Treatment
targets in type 2 diabetes: non-HDL rather than LDL cholesterol?
Michaela Diamant
Diabetes Center/Department of Endocrinology, Vrije Universiteit
Medical Center, Amsterdam, The Netherlands
Correspondence: Dr M. Diamant, Diabetes Center/Department of
Endocrinology,
Vrije Universiteit Medical Center, De Boelelaan 1117, P.O. Box
7057, 1007 MB Amsterdam, The Netherlands. Tel: +31 20 4444444,
fax: +31 20 4440502, e-mail:
m.diamant@azvu.nl
The major cause of mortality in type 2 diabetes
mellitus is coronary heart disease (CHD). Type 2 diabetic patients
have a two- to fourfold increased relative risk of CHD in comparison
with age-matched nondiabetic subjects.[1,2]
The simultaneous presence of multiple ‘classic’ risk factors in
patients with type 2 diabetes only partly accounts for the excessive
risk of developing CHD in this population.[1,2]
Although hyperglycemia is strongly associated with microvascular
complications (retinopathy and nephropathy), the relation with
macrovascular disease in type 2 diabetes is less certain. In particular,
data from the largest and longest trial ever conducted in type
2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS),
showed a nonsignificant 16% decrease in CHD risk at 10 years’
follow-up in a comparison of intensified vs. conventional glycemic
control (ie, averaged glycated hemoglobin 7.0% vs. 7.9%).[3]The
UKPDS did not investigate the effect of lipid-lowering on micro-
and macrovascular endpoints, but in a separate analysis, low-density
lipoprotein (LDL) cholesterol was identified as the major risk
factor for macrovascular disease in the UKPDS population.[4]
This finding may provide one of the possible explanations for
the weak relation between glycemic control and CHD risk in the
UKPDS, as previous studies showed that LDL is barely affected
by glycemia.[5,6]
Patients with type 2 diabetes have an increased frequency of dyslipidemia,
which is invariably linked to the presence of insulin resistance
and central obesity.[7–10] Elevated concentrations
of triglyceride-rich lipoproteins, especially very-low-density
lipoprotein (VLDL), and decreased levels of high-density lipoprotein
(HDL), measured as HDL cholesterol, are the most characteristic
lipoprotein abnormalities in type 2 diabetes.[8,10]
Most patients with type 2 diabetes have concentrations of LDL
cholesterol which are similar to those of nondiabetic subjects;[10]
however, in type 2 diabetes there are important qualitative changes
in LDL, including the preponderance of smaller and denser particles,
and modifications through glycation and oxidation which increase
their atherogenicity.[7–10]
Recently, studies investigating derangements of postprandial lipid
metabolism in type 2 diabetes and their atherogenic potential,[11–13]
have revived interest in the concept that atherosclerosis may
be a postprandial phenomenon, which was formulated by Zilversmit
more than 20 years ago.[14] Indeed, evidence
from clinical studies suggests that postprandial lipemia, characterized
by a long residence time of triglyceride-rich remnants in the
circulation and subsequent decrease in HDL levels, is an independent
risk factor for CHD.[11,15]
In view of their lipid profile, patients with type 2 diabetes
may be regarded as permanently postprandial.
This review elaborates upon the lipoprotein abnormalities in type
2 diabetes and the underlying mechanisms, all of which are strongly
associated with insulin resistance. In view of the interrelationship
of the lipoprotein abnormalities and their atherogenic potential,
it is suggested that both fasting and postprandial levels of triglyceride-rich
lipoproteins (collectively termed non-HDL cholesterol), rather
than LDL cholesterol, may be a more appropriate therapeutic target
in type 2 diabetes.
Physiology of lipoprotein metabolism
In order to enable understanding of the lipoprotein abnormalities
in type 2 diabetes, the physiology of the lipoprotein metabolic
cascades is summarized below.
Lipoprotein metabolism can be divided into two major pathways,
the apolipoprotein (apo) B-lipoprotein and HDL pathways.[16,17]
The apo B-lipoprotein pathway consists of a cascade of lipoproteins
containing either the apo B-48 or the apo B-100 isoform of the
B apolipoprotein secreted from the intestine or liver, respectively.
The triglyceride-rich apo B-48-containing chylomicrons transport
dietary lipids from the intestine to the liver and peripheral
tissues. The catabolism of the triglyceride-rich chylomicrons
is initiated by the endothelial enzyme, lipoprotein lipase (LPL),
which hydrolyzes the triglyceride core of the chylomicrons and
releases fatty acids for energy production in muscle and for storage
in adipose tissue (Figure 1).
Figure 1. Schematic overview of lipoprotein metabolic pathways
in type 2 diabetes. Increased endogenous very-low-density lipoprotein
(VLDL) production, elevated postprandial triglyceride (TG) concentrations,
and impaired endothelial lipoprotein lipase (LPL) activity lead
to raised plasma concentrations of TG-rich lipoproteins (LP).
High TG-rich lipoprotein concentrations increase the transfer
of TG to low-density lipoprotein (LDL) and high-density lipoprotein
(HDL), and simultaneous transfer of cholesteryl esters (CE) from
LDL and HDL to TG-rich lipoproteins, mediated by cholesteryl ester
transfer protein (CETP). Hydrolysis of core TG by hepatic lipase
(HL) produces small, dense (lipid-poor and protein-enriched) LDL
that are modified (eg. by oxidation or glycation). Similarly,
small, dense HDL particles are produced that have a higher catabolic
rate and may be dysfunctional with regard to reverse cholesterol
transport. IDL, intermediate-density lipoprotein; FA, fatty acids.
Adapted from ref. 8.
The chylomicron remnants are taken up by the liver
by the LDL-receptor-related protein and LDL receptors, which have
a high affinity for apo E.[18]
In a parallel cascade, the liver assembles triglyceride-rich VLDL-containing
apo B-100, which, similarly to chylomicrons, undergoes hydrolysis
by LPL and is remodeled to intermediate-density lipoprotein (IDL)
and partly further to LDL (Figure 1). The latter step involves
another enzyme, hepatic lipase (HL). VLDL remnants and IDL-containing
apo E are removed by hepatic LDL receptors and LDL-receptor-related
protein receptors.[18,19] LDL contains only
apo B-100 and is metabolized by two pathways: it may be taken
up into the liver by an LDL-receptor-mediated mechanism, but it
also may become modified or oxidized and removed by the scavenger
receptor-A or CD36 scavenger receptors on macrophages.[18,20]
In the HDL pathway, HDL is synthesized as nascent HDL particles
from both the liver and intestine as well as by transfer of lipids
and apolipoproteins during the metabolism of triglyceride-rich
chylomicrons and VLDL. A major function of HDL is the transport
of excess cellular cholesterol from peripheral cells to the liver,
a process called reverse cholesterol transport (RCT).[21–23]
RCT is initiated by the removal of nonesterified or free cholesterol
from cells mediated by the ATP-binding cassette transporter ABCA1
(formerly ABC1).[24] In plasma, free cholesterol
on nascent HDL is converted to cholesteryl ester (CE) by lecithin
cholesterol acyltransferase.[21,23]
The CE synthesized on HDL can be transferred to apo B-containing
lipoproteins by the cholesteryl ester transfer protein (CETP)
in exchange for triglycerides (Figure 1).[23]
Hepatocytes remove CE from HDL and apo B-containing lipoproteins
either by direct uptake of the whole lipoprotein particle (mediated
by LDL- and LDL-receptor-related protein receptors) or by selective
removal of CE from the particle (mediated by the scavenger receptor
BI).[25]
Lipoprotein metabolism in type 2 diabetes:
the impact of insulin
resistance
In type 2 diabetes, insulin resistance and visceral obesity have
a major impact on the regulatory processes of both the apo B-lipoprotein
and the HDL pathways. Many steps in the lipoprotein metabolic
cascades are insulin-sensitive.[7,8]
Apo B-lipoprotein pathway in type 2 diabetes
The insulin-resistant state impairs the normal suppression of
free fatty acid (FFA) release from the abundantly present adipose
tissue. This increased flux of FFA to the liver is a major stimulus
for overproduction of VLDL.[7,10]
Postprandially, independent of the FFA flux, hepatic VLDL production
is not normally suppressed, resulting in competition for LPL with
exogenous triglycerides carried on chylomicrons.[26]
LPL activity is lower in type 2 diabetics than in nondiabetic
subjects and increases with improved glycemic control.[8]
Thus, the raised concentration of triglyceride-rich lipoproteins
in type 2 diabetes is due to hepatic overproduction of VLDL and
impaired clearance of apo B-containing remnant particles (Figure
1).
The prolonged circulating time of high triglyceride-rich lipoprotein
particles allows longer exposure to CETP, which facilitates transfer
of cholesterol from LDL and HDL to VLDL and chylomicrons in exchange
for triglycerides.[5] The enhanced transfer
of triglycerides to LDL renders them better substrates for HL.
HL hydrolyzes triglycerides from the core of LDL and turns them
into smaller and denser LDL particles. The same holds true for
modification of HDL (see below). Small, dense LDL particles and
triglyceride-rich lipoproteins readily enter the artery wall and
show substantial intimal retention, an important step in the development
of atherosclerosis.[27,28] Retained lipoprotein
particles may then undergo enzymatic or oxidative modifications.[28]
These qualitative changes may increase the atherogenicity of LDL
particles in type 2 diabetes.[8,10]
Epidemiological studies have shown a relation between small-sized
LDL particles and the risk of myocardial infarction in nondiabetic
populations.[29,30] In type 2 diabetes, small
LDL particles from patients were associated with reduced endothelium-dependent
arterial dilation, which is a surrogate marker for cardiovascular
risk.[31] It should be noted, however, that
prospective studies evaluating the role of small, dense LDL particles
in atherogenesis in type 2 diabetes are still awaited.
An inverse relationship exists between hypertriglyceridemia and
the number of small, dense LDL particles.[32,33]
Indeed, lowering triglyceride levels in type 2 diabetes using
fibrates was shown to increase LDL particle size.[34]
HDL pathway in type 2 diabetes
The above-described changes in apo B-lipoprotein metabolism in
type 2 diabetes strongly affect the HDL pathway and consequently
its antiatherogenic potential. In type 2 diabetes, analogous to
LDL, triglyceride-enriched HDL is readily modified into small,
dense HDL, which has an increased metabolic rate and helps to
explain the low HDL concentration. Also, modified HDL in type
2 diabetes has been associated with CHD because its compositional
changes may lead to impaired RCT.[35,36] It
has been suggested that other abnormalities in the RCT cascade
may contribute to the development of CHD in type 2 diabetes. Both
increased and decreased CETP activity have been described in type
2 diabetes.[37,38] Although as yet this controversy
has not been conclusively settled, population studies indicate
that with regard to the development of atherosclerosis, plasma
HDL rather than CETP levels may be of more importance.
Postprandial lipid abnormalities in type
2 diabetes
In healthy subjects, the duration of the postprandial state depends
on the composition of the meal: after a meal consisting mainly
of carbohydrates, a return to the basal state occurs within 2–3
h, after a mixed meal it takes 3–5 h, and after a fat-rich meal
the return to baseline may take as long as 8–10 h.[39]
Since most individuals eat intermittently throughout daylight
hours, they are postprandial for about 18 h of each 24-h day.[40]
In view of their abnormal lipoprotein profile, type 2 diabetic
patients may be regarded as postprandial throughout 24 h. Following
a fat-enriched meal, the rise in triglyceride-rich lipoprotein
concentrations is greater in type 2 diabetic patients than in
nondiabetic subjects, and the fasting level of triglyceride-rich
lipoproteins is positively correlated with the area under the
curve for plasma triglyceride levels after the meal (Figure 2).[41]
 Figure
2. Postprandial changes in triglyceride levels in patients
with type 2 diabetes mellitus: relation to fasting triglyceride
level. Adapted from ref. 41
This postprandial lipemia is due to an impaired
suppression of hepatic VLDL synthesis after meals and the competition
of chylomicrons and their remnants with endogenous VLDL particles
for common removal pathways through LPL (Figure 1). These mechanisms,
which are linked to insulin resistance, collectively result in
prolonged exposure of arteries to potentially atherogenic triglyceride-enriched
particles. Also, postprandial lipid disturbances have been associated
with alterations in coagulation mechanisms that predispose them
to arterial thrombosis.[42,43] Recent studies
have demonstrated impaired endothelium-dependent vasodilation
following a fatty meal both in healthy subjects and in type 2
diabetic patients.[44,45] In addition, an association was found
between postprandial levels of triglyceride-rich remnants and
the severity of coronary artery disease in type 2 diabetic patients.[13]
The true atherogenic potential of postprandial dyslipidemia in
type 2 diabetes, however, still has to be demonstrated in outcome
studies.
Atherogenicity of diabetic dyslipidemia:
the case for non-HDL particles
There have been frequent attempts to determine which of the dyslipidemic
alterations in type 2 diabetes is the most atherogenic, and to
assign an independent risk status to changes in the individual
lipoproteins.
Based on a large body of evidence, current clinical guidelines
have identified LDL as the major atherogenic lipoprotein and the
primary target of lipid-lowering therapy.[46]
As stated before, patients with type 2 diabetes do not have marked
elevations of LDL cholesterol; however, the importance of LDL
as a risk factor for CHD in diabetic patients has been demonstrated
in subgroup analyses of the major secondary prevention trials,
such as the Scandinavian Simvastatin Survival Study, the Cholesterol
and Recurrent Events trial, and the Long-term Intervention with
Pravastatin in Ischemic Disease trial.[47–49]
In all these trials intensive LDL-lowering therapy reduced recurrent
CHD events in type 2 diabetic patients.
