Different cardiometabolic effects of atorvastatin in men with normal vitamin D status and vitamin D insufficiency

Abstract

Background

Vitamin D is suggested to reduce cardiovascular risk.

Hypothesis

Circulating levels of plasma lipids and other cardiovascular risk factors may differ between statin‐treated patients with different vitamin D status.

Methods

We studied 3 age‐ and weight‐matched groups of men with elevated low‐density lipoprotein cholesterol (LDL‐C) levels: vitamin D–naïve men with vitamin D insufficiency (group A, n = 18), men with vitamin D deficiency/insufficiency effectively treated with vitamin D preparations (group B, n = 16), and vitamin D–naïve men with normal vitamin D status (group C, n = 16). All patients were then treated with atorvastatin (20 mg daily) for 4 months. Plasma lipids, glucose homeostasis markers, and plasma levels of uric acid, high‐sensitivity C‐reactive protein (hsCRP), homocysteine, and fibrinogen were assessed before and at the end of atorvastatin therapy.

Results

Study groups did not differ in baseline levels of plasma lipids. Men with vitamin D deficiency or insufficiency effectively treated with vitamin D preparations were characterized by decreased insulin sensitivity and higher circulating levels of hsCRP, homocysteine, and fibrinogen in comparison with the remaining groups of patients. Although atorvastatin decreased plasma levels of total cholesterol and LDL‐C to a similar extent in all study groups, its effect on uric acid, hsCRP, homocysteine, and fibrinogen was more pronounced in patients from groups B and C than in men from group A. Moreover, in patients with vitamin D insufficiency, atorvastatin impaired insulin sensitivity.

Conclusions

The obtained results indicate that the strength of pleiotropic effects of atorvastatin depends on vitamin D status.

1. INTRODUCTION

Statins, or 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitors, are considered the first‐line treatment for dyslipidemia and coronary heart disease and are frequently used in the treatment of patients with diabetes mellitus (DM).1, 2, 3 Both primary and secondary prevention trials evidenced that statins reduced major vascular events and mortality.4, 5, 6, 7, 8 The benefits of statin therapy cannot be explained exclusively by their lipid‐lowering properties; their benefits also derive from non–lipid‐related mechanisms. These so‐called pleiotropic effects include anti‐inflammatory, immunomodulatory, antioxidant, and antithrombotic effects; regulation of the growth and migration of smooth muscle cells; improvement of the functioning of vascular endothelium; as well as the inhibitory effect on coagulation, fibrinolysis, and platelet activities.9, 10, 11

The results of recent studies may suggest that abnormal vitamin D production and/or metabolism may make individuals particularly susceptible to atherosclerosis and its complications.12 In meta‐analyses of observational studies, vitamin D deficiency and low intake of this vitamin have been associated with high incidence of cardiovascular disease.13 ^, 14 Circulating levels of 25‐hydroxyvitamin D correlated with the severity of coronary heart disease.15 Low vitamin D status was associated with increased insulin resistance and decreased levels of high‐density lipoprotein cholesterol (HDL‐C), as well as with increased risk of type 2 DM.16 Its active metabolite, calcitriol, was found to inhibit expression of adhesion molecules and matrix metalloproteinase 9, to increase production of anti‐inflammatory cytokines, as well as to down‐regulate renin‐angiotensin‐aldosterone axis activity.17 Moreover, calcitriol suppressed foam‐cell formation, reduced low‐density lipoprotein cholesterol (LDL‐C) uptake, and increased HDL‐C transport.18

Recently, we have found that the effect of atorvastatin19 as well as fenofibrate,20 which is another lipid‐lowering drug with pleiotropic effects,21 on plasma lipids and circulating levels of cardiometabolic risk factors partially depended on hypothalamic‐pituitary‐thyroid axis activity and was more pronounced in patients with normal thyroid function than in patients with untreated subclinical hypothyroidism. A possible association between vitamin D and vascular disease suggests that the effects of hypolipidemic agents may also be determined by the amount of this vitamin. However, to the best of our knowledge, no previous study has investigated whether vitamin D status plays a role in regulating the strength of statin action on cardiometabolic risk. Therefore, the aim of our study was to compare in patients with different 25‐hydroxyvitamin D levels the effect of atorvastatin on plasma lipids and glucose homeostasis markers as well as on C‐reactive protein, uric acid, homocysteine, and fibrinogen, the increased levels/activities of which correlate with the earlier development and faster progression of atherosclerosis‐related disorders.11, 22, 23, 24, 25

