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Archive for the ‘Cardiovasculars’ Category

Adverse Reactions

In clinical trials, all doses of colesevelam were generally well tolerated. Colesevelam is not absorbed in the digestive tract, reducing the potential for systemic adverse side effects. Also, its water-retaining ability creates a soft, gelatinous material that minimizes the potential for gastrointestinal irritation. The most common side effects reported by patients in clinical trials of colesevelam HCl were flatulence (12% for colesevelam vs. 14% for placebo) and constipation (11% for colesevelam vs. 7% for placebo). The incidence of gastrointestinal side effects was less than that associated with other drugs in its class. Less than 3% of the trial patients discontinued colesevelam therapy as a result of GI tract adverse reactions. There were no clinically significant changes in serum chemistry parameters from baseline to the end of treatment. In general, the change from baseline for indicators of kidney and liver function did not differ among treatment groups, with the exception of a modest, non-dose-related increase in alkaline phosphatase. No clinically significant changes were noted during clinical trials to date for hematologic parameters, serum levels of vitamins A and E, prothrombin time, partial thromboplastin time, estradiol levels, body weight, pulse, and systolic and diastolic blood pressure.

Drug Interactions

In clinical studies, coadministration of colesevelam with atorvastatin, lovastatin, or simvastatin did not interfere with the lipid-lowering activity of the HMG-CoA reductase inhibitor. Colesevelam is reported to decrease the C_max and AUC of sustained-release verapamil (Calan SR) by approximately 31% and 11%, respectively. Since there is a high degree of variability in the bioavailability of verapamil, the clinical significance of this finding is unclear. Colesevelam HCl was found to have no significant effect on the bioavailability of digoxin, lovastatin, metoprolol, quinidine, valproic acid, and warfarin. When administering other drugs for which alterations in blood levels could have a clinically significant effect on safety or efficacy, monitoring drug levels or effects should be considered.

Dosage, Administration and Patient Information

Colesevelam is supplied as an off-white tablet containing 625 mg of the active drug. The recommended initial dose of colesevelam monotherapy is three tablets twice daily or six tablets once daily. Colesevelam should always be taken with a liquid and a meal. The dose of colesevelam may be increased to seven tablets, depending upon the desired therapeutic effect. When used with an HMG-CoA reductase inhibitor, the recommended dose of colesevelam is three tablets taken twice daily with meals or six tablets taken once daily. Colesevelam and the HMG-CoA reductase inhibitor do not need to be administered at the same time. Patients should be instructed to adhere to their National Cholesterol Education Program recommended diet and inform their physicians if they are pregnant, are intending to become pregnant, or are breastfeeding. Colesevelam is contraindicated in individuals with bowel obstruction and in individuals who have shown hypersensitivity to any of the components of the drug product.

Pharmacology and Pharmacokinetics

Bile acids are formed from cholesterol in a series of reactions regulated by the enzyme 7-alpha- hydroxylase. During normal digestion, bile acids are secreted into the intestine. A major portion of bile acids are then absorbed from the intestinal tract and returned to the liver via the enterohepatic circulation. Colesevelam is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed (less than 0.05% absorption) from the GI tract. It binds bile acids in the intestine, impeding their reabsorption and facilitating elimination. As the bile acid pool becomes depleted, the hepatic enzyme cholesterol 7-alpha-hydroxylase is upregulated, increasing the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in both increased transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increased numbers of hepatic low-density lipoprotein (LDL) receptors. These compensatory effects result in increased clearance of LDL-C from the blood, thereby decreasing serum LDL-C levels. Furthermore, studies have shown that the combination of colesevelam and an HMG-CoA reductase inhibitor is effective in further lowering serum total-C and LDL-C levels beyond that achieved by either agent alone.

Therapeutics

The effectiveness of colesevelam in lowering LDL-C has been demonstrated in a number of controlled clinical trials involving approximately 1,400 patients who were treated for 4–50 weeks. Colesevelam taken alone was found to be effective for patients with mild-to-moderate hypercholesterolemia, producing a maximum therapeutic response within two weeks; this effect was maintained during long-term therapy. In a study in patients with LDL-C between 130 and 220 mg/dL (mean 158 mg/dL), colesevelam was given for 24 weeks in divided doses with the morning and evening meals. In this study, the mean LDL-C reductions were 15% with a 3.8 g dose of colesevelam and 18% with a 4.5 g dose. The mean total-C reductions were 7% and 10%, respectively, and the mean Apo B reductions were 12% in both treatment groups. Colesevelam at both doses also resulted in a 3% increase in HDL-C. There were also small increases in triglycerides (TG) at both colesevelam HCl doses but these were not statistically different from placebo.

