Tag: statins

Categories : Cardiovascular Disease COVIDTags :

Paxlovid may Interact with Common Heart Drugs

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Nirmatrelvir-ritonavir (Paxlovid) is often given to heart disease patients with symptomatic COVID to prevent progression to severe disease – but it can interact with some previously prescribed medications. A review paper published in the Journal of the American College of Cardiology examines the potential drug-drug interactions (DDIs) between Paxlovid and commonly used cardiovascular medications, as well as potential options to mitigate severe adverse effects.

“Awareness of the presence of drug-drug interactions of Paxlovid with common cardiovascular drugs is key. System-level interventions by integrating drug-drug interactions into electronic medical records could help avoid related adverse events,” said Sarju Ganatra, MD, senior author of the review.

He continued: “The prescription of Paxlovid could be incorporated into an order set, which allows physicians, whether it be primary care physicians or cardiology providers, to consciously rule out any contraindications to the co-administration of Paxlovid. Consultation with other members of the health care team, particularly pharmacists, can prove to be extremely valuable. However, a health care provider’s fundamental understanding of the drug-drug interactions with cardiovascular medications is key.”

In December 2021, Paxlovid received emergency use authorisation from the US Food and Drug Administration as an oral antiviral agent for the treatment of symptomatic, non-hospitalised adults with mild to moderate COVID infection who are at high risk for progression to severe disease. Patients with heart disease and other risk factors, including diabetes, high blood pressure, chronic kidney disease and smoking make up a large portion of the high-risk population for whom Paxlovid is beneficial.

According to the authors, Paxlovid has been shown to be very effective in patients with existing heart disease, but it has significant DDIs with commonly used cardiovascular medications, highlighting the importance for all clinicians to be familiar with these DDIs. As there is limited clinical information regarding DDI-related adverse events, the authors used existing knowledge and data regarding how therapies like Paxlovid typically react with other medications to provide guidance regarding potential interactions and the associated likely consequences based on the degree of interaction.

The review provides an in-depth overview of a variety of cardiovascular medications used to treat many forms of heart disease. Five of the most important cardiovascular drug interactions with Paxlovid to be aware of include:

  • Anti-arrhythmic agents
    • Many anti-arrhythmic agents are metabolised in a way that increases plasma levels when co-administered with Paxlovid. While it may be possible to start Paxlovid after 2–2.5-day temporary discontinuation of the anti-arrhythmic agents, this may not be feasible from a practical standpoint. Clinicians are advised to consider alternative COVID therapies and avoid co-administration of these agents with Paxlovid. Sotalol, another anti-arrhythmic agent, is renally cleared and does not interact with Paxlovid.
  • Antiplatelet agents and anticoagulants
    • Antiplatelet agents are used for the treatment of coronary artery disease, particularly if a patient has received a stent. Aspirin and prasugrel are safe to co-administer with Paxlovid. There is an increased risk of blood clots when Paxlovid is given alongside clopidogrel and an increased risk of bleeding when given with ticagrelor. When possible, these agents should be switched to prasugrel. If patients have contraindication to taking prasugrel, then co-administration of Paxlovid should be avoided and alternative COVID therapies should be considered.
    • Anticoagulants such as warfarin may be co-administered with Paxlovid but require close monitoring of clotting factors in bloodwork. The plasma levels of all direct oral anticoagulants increase when co-administered with Paxlovid, therefore dose adjustment or temporary discontinuation and use of alternative anticoagulants may be required.
  • Certain statins
    • Co-administration of simvastatin or lovastatin with Paxlovid can lead to increased plasma levels and subsequent myopathy and rhabdomyolysis, a condition in which the breakdown of muscle tissue releases a damaging protein into the bloodstream. These agents should be stopped prior to initiation of Paxlovid. A dose reduction of atorvastatin and rosuvastatin is reasonable when co-administered with Paxlovid. The other statins are considered safe when given along with Paxlovid.
  • Ranolazine
    • Plasma concentration of ranolazine, used to treat angina and other heart-related chest pain, is exponentially increased in the presence of CPY450 inhibitors like Paxlovid, thereby increasing the risk of clinically significant QT prolongation and torsade de pointes (a type of arrhythmia). Co-administration of Paxlovid is therefore contraindicated. Temporary discontinuation of ranolazine is advised if prescribing Paxlovid.
  • Immunosuppressive agents
    • The plasma levels of immunosuppressive agents prescribed for patients who have undergone heart transplantation exponentially rise to toxic levels when co-administered with Paxlovid. Temporary reduction of dosing of immunosuppressive agents would require frequent monitoring and be logistically difficult. Therefore, alternative COVID therapies should be considered in these patients.

