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Jula A, Marniemi J, Huupponen R, Virtanen A, Rastas M, Rönnemaa T. Effects of Diet and Simvastatin on Serum Lipids, Insulin, and Antioxidants in Hypercholesterolemic Men: A Randomized Controlled Trial. JAMA. 2002;287(5):598–605. doi:10.1001/jama.287.5.598
Author Affiliations: Research and Development Centre of the Social Insurance Institution, Turku, Finland (Drs Jula and Marniemi and Mss Virtanen and Rastas); Department of Pharmacology and Clinical Pharmacology (Dr Huupponen), and Department of Medicine (Dr Rönnemaa), University of Turku, Finland.
Context Limited information exists on the interaction between diet and 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors (statins) and the interaction's effect on
serum lipid and lipoprotein levels, insulin sensitivity, and circulating antioxidant
vitamin and provitamin levels.
Objective To evaluate the separate and combined effects of diet and simvastatin
therapy on serum levels of lipids, lipoproteins, antioxidants, and insulin.
Design, Setting, and Participants Randomized, controlled crossover trial conducted from August 1997 to
June 1998 in 120 previously untreated hypercholesterolemic men aged 35 to
64 years who were recruited from the community in Turku, southwestern Finland.
Interventions After a 4- to 6-week placebo run-in period, participants were randomly
allocated to a habitual diet (n = 60) or dietary treatment group (n = 60),
and each of these groups was further randomized in a double-blind crossover
fashion to receive simvastatin (20 mg/d) or placebo, each for 12 weeks (n
= 30 in each group). The main goals of the dietary treatment were to reduce
energy intake from saturated plus trans-unsaturated
fats to no more than 10% by replacing them partly with monounsaturated and
polyunsaturated fats rich in omega-3 fatty acids and to increase intake of
fruits, vegetables, and dietary fiber.
Main Outcome Measures Changes in levels of total, low-density lipoprotein (LDL), and high-density
lipoprotein (HDL) cholesterol; triglycerides; apolipoprotein B; insulin; glucose;
and antioxidants at week 12 of each treatment period, compared among the 4
Results Dietary treatment decreased levels of total cholesterol by 7.6% (P<.001), LDL cholesterol by 10.8% (P<.001), HDL cholesterol by 4.9% (P = .01),
apolipoprotein B by 5.7% (P = .003), serum insulin
by 14.0% (P = .02), and α-tocopherol by 3.5%
(P = .04). Simvastatin decreased levels of total
cholesterol by 20.8%, LDL cholesterol by 29.7%, triglycerides by 13.6%, apolipoprotein
B by 22.4%, α-tocopherol by 16.2%, β-carotene by 19.5%, and ubiquinol-10
by 22.0% (P<.001 for all) and increased levels
of HDL cholesterol by 7.0% (P<.001) and serum
insulin by 13.2% (P = .005). Glucose levels remained
unchanged in all groups. The effects of dietary treatment and simvastatin
were independent and additive.
Conclusions A modified Mediterranean-type diet rich in omega-3 fatty acids efficiently
potentiated the cholesterol-lowering effect of simvastatin, counteracted the
fasting insulin–elevating effect of simvastatin, and, unlike simvastatin,
did not decrease serum levels of β-carotene and ubiquinol-10.
Cholesterol-lowering treatment with 3-hydroxy-3-methylglutaryl coenzyme
A (HMG-CoA) reductase inhibitors (statins) decreases cardiovascular morbidity
and mortality in patients with coronary heart disease1
and in healthy men at high risk for coronary heart disease.2
The cholesterol-lowering effect of HMG-CoA reductase inhibitors is superior
to that produced by different dietary regimens. However, dietary trials in
secondary prevention of coronary heart disease have reported a similar reduction
in cardiovascular morbidity and mortality within 2 to 3 years, as shown by
cholesterol-lowering treatment with statins in 5 to 6 years.3-5
The diets have been characterized by a low intake of saturated fats,4,5 an increased intake of omega-3 fatty
acids of marine3 or plant4,5
origin, and a high intake of legumes, cereals, and fresh fruits and vegetables.4,5
The favorable effects of HMG-CoA reductase inhibitors on cardiovascular
morbidity and mortality have been thought to be mediated mainly through a
decrease in serum low-density lipoprotein cholesterol (LDL-C) and triglycerides
and an increase in serum high-density lipoprotein cholesterol (HDL-C) concentration.