In a study of nearly 100 patients with LDL-C between 145 and 250 mg/dL (mean 169 mg/dL), 3.8 g of colesevelam was given for six weeks as a single dose with breakfast, a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the three dosing regimens, respectively. The reductions with these three regimens were not statistically different from one another. Coadministration of colesevelam and an HMG-CoARI (atorvastatin, lovastatin, or simvastatin) produced an additive reduction of LDL-C in several clinical studies. Colesevelam doses of 2.3 g to 3.8 g resulted in additional 8% to 16% reductions in LDL-C above that seen with the HMG-CoARI alone. It should be noted that the specific effects of colesevelam, either alone or with an HMG-CoA reductase inhibitor, on cardiovascular morbidity and mortality have not been determined at this time.

Based on these studies, colesevelam, administered alone or in combination with an HMG-CoA reductase inhibitor, is indicated as adjunctive therapy to diet and exercise for the reduction of elevated LDL-C in patients with primary hypercholesterolemia who are at significant increased risk for atherosclerotic vascular disease. Prior to initiating colesevelam therapy, it is necessary to first exclude secondary causes of hypercholesterolemia, such as poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease or other drug therapy. Also, a lipid profile should be obtained to assess total-C, HDL-C, and TG and periodic serum cholesterol levels, determined as outlined in the National Cholesterol Education Program (NCEP) guidelines to confirm a favorable initial and long-term response. Colesevelam should be used with caution in patients with gastrointestinal disorders (e.g., dysphagia, swallowing disorders, severe gastrointestinal motility disorders, or major gastrointestinal tract surgery) since the safety and efficacy of this drug has not been established in such patients.

What does the pharmacist need to know to counsel patients about colesevelam?

Development

Epidemiological studies have established that elevated levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipo-protein B (Apo B), as well as decreased levels of HDL-cholesterol (HDL-C), are associated with an increased risk of atherosclerosis and cardiovascular-related mortality. Furthermore, it has been documented through numerous trials that aggressive reduction of lipid levels can significantly reduce the risk of cardiovascular disease. It is estimated that more than 50 million Americans currently have at least mild elevations of cholesterol (hyper-cholesterolemia or Fredrickson Type IIa hyperlipidemia) and would benefit from some form of lipid-lowering therapy. Diet and lifestyle changes generally represent the initial approach toward lipid reduction, but these often produce small and inconsistent results. For patients who continue to have elevated cholesterol levels following diet and lifestyle modifications, drug therapy is recommended. Currently available lipid-lowering drugs include the “statin” hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (HMG-CoARIs), the bile acid sequestrants, nicotinic acid, the fibric acids (gemfibrozil, clofibrate) and probucol. The lipid-lowering market is one of the fastest growing in the nation, generating over $6 billion in sales and nearly 95 million prescriptions over the past year.

For initial cholesterol-lowering therapy, the National Cholesterol Education Program (NCEP) recommends bile acid sequestrant drugs used alone or in combination with other drugs, such as the statin HMG-CoARIs. The safety and efficacy of cholestyramine resin and colestipol hydrochloride, the most commonly prescribed bile acid sequestrants, have been demonstrated repeatedly. These bile acid sequestrants alone reduce LDL-C concentrations by 10% to 30%. Combination therapy of bile acid sequestrants with niacin or an HMG-CoARI produces even larger LDL-C reductions of up to 60%. Despite their proven efficacy and the lack of systemic effects resulting from nonabsorption from the gastrointestinal tract, the bile acid sequestrants currently available have a high drug discontinuation rate due, in large measure, to intolerable GI side effects. Constipation occurs in up to 39% of patients taking currently available bile acid sequestrants and in severe cases, this may result in fecal impaction. Other gastrointestinal side effects, such as bloating, flatulence, and cramping, also occur in a large percentage of patients who are treated with currently available bile acid sequestrants. Therefore, the development of effective cholesterol-lowering agents with greater tolerability than currently available bile acid sequestrants has been a priority of hypercholesterolemic drug research.