2. METHODS

The participants of the study were recruited among men age 30 to 70 years with hypercholesterolemia, defined as plasma levels of total cholesterol >200 mg/dL and LDL‐C >130 mg/dL, complying with lifestyle intervention for ≥3 months before the beginning of the study. Based on 25‐hydroxyvitamin D status, the participants were allocated into 1 of 3 groups. Group A included 18 vitamin D–naïve men with vitamin D insufficiency. Group B consisted of 16 patients who, because of vitamin D deficiency/insufficiency, had been treated with oral vitamin D preparations (2000–4000 IU daily; mean dose, 2875 IU daily) for ≥3 months before the study onset. Group C consisted of 16 vitamin D–naïve men with normal vitamin D status. Vitamin D insufficiency was defined as plasma 25‐hydroxyvitamin D levels between 20 and 30 ng/mL, vitamin D deficiency as plasma 25‐hydroxyvitamin D levels <20 ng/mL, and normal vitamin D status as circulating 25‐hydroxyvitamin D levels between 30 and 60 ng/mL. All participants provided written consent, and the study was approved by the local bioethical committee.

The exclusion criteria were as follows: any form of coronary artery disease, stroke within 6 months preceding the study, symptomatic congestive heart failure, DM, moderate or severe arterial hypertension (European Society of Cardiology/European Society of Hypertension grade 2 or 3), any acute and chronic inflammatory processes, autoimmune disorders, impaired renal or hepatic function, nephrotic syndrome, liver and biliary‐tract diseases, body mass index >35 kg/m², treatment with any hypolipemic agents within 6 months before the beginning of the study, concomitant treatment with calcium supplements, concomitant treatment with drugs affecting plasma lipid levels or calcium/phosphate homeostasis, concomitant treatment with drugs known to interact with statins or vitamin D, and poor patient compliance.

All men were then treated with atorvastatin and continued to comply with dietary recommendations, the goals of which were a reduction in weight of ≥7% if necessary, total fat intake <30% of total energy intake, saturated fat intake <7% of energy consumed, cholesterol intake <200 mg per day, an increase in fiber intake to 15 g per 1000 kcal, and moderate to vigorous exercise for ≥30 minutes per day. Atorvastatin was administered orally once daily (between 8 and 9 pm) at the daily dose of 20 mg for 4 months without any changes in dosage throughout the study. Throughout the entire study period, the patients from group B continued treatment with the same daily dose of vitamin D preparations as before the study onset. To minimize the risk of eventual pharmacokinetic interactions with atorvastatin, vitamin D was administered between 8 and 9 am. Exercise compliance was determined by comparing the participant's self‐report of performed exercise to the investigator's recommendations, and the average dietary adherence was assessed by the food frequency questionnaire and analysis of 3 days of eating diaries. Compliance with atorvastatin treatment, investigated during each visit, was regarded as satisfactory if the number of tablets returned ranged from 0% to 10%.

Venous blood samples for laboratory assays were obtained between 8 and 9 am (to avoid possible circadian fluctuations in the parameters studied) following at least a 12‐hour overnight fasting before and at the end of atorvastatin treatment. All assays were performed in duplicate by a person blinded to clinical data. Plasma lipids (total cholesterol, LDL‐C, HDL‐C, and triglycerides [TG]), as well as plasma glucose, insulin, and uric acid, were assayed by routine laboratory techniques using reagents obtained from Roche Diagnostics (Basel, Switzerland) and Instruments GmbH (Marburg, Germany). LDL‐C levels were measured directly. The homeostatic model assessment 1 of insulin resistance index (HOMA1‐IR), a surrogate index of insulin sensitivity, was calculated by the following formula: HOMA1‐IR = (fasting insulinemia [mU/L] × glycemia [mg/dL])/405. Plasma levels of 25‐hydroxyvitamin D were determined by enzyme immunoassay using reagents purchased from ALPCO Diagnostics (Windham, New Hampshire). Plasma levels of C‐reactive protein were measured using a high‐sensitivity monoclonal antibody assay (hsCRP; MP Biomedicals, Orangeburg, New York). Circulating levels of homocysteine were determined by enzyme‐linked immunosorbent assay (Diazyme Laboratories, San Diego, California). Plasma fibrinogen concentration was measured according to the Clauss method using a commercial enzyme‐linked immunosorbent assay kit (bioMerieux, Marcy l'Etoile, France). The intra‐ and interassay coefficients of variation for the assessed variables were below 6.5% and 8.7%, respectively.

2.1. Statistical analysis

Because of the skewed distributions, outcomes for TG, HOMA1‐IR, hsCRP, homocysteine, and fibrinogen were natural‐log transformed to satisfy assumptions of normality and equal variance. Comparisons between the groups were performed using analysis of covariance followed by Bonferroni post‐hoc tests after consideration of age, smoking, body mass index, blood pressure, and season during which samples were collected as potential confounders. The Student paired t test was used to compare differences between the means of variables within the same group of patients. The χ ² test was employed to compare the proportional data. Pearson r tests were used to test correlations. A P value of <0.05 was regarded as statistically significant.

3. RESULTS

At the beginning of the study, all groups of patients were similar in regard to age, weight, smoking status, clinical characteristics, fasting glucose, and plasma lipids. Circulating levels of hsCRP, fibrinogen, homocysteine, and HOMA1‐IR were lower, whereas circulating levels of 25‐hydroxyvitamin D were higher in groups B and C than in group A. Uric acid levels were insignificantly lower in groups B and C than in group A (P = 0.084 and P = 0.092, respectively; Table 1).

Table 1.

Baseline characteristics of participants¹

Variable	Group A2	Group B3	Group C4
No. of patients	17	16	16
Age, y	48 (6)	46 (7)	49 (7)
BMI, kg/m2	27.9 (4.0)	28.4 (4.2)	27.2 (3.8)
Smokers, %	29	31	25
Metabolic syndrome, %	52	44	44
SBP, mm Hg	138 (14)	134 (12)	132 (16)
DBP, mm Hg	88 (10)	86 (8)	85 (7)
25‐hydroxyvitamin D, ng/mL	25 (5)5, 6	45 (8)	44 (9)
Total cholesterol, mg/dL	259 (32)	270 (40)	264 (39)
LDL‐C, mg/dL	175 (20)	180 (23)	169 (28)
HDL‐C, mg/dL	47 (5)	50 (7)	49 (4)
TG, mg/dL	173 (30)	168 (35)	180 (28)
Fasting glucose, mg/dL	95 (10)	97 (11)	94 (11)
HOMA1‐IR	3.2 (1.1)7, 8	2.1 (0.8)	2.2 (0.9)
Uric acid, µmol/L	371 (93)	311 (81)	320 (90)
hsCRP, mg/L	3.5 (1.1)7, 8	2.4 (0.7)	2.3 (0.6)
Homocysteine, µmol/L	35 (10)7, 8	25 (9)	24 (10)
Fibrinogen, mg/dL	408 (70)9, 10	328 (65)	320 (75)

Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; HDL‐C, high‐density lipoprotein cholesterol; HOMA1‐IR, homeostatic model assessment 1 of insulin resistance index; hsCRP, high‐sensitivity C‐reactive protein; LDL‐C, low‐density lipoprotein cholesterol; SBP, systolic blood pressure; SD, standard deviation; TG, triglycerides.

Data are presented as mean (SD) unless otherwise indicated.

¹ Only data of patients who completed the study were included in the final analyses.

² Vitamin D–naïve men with vitamin D insufficiency.

³ Vitamin D–treated patients with vitamin D deficiency/insufficiency.

⁴ Vitamin D–naïve men with normal vitamin D status.

⁵ P < 0.001 vs group B.

⁶ P < 0.001 vs group C.

⁷ P < 0.05 vs group B.

⁸ P < 0.05 vs group C.

⁹ P < 0.01 vs group B.

¹⁰ P < 0.01 vs group C.

Atorvastatin therapy was well tolerated, and all but 1 patient completed the study protocol. This patient, belonging to group A, was withdrawn because of muscle pains associated with a significant elevation of creatine kinase.

In patients with vitamin D insufficiency, atorvastatin reduced plasma levels of total cholesterol by 23% (P < 0.001), LDL‐C by 34% (P < 0.001), and TG by 17% (P < 0.05), and it tended to increase plasma levels of HDL‐C by 11% (P < 0.058). In this group of patients, atorvastatin decreased hsCRP by 31% (P < 0.05); insignificantly reduced homocysteine (by 17%; P = 0.088); did not have an effect on fasting glucose, plasma levels of uric acid, and fibrinogen; and increased HOMA1‐IR by 34% (P < 0.05; Table 2).

Table 2.

The effect of atorvastatin treatment on plasma lipids, glucose homeostasis markers, and the investigated cardiovascular risk factors in men with low and normal vitamin D status¹

Variable	Group A2	Group B3	Group C4
25‐hydroxyvitamin D, ng/mL
Baseline	25 (5)5, 6	45 (8)	44 (9)
After 4 mo	24 (5)5, 6	47 (11)	46 (10)
Total cholesterol, mg/dL
Baseline	259 (32)	270 (40)	264 (39)
After 4 mo	200 (26)7	205 (24)7	197 (29)7
LDL‐C, mg/dL
Baseline	175 (20)	180 (23)	169 (28)
After 4 mo	115 (18)7	116 (20)7	110 (30)7
HDL‐C, mg/dL
Baseline	47 (5)	50 (7)	49 (4)
After 4 mo	52 (7)	58 (8)8	56 (7)8
TG, mg/dL
Baseline	173 (30)	168 (35)	180 (28)
After 4 mo	144 (27)8	143 (28)	150 (31)8
Fasting glucose, mg/dL
Baseline	95 (10)	97 (11)	94 (11)
After 4 mo	98 (11)	96 (12)	94 (10)
HOMA1‐IR
Baseline	3.2 (1.1)9, 10	2.1 (0.8)	2.2 (0.9)
After 4 mo	4.3 (1.2)5, 6, 8	2.0 (0.7)11	2.4 (0.8)11
Uric acid, µmol/L
Baseline	371 (93)	311 (81)	320 (90)
After 4 mo	415 (84)5, 6	229 (62)8, 12	228 (73)8, 12
hsCRP, mg/L
Baseline	3.5 (1.1)9, 10	2.4 (0.7)	2.3 (0.6)
After 4 mo	2.4 (0.8)5, 6, 8	0.8 (0.6)7, 11	0.9 (0.5)7, 11
Homocysteine, µmol/L
Baseline	35 (10)9, 10	25 (9)	24 (10)
After 4 mo	29 (8)5, 6	15 (7)8, 11	14 (5)8, 11
Fibrinogen, mg/dL
Baseline	408 (70)13, 14	328 (65)	320 (75)
After 4 mo	420 (93)5, 6	260 (59)8, 12	248 (68)8, 12

Abbreviations: HDL‐C, high‐density lipoprotein cholesterol; HOMA1‐IR, homeostatic model assessment 1 of insulin resistance index; hsCRP, high‐sensitivity C‐reactive protein; LDL‐C, low‐density lipoprotein cholesterol; SD, standard deviation; TG, triglycerides.

Data are presented as mean (SD).

¹ Only data of patients who completed the study were included in the final analyses.

² Vitamin D–naïve men with vitamin D insufficiency.

³ Vitamin D–treated patients with vitamin D deficiency/insufficiency.

⁴ Vitamin D–naïve men with normal vitamin D status.

⁵ P < 0.001 vs group B.

⁶ P < 0.001 vs group C.

⁷ P < 0.001 vs baseline value.

⁸ P < 0.05 vs baseline value.

⁹ P < 0.05 vs group B.

¹⁰ P < 0.05 vs group C.

¹¹ P < 0.05 statistically different vs the effect of atorvastatin in group A.

¹² P < 0.001 statistically different vs the effect of atorvastatin in group A.

¹³ P < 0.01 vs group B.

¹⁴ P < 0.01 vs group C.

In men with normal vitamin D status secondary to vitamin D supplementation, atorvastatin decreased circulating levels of total cholesterol by 24% (P < 0.001) and LDL‐C by 36% (P < 0.001) and increased plasma levels of HDL‐C by 16% (P < 0.05). Moreover, atorvastatin decreased uric acid by 26% (P < 0.05), hsCRP by 67% (P < 0.001), homocysteine by 40% (P < 0.05), and fibrinogen by 21% (P < 0.05). In this group of patients, atorvastatin tended to decrease circulating levels of TG by 15% (P = 0.058), but it did not affect fasting glucose, HOMA1‐IR, and 25‐hydroxyvitamin D levels (Table 2).

In vitamin D–naïve patients with normal vitamin D status, atorvastatin reduced plasma levels of total cholesterol by 25% (P < 0.001), LDL‐C by 35% (P < 0.001), and TG by 17% (P < 0.05), and it increased circulating levels of HDL‐C by 14% (P < 0.05). Moreover, the treatment led to a reduction of uric acid by 29% (P < 0.05), hsCRP by 61% (P < 0.001), homocysteine by 42% (P < 0.05), and fibrinogen by 23% (P < 0.05). Fasting glucose, HOMA1‐IR, and 25‐hydroxyvitamin D remained at similar levels as before the study onset (Table 2).

The effect of atorvastatin on plasma lipids did not differ between the study groups. Between‐group comparisons showed that the effect of atorvastatin on uric acid, hsCRP, homocysteine, and fibrinogen was more pronounced and the effect on HOMA1‐IR was less pronounced in men from groups B and C than in men from group A. The impact on plasma lipids and fasting glucose did not differ between the study groups. At the end of the study, groups B and C differed from group A in HOMA1‐IR and circulating levels of uric acid, hsCRP, homocysteine, and fibrinogen (Table 2).

At the beginning of the study, circulating levels of hsCRP, homocysteine, and fibrinogen correlated with plasma levels of total cholesterol (r values between 0.24 [P < 0.05] and 0.34 [P < 0.01]) and LDL‐C (r values between 0.32 [P < 0.01] and 0.39 [P < 0.001]). In men with vitamin D insufficiency, plasma levels of 25‐hydroxyvitamin D correlated negatively with HOMA1‐IR (r = −0.42; P < 0.001) and plasma levels of uric acid (r = −0.26; P < 0.05), hsCRP (r = −0.36; P < 0.01), homocysteine (r = −0.31; P < 0.05), and fibrinogen (r = −0.29; P < 0.05).

There were negative correlations between the effect of atorvastatin on uric acid, hsCRP, homocysteine, fibrinogen, and baseline levels of 25‐hydroxyvitamin D (r values between  − 0.30 [P < 0.01] and −0.43 [P < 0.001]). The effect of atorvastatin on plasma lipids or glucose homeostasis markers did not correlate with treatment‐induced changes in uric acid, hsCRP, homocysteine, and fibrinogen.

4. DISCUSSION

This study shows for the first time that the strength of pleiotropic effects of any HMG‐CoA reductase inhibitor depends on vitamin D status, which contrasts with no differences in its impact on plasma lipids. Pleiotropic effects of atorvastatin were less pronounced in men with vitamin D insufficiency than in individuals with normal vitamin D status, even if normal 25‐hydroxyvitamin D levels were a consequence of its supplementation. Although participants were enrolled during the whole year, seasonal variation in 25‐hydroxyvitamin D concentrations26 does not seem to be responsible for the obtained results, because the season during which samples were collected was regarded in statistical analyses as one of the potential confounders.

Because of the inclusion criteria, total cholesterol and LDL‐C levels were elevated in all participants of our study. However, although vitamin D and cholesterol share a common precursor (7‐dehydrocholesterol),27 patients with normal and low 25‐hydroxyvitamin D levels did not differ in baseline circulating levels of plasma lipids. This finding, which is in line with a neutral effect of vitamin D preparations on plasma lipids levels,28 as well as the lack of correlations between levels of 25‐hydroxyvitamin D and plasma lipids, suggest that vitamin D status plays a relatively small role in the regulation of lipid production and metabolism.

Comparable baseline levels of cardiometabolic risk factors as well as a similar effect of atorvastatin on these factors in patients belonging to groups B and C provide 2 important insights. First, the obtained results suggest that effective vitamin D supplementation resulting in 25‐hydroxyvitamin D levels within the reference range probably reduces cardiometabolic risk. This fact may be considered an argument in favor of using vitamin D preparations in the male population, not only with the aim of preventing osteomalacia, osteoporosis, and bone fractures. Second, initially low vitamin D status does not preclude the benefits associated with non–lipid‐related effects of statin therapy, if patients are effectively treated with vitamin D preparations. It should be underlined that all men from group A had vitamin D insufficiency, whereas group B included not only patients with 25‐hydroxyvitamin D levels between 20 and 30 ng/mL, but also men with 25‐hydroxyvitamin D levels <20 ng/mL before vitamin D supplementation. Taking into account the presence of negative correlations between vitamin D status and plasma levels of cardiovascular risk factors assessed in our study, it may be assumed that initial levels of this vitamin in group B were higher than in group A.

Taking into account the association between high plasma levels of hsCRP, fibrinogen, and homocysteine and cardiovascular disease and DM,22, 23, 24, 25 it seems that relatively small disturbances in vitamin D metabolism may contribute to the earlier development of atherosclerosis and carbohydrate abnormalities, as well as to their faster progression and complications. Because of strict inclusion and exclusion criteria and obtaining a relatively homogenous groups of patients, the results of our study cannot be attributed to coexisting disorders or to side effects of other drugs taken by some patients. It may be speculated that these unfavorable effects of low vitamin D status may be particularly important in the case of patients at high cardiovascular risk and patients with DM. Moreover, these patients may benefit the most from combined treatment with a statin and vitamin D.

In our study, patients from group A were characterized by an increased value of HOMA1‐IR, which is in line with previous findings showing an unfavorable impact on low vitamin D status on glucose homeostasis.16 Low vitamin D level predisposes to carbohydrate abnormalities by disturbing the function of pancreatic β‐cells, impairing insulin sensitivity and inducing systemic inflammation.16 An even more interesting finding was that vitamin D status determined the effect of atorvastatin on insulin sensitivity. In men with vitamin D insufficiency, atorvastatin increased HOMA1‐IR, but this effect was not observed in individuals in whom 25‐hydroxyvitamin D levels were within the reference range. A recent meta‐analysis of most major statin trials has indicated that statin therapy increases the risk of developing DM and that this risk was higher in patients receiving intensive‐dose statins compared with those receiving moderate‐dose therapy.29 Therefore, it is likely that vitamin D, by improving insulin sensitivity, may prevent the deteriorating effect of HMG‐CoA reductase inhibitors on glucose homeostasis. In the case of vitamin D deficiency or insufficiency, the effect of statins may be unopposed, the result of which is an increase in insulin resistance. Our observations may suggest that 25‐hydroxyvitamin D levels should be routinely measured at least in people at high risk of DM who require statin therapy, and, if abnormal values are found, vitamin D should be supplemented.

We can only speculate about the mechanisms responsible for our findings. Vitamin D is produced from 7‐dehydrocholesterol, which is the penultimate product formed before the formation of cholesterol.27 It is likely that low vitamin D status may be associated with increased production of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, 2 key isoprenoids playing a role in the post‐translational prenylation of small guanosine triphosphate‐binding proteins and involved in the regulation of many cellular processes.27 These intermediates in the HMG‐CoA reductase pathway are known to be responsible for mediating pleiotropic effects of statins.30 In line with this explanation, only lipid‐independent, but not lipid‐lowering, effects of atorvastatin differed between the study groups. An alternative mechanism is associated with an inhibitory effect of vitamin D on the nuclear factor κB signaling pathway,31 which may explain why men with vitamin D insufficiency had increased levels of hsCRP. Interestingly, this prototypical proinflammatory signaling pathway is also inhibited by atorvastatin, contributing to its antiatherogenic effects.32 It is possible that vitamin D and a statin may potentiate reciprocally their actions on the nuclear factor κB signaling pathway and maybe also on other signaling pathways regulated by vitamin D and affected by HMG‐CoA reductase inhibitors (toll‐like receptor‐2, toll‐like receptor‐4, p38, p42/42, or activator of transcription 5).33 ^, 34 Finally, it cannot be excluded that pleiotropic effects of statins are mediated by activation of vitamin D receptors, as was previously suggested,35 or are precursors of vitamin D agonists. Therefore, vitamin D receptors may be more potently activated by statins if they are simultaneously stimulated by adequate amounts of vitamin D.

4.1. Study limitations

Our study has several limitations that must be considered. The major one is its short duration and the small sample size. Moreover, we did not investigate clinical outcomes, including morbidity or mortality. It cannot be also ruled out that the impact of atorvastatin may be different in women, who were not enrolled in the study. Finally, from ethical reasons, our study included only men with untreated vitamin D insufficiency. It is likely that pleiotropic effects of atorvastatin are even less pronounced in vitamin D–naïve individuals with vitamin D deficiency, but this question requires further research.

5. CONCLUSION

Our study is the first one to show that pleiotropic effects of any hypolipidemic agent are determined by vitamin D status and that restoration of normal vitamin D levels enhances extralipid effects of HMG‐CoA reductase inhibitors. It seems that vitamin D–insufficient patients who need to be treated with a statin benefit from concomitant treatment with oral vitamin D supplementation. Because of study limitations, this study should be regarded as a pilot one, and larger prospective studies are needed to support our observations.

Conflicts of Iinterest

The authors declare no conflicts of interest.

Krysiak R, Gilowska M and Okopień B. Different cardiometabolic effects of atorvastatin in men with normal vitamin D status and vitamin D insufficiency, Clin Cardiol 2016;39(12):715–720.