- Email: [email protected]
or lipoprotein responses to statins in subjects in primary and secondary prevention
Journal of Clinical Lipidology (2015) 9, 226–233
Gender-related lipid and/or lipoprotein responses to statins in subjects in primary and secondary prevention Giuliana Mombelli, MD*, Raffaella Bosisio, PhD, Laura Calabresi, PhD, Paolo Magni, MD, PhD, Chiara Pavanello, PhD, Franco Pazzucconi, MD, Cesare R. Sirtori, MD, PhD Dipartimento Cardiotoracovascolare, A.O. Ospedale Niguarda Ca Granda, Milano, Italy (Drs Mombelli, Pavanello, Bosisio, and Sirtori); and Department of Pharmacological Sciences, Universita degli Studi di Milano, 20133 Milano, Italy (Drs Calabresi, Pazzucconi, Magni, and Sirtori) KEYWORDS: Gender; HMG-CoA reductase inhibitors; Ischemic heart disease; Lipid disorders/ atherosclerosis; Risk factors
BACKGROUND: Cardiovascular risk in men rises around the fourth decade of life, whereas women appear to be protected by sex hormones until menopause. This, in turn, tends to negatively affect the lipid profile. Since the 1980s, the incidence of cardiovascular diseases has been reported to progressively decline in men, but it has persisted almost unchanged in women. Major clinical trials on statins have been mostly conducted in men and have fostered the introduction of these agents into clinical practice worldwide. However, only few reports have examined a possible differential activity of statins in the 2 genders, providing in some cases opposite findings. OBJECTIVE: To evaluate gender-related differences in statin responses. METHODS: Variations of lipid profile after 1-year of treatment with different statins in 337 dyslipidemic patients (171 men and 166 women). RESULTS: In this series of patients, a significantly attenuated reduction of total cholesterol and lowdensity lipoprotein cholesterol in women vs men on drug treatment was noted after adjustment for dose and statin power (low-density lipoprotein cholesterol: 228.5 6 11.8% in men vs 222.7 6 11.8% in women; P , .001). CONCLUSIONS: The present study indicates that statin treatment has a reduced effectiveness in improving the plasma lipid profile in dyslipidemic women vs men. Whether such gender-related differences may have an impact on clinical outcomes remains to be elucidated. Ó 2015 National Lipid Association. All rights reserved.
Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in women after the age of 50 years in most developed countries.1 Cardiovascular * Corresponding author. Dyslipidemia Center, Niguarda Ca Granda Hospital, Piazza Ospedale Maggiore 3, 20162 Milan, Italy. E-mail address: [email protected] Submitted June 9, 2014. Accepted for publication December 4, 2014.
1933-2874/Ó 2015 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2014.12.003
(CV) morbidity and mortality start to increase at the age of 40 years in men and about 10 years later in women.2 However, in specific conditions, such as immediately after a coronary event or a percutaneous transluminal coronary angioplasty, mortality appears to be higher in women than in men,3 and long-term mortality data after acute myocardial infarction are worse in older women than in men of the same age.4
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Gender-related lipid and/or lipoprotein responses to statins
In men, the presence of risk factors determines the onset of coronary artery disease (CAD) from the third to fourth decade onward, whereas in women, the presence of sex hormones during the reproductive life is associated with a relative risk reduction, the onset of arterial disease being postponed until after surgical or natural menopause.5,6 CV events are less frequent in women until the fifth to sixth decade. Since the mid-1980s, the incidence of CAD in men has declined progressively, whereas it has remained fairly constant in women.7,8 Because statins provide the most effective pharmacologic approach to the reduction of CV risk, a possible differential response both in terms of risk and of lipid changes in the 2 genders has been investigated by some authors. An early meta-analysis by Walsh and Pignone9 on studies conducted with cholesterol-lowering drugs in women reported a definite reduction in CV events in secondary prevention, but this did not clearly occur among those in primary prevention. The meta-analysis on 11 randomized secondary prevention studies by Gutierrez et al10 came to the same conclusion, that is, statin therapy is an effective strategy in the secondary prevention of CV events in both sexes. More recently however Petretta et al11 examined the impact of gender in the primary prevention of CV events and of total mortality with statin therapy. Although a clear reduction of risk, but not of total mortality, was noted in men, statin treatment in women did not appear to exert a clear beneficial effect on total mortality or CV events. The possibility that a reduced lipid-lowering activity of statins may occur in women has been suggested by a number of authors. A multinational study12 reported that women show a reduced cholesterol reduction after statins and a less frequent attainment of the cholesterol goals of the National Cholesterol Education Program Adult Treatment Panel III or of other national guidelines. A similar conclusion, that is, a reduced attainment of treatment targets, was also reached by the e-Registry in Germany.13 Very recently, a retrospective study on 950 CAD patients followed by a large cardiology subspecialty of clinical practice, confirmed a different reduction in low-density lipoprotein cholesterol (LDL-C) levels between the 2 genders, in particular women being less likely to achieve their lipid goals.14 We attempted to confirm these findings in a series of patients of both genders in predominantly primary, but also secondary prevention settings, followed for 1 year or longer and based on our findings offer potential explanations for such interaction.
