Organic Ion Transporters and Statin Drug Interactions.

PURPOSE OF REVIEW: Statin drug-drug interactions (DDIs) are both troublesome to patients as well as costly to medical resources. The ability to predict and avoid these events could lead to improved outcomes as well as patient satisfaction. This review will explore efforts to better understand and predict these interactions specifically related to one drug transport system, the organic anion-transporting polypeptides (OATPs) specifically OATP1B1 and OATP1B3. RECENT FINDINGS: Since the publication of the discovery of OATPs, there have been various pharmacokinetic models that have been proposed to explain the variation in pharmacokinetic and clinical effects related to the OATPs. The effects in transport activity appear to be partially related to the individual polymorphisms studied. Drug-drug interactions can occur when other drugs compete for the metabolic site on the OATPs. Various medications are identified as substrates and/or inhibitors of the OATPs, thereby complicating the ability to fully predict the impact on levels and effects. All of the models reviewed claim successes but show limited clinical utility. There are specific populations that have been identified, predominately various Asian descendants that require lower doses of statins to avoid adverse events. The concept of attributing these actions to the OATPs has been explored, but current models cannot accurately predict statin blood levels or elimination constants. The current research only points to the differences in the human genome and the single-nucleotide polymorphisms that exist between us. Based upon the currently available studies, there is beginning to be a glimmer in the understanding how different populations respond to statin transport and elimination. Additionally and unfortunately, there are other enzymes to be studied to better predict patient differences. Clearly, there has been much work completed, yet many more questions require answering to better understand these transport proteins.

A clinician's guide to statin drug-drug interactions.

The statins are widely used worldwide to reduce risk for cardiovascular events in both the primary and secondary prevention settings. Although generally quite safe, the statins can be associated with a variety of serious side adverse effects, including myalgia, myopathy, and changes in plasma enzymes of hepatic origin. Although rare, the most serious of these is rhabdomyolysis. Several drugs can interfere with the metabolism and disposal of the statins, thereby increasing risk for adverse events. It is important that clinicians treating patients with statins be aware of the potential for drug-drug interactions between each statin and specific other drugs and take measures to prevent them. The prediction of potential drug-drug interactions derives from basic pharmacokinetic principles. Certain drug interactions are predicted by measuring the effect of interacting drugs on blood plasma concentrations of the statin. Individual patient variations resulting in part from polymorphisms in the metabolizing enzymes confound some of these predictions. Based on these known effects, a new classification for predicting statin drug interactions is proposed. This report discusses likely prescription and nonprescription interactions as well as potential alternatives for special populations.

Low vitamin D as a risk factor for the development of myalgia in patients taking high-dose simvastatin: a retrospective review.

BACKGROUND: Statins are the treatment of choice for dyslipidemia, primarily lowering elevated LDL-C levels and reducing the occurrence of major cardiovascular events. In June 2011, the Food and Drug Administration issued a warning regarding the use of high-dose simvastatin 80 mg and its risk of myopathy. OBJECTIVE: The incidence of myalgia, myopathy, and rhabdomyolysis was analyzed in a veteran population prescribed simvastatin 80 mg. Risk factors for myalgia were examined and compared with the results of recently published studies. METHODS: This was a retrospective medical record review of 450 patients who were prescribed simvastatin 80 mg at the Veterans Affairs Western New York Healthcare System between August 1, 2006, and July 31, 2011. Records were examined for evidence of myalgia, myopathy (incipient or definite), and rhabdomyolysis. Variables that may have contributed to the development of myalgia were also collected and analyzed. RESULTS: Myalgia was reported by 50 patients (11.1%), whereas rhabdomyolysis developed in 1 patient (0.22%). No patient fit the criteria for myopathy (incipient or definite). Myalgia was statistically more likely to occur in younger patients, patients with a history of myalgia, and patients with low vitamin D levels. The mean (SD) vitamin D level in patients experiencing myalgia was 26.2 (12.9) versus 36.3 (11.8) ng/mL. The 25-hydroxyvitamin D level in those who reported myalgia was approximately 10 ng/mL lower compared with those who tolerated simvastatin 80 mg (P = 0.0003). There was no statistically significant association between length of therapy and development of myalgia. CONCLUSION: A lower incidence of adverse muscle events with high-dose simvastatin 80 mg was found in patients with higher vitamin D levels, suggesting that correction of 25-hydroxyvitamin D levels before statin therapy initiation may mitigate one risk factor in the development of statin-related myalgia. Vitamin D insufficiency appears to be a risk factor for the development of myalgia.

Effectiveness and safety of dual renin-angiotensin system blockade: a comparison between younger and older cohorts.