In view of the close association between the lipoprotein abnormalities
in type 2 diabetes, mere estimates of LDL cholesterol levels may
underestimate the total atherogenic risk potential associated
with the total apo B-containing lipoprotein fractions and low
(modified) HDL. And, although no prospective trials have been
conducted on the effects of lipid-lowering agents on subsequent
CHD specifically in diabetic populations, several prospective
studies in type 2 diabetics have convincingly shown a strong association
between the different lipoprotein abnormalities and CHD in these
patients. Thus, triglyceride levels were positively associated
with increased risk for CHD in populations with type 2 diabetes.[50–52]
In a 7-year prospective study in type 2 diabetics, low HDL, HDL2
cholesterol, and high levels of total and VLDL triglycerides and
VLDL cholesterol were all found to be powerful risk indicators
for CHD events.[52] In the UKPDS, beside LDL
cholesterol, decreased HDL cholesterol was identified as an indicator
of CHD.[4]
Thus, it appears that in type 2 diabetes all major lipoprotein
abnormalities, including elevated triglyceride-rich lipoproteins,
low (modified) HDL cholesterol, and small, dense (modified) LDL
particles, constitute the atherogenic phenotype independent of
LDL cholesterol levels.[53,54] In patients
with type 2 diabetes, all these derangements are present in the
fasting and, even more so, in the postprandial state. In view
of their atherogenic properties, therapeutic interventions in
patients with type 2 diabetes should be aimed at lowering fasting
and postprandial levels of triglyceride-rich lipoproteins, also
termed non-HDL particles.[53] Table I lists
the lipoprotein abnormalities in type 2 diabetes and their proposed
atherogenic potential, which needs to be confirmed in prospective
studies.
 Table
I. Lipoprotein particles in type 2 diabetes and their atherogenic
potential.
At present, several trials are underway that investigate the effects
of different lipid-lowering strategies on CHD morbidity and mortality
in type 2 diabetic populations or populations containing significant
numbers of type 2 diabetic patients. These trials and their potential
clinical impact have been reviewed only recently.[55]
The results of these trials are awaited with great excitement
since they will provide the evidence base for specific recommendations
for the place of lipid-modifying therapy in these high-risk patients.
Acknowledgment
The author thanks Robert J. Heine for his helpful comments and
criticism of the manuscript.
REFERENCES
-
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George Lyman Duff Memorial Lecture. Atherogenesis in diabetes.
Bierman EL.
Department of Medicine, University of Washington, Seattle 98195.
Publication Types:
 |
Review
|
|
Review, tutorial |
PMID: 1591228 [PubMed - indexed for MEDLINE]
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Diabetes, other risk factors, and 12-yr cardiovascular mortality
for men screened in the Multiple Risk Factor Intervention Trial.
Stamler J, Vaccaro O, Neaton JD, Wentworth D.
Department of Preventive Medicine, Northwestern University Medical
School, Chicago, Illinois 60611-4402.
OBJECTIVE--To assess predictors of CVD mortality among men with
and without diabetes and to assess the independent effect of
diabetes on the risk of CVD death. RESEARCH DESIGN AND METHODS--Participants
in this cohort study were screened from 1973 to 1975; vital
status has been ascertained over an average of 12 yr of follow-up
(range 11-13 yr). Participants were 347,978 men aged 35-57 yr,
screened in 20 centers for MRFIT. The outcome measure was CVD
mortality. RESULTS--Among 5163 men who reported taking medication
for diabetes, 1092 deaths (603 CVD deaths) occurred in an average
of 12 yr of follow-up. Among 342,815 men not taking medication
for diabetes, 20,867 deaths were identified, 8965 ascribed to
CVD. Absolute risk of CVD death was much higher for diabetic
than nondiabetic men of every age stratum, ethnic background,
and risk factor level--overall three times higher, with adjustment
for age, race, income, serum cholesterol level, sBP, and reported
number of cigarettes/day (P < 0.0001). For men both with
and without diabetes, serum cholesterol level, sBP, and cigarette
smoking were significant predictors of CVD mortality. For diabetic
men with higher values for each risk factor and their combinations,
absolute risk of CVD death increased more steeply than for nondiabetic
men, so that absolute excess risk for diabetic men was progressively
greater than for nondiabetic men with higher risk factor levels.
CONCLUSIONS--These findings emphasize the importance of rigorous
sustained intervention in people with diabetes to control blood
pressure, lower serum cholesterol, and abolish cigarette smoking,
and the importance of considering nutritional-hygienic approaches
on a mass scale to prevent diabetes.
Publication Types:
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Multicenter study |
PMID: 8432214 [PubMed - indexed for MEDLINE]
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Erratum in:
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Lancet 1999 Aug 14;354(9178):602 |
Comment in:
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ACP J Club. 1999 Jan-Feb;130(1):2-3
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|
Lancet. 1998 Dec 12;352(9144):1932-3;
discussion 1934
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Lancet. 1998 Dec 12;352(9144):1932;
discussion 1934
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Lancet. 1998 Dec 12;352(9144):1933;
discussion 1934
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Lancet. 1998 Dec 12;352(9144):1934
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Lancet. 1998 Sep 12;352(9131):832-3
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Lancet. 1999 May 29;353(9167):1882 |
Intensive blood-glucose control with sulphonylureas or insulin
compared with conventional treatment and risk of complications
in patients with type 2 diabetes (UKPDS 33). UK Prospective
Diabetes Study (UKPDS) Group.
BACKGROUND: Improved blood-glucose control decreases the progression
of diabetic microvascular disease, but the effect on macrovascular
complications is unknown. There is concern that sulphonylureas
may increase cardiovascular mortality in patients with type
2 diabetes and that high insulin concentrations may enhance
atheroma formation. We compared the effects of intensive blood-glucose
control with either sulphonylurea or insulin and conventional
treatment on the risk of microvascular and macrovascular complications
in patients with type 2 diabetes in a randomised controlled
trial. METHODS: 3867 newly diagnosed patients with type 2 diabetes,
median age 54 years (IQR 48-60 years), who after 3 months' diet
treatment had a mean of two fasting plasma glucose (FPG) concentrations
of 6.1-15.0 mmol/L were randomly assigned intensive policy with
a sulphonylurea (chlorpropamide, glibenclamide, or glipizide)
or with insulin, or conventional policy with diet. The aim in
the intensive group was FPG less than 6 mmol/L. In the conventional
group, the aim was the best achievable FPG with diet alone;
drugs were added only if there were hyperglycaemic symptoms
or FPG greater than 15 mmol/L. Three aggregate endpoints were
used to assess differences between conventional and intensive
treatment: any diabetes-related endpoint (sudden death, death
from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial
infarction, angina, heart failure, stroke, renal failure, amputation
[of at least one digit], vitreous haemorrhage, retinopathy requiring
photocoagulation, blindness in one eye, or cataract extraction);
diabetes-related death (death from myocardial infarction, stroke,
peripheral vascular disease, renal disease, hyperglycaemia or
hypoglycaemia, and sudden death); all-cause mortality. Single
clinical endpoints and surrogate subclinical endpoints were
also assessed. All analyses were by intention to treat and frequency
of hypoglycaemia was also analysed by actual therapy. FINDINGS:
Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in
the intensive group compared with 7.9% (6.9-8.8) in the conventional
group--an 11% reduction. There was no difference in HbA1c among
agents in the intensive group. Compared with the conventional
group, the risk in the intensive group was 12% lower (95% CI
1-21, p=0.029) for any diabetes-related endpoint; 10% lower
(-11 to 27, p=0.34) for any diabetes-related death; and 6% lower
(-10 to 20, p=0.44) for all-cause mortality. Most of the risk
reduction in the any diabetes-related aggregate endpoint was
due to a 25% risk reduction (7-40, p=0.0099) in microvascular
endpoints, including the need for retinal photocoagulation.
There was no difference for any of the three aggregate endpoints
between the three intensive agents (chlorpropamide, glibenclamide,
or insulin). Patients in the intensive group had more hypoglycaemic
episodes than those in the conventional group on both types
of analysis (both p<0.0001). The rates of major hypoglycaemic
episodes per year were 0.7% with conventional treatment, 1.0%
with chlorpropamide, 1.4% with glibenclamide, and 1.8% with
insulin. Weight gain was significantly higher in the intensive
group (mean 2.9 kg) than in the conventional group (p<0.001),
and patients assigned insulin had a greater gain in weight (4.0
kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide
(1.7 kg). INTERPRETATION: Intensive blood-glucose control by
either sulphonylureas or insulin substantially decreases the
risk of microvascular complications, but not macrovascular disease,
in patients with type 2 diabetes.(ABSTRACT TRUNCATED)
Publication Types:
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Clinical trial
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Randomized controlled trial |
PMID: 9742976 [PubMed - indexed for MEDLINE]
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Comment in:
|
BMJ. 1998 Sep 12;317(7160):693-4 |
 
Risk factors for coronary artery disease in non-insulin dependent
diabetes mellitus: United Kingdom Prospective Diabetes Study
(UKPDS: 23)
Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews
DR, Holman RR.
Diabetes Research Laboratories, Nuffield Department of Medicine,
University of Oxford, Radcliffe Infirmary.
OBJECTIVE: To evaluate baseline risk factors for coronary artery
disease in patients with type 2 diabetes mellitus. DESIGN: A
stepwise selection procedure, adjusting for age and sex, was
used in 2693 subjects with complete data to determine which
risk factors for coronary artery disease should be included
in a Cox proportional hazards model. SUBJECTS: 3055 white patients
(mean age 52) with recently diagnosed type 2 diabetes mellitus
and without evidence of disease related to atheroma. Median
duration of follow up was 7.9 years. 335 patients developed
coronary artery disease within 10 years. OUTCOME MEASURES: Angina
with confirmatory abnormal electrocardiogram; non-fatal and
fatal myocardial infarction. RESULTS: Coronary artery disease
was significantly associated with increased concentrations of
low density lipoprotein cholesterol, decreased concentrations
of high density lipoprotein cholesterol, and increased triglyceride
concentration, haemoglobin A1c, systolic blood pressure, fasting
plasma glucose concentration, and a history of smoking. The
estimated hazard ratios for the upper third relative to the
lower third were 2.26 (95% confidence interval 1.70 to 3.00)
for low density lipoprotein cholesterol, 0.55 (0.41 to 0.73)
for high density lipoprotein cholesterol, 1.52 (1.15 to 2.01)
for haemoglobin A1c, and 1.82 (1.34 to 2.47) for systolic blood
pressure. The estimated hazard ratio for smokers was 1.41 (1.06
to 1.88). CONCLUSION: A quintet of potentially modifiable risk
factors for coronary artery disease exists in patients with
type 2 diabetes mellitus. These risk factors are increased concentrations
of low density lipoprotein cholesterol, decreased concentrations
of high density lipoprotein cholesterol, raised blood pressure,
hyperglycaemia, and smoking.
PMID: 9549452 [PubMed - indexed for MEDLINE]
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Persistent abnormalities in lipoprotein composition in noninsulin-dependent
diabetes after intensive insulin therapy.
Bagdade JD, Buchanan WE, Kuusi T, Taskinen MR.
Department of Medicine, Rush Medical College, Chicago, Illinois.
To determine whether rigorous insulin therapy, which normalized
the routinely measured plasma lipids, also reversed qualitative
abnormalities in the composition of lipoproteins in noninsulin-dependent
diabetes mellitus (NIDDM), we studied 18 NIDDM patients (eight
men and 10 women) before and 2 months after intensive insulin
therapy. Glycosylated hemoglobin levels (11.7% vs. 8.7%), plasma
triglyceride (TG) (250 +/- 91 vs. 164 +/- 56 mg/dl, p less than
0.001), and cholesterol (214 +/- 43 vs. 198 +/- 31 mg/dl, p
less than 0.025) all fell, and both HDL2 cholesterol and HDL3
cholesterol increased (59.1% and 10.9%, respectively, p less
than 0.001). However, abnormalities in two indices of lipoprotein
surface constituents, which were present before insulin therapy,
remained so thereafter. The first of these, the new cardiovascular
risk factor, the plasma free cholesterol/lecithin ratio, which
was increased before treatment, fell only slightly after therapy
(pre-therapy 1.02 +/- 0.29 vs. post-therapy 0.90 +/- 0.17, p
less than 0.4; reference group, 0.83 +/- 0.14), and remained
elevated in very low density lipoprotein (VLDL) and low density
lipoprotein (LDL). Secondly, the sphingomyelin/lecithin ratio,
an index of the surface rigidity of lipoproteins, was abnormal
before treatment in VLDL, HDL2, and HDL3, and this alteration
persisted after insulin therapy in HDL3 (p less than 0.001).
Lipoprotein core lipid abnormalities were also present before
treatment: the TG/cholesteryl ester ratio was reduced in VLDL
and increased in LDL, HDL2, and HDL3. Rigorous insulin therapy
improved, but failed to fully correct, this disturbance.(ABSTRACT
TRUNCATED AT 250 WORDS)
PMID: 2180397 [PubMed - indexed for MEDLINE]
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Lipoprotein abnormalities in well-treated type II diabetic
patients.
Manzato E, Zambon A, Lapolla A, Zambon S, Braghetto L, Crepaldi
G, Fedele D.
Department of Internal Medicine, University of Padova, Italy.