Effects of a modified Mediterranean-type diet low in saturated fatty acid
intake and high in omega-3 fatty acid intake may be mediated mainly by factors
other than those associated with serum lipid levels.4
Only limited information exists on the effects of HMG-CoA reductase
inhibitors and dietary therapy on insulin sensitivity, circulating antioxidant
vitamin and provitamin levels, LDL oxidation, and their interactions on circulating
lipids and lipoproteins. Apparently, no data exist on the interaction between
diet and drug treatment and insulin sensitivity and antioxidants. The aim
of this study was to characterize the effects of an HMG-CoA reductase inhibitor
(simvastatin) and a diet low in saturated fatty acids and enriched in monounsaturated
and polyunsaturated fatty acids (especially α-linolenic acid), cereals,
fruits, berries, and vegetables on serum lipids, glucose, insulin, and antioxidants.
Previously untreated hypercholesterolemic men 35 to 64 years of age
were screened from the clients of the occupational health service of 5 industrial
plants and government offices in Turku in southwestern Finland. Subjects with
a fasting serum cholesterol concentration of at least 232 mg/dL (≥6.0 mmol/L)
at screening were invited for briefing about the study. After the subjects
had given their informed consent, their fasting serum cholesterol, triglyceride,
and glucose concentrations were measured and routine biochemical tests were
performed. An electrocardiogram was taken, and blood pressure, weight, and
height were measured. An internist performed a physical examination and checked
questionnaires for medical history and cardiovascular symptoms. If fasting
serum cholesterol concentration was between 232 and 309 mg/dL (6.0 and 8.0
mmol/L) and fasting serum triglyceride concentration was no higher than 266
mg/dL (3.0 mmol/L), the subject could be included in the study. Subjects with
a body mass index higher than 32 kg/m2, coronary artery disease,
cerebrovascular disease, claudication and pharmacologically treated hypertension,
hyperlipidemia, or diabetes were excluded from the study.
Subjects included in the study entered first a 4- to 6-week open placebo
run-in period, at the end of which they were randomly allocated to a habitual
diet or a dietary treatment group (Figure
1). In both groups, a second randomization was performed, and the
subjects received simvastatin (20 mg/d) or a matching placebo for 12 weeks
in a double-blind, crossover fashion. A washout period was not included, since
no period or carryover effects were seen in a preceding pilot study of 20
men. The sample size was calculated with the assumption that a difference
of 15 mg/dL (0.4 mmol/L) in primary outcome variables (cholesterol and LDL-C)
can be detected with 80% power and 5% type I error (n = 88). To ensure a sufficient
sample size, a total of 120 subjects were included in the study. All subjects
completed the study.
The study was conducted according to the latest revision of the Declaration
of Helsinki and was approved by the Ethical Committee of the Social Insurance
Institution of Finland.
Blood pressure and weight were measured, diet was recorded, physical
exercise frequency and intensity were determined, and 12-hour fasting blood
samples were taken before randomization at the end of the placebo run-in period
(baseline) and at the end of both 12-week drug-treatment periods. Two blood
samples were taken 1 week apart at the end of each period. All measurements
and analyses were done blinded to the treatment allocation of the subject.
The serum samples were frozen and stored at –70°C until assayed.
The baseline and follow-up samples were analyzed always in 1 analytical run.
Subjects' body weight was measured while they wore light clothing and no shoes,
with an accuracy of 0.1 kg; height measurements had an accuracy of 1 cm. Seated
blood pressure was measured by a trained nurse with a mercury sphygmomanometer
and averaged across 2 readings. Diet was monitored through 7-day food records
by using household measures. The records were analyzed by means of the Nutrica
(Social Insurance Institution, Turku, Finland) food and nutrient calculation
software and the databases on the nutrient composition of Finnish food.6 Leisure-time physical activity was assessed by a questionnaire
with questions about average frequency (5-point scale: 0, >0 but <1, 1,
2, ≥3 times per week) and intensity (4-point scale: no physical exercise,
0; exercise does not cause sweating or labored breathing, 1; exercise causes
sweating and some degree of labored breathing, 2; exercise causes strong sweating
and labored breathing, 3) during the preceding 12 weeks.
