Effects of the Sodium-Glucose Cotransporter Inhibitors on Cardiovascular Death and All-Cause Mortality: A Systematic Review and Meta-analysis of Randomized Placebo-Controlled Clinical Trials.

BACKGROUND: Patients with diabetes mellitus are at an increased risk of cardiovascular morbidity and all-cause mortality. Heart failure and type 2 diabetes often occur concomitantly, and each disease independently increases the risk for the other. OBJECTIVE: Emerging data have revealed that some sodium-glucose cotransporter inhibitors (SGLTi) improve cardiovascular and renal outcomes, particularly in patients with type 2 diabetes. The magnitude of this effect in patients without any underlying condition remains unclear. As a result, we conducted a meta-analysis of the mortality outcomes of available SGLTi in patients with or without cardiovascular diseases, type 2 diabetes, cardiovascular risk factors, and heart failure. METHODS: We performed a systematic review and meta-analysis of randomized, placebo-controlled major cardiovascular outcome trials of SGLTi in patients regardless of their cardiovascular disease or risk status. PubMed, Cochrane, Google Scholar, MEDLINE, and EMBASE were searched for the relevant studies. Three reviewers extracted study data and three reviewers summarized the strength of the evidence. Efficacy outcomes included all-cause mortality, major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of all-cause mortality, cardiovascular death, or hospitalization for heart failure. Odds ratios with 95% confidence intervals were pooled across trials to calculate the overall effect size. RESULTS: A total of 5043 all-cause mortality events were observed in the study groups. In 42,050 patients who received SGLTi, 2581 events were reported, and 2462 events were reported in 35,491 patients who received placebo (odds ratio = 0.86, 95% confidence interval 0.80-0.93, p = 0.0003). The use of SGLTi significantly reduced cardiovascular mortality compared with control across the patients' population (odds ratio = 0.86, 95% confidence interval 0.79-0.93, p = 0.0001). There was a consistent pattern of mortality beneficial estimates for all patients with different co-morbid conditions in the SGLTi-treated arm compared with the placebo-treated group. The presence or absence of significant cardiovascular disease risk factors (including a family history of premature coronary artery disease, baseline estimated glomerular filtration rate, dyslipidemia, hypertension, smoking, history of cardiovascular disease, and older age) did not affect the estimated mortality benefits. CONCLUSIONS: Sodium-glucose cotransporter inhibitors significantly reduced major adverse cardiovascular events, including hospitalization and all-cause mortality in patients with or without established atherosclerotic cardiovascular disease. We observed a beneficial trend in patients with heart failure with preserved ejection fraction, and no benefits in patients with stroke or myocardial infarction.

Patients with diabetes are at increased risk of cardiac illness and mortality. Heart failure (HF) and type II diabetes mellitus (DM II) often occur concurrently, and each disease independently increases the risk for the other. Evolving data have revealed that medications utilized for diabetes management, specifically, sodium-glucose cotransporter inhibitors (SGLTi) improve cardiac and renal health, particularly in patients with DM II. The impact of this effect in other patients remains unclear. Therefore, we conducted a comprehensive review of the mortality and other benefits of available SGLTi in patients with or without cardiac diseases, DM II, cardiac risk factors, and HF. A total of 5043 mortality events were observed in the study groups. The use of SGLTi significantly reduced cardiac death compared with placebo. There was a reduction in the number of deaths for patients with different conditions in the SGLTi treated arm compared with the placebo group. The presence or absence of cardiac disease, or risk factors did not affect mortality benefits. SGLTi significantly reduced major adverse cardiac events, including hospitalization and mortality in patients with or without cardiac disease.

The Impact of Anticoagulation on COVID-19 (SARS CoV-2) Patient Outcomes: A Systematic Review.