Methods
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from a sample of 7500 men and women regularly followed at the Clinic. Of the initial 7500 patients, we excluded from our analysis those who were well responding to diet alone, patients treated with nutraceuticals or fibrates and those who had experienced side effects with statins. Of patients treated with statins, we took into account only those with baseline LDL-C between 170 and 250 mg/dL and those who were on a stable statin dose for at least 1 year (Fig. 1). The medication compliance was assessed for the duration of the study, considering that patients are regularly followed from the physicians of the Center. Every patient undergoes an average of 3 to 4 clinical examinations and laboratory analyses per year. Clinical and laboratory data are recorded into an electronic clinic chart (Lipid Chart). Dose changes or treatment suspension and adverse events or other particular conditions referred by the patients during the clinical examination are reported in the Lipid Chart. Adherence to treatment was verified with a questionnaire, asking whether patients took the medication, whether it was taken at the right time, and whether medication has stopped for any reason. Patients not entirely compliant were excluded from the analysis. Total CV risk was estimated with the Systematic COronary Risk Evaluation (SCORE) algorithm, used in the clinical management of CV risk in European countries. Subjects were subdivided into 2 different SCORE charts (high and low risks) based on gender, age, total cholesterol (TC), systolic blood pressure, and smoking status, with relative risk chart, qualifiers, and instructions. Four different CV risk levels and LDL-C targets to be achieved are given: very high risk (LDL-C goal ,70 mg/dL and/or $50% when target cannot be reached), high risk (LDL-C goal ,100 mg/ dL), moderate risk (LDL-C goal ,115 mg/dL), and low risk (LDL-C goal not given).15,16
Laboratory procedures A fasting plasma lipid and/or lipoprotein profile was measured at the baseline and after 1 year of treatment. Blood samples were collected in BD Vacutainer SST II Advance tubes after an overnight fast and centrifuged at 4 C at low speed. The determination of plasma concentrations of TC, high-density lipoprotein (HDL-C), and triglycerides was performed with certified methods using an auto-analyzer Integra 400 (Roche Diagnostics), as reported by a number of clinical studies in this Institution.17 Concentrations of LDL-C were calculated using the Friedewald formula.18
Statistical analyses Study subjects In this retrospective observational study, we evaluated a total of 337 dyslipidemic Italian patients of the Lipid Clinic recruited from April 2010. They were selected
Results are expressed as means 6 standard deviation. Lipid values at baseline and after 12 months of treatment with statins were compared by paired t test (z test for binary data) for pretreatment and posttreatment in men and
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Figure 1 Flow chart of patient selection. ESC/EAS, European Society of Cardiology/European Atherosclerosis Society; LDL-C, lowdensity lipoprotein.
women. Variations between groups were analyzed using t test for unpaired data or z test for binary data. Group differences or correlations with P , .05 were considered as
statistically significant. All statistical analyses were performed using the SPSS 19.0 (Statistical Package for the University of Study, Milan, Italy) software system.
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Gender-related lipid and/or lipoprotein responses to statins
Results Study population: baseline lipid parameters The objective of the study was to assess the different response to statins in women compared with men in primary and secondary prevention, after 1 year of treatment. Clinical characteristics and baseline lipid profile of evaluated patients are shown in Table 1. The majority of patients were in primary prevention, with a predominant diagnosis of type IIa hypercholesterolemia. A minority of patients had type 2 diabetes mellitus (3.5% of men and 0.6% of women), whereas a larger number had hypertension (33.3% of men and 36.1% of women). All statins available in Italy were used, that is, atorvastatin, fluvastatin, Table 1
Baseline characteristics of patients
Characteristics Age (y) BMI (kg/m2) TC (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) TG (mg/dL) Glucose (mg/dL) Uric acid (mg/dL) SBP (mm Hg) DBP (mm Hg) CV risk Very high (%) High (%) Moderate (%) Low (%) Atorvastatin 10 mg/d (%) Fluvastatin 80 mg/d (%) Pravastatin 20 mg/d (%) Rosuvastatin 10 mg/d (%) Simvastatin 20 mg/d (%) Smoking (%) Hypertension (%) Diabetes (%) Family Hx of CVD (%) Primary prevention (%)
Men (N 5 171)
Women (N 5 166)
57.5 6 9.2 25.1 6 2.9 280.7 6 28.7 199.6 6 27.7 51.9 6 12.4 146.1 6 67.9 94.1 6 14.2 5.3 6 1.1 129.3 6 15.9 80.3 6 8.6
59.4 6 8.8 .053 25.0 6 3.8 .774 282.2 6 18.0 .545 195.8 6 15.3 .110 59.8 6 13.6 ,.001 133.2 6 60.8 .037 88.6 6 10.8 ,.001 4.2 6 0.9 ,.001 130.7 6 15.0 .379 80.1 6 8.2 .817
38 39 82 12 44
(10.8) (7.8) (73.0) (8.4) (19.3)
.008 ,.001 ,.001 .004 .202
34 (19.9)
51 (30.7)
.031
42 (24.6)
20 (12.0)
.004
20 (11.7)
29 (17.5)
.175
31 (18.1)
33 (19.9)
.778
44 57 6 41 138
(22.2) (22.8) (48.0) (7.0) (25.7)
(25.7) (33.3) (3.5) (24.0) (80.7)
18 13 121 14 32
P
23 60 1 59 160
(13.8) (36.1) (0.6) (35.5) (90.4)
.009 .671 .137 .028 .018
BMI, body mass index; CV, cardiovascular; CVD, cardiovascular disease; DBP, diastolic blood pressure; ESC/EAS, European Society of Cardiology/European Atherosclerosis Society; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; SD, standard deviation; TC, total cholesterol; TG, triglycerides. Values are expressed as means 6 SD. Significant differences from the groups are evaluated by the t test (z test for binary data). *Total CV risk estimated with the score model by ESC/EAS.
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pravastatin, rosuvastatin, and simvastatin, with a prevalence of atorvastatin in men (25.7%) and fluvastatin in women (30.7%). After patient selection, we obtained homogeneous groups of subjects taking: 10 mg/d of atorvastatin or rosuvastatin, 20 mg/d of pravastatin and simvastatin, and 80 mg/d of fluvastatin. Drug doses were the same in the men and women groups. At baseline, TC and LDL-C levels between men and women did not differ (TC, 280.7 6 28.7 vs 282.2 6 18.0 mg/dL; LDL-C, 199.6 6 27.7 vs 195.8 6 15.3 mg/dL, respectively; Table 1).
