A novel direct method to determine adherence to simvastatin therapy in patients with coronary heart disease

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): National Association of Health OnBehalf NORCOR Background Poor adherence to statin therapy remains a public health concern associated with adverse clinical outcome. Reliable classification and detection of statin adherence is needed in clinical practice and for clinical studies with overall aim to improve the lipid management. Simvastatin is a frequently used statin in cardiovascular disease prevention. Purpose To develop a feasible test based on spot blood samples to monitor the adherence to simvastatin therapy in coronary heart disease (CHD) patients. Methods Eighteen CHD patients on an evening dose of simvastatin 20 mg (n = 7), 40 mg (n = 5) and 80 mg (n = 6) were studied at steady-state pharmacokinetics. Ten patients were instructed to avoid simvastatin dosing and return for blood sampling the subsequent three days. Dose-normalized plasma concentrations of simvastatin lactone, simvastatin acid and the sum of the two were evaluated as discriminators between adherent dosing and dose avoidance. Bioanalytical quantifications were performed with liquid chromatography tandem mass spectrometry. Results The dose-normalized plasma concentrations at steady-state demonstrated 23-fold and 39-fold interindividual variabilities for simvastatin lactone and simvastatin acid. A simvastatin acid cut-off at 1.0·10^-2 nmol/L/mg identified 100% of those omitting 2 doses and 60% of those omitting a single dose (Figure 1). Simvastatin acid showed superior ability to discriminate dose avoidance from adherence, and also the best agreement between samples handled at ambient and cool temperature (median deviation 3.5%, interquartile range -2.5 to 13%). A cut-off for morning dose schedule, with similar ability to discriminate, was estimated at 2.0·10^-3 nmol/L/mg. Conclusion A novel method discriminating between good and poor adherence to simvastatin therapy in CHD patients has been developed. The sample handling is feasible for routine practice, and the assessment of adherence can be performed by direct measurements in spot blood samples, according to specific cut-off values. Abstract Figure 1 Drug levels vs dose avoidance

Effect of Dyslipidemia Therapy on Creatinine Kinase Activity Level in Patients with Heart Disease

Cardiovascular disease remains a significant health problem in the Asia Pacific region. Several studies have found that dyslipidemia is a cause of morbidity and mortality and requires high medical costs. Dyslipidemia is a risk factor for atherosclerosis. The most widely used therapy for dyslipidemia is statins. Statins often cause muscle disorders such as myalgia, myopathy, and rhabdomyolysis, which can cause death. A prospective cohort study design was carried out at Airlangga University Hospital, Surabaya, from April to November 2019. A total of 26 sample pairs containing 13 samples were treated with Atorvastatin, and 13 samples were treated with Simvastatin. The subjects were examined for the creatinine kinase activity level using enzymatic methods. The mean creatinine kinase levels in the atorvastatin group before and after treatment was 105.71 IU/L and 100.03 IU/L, respectively, because the subjects were diagnosed with acute coronary syndromes and blood was collected during acute conditions. Median creatinine kinase levels in the Simvastatin group were 85.5 IU/L before therapy and 118.1 IU/L after therapy, indicating significant differences in creatinine kinase levels before and after treatment. Simvastatin is very susceptible to certain drug interactions that can increase the concentration of statins in the serum. There were differences in levels of creatinine kinase activity before and after Simvastatin therapy but not Atorvastatin.

Impact of statin intake on malignant hyperthermia: an in vitro and in vivo swine study

Background Statin intake is associated with muscular side effects, among which the unmasking of latent myopathies and of malignant hyperthermia (MH) susceptibility have been reported. These findings, together with experimental data in small animals, prompt speculation that statin therapy may compromise the performance of skeletal muscle during diagnostic in vitro contracture tests (IVCT). In addition, statins might reduce triggering thresholds in susceptible individuals (MHS), or exacerbate MH progression. We sought to obtain empirical data to address these questions. Methods We compared the responses of 3 different muscles from untreated or simvastatin treated MHS and non-susceptible (MHN) pigs. MHS animals were also invasively monitored for signs of impending MH during sevoflurane anesthesia. Results Muscles from statin treated MHS pigs responded with enhanced in vitro contractures to halothane, while responses to caffeine were unaltered by the treatment. Neither agent elicited contractures in muscles from statin treated MHN pigs. In vivo, end- tide pCO2, hemodynamic evolution, plasma pH, potassium and lactate concentrations consistently pointed to mild acceleration of MH development in statin-treated pigs, whereas masseter spasm and rigor faded compared to untreated MHS animals. Conclusions The diagnostic sensitivity and specificity of the IVCT remains unchanged by a short-term simvastatin treatment in MHS swine. Evidence of modest enhancement in cardiovascular and metabolic signs of MH, as well as masked pathognomonic muscle rigor observed under simvastatin therapy suggest a potentially misleading influence on the clinical presentation of MH. The findings deserve further study to include other statins and therapeutic regimes.