The authors conclude awareness and availability of other COVID therapies enable clinicians to offer alternative treatment options to patients who are unable to take Paxlovid due to DDIs.

Categories : Cardiovascular DiseaseTags :

Link Between LDL-C and CVD not as Strong as Thought

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Source: Wikimedia CC0

New research has shown that the link between low density lipoprotein cholesterol (LDL-C) and cardiovascular disease may not be as strong as previously thought.

The study, published in JAMA Internal Medicine, provides evidence that calls into question the efficacy of statins when prescribed with the goal of lowering LDL-C and consequently cardiovascular disease (CVD) risk.

Numerous prior studies have suggested that using statins to lower LDL-C positively affects cardiovascular health outcomes, findings which are reflected in the various iterations of expert guidelines for the prevention of CVD. Several large clinical trials have indicated that for every 1-mmol/l reduction in LDL-C levels there is a 23% reduction in CVD risk.

The new findings contradict this theory, finding that this relationship was weaker than previously thought. Lowering LDL-C with statins in fact was found to have an inconsistent and inconclusive impact on CVD outcomes such as myocardial infarction (MI), stoke, and all-cause mortality.

Additionally, it indicates that the overall benefit of taking statins may be small and will vary depending on an individual’s personal risk factors.

Commenting on the findings, the paper’s lead author Dr Paula Byrne said: “The message has long been that lowering your cholesterol will reduce your risk of heart disease, and that statins help to achieve this. However, our research indicates that, in reality, the benefits of taking statins are varied and can be quite modest.”

The researchers go on to suggest that this updated information should be communicated to patients through informed clinical decision-making and updated clinical guidelines and policy.

Source: RCSI University

Categories : CancerTags :

Statins Could Slow Metastases, Study Finds

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Melanoma cells. Source: National Cancer Institute.

By screening various drugs to inhibit a cancer-driving gene, researchers have hit upon a familiar drug – statins.

Cancer patients rarely die from the primary tumour, but rather from the metastases – even after successful tumour surgery. This is because cancer cells sometimes metastasise when the tumour is still very small and may not have even been discovered yet. To do this, they must break away from the extracellular matrix and migrate into neighbouring lymphatic vessels or blood vessels that transport them to new tissue, where they settle and proliferate.

Understanding the molecular mechanisms of metastasis is therefore a key piece of the puzzle in the fight against cancer. More than a decade ago, Professor Ulrike Stein and her lab discovered an important driver of this process in human colorectal cancer: the metastasis-associated in colon cancer 1 (MACC1) gene.

When cancer cells express MACC1, their ability to proliferate, move around the body, and invade other tissues is enhanced. “Many types of cancers spread only in patients with high MACC1 expression,” Prof Stein explained. MACC1’s role as a key factor and biomarker of tumour growth and metastasis – in many solid tumours beside colorectal cancer – has since been studied by many other researchers worldwide and confirmed in more than 300 publications. Now together with Dr Robert Preißner of Charité, Stein has discovered what could disrupt metastatic progression in such cases: statins, normally prescribed for lowering cholesterol, can inhibit MACC1 expression in tumour cells. The scientists are presenting their findings in the journal Clinical and Translational Medicine.

In their search for MACC1 inhibitors, the researchers conducted high-throughput drug screening, and independently arrived at statins. Tests on various tumour cell lines were favourable: All seven drugs tested reduced MACC1 expression in the cells, but to varying degrees. The scientists then administered the cholesterol inhibitors to genetically modified mice with increased MACC1 expression. This almost completely suppressed the formation of tumours and metastases in the animals. “What is particularly remarkable is that the benefits continued in the animals even after we reduced the animal dose to a human equivalent dose,” Stein said.

Dr Preißner and collaborators also examined data from a total of 300 000 patients who had been prescribed statins. This analysis found a correlation: “Patients taking statins had only half the incidence of cancer compared to the general population,” Preißner explains.

