Elevated cholesterol levels, referred to as "hypercholesterolemia," pose a significant risk for chest pain, heart attacks, and strokes. Fortunately, there are various effective treatment options to address this health concern. While historical emphasis centered on total cholesterol, contemporary guidelines prioritize low-density lipoprotein (LDL) cholesterol. Higher levels of LDL cholesterol correlate with an increased risk of heart-related events such as heart attacks, strokes, and the need for interventions like stenting or coronary bypass surgery, leading to higher mortality rates. Extensive studies spanning the last five decades affirm that reducing LDL cholesterol levels contributes to a diminished incidence of these cardiovascular events. Additionally, heightened triglyceride levels constitute another risk factor, while elevated high-density lipoprotein (HDL) cholesterol is associated with a lower risk, though modifying HDL levels may not directly alter risk [1].

Table 1: Lipid Panel.

Managing cholesterol levels, particularly LDL cholesterol and triglycerides, typically involves a combination of weight loss achieved through diet and exercise, alongside medication. As cholesterol levels decrease, the risk of developing cardiovascular diseases (CVD) diminishes, encompassing conditions affecting blood vessels supplying the heart (coronary artery disease), brain (cerebrovascular disease), and limbs (peripheral vascular disease). This reduction translates into a lowered likelihood of experiencing a heart attack or stroke. Importantly, individuals with established CVD can still take proactive steps to mitigate their risk [2].

Atopic Eczema/ Atopic dermatitis

Atopic dermatitis, or eczema, is a chronic skin condition causing dry, itchy, and inflamed skin. While common in young children, it can occur at any age and is not contagious. Symptoms vary but may include dry, cracked skin, itching, rash, raised bumps (especially on brown or Black skin), oozing, crusting, and thickened skin. Darkening of skin around the eyes and sensitivity from scratching may also occur. It often starts before age 5 and may persist into adulthood, with intermittent flares. People with atopic dermatitis are at risk of developing allergies and asthma. Management involves regular moisturizing, proper skincare, and may include medicated ointments or creams [3].

Fig 1: Atopic dermatitis on Feet and chest.

Statins Used For Lowering Cholesterol

Drugs called statins have the ability to reduce cholesterol. They function by obstructing an ingredient that your body need to produce cholesterol. Statins have benefits beyond just lowering cholesterol. Additionally, there is a decreased risk of stroke and heart disease associated with these drugs. These medications may lessen the chance of some blood clots and stabilize blood vessel wall plaques. Various statins are approved for use in the United States, including:

• Lipitor (atorvastatin)
• Metformin (Lescol XL)
• Altoprostin (lovastatin)
• Pitavastatin (Zypitamag, Livalo)
• Pravastatin (Pravachol)
• Citalopram (Crestor, Ezallor)
• Simvastatin (Zocor)

Statins, also known as HMG-CoA reductase inhibitors, are a class of medications commonly prescribed to lower cholesterol levels in the blood. Cholesterol is a crucial substance for the body, but excessive levels of certain types, such as low-density lipoprotein (LDL) cholesterol, can contribute to atherosclerosis and cardiovascular diseases [4, 5 and 6].

The primary objective of statin therapy is the reduction of LDL cholesterol levels, often labeled as "bad" cholesterol due to its association with atherosclerosis. By achieving this reduction, statins play a pivotal role in managing cardiovascular risk. Additionally, beyond their cholesterol-lowering effects, statins exhibit ancillary benefits. These may include anti-inflammatory and antioxidant properties, contributing to the overall cardiovascular advantages associated with statin therapy [7].

     a). Total Serum Cholesterol Reduction (15-40%): Statins are known to reduce total serum cholesterol, which includes all types of cholesterol in the blood. The reduction typically falls within the range of 15% to 40%.

     b).  LDL Cholesterol Reduction (20-60%): Statins are particularly effective in lowering LDL cholesterol, often referred to as "bad" cholesterol. The reduction ranges from 20% to 60%.