Serum cholesterol, HDL-C, and triglyceride concentrations were averaged
across 2 fasting blood samples taken at a 1-week interval at the end of each
period. Concentrations were determined by enzymatic methods (Merck Diagnostica,
Darmstadt, Germany). High-density lipoprotein cholesterol was analyzed after
the magnesium-phosphotungstate precipitation of very low-density lipoprotein
and LDL. Except for diene conjugation and total peroxyl radical trapping antioxidant
potential analyses, LDL-C content was estimated by the Friedewald formula.7 Apolipoprotein A1 and B concentrations were determined
immunoturbidimetrically (Orion Diagnostica, Espoo, Finland). Serum glucose
was analyzed enzymatically (Merck Diagnostica). Serum insulin was determined
by microparticle enzyme immunoassay (Abbott Laboratories, Dainabot, Tokyo,
Japan). The homeostasis model assessment formula was used to assess insulin
resistance as follows: insulin resistance = (fasting insulin × fasting
glucose level)/22.5.8 Serum α-tocopherol
(the most active form of vitamin E) and β-carotene were analyzed simultaneously
by high-performance liquid chromatography.9
The concentration of serum ascorbic acid (vitamin C) was determined spectrophotometrically.10 Erythrocyte folate levels were assayed by radioimmunoassay
(ICN Pharmaceuticals, Orangeburg, NY). Concentrations of serum ubiquinol-10
were measured by high-performance liquid chromatography with spectrophotometric
detection.11 Serum homocysteine concentrations
were determined by fluorescence polarization immunoassay (Abbott Laboratories,
Abbott Park, Ill) after enzymatic conversion of total homocysteine to S-adenosyl-L-homocysteine. Serum
LDL fraction for determinations of diene conjugation and total peroxyl radical
trapping antioxidant potential was isolated with buffered heparin.12 Oxidation of LDL was estimated by measuring spectrophotometrically
the baseline level of diene conjugation in LDL particles.13
The antioxidant potential of isolated LDL samples was measured luminometrically
Capsules containing simvastatin or placebo were prepared in a local
pharmacy according to the European Pharmacopoeia. Commercially available tablets
containing 20 mg of simvastatin were powdered and mixed with wheat starch.
One hundred tablets were used in each manufacturing run. The mixture was divided
into 100 gelatin capsules with an accuracy of 10%. Placebo capsules indistinguishable
from the active drug capsules contained wheat starch and additives to guarantee
the blinding. Each patient received his or her own bottle containing the capsules
for each study period. Compliance with the drug treatment was controlled by
counting the number of returned capsules.
The targeted composition of the weight-stable, modified, Mediterranean–type
diet was the following: no more than 10% energy from saturated and trans-unsaturated fatty acids; cholesterol intake no more than 250
mg/d; omega-3 fatty acid intake of plant origin (α-linolenic acid) and
marine origin of at least 4 g/d and the ratio of omega-6/omega-3 polyunsaturated
fatty acids less than 4; and increased intakes of fruits, vegetables, and
The subjects randomized to the dietary treatment were advised to use
leaner meat products, low-fat cheese, skim milk, fat-free sour milk, and low-fat
yogurt. Fish was recommended as a main meal once or twice a week. Rapeseed
margarine was recommended as a replacement for butter, a mixture of butter
and vegetable oils, and sunflower margarine. Rapeseed margarine and oil, oat
bran (20 g/d), and frozen berries (blueberry, lingonberry, or black currant
at 50 g/d) were supplied free to study subjects. The experimental diet was
supervised by a nutritionist in 1 individual session and in 2 group counseling
sessions at the beginning of the treatment and in 5 subsequent monthly group
brush-up sessions during the dietary treatment.
The subjects randomized to the habitual diet group were advised to continue
eating their usual diet during the study period.
Baseline (end of the placebo run-in period) comparisons between the
dietary treatment and habitual diet groups were made with a t test for continuous variables and by a χ2 test for
categorical variables to verify the success of the randomization. Analysis
of variance for repeated measures of variance, with contrasts between baseline
and simvastatin or placebo treatment periods, was used to test the significance
of dietary changes within the dietary treatment and habitual diet groups.
The analysis of variance model was fitted separately to the dietary treatment
and habitual diet groups, where period and carryover effects were tested.
Because no period or carryover effects were observed and baseline values affected
the outcome, repeated analyses of covariance with baseline values as covariates,
dietary treatment and habitual diet as intersubject factors, and placebo and
simvastatin treatment as intrasubject factors were included in the final models.
Validity of the models was evaluated with residual analysis. Normality of
residuals was checked with the Shapiro-Wilk statistics and constancy of residuals
by a graphic analysis. Log or square root transformations were applied if
necessary. Because statistical inferences after transformation were unchanged,
raw results are reported. The association between triglyceride and insulin
was tested by repeated analysis of covariance with triglyceride as the variable
covariate, baseline insulin as the fixed covariate, drug treatment (placebo
or simvastatin) as the intrafactor, and dietary treatment (dietary treatment
or habitual diet) as the interfactor. Polytomous response models were used
to test changes in the frequency and intensity of leisure-time physical activity.
The data are given as mean (SE) values with 95% confidence intervals for the
mean changes. One subject with a nonfasting blood sample at baseline was not
included in the analyses (Figure 1).
We set .05 as the level of significance. All statistical analyses were conducted
with SAS version 6.12 (SAS Institute, Cary, NC).
The baseline characteristics of subjects randomized to the dietary treatment
or habitual diet groups are summarized in Table 1 and Table 2.
Compliance with the drug treatment was good: subjects in the dietary
and habitual diet groups took 91% to 95% of the prescribed capsules during
the placebo run-in period and the 12-week drug treatment.
In the dietary treatment group, mean (SD) body weight was 82.4 (9.3)
kg at baseline and 82.7 (9.5) and 82.8 (9.2) kg after 12 weeks' treatment
with placebo and simvastatin, respectively. In the habitual diet group, mean
body weight was 81.2 (9.7), 82.1 (9.6), and 82.1 (9.8) kg at baseline and
after placebo and simvastatin treatments, respectively. The small weight gain
was not associated with simvastatin or dietary treatment (analysis of covariance).
On average, the dietary treatment group achieved the predetermined target
values (Table 2). Daily intake
of cholesterol fell to less than 250 mg. The proportion of fats in total energy
intake remained unchanged. Energy derived from saturated fatty acids decreased
to less than 10%. The percentages of energy from monounsaturated and polyunsaturated
fatty acids increased, reflecting decreased saturated fatty acid intake and
increased intake of rapeseed oil. The mean ratio of omega-6 to omega-3 polyunsaturated
fatty acids fell to 3 or less. The intake of linolenic acid nearly quadrupled,
and that of linolic acid nearly doubled, resulting in a 2-fold linolenic to
linolic acid ratio. Dietary intake of fiber, ascorbic acid, and vitamin E
increased because of increased daily intake of oat bran (17 g), bread (15
g), vegetables (6 g), fruits (1 g), and berries (46 g). In the habitual diet
group, nutrient intake remained virtually unchanged.
In the habitual diet and dietary treatment groups, the frequency (P = .42) and intensity (P = .58)
of physical activity did not change from baseline during placebo and simvastatin
Dietary treatment decreased average serum cholesterol concentration
by 7.6%, LDL-C by 10.8%, HDL-C by 4.9%, and apolipoprotein B by 5.7% (Table 3). The treatment also decreased
insulin levels by 14.0% and insulin resistance by 15.1% (Figure 2). Serum triglyceride, apolipoprotein A1, and glucose levels
Simvastatin treatment decreased average serum cholesterol concentration
by 20.8%, triglyceride levels by 13.6%, and apolipoprotein B levels by 22.4%.
The treatment increased HDL-C levels by 7.0% and apolipoprotein A1 levels
by 2.4% (Table 3). It also increased
insulin levels and insulin resistance and decreased LDL-C levels (Figure 2). Glucose levels remained unchanged.
The combined effect of diet and simvastatin on serum lipid, lipoprotein,
glucose, and insulin levels was equal to the sum of the components (Table 3, Figure 2). For HDL-C, fasting serum insulin levels, and insulin
resistance, the effects were opposite, with simvastatin increasing the levels
and dietary treatment decreasing them. Dietary treatment (P = .049) and a decrease in triglyceride levels (P<.001) were associated with a decrease in serum insulin levels
(analysis of covariance); simvastatin (P<.001)
was associated with an increase.
Neither dietary treatment nor simvastatin affected blood pressure (data
Dietary treatment decreased serum α-tocopherol levels by 3.5%,
total peroxyl radical trapping potential of serum LDL by 4.9%, and estimated
actual level of oxidized LDL in circulation (LDL diene conjugation) by 8.3%
(Table 3, Figure 2). Relative antioxidant power of LDL preparations (LDL-TRAP/mmol
of LDL-C) increased by 8.8%. Ascorbic acid, β-carotene, homocysteine,
ubiquinol-10, and erythrocyte folate levels and the relative level of oxidized
LDL (LDL diene conjugation/mmol of LDL-C) remained unchanged.
Simvastatin treatment decreased serum α-tocopherol levels by 16.2%, β-carotene
levels by 19.5%, ubiquinol-10 levels by 22.0%, and total peroxyl radical trapping
potential of serum LDL by 16.9% (Table 3, Figure 2). Because of
decreased serum LDL-C levels, relative antioxidant power of LDL preparations
(LDL TRAP/mmol of LDL-C) increased by 17.4%. The estimated actual level of
oxidized LDL in circulation (LDL diene conjugation) decreased by 16.0%, but
the relative level of oxidized LDL (LDL diene conjugation/mmol of LDL-C) increased
by 13.1%. Simvastatin treatment did not change serum ascorbic acid, homocysteine,
or erythrocyte folate levels.
There were no interactions between the effects of diet and simvastatin
on levels of serum α-tocopherol, ascorbic acid, β-carotene, homocysteine,
ubiquinol-10, and erythrocyte folate and on serum LDL fraction for diene conjugation
and antioxidant potential (Table 3).
The separate effects of dietary treatment and simvastatin on plasma
lipid and lipoprotein levels were consistent with published data.1,14-16 An
important finding was that their effects on levels of lipids, lipoproteins,
glucose, insulin, α-tocopherol, ascorbic acid, β-carotene, homocysteine,
ubiquinol-10, and erythrocyte folate and on the indicators of LDL oxidation
(LDL TRAP and LDL diene conjugation) were independent and additive. For example,
dietary treatment alone, simvastatin treatment alone, and the treatments combined
lowered LDL-C levels by 11%, 30%, and 41%, respectively. The independent and
additive effects of dietary treatment and simvastatin on lipoprotein levels
agree with those in a previous article reporting 5%, 27%, and 32% decreases
in LDL-C in patients treated with a National Cholesterol Education Program
Step II diet alone, lovastatin (20 mg/d) alone, or a combination.17 Unlike in our study, decreased cholesterol and saturated
fatty acid intakes were accompanied by a decreased intake of monounsaturated
fatty acids and a decreasing trend in the intake of polyunsaturated fatty
acids. The authors concluded that the reduction in LDL-C was small, and its
benefit was possibly offset by the observed reduction in HDL-C.
In this study, dietary treatment decreased average serum cholesterol
concentration by 19 mg/dL (0.5 mmol/L). This effect resulted mainly from dietary
replacement of saturated fat with monounsaturated and polyunsaturated fats.