Prof Stein warned against taking statins as a preventive measure without consulting a doctor and having their lipid levels checked.

“We are still at the very beginning,” Dr Stein cautioned. “Cell lines and mice are not human beings, so we cannot directly transfer the results.” The experimental studies and retrospective data analysis will now be followed up by a clinical trial, she said. Only after that will it be possible to say with certainty whether statins actually prevent or reduce metastasis in patients with high MACC1 expression.

Source: Max Delbrück Center for Molecular Medicine

Categories : Cardiovascular Disease COVIDTags :

Large Study Finds Statins Ineffective, Possibly Worsen COVID

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Though small studies have suggested that statins, which lower low-density lipoprotein (LDL), may also reduce COVID severity or mortality, findings from a large study suggest that it has no effect and may even worsen the disease.

In the effort to fight COVID, researchers have attempted to find existing medications that might have an effect on the outcome of the disease, and statins were one readily available candidate that appeared to have some effect. However, a new study published in the journal PLOS ONE suggests they may not be suitable.

“Despite the apparent beneficial effect of statins on the outcomes of various infectious diseases, our study revealed that their specific use to treat COVID is probably not merited,” said senior study author Petros Karakousis, MD, professor of medicine at the Johns Hopkins University School of Medicine. “Compared with earlier research, we looked at a larger and more widely varied inpatient population, and had better criteria for defining disease severity, thereby enabling our results to be more relevant for predicting the impact of statins on COVID outcomes in hospitalised patients.”

In the study, researchers reviewed the records of 4447 hospitalised patients, ages 18 years or older, who had been diagnosed with SARS-CoV-2 infection between March 1 and June 30, 2020. Of these, 594 (13%) were receiving statins at admission, with most statin users being men (57%) and older (ages 52–78 compared with ages 29–62) than the non-statin users. The highest percentage of statin users were black (47%), had hypertension (74%) or diabetes (53%), and were more likely to take medications for lowering blood pressure – along with statins to reduce their LDL cholesterol.

After accounting for confounding factors, statin use was found to have no significant effect on COVID mortality. However, they did find that patients hospitalised with COVID and taking statins had an 18% increased risk for having a more severe form of the disease.

“One plausible explanation for this finding is that statins increase cellular production of angiotensin-converting enzyme 2 [ACE2], the receptor on a cell’s surface through which SARS-CoV-2 gains entry,” said Prof Karakousis. “Therefore, statins may lower a cell’s resistance to infection and in turn, increase the odds that the patient will have a more severe case of COVID.”

Prof Karakousis said future studies should attempt to better define the relationship between statin use and COVID, noting that all previous ones were retrospective and had factors that could not be eliminated, such as many statin users being overweight.

The only way to definitively determine if statins have any benefit for patients with COVID is to conduct a randomised, placebo-controlled clinical trial.

Source: Johns Hopkins Medicine

Categories : Cardiovascular Disease NeurologyTags :

Statins not Associated With Cognitive Decline

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Photo by Matteo Vistocco on Unsplash

A new study has found that statin use in adults 65 years old or older is not associated with incident dementia, mild cognitive impairment (MCI) or decline in individual cognition domains.

Major health concerns in the elderly, cognitive decline and dementia affect about 10% of people over 60 years old. Statins are used to reduce low-density lipoprotein cholesterol, and are a fundamental treatment for prevention of primary and secondary cardiovascular disease (CVD) events. 
In 2012 the Food and Drug Administration issued a warning about cases of apparent short-term cognitive impairment with statin use, while acknowledging that the cardiovascular benefits outweigh their risks. Systematic reviews have since shown insufficient evidence on the impact of statins, and research has shown mixed results, with some showing a neurocognitive benefit of statins and others reporting a null effect.

“With statins being increasingly prescribed to older adults, their potential long-term effects on cognitive decline and dementia risk have attracted growing interest,” said lead author Zhen Zhou, PhD, Menzies Institute for Medical Research at the University of Tasmania. “The present study adds to previous research by suggesting that statin use at baseline was not associated with subsequent dementia incidence and long-term cognitive decline in older adults.”