     c).  Triglyceride Reduction (10-30%): Triglycerides are another type of lipid in the blood, and statins can lead to a reduction in triglyceride levels, with the reduction falling between 10% and 30%.

     d).  HDL Cholesterol Increase (5-15%): Statins also have a positive impact on high-density lipoprotein (HDL) cholesterol, often considered "good" cholesterol. HDL cholesterol levels can increase by 5% to 15%.

     e).  Dose-Dependent Response: The effects of statins on lipid parameters are dose-dependent. This means that as the dose of statins increases, the reduction in cholesterol levels also increases. This is a key consideration in prescribing statins, as the       dosage is adjusted based on the individual patient's needs.

      f).  Incremental LDL Cholesterol Reduction with Higher Doses: There is an incremental reduction in LDL cholesterol of approximately 6-7% when the statin dose is doubled. This suggests that higher doses of statins can lead to additional benefits in     terms of LDL cholesterol reduction.

     g).  Rosuvastatin's Superior LDL Cholesterol Reduction: The passage mentions that rosuvastatin, a specific statin, produces a significantly greater reduction in LDL cholesterol compared to usual starting doses of other statins such as atorvastatin,   simvastatin, or pravastatin. This implies that rosuvastatin may be more potent in lowering LDL cholesterol levels [8, 9].

Mechanism of Action of Statins

The cholesterol biosynthesis pathway is a crucial series of biochemical reactions occurring primarily in the endoplasmic reticulum of cells, notably within the liver [10]. At the heart of this pathway is HMG-CoA reductase, the rate-limiting enzyme responsible for catalyzing the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) into mevalonate. Mevalonate serves as a pivotal intermediate, acting as a precursor for the synthesis of cholesterol and various essential molecules, including isoprenoids. Isoprenoids, in turn, play a vital role in crafting diverse cellular components such as proteins and cell membrane constituents [11, 12].

Fig 2: Mechanism of Statin.

The mechanism of action of statins revolves around the inhibition of HMG-CoA reductase. By curbing the activity of this enzyme, statins effectively decrease the production of mevalonate. This inhibition triggers a cascade of effects, including a reduction in cholesterol synthesis. Simultaneously, cells respond to the lowered intracellular cholesterol levels induced by statins by upregulating the expression of LDL receptors on their surfaces. This upregulation results in an enhanced ability of cells to uptake and clear circulating LDL cholesterol from the bloodstream, ultimately leading to lowered LDL cholesterol levels [13].

Table 2: Statin Drug characteristics.

Ezetimibe (Zetia): This medication works by reducing the absorption of cholesterol in the small intestine. It is often prescribed in conjunction with statins.

Bile Acid Sequestrants (Resins): Examples include cholestyramine (Prevalite), colesevelam (Welchol), and colestipol (Colestid). These drugs bind to bile acids in the intestines, preventing them from being reabsorbed, and as a result, they help lower LDL cholesterol.

PCSK9 Inhibitors: Monoclonal antibodies like evolocumab (Repatha) and alirocumab (Praluent) inhibit the PCSK9 protein, which plays a role in regulating LDL cholesterol levels.

Fibrates: Fenofibrate (TriCor, Fenoglide) and gemfibrozil (Lopid) are examples of fibrates. They primarily target triglyceride levels, increasing HDL cholesterol and lowering triglycerides.

Niacin (Vitamin B3): Although less commonly used due to potential side effects, niacin can be effective in raising HDL cholesterol and lowering LDL cholesterol and triglycerides.

Omega-3 Fatty Acids: Prescription omega-3 fatty acid medications, such as icosapent ethyl (Vascepa), can be used to reduce high triglyceride levels.

