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Cholesterol disorders do not manifest identically in every patient. There can be three main types of disturbances in the blood lipid profile:
1- Predominant LDL elevation (hypercholesterolemia),
2- Predominant triglyceride elevation (hypertriglyceridemia), or
3- Combined disorder with low HDL. In each case, treatment selection varies.
In predominant LDL elevation, the primary goal is to lower LDL. Dietary changes (restriction of saturated fats, increased fiber intake, plant sterols), physical activity, and weight control are the first steps. However, if this is insufficient, drug therapy is considered. Statins (HMG-CoA reductase inhibitors) are the classic drug group for lowering LDL. The most common side effects of statin drugs (e.g., atorvastatin, rosuvastatin, simvastatin) are usually related to muscles and the digestive system. The most frequently reported side effect is muscle pain or tenderness; this is usually mild but can rarely develop into severe muscle damage such as myositis or rhabdomyolysis (Stroes et al., 2015). Mild elevations in liver enzymes (ALT, AST) are common, but clinically significant hepatotoxicity is quite rare (Armitage, 2007). Some patients have reported gastrointestinal complaints (gas, nausea, constipation, or diarrhea), headache, and mild sleep disturbances (Ward et al., 2019). More rarely, peripheral neuropathy, skin rash, or cognitive complaints (“forgetfulness,” “mental fog”) have been reported; however, these neurocognitive effects are temporary and usually resolve with drug discontinuation (Richardson et al., 2013). Consequently, statins are generally well-tolerated; serious side effects are rare, and for most patients, the cardiovascular benefit far outweighs the potential risk. In cases of intolerance and excessive side effects, ezetimibe (an agent that inhibits enteric absorption), tyrosine kinase inhibitors, PCSK9 inhibitors, sometimes bile acid sequestrants, or bempedoic acid are included in guidelines (Grundy et al., 2019).
I generally prefer to use red yeast rice in patients who are biased against statin drugs. The main advantage of red yeast rice (RYR) over statins is that it contains a lower dose of monacolin K and is better tolerated in some patients. Clinically, the most important difference is that red yeast rice has been reported to have milder muscle side effects and less liver enzyme elevation compared to statins (Gerards et al., 2015; Li et al., 2019). This is because the supplements used are usually low-dose (3–10 mg/day monacolin K), and some products contain isoflavones, phytosterols, and antioxidant compounds that provide additional protective effects (Cicero et al., 2021). Beyond lowering LDL, these synergistic components can provide additional benefits on endothelial function, oxidative stress, and inflammation (Heber et al., 1999).
There are also differences between statins. Traditionally, atorvastatin is still the most preferred preparation by most physicians. However, recent scientific studies have highlighted rosuvastatin.
The fundamental pharmacological difference between atorvastatin and rosuvastatin is the LDL-cholesterol lowering power per dose. In head-to-head comparisons, rosuvastatin has provided approximately 8–10% more LDL reduction and slightly more HDL increase compared to atorvastatin in equivalent dose ranges; these findings appear consistent in the STELLAR program and high-dose comparisons (Jones et al., 2003; Leiter et al., 2007). Looking at clinical outcomes, the answer to the question “which statin is superior?” often depends more on the intensity and LDL level achieved than on the drug’s identity: Atorvastatin 80 mg significantly reduced events in PROVE-IT/TIMI-22 after acute coronary syndrome; rosuvastatin 20 mg reduced major vascular events and hs-CRP in JUPITER in primary prevention (Cannon et al., 2004; Ridker et al., 2008). In SATURN, which monitored plaque burden with IVUS, similar levels of regression in coronary atheroma volume were observed with rosuvastatin 40 mg and atorvastatin 80 mg over two years; rosuvastatin achieved slightly lower values and higher HDL production at cholesterol targets but did not show significant superiority in the primary endpoint (Nicholls et al., 2011).
Safety and interaction profiles are decisive in the selection. Atorvastatin is significantly metabolized via CYP3A4; the risk of muscle toxicity may increase with strong CYP3A4 inhibitors. Rosuvastatin is less dependent on the CYP2C9 and partially CYP2C19 pathways, and its drug interaction potential is generally lower; however, dose adjustment is required in moderate-to-advanced chronic kidney disease, and transient proteinuria/hematuria has been reported at high doses (Kellick et al., 2014; Wiggins et al., 2016). Regarding the development of new diabetes, observational cohorts have reported similar small increases with high-potency statins (both atorvastatin and rosuvastatin); however, the absolute magnitude of this risk is low and remains secondary to cardiovascular benefits (Carter et al., 2013).
In addition, some scientific evaluations suggest that rosuvastatin may also be advantageous in terms of reducing the risk of Alzheimer’s disease and dementia. Systematic reviews and meta-analyses have reported that statin use reduces the risk of dementia by 14–20%; a subgroup analysis of rosuvastatin found a risk reduction of approximately 28% (HR ~0.724). In particular, rosuvastatin may carry a low risk of side effects due to its non-lipophilic (hydrophilic) structure, which prevents uncontrolled distribution to brain tissue (statin-dementia meta-analysis). Another study reported rosuvastatin as the statin that showed the strongest protective effect in terms of dementia incidence (HR 0.82, 18% risk reduction) (Korean cohort study). These findings are promising in that rosuvastatin may be superior to other statins in terms of neurological protective effects. Considering that older people use this group of drugs more intensively, preparations that provide neurological protection should be highlighted. Furthermore, a synergistic effect slowing cognitive decline has been observed in animal models using rosuvastatin with telmisartan (Frontiers Neuroscience). However, these data are largely based on observational and preclinical studies.
In the case of elevated triglycerides, omega-3 fatty acids (high-dose EPA/DHA), fibrates, niacin, or statin plus additional treatments may be considered (Skulas-Ray et al., 2019). However, the routine use of niacin supplementation is not routinely recommended by current guidelines because its ASCVD preventive effect is limited (Last et al., 2017). Additionally, the AIM-HIGH study showed that niacin supplementation did not provide a significant advantage in addition to statin therapy in individuals with low HDL and high triglycerides (Boden et al., 2011). However, it may be appropriate to prefer niacin use in patients with chronic kidney failure because it has shown positive effects in this group of patients. This can be decided with a multidisciplinary approach.
I generally prefer to start with lifestyle changes, omega-3 supplementation, and, in some cases, red yeast rice for triglyceride elevations in the first stage. The person’s lipid profile and other health parameters also play an important role in this regard, of course. Just as the same approach is not shown to every patient, it is important to effectively reduce the risks.
In low HDL, direct drug strategies to increase HDL (such as niacin, CETP inhibitors) have not shown the expected benefit in the long term. Therefore, lifestyle-oriented approaches (exercise, smoking cessation, weight control) are more often recommended in people with a normal lipid profile but low HDL levels.
Can Cholesterol Levels Be Improved Without Medication?
Lowering cholesterol and triglyceride levels without medication, through natural means, is possible for most individuals, and this approach is recommended as the first step, especially in cases of mild-to-moderate hyperlipidemia. Clinical studies show that diet, exercise, and lifestyle changes significantly improve lipid metabolism. In particular, the Mediterranean diet, rich in olive oil, fish, vegetables, whole grains, and nuts, lowers LDL cholesterol while protecting HDL and reducing oxidative stress and inflammation (Estruch et al., 2018). Soluble fiber (oat beta-glucan, barley, psyllium) and plant sterols lower LDL cholesterol by an average of 10–15% by reducing synthesis and absorption mechanisms at the liver level (Katan et al., 2003; Brown et al., 1999). Omega-3 fatty acids (EPA and DHA) are particularly effective in reducing triglyceride levels; they suppress liver VLDL production, resulting in a 20–30% reduction (Bays et al., 2021).
Regular aerobic exercise also increases HDL cholesterol while lowering LDL and triglycerides; meta-analyses have reported that 150 minutes of moderate-intensity physical activity per week makes a clinically significant contribution to the serum lipid profile (Kodama et al., 2007). In addition, reducing body weight by 5–10%, especially through the reduction of visceral fat tissue, significantly corrects insulin resistance and triglyceride elevation (Jensen et al., 2014). Limiting alcohol intake, restricting refined carbohydrates, and getting enough sleep are also effective in lipid regulation. Some natural compounds such as red yeast rice, bergamot extract, berberine, and policosanol can lower LDL levels through statin-like mechanisms of action, but they should be used under medical supervision in terms of standardization and safety (Cicero et al., 2021). In conclusion, scientific evidence shows that lipid balance can be regulated naturally with diet, exercise, and weight management. Taking a step towards a healthier life as the first step will be a behavior that will improve not only cholesterol but also our general health status. These strategies will also form a synergistic basis that enhances treatment effectiveness in cases where drug therapy may be required.
Let’s take the first step together today. Let’s remove simple carbohydrates and ultra-processed packaged foods from our evening meals, adopt a vegetable and protein-based diet (especially if we do not have a restrictive health condition), and contribute to our blood sugar levels and cardiometabolic health with a 15-20 minute walk after meals. Every small step will allow us to achieve great gains in the long run.
Wishing you healthy days,
Dr. Ahmet Özyiğit
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