Changes in lipid parameters with different statins Table 2 shows the distribution of the patients into 5 subgroups according to the different statins being used. In the atorvastatin subgroup, a significant decrease of lipid parameters in men, compared with women, was noted (N 5 44 men and 33 women, TC 222.5 6 10.8% vs 216.8 6 8.2%, P , .05; LDL-C 230.1 6 10.9% vs 222.7 6 10.3%, P , .05; men vs women, respectively). In the subgroup of patients treated with simvastatin, statistically significant differences in men compared with women were also recorded (N 5 31 men and 33 women, TC 220.6 6 8.5% vs 213.8 6 9.3%, P , .05; LDL-C 228.3 6 10.8% vs 220.6 6 12.7%, P , .05; men vs women, respectively). Gender-related variations of LDL-C in the subgroup treated with fluvastatin of 80 mg/d only reached borderline significance (34 men and 51 women, 229.1 6 14.0% vs 223.7 6 12.9%, P 5 .055; men vs women, respectively). A higher reduction of TC and LDL-C levels in men vs women was also found in the pravastatin and rosuvastatin groups, but statistical significance was not reached. The mean total and LDL-C reductions after all statins combined were highly significantly lower in women vs men (TC 220.7 6 9.6% in men vs 216.8 6 9.4% in women, P , .001; LDL-C 228.5 6 11.8% in men vs 222.7 6 11.8% in women, P , .001). In the simvastatin group, a significant decrease in HDL-C in men (23.5 6 15.2%) vs a significant increase in women (6.1 6 21.2%, P , .05 vs men) was found. With rosuvastatin, a significant increase in HDL-C was found in both genders, higher in men vs women (11.5 6 12.3 vs 2.5 6 17.9%, P , .05; Table 2). Changes in triglyceride levels between genders were not statistically significant in any subgroup (Table 2). Finally, when considering only patients with marked LDL-C elevations, that is, .190 mg/dL, all statins proved to be significantly less hypocholesterolemic in women vs men (Supplementary Table 1).
Evaluation of the attainment of the LDL-C target according to CV risk To evaluate the relative benefit of the different statins in 2 genders, risk changes were calculated according to the
recent guidelines of the European Society of Cardiology/ European Atherosclerosis Society (ESC/EAS), providing practical indications on how to classify patients into high, intermediate, or low CV risk (considering that Italy is in the group of countries at low risk). Based on this evaluation, it could be noted that the LDL-C target for the different subgroups was achieved only in 28 (16.4%) men and 29 (17.5%) women (P: ns). However, when considering the percentage LDL-C reduction, this was very similar in men with low, moderate, high, or very high risk, that is, always around 30%, whereas in the case of women, the LDL-C reduction was identical, that is, around 22% in patients with, low, moderate, and high risk, increasing significantly to 26.3% in those at very high CV risk. HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; TC, total cholesterol; TG, triglycerides. Values are expressed as mean 6 SD. Significant differences between the different groups (men vs women) by the unpaired t test. # P , .05. Differences between the various statin were not significant.
Number (%) TC (%) TG (%) LDL-C (%) HDL-C (%)
Fluvastatin (80)
M F M
Rosuvastatin (10)
F Pravastatin (20)
M F
Simvastatin (20)
M F
Atorvastatin (10)
Male/Female M
Statins (mg/d)
Changes in lipid parameters after 1-year treatment with different statins in men and women Table 2
44 (25.7) 33 (19.9) 31 (18.1) 33 (19.9) 42 (24.6) 20 (12.0) 20 (11.7) 29 (17.5) 34 (19.9) 51 (30.7) 222.5 6 10.8 216.8 6 8.2# 220.6 6 8.5 213.8 6 9.3# 218.6 6 7.6 215.8 6 7.3 219.2 6 10.5 218.5 6 11.5 221.2 6 9.8 218.5 6 9.4 27.7 6 43.4 25.6 6 37.0 24.2 6 35.2 8.3 6 87.4 26.7 6 33.1 23.1 6 32.1 21.7 6 41.2 26.9 6 33.8 7.4 6 38.7 24.6 6 51.9 230.1 6 10.9 222.7 6 10.3# 228.3 6 10.8 220.6 6 12.7# 225.4 6 11.0 220.9 6 8.0 230.3 6 12.3 225.2 6 12.9 229.1 6 14.0 223.7 6 12.9 6.6 6 24.7 1.4 6 20.8 23.5 6 15.2 6.1 6 21.2# 4.2 6 20.8 20.7 6 16.8 11.5 6 12.3 2.5 6 17.9# 0.7 6 17.0 21.8 6 18.9
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F
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Discussion Although numerous clinical studies have demonstrated a general benefit of lipid-lowering treatments in decreasing mortality from CV disease, they have not provided uniform findings in some subgroups, in particular women in primary prevention.11 Sex-related differences in terms of lipid response in the 2 genders have generally not been clarified because women are underrepresented in statin trials. The percentage reductions in LDL-C in women were found to be similar to those of men. Very few trials have included a sufficient number of women to allow a separate statistical analysis between the 2 genders in terms of lipid reduction and regression of atherosclerotic lesions. Available data appear to indicate that lipid-lowering treatments with statins in women show the best effects in those with a high CV risk, or in secondary prevention.19,20 The link between risk changes and lipid responses to statins has not been clearly provided. The objective of the present study was the evaluation of the lipid and/or lipoprotein responses in men vs women on treatment with statins for 1 year. Overall, there was clear evidence that, when evaluating patients with a similar type and dose of statin treatment, a more favorable biochemical response of men vs women is detectable (Table 2). These results contrast with the conclusions of Nakajima et al21 from the Saitama Postmenopausal Lipid Intervention Study (S-POLIS) reporting a larger decrease of TC (220 6 9% vs 215 6 9%) and LDL-C (228 6 12% vs 220 6 13%) in women vs men. A more detailed analysis of the 2 studies shows that S-POLIS included a total of only 177 patients (122 women and 55 men) treated only with simvastatin at different daily doses, compared with the 337 patients (171 men and 166 women) in our study, treated with all major statins. Furthermore, a statistically significant difference in TC and LDL-C between the 2 genders was present at baseline in S-POLIS21 vs no differences in the present report (Table 1). Two studies in Chinese populations reported instead a lesser cholesterol reduction in statintreated women, after adjustment for a number of covariates22 and a reduced number of coronary heart disease in