Сhanges in the functional state of the epithelium of the proximal renal tubules in patients with the initial stage of chronic heart failure during simvastatin therapy

To assess the change in the functional state of the proximal renal tubule epithelium in patients with dyslipidemia on the background of obesity, by determining the concentration in the urine of the examined level of cystatin C and the degree of activity of the renal organ-specific enzymes neutral α-glucosidase (NAG) and L-alaninaminopeptidase (laap) during simvastatin therapy at a daily dose of 20 mg for 6 months. The study involved 88 people who were divided into three groups: control, comparison and main. The control group is a group of practically healthy individuals: 30 people, average age 20.67 ± 0.18 years, body mass index (BMI) 21.36 ± 0.4 kg/m2. Comparison group (obese): 27 people, average age 22.38 ± 0.76 years, BMI 31.48 ± 0.56 kg / m2. Patients of the main group were divided into 2 subgroups. The first main subgroup of persons with chronic heart failure stage I (CHF I) without type 2 diabetes mellitus (DM 2)) - 15 observed: average age 56.8 ± 1.8 years, BMI 30.28 ± 1.11 kg / m2. The second main subgroup (CHF I with DM 2) - 16 observed: average age 48.25 ± 2.45 years, BMI 30.37 ± 1.11 kg/m2. The study found that simvastatin therapy does not affect glomerular filtration rate in patients with asymptomatic heart dysfunction. There was an increased level of cystatin C in the urine of the comparison group compared to the control group, the concentration of cystatin C in the main subgroups was statistically significantly higher than the control group. On the background of simvastatin therapy for 6 months, the level of this analyte is statistically significantly increased. The activity of LAAP and NAG during simvastatin therapy during the follow-up period in the CHF I subgroup without DM2 significantly decreased. In the subgroup of CHF I + DM2, a decrease in the concentration of LAAP and an increase in the activity of NAG was revealed, which may indicate that the brush border epithelium dystrophy occurred during simvastatin therapy. Simvastatin therapy for 6 months in patients with the initial stage of heart failure at a daily dosage of 20 mg does not impair glomerular function in the form of reduced glomerular filtration rate (GFR). Cystatin C levels are higher in obese individuals without heart failure and significantly higher in those with asymptomatic heart failure. When treating dyslipidemia with simvastatin at a dose of 20 mg / day, there is a decrease in the activity of NAG and laap in patients with CHF I without DM2. In the result of lipid-lowering therapy with simvastatin in a daily dosage of 20 mg in patients with CHF I+D2M there is increased activity of NAG while reducing the concentration of the LAAP, which may be due to degeneration of the proximal tubular epithelium, amid additional load on a partially renal route of metabolism of simvastatin.

Severe rhabdomyolysis induced by possible drug–drug interaction between Ribociclib and Simvastatin

Introduction Drug–drug interactions with cyclin-dependent kinases inhibitors 4 and 6 (CDK4/6) are known and should be taken into account. Case report A 68-year-old woman, on prior Simvastatin therapy, developed severe rhabdomyolysis after three weeks of Ribociclib initiation. She showed general weakness with mobility problems and was admitted to our hospital. Management and Outcome Ribociclib and Simvastatin were discontinued and the patient received intensive intravenous hydration. She finally recovered her mobility after two weeks. Discussion We hypothesize that Simvastatin induced rhabdomyolysis by possible interaction with Ribociclib. Ribociclib is a strong inhibitor of CYP 3A4 and a potential inhibitor of OATP1B1 membrane transporter. Simvastatin plasma concentration may reach toxic levels due to Ribociclib inhibition. To assess the relevance of our hypothesis, we used the Drug Interaction Scale. With a total score of 7, the interaction is considered as “probable.” Because of the high risk of severe rhabdomyolysis, the concomitant use of Simvastatin with Ribociclib should be avoided or otherwise careful monitoring of creatine kinase is warranted.