Researchers of this study analysed data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. ASPREE was a large prospective, randomized placebo-controlled trial of daily low-dose aspirin with adults 65 or older. One of the key selection criteria of ASPREE was that participants had to have a score of 78 for the Modified Mini-Mental State Examination test, a screening test for cognitive abilities, at enrollment.

The study had 18 846 participants, grouped by their baseline statin use (31.3% of participants) versus non-statin use. The study aimed to measure outcomes including incident dementia and its subclassifications (probable Alzheimer’s disease [AD], mixed presentations); MCI and its subclassifications (MCI consistent with AD, MCI-other); changes in domain-specific cognition including global cognition, memory, language and executive function, and psychomotor speed; and in the composite of these domains.

After a median of 4.7 years of follow-up, researchers found 566 incident cases of dementia (including probable AD and mixed presentations). Compared with no statin use, statin use was not associated with risk of all-cause dementia, probable AD or mixed presentations of dementia. There were 380 incident cases of MCI found (including MCI consistent with AD and MCI-other). Compared to no statin use, statin use was not associated with risk of MCI, MCI consistent with AD or other MCI. No statistically significant difference in the change of composite cognition and any individual cognitive domains between statin users versus non-statin users was seen. However, researchers did find interaction effects between baseline cognitive ability and statin therapy for all dementia outcomes.

The researchers acknowledged several limitations, including observational study bias and lack of data on the length of prior use of statins; and the dose of statins was not recorded in the ASPREE trial, so their effects could not be fully explored. Researchers conclude the study must be interpreted with caution and will require confirmation by randomized clinical trials designed to explore the neurocognitive effects of statins in older populations.

In an accompanying editorial comment, Christie M. Ballantyne, MD, professor at Baylor College of Medicine in Houston, noted study limitations that the authors address, but agreed the findings suggest statins do not contribute to cognitive decline.

“Overall, the analysis was well done, and its main strengths are a large cohort with a battery of standardised tests that allowed the investigators to track both cognition and incidence of dementia and its subtypes over time,” Ballantyne said. “Lingering questions such as the one raised by this analysis regarding potential adverse effects of statins in individuals with mildly impaired cognition can only be answered in randomised controlled trials in the appropriate age group and population and with appropriate testing and adequate follow-up. In the meantime, practising clinicians can have confidence and share with their patients that short-term lipid lowering therapy in older individuals, including with statins, is unlikely to have a major impact on cognition.”

Source: American College of Cardiology

Categories : Cancer Cardiovascular DiseaseTags :

Simvastatin Treatment Hope for Subtype of Ovarian Cancer

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Researchers have found that simvastatin has anti-proliferative potential against ovarian clear cell carcinoma, a highly lethal gynaecological cancer.

Dr Ingrid Hedenfalk from The Lund University explained: “Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) accounting for 5–10% of cases diagnosed in Europe and America, while the incidence in Asia is reported to be higher (10–20%).”

GTPases are a range of enzymes that hydrolyse guanosine triphosphate (GTP) to guanosine diphosphate (GDP). They are also involved in cells as switches and timers. Rho GTPases have been studied for their role in cancers. However, it is difficult to target Rho GTPases directly, so research has involved indirect strategies.

The researchers tested three cell lines of OCCC and one line of high-grade serous ovarian carcinoma (HGSOC) with simvastatin, which is a Rho GTPase interfering drug, and another GTPase interfering drug, CID-1067700, as a control. CID-1067700 is a pan-GTPase, which makes it useful as a comparator.

The research was motivated by a study which found deregulated expression of both Rho GTPases and cytoskeletal pathways in primary human OCCC tumours. The OCCC cell lines treated with simvastatin showed reduced c-Myc protein expression and signs of cell death, as well as curbing proliferation and migration.

Simvastatin could act through Rho GTPase interference as simvastatin affects the cytoskeletal integrity of OCCC cells at clinically relevant levels. However, the mechanism involved is different from Rho GTPase inhibition by CID-1067700.

However, caution is warranted with simvastatin as combination with chemotherapy may yield an antagonistic response. Further research is warranted to develop simvastatin as a potential drug candidate for the treatment of OCCC. 

Source: Oncotarget

Journal information: Arildsen N, Hedenfalk I. Simvastatin is a potential candidate drug in ovarian clear cell carcinomas. Oncotarget. 2020;11(40):3660-3674. doi:10.18632/oncotarget.27747