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women vs men achieving the LDL-C target, despite a large prescription of statin therapy.23 Finally, a specific gender analysis of data from the JUPITER study allowed Mora et al24 to detect decreases of LDL-C and high-sensitivity C-reactive protein (25.1 and 21.8 mg/dL, respectively) in normocholesterolemic women after rosuvastatin, not significantly different from those of men. The present study allows a broader view of the different responses to statins between the 2 genders. Clear-cut gender-related differences in pharmacokinetics and pharmacodynamics of different drugs have been repeatedly reported.25 Because, with the exception of pravastatin, mainly handled by an organic anion-transporting polypeptide efflux mechanism, all major statins are metabolized by the highly polymorphic hepatic cytochrome P-450. In particular, atorvastatin and simvastatin are predominantly metabolized by CYP3A4, expressed at 2-fold higher levels in women compared with men,26 leading to a faster and more extensive statin metabolism and consequently to a reduced activity compared with men. This difference could possibly explain the lesser efficacy in LDL-C lowering of these 2 agents in the present report (Table 2). Although the relevant physiological modulators, responsible for the different lipid metabolism between men and women, have yet to be elucidated, it is not unlikely that lipid responses to drugs, both mediated by nonhormonal physiological modulators26 and by microsomal and efflux mechanisms, may result in different responses in the 2 genders. In general, women have a lower body mass index and smaller size of organs, more adipose tissue (which may affect the pharmacokinetic profiles by increasing the volume of distribution for lipophilic drugs) as well as different plasma adipokine concentrations and reduced glomerular filtration rate compared with men.27 The greater expression of CYP3A4 is well confirmed by the twice larger messenger RNA expression in liver biopsies from women vs men.26 All these aspects should be carefully assessed in relation to any possible implications in clinical practice and may provide at least a partial answer to the, as yet, not convincing conclusions on the efficacy of statins in women in primary prevention.28 Although lipid patients are generally believed to be compliant to statin therapy, the recent meta-analysis of Lewey et al,29 including studies from a total of about 2.7 million patients, indicated an increased risk for nonadherence to statin therapy in women. The result of a more recent European study contradicts, however, this conclusion, reporting a nonsignificant relation between gender and adherence to therapy. Nonadherence was rather associated with younger age and knowledge of a reduced response to therapy.30 Confirming this conclusion, a retrospective Italian study identifies in the female sex one of the main determinants of better long-term adherence to therapy, along with a family history of early CAD and elevated baseline LDL-C.31 In the guidelines originated by American Heart Association for the prevention of CVD in women, a transition from ‘‘evidence-based’’ to ‘‘effectiveness-based’’ guidelines
231
is clearly suggested, thus recommending therapies that have been shown to provide sufficient clinical benefit for CVD outcomes.32 By evaluating the risk distribution in the 2 genders, it is quite clear that the LDL-C reduction in men is essentially unrelated to baseline risk, whereas women show the best LDL-C reduction in the very high-risk subgroup, that is, 4% higher vs the other subgroups that show instead a similar reduction. Considering that the EAS/ESC guidelines do not indicate a target LDL-C value for patients with low-intermediate risk, the numbers reaching target levels was similar in 2 genders but definitely higher in patients in the lower risk subgroups. It should be noted, on the other hand, that recently Hayward and Krumholz33 discouraged wide application of target levels to clinical therapy because these levels have been mainly derived from statin only trials and, further, in many cases were based on extrapolations from clinical trial findings. This conclusion is, to some extent, shared by the 2013 American Heart Association/The American College of Cardiology Guidelines in the Treatment of Blood Cholesterol.34
Conclusions From the comparative evaluation of 1-year treatment with statins, it appears that women, predominantly in primary prevention in our study, achieved a lesser LDL-C reduction compared with men. In addition, unlike in men, the relative impact of statin therapy on LDL-C in women may be related to baseline clinical risk profile as has been reported by others.12 In another report, an overtreatment of women with a low CV risk and undertreatment in cases of higher risk vs men was also suggested.13 Interestingly, in the cholesterol treatment trialists’ meta-analysis, women had a lower CV risk reduction per millimole per liter LDL-C lowering vs men, that is, 17% and 23%.35 Whatever the mechanism, careful and improved monitoring of lipid-lowering therapy should be advocated in women to confirm optimal drug compliance, choice of most appropriate statin, and reassessment of goals is necessary. Future prospective studies should be directed toward a large inclusion of high CV risk women, to optimize lipid treatment goals and assess effects on CVD risk reduction.
Study limitations The present study has several limitations. It should be remembered that it concerns a retrospective evaluation of statin effects in patients, who were, therefore, not randomized to any medications doses studied. The number of participant was relatively small and limited to Italian population. Furthermore, the duration of the follow-up was relatively short. A longer follow-up might have been required to ascertain whether there is an achievement of LDL-C target suggested by the EAS/ESC Risk SCORE charts, with the option of changing the lipid-lowering
232 therapy, using different dosage in case that the target is not attained. An additional limit is the lack of assessment of the CV end points, which will be probably included in future studies. Finally, no direct association between lipid changes and marker of subclinical atherosclerosis was evaluated (ie, intima-media thickness of carotid artery).
Acknowledgments None. Conflict of interest: The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the article. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received. No writing assistance was used in the production of this article.
Journal of Clinical Lipidology, Vol 9, No 2, April 2015
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Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jacl.2014.12.003.
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34. Stone NJ, Robinson JG, Lichtenstein AH, et al, American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014; 63:2889–2934. 35. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–1681.
Gender-related lipid and/or lipoprotein responses to statins in subjects in primary and secondary prevention Giuliana Mombelli, MD*, Raffaella Bosisio, PhD, Laura Calabresi, PhD, Paolo Magni, MD, PhD, Chiara Pavanello, PhD, Franco Pazzucconi, MD, Cesare R. Sirtori, MD, PhD Dipartimento Cardiotoracovascolare, A.O. Ospedale Niguarda Ca Granda, Milano, Italy (Drs Mombelli, Pavanello, Bosisio, and Sirtori); and Department of Pharmacological Sciences, Universita degli Studi di Milano, 20133 Milano, Italy (Drs Calabresi, Pazzucconi, Magni, and Sirtori) KEYWORDS: Gender; HMG-CoA reductase inhibitors; Ischemic heart disease; Lipid disorders/ atherosclerosis; Risk factors
BACKGROUND: Cardiovascular risk in men rises around the fourth decade of life, whereas women appear to be protected by sex hormones until menopause. This, in turn, tends to negatively affect the lipid profile. Since the 1980s, the incidence of cardiovascular diseases has been reported to progressively decline in men, but it has persisted almost unchanged in women. Major clinical trials on statins have been mostly conducted in men and have fostered the introduction of these agents into clinical practice worldwide. However, only few reports have examined a possible differential activity of statins in the 2 genders, providing in some cases opposite findings. OBJECTIVE: To evaluate gender-related differences in statin responses. METHODS: Variations of lipid profile after 1-year of treatment with different statins in 337 dyslipidemic patients (171 men and 166 women). RESULTS: In this series of patients, a significantly attenuated reduction of total cholesterol and lowdensity lipoprotein cholesterol in women vs men on drug treatment was noted after adjustment for dose and statin power (low-density lipoprotein cholesterol: 228.5 6 11.8% in men vs 222.7 6 11.8% in women; P , .001). CONCLUSIONS: The present study indicates that statin treatment has a reduced effectiveness in improving the plasma lipid profile in dyslipidemic women vs men. Whether such gender-related differences may have an impact on clinical outcomes remains to be elucidated. Ó 2015 National Lipid Association. All rights reserved.
Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in women after the age of 50 years in most developed countries.1 Cardiovascular * Corresponding author. Dyslipidemia Center, Niguarda Ca Granda Hospital, Piazza Ospedale Maggiore 3, 20162 Milan, Italy. E-mail address: [email protected] Submitted June 9, 2014. Accepted for publication December 4, 2014.
1933-2874/Ó 2015 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2014.12.003
(CV) morbidity and mortality start to increase at the age of 40 years in men and about 10 years later in women.2 However, in specific conditions, such as immediately after a coronary event or a percutaneous transluminal coronary angioplasty, mortality appears to be higher in women than in men,3 and long-term mortality data after acute myocardial infarction are worse in older women than in men of the same age.4
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In men, the presence of risk factors determines the onset of coronary artery disease (CAD) from the third to fourth decade onward, whereas in women, the presence of sex hormones during the reproductive life is associated with a relative risk reduction, the onset of arterial disease being postponed until after surgical or natural menopause.5,6 CV events are less frequent in women until the fifth to sixth decade. Since the mid-1980s, the incidence of CAD in men has declined progressively, whereas it has remained fairly constant in women.7,8 Because statins provide the most effective pharmacologic approach to the reduction of CV risk, a possible differential response both in terms of risk and of lipid changes in the 2 genders has been investigated by some authors. An early meta-analysis by Walsh and Pignone9 on studies conducted with cholesterol-lowering drugs in women reported a definite reduction in CV events in secondary prevention, but this did not clearly occur among those in primary prevention. The meta-analysis on 11 randomized secondary prevention studies by Gutierrez et al10 came to the same conclusion, that is, statin therapy is an effective strategy in the secondary prevention of CV events in both sexes. More recently however Petretta et al11 examined the impact of gender in the primary prevention of CV events and of total mortality with statin therapy. Although a clear reduction of risk, but not of total mortality, was noted in men, statin treatment in women did not appear to exert a clear beneficial effect on total mortality or CV events. The possibility that a reduced lipid-lowering activity of statins may occur in women has been suggested by a number of authors. A multinational study12 reported that women show a reduced cholesterol reduction after statins and a less frequent attainment of the cholesterol goals of the National Cholesterol Education Program Adult Treatment Panel III or of other national guidelines. A similar conclusion, that is, a reduced attainment of treatment targets, was also reached by the e-Registry in Germany.13 Very recently, a retrospective study on 950 CAD patients followed by a large cardiology subspecialty of clinical practice, confirmed a different reduction in low-density lipoprotein cholesterol (LDL-C) levels between the 2 genders, in particular women being less likely to achieve their lipid goals.14 We attempted to confirm these findings in a series of patients of both genders in predominantly primary, but also secondary prevention settings, followed for 1 year or longer and based on our findings offer potential explanations for such interaction.
