Can LDL cholesterol be too low? Possible risks of extremely low levels.

Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important.

Cardiovascular outcomes and their relationships to lipoprotein components in patients with and without chronic kidney disease: results from the IDEAL trial.

OBJECTIVES: In Incremental Decrease in Endpoints through Aggressive Lipid-lowering (IDEAL), we compared cardiovascular outcomes in patients with and without chronic kidney disease (CKD) (estimated glomerular filtration rate <60 mL min(-1) 1.73 m(-2)) and analysed relationships between lipoprotein components (LC) and major coronary events (MCE) and other cardiovascular (CV) events. DESIGN: Exploratory analysis of CV endpoints in a randomized trial comparing high dose of atorvastatin to usual dose of simvastatin on MCE. SETTINGS: Patients with CKD were compared with the non-CKD patients. Cox regression models were used to study the relationships between on-treatment levels of LC and incident MCE. FINDINGS: Chronic kidney disease was strongly associated with cardiovascular end-points including total mortality. In patients with CKD, a significant benefit of high dose atorvastatin treatment was found for any CV events, stroke and peripheral artery disease, but not for MCE. However, all cardiovascular end-points except stroke and CV mortality were reduced in the non-CKD group. Differential changes in LC or relationships to LC could not explain the different treatment outcomes in MCE in the two groups. INTERPRETATION: Chronic kidney disease was a powerful risk factor for all cardiovascular end-points. The reason why the significant reductions achieved by high-dose statin treatment in most CV end-points in the non-CKD group were only in part matched by similar reductions in the CKD patients is not apparent. This difference did not result from differential changes in or relations to LC, but limited power may have increased the possibility of chance findings.

Well-being in patients with amyotrophic lateral sclerosis and their next of kin over time.

OBJECTIVES: The well-being and physical function among patients with ALS and their next of kin was studied over time. MATERIALS AND METHODS: Thirty-five patients with ALS and their next of kin were studied with respect to physical, general and psychological well-being by the visual analogue scale (VAS) every 4-6 months. Physical function in patients was rated by the ALSFRS-R and the Norris scale. Patients and next of kin rated the well-being of themselves and their counterpart. RESULTS: The well-being was stable and there was a relation between the well-being of patients and next of kin throughout the time studied. Next of kin rated the well-being of the patients worse than patients rated themselves, while patients rated the well-being of their next of kin at the same level as their counterpart. CONCLUSIONS: The basic state of well-being as well as the interaction between patient and next of kin seem to be factors that influence the well-being of both patients and their next of kin.

HDL and LDL as therapeutic targets for cardiovascular disease prevention: the possible role of niacin.

Recently two studies on the effect of addition of extended-release niacin to statin treatment on measures of carotid atherosclerosis were estimated in the ARBITER 6-HALTS study (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) study and the Oxford Niacin Study were published. Adding niacin to statin treatment significantly diminished carotid atherosclerosis as measured by ultrasound carotid intima-media thickness or magnetic resonance imaging. An inhibitor of niacin induced flushing, laropiprant has been developed and demonstrated to considerably improve the tolerability of niacin therapy without impeding on its effect on lipoproteins. Still however clear evidence for the clinical benefit of long-term niacin treatment on cardiovascular morbidity and mortality is lacking. The development situation for ezetimibe is similar to that of niacin. Long-term interventional studies with hard endpoints of both therapies are ongoing. Also both drugs, when proven efficient and safe, are eagerly needed in the prevention of cardiovascular disease.

Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia.

