Showing papers by "Scott M. Grundy published in 1990"
TL;DR: At present it appears that carbohydrates and monounsaturated fatty acids represent the preferred replacements for saturated fatty acids, although modest increases in polyunsaturated fatty acid and stearic acid, at the expense of cholesterol-raising saturates, probably are safe and may provide for greater variety in the diet.
1,048 citations
552 citations
TL;DR: Familial defective apolipoprotein B-100 appears to be a significant genetic cause of hypercholesterolemia in Western societies.
457 citations
296 citations
TL;DR: Despite improvement in lipid and lipoprotein concentrations, nicotinic acid must be used with caution in patients with non-insulin-dependent diabetes mellitus with dyslipidemia, because of worsening hyperglycemia and the development of hyperuricemia.
Abstract: Recently, nicotinic acid has been recommended as a first-line hypolipidemic drug. To determine the effectiveness of nicotinic acid in dyslipidemic patients with non-insulin-dependent diabetes mellitus, 13 patients were treated in a randomized crossover trial. Patients received either nicotinic acid (1.5 g three times daily) or no therapy (control period) for 8 weeks each. Compared with the control period, nicotinic acid therapy reduced the plasma total cholesterol level by 24%, plasma triglyceride level by 45%, very-low-density lipoprotein cholesterol level by 58%, and low-density lipoprotein cholesterol level by 15%, and it increased the high-density lipoprotein cholesterol level by 34%. However, nicotinic acid therapy resulted in the deterioration of glycemic control, as evidenced by a 16% increase in mean plasma glucose concentrations, a 21% increase in glycosylated hemoglobin levels, and the induction of marked glycosuria in some patients. Furthermore, a consistent increase in plasma uric acid levels was observed. Therefore, despite improvement in lipid and lipoprotein concentrations, because of worsening hyperglycemia and the development of hyperuricemia, nicotinic acid must be used with caution in patients with non-insulin-dependent diabetes mellitus with dyslipidemia. We suggest that the drug not be used as a first-line hypolipidemic drug in patients with non-insulin-dependent diabetes mellitus.
284 citations
TL;DR: Ascorbate in physiologic concentrations should inhibit the oxidate modification of LDL in vivo, indicating that in this cell-free system (2.5 microM Cu2+), ascorbates is a more potent antioxidant than alpha-tocopherol.
283 citations
TL;DR: The National Cholesterol Education Program recently issued guidelines for treatment of hyperlipidemia in adults including diabetic patients as discussed by the authors, which suggest that certain modifications in these guidelines be made to meet specific needs of diabetic patients.
Abstract: Coronary heart disease is the leading cause of death among patients with non-insulin-dependent diabetes mellitus (NIDDM). NIDDM patients have a high frequency of dyslipidemia, which along with obesity, hypertension, and hyperglycemia may contribute significantly to accelerated coronary atherosclerosis. Because risk factors for coronary heart disease are additive and perhaps multiplicative, even mild degrees of dyslipidemia may enhance coronary heart disease risk. Therefore, therapeutic strategies for management of NIDDM should give equal emphasis to controlling hyperglycemia and dyslipidemia. The National Cholesterol Education Program recently issued guidelines for treatment of hyperlipidemia in adults including diabetic patients. Because of the unique features of diabetic dyslipidemia, however, we suggest that certain modifications in these guidelines be made to meet specific needs of diabetic patients. For example, therapeutic goals for serum cholesterol reduction should be lower in diabetic patients than in nondiabetic subjects. Particular emphasis should be given to weight reduction in NIDDM patients. In some diabetic patients, monounsaturated fatty acids may be a better replacement for saturated fatty acids than carbohydrates. The target for cholesterol lowering should include both very-low-density lipoprotein and low-density lipoprotein (LDL) (non-high-density lipoprotein) rather than LDL alone. To obtain a substantial reduction of cholesterol levels, drug therapy may be required in many patients. However, first-line drugs for nondiabetic patients (nicotinic acid and bile acid sequestrants) may be less desirable in NIDDM patients than hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors and even fibric acids. In fact, HMG CoA reductase inhibitors may be the drugs of choice for NIDDM patients with elevated LDL cholesterol and borderline hypertriglyceridemia, whereas gemfibrozil appears preferable for NIDDM patients with severe hypertriglyceridemia.