Methods
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from a sample of 7500 men and women regularly followed at the Clinic. Of the initial 7500 patients, we excluded from our analysis those who were well responding to diet alone, patients treated with nutraceuticals or fibrates and those who had experienced side effects with statins. Of patients treated with statins, we took into account only those with baseline LDL-C between 170 and 250 mg/dL and those who were on a stable statin dose for at least 1 year (Fig. 1). The medication compliance was assessed for the duration of the study, considering that patients are regularly followed from the physicians of the Center. Every patient undergoes an average of 3 to 4 clinical examinations and laboratory analyses per year. Clinical and laboratory data are recorded into an electronic clinic chart (Lipid Chart). Dose changes or treatment suspension and adverse events or other particular conditions referred by the patients during the clinical examination are reported in the Lipid Chart. Adherence to treatment was verified with a questionnaire, asking whether patients took the medication, whether it was taken at the right time, and whether medication has stopped for any reason. Patients not entirely compliant were excluded from the analysis. Total CV risk was estimated with the Systematic COronary Risk Evaluation (SCORE) algorithm, used in the clinical management of CV risk in European countries. Subjects were subdivided into 2 different SCORE charts (high and low risks) based on gender, age, total cholesterol (TC), systolic blood pressure, and smoking status, with relative risk chart, qualifiers, and instructions. Four different CV risk levels and LDL-C targets to be achieved are given: very high risk (LDL-C goal ,70 mg/dL and/or $50% when target cannot be reached), high risk (LDL-C goal ,100 mg/ dL), moderate risk (LDL-C goal ,115 mg/dL), and low risk (LDL-C goal not given).15,16
Laboratory procedures A fasting plasma lipid and/or lipoprotein profile was measured at the baseline and after 1 year of treatment. Blood samples were collected in BD Vacutainer SST II Advance tubes after an overnight fast and centrifuged at 4 C at low speed. The determination of plasma concentrations of TC, high-density lipoprotein (HDL-C), and triglycerides was performed with certified methods using an auto-analyzer Integra 400 (Roche Diagnostics), as reported by a number of clinical studies in this Institution.17 Concentrations of LDL-C were calculated using the Friedewald formula.18
Statistical analyses Study subjects In this retrospective observational study, we evaluated a total of 337 dyslipidemic Italian patients of the Lipid Clinic recruited from April 2010. They were selected
Results are expressed as means 6 standard deviation. Lipid values at baseline and after 12 months of treatment with statins were compared by paired t test (z test for binary data) for pretreatment and posttreatment in men and
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Figure 1 Flow chart of patient selection. ESC/EAS, European Society of Cardiology/European Atherosclerosis Society; LDL-C, lowdensity lipoprotein.
women. Variations between groups were analyzed using t test for unpaired data or z test for binary data. Group differences or correlations with P , .05 were considered as
statistically significant. All statistical analyses were performed using the SPSS 19.0 (Statistical Package for the University of Study, Milan, Italy) software system.
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Results Study population: baseline lipid parameters The objective of the study was to assess the different response to statins in women compared with men in primary and secondary prevention, after 1 year of treatment. Clinical characteristics and baseline lipid profile of evaluated patients are shown in Table 1. The majority of patients were in primary prevention, with a predominant diagnosis of type IIa hypercholesterolemia. A minority of patients had type 2 diabetes mellitus (3.5% of men and 0.6% of women), whereas a larger number had hypertension (33.3% of men and 36.1% of women). All statins available in Italy were used, that is, atorvastatin, fluvastatin, Table 1
Baseline characteristics of patients
Characteristics Age (y) BMI (kg/m2) TC (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) TG (mg/dL) Glucose (mg/dL) Uric acid (mg/dL) SBP (mm Hg) DBP (mm Hg) CV risk Very high (%) High (%) Moderate (%) Low (%) Atorvastatin 10 mg/d (%) Fluvastatin 80 mg/d (%) Pravastatin 20 mg/d (%) Rosuvastatin 10 mg/d (%) Simvastatin 20 mg/d (%) Smoking (%) Hypertension (%) Diabetes (%) Family Hx of CVD (%) Primary prevention (%)
Men (N 5 171)
Women (N 5 166)
57.5 6 9.2 25.1 6 2.9 280.7 6 28.7 199.6 6 27.7 51.9 6 12.4 146.1 6 67.9 94.1 6 14.2 5.3 6 1.1 129.3 6 15.9 80.3 6 8.6
59.4 6 8.8 .053 25.0 6 3.8 .774 282.2 6 18.0 .545 195.8 6 15.3 .110 59.8 6 13.6 ,.001 133.2 6 60.8 .037 88.6 6 10.8 ,.001 4.2 6 0.9 ,.001 130.7 6 15.0 .379 80.1 6 8.2 .817
38 39 82 12 44
(10.8) (7.8) (73.0) (8.4) (19.3)
.008 ,.001 ,.001 .004 .202
34 (19.9)
51 (30.7)
.031
42 (24.6)
20 (12.0)
.004
20 (11.7)
29 (17.5)
.175
31 (18.1)
33 (19.9)
.778
44 57 6 41 138
(22.2) (22.8) (48.0) (7.0) (25.7)
(25.7) (33.3) (3.5) (24.0) (80.7)
18 13 121 14 32
P
23 60 1 59 160
(13.8) (36.1) (0.6) (35.5) (90.4)
.009 .671 .137 .028 .018
BMI, body mass index; CV, cardiovascular; CVD, cardiovascular disease; DBP, diastolic blood pressure; ESC/EAS, European Society of Cardiology/European Atherosclerosis Society; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; SD, standard deviation; TC, total cholesterol; TG, triglycerides. Values are expressed as means 6 SD. Significant differences from the groups are evaluated by the t test (z test for binary data). *Total CV risk estimated with the score model by ESC/EAS.
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pravastatin, rosuvastatin, and simvastatin, with a prevalence of atorvastatin in men (25.7%) and fluvastatin in women (30.7%). After patient selection, we obtained homogeneous groups of subjects taking: 10 mg/d of atorvastatin or rosuvastatin, 20 mg/d of pravastatin and simvastatin, and 80 mg/d of fluvastatin. Drug doses were the same in the men and women groups. At baseline, TC and LDL-C levels between men and women did not differ (TC, 280.7 6 28.7 vs 282.2 6 18.0 mg/dL; LDL-C, 199.6 6 27.7 vs 195.8 6 15.3 mg/dL, respectively; Table 1).