Colesevelam (WelChol/Sankyo) is a new, nonabsorbed polymer (water-absorbing hydrogel) that has been specifically designed to bind to bile acids in the GI tract. It is a poly-allylamine cross-linked with epichlorohydrin and alkylated with 1-bromodecane and brom hexyltrimethylammonium bromide. Colesevelam has a high affinity for both trihydroxy and dihydroxy bile acids in the intestine, leading to increased fecal bile acid excretion. Preliminary in vivo and in vitro studies suggest that colesevelam has superior bile acid binding efficacy compared to cholestyramine. Furthermore, its water-retaining characteristic creates a soft, gelatinous-like material that minimizes the potential for gastrointestinal irritation relative to other bile acid sequestrants.

By lowering cholesterol, drug reduces stroke events.

By analyzing 28 studies involving use of HMGcoA reductase inhibitors or other anti-lipidemic agents in more than 100,000 patients, researchers have concluded that those patients given the HMGcoA inhibitors were 0.76 times as likely to develop strokes as those in the control groups. The stroke rate in patients given fibrates, resins or dietary intervention did not significantly differ from the control groups. Patients given the reductase inhibitors were also less likely to die of coronary heart disease or from other causes. Their analysis of these studies, said the authors, indicates that elevated cholesterol levels are a risk factor for stroke and may have a causal role in stroke formation.

Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) have traditionally been used to decrease serum cholesterol levels and to reduce morbidity and mortality associated with cardiovascular disease in patients with hyperlipidemia. Animal and human studies also suggest that HMG-coenzyme A reductase inhibitors may increase bone formation and bone mineral density. In humans, an increase in bone mineral density can decrease the risk of fractures, especially in patients with osteoporosis. Fracture risk is increased 1.5-2.5 times for every standard deviation below average peak bone mass.

Osteoporotic fractures are recognized as a common and important cause of disability and death; 1.5 million fractures are attributed to osteoporosis annually. Although several recently approved medications effectively prevent and treat osteoporosis, no currently approved drug stimulates bone formation by acting upon the bone-forming cells, known as osteoblasts. Recent animal studies suggested statins may have the potential to enhance osteoblastic activity, which allows for an increase in bone formation and bone mineral density.

Statins may affect bone formation by increasing the expression of protein 2, a protein in the bone that stimulates osteoblastic differentiation. The inhibitory effect of statins on mevalonate synthesis, a mechanism seen with many bisphosphonates, may also explain their positive effects on bone. Mevalonate, needed in the synthesis of cholesterol, is also a precursor to proteins involved in regulating osteoclast activity. Since statins inhibit mevalonate synthesis, osteoclast action is suppressed, resulting in decreased bone removal.

It is unknown whether the effect of statins on osteoblasts and osteoclasts is related to decreased fracture risk in humans. The following retrospective studies describe the association between statins and fracture risk in humans.

Clinical Trials

The largest trial to date was conducted by van Staa et al. to evaluate the risk of fracture in patients using statin drugs.81,880 patients aged 50 years and older with documented fracture of the vertebrae, clavicle, humerus, radius/ulna, carpus, hip, ankle or foot from patient enrollment through July 1999 were compared with an age-, sex- and practice- matched control group of the same number of patients in the database who did not have a fracture. Information was extracted from the United Kingdom’s General Practice Research Database, a computerized medical record system that contains data from 683 general practices and encompasses 6.5% of the population of England and Wales. Prescription data were accessed to determine whether patients received any statin prescription. Current use was defined as a statin prescribed within 6 months of the fracture date; past users were defined as patients receiving one or more statin prescriptions previously but who had stopped more than 6 months from the index date. Non-statin lipid-lowering prescriptions were also evaluated.

Results were reported as odds ratios (OR), which in this case is the odds of having a fracture while on a statin versus the odds of fracture if the patient was not on a statin. If the odds ratio is less than one, there is a decreased risk of fracture associated with statin use. If the odds ratio is greater than one, the risk of fracture is higher with statin use. In current statin users, the trial showed an odds ratio of 1.01, with a possible range of 0.88-1.16. In the simplest terms, this suggests that the risk of having a fracture in a current statin user was 1.01 times that of a nonuser. This finding suggests that current statin use did not influence the risk of fracture. However, when the location of the fracture is considered, statin use decreased, increased, or had no effect when compared to patients who did not use statin drugs. For example, patients on statins had decreased risk of hip fracture (OR = 0.59) when compared with patients not on statins. Patients who developed forearm and vertebral fractures were at no additional or slightly higher risk of fracture in the current statin user group (OR = 1.01 and 1.15, respectively).