264 citations
Journal Article•
TL;DR: It is suggested that overnutrition produces clinical diseases only in individuals who already possess a metabolic weakness or "defect" in a given system, and in the absence of such underlying defects, overnutrition, or obesity, is well tolerated.
Abstract: Overnutrition manifested by obesity has emerged as a major health problem in affluent countries. In spite of increased interest in fitness, obesity is on the increase in the United States. This is particularly so among children and adolescents. Although obesity is associated with many risk factors for diseases, the mechanisms whereby it enhances disease risk are not fully understood. Such an understanding is needed to develop strategies for management of these conditions. In this report we suggest that overnutrition produces clinical diseases only in individuals who already possess a metabolic weakness or "defect" in a given system. In the absence of such underlying defects, overnutrition, or obesity, is well tolerated. One of the most common consequences of obesity is dyslipidemia, that is, elevations of very low-density lipoprotein (VLDL) triglycerides and low-density lipoprotein (LDL) cholesterol and low concentrations of high-density lipoprotein (HDL) cholesterol. The major effect of overnutrition on lipoprotein metabolism is to stimulate the production of VLDL. For patients who have an underlying defect in lypolysis of VLDL triglycerides, hypertriglyceridemia will develop in the obese state. For those who have defective clearance of LDL, obesity will accentuate hypercholesterolemia. Both of these effects can be explained by overproduction of VLDL, due to obesity, combined with a genetic defect in clearance of VLDL or LDL. The mechanism whereby obesity causes a lowering of HDL cholesterol is uncertain, although it could enhance removal of HDL by an excess of adipose tissue. Another disease associated with obesity is cholesterol gallstones. The presence of obesity more than doubles the risk for gallstones. Two underlying factors increase the danger for gallstones: a deficiency of hepatic secretion of bile acids and a tendency for formation of cholesterol crystals in bile. Overnutrition promotes the synthesis of whole-body cholesterol, and the only route for excretion of this excess cholesterol is through the biliary tree.(ABSTRACT TRUNCATED AT 400 WORDS)
145 citations
TL;DR: Pravastatin seemingly reduced input rates for all apo B‐containing lipoproteins, consistent with previous studies, this response was most likely the result of enhanced removal of nascent lipoproteinins by increased activity of LDL receptors, although decreased synthesis of apO B in the liver is a possible second action.
Abstract: . This study examined the actions of pravastatin on the metabolism of apolipoprotein B (apo B) in very low-, intermediate-, and low-density lipoproteins (VLDL, IDL, and LDL) in 10 patients with primary moderate hypercholesterolaemia. 131I-VLDL apo B was used as a tracer, and appearance of label was followed into IDL apo B and LDL apo B. Compared to placebo, pravastatin therapy reduced levels of cholesterol in total plasma, LDL, VLDL, and IDL cholesterol by 25%, 29%, 31%, and 47%, respectively. Pravastatin treatment also significantly decreased concentrations of apo B in LDL, IDL, and VLDL. The drug significantly reduced the mean production rate for VLDL apo B by 40%, and decreased production rates for LDL apo B in eight of 10 patients. In contrast, fractional catabolic rates (FCRs) were not altered significantly in any of the three lipoprotein fractions on pravastatin therapy. Further, pravastatin produced no consistent changes in LDL particle size, composition, or LDL subclass pattern. Thus pravastatin seemingly reduced input rates for all apo B-containing lipoproteins. Consistent with previous studies, this response was most likely the result of enhanced removal of nascent lipoproteins by increased activity of LDL receptors, although decreased synthesis of apo B in the liver is a possible second action.
125 citations
TL;DR: Active medical management of high cholesterol levels should be restricted to a limited fraction of elderly patients who are most likely to benefit from long-term therapy.
Abstract: Of all age groups, men and women over 60 years of age have the highest prevalence of elevated serum cholesterol levels. Now that detection and treatment of high serum cholesterol levels ar...
113 citations
TL;DR: For people with high cholesterol levels, dietary modification is undoubtedly the first step of management, but the fraction of people responding adequately to dietary change remains to be determined.
Abstract: The importance of high serum cholesterol levels as a risk factor for coronary heart disease and the benefit of lowering cholesterol levels for reducing risk are being increasingly accepted. A broad consensus to this effect has led to the establishment of the National Cholesterol Education Program. Although the available evidence fully justifies this program, its practical application to the American public has generated a series of new questions that must be explored. For example, it can be questioned whether reduction in coronary risk through lowering cholesterol levels extends to both sexes and all age groups. For people with high cholesterol levels, dietary modification is undoubtedly the first step of management, but the fraction of people responding adequately to dietary change remains to be determined. Finally, indications for drug therapy and choice of drugs need further exploration, particularly in the area of cost vs benefit. Thus, continuing research must be carried out in parallel with clinical and public health application of cholesterol education. ( JAMA . 1990;264:3053-3059)
TL;DR: To justify introducing complex and expensive new methodology for apolipoproteins, it must be demonstrated that the total apo B level is definitely superior to total lipids and lipoprotein cholesterols for predicting CHD risk or for monitoring therapy.
Abstract: In the accompanying editorial, Sniderman and Silberberg raise the question, \"Is It Time To Measure Apolipoprotein B\"? If this question means whether it is time to measure apolipoprotein B-100 (apo B) clinically to estimate the risk for coronary heart disease (CHD) or to guide in lipid-lowering therapy, our answer is an unqualified \"No.\" Whether measurement of apo B will prove valuable in the future is another question; the answer is \"Maybe.\" Sniderman and associates made an important contribution with the recognition that some patients have high concentrations of apo B in the presence of \"normal\" serum cholesterol levels. Without question, low density lipoprotein (LDL) apo B levels can be disproportionately high compared to cholesterol levels. The condition of elevated LDL apo B and normal LDL cholesterol they called \"hyperapobetalipoproteinemia.\" In their initial definition, \"elevated\" apo B was confined to the LDL fraction. More recently, their definition seemingly has been expanded to include serum total apo B, and a simple term for high total apo B is \"hyperapo B.\" Total apo B includes apo B in LDL, intermediate density lipoprotein (IDL), and very low density lipoprotein (VLDL). For each of these classes, there is one molecule of apo B per lipoprotein particle; hence, measurement of total apo B concentration yields the total number of apo B-containing lipoproteins in a volume of plasma. The critical question raised by the research of Sniderman et al . 3 is whether total apo B levels better predict CHD than does the total cholesterol level or another cholesterol parameter. What are the data related to this question? The evidence is based on small, retrospective studies and not on large, prospective studies. The latter are required before apo B determination can be considered superior to cholesterol measurement. Retrospective surveys are notorious for giving suggestive evidence that is not confirmed by large prospective studies. At this time, therefore, we cannot assume that total apo B is better than total cholesterol for detection of high-risk individuals. Moreover, the predictive power of total cholesterol measurement is enhanced by adding triglycerides, LDL cholesterol, HDL cholesterol, non-HDL cholesterol, and cholesterol ratios. To justify introducing complex and expensive new methodology for apolipoproteins, it must be demonstrated that the total apo B level is definitely superior to total lipids and lipoprotein cholesterols for predicting CHD risk or for monitoring therapy. In recommending total apo B measurements, Sniderman and Silberberg seemingly postulate that all apo Bcontaining lipoproteins are similarly atherogenic. Accordingly, one VLDL particle would have the same atherogenecity as one LDL particle, or within the LDL density class, small LDL particles would have similar atherogenecity as large LDL particles. Although this is an intriguing hypothesis, it is not universally accepted. Apo B-containing lipoproteins vary in size, types of apolipoproteins, and contents of apolipoproteins, triglycerides, and cholesterol. It, therefore, would be surprising if all lipoprotein species are equally atherogenic. This conceptual stumbling block probably stands in the way of universal acceptance of total apo B level as a predictor of CHD risk.
TL;DR: Lovastatin seems to have certain advantages over gemfibrozil for treatment of elevated plasma triglyceride levels accompanied by borderline high total cholesterol and raised apolipoprotein B levels; therefore, lovastatin therapy should be considered as one approach for management of this condition.