Changes in lipid parameters with different statins Table 2 shows the distribution of the patients into 5 subgroups according to the different statins being used. In the atorvastatin subgroup, a significant decrease of lipid parameters in men, compared with women, was noted (N 5 44 men and 33 women, TC 222.5 6 10.8% vs 216.8 6 8.2%, P , .05; LDL-C 230.1 6 10.9% vs 222.7 6 10.3%, P , .05; men vs women, respectively). In the subgroup of patients treated with simvastatin, statistically significant differences in men compared with women were also recorded (N 5 31 men and 33 women, TC 220.6 6 8.5% vs 213.8 6 9.3%, P , .05; LDL-C 228.3 6 10.8% vs 220.6 6 12.7%, P , .05; men vs women, respectively). Gender-related variations of LDL-C in the subgroup treated with fluvastatin of 80 mg/d only reached borderline significance (34 men and 51 women, 229.1 6 14.0% vs 223.7 6 12.9%, P 5 .055; men vs women, respectively). A higher reduction of TC and LDL-C levels in men vs women was also found in the pravastatin and rosuvastatin groups, but statistical significance was not reached. The mean total and LDL-C reductions after all statins combined were highly significantly lower in women vs men (TC 220.7 6 9.6% in men vs 216.8 6 9.4% in women, P , .001; LDL-C 228.5 6 11.8% in men vs 222.7 6 11.8% in women, P , .001). In the simvastatin group, a significant decrease in HDL-C in men (23.5 6 15.2%) vs a significant increase in women (6.1 6 21.2%, P , .05 vs men) was found. With rosuvastatin, a significant increase in HDL-C was found in both genders, higher in men vs women (11.5 6 12.3 vs 2.5 6 17.9%, P , .05; Table 2). Changes in triglyceride levels between genders were not statistically significant in any subgroup (Table 2). Finally, when considering only patients with marked LDL-C elevations, that is, .190 mg/dL, all statins proved to be significantly less hypocholesterolemic in women vs men (Supplementary Table 1).
Evaluation of the attainment of the LDL-C target according to CV risk To evaluate the relative benefit of the different statins in 2 genders, risk changes were calculated according to the
recent guidelines of the European Society of Cardiology/ European Atherosclerosis Society (ESC/EAS), providing practical indications on how to classify patients into high, intermediate, or low CV risk (considering that Italy is in the group of countries at low risk). Based on this evaluation, it could be noted that the LDL-C target for the different subgroups was achieved only in 28 (16.4%) men and 29 (17.5%) women (P: ns). However, when considering the percentage LDL-C reduction, this was very similar in men with low, moderate, high, or very high risk, that is, always around 30%, whereas in the case of women, the LDL-C reduction was identical, that is, around 22% in patients with, low, moderate, and high risk, increasing significantly to 26.3% in those at very high CV risk. HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; TC, total cholesterol; TG, triglycerides. Values are expressed as mean 6 SD. Significant differences between the different groups (men vs women) by the unpaired t test. # P , .05. Differences between the various statin were not significant.
Number (%) TC (%) TG (%) LDL-C (%) HDL-C (%)
Fluvastatin (80)
M F M
Rosuvastatin (10)
F Pravastatin (20)
M F
Simvastatin (20)
M F
Atorvastatin (10)
Male/Female M
Statins (mg/d)
Changes in lipid parameters after 1-year treatment with different statins in men and women Table 2
44 (25.7) 33 (19.9) 31 (18.1) 33 (19.9) 42 (24.6) 20 (12.0) 20 (11.7) 29 (17.5) 34 (19.9) 51 (30.7) 222.5 6 10.8 216.8 6 8.2# 220.6 6 8.5 213.8 6 9.3# 218.6 6 7.6 215.8 6 7.3 219.2 6 10.5 218.5 6 11.5 221.2 6 9.8 218.5 6 9.4 27.7 6 43.4 25.6 6 37.0 24.2 6 35.2 8.3 6 87.4 26.7 6 33.1 23.1 6 32.1 21.7 6 41.2 26.9 6 33.8 7.4 6 38.7 24.6 6 51.9 230.1 6 10.9 222.7 6 10.3# 228.3 6 10.8 220.6 6 12.7# 225.4 6 11.0 220.9 6 8.0 230.3 6 12.3 225.2 6 12.9 229.1 6 14.0 223.7 6 12.9 6.6 6 24.7 1.4 6 20.8 23.5 6 15.2 6.1 6 21.2# 4.2 6 20.8 20.7 6 16.8 11.5 6 12.3 2.5 6 17.9# 0.7 6 17.0 21.8 6 18.9
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F
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Discussion Although numerous clinical studies have demonstrated a general benefit of lipid-lowering treatments in decreasing mortality from CV disease, they have not provided uniform findings in some subgroups, in particular women in primary prevention.11 Sex-related differences in terms of lipid response in the 2 genders have generally not been clarified because women are underrepresented in statin trials. The percentage reductions in LDL-C in women were found to be similar to those of men. Very few trials have included a sufficient number of women to allow a separate statistical analysis between the 2 genders in terms of lipid reduction and regression of atherosclerotic lesions. Available data appear to indicate that lipid-lowering treatments with statins in women show the best effects in those with a high CV risk, or in secondary prevention.19,20 The link between risk changes and lipid responses to statins has not been clearly provided. The objective of the present study was the evaluation of the lipid and/or lipoprotein responses in men vs women on treatment with statins for 1 year. Overall, there was clear evidence that, when evaluating patients with a similar type and dose of statin treatment, a more favorable biochemical response of men vs women is detectable (Table 2). These results contrast with the conclusions of Nakajima et al21 from the Saitama Postmenopausal Lipid Intervention Study (S-POLIS) reporting a larger decrease of TC (220 6 9% vs 215 6 9%) and LDL-C (228 6 12% vs 220 6 13%) in women vs men. A more detailed analysis of the 2 studies shows that S-POLIS included a total of only 177 patients (122 women and 55 men) treated only with simvastatin at different daily doses, compared with the 337 patients (171 men and 166 women) in our study, treated with all major statins. Furthermore, a statistically significant difference in TC and LDL-C between the 2 genders was present at baseline in S-POLIS21 vs no differences in the present report (Table 1). Two studies in Chinese populations reported instead a lesser cholesterol reduction in statintreated women, after adjustment for a number of covariates22 and a reduced number of coronary heart disease in