OBJECTIVE--To investigate lipoprotein levels and composition
in well-treated type II diabetic patients. RESEARCH DESIGN AND
METHODS--Cholesterol and triglyceride levels were measured in
plasma, VLDL, LDL, and HDL in 120 type II diabetic patients
in good to fair metabolic control (HbA1c, 7.2 +/- 1.6%) and
in 30 normal control subjects. ApoAI, AII, B, CII, CIII, and
E levels in plasma were also determined. RESULTS--The diabetic
patients have significantly higher levels of mean plasma cholesterol
(5.85 vs. 5.43 mM, P = 0.03), LDL triglycerides (0.41 vs. 0.31
mM, P = 0.003), and HDL triglycerides (0.24 vs. 0.19 mM, P =
0.02), whereas total triglycerides, VLDL cholesterol and triglycerides,
LDL cholesterol, and HDL cholesterol are not significantly different
from normal control subjects. ApoB (150 vs. 135 mg/dl, P = 0.02)
and apoCIII (10.6 vs. 8.4 mg/dl, P = 0.01) are significantly
higher in diabetic patients compared with control subjects.
No significant differences are observed in all the parameters
among diabetic patients treated with diet only, sulphonylurea,
sulphonylurea plus biguanides, or insulin. Body weight is significantly
related to VLDL lipids. The VLDL triglycerides are inversely
related to the HDL cholesterol in both diabetic patients and
control subjects. The VLDL triglycerides are directly related
to the HDL triglycerides only in diabetic patients. No other
lipid or lipoprotein parameters are significantly related to
body weight or metabolic control. CONCLUSIONS--Type II diabetic
patients in good to fair metabolic control are characterized
by minor alterations of the plasma lipids, but LDL and HDL triglycerides,
apoB, and apoCIII are increased, thus indicating that the lipoprotein
composition is altered, possibly because of an abnormal triglyceride
metabolism and/or lipid transfer activity.
PMID: 8432219 [PubMed - indexed for MEDLINE]
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Hyperlipidaemia in diabetes.
Taskinen MR.
Currently our knowledge of the role of lipid abnormalities as
risk factors for CHD in diabetes is insufficient. We need to
define exact risk parameters to target correctly the therapy
of lipid disorders and to outline optimum therapeutic strategies.
Therefore it is necessary to identify quantitative and qualitative
abnormalities of lipoproteins and apoproteins which signify
the risk of CHD and to define their predictive power in prospective
trials. Obviously we need to know more about the pathophysiology
of lipid abnormalities and the action of insulin. Because diabetic
patients carry a high inherent risk of CHD, target values recommended
for non-diabetic populations may not be optimal for diabetic
populations, but should be lower. To date no primary or secondary
intervention trials in diabetic populations have been carried
out to show that the lowering of lipid values (serum and LDL
cholesterol) will reduce the risk of CHD morbidity or mortality
or will prevent the progression of CHD in diabetes. Since hypertriglyceridaemia
and low HDL levels are typical abnormalities in NIDDM it is
a unique target group to test whether lowering of triglycerides
and raising of HDL cholesterol levels will reduce the risk of
CHD. Therefore there is a pressing need for clinical trials
in both IDDM and NIDDM to provide adequate information on the
benefits of lipid-lowering therapy and to confirm treatment
strategies.
Publication Types:
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Review
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|
Review, tutorial |
PMID: 2082905 [PubMed - indexed for MEDLINE]
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Lipids and lipoproteins as coronary risk factors in non-insulin-dependent
diabetes mellitus.
Syvanne M, Taskinen MR.
Division of Cardiology, Department of Medicine, Helsinki University
Central Hospital, Finland.
Publication Types:
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Review
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Review, tutorial |
PMID: 9250279 [PubMed - indexed for MEDLINE]
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Dyslipoproteinemia and diabetes.
Garg A.
Department of Internal Medicine, University of Texas Southwestern
Medical Center at Dallas, USA.
Dyslipidemia in patients with diabetes constitutes quantitative
and qualitative abnormalities in all classes of lipoproteins
and may be a significant contributor to the high risk of atherosclerosis
in these patients. A step-care approach to therapy of diabetic
dyslipidemia, including hygienic measures (diet and increased
physical activity), hypoglycemic drugs, and lipid-lowering drugs,
is recommended. The choice of lipid-lowering drugs depends on
severity of hypertriglyceridemia. Statins and bile-acid-binding
resins are the choice of therapy for diabetic dyslipidemia;
however, for severely hypertriglyceridemic patients, fibric
acid derivatives should be used. Nicotinic acid worsens hyperglycemia
and, therefore, should be avoided. The value of estrogen replacement
therapy in postmenopausal women with diabetes has not been established.
Publication Types:
|
Review
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|
Review, tutorial |
PMID: 9785056 [PubMed - indexed for MEDLINE]
-
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Diabetic dyslipidaemia.
Betteridge DJ.
Department of Medicine, University College, London, UK.
Type 2 diabetic patients have an increased risk of cardiovascular
disease and, although many factors contribute to this risk,
it is likely that diabetic dyslipidaemia plays an important
role. Dyslipidaemia in Type 2 diabetic patients is characterized
by low levels of HDL cholesterol and high triglyceride levels.
In Type 2 diabetes, the total amount of LDL cholesterol is the
same as in healthy people, but there are qualitative changes,
e.g. a shift to smaller, denser LDL particles and an increased
susceptibility to oxidation. Oxidized LDL may promote the development
of atherosclerosis. It is possible to modify the major abnormalities
of diabetic dyslipidaemia by combining lifestyle modifications
(e.g. increased physical activity, cessation of smoking and
weight reduction) with improved glycaemic control and hypolipidaemic
drugs to reduce the burden of CVD within this high-risk population.
Publication Types:
|
Review
|
|
Review, tutorial |
PMID: 10383605 [PubMed - indexed for MEDLINE]
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-
Postprandial state and atherosclerosis.
Ebenbichler CF, Kirchmair R, Egger C, Patsch JR.
Department of Medicine, University of Innsbruck, Austria.
Accumulating evidence suggests that triglyceride-rich lipoproteins
are an independent risk factor for atherosclerosis. This epidemiological
evidence first emerged as a result of studying postprandial
lipaemia that characterized the metabolic capacity of triglycerides
in the postabsorptive state, that is, under challenge. Studies
of postprandial lipaemia were helpful to explain several effects
of triglyceride-rich lipoproteins on cholesteryl-ester-rich
lipoproteins. From these studies it became apparent that peculiarities
of cholesteryl-ester-rich lipoproteins, such as small LDL and
small HDL, which have been associated with risk for atherosclerosis,
were caused by impaired triglyceride metabolism.
Publication Types:
|
Review
|
|
Review, tutorial |
PMID: 8520851 [PubMed - indexed for MEDLINE]
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Triglyceride-rich lipoproteins in non-insulin-dependent diabetes
mellitus: post-prandial metabolism and relation to premature
atherosclerosis.
De Man FH, Cabezas MC, Van Barlingen HH, Erkelens DW, de
Bruin TW.
Department of Internal Medicine, University Hospital, Utrecht
University, The Netherlands.
Non-insulin-dependent diabetes mellitus is frequently associated
with premature atherosclerosis. Abnormalities in lipid and lipoprotein
metabolism contribute to the increased risk of coronary heart
disease. One of the most common lipid abnormalities in non-insulin-dependent
diabetes mellitus is hypertriglyceridaemia. In the present paper,
the authors review the metabolism of triglyceride-rich lipoproteins,
with special emphasis on the post-prandial state. Several studies
have demonstrated that levels of atherogenic post-prandial lipoproteins
are increased in patients with non-insulin-dependent diabetes
mellitus. An increased supply of glucose and free fatty acids
contributes to overproduction of very low-density lipoproteins,
increasing the burden of triglyceride-rich lipoproteins on the
common lipolytic pathway at the level of lipoprotein lipase.
Low lipoprotein lipase activity and increased amounts of lipolysis-inhibiting
free fatty acids further impair lipolysis of post-prandial lipoproteins.
The clearance of atherogenic remnants is also delayed in non-insulin-dependent
diabetes mellitus. There is evidence that a relative hepatic
removal defect exists, secondary to impaired remnant-receptor
interaction and increased competition with very low density
lipoprotein remnants. Correction of the increased post-prandial
lipaemia in non-insulin-dependent diabetes mellitus is advisable,
as it may contribute to attenuation of the risk on premature
atherosclerosis. When dietary measures and hypoglycaemic agents
have failed to achieve acceptable lipid levels, lipid-lowering
drugs should be advised. Fibric acids and hydroxymethyl-glutaryl
coenzyme A (HMG CoA) reductase inhibitors are the drugs of choice.
Publication Types:
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Review
|
|
Review, academic |
PMID: 8904518 [PubMed - indexed for MEDLINE]
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Postprandial metabolism of apolipoprotein B-48- and B-100-containing
particles in type 2 diabetes mellitus: relations to angiographically
verified severity of coronary artery disease.
Mero N, Malmstrom R, Steiner G, Taskinen MR, Syvanne M.
Department of Medicine, Division of Endocrinology and Diabetes,
University of Helsinki, Helsinki, Finland.
The aim of the present cross-sectional angiographic study was
to examine if there is a relationship between the severity of
CAD and postprandial lipemia in patients with type 2 diabetes
mellitus. Special emphasis was directed to determining the contribution
of apolipoprotein B-48 (apoB-48)-containing and B-100 (apoB-100)-containing
triglyceride-rich particles to the magnitude of postprandial
lipemia and degree of CAD. The role of apolipoprotein E (apoE)
phenotype as a modulator of postprandial lipemia was also evaluated.
The severity of CAD was determined by a quantitative coronary
angiography and the subjects were classified into two groups
based on the presence (severe CAD) or absence (mild CAD) of
at least 50% stenosis in a major coronary vessel. The study
population consisted of 43 subjects (31 men and 12 women) with
fair glycemic control and comparable fasting lipids and body
mass index. Postprandial responses of TG, apoB-48 and apoB-100
in lipoprotein subfractions (chylomicrons, VLDL1, VLDL2 and
IDL) were determined after a fat load. Type 2 diabetic patients
exhibited the classical dyslipidemia of the insulin resistance
syndrome and delayed clearance of both hepatic and intestinal
particles. Fasting or postprandial lipid or lipoprotein measurements,
including apoB-48 and apoB-100 concentrations, did not differ
between the groups. The presence or absence of apoE-4 allele
did not significantly influence postprandial lipemia. The severity
of the most significant coronary stenosis in angiography correlated
with plasma and with chylomicron area under curve (AUC) for
TG (n=27) and chylomicron AUC for apoB-48 (n=20). The strongest
correlate of maximal stenosis was area under incremental curve
(AUIC) for apoB-100 in IDL fraction (r=0.548, P=0. 012, n=20).
In conclusion, postprandial apoB-48 and apoB-100 metabolism
in triglyceride rich lipoproteins is distorted in type 2 diabetic
patients, even in those with only mild CAD. The data suggest
that postprandial change in small remnant particle numbers may
contribute to the severity of CAD in type 2 diabetes.
PMID: 10781648 [PubMed - indexed for MEDLINE]-
Atherogenesis: a postprandial phenomenon.
Zilversmit DB.
The hypothesis that plasma chylomicrons in persons who ingest
a cholesterol-rich diet are atherogenic is evaluated. Evidence
is presented that in humans, and experimental animals, chylomicron
remnants as well as low-density lipoproteins are taken up by
arterial cells. In persons who do not have familial hyperlipoproteinemia,
atherogenesis may occur during the postprandial period. Research
directions that may contribute to the evaluation of chylomicron
remnants as a risk factor for atherogenesis are discussed. Lipoprotein
studies after administration of a test meal containing fat and
cholesterol are urgently needed.
PMID: 222498 [PubMed - indexed for MEDLINE]
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Relation of triglyceride metabolism and coronary artery disease.
Studies in the postprandial state.
Patsch JR, Miesenbock G, Hopferwieser T, Muhlberger V, Knapp
E, Dunn JK, Gotto AM Jr, Patsch W.
Department of Medicine, University of Innsbruck, Austria.
The status of fasting triglycerides as a risk factor for coronary
artery disease (CAD) has been considered weak because in multivariate
analyses, triglycerides tend to be eliminated by high density
lipoprotein (HDL) cholesterol. To further evaluate the role
of triglycerides in CAD, we employed postprandial lipemia as
a more informative means of characterizing triglyceride metabolism.
In 61 male subjects with severe CAD and 40 control subjects
without CAD as verified by angiography, we measured cholesterol;
triglycerides; HDL cholesterol; HDL2 cholesterol; and apolipoproteins
A-I, A-II, and B in fasting plasma and triglycerides before
and 2, 4, 6, and 8 hours after a standardized test meal. Both
the maximal triglyceride increase and the magnitude of postprandial
lipemia (area under the triglyceride curve over 8 hours after
the meal) were higher in cases than in control subjects. Single
postprandial triglyceride levels 6 and 8 hours after the meal
were highly discriminatory (p < 0.001), and by logistic-regression
analysis displayed an accuracy of 68% in predicting the presence
or absence of CAD. In this respect, accuracy was higher than
that of HDL2 cholesterol (64%) and equal to that of apolipoprotein
B (68%), the most discriminatory fasting parameter. Multivariate
logistic-regression analysis was performed to reduce the number
of risk factors to those that were statistically independent.
This statistical procedure selected postprandial but not fasting
triglycerides into the most accurate multivariate model, which
also contained the accepted risk factors HDL2 cholesterol, apolipoprotein
B, and age. This model classified 82% of subjects correctly.