BACKGROUND: Improving lipids beyond low-density lipoprotein cholesterol (LDL-C) lowering with statin monotherapy may further reduce cardiovascular risk. Niacin has complementary lipid-modifying efficacy to statins and cardiovascular benefit, but is underutilised because of flushing, mediated primarily by prostaglandin D(2) (PGD(2)). Laropiprant (LRPT), a PGD(2) receptor (DP1) antagonist that reduces niacin-induced flushing has been combined with extended-release niacin (ERN) into a fixed-dose tablet. METHODS AND RESULTS: Dyslipidaemic patients were randomised to ERN/LRPT 1 g (n = 800), ERN 1 g (n = 543) or placebo (n = 270) for 4 weeks. Doses were doubled (2 tablets/day; i.e. 2 g for active treatments) for 20 weeks. ERN/LRPT 2 g produced significant changes vs. placebo in LDL-C (-18.4%), high-density lipoprotein cholesterol (HDL-C; 20.0%), LDL-C:HDL-C (-31.2%), non-HDL-C (-19.8%), triglycerides (TG; -25.8%), apolipoprotein (Apo) B (-18.8%), Apo A-I (6.9%), total cholesterol (TC; -8.5%), TC:HDL-C (-23.1%) and lipoprotein(a) (-20.8%) across weeks 12-24. ERN/LRPT produced significantly less flushing than ERN during initiation (week 1) and maintenance (weeks 2-24) for all prespecified flushing end-points (incidence, intensity and discontinuation because of flushing). Except for flushing, ERN/LRPT had a safety/tolerability profile comparable with ERN. CONCLUSION: Extended-release niacin/LRPT 2 g produced significant, durable improvements in multiple lipid/lipoprotein parameters. The improved tolerability of ERN/LRPT supports a simplified 1 g-->2 g dosing regimen of niacin, a therapy proven to reduce cardiovascular risk.

Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S.

BACKGROUND: Patients with low HDL cholesterol (HDL-C) and elevated triglyceride had an increased risk for coronary heart disease (CHD) events and received the greatest benefit with fibrate therapy in substudy analyses of the Helsinki Heart Study and the Bezafibrate Infarction Prevention Study. METHODS AND RESULTS: In this post hoc analysis of the Scandinavian Simvastatin Survival Study, which enrolled patients with elevated LDL cholesterol (LDL-C) and CHD, subgroups defined by HDL-C and triglyceride quartiles were compared to examine the influence of HDL-C and triglyceride on CHD events and response to therapy. Patients in the lowest HDL-C (<1.00 mmol/L [39 mg/dL]) and highest triglyceride (>1.80 mmol/L [159 mg/dL]) quartiles (lipid triad; n=458) had increased proportions of other features of the metabolic syndrome (increased body mass index, hypertension, diabetes), men, prior myocardial infarction, prior revascularization, and beta-blocker use than patients in the highest HDL-C (>1.34 mmol/L [52 mg/dL]) and lowest triglyceride (<1.11 mmol/L [98 mg/dL]) quartiles (isolated LDL-C elevation; n=545). The major coronary event rate was highest in lipid triad patients on placebo (35.9%), and this subgroup had the greatest event reduction (relative risk 0.48, 95% CI 0.33 to 0.69); a significant treatment-by-subgroup interaction (P=0.03) indicated a greater treatment effect in the lipid triad subgroup than the isolated LDL-C elevation subgroup. CONCLUSIONS: Patients with elevated LDL-C, low HDL-C, and elevated triglycerides were more likely than patients with isolated LDL-C elevation to have other characteristics of the metabolic syndrome, had increased risk for CHD events on placebo, and received greater benefit with simvastatin therapy.

Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study.

BACKGROUND: Long-term safety is an important consideration in the selection and use of drugs, such as lipid-lowering agents, that are prescribed to reduce the risk of clinical events during long periods. METHODS: The Scandinavian Simvastatin Survival Study was designed to evaluate the effects of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease. The 4444 patients aged 35 to 70 years (mean, 58.9 years) with angina pectoris or previous myocardial infarction and serum cholesterol levels of 5.5 to 8.0 mmol/L (213-310 mg/dL) receiving a lipid-lowering diet were randomly assigned to take double-blind treatment with simvastatin, 20 to 40 mg once daily, or placebo. In addition to previously reported end-point events, detailed clinical and laboratory safety data were collected during a median follow-up period of 5.4 years (range in survivors, 4.9-6.2 years). RESULTS: The only clearly drug-related serious adverse event during the 5.4-year median follow-up period was a single reversible case of myopathy. The frequencies of persistent elevations of hepatic aminotransferase levels above 3 times the upper limit of normal and of nonviral hepatitis in the simvastatin and placebo treatment groups were not significantly different. Examination of the lens showed no between-group differences, and no previously unrecognized adverse effects of the drug were observed. There were no significant between-group differences in adverse events in any body system. In particular, the frequency of adverse events related to the central nervous system was similar in both groups. CONCLUSION: The safety profile of simvastatin, 20 to 40 mg daily, over 5 years was excellent.

Long-term improvement of glycemic control by insulin treatment in NIDDM patients with secondary failure.

OBJECTIVE: To evaluate the long-term efficacy of insulin treatment of patients with non-insulin-dependent diabetes mellitus (NIDDM) and secondary failure to oral hypoglycemic agents. RESEARCH DESIGN AND METHODS: Twenty-one NIDDM patients with secondary failure were studied while they were still on oral agents. Then they were switched to insulin treatment, and after a median of 27 months, a long-term evaluation was conducted. RESULTS: At the long-term evaluation, metabolic control was still markedly improved by insulin treatment, with reduction of HbA1c from 8.8 +/- 0.2 (mean +/- SE) to 6.9 +/- 0.3% (P < 0.0001), lowering of very-low-density lipoprotein (VLDL) cholesterol concentration from 0.97 +/- 0.3 to 0.69 +/- 0.1 mM (P < 0.03), and lowering of total triglycerides from 2.8 +/- 0.6 to 1.8 +/- 0.3 mM (P < 0.005), mainly due to reduction of VLDL triglycerides. Body weight increased during the first year, but not thereafter (71.3 +/- 2.5 kg during oral treatment, 78.9 +/- 2.9 and 79.8 +/- 3.2 kg after 12 and 36 months of insulin treatment, respectively). Blood pressure did not change. Fasting and postprandial insulin concentrations increased, and C-peptide concentrations were lowered. CONCLUSIONS: Improvements of glycemic control and lipoprotein concentrations in patients with NIDDM and secondary failure persist also after insulin treatment for 2-3 years in spite of weight gain and hyperinsulinemia.

Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S)

OBJECTIVE: To assess in diabetic patients with coronary heart disease (CHD) the effect of cholesterol lowering with simvastatin on mortality and the risk of CHD and other atherosclerotic events. RESEARCH DESIGN AND METHODS: A post hoc subgroup analysis was carried out on data from 202 diabetic patients and 4,242 nondiabetic patients with previous myocardial infarction or angina pectoris, serum total cholesterol 5.5-8.0 mmol/l, and serum triglycerides < or = 2.5 mmol/l who were participating in the Scandinavian Simvastatin Survival Study (4S). Participants in the 4S were randomly assigned to double-blind treatment with simvastatin, 20 mg daily, with blinded dosage titration up to 40 mg daily, according to cholesterol response during the first 6-18 weeks, or placebo. Endpoints were 1) total mortality, 2) major CHD events (CHD death or nonfatal myocardial infarction), 3) other acute atherosclerotic events, 4) myocardial revascularization procedures. RESULTS: Over the 5.4-year median follow-up period, simvastatin treatment produced mean changes in serum lipids in diabetic patients similar to those observed in nondiabetic patients. The relative risks (RRs) of main endpoints in simvastatin-treated diabetic patients were as follows: total mortality 0.57 (95% CI, 0.30-1.08; P = 0.087), major CHD events 0.45 (95% CI, 0.27-0.74; P = 0.002), and any atherosclerotic event 0.63 (95% CI, 0.43-0.92; P = 0.018). The corresponding RRs in nondiabetic patients were the following: 0.71 (95% CI, 0.58-0.87; P = 0.001), 0.68 (95% CI, 0.60-0.77; P < 0.0001), and 0.74 (95% CI, 0.68-0.82; P < 0.0001). CONCLUSIONS: The results strongly suggest that cholesterol lowering with simvastatin improves the prognosis of diabetic patients with CHD. The absolute clinical benefit achieved by cholesterol lowering may be greater in diabetic than in nondiabetic patients with CHD because diabetic patients have a higher absolute risk of recurrent CHD events and other atherosclerotic events.

Reduction of exercise-induced ST segment depressions following long-term serum lipid lowering by drugs in hyperlipoproteinaemia.

The effect of serum lipid-lowering drug treatment for a mean time of more than 5 years on the development of ischaemic ECG response to exercise has been studied in 34 asymptomatic subjects with hyperlipoproteinaemia. Seventy percent of the subjects had ischaemic exercise response at a first test. After treatment 10 subjects had improved and 9 deteriorated. Improvement of the ischaemic response was related to a decrease in low density lipoprotein (LDL) cholesterol as the only parameter significantly differing from those who developed a more marked ischaemia. For confirmation, controlled study of the influence of serum lipid lowering on the ischaemic exercise ECG response are necessary. The present finding indicates that marked lowering of LDL cholesterol might decrease the ischaemic response seen in hyperlipidaemia.

Prostaglandin E1 inhibits DNA synthesis in arterial smooth muscle cells stimulated with platelet-derived growth factor.

The effect of prostaglandins (PG) on initiation of DNA synthesis in arterial smooth muscle cells (SMC) stimulated with platelet-derived growth factor (PDGF) was examined. A concentration of 10 ng/ml PGE1 inhibited DNA synthesis, measured as autoradiographically labeled nuclei, by about 70%. Similar results were obtained with PGE2 and PGD2 but at concentrations 10-20 times higher, whereas PGF2 alpha lacked effect. The inhibitory action of the prostaglandins was restricted to the first 6 h of the lag phase. Treatment with PGE1 also raised the intracellular concentration of cyclic AMP, indicating that the inhibition may be mediated via changes in the levels of cyclic nucleotides.

Acute effects of cholestyramine on serum lipoprotein concentrations in type II hyperlipoproteinaemia.

Twelve subjects with primary type IIA hyperlipoproteinaemia were treated with cholestyramine under metabolic ward conditions in order to study the timing of effects of different serum lipoprotein classes. After 1 day's treatment changes occurred in all 3 classes, i.e., very low (VLDL), low (LDL) and high (HDL) density lipoprotein classes. VLDL increased abruptly and remained constant during treatment. The ratio of cholesterol/triglycerides decreased suggesting the formation of larger particles. LDL cholesterol decreased continuously suggesting a different mechanism behind this effect than that on VLDL. LDL triglyceride remained constant indicating a relative increase of LDL1. HDL cholesterol decreased while HDL triglycerides increased. All changes made the lipoprotein pattern more "type IV-like". The findings were in agreement with an increased formation of VLDL and an increased flux of lipoprotein through the cascade VLDL-IDL-LDL1-LDL2.

Dose-response study of the effect of ciprofibrate on serum lipoprotein concentrations in hyperlipoproteinaemia.

The effect of ciprofibrate, 2[p-(2,2-dichlorocyclopropyl)-phenoxyl]-2-methyl propionic acid, in daily doses of 50, 100, and 200 mg was studied in 50 patients with hyperlipoproteinaemia (21 type IIA, 10 type IIB and 19 type IV). Ciprofibrate was convenient to take and was without subjective side effects. The greatest hypolipidaemic effects were reached for all lipoproteins with 200 mg daily. In type IIA and IIB, mean low density lipoprotein (LDL) cholesterol was normalized on the 200 mg dose. The effect was highly dependent on initial LDL cholesterol concentrations, decreases being observed above 4 mmol/l and increases below that concentration. Mean very low density lipoprotein (VLDL) triglyceride concentrations decreased on 200 mg per day by 48-59%. HDL cholesterol increased in all types of hyperlipoproteinaemia by 6-19%, the change being unrelated to changes in VLDL lipids. With a dosage of 200 mg daily the effects were maintained for the following period of 6 months. It is concluded from this study that it would be appropriate to start patients on 100 mg daily and then titrate their dose according to response. The optimal dosage for ciprofibrate seems to be 200 mg daily.

Effects of combined procetofene--nicotinic acid therapy in treatment of hypertriglyceridaemia.

