholesterol Nutr 2000; 54: 671–77). “This is of values by more than 10% compared practical relevance”, notes Mensink, with the control margarine, and, “because it is easier notes Cater, “there for patients to were no significant consume their daily changes in serum Rights were not dose at one go by concentrations of granted to include using several prodcarotenoids and this image in ucts than to include fat-soluble vitamins a stanol source in when the margarines electronic media. every meal”. were consumed as Please refer to the As with all other part of a low-fat printed journal. studies on these diet with plenty of esters, neither trial vegetables”. By was of sufficient contrast, some previlength to be able to ous studies have assess effects on carfound that serum Spread it on thick! diovascular events, concentrations of but, says Cater, “this endpoint is not carotenoids are reduced when needed because we know that any the margarines are added to a intervention to reduce LDL choleshigh-fat diet. terol reduces risk”. The interim final In the second study, Ronald FDA rule (www.fda.gov/bbs/topics/ Mensink (Maastricht University, ANSWERS/ANS01033.html) recogNetherlands) and co-workers asked nises this, he says, and is important whether stanol esters need to be “because it will help the public to included in every meal or whether a understand that products containing single daily dose is effective. 39 plant stanol esters are more than just healthy volunteers ate no stanol foods low in saturated fat”. esters, 2·5 g at lunch, or 2·5 g spread over three meals for 4 weeks each. Both dosing strategies produced a Jane Bradbury
Scientists gain better understanding of heparin pharmacology
N
ew and rapidly developing mass spectrometric and electrophoretic technologies can now determine the precise sequence of biologically active saccharides. One of the first compounds to be subjected to scrutiny is heparin. This week, Ram Sasisekharan (Massachusetts Institute of Technology, Cambridge, MA, USA) and colleagues describe how they determined the exact sequence of a heparin oligosaccharide fragment (Proc Natl Acad Sci 2000; 97: 10359–64). A sister paper reveals the precise molecular mechanism that mediates the fragment’s anticoagulant activity (Proc Natl Acad Sci 2000; 97: 10365-70). “Although heparins have been used effectively for more than 60 years, poor understanding of the exact mechanism of their anticoagulation and antithrombotic activity has seriously limited quality control of these drugs”, says Sasisekharan. Currently used heparin preparations, even those of low-molecular weight, are a collection of oligosaccharides. The pharmaceutical grade
1006
products contain only a small percentage of the clinically active component. No current assay is able to reflect accurately heparin’s antithrombotic effect in the body. “Clinicians rely on laboratory anticoagulant activity assays for indirect measurement of drug levels, but these do not correlate directly with clinical activity”, explains Sasisekharan. Mike Greaves of Aberdeen University, UK, and Chair of a UK Taskforce on Haemostasis and Thrombosis agrees. “Heparin monitoring systems that are quantitative and that correlate accurately with clinical activity would be a big step forward”, he says. When large efficacy studies were carried out for the low molecular weight heparins, they were done on the basis of no monitoring, explains Greaves. This was possible, he adds, because a standard population was used; unfortunately extrapolating the data to non-standard patients such as obese people, pregnant women, and patients with kidney disease is not possible. “With a more
effective monitoring system, these subgroups of patients could receive heparin treatment much more safely”, says Greaves. In the future, this new technology should enable the development of better monitoring systems for blood concentrations and also more effective heparins. “We have already begun to develop strategies that have the potential to generate tailormade products that could have less adverse effects such as heparin induced thrombocytopenia (HIT) and osteoporosis”, says Sasisekharan. The groups involved are also poised to embark on detailed structure–activity studies of the heparan sulphates, which are emerging as a related family of multifunctional polysaccharides responsible for cell regulation. “Here, we have only just begun to scratch the surface, but the advent of new sequencing technologies is accelerating advances in this field”, concludes co-author Jeremy Turnbull (University of Birmingham, UK). Kathryn Senior
THE LANCET • Vol 356 • September 16, 2000
For personal use only. Not to be reproduced without permission of The Lancet.