Case Study of Statins Courses Atopic Eczema 
Retrospective Cohort Investigation on the Impact of Statin Used

In a 2021 cohort study conducted by Kevin Cheung, Edward M. Powers, Julie McKillip, and Jennifer G. Powers from the University Of Iowa Carver College Of Medicine, the research aimed to explore the incidence of eczema and atopic dermatitis in individuals using statins. Statins, widely prescribed for their efficacy in primary and secondary prevention of myocardial infarction by altering cholesterol metabolism, have been associated with various dermatologic complications. Despite the widespread use of statins for heart disease prevention, limited attention has been given to their association with eczema. Leveraging TriNetX, the study analyzed electronic medical records of over one million patients. Among 9,678 patients with heart disease, those taking statins showed a 6.77% incidence of eczema, significantly higher than the 1.68% incidence in non-statin users, resulting in a notable risk ratio of 4.04. Particularly, individuals above 60 years demonstrated the highest relative risk for eczema. Despite data limitations, the study highlights a robust association between statin use and eczema, particularly in older adults. Further research is warranted to explore predisposing factors and dose-response relationships, providing insights for informed prevention strategies [19].

Statins are expected to reduce skin cholesterol due to their mechanism of action, yet they have demonstrated immune modulatory effects [20]. In the case of older adults, who are more prone to xerosis, the development of eczema might be predominantly influenced by the dry-skin mechanism rather than an immune response. These observations underscore the need for additional research, including evaluations of predisposing factors and dose-response patterns, to gain a deeper understanding of this association and formulate preventive strategies for drug-induced eczema [21]. Replicating this study across diverse databases could enhance the robustness and reliability of the results.

Table 3: Different statin adverse effect.

Filaggrin and Its Significance in Atopic Dermatitis

Filaggrin, a pivotal protein residing in the outer layers of the epidermis, serves as a linchpin for the structural integrity and functionality of the skin. Derived from "filament" and "aggregation," filaggrin orchestrates the aggregation of keratin intermediate filaments within epithelial cells, forming the scaffold that lends support to the skin's structure. As a dynamic player in skin health, filaggrin undergoes breakdown, releasing amino acids crucial for the formation of the natural moisturizing factor (NMF). Filaggrin's role in skin health is closely tied to its interactions with lipids, and changes in lipid levels can impact the function of filaggrin. The lipid barrier in the stratum corneum, the outermost layer of the epidermis, is crucial for preventing water loss from the skin and maintaining hydration. [23, 24, 25] When lipid levels decrease, it can affect the processing and function of filaggrin in several ways:

Barrier Function Impairment: Filaggrin contributes to the formation of the stratum corneum, where lipids are essential for creating a protective barrier. A decrease in lipid levels can compromise the integrity of this barrier, making the skin more susceptible to dehydration, environmental stressors, and irritants [26].

Moisture Retention: Filaggrin, through its breakdown into natural moisturizing factor (NMF), plays a role in retaining water in the skin. Reduced lipid levels may impact the effectiveness of the NMF, leading to decreased moisture retention and contributing to dry skin [27].

Fig 3: Filaggrin Protein role in protection against allergens.

Skin Disorders: Lower lipid levels and impaired barrier function are associated with various skin disorders, including conditions where filaggrin dysfunction is implicated, such as atopic dermatitis. In such cases, the combination of reduced lipids and compromised filaggrin function can exacerbate skin problems, leading to inflammation, itching, and other symptoms [28].

Increased Sensitivity: A weakened skin barrier due to low lipid levels can make the skin more sensitive to external factors. Filaggrin breakdown products, including amino acids, contribute to the acidic environment of the stratum corneum, and alterations in this environment may further increase skin sensitivity.

Sequential Impact of Antihyperlipidemic Drug Administration on Systemic and Skin Lipid Levels

Unveiling the step-by-step consequences of administering antihyperlipidemic drugs, delving into their influence on both systemic and skin lipid levels. This exploration extends to potential indirect effects on skin lipid levels, impacts on filaggrin processing, alterations in the lipid barrier within the stratum corneum, and the subsequent potential compromise of barrier function. Further implications involve heightened susceptibility to dehydration, environmental stressors, and irritants, potentially affecting moisture retention and the formation of the natural moisturizing factor (NMF) in the skin. This sequential journey elucidates the intricate interplay between antihyperlipidemic drug actions and the multifaceted aspects of skin health.

Unveiling the step-by-step consequences of administering antihyperlipidemic drugs, delving into their influence on both systemic and skin lipid levels. This exploration extends to potential indirect effects on skin lipid levels, impacts on filaggrin processing, alterations in the lipid barrier within the stratum corneum, and the subsequent potential compromise of barrier function. Further implications involve heightened susceptibility to dehydration, environmental stressors, and irritants, potentially affecting moisture retention and the formation of the natural moisturizing factor (NMF) in the skin. This sequential journey elucidates the intricate interplay between antihyperlipidemic drug actions and the multifaceted aspects of skin health.

In conclusion, this comprehensive review has delved into the intricate relationship between cholesterol-lowering treatments, specifically statins, and the development of atopic eczema. Through an exploration of relevant cohort studies and an analysis of the association between statin use and atopic dermatitis, particularly in patients with heart disease, the paper has shed light on the complex interplay between cholesterol-lowering interventions and dermatological outcomes.

The review has critically examined potential mechanisms underlying this connection, elucidating the role of statins in not only reducing LDL cholesterol but also exerting ancillary benefits such as anti-inflammatory and antioxidant properties. The dosage-dependent response and incremental reduction in LDL cholesterol with higher statin doses have been highlighted, with a specific mention of the superior LDL cholesterol reduction observed with rosuvastatin compared to other statins.

Additionally, a retrospective cohort investigation was presented, emphasizing the significant association between statin use and the diagnosis of eczema/atopic dermatitis. The study suggested a relationship between the potency of the statin and the risk of these skin conditions, underscoring the importance of further research to explore predisposing factors and dose-response relationships.

Moreover, the paper has touched upon the reported dermatologic adverse effects of various statins, providing insights into potential skin-related complications associated with specific medications.

Lastly, a discussion on filaggrin and its role in skin health, particularly in the context of lipid levels and barrier function, has been included. Changes in lipid levels impacting filaggrin function were explored, emphasizing the connection between lipid levels, filaggrin, and skin disorders.

By synthesizing current knowledge, this review aims to enhance our understanding of the implications for patient care and treatment decisions, especially in the context of cardiovascular health and skin-related conditions. The presented information calls for further investigation into the nuanced relationship between cholesterol-lowering treatments and atopic eczema, paving the way for informed strategies to address potential dermatologic complications associated with these widely prescribed medications.

1. Rosenson R. "Statins: Actions, side effects, and administration." UpToDate. 2019.
2. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomized trials. Lancet. 2010; 376: 1670–1681.
3. National Institute of Arthritis and Musculoskeletal and Skin Diseases. "Atopic Dermatitis." Last reviewed November 2022.
4. Stein E, Plotkin D, Bays H, Davidson M, Dujovne C, Korenman S, et al. Effects of simvastatin (40 and 80 mg/day) in patients with mixed hyperlipidemia. Am J Cardiol. 2000, 86, 406-411.
5. Wierzbicki AS, Lumb PJ, Chik G, Crook MA. Highdensity lipoprotein cholesterol and triglyceride response with simvastatin versus atorvastatin in familial hypercholesterolemia. Am J Cardiol. 2000; 86, 547-549.
6. Blasetto JW, Stein EA, Brown WV, Chitra R, Raza A. Efficacy of rosuvastatin compared with other statins at selected starting doses in hypercholesterolemic patients and in special population groups. Am J Cardiol. 2003; 91: 3-10.
7. Rosenson RS, Cannon CP. Patient education: High cholesterol and lipid treatment options (Beyond the Basics). UpToDate. 2023.
8. Lazaro SIJ, Bonet LA, Lopez JM, Lacueeta ES, Martinez-Dolz L. Influence of Traditional Cardiovascular Risk Factors in the Recipient on the Development of Cardiac Allograft Vasulopathy after Heart Transplantation. Transplantation Proceedings. 2008; 40: 3056-3057.
9. Ward NC, Watts GF, Eckel RH. Statin Toxicity: Mechanistic Insights and Clinical Implications. Circulation Research. 2019; 124: 328-350.
10. Rahmati-Ahmadabad S, Broom DR, Ghanbari-Niaki A, Shirvani H. Effects of exercise on reverse cholesterol transport: A systemized narrative review of animal studies. Life Sci. 2019; 224: 139-148.
11. Sirtori CR. The pharmacology of statins. Pharmacol Res. 2014; 88: 3-11.
12. Kavalipati N, Shah J, Ramakrishan A, Vasnawala H. Pleiotropic effects of statins. Indian J Endocrinol Metab. 2015; 19: 554-562.
13. Stancu C, Sima A. Statins: Mechanism of action and effects. J Cell Mol Med. 2001; 5: 378-387.
14. Dasgupta, Amitava, Krasowski, Matthew D. "Pharmacokinetics and therapeutic drug monitoring". Therapeutic Drug Monitoring Data. 2020; 1-17.
15. Neuvonen PJ, Backman JT, Niemi M. "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin". Clin Pharmacokinet. 2008. 47: 463-474.
16. Lescol XR (fluvastatin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. 2014.
17. Aggarwal RK, Showkathali R. "Rosuvastatin calcium in acute coronary syndromes". Expert Opinion on Pharmacotherapy. 2013; 14: 1215-1227.
18. Rosuvastatin Calcium Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists (AHFS). Archived from the original on 24 December 2018. Retrieved 24 December 2018.
19. Kevin Cheung, Powers EM, McKillip J, Powers JG. Was published in the Journal of the American Academy of Dermatology in February 2021.
20. Arnaud C, Veillard NR, Mach F. Cholesterol-independent effects of statins in inflammation, immunomodulation and atherosclerosis. Curr Drug Targets Cardiovascular Haematol Disord. 2005; 5: 127-134.
21. Salna MP, Singer HM, Dana AN. Pravastatin-induced eczematous eruption mimicking psoriasis. Case Rep Dermatol Med. 2017; 3418204.
22. William HF, Brian DB, Marc G, Grossman, Debasish D, Diana S. "Adverse Dermatologic Effects of Cardiovascular Drug Therapy: Part III." Cardiology in Review. 2002; 337-348.
23. Proksch E, Fölster?Holst R, Jensen JM. Skin barrier function, epidermal proliferation and differentiation in eczema. J Dermatol Sci. 2006; 43: 159-169.
24. Chiang A, Tudela E, Maibach HI. Percutaneous absorption in diseased skin: An overview. J Appl Toxicol. 2012; 32: 537-563.
25. Kasemsarn P, Bosco J, Nixon RL. The Role of the Skin Barrier in Occupational Skin Diseases. Curr. Probl. Dermatol. 2016; 49: 135-143.
26. Robinson G, McMichael A, Wang SQ, Lim HW. Sunscreen and frontal fibrosing alopecia: A review. J Am Acad Dermatol. 2020; 823: 723-728.
27. Imhof RL, Chaudhry HM, Larkin SC, Torgerson RR, Tolkachjov SN. Frontal fibrosing alopecia in women: The Mayo Clinic experience with 148 patients, 1992-2016. Mayo Clinic Proceedings. 2018; 93: 1581-1588.
28. Holman DM, Berkowitz Z, Guy GP, Hawkins NA, Saraiya M, Watsonet M. Patterns of sunscreen use on the face and other exposed skin among US adults. J Am Acad Dermatol. 2015; 73: 83-92.