Statin dose and duration may also influence outcomes. Higher statin doses defined as 40 mg daily or more (standardized to simvastatin) were associated with a lower risk of fracture (OR = 0.85) compared to lower doses of 20-39.9 mg (OR = 1.07) and less than 20 mg daily (OR = 1.13). Interestingly, shorter duration of statin use appeared to be associated with odds ratios closer to one, compared to longer durations, which were greater than one. For example, statin use for 0-3 months had an OR of 0.71, compared to statin use for durations of 6-12 months (OR = 1.14) and more than 12 months (OR = 1.17). Fracture risk in patients receiving non-statin lipid-lowering agents was similar to statin users (OR = 1.02).

Overall, it appears from this study that statin use does not have a positive association in reducing fracture risk, with the possible exception of hip fractures. However, it is important to identify a few biases in the trial, summarized concisely in an editorial following its publication. The trial did not control for differences in body mass indexes between groups; increased BMI may decrease the risk of osteoporotic fractures. Differences in the amount of physical activity and calcium intake between groups may also influence the interpretation of the author’s findings.

In contrast to this trial, Meier et al. found that current statin users had almost half the risk of developing fracture when compared to non-statin users (OR = 0.55). Interestingly, despite the conflicting results, investigators also used the United Kingdom-based General Practice Research Database (but limited data extraction to 300 practices) over a period from the late 1980s to September 1998. They used a case-control study design to determine whether use of statins, fibrates, or other lipid-lowering drugs is associated with a decrease in bone fracture risk. Patients were excluded from the study only if they had osteoporosis, osteomalacia, cancer (other than non-melanoma skin cancer), alcoholism, or used bisphosphonates. A base population of 91,611 individuals was identified and separated into the following three groups: 1) patients, ages 50-89, who received at least one prescription for a statin, fibrate, or other lipid-lowering drug (n = 28,349); 2) patients with a diagnosis of hyperlipidemia without the use of lipid-lowering drugs (n = 13,271); and 3) a random sample of patients without hyper-lipidemia or use of any lipid-lowering agents (n = 50,000). Patients were followed until they developed a fracture, left the practice, or died. Fractures were identified using ICD-8 codes.

During follow-up, 3,940 patients experienced a bone fracture (group 1: n = 705; group 2: n = 681; group 3: n = 2,554). Patients currently using statin drugs had a lower adjusted odds ratio (OR), adjusted for smoking, number of general practice visits, body mass index, and steroid or estrogen use (OR = 0.55), compared to patients currently using fibrate drugs (OR = 0.87), and patients using other lipid-lowering drugs (OR = 0.76). Statins decreased the risk of fracture to the femur (OR = 0.2), hand, wrist, or arm (OR = 0.58), vertebrae (OR = 0.14), and foot (OR = 0.58). Similar to the van Staa trial, the odds of developing a hip fracture on a statin were lower compared to patients not on a statin (OR = 0.12).

Exposures were further stratified into number of prescriptions obtained, and past versus current use. Fibrates were associated only with significantly decreased vertebrae fractures (OR = 0.21) and fractures in men (OR = 0.05). The findings suggest that statins decrease fracture risk even with short exposure (1-4 prescriptions of statin medication). The reduced fracture risk was observed at various skeletal sites. There was little evidence of a decrease in fracture risk for fibrates and other lipid-lowering agents.

The main source of potential bias in this study is associated with the use of estrogens and corticosteroids. It appears there was a greater number of case patients taking chronic corticosteroids (n = 36 or 0.9%) and a greater number of control patients taking estrogens (n = 111 or 0.5%) with an OR of 2.03 (CI 1.39-2.96; p < 0.001). Estrogens increase bone mineral density and decrease fracture risk compared to corticosteroids, which cause osteoporosis if used long-term. Furthermore, the inclusion/exclusion criteria of this study were loosely regimented. Many disease states and medications (e.g., osteopenia, Rickett’s, bisphosphonate use, calcium use) may change bone mineral density and integrity. Psychotropic/CNS medications that alter the CNS and may have predisposed patients to falls were not evaluated prior to study inclusion. A person’s lifestyle can also affect the results: patients leading a sedentary lifestyle may be at a greater risk of fracture compared to those who exercise frequently. It is also unknown how often the information in the GPRD is updated. If information is not updated on a prompt basis, data pertinent to the study may be omitted.