We conclude that triglycerides are independent predictors of
CAD in multivariate analyses including HDL cholesterol, provided
that a challenge test of triglyceride metabolism such as postprandial
lipemia is used. The study suggests that the metabolism of triglycerides
is a critical determinant of cholesterol metabolic routing.
The findings support the concept that the negative association
between HDL cholesterol levels and CAD actually originates in
part from a positive relation between CAD and plasma triglycerides,
as ascertained in the postprandial state.
PMID: 1420093 [PubMed - indexed for MEDLINE]
16. Brewer HB Jr, Santamarina-Fojo
S, Hoeg JM. Disorders of lipoprotein metabolism. In: DeGroot LJ,
Besser M, Jameson JL, et al, eds. Endocrinology. Philadelphia,
PA: WB Saunders; 1995:2731–2753.
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Hypertriglyceridemia: changes in the plasma lipoproteins
associated with an increased risk of cardiovascular disease.
Brewer HB Jr.
National Heart, Lung, and Blood Institute, National Institutes
of Health, Bethesda, Maryland 20892-1666, USA.
There is a growing body of evidence from epidemiologic, clinical,
and laboratory data that indicates that elevated triglyceride
levels are an independent risk factor for cardiovascular disease.
Identification and quantification of atherogenic lipoproteins
in patients with hypertriglyceridemia are important steps in
the prevention of cardiovascular disease. Increased levels of
apoC-III, apoC-I, or apoA-II on the apoB-containing lipoproteins
may alter lipoprotein metabolism and result in the accumulation
of atherogenic remnants. Hypertriglyceridemic patients at risk
for cardiovascular disease often develop a lipoprotein profile
characterized by elevated triglyceride, dense LDL, and low HDL
cholesterol. Understanding that each of these factors contributes
separately to the patient's risk of cardiovascular disease can
help physicians provide patients with more effective risk-reduction
programs for cardiovascular disease.
Publication Types:
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Review
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Review, tutorial |
PMID: 10357568 [PubMed - indexed for MEDLINE]
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-
Structures and functions of multiligand lipoprotein receptors:
macrophage scavenger receptors and LDL receptor-related protein
(LRP).
Krieger M, Herz J.
Department of Biology, Massachusetts Institute of Technology,
Cambridge 02139.
Publication Types:
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Review
|
|
Review, academic |
PMID: 7979249 [PubMed - indexed for MEDLINE]
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-
Receptor-mediated endocytosis: concepts emerging from the
LDL receptor system.
Goldstein JL, Brown MS, Anderson RG, Russell DW, Schneider
WJ.
Publication Types:
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Review |
PMID: 2881559 [PubMed - indexed for MEDLINE]
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-
Comment in:
|
N Engl J Med. 1989 Oct 26;321(17):1196-7 |
Beyond cholesterol. Modifications of low-density lipoprotein
that increase its atherogenicity.
Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum
JL.
Division of Endocrinology and Metabolism, University of California,
San Diego, La Jolla 92093-0613.
Publication Types:
|
Review
|
|
Review, academic |
PMID: 2648148 [PubMed - indexed for MEDLINE]
21. Glosmet JA. The plasma lecithin:cholesterol
acyl transferase reaction. J Lipid Res. 1968;9:155–167.
-
Molecular physiology of reverse cholesterol transport.
Fielding CJ, Fielding PE.
Department of Physiology, University of California Medical Center,
San Francisco 94143, USA.
Reverse cholesterol transport (RCT) is the pathway by which
peripheral cell cholesterol can be returned to the liver for
catabolism. Evidence of specific functions for molecular structures
within individual plasma lipoprotein species has rapidly accumulated
from recent studies using molecular and cellular physiology
techniques. The removal of cholesterol from cells, like its
delivery, appears to be specific and well regulated. Although
further research will be needed, RCT can now be understood in
molecular terms.
Publication Types:
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Review
|
|
Review, tutorial |
PMID: 7751809 [PubMed - indexed for MEDLINE]
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-
Cholesteryl ester transfer proteins, reverse cholesterol
transport, and atherosclerosis.
Bruce C, Tall AR.
Department of Medicine, Columbia University, New York, USA.
Plasma cholesteryl ester transfer protein plays a central role
in lipoprotein metabolism by exchanging cholesteryl esters with
triglycerides. Human genetic deficiency is associated with increased
HDL-cholesterol levels, whereas cholesteryl ester transfer protein
overexpression in transgenic mice results in decreased HDL-cholesterol.
Thus, it has been proposed that cholesteryl ester transfer protein
deficiency is an antiatherogenic state. However, recent observations
in human cholesteryl ester transfer protein deficiency and cholesteryl
ester transfer protein transgenic mice also suggest antiatherogenic
effects of the expression of this protein, probably reflecting
its role in reverse cholesterol transport.
Publication Types:
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Review
|
|
Review, tutorial |
PMID: 8520853 [PubMed - indexed for MEDLINE]
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-
ABCA1-mediated transport of cellular cholesterol and phospholipids
to HDL apolipoproteins.
Oram JF, Vaughan AM.
Department of Medicine, University of Washington, Seattle 98195,
USA. joram@u.washington.edu
Lipid-poor apolipoproteins remove cellular cholesterol and phospholipids
by an active transport pathway controlled by an ATP binding
cassette transporter called ABCA1 (formerly ABC1). Mutations
in ABCA1 cause Tangier disease, a severe HDL deficiency syndrome
characterized by a rapid turnover of plasma apolipoprotein A-I,
accumulation of sterol in tissue macrophages, and prevalent
atherosclerosis. This implies that lipidation of apolipoprotein
A-I by the ABCA1 pathway is required for generating HDL particles
and clearing sterol from macrophages. Thus, the ABCA1 pathway
has become an important therapeutic target for mobilizing excess
cholesterol from tissue macrophages and protecting against atherosclerosis.
Publication Types:
|
Review
|
|
Review, tutorial |
PMID: 10882340 [PubMed - indexed for MEDLINE]
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-
Comment in:
|
Science. 1996 Jan 26;271(5248):460-1 |
Identification of scavenger receptor SR-BI as a high density
lipoprotein receptor.
Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger
M.
Department of Biology, Massachusetts Institute of Technology,
Cambridge 02139, USA.
High density lipoprotein (HDL) and low density lipoprotein (LDL)
are cholesterol transport particles whose plasma concentrations
are directly (LDL) and inversely (HDL) correlated with risk
for atherosclerosis. LDL catabolism involves cellular uptake
and degradation of the entire particle by a well-characterized
receptor. HDL, in contrast, selectively delivers its cholesterol,
but not protein, to cells by unknown receptors. Here it is shown
that the class B scavenger receptor SR-BI is an HDL receptor.
SR-BI binds HDL with high affinity, is expressed primarily in
liver and nonplacental steroidogenic tissues, and mediates selective
cholesterol uptake by a mechanism distinct from the classic
LDL receptor pathway.
PMID: 8560269 [PubMed - indexed for MEDLINE]
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Defective regulation of triglyceride metabolism by insulin
in the liver in NIDDM.
Malmstrom R, Packard CJ, Caslake M, Bedford D, Stewart P,
Yki-Jarvinen H, Shepherd J, Taskinen MR.
Department of Medicine, University of Helsinki, Finland.
Insulin administration to healthy subjects inhibits the production
of very low density lipoprotein (VLDL)1 (Svedbergs flotation
(Sf) rate 60-400) without affecting that of VLDL2 (Sf 20-60)
sub-class. This study was designed to test whether this hormonal
action is impaired in non-insulin-dependent diabetes mellitus
(NIDDM). We studied six men with NIDDM (age 53 +/- 3 years,
body mass index 27.0 +/- 1.0 kg/m2, plasma triglycerides 1.89
+/- 0.22 mmol/l) during an 8.5 h infusion of saline (control)
and then in hyperinsulinaemic (serum insulin approximately 540
pmol/l) conditions during 8.5 h infusions of glucose and insulin
to give either hyper- and normoglycaemic conditions. [3-2H]-leucine
was used as tracer and kinetic constants derived using a non-steady-state
multicompartmental model. Compared to the control study, patients
with NIDDM reduced VLDL1 apo B production by only 3 +/- 8% after
8.5 h of hyperinsulinaemia (701 +/- 102 vs 672 +/- 94 mg/day
respectively, NS) in hyperglycaemic conditions and by 9 +/-
21% under normoglycaemic conditions (603 +/- 145 mg/day). In
contrast, in normal subjects insulin induced a 50 +/- 15% decrement
in VLDL1 apo B production (p < 0.05). Direct synthesis of
VLDL2 apo B in patients with NIDDM was not markedly affected
by insulin. We conclude that a contributory factor to hypertriglyceridaemia
in NIDDM is the inability of insulin to inhibit acutely the
release of VLDL1 from the liver, despite efficient suppression
of serum nonesterfied fatty acids.
PMID: 9112023 [PubMed - indexed for MEDLINE]
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Retention of chylomicron remnants by arterial tissue; importance
of an efficient clearance mechanism from plasma.
Mamo JC, Proctor SD, Smith D.
Department of Medicine, University of Western Australia, Perth,
Australia. jmamo@cyllene.uwa.edu.au
Atherosclerosis is thought to begin with the trapping of cholesterol
rich lipoproteins within the intima of arterial vessels. Thereafter
a complex inflammatory cascade involving recruitment and transformation
of leukocytes, accumulation of sterols in macrophages and cellular
proliferation, can lead to a progressive occlusion in blood
flow, or an unstable arterial lesion prone to prothrombotic
events. Primary intervention strategies aimed at reducing atherogenesis
are designed to achieve reductions in sterol rich lipoproteins,
primarily low density lipoproteins, given the hypothesis that
decreased exposure will attenuate the rate of arterial cholesterol
accumulation. Epidemiological evidence has clearly identified
a positive relationship between poor dietary (fat) habits and
the onset and progression of atherosclerosis. However lipoproteins
which mediate the transport of dietary lipid, that is chylomicrons,
are not normally considered to be directly involved in atherogenesis,
because of their larger size and inability to efficiently penetrate
arterial tissue. In contrast, this article reviews recent evidence
which suggests that once chylomicrons are hydrolysed to their
remnant form, the triglyceride depleted chylomicron remnants
penetrate arterial tissue and moreover, become preferentially
trapped within the subendothelial space as concentrated focii.
Ongoing studies demonstrate that significant chylomicron remnant
accumulation can occur in a number of primary and secondary
lipid disorders and in normolipidemic subjects with coronary
artery disease. Chylomicron remnant dyslipidemia in conditions
prone to premature atherosclerosis is consistent with the putative
atherogenicity of these particles and can be explained by increased
arterial exposure to cholesterol rich chylomicron remnants.
Publication Types:
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Review
|
|
Review, tutorial |
PMID: 9888645 [PubMed - indexed for MEDLINE]
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Nonoxidative modifications of lipoproteins in atherogenesis.
Tabas I.
Department of Medicine and Anatomy, Columbia University, New
York, New York 10032, USA. iat1@columbia.edu
The key initiating event in atherosclerosis is the retention
of plasma lipoproteins in the subendothelial matrix. Subsequently,
a series of biological responses to this retained material leads
to specific molecular and cellular processes that promote lesion
formation. There is considerable evidence that many of these
biological responses, notably macrophage cholesteryl ester loading
(foam cell formation), require subendothelial modification of
the retained lipoproteins. Oxidation of lipoproteins is one
such modification that likely occurs in vivo and promotes certain
atherogenic events, but oxidation cannot explain all aspects
of atherogenesis, including certain elements of macrophage foam
cell formation. For this reason, there has been renewed interest
in other modifications of lipoproteins that may be important
in atherogenesis. This review addresses five such lipoprotein
modifications, namely aggregation, glycation, immune complex
formation, proteoglycan complex formation, and conversion to
cholesterol-rich liposomes. The focus is on the evidence that
these modifications occur in atherosclerotic lesions and on
the potential role of these modified lipoproteins in atherogenesis,
with an emphasis on macrophage foam cell formation.
Publication Types:
|
Review
|
|
Review, academic |
PMID: 10448519 [PubMed - indexed for MEDLINE]
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-
Comment in:
|
ACP J Club. 1997 Mar-Apr;126(2):49
|
|
JAMA. 1996 Sep 18;276(11):914-5 |
A prospective study of triglyceride level, low-density lipoprotein
particle diameter, and risk of myocardial infarction.
Stampfer MJ, Krauss RM, Ma J, Blanche PJ, Holl LG, Sacks
FM, Hennekens CH.
Channing Laboratory, Brigham and Women's Hospital and Harvard
Medical School, Boston, Mass 02115, USA.
OBJECTIVE: To test whether a predominance of small, dense low-density
lipoprotein (LDL) particles and elevated triglyceride levels
are independent risk factors for myocardial infarction (MI).
DESIGN: Nested case-control study with prospectively collected
samples. SETTING: Prospective cohort study. PARTICIPANTS: Blood
samples were collected at baseline (85% nonfasting samples)
from 14916 men aged 40 to 84 years in the Physicians' Health
Study. MAIN OUTCOME MEASUREMENTS: Myocardial infarction diagnosed
during 7 years of follow-up. RESULTS: Cases (n=266) had a significantly
smaller LDL diameter (mean [SD], 25.6 [0.9] nm) than did controls
(n=308) matched on age and smoking (mean [SD], 25.9 [8] nm;
P<.001). Cases also had higher median triglyceride levels
(1.90 vs 1.49 mmol/L [168 vs 132 mg/dL]; P<.001). The LDL
diameter had a high inverse correlation with triglyceride level
(r=-0.71), and a high direct correlation with high-density lipoprotein
cholesterol (HDL-C) level (r=0.60). We observed a significant
multiplicative interaction between triglyceride and total cholesterol
(TC) levels (P=.01). After simultaneous adjustment for lipids
and a variety of coronary risk factors, LDL particle diameter
was no longer a statistically significant risk indicator, with
a relative risk (RR) of 1.09 (95% confidence interval [CI],
0.85-1.40) per 0.8-nm decrease. However, triglyceride level
remained significant with an RR of 1.40 (95% CI, 1.10-1.77)
per 1.13 mmol/L (100-mg/dL) increase. The association between
triglyceride level and MI risk appeared linear across the distribution;
men in the highest quintile had a risk about 2.5 times that
of those in the lowest quintile. The TC level, but not HDL-C
level, also remained significant, with an RR of 1.80 (95% CI,
1.44-2.26) per 1.03-mmol/L (40-mg/dL) increase. CONCLUSIONS:
These findings indicate that nonfasting triglyceride levels
appear to be a strong and independent predictor of future risk
of MI, particularly when the total cholesterol level is also
elevated. In contrast, LDL particle diameter is associated with
risk of MI, but not after adjustment for triglyceride level.
Increased triglyceride level, small LDL particle diameter, and
decreased HDL-C levels appear to reflect underlying metabolic
perturbations with adverse consequences for risk of MI; elevated
triglyceride levels may help identify high-risk individuals.
PMID: 8782637 [PubMed - indexed for MEDLINE]
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-
Comment in:
|
JAMA. 1998 Dec 16;280(23):1990-1 |
Fasting insulin and apolipoprotein B levels and low-density
lipoprotein particle size as risk factors for ischemic heart
disease.
Lamarche B, Tchernof A, Mauriege P, Cantin B, Dagenais GR,
Lupien PJ, Despres JP.
Lipid Research Center, Laval University Hospital Research Center,
Ste-Foy, Quebec, Canada.
CONTEXT: Epidemiological studies have established a relationship
between cholesterol and low-density lipoprotein cholesterol
(LDL-C) concentrations and the risk of ischemic heart disease
(IHD), but up to half of patients with IHD may have cholesterol
levels in the normal range. OBJECTIVE: To assess the ability
to predict the risk of IHD using a cluster of nontraditional
metabolic risk factors that includes elevated fasting insulin
and apolipoprotein B levels as well as small, dense LDL particles.
DESIGN: Nested case-control study. SETTING: Cases and controls
were identified from the population-based cohort of the Quebec
Cardiovascular Study, a prospective study conducted in men free
of IHD in 1985 and followed up for 5 years. PARTICIPANTS: Incident
IHD cases were matched with controls selected from among the
sample of men who remained IHD free during follow-up. Matching
variables were age, smoking habits, body mass index, and alcohol
consumption. The sample included 85 complete pairs of nondiabetic
IHD cases and controls. MAIN OUTCOME MEASURES: Ability of fasting
insulin level, apolipoprotein B level, and LDL particle diameter
to predict IHD events, defined as angina, coronary insufficiency,
nonfatal myocardial infarction, and coronary death. RESULTS:
The risk of IHD was significantly increased in men who had elevated
fasting plasma insulin and apolipoprotein B levels and small,
dense LDL particles, compared with men who had normal levels
for 2 of these 3 risk factors (odds ratio [OR], 5.9; 95% confidence
interval [CI], 2.3-15.4). Multivariate adjustment for LDL-C,
triglycerides, and high-density lipoprotein cholesterol (HDL-C)
did not attenuate the relationship between the cluster of nontraditional
risk factors and IHD (OR, 5.2; 95% CI, 1.7-15.7). On the other
hand, the risk of IHD in men having a combination of elevated
LDL-C and triglyceride levels and reduced HDL-C levels was no
longer significant (OR, 1.4; 95% CI, 0.5-3.5) after multivariate
adjustment for fasting plasma insulin level, apolipoprotein
B level, and LDL particle size. CONCLUSION: Results from this
prospective study suggest that the measurement of fasting plasma
insulin level, apolipoprotein B level, and LDL particle size
may provide further information on the risk of IHD compared
with the information provided by conventional lipid variables.
PMID: 9643858 [PubMed - indexed for MEDLINE]
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Influence of low density lipoprotein (LDL) subfraction profile
and LDL oxidation on endothelium-dependent and independent vasodilation
in patients with type 2 diabetes.
Tan KC, Ai VH, Chow WS, Chau MT, Leong L, Lam KS.
Department of Medicine, University of Hong Kong, Hong Kong.
Recent studies have suggested that hypercholesterolemia is associated
with endothelial dysfunction. In patients with type 2 diabetes
mellitus, dyslipidemia is mainly characterized by hypertriglyceridemia,
low high density lipoprotein, and a preponderance of small dense
low density lipoprotein (LDL) particles. We have examined the
relationships among LDL subfractions, the susceptibility of
LDL to oxidation in vitro, and endothelial function in type
2 diabetes mellitus. LDL subfractions were measured by density
gradient ultracentrifugation. The susceptibility of LDL to oxidation
was determined by measuring the kinetics of conjugated dienes
formation during copper-mediated oxidation of LDL. Endothelium-dependent
and independent vasodilation of the brachial artery were assessed
by high resolution vascular ultrasound. Diabetic patients had
a higher concentration of small dense LDL-III than matched controls
(P < 0.01). The lag phase of conjugated dienes formation
was shorter in the diabetic patients (P < 0.05), and the
rate of LDL oxidation was faster (P < 0.05). Both endothelium-dependent
(P < 0.01) and independent dilation of the brachial artery
(P < 0.01) were impaired in the diabetic patients. On multivariate
analysis, the rate of oxidation and LDL-III concentration accounted
for 12% and 6%, respectively, of the variation in endothelium-dependent
vasodilation (adjusted r2 = 0.18; P < 0.05), whereas LDL-III
concentration and the maximum amount of conjugated dienes formed
accounted for 27% and 5%, respectively, of the variation in
endothelium-independent vasodilation (adjusted r2 = 0.32; P
< 0.01) in the diabetic patients. In conclusion, endothelial
and smooth muscle cell dysfunction in type 2 diabetes were related
to abnormalities in LDL subfractions and in LDL oxidation.
PMID: 10487689 [PubMed - indexed for MEDLINE]
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Measurement of LDL particle size in whole plasma and serum
by high performance gel-filtration chromatography using a fluorescent
lipid probe.
Scheffer PG, Bakker SJ, Heine RJ, Teerlink T.
Department of Clinical Chemistry, Research Institute for Endocrinology,
Reproduction and Metabolism, Academic Hospital Vrije Universiteit,
Amsterdam, The Netherlands. p.scheffer@azvu.nl
We have recently described a technique for measuring LDL size
by high performance gel-filtration chromatography (HPGC) with
UV detection (Scheffer et al., Clin Chem 1997;43:1904-12). A
drawback of this method is the necessity of LDL isolation before
chromatography. We now describe a modification of this method
based on selective detection of lipoproteins by postcolumn labeling
with parinaric acid, a fluorescent lipid probe. Measuring the
size of isolated LDL by HPGC in 56 subjects, we obtained diameters
of 25.72 +/- 0.60 nm with UV detection and of 25.74 +/- 0.58
nm with fluorescence detection. The modified method is suitable
for LDL size measurement in whole plasma or serum. LDL sizes
measured in whole plasma correlated strongly with the respective
values in isolated LDL (r = 0.976) but were on average 0.18
nm larger (P < 0.001). CVs for within- and between-series
imprecision were <0.25%. The present method requires only
5 microL plasma or serum without sample preparation and is suitable
for the unattended analysis of large series of samples.
PMID: 9761248 [PubMed - indexed for MEDLINE]
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Important contribution of lipoprotein particle number to
plasma triglyceride concentration in type 2 diabetes.
Steiner G, Tkac I, Uffelman KD, Lewis GF.
WHO Collaborating Center for the Study of Atherosclerosis in
Diabetes, Department of Medicine, The Toronto Hospital (General
Division), University of Toronto, Ont., Canada.
The aim of the present study was to determine the contributions
of particle size versus number to differences in plasma triglyceride-rich
lipoprotein concentrations in patients with type 2 diabetes.
Fasting plasma was obtained from 174 consecutive eligible men
and women with type 2 diabetes (with or without insulin treatment,
mean age 57.0 + 6.3 years) who were undergoing coronary angiography.
The triglyceride-rich (Sf 12-400) lipoproteins (TRL) were subfractionated
into the Sf 12-60 and Sf 60-400 subfractions. Particle numbers,
estimated by measuring apolipoprotein B by electroimmunoassay,
in each of these lipoprotein fractions were related to enzymatically
determined triglyceride levels in the triglyceride-rich lipoproteins.
Approximately 87% of the triglyceride-rich lipoprotein particles
were in the Sf 12-60 fraction and 13% in the Sf 60-400 fraction.
Multiple linear regression indicated that 69% (i.e. r2=0.69)
of the variance in the triglyceride levels could by explained
by differences in TRL particle number and 17% (i. e. r2=0.17)
by the differences in particle triglyceride content. These observations
are similar in each gender and in those with or without insulin
treatment. In conclusion, in type 2 diabetes, the vast majority
of triglyceride-rich lipoproteins are smaller particles which
are in the Sf 12-60 fraction. Differences in particle number,
rather than triglyceride content, account for approximately
70% of the differences in triglyceride levels observed between
individuals. Previous demonstrations, in those without diabetes,
of an association between small triglyceride-rich lipoproteins
with coronary artery disease suggest the importance of these
findings to the increased atherosclerosis in diabetes.
PMID: 9568754 [PubMed - indexed for MEDLINE]
-
-
Effects of gemfibrozil on low-density lipoprotein particle
size, density distribution, and composition in patients with
type II diabetes.
Lahdenpera S, Tilly-Kiesi M, Vuorinen-Markkola H, Kuusi T,
Taskinen MR.
Second Department of Medicine, University of Helsinki, Finland.
OBJECTIVE--To study the effects of gemfibrozil treatment on
LDL particle size, density distribution, and composition in
NIDDM patients. RESEARCH DESIGN AND METHODS--We performed LDL
analyses on 16 NIDDM patients with stable glycemic control.
They were randomly allocated to receive either gemfibrozil (n
= 8) or a placebo (n = 8) for 3 mo in a double-blind study.
The LDL particle size distribution and the particle diameter
of the major LDL peak were measured with nondenaturing polyacrylamide
gradient gel electrophoresis. The density distribution and composition
of LDL were determined with the density gradient ultracentrifugation
method. RESULTS--In the gemfibrozil group the mean serum TG
concentration decreased by 38%, HDL cholesterol concentration
increased by 10%, and LDL cholesterol concentration by 17% (P
< 0.05). During gemfibrozil therapy the mean particle diameter
of the major LDL peak increased from 244 to 251 A (P < 0.05),
whereas in the placebo group the mean LDL particle diameter
remained unchanged. We found an inverse correlation between
the changes of serum TG and the particle diameters of the major
LDL peak (r = 0.85, P < 0.01). Gemfibrozil produced a shift
in the LDL density distribution toward lower density. The mean
peak density decreased from 1.0371 to 1.0345 g/ml because of
a significant rise in the light LDL concentration from 141.0
to 183.2 mg/dl (P < 0.05), whereas the concentration of dense
LDL had a tendency to decrease. In the placebo group the LDL
density distribution did not change. Gemfibrozil increased the
CE-to-TG ratio in LDL core lipids by 27% (P < 0.05); otherwise,
the LDL composition was only slightly affected. CONCLUSIONS--The
results indicate gemfibrozil-induced changes in LDL properties
in NIDDM patients are similar to those previously reported in
nondiabetic individuals and are related to changes in serum
TG level.
Publication Types:
|
Clinical trial
|
|
Randomized controlled trial |
PMID: 8462384 [PubMed - indexed for MEDLINE]
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High density lipoprotein subfractions in non-insulin-dependent
diabetes mellitus and coronary artery disease.
Syvanne M, Ahola M, Lahdenpera S, Kahri J, Kuusi T, Virtanen
KS, Taskinen MR.
First Department of Medicine, University of Helsinki, Finland.
High density lipoprotein (HDL) subfractions (2b, 2a, 3a, 3b,
and 3c) separated by gradient gel electrophoresis (GGE) and
defined by Gaussian summation analysis, and the compositions
of HDL2 and HDL3, separated by preparative ultracentrifugation,
were studied in four groups of men with or without non-insulin-dependent
diabetes mellitus (NIDDM) and coronary artery disease (CAD):
group 1 (DM+CAD+, n = 50); group 2 (DM-CAD+, n = 50); group
3 (DM+CAD-, n = 50); and group 4 (DM-CAD-, n = 31). HDL GGE
subfraction distributions, available in 125 subjects, were not
significantly different among the groups. In contrast, dividing
the whole study population into quartiles of serum triglyceride
(TG) concentration showed that high TG levels were significantly
associated with low HDL2b and high HDL3b concentrations. In
a multivariate linear regression model, postheparin plasma hepatic
lipase (HL) activity, and fasting serum insulin and TG concentrations
were all associated independently and inversely with low HDL2b,
but lipoprotein lipase or cholesteryl ester transfer protein
activities were not correlated with HDL2b concentrations. Group
1 tended to have the smallest mean particle sizes in the HDL
subfractions, significantly (P < 0.03, CAD vs. non-CAD) for
HDL2b and for HDL2a. These differences were independent of TG,
insulin and HL, but lost their significance when adjusted for
beta-blocker therapy. Both HDL2 and HDL3 particles in group
1 were significantly depleted of unesterified cholesterol, and
their HDL2 was TG-enriched (P = 0.053). A high HL activity,
hyperinsulinemia and hypertriglyceridemia are independently
associated with low levels of HDL2b and generally small HDL
particle size. HDL particles in subjects with NIDDM and CAD
are small-sized and have a low free cholesterol content. Both
these characteristics may be markers of impaired reverse cholesterol
transport.
PMID: 7775869 [PubMed - indexed for MEDLINE]
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Cholesterol efflux from Fu5AH hepatoma cells induced by plasma
of subjects with or without coronary artery disease and non-insulin-dependent
diabetes: importance of LpA-I:A-II particles and phospholipid
transfer protein.
Syvanne M, Castro G, Dengremont C, De Geitere C, Jauhiainen
M, Ehnholm C, Michelagnoli S, Franceschini G, Kahri J, Taskinen
MR.
Department of Medicine, Helsinki University Central Hospital,
Finland.
We measured the capacity of human plasma to induce cholesterol
efflux from Fu5AH rat hepatoma cells in four groups of men with
or without non-insulin-dependent diabetes mellitus (NIDDM) and
coronary artery disease (CAD). Plasma from men with both NIDDM
and CAD (n = 47) had the lowest efflux capacity (17.3 +/- 3.6%)
whereas healthy control subjects with neither diabetes nor CAD
(n = 25) had the highest capacity (19.8 +/- 3.4%). The groups
with CAD but no diabetes (n = 44) and with NIDDM but no CAD
(n = 35) had intermediate efflux values (18.5 +/- 3.8 and 18.5
+/- 3.9%, respectively). In a 2 x 2 factorial ANOVA, the differences
were significant with respect to the presence of CAD (P = 0.038)
and NIDDM (P = 0.041), with no interaction between the factors.
The concentration of HDL particles containing apolipoprotein
(apo) A-I but no apo A-II (LpA-I) was not related to efflux
capacity in univariate or multivariate analyses. A multivariate
regression analysis showed that when controlled for the presence
of NIDDM and CAD, the concentration of particles containing
both apo A-I and apo A-II (LpA-I:A-II) and plasma phospholipid
transfer protein activity were both positively, independently,
and significantly (P < 0.001) related to cholesterol efflux
capacity.
PMID: 9125315 [PubMed - indexed for MEDLINE]
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Increased esterification of cholesterol and transfer of cholesteryl
ester to apo B-containing lipoproteins in Type 2 diabetes: relationship
to serum lipoproteins A-I and A-II.
Jones RJ, Owens D, Brennan C, Collins PB, Johnson AH, Tomkin
GH.
Department of Clinical Medicine, Trinity College, Dublin, Ireland.
This study examines the activity of two key enzymes of reverse
cholesterol transport, cholesterol ester transfer protein (CETP)
and lecithin:cholesterol acyl transferase (LCAT) in 21 patients
with non-insulin dependent diabetes mellitus (NIDDM) and 21
control subjects. Serum CETP was assessed by measuring plasma-mediated
cholesteryl ester transfer between pooled exogenous lipoprotein
with endogenous LCAT inhibited--an estimate of CETP mass. CETP
activity was determined as cholesteryl ester transfer in the
presence of the patients' lipoproteins and LCAT (endogenous
assay). LCAT activity was determined in the same assay. There
was no significant difference in CETP mass between the diabetic
and non-diabetic subjects and there was no correlation between
CETP mass and LCAT activity. Using the endogenous lipoprotein
assay, CETP was elevated in serum from diabetic patients compared
to control subjects (10.05 +/- 1.89 vs. 5.50 +/- 0.53 nmol/ml/h
P < 0.05). LCAT was also increased in the diabetic patients
(53.63 +/- 4.70 vs. 41.22 +/- 3.40 nmol/ml/h P < 0.05). Serum
free cholesterol from diabetic and control subjects correlated
with CETP activity measured using endogenous lipoprotein assay
(r = 0.77, P < 0.001 and r = 0.82, P < 0.001), and also
with LCAT activity (r = 0.76, P < 0.01 and r = 0.79, P <
0.01). There was a negative correlation between CETP activity
with the endogenous lipoprotein assay and serum high density
lipoprotein (HDL) cholesterol in the diabetic patients (r =
-0.38, P < 0.01), but not in control subjects. In a subgroup
of 10 control subjects, there was a positive correlation between
LCAT activity and apolipoprotein (apo) A-I (r = 0.49, P <
0.05) and apo A-II (r = 0.51, P < 0.05) and also between
CETP activity (endogenous assay) and apo A-I (r = 0.87, P =
0.001) and apo A-II (r = 0.63, P < 0.05). No relationship
was observed between CETP activity and apo A-I or apo A-II in
the diabetic subjects. Thus, serum CETP mass was normal in Type
2 diabetes but CETP activity (endogenous assay) was increased
and was related to free cholesterol levels and LCAT activity
in both diabetic and non-diabetic subjects.
PMID: 8808492 [PubMed - indexed for MEDLINE]
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-
Reverse cholesterol transport in diabetes mellitus.
Quintao EC, Medina WL, Passarelli M.
Lipid Metabolism Laboratory (LIM 10), Hospital das Clinicas,
The University of Sao Paulo Medical School, Sao Paulo, Brazil.
lipideq@usp.br
There are epidemiological data and experimental animal models
relating the development of premature atherosclerosis with defects
of the reverse cholesterol transport (RCT) system. In this regard,
the plasma concentrations of the high density lipoprotein (HDL)
subfractions, of cholesteryl ester transfer protein (CETP),
as well as the activity of the enzyme lecithin-cholesterol acyl
transferase (LCAT) play critical roles. However, there has been
plenty of evidence that atherosclerosis in diabetes mellitus
(DM) is ascribed to a greater arterial wall cell uptake of modified
apoB-containing lipoproteins whereas a primary or predominant
defect of the RCT system is still a subject of debate. In other
words, in spite of the fact that in DM the composition and rates
of metabolism of the HDL particles are greatly altered and display
a diminished in vitro efficiency to remove cell cholesterol,
definitive in vivo demonstration of the importance of this fact
in atherogenesis is lacking. Furthermore, the roles played by
LCAT and CETP in RCT in DM are difficult to interpret because
the in vitro procedures of measurement utilized have either
been inadequate, or inappropriately interpreted. Knock-out or
transgenic mice are much needed models to investigate the roles
of LCAT, CETP, phospholipid transfer protein (PLTP), and of
a CETP inhibitor in the development of atherosclerosis of experimental
DM.
Publication Types:
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Review
|
|
Review, academic |
PMID: 10934452 [PubMed - indexed for MEDLINE]
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The phenomenon of a high triglyceride response to an oral
lipid load in healthy subjects and its link to the metabolic
syndrome.
Schrezenmeir J, Keppler I, Fenselau S, Weber P, Biesalski
HK, Probst R, Laue C, Zuchhold HD, Prellwitz W, Beyer J.
3rd Medical Clinic, Johannes Gutenberg-University, Mainz, Germany.
Excessive postprandial triglyceride (TG) responses despite normal
fasting TG levels have been described in single cases within
small groups of healthy subjects and in patients with obesity
or precocious atherosclerosis, known to be associated with high
insulin fasting levels. To clarify this association, fasting
and postprandial TG and insulin levels were studied in 113 healthy
young (25.7 +/- 2.6 years), normal weight (body mass index 20.8
+/- 2.3 kg/m2) male subjects who were selected from among 117
subjects on the basis of TG fasting levels < 200 mg/dl. After
a 12-hour fast a standardized liquid lipid load was administered
containing 58 g mainly saturated fat and 1,017 kcal energy.
Both fasting TG values and postprandial TG peak values showed
bimodal frequency distributions. Statistical analysis of fasting
TG discriminated two groups: a low fasting TG group with normally
distributed values < 150 mg/dl (mean +/- SEM: 79.5 +/- 2.7
mg/dl; n = 104) and a high fasting TG group > 150 mg/dl (194.5
+/- 7.2 mg/dl; n = 13). Likewise, two groups could be differentiated
according to their maximal postprandial TG response (TG max)
to the lipid load: (1) normal responders with TG max < 260
mg/dl (mean +/- SEM: 123 +/- 4.8 mg/dl; n = 96) and (2) high
responders with TG max > 260 mg/dl (272.5 +/- 20.5 mg/dl;
n = 17). Fasting TG and TG max were highly correlated (r = 0.745;
p < 0.0001). However, 9 of 17 (53%) high responders had fasting
TG < 150 mg/dl, which means that the prediction of high response
is only 47.0% based on fasting TG values. Fasting insulin levels
were significantly higher in high responders than in normal
responders, whereas they did not differ between the low and
high fasting TG group. In conclusion, the bimodal frequency
distribution of TG max after a lipid load permitted the differentiation
of two groups, normal responders and high responders, with higher
fasting insulin levels, which might indicate a link to the metabolic
syndrome.
PMID: 8352452 [PubMed - indexed for MEDLINE]
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-
Diabetic dyslipidemia.
Kreisberg RA.
Department of Medicine, Baptit Health System, Birmingham, Alabama
35213, USA.]
Usual risk factors for coronary artery disease account for only
25-50% of increased atherosclerotic risk in diabetes mellitus.
Other obvious risk factors are hyperglycemia and dyslipidemia.
However, hyperglycemia is a very late stage in the sequence
of events from insulin resistance to frank diabetes, whereas
lipoprotein abnormalities are manifested during the largely
asymptomatic diabetic prodrome and contribute substantially
to the increased risk of macrovascular disease. The insulin-resistant
diabetes course affects virtually all lipids and lipoproteins.
Chylomicron and very-low-density lipoprotein (VLDL) remnants
accumulate, and triglycerides enrich high-density lipoprotein
(HDL) and low-density lipoprotein (LDL), leading to high levels
of potentially atherogenic particles and low levels of HDL cholesterol.
Hyperglycemia eventually impairs removal of triglyceride-rich
lipoproteins, the accumulation of which accentuates hypertriglyceridemia.
As triglycerides increase-still within the so-called normal
range-abnormalities in HDL and LDL became more apparent. Thus,
when triglycerides are >200 mg/dL, LDL particles are small
and dense (when they are <90 mg/dL, the particles are of
the large, buoyant variety). The atherogenicity of small, dense
LDL particles is attributed to their increased susceptibility
to oxidation, but in many patients they may be a marker for
insulin resistance or the presence of atherogenic VLDL. Hypertriglyceridemia
is associated with atherosclerosis because (1) it is a marker
for insulin resistance and atherogenic metabolic abnormalities;
and (2) the small size of triglyceride-enriched lipoproteins
enables them to infiltrate the blood vessel wall where they
are oxidized, bind to receptors on macrophages, and ingested,
leading to the development of the atherosclerotic lesion. Various
studies (primary prevention with gemfibrozil: Helsinki Heart
Study; secondary prevention with simvastatin and pravastatin:
Scandinavian Simvastatin Survival Study [4S] and Cholesterol
and Recurrent Events [CARE], respectively) have demonstrated
that lipid-lowering therapy in type 2 diabetes is effective
in decreasing the number of cardiac events. Risk reduction was
22% to 50% (statins) and approximately 65% (fibrate) relative
to placebo. It was also noted (in 4S and CARE) that the risk
of major coronary events in untreated diabetic patients was
1.5-1.7-fold greater than in untreated nondiabetic patients.
Although gemfibrozil (fibric acid derivative) is more effective
in decreasing triglycerides and increasing HDL cholesterol in
diabetic patients than the statins, it does not change and may
even increase LDL-cholesterol levels (fenofibrate may be an
exception, decreasing LDL cholesterol by 20-25% in some studies).
However, gemfibrozil does increase LDL particle size. Nevertheless,
the statins are the current lipid-lowering drugs of choice because
the change in LDL-cholesterol-to-HDL-cholesterol ratio is better
than with gemfibrozil. Moreover, the diabetic patient may be
more likely to benefit from statin therapy than the nondiabetic
patient. It should be noted that, in theory, nicotinic acid
can correct or improve all lipid or lipoprotein abnormalities
in patients with type 2 diabetes. Unfortunately, it is relatively
contraindicated because it causes insulin resistance and may
precipitate or aggravate hyperglycemia (in addition to its other
well-known side effects such as flushing, gastric irritation,
development of hepatotoxicity, and hyperuricemia). It is unknown
at present whether newer formulations such as once-daily Niaspan
may be better tolerated in diabetes. In any case, most patients
with type 2 diabetes have risk factors for coronary artery disease
and qualify for aggressive LDL cholesterol-lowering therapy.
At the same time, it is presently unknown whether improved glycemic
control decreases coronary artery disease risk in such patients.
Publication Types:
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Review
|
|
Review, tutorial |
PMID: 9915665 [PubMed - indexed for MEDLINE]
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Fasting hypertriglyceridemia in noninsulin-dependent diabetes
mellitus is an important predictor of postprandial lipid and
lipoprotein abnormalities.
Lewis GF, O'Meara NM, Soltys PA, Blackman JD, Iverius PH,
Pugh WL, Getz GS, Polonsky KS.
Department of Medicine, University of Chicago, Pritzker School
of Medicine, Illinois 60637.