Eight males with hypertriglyceridaemia were treated with a combination of procetofene (400 mg/day) and nicotinic acid (4 g/day) for 6 weeks. Previous therapy with only procetofene (400 mg/day) had given a certain, but not complete degree of normalisation. The combined treatment lowered the VLDL TG concentration values from 3.21 to 1.11 mmol/l and increased the HDL cholesterol concentration from 1.04 to 1.43 mmol/l (P less than 0.05 for both). The significant LDL cholesterol increase from 4.45 to 5.27 mmol/l, observed during treatment with procetofene only, reverted to 4.05 mmol/l when combined therapy was given. This drug combination may be a valuable tool to obtain maximum reduction of elevated TG in the therapy of hypertriglyceridaemia.

Dose-response study of bezafibrate on serum lipoprotein concentrations in hyperlipoproteinanemia.

The effect of bezafibrate in the dosages 450, 900 and 1350 mg daily on serum lipoprotein concentrations were studied in 20 subjects with primary hyperlipoproteinaemia (16 of type IV, 2 of type II B, 1 of type III). Except for LDL cholesterol maximum effects were obtained with 450 mg daily. Total serum cholesterol and triglycerides (TG) fell significantly. Mean very low density lipoprotein (VLDL) TG fell by 54%. The maximum effect on low density lipoprotein was obtained with 900 mg daily. The effect was highly dependent on initial concentrations, decreases being observed above 4 mmoles/l and increases below that concentration. High density lipoprotein cholesterol increased by 31% (P less than 0.01) independently of the VLDL decrease. Three subjects suffered gastrointestinal side-effects on 1350 mg daily. Only benign reversible changes were noted on non-lipid measurements. Bezafibrate is a well-tolerated drug with a good VLDL TG lowering effect. It is particularly effective in increasing HDL cholesterol concentrations.

One-year study of the effect of bezafibrate on serum lipoprotein concentrations in hyperlipoproteinaemia.

The effect of bezafibrate (2-(4-[2-(4-chlorobenzamido)-ethyl]-phenoxy)-2-methylporopionic acid) (450 mg daily) on serum lipoprotein concentrations was studied for 1 year in 14 subjects with hyperlipoproteinaemia (3 of type II A, 2 of type II B, 2 of type III and 7 of type IV). After 2 months serum cholesterol decreased from 7.12--6.08 mmoles/l (15% P less than 0.01), triglycerides from 2.52--1.96 mmoles/l (22%, P less than 0.01), very low density lipoprotein triglycerides from 1.48--0.86 mmoles/l (42%, P less than 0.01) and low density lipoprotein cholesterol from 5.00--3.81 mmoles/l (24%, P less than 0.01). While triglyceride concentrations of serum and lipoproteins remained constant for 1 year, serum and LDL cholesterol concentrations increased slightly after 6 and 12 months. The former rise was partly due also to a rise of the possibly beneficial high density lipoprotein cholesterol from 1.27--1.68 mmoles/l (32%, P less than 0.01) after 6 months, making the effect on total cholesterol less pronounced. Subjective side-effects were nausea in one patient. No severe biochemical side-effects were noted.

Plasma high density lipoprotein particle size alteration by simvastatin treatment in patients with hypercholesterolaemia.

Twenty-two patients with pronounced hypercholesterolaemia were treated with simvastatin in increasing doses, i.e. 10, 20 and 40 mg O.D. Each treatment regimen had a duration of 6 weeks. In addition to the expected low density lipoprotein (LDL)-lowering effect, simvastatin altered the plasma HDL particle size spectrum by selective elevation of the plasma HDL2b and HDL3a levels, as defined by polyacrylamide gradient gel electrophoresis (gge). While the reduction in LDL cholesterol by simvastatin was dose dependent, the effect on HDL was maximal already at 10 mg daily. On treatment with simvastatin 10 mg O.D., the plasma HDL2b and HDL3a concentrations increased by 30% (P less than 0.001) and 12% (P less than 0.01) respectively. On the corresponding treatment with simvastatin LDL cholesterol decreased by 31% (P less than 0.001). The very low density lipoprotein (VLDL) cholesterol to triglyceride ratio was significantly lowered by treatment with 10 mg simvastatin O.D. suggesting a compositional change in VLDL. Positive univariate correlations between treatment-induced decreases in plasma HDL3b/3c levels and VLDL triglyceride concentration were seen. It is suggested that inhibition of cholesterol synthesis in hypercholesterolaemic subjects by simvastatin treatment alters the composition of VLDL, which may affect the close relation between HDL and VLDL, in turn producing selective elevations of the plasma HDL2b and HDL3a levels.