Wang et al. conducted a case-control analysis to determine whether the use of statin drugs is associated with a reduced hip fracture risk. Subjects were accessed using data extracted from New Jersey Pharmacy Assistance for the Aged and Disabled (PAAD), and New Jersey Medicaid from 1/1/93 to 6/30/95. Patients were included in the study if they were at least 65 years old, had at least one medical service during 1994, and filled at least one prescription for any medication through Medicaid or PAAD programs in each of four consecutive six-month periods beginning 1/1/93. Patients were excluded if they had a diagnosed hip fracture, evidence of hip fracture surgery prior to the index date, or were hospitalized in the month prior to the index date. A base population of 6,110 patients was identified and separated into the following four equal groups: 1) patients who used statin drugs 180 days prior to the index date (date of hip surgery due to a fracture); 2) patients who used statin drugs three years prior to the index date; 3) patients who used non-statin lipid-lowering agents 180 days prior to the index date; and 4) patients who used non-statin lipid-lowering agents three years prior to index date.

During follow-up, 1,222 patients underwent hip surgery to repair a fracture (4,888 were control patients). The results indicate that statin use within 180 days and three years prior to the index date are associated with an approximate 50% reduction in hip fracture risk (OR = 0.5 and OR = 0.57, respectively). Non-statin lipid-lowering agents used 180 days and three years prior to index date were associated with reductions in fracture risk (OR = 0.8 and OR = 0.87, respectively). Similar to previous studies discussed, it was calculated that recent statin use had a stronger association with reduced hip fractures compared to past statin use (OR = 0.2 vs. OR = 0.60). The study suggests that the use of statin drugs is associated with a 50% decrease in the risk of hip fractures after controlling for confounding variables, compared to the use of non-statin lipid-lowering agents.

There are a few areas where bias could have been introduced into this study. The study only evaluated fractures of the hip in elderly patients. Most of the patients in this study were at least 75 years old. This may skew the results because these patients may have increased fracture risk due to their age. The use of corticosteroids could have also affected the results. Among the case patients, 4.5% (n = 55) used corticosteroids compared to 3.9% (n = 192) in the control group. Statistics, such as a modified Charlson Comorbidity Index Score, were used to adjust for estrogen, oral corticosteroid, thiazides, and psychoactive drug use, as well as congestive heart failure, ischemic heart disease, diabetes and cancer. Although the statistical adjustments can help eliminate confounding variables, each of these characteristics may still clinically influence study findings. Results did not indicate whether statistical significance was achieved between group comparisons.

Chan et al. evaluated the effects of statins on decreasing fracture risk in women 65 years and older. There were 3,675 women enrolled in the case-controlled analysis (n = 928 cases; 2,747 controls). Subjects were accessed using data derived from six health maintenance organizations from 10/94 to 9/97.

The base population was divided into two groups: those who used statins two years before the fracture date, and those who used other non-statin lipid-lowering drugs two years before the fracture date. The fracture date was the date of the first fracture code after 10/96. Women were excluded if they had a diagnostic code for major trauma, cancer of the breast, bone, colon or lung, multiple myeloma, metastatic cancer, pathological fractures between 10/94 and 9/97, or if they were taking hormone replacement therapy, bisphosphonates, calcitonin, anticonvulsants, or thyroid hormone.

During follow-up, 928 cases of fracture were reported. Of the cases, 262 had hip fracture, 196 had humerus fracture, 152 had fractures of the distal tibia, and 253 had wrist fractures. It is unknown whether any patients had more than one fracture. The general health status of the cases was generally poorer than the controls (the reason for this is unknown). The patients in the statin and non-statin groups were evaluated based on the number of prescriptions dispensed. Unlike previous trials, there appeared to be a positive correlation between the length of statin therapy and the reduction in fracture risk. In the statin group, patients receiving more than 13 prescriptions had the strongest association for decreasing fracture risk (OR = 0.5). Patients receiving 1-6 and 7-12 statin prescriptions also had an associated reduction in fractures (OR = 0.62 and OR = 0.81, respectively). In the non-statin group, no definitive associations can be determined due to wide confidence intervals noted with the data. The study suggests statins are protective against nonpathological fractures among older women. Similar to the previous trial, regular statin use was associated with a 50% decrease in fracture risk.

There are areas of bias in this study that could potentially affect the results. The study did not assess the differences in body weight index, lifestyle (e.g., smoking, exercise, diet), or corticosteroid use. These factors can affect the incidence of fractures among older women. Although the Mann Whitney U test was used to attempt to control confounding variables by comparing the chronic disease scores of cases and controls, many confounding variables were not accounted for. It is unknown how many case versus control patients were taking corticosteroids or other medications that may influence bone metabolism. It was stated that the general health of the case patients was poorer than that of the control patients (for unknown reasons). This suggests the case patients may have been at a greater risk of fracture due to their health status.