Our finding is supported by a meta-analysis in which replacement of 7% of
energy from saturated fat with either monounsaturated or polyunsaturated fats
decreased total cholesterol levels by roughly 25 mg/dL (0.65 mmol/L).14 Dietary intake of cholesterol decreased by approximately
80 mg/d in the dietary treatment group, which would decrease serum cholesterol
levels by only 2 mg/dL (0.05 mmol/L).15 Also,
increased fiber intake's contribution to reduced serum cholesterol concentration
was probably limited. According to a recent meta-analysis, eating 20 g of
oats daily (corresponding to 3.4 g of fiber and 0.7 g of soluble fiber) decreases
total cholesterol concentration in serum by 1 mg/dL (0.03 mmol/L).16 We observed an intake increase of 2.2 g of soluble
fiber daily in the dietary treatment group, which would result in a decrease
of approximately 3 mg/dL (0.09 mmol/L) in total cholesterol.
Another important finding was that simvastatin treatment decreased serum
concentrations of some antioxidant vitamins and provitamins. The concentrations
of α-tocopherol, β-carotene, and ubiquinol-10 were lowered by 16%
to 22%. Despite the increased dietary intake of α-tocopherol, cholesterol-lowering
dietary treatment was associated with small decreases in serum α-tocopherol
levels. Dietary treatment had no effects on serum β-carotene and ubiquinol-10
The decreased serum ubiquinol-10 concentration during simvastatin treatment
agrees with findings of previous studies.18-20
Ubiquinone is a by-product of cholesterol synthesis, and its decrease during
simvastatin treatment may explain why the drug reduced serum ubiquinol levels,
whereas dietary treatment did not.
In our study, LDL-C concentration decreased by 30% and HDL-C concentration
increased by 7% during simvastatin treatment. Circulating α-tocopherol
is bound to lipoproteins. In men, approximately 30% of α-tocopherol
is bound to HDL-C; 60%, to LDL-C.21 Thus, the
observed changes in serum lipid concentrations are expected to result in a
16% decrease in serum α-tocopherol concentration, which also was the
Whether reduction in circulating concentrations of ubiquinone, α-tocopherol,
and β-carotene would decrease their concentrations in human tissues is
largely unknown. According to an uncontrolled study,20
simvastatin (20 mg/d for 6 months) did not change ubiquinone levels in human
skeletal muscle. Whether changes in serum α-tocopherol, β-carotene,
and ubiquinone levels have any impact on platelet function, cell proliferation,
immune responses, mitochondrial function, antioxidative processes other than
LDL oxidation, and clinical outcomes has to be clarified in further studies.
In our study, reductions in serum LDL antioxidant potential during dietary
and simvastatin treatments are in line with changes in serum concentrations
of fat-soluble antioxidant vitamins and provitamins. However, the relative
antioxidant potential of LDL increased during simvastatin and dietary treatment,
mainly because of decreases in LDL concentrations.
The oxidized form of LDL may play a key role in atherogenesis. Most
studies have regarded the susceptibility of isolated LDL to oxidation ex vivo
as an indicator of LDL oxidation in vivo. We measured real end products of
lipid peroxidation (formed diene conjugates of isolated LDL) in vivo to estimate
oxidation of circulating LDL. In our study, both dietary and simvastatin treatments
decreased serum concentrations of LDL diene conjugates. However, the formation
of LDL diene conjugates relative to LDL-C increased during simvastatin treatment
but remained unchanged during dietary treatment, suggesting qualitative deterioration
of LDL by simvastatin but not by dietary treatment. Recently, an uncontrolled
study22 reported that simvastatin (20 mg/d)
did not change LDL diene formation ex vivo when expressed per mole of LDL.
Simvastatin increases the proportion of protein and decreases proportions
of free cholesterol and cholesterol esters in LDL, which may result in a change
not only in the amount but also in the composition of LDL.23
Thus, differences in measurement techniques and expression of diene conjugation
may explain the apparent differences in our data and those of a recently published
study.22 Simvastatin has been reported to possess
antioxidant potential in vitro.23 Our study
does not support that this property would have any significant impact on circulating
LDL, possibly because of decreased concentrations of circulating fat-soluble
antioxidant vitamins and provitamins and possibly because of preferred hepatic
uptake of native (nonoxidized) LDL compared with oxidized LDL.
Dietary intervention with reduced saturated fatty acid intake and increased
monounsaturated and polyunsaturated fatty acid intake decreased, while simvastatin
treatment increased, fasting serum insulin levels. The effects of the diet
agree with previous data from cross-sectional and experimental studies. Increased
fasting serum insulin levels and decreased insulin sensitivity have been associated
with decreased concentrations of long-chain polyunsaturated fatty acids within
muscle-membrane phospholipids24 and with a
decreased ratio of omega-6 polyunsaturated fatty acids to saturated fatty
acids in serum phospholipids.25 A diet low
in saturated fat and rich in monounsaturated and polyunsaturated fats improves
glucose tolerance in healthy women.26 Fatty
acid composition of cell membranes, reflecting fatty acid intake and metabolism,
may modulate insulin binding and glucose transport.27
Polyunsaturated fatty acids may also influence the action of insulin by acting
as precursors for the generation of second messengers such as eicosanoids
Only a few randomized controlled studies, all in patients with type
2 diabetes mellitus, have examined the effects of simvastatin on fasting serum
insulin levels or insulin sensitivity.29-32
The results have been contradictory. Ohrvall and colleagues29
found that simvastatin (10 mg/d for 4 months) increased fasting insulin concentrations
by 21% and decreased insulin sensitivity by 28% but did not affect fasting
triglyceride concentrations. In 2 small placebo-controlled studies, simvastatin
produced nonsignificant changes in various determinants of insulin sensitivity.30,31 In the most recent study, with 61
patients randomized to simvastatin and 67 to placebo, simvastatin decreased
insulin resistance by 9%.32 Changes in insulin
levels were not shown. As in our study, a decrease in serum triglyceride level
was a significant determinant for an increase in insulin sensitivity. In our
study, simvastatin (20 mg/d for 12 weeks) increased fasting serum insulin
levels of 120 nondiabetic hypercholesterolemic men by 13% and insulin resistance
by 14%, despite concomitant favorable effects on serum triglyceride concentrations.
Although we did not measure insulin sensitivity directly, the modest increase
in fasting insulin levels together with completely unchanged glucose concentrations
may indicate a slight decrease in insulin sensitivity after simvastatin treatment.
On the other hand, the increase in serum insulin levels was fully counteracted
by concomitant dietary treatment. Further studies are needed to explore the
mechanisms by which simvastatin may result in increased serum insulin levels.
There were some important limitations in our study. We performed the
dietary treatment single-blind, since it is impossible to accomplish this
kind of dietary intervention in a double-blind fashion. To avoid the confounding
influence of menstrual cycle, oral contraceptives, and estrogen replacement
therapy, only men were included in this study, so the findings may be valid
only for hypercholesterolemic men. Only a 12-week study period was long enough
to show the effectiveness of dietary and statin treatments on the measured
biochemical variables, but feasibility of the treatments should be evaluated
in long-term studies. Further studies are needed to evaluate other potential
cardioprotective effects of separate and combined dietary and simvastatin
treatments not addressed in this study: effects on platelet aggregation, hemostasis,
fibrinolysis, and endothelial function and the propensity for arrhythmia.
Both simvastatin treatment and a diet low in saturated fat intake but
enriched in monounsaturated and polyunsaturated fatty acids, including α-linolenic
acid, cereals, fruits, berries, and vegetables, significantly affected levels
of serum lipids, insulin, and antioxidants. Both simvastatin and the diet
reduced total cholesterol and LDL-C concentrations, with the effect of simvastatin
being 3-fold that of dietary treatment. Simvastatin decreased the concentrations
of 3 important antioxidant vitamins or provitamins, α-tocopherol, β-carotene,
and ubiquinol-10, in serum by 16% to 22%, whereas dietary treatment decreased α-tocopherol
concentration only slightly. Dietary treatment and simvastatin had opposite
effects on fasting serum insulin levels, which were increased by simvastatin.
To conclude, the combination of a modified Mediterranean-type diet and
statin treatment of hypercholesterolemia in nondiabetic men not only results
in a beneficial additive effect on lowering serum total cholesterol and LDL-C
concentration but also counteracts the elevating influence on fasting insulin
level associated with simvastatin treatment. The combination is clinically
sound, and the importance of diet as an integral part of statin treatment
of hypercholesterolemic patients should be emphasized.
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