OBJECTIVE: The purpose of this review was to evaluate blood pressure (BP) reductions and adverse events between patients younger than 65 and older than 65 years of age receiving a combination of an angiotensin converting enzyme inhibitor (ACE-I) and an angiotensin receptor blocker (ARB). DESIGN: A retrospective cohort study comparing the effectiveness of ACE-I and ARB combination in patients < 65 (younger) and ≥ 65 years of age (elderly). SETTING: This study was conducted at the VA Western New York Healthcare System. PARTICIPANTS: A total of 176 patients: 54 patients in the younger group and 122 in the elderly cohort. INTERVENTIONS: No specific interventions were performed. MAIN OUTCOME MEASURES: The purpose was to evaluate differences in BP reductions and incidence of adverse events in younger and elderly patients receiving a combination of an ACE-I and an ARB. RESULTS: In the elderly group (mean age 76), the mean reduction in standing blood pressure (SBP) was 14.2 ± 15.6 mmHg (95% confidence interval [CI] 11.2-17.3; P < 0.0001). Similar results were obtained in the younger group (mean age 59), with a mean SBP reduction of 10 ± 14.9 (95% CI 5.6-14.5; P < 0.0001). The mean SBP reduction was not significantly different between the two age cohorts (P = 0.57). The incidence of adverse events was not different between the two age groups (cough P = 0.67, hyperkalemia P = 1.0, angioedema P = 0.31). CONCLUSION: There was no significant difference in effectiveness or safety between the elderly and younger cohorts. The pharmacist monitoring elderly patients on combination therapy should still closely follow these patients; however it is reassuring that elderly patients do not experience adverse reactions at rates higher than do younger patients.

Hypertriglyceridemia: management of atherogenic dyslipidemia.

Elevated triglycerides are now considered an independent risk factor for coronary heart disease and continue to be a major risk for acute pancreatitis, especially when levels exceed 1000 mg/dL (SOR: B). Elevated triglycerides are a component of atherogenic dyslipidemia and often signal the presence of other conditions (eg, metabolic syndrome, type 2 diabetes mellitus) associated with an increased cardiovascular risk (SOR: A). When evaluating a patient with elevated triglycerides, it is important to be cognizant of all atherogenic lipoproteins to more accurately determine the risk of coronary heart disease (SOR: C). Patients with hypertriglyceridemia should first achieve their low-density lipoprotein cholesterol goal, followed by their non-high-density lipoprotein cholesterol goal (SOR: C). Fibrates, niacin, and omega-3 acid ethyl esters are highly effective at reducing triglycerides, while statins are considered moderately efficacious (SOR: A).

Improvements in glycemic control in type 2 diabetes patients switched from sulfonylurea coadministered with metformin to glyburide-metformin tablets.

OBJECTIVE: To evaluate the change in hemoglobin A1C (A1C) in patients with type 2 diabetes switched from coadministration of a sulfonylurea (SU), glyburide or glipizide, and metformin (SU+Met) to a single glyburide-metformin tablet. METHODS: A retrospective cohort study design of patients with type 2 diabetes treated at 3 Veterans Affairs Medical Centers and 1 Department of Defense Medical Center was utilized. One hundred percent of patients receiving glyburide-metformin tablets were screened for inclusion. Patients with at least 6 months of prior SU+Met combination therapy and a baseline A1C measured within 35 days prior to or 3 days after switch to glyburide-metformin tablets were included. At least one documented follow-up A1C at >or=90 days after the switch to glyburide-metformin was required for inclusion. Glycemic control, complications, lipid parameters, concomitant medications, and weight were analyzed prior to and following the switch to glyburide-metformin. RESULTS: Seventy-two patient records were included after the disqualification criteria excluded 488 prospective patients. The mean age of the 72 patients was 62 years; average body mass index was 32.9 kg/m2, average baseline A1C was 8.3%, and the average time since diagnosis was 7.6 years. The mean reduction in A1C was 0.6% (P=0.002) at a mean follow-up of 196 days after the switch to glyburide-metformin tablets. Improvement in glycemic control was predominantly seen in patients with a baseline A1C >or=8% in whom a 1.3% mean reduction in A1C (P=0.0002) was achieved despite a lower mean final dose of glyburide. CONCLUSION: The results of this study suggest that in type 2 diabetic patients with an A1C >or=8%, switching from coadministration of a sulfonylurea plus metformin to combination glyburide-metformin tablets may provide an improvement in glycemic control in the range of a 1.2 to 1.4 absolute percentage point decrease in A1C. A randomized, prospective trial comparing these 2 methods of treatment is needed, however, to determine the precise effect provided by the unique formulation of glyburide in the glyburide-metformin tablet.