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women vs men achieving the LDL-C target, despite a large prescription of statin therapy.23 Finally, a specific gender analysis of data from the JUPITER study allowed Mora et al24 to detect decreases of LDL-C and high-sensitivity C-reactive protein (25.1 and 21.8 mg/dL, respectively) in normocholesterolemic women after rosuvastatin, not significantly different from those of men. The present study allows a broader view of the different responses to statins between the 2 genders. Clear-cut gender-related differences in pharmacokinetics and pharmacodynamics of different drugs have been repeatedly reported.25 Because, with the exception of pravastatin, mainly handled by an organic anion-transporting polypeptide efflux mechanism, all major statins are metabolized by the highly polymorphic hepatic cytochrome P-450. In particular, atorvastatin and simvastatin are predominantly metabolized by CYP3A4, expressed at 2-fold higher levels in women compared with men,26 leading to a faster and more extensive statin metabolism and consequently to a reduced activity compared with men. This difference could possibly explain the lesser efficacy in LDL-C lowering of these 2 agents in the present report (Table 2). Although the relevant physiological modulators, responsible for the different lipid metabolism between men and women, have yet to be elucidated, it is not unlikely that lipid responses to drugs, both mediated by nonhormonal physiological modulators26 and by microsomal and efflux mechanisms, may result in different responses in the 2 genders. In general, women have a lower body mass index and smaller size of organs, more adipose tissue (which may affect the pharmacokinetic profiles by increasing the volume of distribution for lipophilic drugs) as well as different plasma adipokine concentrations and reduced glomerular filtration rate compared with men.27 The greater expression of CYP3A4 is well confirmed by the twice larger messenger RNA expression in liver biopsies from women vs men.26 All these aspects should be carefully assessed in relation to any possible implications in clinical practice and may provide at least a partial answer to the, as yet, not convincing conclusions on the efficacy of statins in women in primary prevention.28 Although lipid patients are generally believed to be compliant to statin therapy, the recent meta-analysis of Lewey et al,29 including studies from a total of about 2.7 million patients, indicated an increased risk for nonadherence to statin therapy in women. The result of a more recent European study contradicts, however, this conclusion, reporting a nonsignificant relation between gender and adherence to therapy. Nonadherence was rather associated with younger age and knowledge of a reduced response to therapy.30 Confirming this conclusion, a retrospective Italian study identifies in the female sex one of the main determinants of better long-term adherence to therapy, along with a family history of early CAD and elevated baseline LDL-C.31 In the guidelines originated by American Heart Association for the prevention of CVD in women, a transition from ‘‘evidence-based’’ to ‘‘effectiveness-based’’ guidelines
231
is clearly suggested, thus recommending therapies that have been shown to provide sufficient clinical benefit for CVD outcomes.32 By evaluating the risk distribution in the 2 genders, it is quite clear that the LDL-C reduction in men is essentially unrelated to baseline risk, whereas women show the best LDL-C reduction in the very high-risk subgroup, that is, 4% higher vs the other subgroups that show instead a similar reduction. Considering that the EAS/ESC guidelines do not indicate a target LDL-C value for patients with low-intermediate risk, the numbers reaching target levels was similar in 2 genders but definitely higher in patients in the lower risk subgroups. It should be noted, on the other hand, that recently Hayward and Krumholz33 discouraged wide application of target levels to clinical therapy because these levels have been mainly derived from statin only trials and, further, in many cases were based on extrapolations from clinical trial findings. This conclusion is, to some extent, shared by the 2013 American Heart Association/The American College of Cardiology Guidelines in the Treatment of Blood Cholesterol.34
Conclusions From the comparative evaluation of 1-year treatment with statins, it appears that women, predominantly in primary prevention in our study, achieved a lesser LDL-C reduction compared with men. In addition, unlike in men, the relative impact of statin therapy on LDL-C in women may be related to baseline clinical risk profile as has been reported by others.12 In another report, an overtreatment of women with a low CV risk and undertreatment in cases of higher risk vs men was also suggested.13 Interestingly, in the cholesterol treatment trialists’ meta-analysis, women had a lower CV risk reduction per millimole per liter LDL-C lowering vs men, that is, 17% and 23%.35 Whatever the mechanism, careful and improved monitoring of lipid-lowering therapy should be advocated in women to confirm optimal drug compliance, choice of most appropriate statin, and reassessment of goals is necessary. Future prospective studies should be directed toward a large inclusion of high CV risk women, to optimize lipid treatment goals and assess effects on CVD risk reduction.
Study limitations The present study has several limitations. It should be remembered that it concerns a retrospective evaluation of statin effects in patients, who were, therefore, not randomized to any medications doses studied. The number of participant was relatively small and limited to Italian population. Furthermore, the duration of the follow-up was relatively short. A longer follow-up might have been required to ascertain whether there is an achievement of LDL-C target suggested by the EAS/ESC Risk SCORE charts, with the option of changing the lipid-lowering
232 therapy, using different dosage in case that the target is not attained. An additional limit is the lack of assessment of the CV end points, which will be probably included in future studies. Finally, no direct association between lipid changes and marker of subclinical atherosclerosis was evaluated (ie, intima-media thickness of carotid artery).
Acknowledgments None. Conflict of interest: The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the article. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received. No writing assistance was used in the production of this article.
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Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jacl.2014.12.003.
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