Introduction

Cardiovascular disease (CVD) remains the second leading cause (19.9%) of death in Asia-Pacific women after cancers (26.6%).1

Statins ( HMG-CoA reductase inhibitors) diminish the burden of atherogenic lipoprotein in serum.2 Statins are the basis for lipid-lowering treatment worldwide in cardiovascular (CV) pharmacotherapy3 in patients with dyslipidemia,4 coronary artery disease (CAD), stroke, diabetes mellitus (DM), hypertension, and chronic kidney disease (CKD).5 It has attributed the decrease in the incidence of CV mortality worldwide to prevent CAD and total CVD by lowering of cholesterol.6

The beneficial role of statins is most intensively studied in both primary and secondary prevention.7 8 9 A study done by Cholesterol Treatment Trialists’ (CTT) Collaboration showed a 21% decrease in CVD mortality and morbidity, a 12% reduction in all-cause mortality by lowering 1.0 mmol/L low-density lipoprotein cholesterol (LDL-C).10 11

Statins are safe and well endured, but all patients cannot use statins due to their intolerance. Muscle-related adverse events are most frequently attributed with statin intolerance.12 13 Even among patients with CVD, statin discontinuation rates remain high.14 15 There is a strong correlation of statin nonadherence with acute CV event risk and increasing the risk for recurrent MI and CVD.16

In high-risk women, statins reduce coronary events and stroke by ~20%,10 but >50% of the CV events occur in low-risk women. In women, the benefits and risks of statin therapy for primary prevention remain less well defined. Primary prevention studies have shown that statin treatment lowers the rate of cardiovascular events by ~20%, the study populations predominantly included men; hence, questions remain about the safety and efficacy of statins to prevent CVD in women. In secondary prevention settings, statins reduce risk of recurrent CVD events and CVD mortality, with benefits of comparable magnitude in men and women.17

Risk of CVD in Men and Women

CVD is the foremost killer of both men and women. Women develop CAD at an older age (usually ~10 years later) than men. By then, women may already have coexisting CV risks such as diabetes and high blood pressure. Women are more likely to have coronary microvascular disease than men. This damage is harder to detect early with standard tests and may delay treatment that can help reduce related symptoms.

The 2013 ACC/AHA guidelines are the first to encompass identification of candidates using a CVD risk calculator that takes sex into account, recommend statin therapy for four specific patient populations7:

1. With established CVD.

2. With LDL-C≥190 mg/dL.

3. Aged between 40 and 75 years with type 1 or type 2 diabetes mellitus and LDL-C 70 to 189 mg/dL.

4. Aged between 40 and 75 years with LDL-C 70 to 189 mg/dL and 10-year risk for CVD ≥ 7.5%.

This risk calculator uses a formula that estimates 10 years and lifetime atherosclerotic cardiovascular disease (ASCVD) risk, defined as risk for first nonfatal MI, death due to coronary heart disease (CHD), and stroke.18 The calculation considers age, sex, race, a habit of smoking, DM, blood pressure, treatment for hypertension, total and high-density lipoprotein cholesterol (HDL-C).

The purpose of risk assessment is to identify higher-risk individuals for primary prevention. The guidelines first recommend lifestyle changes including diet, exercise, and weight loss for CVD primary prevention before starting statin therapy. Family history of premature CVD, hsCRP levels, coronary artery calcium score, and ankle-brachial index can be considered as additional parameters for the assessment of 10-year risk between 5% and 7.5%.

Novel Risk Factors of CVD in Women

Traditional risk factors may underestimate the risk in women. Novel risk factors that may improve the risk detection are19 20 the following:

1. Abdominal obesity.

2. Metabolic syndrome.

3. Depression.

4. Low estrogen levels.

5. Elevated C-reactive protein (CRP).

6. Elevated levels of testosterone.

7. Polycystic ovary syndrome (PCOS).

Randomized clinical trials (RCTs) of statins with metabolic syndrome (MetS) patients showed benefits on LDL-C, measures of endothelial function and inflammation, especially in lowering hsCRP, and subsequent contribution in reduction of CV events in patients with MetS.21

Depression is a common problem associated with many chronic medical conditions such as CAD, hypertension, and diabetes. Statins provide protection against coronary and cerebrovascular diseases by decreasing cholesterol synthesis in the liver. Statins also have potential anti-inflammatory activity. Since the pathophysiology of depression involves inflammation, statins could have a role in the treatment of mood disorders and might become a pharmacotherapy option for patients experiencing depression.22

Statins improve clinical, metabolic, and endocrine profiles of PCOS women. Despite an overall favorable risk profile, use of statins in reproductive-age women should be recommended with caution due to their potential teratogenic effects.23

Statins may function by lowering testosterone. In a study with 368 young women with PCOS, statins lowered testosterone by −0.40 nmol/L. Overall statins lowered testosterone by −0.44 nmol/L.24

Statins

Due to their beneficial effect on lipid and lipoprotein metabolism, statins have become extensively prescribed in the primary and secondary prevention of CVD.17

Statins help to prevent CAD in patients without CVD history (primary prevention) and in patients who are at high risk of developing CVD or have had a CVD and cerebrovascular accident (CVA) (secondary prevention).

A reduction of 20 to 44% in cardiac events after the initiation of statin therapy was reported with equivalent cardioprotective advantages in both the genders.17 25 26 The safety concerns regarding statins are important in women. The most common side effect of statin therapy is myalgia, which has reported in 20% of women and is a major cause of intolerance and discontinuation.27 Statins may be teratogenic and should be avoided in pregnant women and women who are planning to become pregnant. The FDA recognizes that while liver injury is a rare side effect of statin therapy, FDA has recommended to check liver enzymes before starting statin therapy or if symptoms of liver damage emerge. Statins are associated with 12% increased risk for developing elevated blood sugar or diabetes.28 FDA has also reported rare cases of nonsevere cognitive impairment.

Mechanism of Action

Statins inhibit the rate-limiting enzyme of the hepatic cholesterol synthetic pathway HMG-CoA reductase, which converts HMG-CoA to mevalonic acid (a precursor in the de novo biosynthetic pathway of cholesterol). Statins inhibit HMG-CoA reductase function through competitive inhibition which leads to decreased cholesterol production (Fig. 1).29

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Fig. 1 Mechanism of action of statins.

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Fig. 1 Mechanism of action of statins.

Objectives of Statin Therapy

Landmark trials have supported the statin therapy for preventing the onset and progression of ASCVD.30 31 It has been established that the development of ASCVD is associated with elevated levels of LDL-C, and the overall incidence and prevalence of mortalities associated with ASCVD can be reduced by lowering LDL-C levels through statins. In high-risk patients, statins are used in primary prevention to maintain normal levels of LDL-C, whereas statins are used to reduce the risk of CV events by lowering LDL-C levels in ASCVD confirmed patients. Statins have pleiotropic effects on multiple sclerosis, rheumatoid arthritis, strokes, systemic lupus erythematosus, inflammatory bowel diseases, cancer, chronic pulmonary obstructive pulmonary disease, Parkinson’s disease, Alzheimer’s disease, and HIV and bacterial infections.32

Primary Prevention of CVD

In women, the effect of statin therapy is less clear in primary prevention. The primary prevention of CVD in women ought to incorporate therapeutic lifestyle changes which can benefit the controlling of physical inactivity and obesity.33

CVD primary prevention trials have been grossly underpowered regarding enrolment of women, limiting the ability to stratify results by sex. This lack of adequate data has interpreted as a lack of statin efficacy for primary prevention in women. However, a large meta-analysis of 22 statin therapy trials with >174,000 participants (27% women) showed that statin therapy has similar effectiveness for preventing both primary and secondary major CV events and CV-related mortality in women and men.30 The results showed that for every 1 mmol/L (18 mg/dL) reduction of LDL-C, the CV events in women were 15% reduced in primary prevention. Among women with a 5-year risk <10% statin therapy lowered risk by 26%.34

JUPITER (Justification for the Use of Statins in Prevention) study,35 an interventional primary prevention trial with rosuvastatin, enrolled 17,802 study participants in which 38% were women. This trial tested the efficacy of statin therapy in individuals with low LDL-C (<130 mg/dL) levels but elevated (≥2 mg/dL) high-sensitivity C-reactive protein (hsCRP). Statin therapy prevented some CV events in women; the 5-year number needed to treat to prevent a major CV event was 31 and 17 for women versus men, respectively, reflecting the lower baseline risk.35

The CV and mortality advantages of statin treatment surpassed the diabetes hazard, even in those at higher risk for developing diabetes. For a long-term follow-up period of 5 years, 86 CV events/deaths were avoided, with no incident of new-onset diabetes (NOD) in patients with no significant diabetes risk factors. In patients diagnosed to have at least one factor for diabetes development, 93 CV events or deaths were avoided for each 54 NOD cases. Statin treatment was linked with time to NOD of just 5.4 weeks compared with placebo.36 While getting statin treatment, and patients ought to be encouraged to practice physical activity, reduce caloric intake, get more fit by losing weight, and smoking cessation to reduce the risk of NOD.

In patients with NOD, it is recommended to continue statin therapy and advised the management of these patients with hypoglycemic diet, loss of weight, and administration of antidiabetic drugs, if required.37 When nonpharmacological therapy is not effective in primary prevention of overweight or obese patients, the lipid-lowering approach is to introduce statins after the careful estimation of CV risk.38 There was a significant 20% reduction in total mortality (mortality benefits are equal in both the genders). This is further confirmed by a statin primary prevention meta-analysis in women where a 37% reduction in mortality was observed (relative risk [RR]: 0.63; P < 0.001).39

A meta-analysis (sex-specific) by Bukkapatnam and associates40 comprising 6 primary prevention trials, reported 144 mg/dL baseline LDL-C levels was found with a significant decrease in CHD in women, but not with all-cause mortality (RR: 0.78 0.90, respectively). In another meta-analysis comprising both primary and secondary prevention trials, statin therapy was benefited in women for prevention of primary events, but substantial advantage was observed in the lowest risk category (odds ratio [OR]: 0.59 for low risk; OR: 0.75 for medium risk; and OR: 0.88 for high risk).41

In a meta-analysis conducted by CTT Collaborations in patients with secondary and high-risk primary prevention, the CV risk reductions were 17% and 22% in women and men, respectively.11 In another meta-analysis in which the outcome was measured with the effects per 1.0 mmol/L (38 mg/dL) reduction in LDL-C, results showed that the proportional declines in LDL-C were similar for women and men (RR: 0.84 vs. RR: 0.78, p = 0.33).10 26

Results of a meta-analysis of low-risk primary prevention of both the genders at <10% predicted 10-year risk, showed insignificant differences in proportional reductions by gender (p = 0.11). A significant reduction in total mortality was observed in both the genders with statin therapy. The study concluded that the statin therapy provides similar benefits in both the genders at the same risk of CVD.34 Because of their capability to cause birth defects statins are contraindicated in women during pregnancy; otherwise they are safe in men and women for long-term use.42 Trials on statins comparing primary events in men and women are summarized in Table 1.

Secondary Prevention of CVD

Although women are under-represented with <20% of total participants in secondary prevention trials, reports of major studies support the prescription of statins in either genders with established CVD. A meta-analysis with secondary prevention trials provided gender-based analysis, which presumed that statin treatment had decreased the risk of CVD equally in both women and men (corresponding relative risks [RRs] are 0.81 and 0.82, respectively).17 Some of the studies concluded that statins reduced the risk of stroke and all-cause mortality only in men but not in women, which is due to less statistical power in women in those studies.

In PROVE IT-TIMI 22 trial (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22),43 investigators evaluated the outcome of the lipid-lowering capacity of pravastatin 40 mg (standard) after acute coronary syndromes (ACS) with atorvastatin 80 mg (intensive therapy) for two years. Women in intensive statin therapy group had more reduction in CV events and mortality. Women had benefited with statin therapy for secondary prevention.

After ACS, women randomized to high-dose statin therapy (80 mg atorvastatin daily) versus standard therapy (20 mg pravastatin daily) experienced a 25% reduction in CVD events and mortality.43 Two separate meta-analyses have also reported similar findings. The first included 11,000 women from 11 secondary prevention trials and found that statin therapy reduces CVD risk by 19%; the other included >40,000 women from 18 trials and found clear benefit for both CVD (OR: 0.78) and stroke (OR: 0.74).17 41

Risks and Adverse Effects of Statins

Adverse effects with statins are not common, occurring only in up to 3% of individuals in RCTs on statins and most are not serious. The common adverse effects of statins are the following:

• Muscle related side effects:

  • Myalgia or soreness or aching without associated injury (1.5–3.5%).

  • Myopathy or muscle soreness associated with muscle injury.

  • Rhabdomyolysis (occurs in 5 of every 10,000 statins users).

• Liver abnormalities (<1% of people taking statins).

• Diabetes.

• Gastrointestinal symptoms such as constipation, nausea, or indigestion.

• Headache.

• Cognitive impairment.

The most commonly reported adverse effects of statins in most of the RCTs are statin-associated muscle symptoms (SAMS).44 45 SAMS are the very common reason for the discontinuation of statin treatment regardless of the notable CV benefits.45 46

SAMS include myalgia, cramps, and weakness. The incidence of SAMS ranges from 10 to 29% in patients on statin therapy, the incidence of rhabdomyolysis and myopathy with elevated plasma creatine kinase are very rare.47

A clinical myalgia scoring system called Statin Myalgia Clinical Index (SMCI) was proposed by the National Lipid Association (NLA) and is useful in deciding the likelihood that the muscle symptoms are statin-related.47 PRIMO44 and STOMP48 are studies that are related to SMCI.

High doses and increased serum concentration of statins, use of statin-interacting drugs which can hinder statin catabolism, hypothyroidism, decreased muscle mass, and increased physical activity can boost the risk of SAMS.44 49 50 In addition, elderly age, female gender, physical weakness, and alcohol use can also likewise expand the hazard of SAMS.50 Azole antifungals and macrolide antibiotics, which are metabolized by CYP3A4, protease inhibitors, Ca channel blockers, and warfarin can rise the serum concentrations of statins.51

ASCOT-LLA study52 53 (Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm) evaluated numerous adverse effects of statins. The study findings revealed the rate of muscle-related events in the blinded phase as 2.0% and 2.03% in placebo and statin groups, respectively. Whereas in unblinded phase, the rate of muscle-related events was found 1.00% and 1.26% in placebo and statin groups, respectively. Statin therapy may cause raised blood glucose and risk of diabetes mellitus, which is supported by a meta-analysis in which a 12% increased diabetes risk was found.28 The American Heart Association (AHA) and the American Diabetes Association (ADA) have affirmed, however, that the cardiovascular benefits of statin therapy overweigh the potential risk of developing diabetes.

Statin Intolerance

Statin intolerance is defined as a failure to endure at least two different statins, with one statin assessed at its lowest effective dose.54 55 The most common cause of statin intolerance is SAMS. Benefits and potential adverse effects of statin therapy are explained in Table 2.56

IMPROVE-IT57 (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) demonstrated that the combination of statin therapy (ezetimibe + simvastatin) did not increase the incidence of SAMS compared with simvastatin alone.53 In patients with statin intolerance, studies have recommended that PCSK9 inhibitors can be used safely in those patients.58 59 60

Diabetes mellitus: It has been evidenced by JUPITER study26 that the relative risk of NOD was significantly increased by 25% with rosuvastatin (20 mg daily dose) when compared with placebo. Even in patients at high risk of developing diabetes the cardiovascular and mortality benefits exceeded the risk of diabetes.36

When compared between more-intensive and less-intensive statin therapies, a significantly higher risk of NOD was associated with more-intensive statin therapy. This finding was proven by the TNT (Treating to New Targets),61 IDEAL (Initiating Dialysis Early and Late),62 PROVE-IT TIMI,63 A to Z,64 and SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine)65 studies.

Liver considerations: As the statin metabolism uses cytochrome P450 pathway in the liver, it has been assumed that they have potential hepatotoxicity. Hepatologists use Hy’s law to determine drug-induced liver injury.66

Hepatitis C: The hepatitis C virus (HCV) replication involves the LDL receptor and enzymes involved in cholesterol biosynthesis. HCV viral replication may be interrupted by statins. Studies have revealed that statin use is linked to improvements in viral response to HCV treatments.67

NAFLD and NASH: Approximately 9 to 37% of people worldwide have non-alcoholic fatty liver disease (NAFLD), and 3 to 5% have nonalcoholic steatohepatitis (NASH), with greater occurrence in obesity patients.66 Statin use in these patients is associated with a decrease in transaminase levels, with improvements in steatosis and the liver necroinflammatory grade. However, no change in the grade of liver fibrosis was observed.68 69

Cognition: Few studies did not show relationship between statin therapy and cognitive impairment.70 The PROSPER71 and HPS72 studies have prospectively analyzed cognitive function and showed no association of statin therapy on cognitive function during the trial.73

Hemorrhagic stroke: The CTT meta-analysis demonstrated that treatment with statins will decrease the overall risk of stroke and ischemic stroke by 16% and 21% per 1 mmol/L reduction in LDL-C levels.10 A meta-analysis reported no association between statin therapy and increased risk of intracerebral stroke.74

SPARCL trial (Stroke Prevention by Aggressive Reduction in Cholesterol Levels)75 showed a significant increase in hemorrhagic stroke with atorvastatin. Therefore, any potential risk of hemorrhagic stroke is outweighed by the greater decline seen in overall stroke and major cardiovascular events.

Conclusions

Primary and secondary prevention trials of CVD have been grossly underpowered regarding enrolment of women, limiting the ability to stratify results by sex. Statins are safe and well tolerated in both the genders, but all patients cannot use statins. SAMS are the most common adverse effects in statin intolerance. Statins reduce coronary events and stroke in high-risk women. Benefits and risks of statin therapy in women for primary prevention remain less well defined than in men. CVD prevention includes lifestyle modification for all women and medical treatment for those with prevailing CVD risk factors or known disease. It has been proved that statins reduce the rates of cardiovascular events and mortality. RCTs showed that statins are safe in most of the patients with the previous history of stroke. In populations at high baseline risk of CVD, cardiovascular benefits of statin therapy overweigh the potential risk of increased serum glucose levels.

By considering the safety concerns and significance to women, statins should be targeted to women at high-risk and must be avoided in low-risk group women with respect to CVD.