BACKGROUND: Emerging data suggest that coagulopathy, cytokine storm, and acute respiratory distress syndrome are associated with the 2019 coronavirus disease (COVID-19). The prevalence of hypercoagulable state in these patients is unknown, but appears to be higher compared to those with other critically ill patients. Elevated D-dimer, large blood vessels clots, deep vein thrombosis, pulmonary embolism and disseminated intravascular coagulation have been reported in patients diagnosed with COVID-19 either on admission or during hospitalization and may be predictors of poor outcomes. METHODS: We performed a comprehensive literature review using the search terms of COVID-19; severe acute respiratory syndrome coronavirus-2, coagulopathy, thrombosis and anticoagulation in PubMed, Ovid, google scholar, Medline and EMBASE databases from December 2019 to May 30, 2020. RESULTS: A total of 64 relevant studies were reviewed; of which, 4 studies met the inclusion criteria and were included for analysis. The majority of the studies were retrospective involving 525 critically ill COVID-19 patients. The most commonly studied anticoagulant administered was low molecular weight heparins. Anticoagulation dosing varied throughout the studies and may be classified as standard venous thromboembolism prophylaxis, intermediate dosing, or full dose anticoagulation. The most studied objective was improvement in coagulopathy. Significant reduction in D-dimer, improvement in coagulopathy markers such as Interlukin-6, fibrinogen degradation product level, as well as lymphocyte count were reported. CONCLUSION: Despite the limited quality of studies analyzed, prophylaxis and higher intensity dosed anticoagulation is associated with improved pulmonary oxygenation, decreased coagulopathy markers and decreased mortality in COVID-19 patients.

Treatment of Community-Acquired Pneumonia: A Focus on Lefamulin.

OBJECTIVE: The goal of this article is to review the clinical pharmacology, pharmacokinetics, efficacy, and safety of lemafulin. DATA SOURCES: We performed a systematic literature review using the search terms of lefamulin and BC-3781 in the PubMed and EMBASE databases. We also cross-referenced the pertinent articles and searched ClinicalTrials.gov to identify ongoing and nonpublished studies. STUDY SELECTION AND DATA EXTRACTION: Published data from 2005 to 2019 evaluating the clinical pharmacology, efficacy, and safety studies of lefamulin were analyzed. DATA SYNTHESIS: In phase 3 clinical trials, two multicenter, randomized double-blinded studies-Lefamulin Evaluation Against Pneumonia 1 and 2 (LEAP 1 and 2)-compared the efficacy and safety of lemafulin with moxifloxacin in patients diagnosed with community-acquired bacterial pneumonia (CABP). Lemafulin given in doses of 600 mg orally or 150 mg intravenously were reported to have comparable efficacy to those of moxifloxacin with or without linezolid in patients with CABP. After the trial, the lefamulin group had an early clinical response (ECR) of 87.3% and the moxifloxacin group had an ECR of 90.2%. The difference of - 2.9% in the ECR was non-significant (CI - 8.5, 2.8). RELEVANCE TO PATIENTS AND CLINICAL PRACTICE: Lemafulin exhibits a unique binding property; therefore, it possess a potentially lower predisposition for the development of bacterial resistance and cross-resistance to other antimicrobial classes. Lefamulin is active against gram-positive including methicillin-resistant strains and atypical organisms which are often implicated in CABP. Lefamulin may be a safe alternative for adult patients with CABP who may not be candidates for respiratory fluoroquinolones. Lefamulin demonstrates both bactericidal and bacteriostatic activity against gram-positive, fastidious gram-negatives, atypical pathogens, and some gram-negative anaerobes. It is bactericidal in vitro against Streptococcus pneumoniae, Haemophilus influenzae, and Mycoplasma pneumoniae (including macrolide-resistant strains) at concentrations of 0.06, 0.5, and 0.008 µg/ml respectively, and bacteriostatic against Staphylococcus aureus and Streptococcus pyogenes. The agent also demonstrates both time- and concentration-dependent killing against the pathogens S. pneumoniae and S. aureus. In vitro susceptibility testing demonstrated an MIC50/90 of 0.06/0.12 µg/ml against S. pneumoniae and S. aureus. The SENTRY Antimicrobial Surveillance Program found that at a concentration ≤ 1 µg/ml, lefamulin inhibited 100% S. pneumoniae isolates, 99.8% of S. aureus isolates, and 99.6% of methicillin-resistant S. aureus isolates. It was not affected by resistance to various antibiotic classes such as beta-lactams, fluoroquinolones, or macrolides.

Lefamulin is the first pleuromutilin antibiotic approved for the treatment of bacterial infections in humans. Pleuromutilin antibiotics exert their unique mechanism of action which makes them less susceptible to the development of bacterial resistance and low probability of cross-resistance to the other antimicrobial classes.The authors present a critical review of the pharmacology, pharmacokinetics (PK), pharmacodynamics (PD), and data from two pivotal clinical trials of lefamulin in patients with community-acquired bacterial pneumonia (CABP).Lefamulin exhibits both bactericidal and bacteriostatic activity against gram-positive, fastidious gram-negatives, atypical pathogens, and some gram-negative anaerobes. It has shown activity against organisms known to cause sexually transmitted infections, including Mycoplasma genitalium and drug-resistant Neisseria gonorrhoeae. Lefamulin demonstrated no activity against Enterobacteriaceae or Pseudomonas aeruginosa.Pharmacokinetic studies involving lefamulin in acutely ill patients at least 18 years of age with three or more CABP symptoms failed to reveal any clinically significant differences in the PK parameters on the basis of age, sex, race, weight, or renal impairment. Lefamulin 600 mg tablets had a mean oral bioavailability of 25%. Consumption of high-fat meals may slightly reduce the blood level of the drug.In two phase 3 clinical trials, The Lefamulin Evaluation Against Pneumonia 1 and 2 (LEAP 1 and 2) compared the efficacy and safety of lemafulin with moxifloxacin in patients diagnosed with CABP. Lemafulin administered in doses of 600 mg orally or 150 mg intravenously were reported to have comparable efficacy to those of moxifloxacin with or without linezolid in patients with CABP.

Emerging Pharmacotherapy to Reduce Elevated Lipoprotein(a) Plasma Levels.

Lipoprotein(a) is a unique form of low-density lipoprotein. It is associated with a high incidence of premature atherosclerotic disease such as coronary artery disease, myocardial infarction, and stroke. Plasma levels of this lipoprotein and its activities are highly variable. This is because of a wide variability in the size of the apolipoprotein A moiety, which is determined by the number of repeats of cysteine-rich domains known as "kringles." Although the exact mechanism of lipoprotein(a)-induced atherogenicity is unknown, the lipoprotein has been found in the arterial walls of atherosclerotic plaques. It has been implicated in the formation of foam cells and lipid deposition in these plaques. Pharmacologic management of elevated levels of lipoprotein(a) with statins, fibrates, or bile acid sequestrants is ineffective. The newer and emerging lipid-lowering agents, such as the second-generation antisense oligonucleotides, cholesteryl ester transfer protein inhibitors, and proprotein convertase subtilisin/kexin type 9 inhibitors offer the most effective pharmacologic therapy.

Treatment of Seizures Associated with Lennox-Gastaut and Dravet Syndromes: A Focus on Cannabidiol Oral Solution.

Cannabidiol oral solution for seizures associated with Lennox-Gastaut and Dravet syndromes.

Detoxification from high-dose zolpidem using diazepam.

OBJECTIVE: To report a rare case of physical and psychological addiction to an excessive dose of zolpidem and subsequent completed detoxification using diazepam. CASE SUMMARY: A 46-year-old white man with a history of polysubstance abuse received a prescription for zolpidem 2 years prior to his hospital detoxification. During that time, he gradually escalated the total dosage to an amount of 400 mg/day in divided doses. Upon hospitalization, he was detoxified using a standard benzodiazepine 7-day diazepam tapering regimen. DISCUSSION: Zolpidem is a nonbenzodiazepine medication approved for the short-term treatment of insomnia. Its mechanism is a selective benzodiazepine type 1 receptor agonist. The selectivity of the drug for the type 1 receptor may not be absolute and is inversely dose dependent. Compared with the benzodiazepines, zolpidem addiction is rare. However, at higher than recommended doses for extended periods of time, its addictive potential may be similar to that of the benzodiazepines. CONCLUSIONS: Given the similarities in receptor binding and pharmacologic activities of zolpidem and the benzodiazepines, we chose to use a standard benzodiazepine detoxification protocol to treat zolpidem withdrawal. Confirmation of this has been evidenced by successful zolpidem detoxification using a standard 7-day benzodiazepine/diazepam taper regimen.