Postprandial lipoprotein metabolism may be important in atherogenesis
and has not been studied in detail in noninsulin-dependent diabetes
mellitus (NIDDM). We used the vitamin A fat-loading test to
label triglyceride-rich lipoprotein particles of intestinal
origin after ingestion of a high fat mixed meal containing 60
g fat/m2 and 60,000 U vitamin A/m2 in 12 untreated NIDDM subjects
with normotriglyceridemia (NTG; triglycerides, less than 1.7
mmol/L), 7 untreated NIDDM subjects with moderate hypertriglyceridemia
(HTG; triglycerides, 1.7-4.7 mmol/L), and 8 age- and weight-matched
normotriglyceridemic nondiabetic controls. The postprandial
triglyceride increment was greater in NIDDM with HTG (P = 0.0001)
and correlated strongly in all groups with the fasting triglyceride
concentration (r = 0.83; P = 0.0001). Retinyl palmitate measured
in whole plasma, an Sf greater than 1000 chylomicron fraction,
and an Sf less than 1000 nonchylomicron fraction was also significantly
greater in NIDDM with HTG, but did not differ significantly
between NIDDM with NTG and controls. In NIDDM with HTG, chylomicrons
appeared to be cleared at a slower rate, as evidenced by the
significantly later intersection of the chylomicron and nonchylomicron
retinyl palmitate response curves (13.7 h in HTG NIDDM vs. 8.5
h in NTG NIDDM vs. 7.3 h in controls; P less than 0.01). Although
fasting FFA levels were similar in all three groups, the HTG
diabetic subjects had a late postprandial surge in FFAs that
lasted for up to 14 h. The postprandial FFA elevation in all
groups correlated with the fasting triglyceride concentration
(r = 0.57; P less than 0.002) and postprandial triglyceride
increment (r = 0.80; P = 0.0001). The fasting core triglyceride
content of the HDL particles in NIDDM with HTG was significantly
elevated compared to those in NIDDM with NTG and controls (21.0%
vs. 14.0% vs. 14.1% respectively; P less than 0.05), and this
increased proportionately in all groups after the meal at the
expense of cholesteryl ester, the increase correlating with
total plasma postprandial triglyceride increment (r = 0.51;
P less than 0.01). We conclude that moderate fasting hypertriglyceridemia
in NIDDM is predictive of a constellation of postprandial changes
in lipids and lipoproteins that may potentiate the already unfavorable
atherogenic fasting lipid profile in these subjects.
PMID: 2005221 [PubMed - indexed for MEDLINE]
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In vivo demonstration in humans that large postprandial triglyceride-rich
lipoproteins activate coagulation factor VII through the intrinsic
coagulation pathway.
Silveira A, Karpe F, Johnsson H, Bauer KA, Hamsten A.
Atherosclerosis Research Unit, King Gustaf V Research Institute,
Karolinska Hospital, Stockholm, Sweden. silveira@instmed.ks.se
In vitro studies in purified plasma systems have suggested that
triglyceride-rich lipoproteins such as chylomicrons, very low
density lipoproteins, and their remnants promote activation
of factor VII through activated factor XII (XIIa) and the intrinsic
coagulation pathway. We specifically examined the roles of factors
XII, XI, and IX in activation of factor VII during alimentary
lipemia in vivo in humans and addressed the issue of whether
generation of activated factor VII (VIIa) is accompanied by
increased thrombin production. For this purpose XIIa, factor
IX activation peptide (IXP), VIIa, prothrombin fragment 1 +
2 (F1 + 2), and thrombin-antithrombin complex (TAT) were determined
in plasma samples taken before and 3, 6, and 9 hours after intake
of a mixed meal type of oral fat load in 24 healthy men The
VIIa response to fat intake was also determined in 7 patients
with single coagulation-factor deficiency, of whom 2 were deficient
in factor XII, 2 in factor XI, and 3 in factor IX. Postprandial
activation of factors IX and VII occurred in the healthy individuals,
whereas the plasma levels of XIIa did not change in response
to the test meal. Of note, plasma concentrations of F1 + 2 were
unaltered during alimentary lipemia, and TAT levels showed a
small decrease (P < .05) in the 3-hour sample compared with
the fasting level, indicating that thrombin generation is not
stimulated in the postprandial state, despite the generation
of activated factor IX (IXa) and VIIa. Factor VIIa increased
in the postprandial period in the 2 factor XII-deficient patients
who underwent the oral fat tolerance test but appeared to remain
unchanged in the factor XI- and factor IX-deficient patients.
Therefore, the current concept that activation of factor XII
plays a pivotal role in initiating the sequence of events linking
postprandial lipemia to activation of factor VII is contradicted
by the present study. Whether activation of factor XI by triglyceride
rich lipoproteins initiates these reactions needs to be demonstrated
in future studies.
PMID: 8911271 [PubMed - indexed for MEDLINE]
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-
Differences in the metabolism of postprandial lipoproteins
after a high-monounsaturated-fat versus a high-carbohydrate
diet in patients with type 1 diabetes mellitus.
Georgopoulos A, Bantle JP, Noutsou M, Swaim WR, Parker SJ.
Minneapolis Veterans Affairs Medical Center, MN 55417, USA.
georg003@maroon.tc.umn.edu
There is little information comparing the effects of a high-monounsaturated
(Mono)-fat versus a high-carbohydrate (CHO) diet in patients
with type 1 diabetes mellitus. In the present study, the effects
of these diets on a number of metabolic parameters were compared.
Seventeen normolipidemic, nonobese patients with type 1 diabetes
were provided with the diets for 4 weeks each in a randomized,
crossover design. The percentages of Mono fat of the two diets
were 25 Mono versus 9 CHO, with a corresponding total fat content
of 40% versus 24% and a total CHO content of 45% versus 61%.
At the end of each dietary period, parameters of glycemic control,
coagulation factors, and fasting and postprandial lipoproteins
were assessed. There were no differences in weight, glycemia,
insulin dose, fasting lipid profile, or coagulation factors
between the two diets. However, the metabolism of postprandial
lipoproteins after a fat load differed; viz, after the Mono
diet compared with the CHO diet, mean plasma triglyceride levels
over 10 hours were higher (P=.0025, by repeated-measures ANOVA).
The levels of triglyceride (P=.0045) and retinyl esters (P=.0046)
in chylomicrons (Sf>400) and chylomicron remnants (Sf 100
to 400) (P=.0047 and P=.043, respectively), and the total particle
number (apolipoprotein B levels) in chylomicron remnants (P=.001)
and small, very low density lipoprotein (Sf 20 to 100, P=.016)
were also higher. Our data suggest that in patients with type
1 diabetes, a CHO diet might be preferable to a Mono diet, since
adherence to the former results in a lower number of circulating
postprandial lipoprotein particles that are potentially atherogenic.
Publication Types:
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Clinical trial
|
|
Randomized controlled trial |
PMID: 9598837 [PubMed - indexed for MEDLINE]
-
Effect of a single high-fat meal on endothelial function
in healthy subjects.
Vogel RA, Corretti MC, Plotnick GD.
Department of Medicine, University of Maryland School of Medicine,
Baltimore 21201-2595, USA.
Although there is a well-established relation between serum
cholesterol and coronary artery disease risk, individual and
national variations in this association suggest that other factors
are involved in atherogenesis. High-fat diet associated triglyceride-rich
lipoproteins have also been suggested to be atherogenic. To
assess the direct effect of postprandial triglyceride-rich lipoproteins
on endothelial function, an early factor in atherogenesis--10
healthy, normocholesterolemic volunteers--were studied before
and for 6 hours after single isocaloric high- and low-fat meals
(900 calorie; 50 and 0 g fat, respectively). Endothelial function,
in the form of flow-mediated vasoactivity, was assessed in the
brachial artery using 7.5-MHz ultrasound as percent arterial
diameter change 1 minute after 5 minutes of upper-arm arterial
occlusion. Serum lipoproteins and glucose were determined before
eating and 2 and 4 hours postprandially. Serum triglycerides
increased from 94 +/- 55 mg/dl preprandially to 147 +/- 80 mg/dl
2 hours after the high-fat meal (p = 0.05). Flow-dependent vasoactivity
decreased from 21 +/- 5% preprandially to 11 +/- 4%, 11 +/-
6%, and 10 +/- 3% at 2, 3, and 4 hours after the high-fat meal,
respectively (all p <0.05 compared with low-fat meal data).
No changes in lipoproteins or flow-mediated vasoactivity were
observed after the low-fat meal. Fasting low-density lipoprotein
cholesterol correlated inversely (r = -0.47, p = 0.04) with
preprandial flow-mediated vasoactivity, but triglyceride level
did not. Mean change in postprandial flow-mediated vasoactivity
at 2, 3, and 4 hours correlated with change in 2-hour serum
triglycerides (r = -0.51, p = 0.02). These results demonstrate
that a single high-fat meal transiently impairs endothelial
function. These findings identify a potential process by which
a high-fat diet may be atherogenic independent of induced changes
in cholesterol.
PMID: 9036757 [PubMed - indexed for MEDLINE]
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Endothelium-dependent flow-mediated vasodilation in the postprandial
state in type 2 diabetes mellitus.
Shige H, Ishikawa T, Suzukawa M, Ito T, Nakajima K, Higashi
K, Ayaori M, Tabata S, Ohsuzu F, Nakamura H.
First Department of Internal Medicine, National Defense Medical
College, Saitama, Japan.
This study examined the effects of fat- plus sucrose-rich meals
on endothelium-dependent flow-mediated vasodilation in diabetic
patients. Flow-mediated vasodilation in the postprandial state
decreased significantly, and the decrease correlated inversely
with the magnitude of postprandial hyperglycemia, suggesting
that endothelial function in diabetic patients becomes impaired
postprandially.
PMID: 10569346 [PubMed - indexed for MEDLINE]
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-
Comment in:
|
JAMA. 1994 Jan 12;271(2):101-2 |
Comment on:
|
JAMA. 1993 Jun 16;269(23):3002-8
|
|
JAMA. 1993 Jun 16;269(23):3009-14 |
Summary of the second report of the National Cholesterol
Education Program (NCEP) Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol in Adults (Adult Treatment
Panel II)
Publication Types:
|
Comment |
PMID: 8501844 [PubMed - indexed for MEDLINE]
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-
Comment in:
|
ACP J Club. 1997 Mar-Apr;126(2):29
|
|
N Engl J Med. 1997 Mar 27;336(13):961;
discussion 962 |
The effect of pravastatin on coronary events after myocardial
infarction in patients with average cholesterol levels. Cholesterol
and Recurrent Events Trial investigators.
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD,
Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald
E.
Department of Medicine, Brigham and Women's Hospital and Harvard
Medical School, Boston, MA 02115, USA.
BACKGROUND: In patients with high cholesterol levels, lowering
the cholesterol level reduces the risk of coronary events, but
the effect of lowering cholesterol levels in the majority of
patients with coronary disease, who have average levels, is
less clear. METHODS: In a double-blind trial lasting five years
we administered either 40 mg of pravastatin per day or placebo
to 4159 patients (3583 men and 576 women) with myocardial infarction
who had plasma total cholesterol levels below 240 mg per deciliter
(mean, 209) and low-density lipoprotein (LDL) cholesterol levels
of 115 to 174 mg per deciliter (mean, 139). The primary end
point was a fatal coronary event or a nonfatal myocardial infarction.
RESULTS: The frequency of the primary end point was 10.2 percent
in the pravastatin group and 13.2 percent in the placebo group,
an absolute difference of 3 percentage points and a 24 percent
reduction in risk (95 percent confidence interval, 9 to 36 percent;
P = 0.003). Coronary bypass surgery was needed in 7.5 percent
of the patients in the pravastatin group and 10 percent of those
in the placebo group, a 26 percent reduction (P=0.005), and
coronary angioplasty was needed in 8.3 percent of the pravastatin
group and 10.5 percent of the placebo group, a 23 percent reduction
(P=0.01). The frequency of stroke was reduced by 31 percent
(P=0.03). There were no significant differences in overall mortality
or mortality from noncardiovascular causes. Pravastatin lowered
the rate of coronary events more among women than among men.
The reduction in coronary events was also greater in patients
with higher pretreatment levels of LDL cholesterol. CONCLUSIONS:
These results demonstrate that the benefit of cholesterol-lowering
therapy extends to the majority of patients with coronary disease
who have average cholesterol levels.
Publication Types:
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Clinical trial
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Multicenter study
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Randomized controlled trial |
PMID: 8801446 [PubMed - indexed for MEDLINE]
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Comment in:
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ACP J Club. 1999 Mar-Apr;130(2):31
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N Engl J Med. 1998 Aug 20;339(8):489-97
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N Engl J Med. 1999 Apr 8;340(14):1115-6;
discussion 1116-7 |
Prevention of cardiovascular events and death with pravastatin
in patients with coronary heart disease and a broad range of
initial cholesterol levels. The Long-Term Intervention with
Pravastatin in Ischaemic Disease (LIPID) Study Group.
BACKGROUND: In patients with coronary heart disease and a broad
range of cholesterol levels, cholesterol-lowering therapy reduces
the risk of coronary events, but the effects on mortality from
coronary heart disease and overall mortality have remained uncertain.
METHODS: In a double-blind, randomized trial, we compared the
effects of pravastatin (40 mg daily) with those of a placebo
over a mean follow-up period of 6.1 years in 9014 patients who
were 31 to 75 years of age. The patients had a history of myocardial
infarction or hospitalization for unstable angina and initial
plasma total cholesterol levels of 155 to 271 mg per deciliter.
Both groups received advice on following a cholesterol-lowering
diet. The primary study outcome was mortality from coronary
heart disease. RESULTS: Death from coronary heart disease occurred
in 8.3 percent of the patients in the placebo group and 6.4
percent of those in the pravastatin group, a relative reduction
in risk of 24 percent (95 percent confidence interval, 12 to
35 percent; P<0.001). Overall mortality was 14.1 percent
in the placebo group and 11.0 percent in the pravastatin group
(relative reduction in risk, 22 percent; 95 percent confidence
interval, 13 to 31 percent; P<0.001). The incidence of all
cardiovascular outcomes was consistently lower among patients
assigned to receive pravastatin; these outcomes included myocardial
infarction (reduction in risk, 29 percent; P<0.001), death
from coronary heart disease or nonfatal myocardial infarction
(a 24 percent reduction in risk, P<0.001), stroke (a 19 percent
reduction in risk, P=0.048), and coronary revascularization
(a 20 percent reduction in risk, P<0.001). The effects of
treatment were similar for all predefined subgroups. There were
no clinically significant adverse effects of treatment with
pravastatin. CONCLUSIONS: Pravastatin therapy reduced mortality
from coronary heart disease and overall mortality, as compared
with the rates in the placebo group, as well as the incidence
of all prespecified cardiovascular events in patients with a
history of myocardial infarction or unstable angina who had
a broad range of initial cholesterol levels.
Publication Types:
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Clinical trial
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Multicenter study
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Randomized controlled trial |
PMID: 9841303 [PubMed - indexed for MEDLINE]
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Comment in:
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Arch Intern Med. 1999 Dec
13-27;159(22):2627-8 |
Reduced coronary events in simvastatin-treated patients with
coronary heart disease and diabetes or impaired fasting glucose
levels: subgroup analyses in the Scandinavian Simvastatin Survival
Study.
Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner
TA, Pedersen TR, Kjekshus J, Pyorala K.
Department of Medicine, University of Texas Health Science Center
at San Antonio, 78284-7873, USA. haffner@UTHSCSA.edu
BACKGROUND: Patients with diabetes mellitus (DM) have a marked
increase in coronary heart disease (CHD) events relative to
those without DM. In a previous report from the Scandinavian
Simvastatin Survival Study using a clinical case definition
of DM (n = 202), simvastatin-treated patients had significantly
fewer CHD events compared with placebo-treated control subjects.
OBJECTIVE: To examine the effect of simvastatin therapy on CHD
in patients with DM and impaired fasting glucose levels. METHODS:
Using the 1997 American Diabetes Association diagnostic criteria,
we assessed the effect of simvastatin therapy post hoc for an
average of 5.4 years in Scandinavian Simvastatin Survival Study
patients with normal fasting glucose (n = 3237), impaired fasting
glucose (n = 678), and DM (n = 483). RESULTS: Simvastatin-treated
patients with DM had significantly reduced numbers of major
coronary events (relative risk [RR] = 0.58; P = .001) and revascularizations
(RR = 0.52; P = .005). Total (RR = 0.79; P = .34) and coronary
(RR = 0.72; P = .26) mortality were also reduced in DM, but
not significantly, due to small sample size. In impaired fasting
glucose (IFG) subjects, simvastatin use significantly reduced
the number of major coronary events (RR = 0.62; P = .003), revascularizations
(RR = 0.57; P = .009), and total (RR = 0.57; P = .02) and coronary
(RR = 0.45; P = .007) mortality. CONCLUSION: Our results extend
previous findings in patients with DM to a larger cohort, confirming
the benefit of cholesterol lowering with simvastatin treatment
on CHD events. In addition, significant decreases in total mortality,
major coronary events, and revascularizations were observed
in simvastatin-treated patients with impaired fasting glucose
levels. These results strongly support the concept that cholesterol
lowering with simvastatin therapy improves the prognosis of
patients with elevated fasting glucose levels (> or =6.0
mmol/L [> or =110 mg/ dL]) or DM and known CHD.
Publication Types:
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Clinical trial
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Multicenter study
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Randomized controlled trial |
PMID: 10597756 [PubMed - indexed for MEDLINE]
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Hypertriglyceridaemia as a risk factor of coronary heart
disease mortality in subjects with impaired glucose tolerance
or diabetes. Results from the 11-year follow-up of the Paris
Prospective Study.
Fontbonne A, Eschwege E, Cambien F, Richard JL, Ducimetiere
P, Thibult N, Warnet JM, Claude JR, Rosselin GE.
INSERM Unite 21, Villejuif, Paris, France.
The Paris Prospective Study is a long-term investigation of
the incidence of coronary heart disease in a large population
of working men. The first follow-up examination involved 7,038
men, aged 43-54 years. Subjects with impaired glucose tolerance
or diabetes (n = 943) were selected from the total population
for a separate analysis of coronary heart disease mortality
risk factors. During a mean follow-up of 11 years, 26 of these
943 subjects with abnormal glucose tolerance died from coronary
heart disease. Univariate analysis showed that plasma triglyceride
level (p less than 0.006), plasma cholesterol level (p less
than 0.02), and plasma insulin level both fasting and 2-h post-glucose
load (p less than 0.02), were significantly higher in subjects
who died from coronary heart disease compared to those who did
not. In multivariate regression analysis using the Cox model,
plasma triglyceride level was the only factor positively and
significantly associated with coronary death. The distribution
of plasma triglyceride levels was clearly higher for the subjects
who died from coronary heart disease compared to those who did
not die from this cause or were alive at the end of the follow-up.
This new epidemiological evidence that hypertriglyceridaemia
is an important predictor of coronary heart disease mortality
in subjects with impaired glucose tolerance or diabetes suggests
a possible role of dyslipidaemia in the excessive occurrence
of atherosclerotic vascular disease in this category of subjects.
PMID: 2666216 [PubMed - indexed for MEDLINE]
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Dyslipidemia and hyperglycemia predict coronary heart disease
events in middle-aged patients with NIDDM.
Lehto S, Ronnemaa T, Haffner SM, Pyorala K, Kallio V, Laakso
M.
Department of Medicine, Kuopio University Hospital, Finland.
Patients with NIDDM are at increased risk for coronary heart
disease (CHD). However, information on the predictive value
of cardiovascular risk factors and the degree of hyperglycemia
with respect to the risk for CHD in diabetic patients is still
limited. Therefore, we carried out a prospective study on risk
factors for CHD, including a large number of NIDDM patients.
At baseline, risk factor levels of CHD were determined in 1,059
NIDDM patients (581 men and 478 women), aged from 45 to 64 years.
These patients were followed up to 7 years with respect to CHD
events. Altogether, 158 NIDDM patients (97 men [16.7%] and 61
women [12.8%]) died of CHD and 256 NIDDM patients (156 men [26.8%]
and 100 women [20.9%]) had a serious CHD event (death from CHD
or nonfatal myocardial infarction). A previous history of myocardial
infarction, low HDL cholesterol level (<1.0 mmol/l), high
non-HDL cholesterol (> or =5.2 mmol/l), high total triglyceride
level (>2.3 mmol/l), and high fasting plasma glucose (>13.4
mmol/l) were associated with a twofold increase in the risk
of CHD mortality or morbidity, independently of other cardiovascular
risk factors. High calculated LDL cholesterol level (> or
=4.1 mmol/l) was significantly associated with all CHD events.
The simultaneous presence of high fasting glucose (>13.4
mmol/l) with low HDL cholesterol, low HDL-to-total cholesterol
ratio, or high total triglycerides further increased the risk
for CHD events up to threefold. Our 7-year follow-up study provides
evidence that dyslipidemia and poor glycemic control predict
CHD mortality and morbidity in patients with NIDDM.
PMID: 9231662 [PubMed - indexed for MEDLINE]
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Comment in:
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Circulation. 1993 Oct;88(4
Pt 1):1952-3 |
Lipids and lipoproteins predicting coronary heart disease
mortality and morbidity in patients with non-insulin-dependent
diabetes.
Laakso M, Lehto S, Penttila I, Pyorala K.
Department of Medicine, Kuopio University Hospital, Finland.
BACKGROUND. The aim of this study was to investigate the association
of lipoprotein fractions with the future risk of coronary heart
disease (CHD) in patients with non-insulin-dependent diabetes
(NIDDM). METHODS AND RESULTS. At baseline, lipoprotein fractions
were determined in 313 diabetic patients with NIDDM (153 men
and 160 women), and these patients were followed up for 7 years
with respect to CHD events (CHD death or all CHD events including
CHD death or nonfatal myocardial infarction). Altogether, 56
NIDDM patients (28 men and 28 women) died from CHD and 25 had
a nonfatal myocardial infarction (17 men and 8 women) during
the follow-up. NIDDM patients having these CHD events during
the follow-up had higher levels of total and very-low-density
lipoprotein (VLDL) triglycerides and VLDL cholesterol and lower
levels of high-density lipoprotein (HDL) and HDL2 cholesterol
than those without CHD events. The risk for CHD death was fourfold
and for all CHD events, twofold higher among diabetics with
low HDL cholesterol (< 0.9 mmol/L) than among diabetics with
HDL cholesterol > or = 0.9 mmol/L. High triglyceride level
(> 2.3 mmol/L) was associated with a twofold increase in
the risk of CHD events. In multiple logistic regression analyses,
HDL was inversely associated with CHD events and VLDL triglycerides
with CHD events in NIDDM patients with low HDL cholesterol level
(< or = 1.12 mmol/L). CONCLUSIONS. Our 7-year follow-up study
gives evidence that low HDL and HDL2 cholesterol, high VLDL
cholesterol, and high total and VLDL triglycerides are powerful
risk indicators for CHD events in patients with NIDDM.
PMID: 8403288 [PubMed - indexed for MEDLINE]
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Treatment of diabetic dyslipidemia.
Garg A.
Center for Human Nutrition and the Department of Clinical Nutrition,
University of Texas Southwestern Medical Center at Dallas, and
the Department of Veterans Affairs Medical Center, 75235-9052,
USA.
Patients with diabetes mellitus have an increased risk for coronary
artery disease due to hyperglycemia, hypertension, dyslipidemia,
and other risk factors. The diabetic dyslipidemia in these patients
is characterized by moderately high levels of (1) serum cholesterol
and triglycerides; (2) small, dense low-density lipoprotein
(LDL) particles; and (3) low high-density lipoprotein (HDL)
cho-lesterol concentrations. Recent clinical trials have demonstrated
the benefits of cholesterol-lowering therapy in both diabetic
and nondiabetic patients, thus supporting aggressive treatment
of diabetic dyslipidemia for coronary artery disease prevention.
A 3-step approach is recommended for the treatment of diabetic
dyslipidemia. First, modification of diet and lifestyle, including
decreased intakes of cholesterol, cholesterol-raising fats,
and total energy, and increased physical activity should be
advised. Second, good glycemic control should be achieved with
diet and hypoglycemic drugs, if needed. Third, lipid-lowering
drugs should be used, if necessary. Non-HDL cholesterol levels,
which include both very-low-density lipoprotein (VLDL) and LDL
cholesterol, should be the target of cholesterol-lowering therapy.
The use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
(the "statins") has become the first-line drug therapy
for diabetic dyslipidemia. Bile acid sequestrants are effective
cholesterol-lowering agents in normotriglyceridemic patients
with non-insulin-dependent diabetes mellitus (NIDDM). Patients
with severe hypertriglyceridemia may require fibric acids or
n-3 polyunsaturated fatty acids. Nicotinic acid worsens hyperglycemia;
therefore, it should be avoided in most cases. The efficacy
and safety of estrogen-replacement therapy in postmenopausal
women with diabetes needs to be determined. The combination
of two lipid-lowering agents may be appropriate for some NIDDM
patients but should be used judiciously.
Publication Types:
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Review
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Review, tutorial |
PMID: 9526814 [PubMed - indexed for MEDLINE]
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Hypertriglyceridemia, insulin resistance, and the metabolic
syndrome.
Grundy SM.
Center for Human Nutrition, University of Texas, Dallas 75235-9052,
USA.
The metabolic syndrome consists of a cluster of metabolic disorders,
many of which promote the development of atherosclerosis and
increase the risk of cardiovascular disease events. Insulin
resistance may lie at the heart of the metabolic syndrome. Elevated
serum triglycerides commonly associate with insulin resistance
and represent a valuable clinical marker of the metabolic syndrome.
Abdominal obesity is a clinical marker for insulin resistance.
The metabolic syndrome manifests 4 categories of abnormality:
atherogenic dyslipidemia (elevated triglycerides, increased
small low-density lipoproteins, and decreased high-density lipoproteins),
increased blood pressure, elevated plasma glucose, and a prothrombotic
state. Various therapeutic approaches for the patient with the
metabolic syndrome should be implemented to decrease the risk
of cardiovascular disease events. These interventions include
decreasing obesity, increasing physical activity, and managing
dyslipidemia; the latter may require the use of pharmacotherapy
with cholesterol-lowering and triglyceride-lowering drugs.
Publication Types:
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Review
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Review, tutorial |
PMID: 10357572 [PubMed - indexed for MEDLINE]
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Status report of lipid-lowering trials in diabetes.
Betteridge DJ, Colhoun H, Armitage J.
Department of Medicine, University College, London, UK. j.betteridge@ucl.ac.uk
The prevention and treatment of coronary heart disease is a
major challenge in the overall management of the patient with
type 2 diabetes. Diabetic dyslipidaemia is an important risk
factor and is open to therapeutic intervention. However, as
yet there are no primary or secondary coronary heart disease
prevention trials of lipid-lowering therapy reported in diabetic
populations. In this review, on-going clinical trials of lipid-lowering
therapy in specific diabetic populations will be described.
PMID: 11086336 [PubMed - indexed for MEDLINE]
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