Second Line and Exceptional Treatments for Hypercholesterolemic Patients

Cholesterol absorption inhibitors

Inhibitors of cholesterol absorption in the intestine play an important role in the treatment of hypercholesterolemia, as these drugs not only inhibit the absorption of cholesterol from the diet, but also prevent the absorption of bile cholesterol, which has been excreted in bile by the liver and which will return to the body by the enterohepatic circulation. Bile acid sequestering resins - in Brazil, only cholestyramine is available for clinical use. These are effective drugs for the reduction of low-density lipoprotein cholesterol (LDL-C), useful in patients who are contraindicated to the use of vastatins, in the treatment of family hypercholesterolemia in children and as an association with other lipid-lowering agents.

Mechanism of action: This ionic resin binds in the intestine to bile acids that are high in cholesterol, increasing fecal excretion from those and disrupting the enterohepatic circulation. This decrease in absorption leads to a deviation in the hepatic flow of cholesterol to the production of bile acids due to a growth in the activity of the enzyme 7a-hydroxylase, which is responsible for catalyzing the limiting reaction in the synthesis of these acids. The decrease in intrahepatic cholesterol increases the expression of LDL receptors, responsible for the absorption of LDL particles from plasma. There is also a growth in intracellular cholesterol synthesis by increased activity of 3-hydroxy-3-methylglutaril- CoA reductase (HMG-CoA reductase), attenuating the effect on LDL reduction. At the same time, there is an increase in the hepatic synthesis of Very Low-Density Lipoprotein (VLDL), with an increase in the rate of triglycerides.

Effectiveness: Resins decrease LDL-C by approximately 15 to 30% and increase High Density Lipoprotein Cholesterol (HDL-C) by about 2 to 5%. They are very efficient when associated with vastatins. As mentioned earlier, doubling the dose of a vastatin, there is on average an additional reduction of LDL-C of only 6%. However, with the addition of a resin, this additional reduction will be 12 to 15%.

Safety and tolerability: Resins are very safe drugs because, not being absorbed, they do not present systemic toxicity and can be used even in children. They are excreted entirely by the digestive system. However, there are two problems with them: tolerability and interference in intestinal absorption of other substances. Resins have low tolerability because, in addition to not being palatable, they cause unpleasant digestive symptoms, such as dyspepsia, intestinal constipation, flatulence, nausea and bloating. Consequently, there is low treatment adhering. Resins also lead to malabsorption of other drugs, such as digitoxin, warfarin, thyroxin, thiazoid diuretics, beta-blockers, and also diet substances such as fat-soluble vitamins and folic acid.

Dosage: The dose of cholestyramine is 4 to 16g/day, taken at meals. Other medicines used by patients should be administered 1 to 2h before or 4h after resins. Generally, pediatric patients require vitamin supplementation and folic acid.

Contraindications: Resins are absolutely contraindicated in biliary obstruction and in cases of hypertriglyceridemia with triglycerides above 400mg/dl. With triglycerides between 200 and 400mg/dl, contraindication is relative, and these levels should be monitored. In patients with diabetes and intestinal autonomic neuropathy, there is a risk of the occurrence of severe intestinal constipation with possible fecaloma formation.

Ezetimibe

Unlike resins, ezetimibe is a selective inhibitor of intestinal cholesterol absorption, not inhibiting the absorption of bile acids and other fats.

Mechanism of action: Ezetimibe inhibits intestinal absorption of cholesterol by inhibiting the Niemann-Pick C1 Like1 protein on the enterocyte surface. This protein is responsible for the absorption of cholesterol, but not of other fats in the intestine. Kramer et al. [1] described another possible mechanism of action of ezetimibe: interference with another membrane protein, aminopeptidase N (CD 13), leading to endocytosis blockage of cholesterol-rich membrane microdomains.

Effectiveness: Ezetimibe, at a daily dose of 10mg, alone, leads to a decrease in LDL-C by an average of 20%. Its greatest advantage, however, is in the association with a vastatin, in a treatment strategy called double inhibition (inhibition of cholesterol synthesis by vastatin and its intestinal absorption by ezetimibe). In this case, when 10mg of ezetimibe is added to a vastatin, the LDL-C reducing power of the combination increases by 18% compared to vastatin alone. Just for comparison, as discussed earlier, doubling the dose of vastatin, the increase would be only 6%.
However, the Enhance [2], study compared, in patients with heterozygous family hypercholesterolemia, the use of 80mg in simvastatin with the combination of 80mg/ezetimibe 10mg and showed no statistically significant difference in the primary endpoint, which was the non-progression of the intima-media of carotid strains between the two groups, although the LDL-C achieved with the medication was significantly lower than that achieved with isolated simvastatin (141.3mg/dl and 192.7mg/dl, respectively).
The latest SHARP study, which allocated 9,270 patients with chronic kidney disease, during a mean follow-up of 4.9 years, comparing the use of the combination of simvastatin plus ezetimibe with placebo, led to a decrease of about 32.86mg/dl of LDL-C and a 17% reduction in the incidence of atherosclerotic events, including ischemic stroke, vascular death, acute myocardial infarction, or revascularization procedures; this difference is maintained in patients undergoing dialysis procedures or not. The authors concluded that the decrease in LDL-C by combining 20mg with ezetimibe 10mg/day safely reduced the incidence of atherosclerotic events in patients with advanced chronic renal failure [3].

Safety and tolerability: Side effects of ezetimibe include diarrhea, abdominal pain, low back pain, arthralgia and sinusitis. Hypersensitivity reactions such as angioedema and rash, pancreatitis, hepatitis, and myopathy rarely occur. Ezetimibe, despite being absorbed and its effect is systemic, is not metabolized by cytochrome P450 3A4 (CYP3A4), with no interference with most drugs. However, when used with cyclosporine, there is an important increase in its plasma concentration, which may lead to an increase in the incidence of its side effects. Unlike resins, it is very well tolerated. Another advantage is the non-interference with the absorption of bile acids, fat-soluble vitamins, folic acid and other drugs.

Dosage: Ezetimibe is used in a single dose of 10mg/day in a single take and can be given together with vastatins. Its use with fibrates seems to be safe, but there are ongoing studies for this evaluation.

Contraindications: It should not be used in case of active liver disease and in women during pregnancy and lactation.

Orlistat

Although used as an anti-obesity drug, orlistat, a pancreatic lipase inhibitor, besides being able to lead to a reduction of up to 10% in weight, can act by decreasing triglycerides and LDL-C.

Phytosterols

Compete in intestinal cholesterol absorption, leading to a slight decrease in LDL-C. To act efficiently, they must be ingested before three meals.

Nicotinic acid

Nicotinic acid, which has been used as a lipid-lowering agent since 1955, is suitable for the treatment of all types of dyslipidemia except family chylomicronemia. It can be used alone or associated with any lipid-lowering agent.

Mechanism of action: the main mechanism of action of nicotinic acid is by inhibiting peripheral lipolysis, inhibiting the mobilization of fatty acids to the liver. In addition, it decreases liver synthesis and secretion of lipoproteins rich in apolipoprotein-B.

Effectiveness: