The subcutaneous adipose tissue and the visceral adipose tissue are genetically different. They have very different metabolic activity. Since visceral adipose tissue is located in the viscera, its drainage directly goes to the liver, which is the major metabolic organ. The release of these free fatty acids in the liver results in hypertriglyceridemia which might be accompanied with low HDL-C. Hence, visceral adipose tissue is metabolically very active whereas subcutaneous adipose tissue is not much metabolically active.
However, subcutaneous tissue can also be pathogenic. Let us take an example of a person who has some degree of visceral fat and increased subcutaneous fat. If this person continues to have positive caloric balance and the subcutaneous fat is unable to adequately store that due to genetics or some environmental reasons then, this will get stored as visceral fat. Further, this visceral fat will go to the liver and muscles. The reason for increased fat in the visceral areas, liver and muscles could be due to the inability to store that fat in the subcutaneous adipose tissue. Thus, we can't just say that subcutaneous fat is good and visceral fat is bad. If the subcutaneous fat has adiposopathy, then it will be as pathogenic as the visceral fat. Most people believe that the free fatty acids in the portal system come from the visceral fat but there are evidences to show that more than half of those free fatty acids actually come from subcutaneous fat. This is because there is increased subcutaneous fat and it is this subcutaneous fat that would transport free fatty acids to the systemic organs.
I would conclude by saying that, the concept of visceral and subcutaneous fat is complex and is not as simple as saying visceral fat is bad and subcutaneous fat is good.
Clinical trials have shown that high doses of statins are efficacious in reducing the cardiovascular risk. However, it is important to bear in mind that many of the patients that are encountered during clinical practice are not the kind of patients that would be included in a clinical trial. Most of the patients encountered in clinical practice have multiple medical problems, may be taking multiple medications or may have other issues like renal insufficiency, etc. Hence, we have to be careful about using the absolute highest dose of statin in such patients. Clinical trial data should only be used as a guide. If your patient is otherwise healthy and not on multiple medications, then the highest dose of statin can be safely given to such a patient. Such patients are, however, rare to find in clinical practice.
Medicine is not just a science, but also an art.
I believe that as long as your patient is not at risk of developing complications due to high dose of statins, then you can use high doses of statin or titrate the lower dose to the higher dose of statin. This approach has also been supported by clinical trials. In patients where you have concerns regarding the use of highest dose of statins like geriatrics, those having potential for drug interactions or taking multiple medications, having renal insufficiency etc., you will have to be cautious about using the highest dose of statins for safety purposes and not for efficacy purposes
There is no definitive trial but data based on sub-analysis and post-hoc analysis have shown that fibrates are efficacious in patients with hypertriglyceridemia. As clinicians, if we do not have the efficacy data to determine the best therapy for our patients, then we have to take the decision based on the available data. If a patient has marked elevations in triglycerides,say ≥ 500 mg/dL, then fibrates or fish oils can be definitely used. There is clinical evidence suggesting that fibrates confer macrovascular and microvascular risk reduction in patients with high triglycerides levels.
I would re-enforce my statement that as clinicians, sometimes, we have to use the 'art' of medicine as much as the 'science' of medicine. Hence, if you have a patient with high TG and normal LDL-C and you think that statins are not the ideal choice of primary therapy, then use of fibrates can be considered.
These formulations may differ with respect to the speed with the plasma concentration of fenofibrate is achieved. Differences in manufacturing processes or use of innovative technologies can result in formulations which have a lower strength of fenofibrate but yet manage to be bioequivalent in terms of blood levels attained or reduction in blood levels achieved. I cannot comment on the clinical differences between these different formulations of fenofibrate because, I am not aware of any head-to-head trials comparing them.
Guidelines recommend that the primary goal in management of dyslipidemia is LDL-C. Once LDL-C has been optimally controlled with a statin, if triglycerides are ≥ 200 mg/dL then the secondary goal becomes non-HDL-C.
Non-HDL-C is the cholesterol carried by all atherogenic lipoproteins except HDL-C. You can only attain non-HDL-C goals by first achieving LDL-C goals probably with a statin and then if triglycerides continue to be elevated, you can consider adding fenofibrate.
I understand the difficulty associated with the diagnosis of metabolic syndrome. Clinicians should understand that metabolic syndrome does not describe a unified pathophysiological process, nor was it ever intended to do so. It refers to the residual risk factors apart from LDL-C that clinicians might want to evaluate in a patient. Hence, metabolic syndrome is a cluster of atherosclerotic risk factors that tend to appear together in certain kinds of patients. The objective of naming this cluster as 'metabolic syndrome' was to give certain targets for look for in patients. I believe that, the unified pathophysiological process that contributes to all the components of metabolic syndrome is 'adiposopathy' or 'sick fat'.
If a patient has significant dyslipidemia then you have to take steps to reduce the patient's macrovascular and microvascular risk. Hence, to some extent it really does not matter whether you have diagnosed 'metabolic syndrome'; what really matters is that, you identify its components and treat them appropriately to reduce the macrovascular and microvascular risk.
The best thing would be that overweight patients lose weight through proper nutrition and by increased physical activity. This might result in reduced size of adipocytes. This will further reflect in the form of reduced visceral adiposity and this of-its-own might take care of the components of metabolic syndrome.
The other thing, that can be done, which is very interesting, is that more functional fat could be added to treat fat-related metabolic disease. Is there a drug that we use that increases the recruitment and the depreciation of new fat cells? In another words, can we think of a drug that we use that increases body fat to treat a fat-related metabolic disease? And the answer is the PPAR-? agonists, the thiazolidinediones, like pioglitazone. Patients taking glitazones might gain body fat because it is adding functional fat to improve fat-related metabolic syndrome.
Another approach would be identify the various components of metabolic syndrome in a patient and treat each of them appropriately.
As far as improvement in lipid parameters is concerned, rosuvastatin is more efficacious as compared to atorvastatin. Hence, rosuvastatin-fenofibrate combination would give better improvement in lipid parameters as compared to atorvastatin-fenofibrate combination. This has been proven in clinical trials. However, I am unable to answer whether such a difference would result in superiority in reducing atherosclerotic events as there are no head-to-head trials which have examined this issue.
Earlier, when the issue of myopathy with statins first arose, I used to routinely monitor CK levels in patients taking statins. But, now I have stopped doing that because increase in CK levels can often be due to other reasons. An episodic increase in CK level is a common situation, for e.g. one of the clinical reasons for increase in CK levels that I have experienced during my clinical practice, is the physical activity for which the concerned person is not accustomed. So, whenever you come across an elevation in CK levels, a very careful and meticulous history of the patient should be considered to find out if that person has undergone any kind of atypical physical activity.
After I am sure that the increase in CK level is not due to any atypical physical activity, then I repeat the CK and if it is ≥3 times the upper limit of normal, then I would consider stopping the treatment or reducing the dose of treatment. If therapy is stopped, I would consider restarting the treatment after a certain time period.