Alfalfa seeds lower low density lipoprotein cholesterol and apolipoprotein B concentrations in patients with type II hyperlipoproteinemia.

Fifteen patients with hyperlipoproteinemia (HLP), types IIA (n = 8), IIB (n = 3) and IV (n = 4) were given 40 g of heat prepared alfalfa seeds 3 times daily at mealtimes for 8 weeks with otherwise unchanged diet. In patients with type II HLP alfalfa treatment caused after 8 weeks a maximal lowering of pretreatment median values of total plasma cholesterol from 9.58 to 8.00 mmol/l (P less than 0.001) and low density lipoprotein (LDL) cholesterol from 7.69 to 6.33 mmol/l (P less than 0.01), which corresponds to decreases of 17% and 18%, respectively. Maximal decrease was 26% in total cholesterol and 30% in LDL cholesterol. In two patients with hypercholesterolemia the LDL cholesterol decreased less than 5%. Apolipoprotein B decreased in the same period from 2.17 to 1.43 g/l (P less than 0.05) in type II HLP, corresponding to 34% decrease, whereas apolipoprotein A-I did not change. Body weight increased slightly during the first 4 weeks of alfalfa treatment (P less than 0.001) probably because of the caloric content in the alfalfa seeds. After cessation of treatment, all lipoprotein concentrations returned to pretreatment levels. We conclude that alfalfa seeds can be added to the diet to help normalize serum cholesterol concentrations in patients with type II HLP.

Acute effect of dietary therapy of type IV hyperlipoproteinaemia on the serum and lipoprotein concentrations and relative composition.

In a detailed study the acute effect of diet and hospital admission on the plasma and lipoprotein lipid concentrations and composition was studied in 28 patients with type IV hyperlipoproteinaemia. Within 6 days there were significant falls in the mean serum cholesterol and triglycerides, very low density lipoprotein (VLDL) cholesterol and triglycerides and in high density lipoprotein triglycerides. These changes were accompanied by a significant rise in the mean low density lipoprotein (LDL) cholesterol concentrations. Using multiple regession models highly significant predictions of the change in VLDL triglyceride (R2 = 0.71) and LDL cholesterol (R2 = 0.47) were obtained utilising the pre-treatment lipoprotein levels as independant variables. Since elevated LDL cholesterol concentations are associated with atherosclerotic disease such models may have important therapeutic applications.

Dose-response effect of single and combined clofibrate (Atromidin) and niceritrol (Perycit) treatment on serum lipids and lipoproteins in type II hyperlipoproteinaemia.

The dose-response effects of clofibrate and niceritrol on serum cholesterol and triglycerides (TG) were studied in 29 patients with Type IIa and IIb hyperlipoproteinaemia. In 17 patients, clofibrate and niceritrol were then given as combined treatment, and the effects of this combination on serum lipoproteins were studied. Clofibrate was given in three doses: 1.5,2 and 2.5 g/day. The optimum effect on serum TG and cholesterol in patients with Type IIa was observed with the 1.5 g dose and higher doses did not lower the serum lipids further. In patients with Type IIb the optimal clofibrate dose was 1.5-2 g/day. Niceritrol was then given in three doses: 3,45 and 6 g/day. In patients with Type IIa the serum TG concentration was not significantly affected by any dose used, whereas the reduction of the serum cholesterol concentration was dose dependent. In patients with Type IIb the reduction of both serum TG and cholesterol was dose dependent. Combined treatment with 2 g clofibrate and 3 g niceritrol resulted in a normal lipoprotein pattern i 15 out of 17 patients. The reduction of the serum lipids was approximately the same as during treatment with 6 g niceritrol/day. No additional side-effects were observed during combined treatment.