Abstract: A common pattern of dyslipidemia is elevated levels of plasma triglyceride, borderline high total cholesterol, reduced high-density lipoprotein, and increased apolipoprotein B. This pattern of dyslipidemia frequently is associated with premature coronary heart disease. Nicotinic acid is the drug of first choice for this pattern. In this study, gemfibrozil and lovastatin were compared for their effects on the overall lipoprotein profile in 13 men with this type of dyslipidemia. Both drugs significantly reduced very-low—density lipoprotein and intermediate-density lipoprotein cholesterol levels, and both modestly raised high-density lipoprotein cholesterol levels. Gemfibrozil therapy, however, failed to reduce total cholesterol or total apolipoprotein B levels, whereas lovastatin therapy lowered levels of total cholesterol by 28%, low-density lipoprotein cholesterol by 33%, and total apolipoprotein B by 32%. Moreover, lovastatin therapy caused greater declines in lipoprotein cholesterol ratios than gemfibrozil therapy. Lovastatin thus seems to have certain advantages over gemfibrozil for treatment of elevated plasma triglyceride levels accompanied by borderline high total cholesterol and raised apolipoprotein B levels; therefore, lovastatin therapy should be considered as one approach for management of this condition. (JAMA. 1990;264:2759-2763)
TL;DR: Hydrogenated vegetable oils in shortenings and margarines are important components of the diet in many industrialized societies.
Abstract: Hydrogenated vegetable oils in shortenings and margarines are important components of the diet in many industrialized societies. Hydrogenation (adding hydrogen atoms to double bonds) is carried out...
TL;DR: The HICHO diet decreased the activity of mechanisms that convert VLDL to LDL, which contributed to the decrease in LDLC in all subjects, and there was also evidence in some subjects for increased activity of LDL apoB clearance mechanisms, and a decrease in the LDLC/apoB ratio.
Abstract: The mechanisms by which high-carbohydrate, low-saturated-fat diets lower LDL cholesterol (LDLC) concentrations are unknown. In this study, kinetics of VLDL, intermediate density lipoprotein (IDL), and LDL apoprotein B and VLDL triglyceride were determined in seven nondiabetic (ND) and seven non-insulin-dependent diabetic (NIDDM) Pima Indian subjects on high-fat and high-carbohydrate (HICHO) diets. Metabolic changes were similar in ND and NIDDM. On the HICHO diet, LDLC decreased (131 +/- 8 vs. 110 +/- 7 mg/dl, P less than 0.0001) in all subjects. Mean fasting and 24-h triglyceride (TG) concentrations were unchanged, as were mean production rates and fractional clearance rates (FCR) of VLDL apoB and VLDL TG. The mean VLDL apoB pool size (303 +/- 20 vs. 371 +/- 38 mg, P = 0.01) increased owing to a decrease in the mean transport rate (10.7 +/- 1.1 vs. 8.4 +/- 0.9 mg/kg fat-free mass (ffm) per day, P less than 0.0001) and the mean rate constant (2.3 +/- 0.2 vs. 1.5 +/- 0.2, P less than 0.001) for the VLDL apoB to IDL apoB conversion pathway. The mean transport rate of VLDL apoB to LDL apoB via IDL (10.2 +/- 0.9 vs. 8.0 +/- 0.8 mg/kg ffm per day, P less than 0.001) decreased. Mean LDL apoB concentrations decreased (70 +/- 5 vs. 61 +/- 5 mg/dl, P less than 0.001) on the HICHO diet. Means for total LDL apoB transport rate, LDL apoB FCR, and LDLC/apoB ratios were unchanged. In summary, the HICHO diet decreased the activity of mechanisms that convert VLDL to LDL, which contributed to the decrease in LDLC in all subjects. There was also evidence in some subjects for increased activity of LDL apoB clearance mechanisms, and a decrease in the LDLC to apoB ratio.
TL;DR: The wide spectrum of this loss pathway indicates that previous estimates of VLDL apoB production rate using the radioiodinated methodology probably represent lower bounds for the true physiologic variable.
TL;DR: Compared with lovastatin alone, Lovastatin plus gemfibrozil produced greater decreases in very-low-density plus intermediate-density lipoprotein cholesterol levels and an increase in high-density cholesterol levels, but, in view of the higher risk for severe myopathy with this combination, lovASTatin used alone may be adequate therapy for many patients with mixed hyperlipidemia.
Abstract: Many patients with high levels of serum total cholesterol have a concomitant elevation of serum triglyceride levels and thus have mixed hyperlipidemia. In this study, 13 patients with mixed hyperlipidemia were treated with the cholesterol-lowering drug lovastatin to determine its effectiveness. In 9 of these patients, lovastatin therapy used alone was compared with the drug combination of lovastatin and gemfibrozil. In the 13 patients, lovastatin therapy produced a 31% reduction in total cholesterol level and a 32% decrease in triglyceride levels compared with placebo. It lowered very-low-density plus intermediate-density lipoprotein cholesterol levels by 40%, low-density lipoprotein cholesterol levels by 36%, and total apolipoprotein B levels by 28%. Concentrations of high-density lipoprotein cholesterol and apolipoprotein A-I were unchanged, but total cholesterol (and low-density lipoprotein cholesterol)/high-density lipoprotein cholesterol ratios were markedly reduced. Compared with lovastatin alone, lovastatin plus gemfibrozil produced greater decreases in very-low-density plus intermediate-density lipoprotein cholesterol levels and an increase in high-density lipoprotein cholesterol levels, but, in view of the higher risk for severe myopathy with this combination, lovastatin used alone may be adequate therapy for many patients with mixed hyperlipidemia.
TL;DR: Basic physiologic and biochemical processes regulating serum cholesterol levels will be considered and serve as an introduction to a more detailed consideration of the pathogenesis of hypercholesterolemia.
Abstract: Anational effort is underway to detect and treat patients with high serum cholesterol levels (hypercholesterolemia) and to modify lifestyles of all Americans to reduce average cholesterol concentrations. This effort is founded on the recognition that hypercholesterolemia is a major risk factor for coronary heart disease (CHD) and that therapeutic lowering of cholesterol levels will decrease the risk for CHD. The National Cholesterol Education Program (NCEP)1 is generating widespread interest and concern among Americans about the dangers of high cholesterol levels, and new questions regarding the best approach to this major publichealth problem are emerging. Generally, in management of medical conditions, an understanding of pathogenesis underlies rational therapy. Hypercholesterolemia is no exception. Unfortunately, we lack adequate explanations for the \"mass hypercholesterolemia\" in the US public. Whereas it is widely assumed that dietary excesses are the major cause, growing evidence implicates genetics as an important factor in many individuals. Available information on causes of hypercholesterolemia is reviewed, and current definitions of what constitutes an elevated serum cholesterol concentration will be examined. Basic physiologic and biochemical processes regulating serum cholesterol levels will be considered and serve as an introduction to a more detailed consideration of the pathogenesis of hypercholesterolemia.
Book•
01 Jun 1990
TL;DR: Cholesterol, atherosclerosis and coronary heart disease classification of lipid disorders diet treatment drug therapy.
Abstract: Cholesterol, atherosclerosis and coronary heart disease classification of lipid disorders diet treatment drug therapy.
TL;DR: In this paper, the authors compared high carbohydrate diets (60% carbohydrate and 25% fat) with high fat diets (50% fat and 35% carbohydrate) for effects on metabolism of calcium and other minerals in eight normal subjects and eight euglycemic patients with noninsulin-dependent diabetes mellitus.
Abstract: Transient hypercalciuria has been noted after high carbohydrate meals which is independent of dietary calcium and is probably due to impaired renal calcium reabsorption mediated by an increase in plasma insulin levels. Based on these observations, some investigators believe that long term intake of high carbohydrate diets may increase the risk of nephrolithiasis and possibly osteoporosis. Using a randomized cross-over design, we compared high carbohydrate diets (60% carbohydrate and 25% fat) with high fat diets (50% fat and 35% carbohydrate) for effects on metabolism of calcium and other minerals in eight normal subjects and eight euglycemic patients with noninsulin-dependent diabetes mellitus. All other dietary constituents, such as protein, fiber, fluid, minerals (including Ca, Mg, Na, K, and P), and caffeine intake, were kept constant. Despite higher daylong levels of plasma insulin on the high carbohydrate diets compared to the high fat diet in both normal and noninsulin-dependent diabetic subjects, no changes in daily urinary excretion of calcium or other constituents, associated with renal stone risk, were observed. Furthermore, there was no change in fractional intestinal 47Ca absorption. Although hypercalciuria may ensue transiently after high carbohydrate meals, we conclude that substitution of simple or complex carbohydrates for fats in an isocaloric manner for a longer duration does not result in significant urinary calcium loss, and therefore, high intakes of digestible carbohydrates may not increase the risk of nephrolithiasis or osteoporosis via this mechanism.
TL;DR: It is shown that lovastatin modifies the composition of the major apo B-containing lipoproteins as well as reducing their concentrations as shown by decreasing the cholesterol/apo B and raising HDL-cholesterol concentrations.
TL;DR: Since the serum lipoproteins undoubtedly play an important role in atherogenesis, it is reasonable to ask whether serum levels of apolipoproteins can be used as predictors of coronary heart disease (CHD) in the same way that serum cholesterol levels are used for this purpose.
Abstract: Enormous advances have been made in our understanding of the role of apolipoproteins in the transport of plasma lipids. The apolipoproteins are essential for the packaging of lipoproteins in the liver and intestine, for the interconversion of lipoproteins in the circulation, and for their uptake by tissues. In a sense, the apolipoproteins are the "business end" of the lipoproteins. Since the serum lipoproteins undoubtedly play an important role in atherogenesis, it is reasonable to ask whether serum levels of apolipoproteins can be used as predictors of coronary heart disease (CHD) in the same way that serum cholesterol levels are used for this purpose. The two apolipoproteins that have received the most attention are apolipoprotein B and apolipoprotein A-I. Consideration might be given to the potential value of measurement of each.
TL;DR: It is indicated that the damaging effects of aspirin on the gastric mucosa are not influenced by dietary fish oil, despite the fact that fish oil reduced serum triglyceride concentrations significantly.
TL;DR: Drugs of this type appear to have the potential for effective therapy of various forms of dyslipidemia beyond primary severe hypercholesterolemia and may even increase levels of high-density lipoproteins in some patients.
Abstract: The inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase are highly effective in treating severe elevations of serum cholesterol, and are being widely used for this purpose. In our laboratory, these drugs have been used for the treatment of other forms of dyslipidemia including primary moderate hypercholesterolemia, primary mixed hyperlipidemia, diabetic dyslipidemia, hyperlipidemia of the nephrotic syndrome, and primary hypoalphalipoproteinemia. In these conditions, the HMG CoA reductase inhibitors proved effective in substantially decreasing levels of both low-density lipoproteins and very low density lipoproteins, as well as apolipoprotein B. In some patients, they may even increase levels of high-density lipoproteins. The primary mode of action of HMG CoA reductase inhibitors appears to be to increase the synthesis of hepatic receptors for lipoproteins containing apolipoprotein B, although a reduction in synthesis of these lipoproteins has not been ruled out with certainty. Regardless of mechanisms, drugs of this type appear to have the potential for effective therapy of various forms of dyslipidemia beyond primary severe hypercholesterolemia.
Journal Article•
TL;DR: The evidence for the existence of lipoprotein overproduction as a cause for hyperlipidemia is considered and the available data related to this question are examined.
Abstract: Several mechanisms have been implicated in the development of hyperlipidemia. These include reduced activity of receptors for low density lipoproteins (LDL), deficiencies in lipoprotein lipase (LPL), abnormalities in the primary structures of apolipoproteins C-II, E, and B-100, and overproduction of lipoproteins containing apolipoprotein B-100 (apo B) . All of these except the last are well documented. On the other hand, many researchers believe that overproduction of apo B-containing lipoproteins is one of the more common causes of hyperlipidemia. Therefore, it is worthwhile to consider the evidence for the existence of lipoprotein overproduction as a cause for hyperlipidemia. The present paper will examine the available data related to this question.