A recent abstract by Bauer et al. evaluated the effect of statin use on bone mineral density and the relative risk of hip fracture in a combined analysis of two large prospectively designed trials. The first trial, also known as the “Study of Osteoporotic Fractures” (SOF), enrolled 8,412 women ages 65 and older and followed them for a mean of 4.2 years. The second trial, also known as the “Fracture Intervention Trial” (FIT), enrolled 6,459 women aged 55-80 years old. Of these women, 314 and 284 women were statin users in the SOF and FIT trial respectively. A combined relative risk of hip fractures and non-spine fractures was reduced in the statin treated patients [RR = 0.3 (0.08-1.18) and 0.83 (0.61-1.15) respectively]. Similar to previous study results, no definitive associations were noted for patients receiving non-statin lipid-lowering agents. Because this trial is not yet published, additional details need to be determined before the results can be appropriately interpreted.

Conclusion

Each of the studies was similar with respect to study design, objectives and results. All limited in interpretation due to the retrospective study design and the potential for confounding variables. Some potential flaws include lack of compliance assessments; misdiagnosed injuries; severity of injuries; lifestyle of patients; baseline health of subjects; dosages of statin medications; severity of hyperlipidemia; risk factors for osteoporosis, calcium and vitamin D intake; and the fact that concomitant medications were not screened in detail. It is also unknown how often the databases were updated, and if results were properly added to the system.

Based on the available data, there may be an association between regular use of statin drugs and a decreased bone fracture risk, particularly in the hip. However, it is still not clear what fracture locations may be most affected, if there are any dose/product/duration differences, and whether gender response plays a role in bone response to statins. Since osteoporosis in men is pathophysiologically linked to osteoblast reduction, it is speculative that men may be more responsive than women, since women have increased bone resorption after menopause. Despite the promising results revealed in these studies, prospective controlled clinical trials need to be performed to definitively correlate statin-associated reductions in fracture risk. Although statins remain a valuable tool in decreasing morbidity and mortality associated with cardiovascular disease in patients at risk, statin therapy cannot be recommended solely for the prevention of fracture risk at this time.

Atorvastatin (Lipitor) is a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor or “statin.” HMG-CoA reductase is the enzyme responsible for converting HMG-CoA to mevalonate; this occurs at an early and rate-limiting step in the biosynthesis of cholesterol (see figure).

Mechanism of action of Lipitor (atorvastatin)

Although a number of “statins” are now available, atorvastatin is the only drug in this class indicated as an adjunct to diet in the reduction of elevated total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo-B), and triglyceride (TG) levels in patients with primary hypercholesterolemia and mixed dyslipidemia. It is the first drug of its class specifically indicated for lowering both low-density lipoprotein cholesterol and triglyceride levels. It is also the only statin indicated for the reduction of total cholesterol and low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia, a rare, serious, life-threatening, autosomal dominant, inherited disorder of lipid metabolism.

Clinical Tips

In head-to-head clinical trials when starting doses were compared, atorvastatin was superior to lovastatin, pravastatin, and simvastatin in reducing elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides. In two placebo-controlled, dose-response studies in hypercholesterolemic patients, once-daily administration of atorvastatin significantly reduced low-density lipoprotein cholesterol by 39% to 60% across the dose range of 10 mg to 80 mg. In addition, atorvastatin reduced triglyceride levels by 19% to 37% across the dose range. In a large clinical study, the number of patients meeting the National Cholesterol Education Program – Adult Treatment Panel II target levels, while taking daily 10-mg doses of Lipitor, was assessed. After 16 weeks, 93% of patients with fewer than two risk factors for coronary heart disease and a baseline low-density lipoprotein cholesterol of 190 mg/dL or lower reached a target of 160 mg/dL or lower, and 19% of those with coronary heart disease and an low-density lipoprotein cholesterol of 130 mg/dL or more reached a target of 100 mg/dL low-density lipoprotein cholesterol or lower.

The most frequent treatment-related adverse events are constipation, flatulence, dyspepsia, and abdominal pain. Fewer than 2% of patients treated with Lipitor in controlled studies discontinued treatment because of drug-related adverse events. Elevations of serum transaminases occurred in fewer than 1% of patients, but it is recommended that liver function tests be performed before the start of treatment, after 6 and 12 weeks, and periodically thereafter. As with other statins, the risk of myopathy is increased when the drug is taken with cyclosporine, fibric acid derivatives, niacin, erythromycin, or azole antifungals. Patients should be advised to report unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever.