Effect of Various Dosing Schedules on the Pharmacokinetics of Oral Semaglutide: A Randomised Trial in Healthy Subjects.

BACKGROUND: Prescribing information instructs taking oral semaglutide (a glucagon-like peptide-1 analogue) in the fasting state, followed by a post-dose fasting period of ≥ 30 min. This trial compared the recommended dosing schedule with alternative schedules. METHODS: This was a randomised, single-centre, multiple-dose, open-label, five-armed, parallel-group trial in healthy subjects who received once-daily oral semaglutide (3 mg for 5 days followed by 7 mg for 5 days). Subjects (n = 156) were randomised to five dosing schedules: 2-, 4-, or 6-h pre-dose fast followed by a 30-min post-dose fast (treatment arms: 2 h-30 min, 4-30 min, 6 h-30 min); 2-h pre-dose fast followed by an overnight post-dose fast (treatment arm: 2 h-night); or overnight pre-dose fast followed by a 30-min post-dose fast (reference arm: night-30 min). Semaglutide plasma concentration was measured regularly until 24 h after the 10th dose. Endpoints included area under the semaglutide plasma concentration-time curve during a 24-h interval after the 10th dose (AUC0-24h) (primary endpoint) and maximum observed semaglutide plasma concentration after the 10th dose (Cmax) (secondary endpoint). RESULTS: Compared with an overnight pre-dose fast (reference arm: night-30 min), shorter pre-dose fasting times in the 2 h-night, 2 h-30 min, 4 h-30 min, and 6 h-30 min treatment arms resulted in significantly lower semaglutide AUC0-24h and Cmax after the 10th dose (estimated treatment ratio ranges: 0.12-0.43 and 0.11-0.44, respectively; p < 0.0001 for all comparisons). Semaglutide AUC0-24h and Cmax after the 10th dose were similar for the 2 h-30 min and 2 h-night treatment arms. CONCLUSION: This trial supports dosing oral semaglutide in accordance with prescribing information, which requires dosing in the fasting state. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04513704); registered August 14, 2020.

Oral semaglutide is a human glucagon-like peptide-1 analogue that has been approved for the treatment of type 2 diabetes. It has been established that taking oral semaglutide with food or large volumes of water decreases absorption of the drug in the body. Current prescribing information instructs taking oral semaglutide on an empty stomach (known as the fasting state), with 120 mL/4 oz of water, then waiting for at least 30 min before consuming any food, water, or taking other oral medications. This study investigates whether different dosing schedules for oral semaglutide could potentially offer more flexibility to patients in the timing of their oral semaglutide dosing. The trial, conducted in healthy volunteers, compares the dosing schedule described in the prescribing information with different fasting times before (pre-dose) and after (post-dose) taking oral semaglutide during the day or evening, to see if there were any effects on the concentration of drug in the body. Compared to the recommended overnight fasting period, shorter pre-dose fasting periods of 2­6 h with a 30-min post-dose fast considerably reduced semaglutide exposure in the body. Similarly, semaglutide exposure was also reduced with a 2-h pre-dose fast combined with post-dose overnight fasting. These findings further support the current prescribing information, which states that patients should take their oral semaglutide dose after an overnight fast.

Dipeptidyl Peptidase-4 Inhibitors, Glucagon-like Peptide-1 Receptor Agonists, and Sodium-Glucose Cotransporter-2 Inhibitors and COVID-19 Outcomes.

PURPOSE: It has been reported that dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have a role in modulation of inflammation associated with coronavirus disease 2019 (COVID-19). This study assessed the effect of these drug classes on COVID-19-related outcomes. METHODS: Using a COVID-19 linkable administrative database, we selected patients aged ≥40 years with at least 2 prescriptions of DPP-4i, GLP-1 RA, or SGLT-2i or any other antihyperglycemic drug and a diagnosis of COVID-19 from February 15, 2020, to March 15, 2021. Adjusted odds ratios (ORs) with 95% CIs were used to calculate the association between treatments and all-cause and in-hospital mortality and COVID-19-related hospitalization. A sensitivity analysis was performed by using inverse probability treatment weighting. FINDINGS: Overall, 32,853 subjects were included in the analysis. Multivariable models showed a reduction of the risk for COVID-19 outcomes for users of DPP-4i, GLP-1 RA, and SGLT-2i compared with nonusers, although statistical significance was reached only in DPP-4i users for total mortality (OR, 0.89; 95% CI, 0.82-0.97). The sensitivity analysis confirmed the main results reaching a significant reduction for hospital admission in GLP-1 RA users and in-hospital mortality in SGLT-2i users compared with nonusers. IMPLICATIONS: This study found a beneficial effect in the risk reduction of COVID-19 total mortality in DPP-4i users compared with nonusers. A positive trend was also observed in users of GLP-1 RA and SGLT-2i compared with nonusers. Randomized clinical trials are needed to confirm the effect of these drug classes as potential therapy for the treatment of COVID-19.

Glucometabolic Perturbations in Type 2 Diabetes Mellitus and Coronavirus Disease 2019: Causes, Consequences, and How to Counter Them Using Novel Antidiabetic Drugs - The CAPISCO International Expert Panel.

The growing amount of evidence suggests the existence of a bidirectional relation between coronavirus disease 2019 (COVID-19) and type 2 diabetes mellitus (T2DM), as these two conditions exacerbate each other, causing a significant healthcare and socioeconomic burden. The alterations in innate and adaptive cellular immunity, adipose tissue, alveolar and endothelial dysfunction, hypercoagulation, the propensity to an increased viral load, and chronic diabetic complications are all associated with glucometabolic perturbations of T2DM patients that predispose them to severe forms of COVID-19 and mortality. Severe acute respiratory syndrome coronavirus 2 infection negatively impacts glucose homeostasis due to its effects on insulin sensitivity and ß-cell function, further aggravating the preexisting glucometabolic perturbations in individuals with T2DM. Thus, the most effective ways are urgently needed for countering these glucometabolic disturbances occurring during acute COVID-19 illness in T2DM patients. The novel classes of antidiabetic medications (dipeptidyl peptidase 4 inhibitors (DPP-4is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are considered candidate drugs for this purpose. This review article summarizes current knowledge regarding glucometabolic disturbances during acute COVID-19 illness in T2DM patients and the potential ways to tackle them using novel antidiabetic medications. Recent observational data suggest that preadmission use of GLP-1 RAs and SGLT-2is are associated with decreased patient mortality, while DPP-4is is associated with increased in-hospital mortality of T2DM patients with COVID-19. Although these results provide further evidence for the widespread use of these two classes of medications in this COVID-19 era, dedicated randomized controlled trials analyzing the effects of in-hospital use of novel antidiabetic agents in T2DM patients with COVID-19 are needed.

[Benefits of telematic monitoring for weight loss in overweight and obese patients in times of confinement]. / Beneficios del seguimiento telemático en la pérdida de peso de pacientes con sobrepeso y obesidad en tiempos de confinamiento.

Introduction: Introduction: the pandemic originated by SARS-Cov-2 in 2019 led to eating habits and physical exercise changes due to home confinement measures. The follow-up of patients in treatment for weight loss through telematic consultation could be a useful tool to prevent treatment failure. Objective: to describe the evolution of anthropometric parameters of patients under follow-up for weight loss through telematic consultation. Methods: a two-stage prospective study (before and after confinement) with a telematic intervention in adult patients under regular follow-up for overweight and obesity. Demographic variables and body composition parameters were analyzed by bioimpendance. In addition, the differences in the presence of drug treatment with GLP-1 hormone (liraglutide or semaglutide) adjuvants were also analyzed. The variables were studied using Wilcoxon's test, Mann-Whitney U-test, and Spearman's correlation. Significance was considered for p ≤ 0.05. Results: a total of 97 patients were included, before confinement 42.3 % were overweight (BMI < 30 kg/m2), 36.1 % were obese grade I (BMI = 30-34.9 kg/m2), 16.4 % were obese grade II (BMI = 35-39.9 kg/m2), and 5.2 % had BMI > 40 kg/m2. In all, 30.9 % had prediabetes and 9.3 % had type-2 diabetes. Between both consultations, 81.4 % of patients lost 4.2 ± 3.4 % of their weight, with a significant mean decrease in fat mass of 3.16 ± 4.4 kg. The group on pharmacological treatment with GLP-1 hormone analogs presented a significantly higher average fat loss without significant loss of skeletal muscle mass. Conclusions: telematic monitoring seems to be a useful tool to prevent weight gain in patients with restricted mobility. A telematic intervention that contains dietary advice and exercise, as a reinforcement to hypocaloric diet, helps to achieve weight loss with a predominant fat component. The presence of drug treatment with GLP-1 hormone analogues appears to significantly help maintain skeletal muscle mass during weight loss.

Introducción: Introducción: la pandemia originada en 2019 por el SARS-CoV-2 supuso un cambio en los hábitos de alimentación y ejercicio físico por causa de las medidas de confinamiento domiciliario. El seguimiento de pacientes en tratamiento de pérdida de peso mediante una consulta telemática podría ser una herramienta útil para prevenir el fracaso terapéutico. Objetivo: describir la evolución de los parámetros antropométricos de pacientes en seguimiento para pérdida de peso mediante una consulta telemática. Métodos: estudio prospectivo en 2 tiempos (antes y después del confinamiento) de una intervención telemática sobre pacientes adultos en seguimiento habitual por sobrepeso y obesidad. Se analizaron las variables demográficas y los parámetros de composición corporal mediante bioimpendancia. Además se analizaron las diferencias en cuanto a presencia de tratamiento farmacológico adyuvante del tipo de los análogos de la hormona GLP1 (liraglutida o semaglutida). Las variables se estudiaron mediante la prueba de Wilcoxon, la U de Mann-Whitney y la correlación de Spearman. Se consideró la significación si p ≤ 0,05. Resultados: se incluyeron 97 pacientes. Antes del confinamiento, el 42,3 % presentaban sobrepeso (IMC < 30 kg/m2), el 36,1 % tenían obesidad de grado I (IMC = 30-34,9 kg/m2), el 16,4 % la tenían de grado II (IMC = 35-39,9 kg/m2) y el 5,2 % tenían un IMC > 40 kg/m2. El 30,9 % presentaban prediabetes y el 9,3 % tenían diabetes de tipo 2. Entre ambas visitas presenciales, el 81,4 % de los pacientes perdieron un 4,2 ± 3,4 % del peso, con una disminución media significativa de la masa grasa de 3,16 ± 4,4 kg. El grupo en tratamiento farmacológico con análogos de la hormona GLP-1 presentó una pérdida de masa grasa media significativamente superior sin pérdida de masa muscular esquelética significativa. Conclusiones: el seguimiento telemático parece una herramienta útil para prevenir la ganancia de peso en los pacientes con restricción de la movilidad. Una intervención telemática que contenga consejo dietético y ejercicio como refuerzo de la dieta hipocalórica ayuda a conseguir perder peso, predominando el componente graso. La presencia de un tratamiento farmacológico con análogos de la hormona GLP-1 parece ayudar significativamente al mantenimiento de la masa muscular esquelética durante la pérdida de peso.

GLP-1 Mediates Regulation of Colonic ACE2 Expression by the Bile Acid Receptor GPBAR1 in Inflammation.

BACKGROUND & AIMS: ACE2, a carboxypeptidase that generates Ang-(1-7) from Ang II, is highly expressed in the lung, small intestine and colon. GPBAR1, is a G protein bile acid receptor that promotes the release of the insulinotropic factor glucagon-like peptide (GLP)-1 and attenuates intestinal inflammation. METHODS: We investigated the expression of ACE2, GLP-1 and GPBAR1 in two cohorts of Crohn's disease (CD) patients and three mouse models of colitis and Gpbar1-/- mice. Activation of GPBAR1 in these models and in vitro was achieved by BAR501, a selective GPBAR1 agonist. RESULTS: In IBD patients, ACE2 mRNA expression was regulated in a site-specific manner in response to inflammation. While expression of ileal ACE2 mRNA was reduced, the colon expression was induced. Colon expression of ACE2 mRNA in IBD correlated with expression of TNF-α and GPBAR1. A positive correlation occurred between GCG and GPBAR1 in human samples and animal models of colitis. In these models, ACE2 mRNA expression was further upregulated by GPABR1 agonism and reversed by exendin-3, a GLP-1 receptor antagonist. In in vitro studies, liraglutide, a GLP-1 analogue, increased the expression of ACE2 in colon epithelial cells/macrophages co-cultures. CONCLUSIONS: ACE2 mRNA expression in the colon of IBD patients and rodent models of colitis is regulated in a TNF-α- and GLP-1-dependent manner. We have identified a GPBAR1/GLP-1 mechanism as a positive modulator of ACE2.

Semaglutide, a glucagon like peptide-1 receptor agonist with cardiovascular benefits for management of type 2 diabetes.

Semaglutide, a glucagon like peptide-1 (GLP-1) receptor agonist, is available as monotherapy in both subcutaneous as well as oral dosage form (first approved oral GLP-1 receptor agonist). It has been approved as a second line treatment option for better glycaemic control in type 2 diabetes and currently under scrutiny for anti-obesity purpose. Semaglutide has been proved to be safe in adults and elderly patients with renal or hepatic disorders demanding no dose modification. Cardiovascular (CV) outcome trials established that it can reduce various CV risk factors in patients with established CV disorders. Semaglutide is well tolerated with no risk of hypoglycaemia in monotherapy but suffers from gastrointestinal adverse effects. A large population affected with COVID-19 infection were diabetic; therefore use of semaglutide in diabetes as well as CV patients would be very much supportive in maintaining health care system during this pandemic situation. Hence, this peptidic drug can be truly considered as a quintessential of GLP-1 agonists for management of type 2 diabetes.

Anosmia and dysgeusia amongst COVID-19 patients are associated with low levels of serum glucagon-like peptide 1.

PURPOSE: Anosmia and dysgeusia (AD) are common amongst COVID-19 patients. These symptoms are not frequently associated with rhinorrhea or nasal congestion and the underlying mechanism is unclear. Previous reports suggested that glucagon-like peptide-1 (GLP-1) signalling plays a role in the modulation of olfaction and ageusia. We aimed to assess the correlation between GLP-1 and COVID-19-associated AD. METHODS: Blood samples obtained from COVID-19 patients with and without AD were tested for serum GLP-1 levels using enzyme-linked immunosorbent assay (ELISA). A second control group comprised of COVID-19-negative volunteers. RESULTS: Forty-nine subjects were included in the study. Nineteen were positive for COVID-19. Of the 19 patients, 10 had AD and 9 declined such complaints. Age and basic metabolic rate were similar amongst all study groups. Serum GLP-1 levels were significantly lower amongst patients with AD compared with patients without AD and COVID-19-negative individuals (1820 pg/mL vs 3536 pg/mL vs 3014 pg/mL, respectively, P < .02). CONCLUSION: COVID-19 patients who reported AD had lower serum levels of GLP-1 compared with those lacking AD symptoms and COVID-19-negative individuals. These results suggest that GLP-1 may be involved in the pathogenesis of AD. However, further larger scale studies should corroborate our findings.

Anti-Diabetic Drugs GLP-1 Agonists and DPP-4 Inhibitors may Represent Potential Therapeutic Approaches for COVID-19.

The fast spread of coronavirus 2019 (COVID-19) calls for immediate action to counter the associated significant loss of human life and deep economic impact. Certain patient populations like those with obesity and diabetes are at higher risk for acquiring severe COVID-19 disease and have a higher risk of COVID-19 associated mortality. In the absence of an effective and safe vaccine, the only immediate promising approach is to repurpose an existing approved drug. Several drugs have been proposed and tested as adjunctive therapy for COVID-19. Among these drugs are the glucagon-like peptide-1 (GLP-1) 2 agonists and the dipeptidylpeptidase-4 (DPP-4) inhibitors. Beyond their glucose-lowering effects, these drugs have several pleiotropic protective properties, which include cardioprotective effects, anti-inflammatory and immunomodulatory activities, antifibrotic effects, antithrombotic effects, and vascular endothelial protective properties. This narrative review discusses these protective properties and addresses their scientific plausibility for their potential use as adjunctive therapy for COVID-19 disease.

Anti-inflammatory effects of GLP-1 in patients with COVID-19.

INTRODUCTION: Understanding the pathogenesis and risk factors to control the coronavirus disease 2019 (COVID-19) is necessary. Due to the importance of the inflammatory pathways in the pathogenesis of COVID-19 patients, evaluating the effects of anti-inflammatory medications is important. Glucagon-like peptide 1 receptor agonist (GLP-1 RA) is awell-known glucose-lowering agent with anti-inflammatory effects. AREAS COVERED: Resources were extracted from the PubMed database, using keywords such as glucagon-like peptide-1, GLP-1 RA, SARS-CoV-2, COVID-19, inflammation, in April2021. In this review, the effects of GLP-1RA in reducing inflammation and modifying risk factors of COVID-19 severe complications are discussed. However, GLP-1 is degraded by DPP-4 with aplasma half-life of about 2-5 minutes, which makes it difficult to measure GLP-1 plasma level in clinical settings. EXPERT OPINION: Since no definitive treatment is available for COVID-19 so far, determining promising targets to design and/or repurpose effective medications is necessary.

Evaluation of Dual Inhibitory Effect of Anagliptin, Ramipril and Lisinopril on Angiotensin-Converting Enzyme and DPP-4 Activities.

BACKGROUND: We previously tested two angiotensin-converting enzyme (ACE) inhibitors and two dipeptidyl peptidase-4 (DPP-4) inhibitors for dual enzyme inhibitory effect. Only two DPP-4 inhibitors, linagliptin and sitagliptin, were able to inhibit ACE. OBJECTIVE: In the present study, we investigated if other inhibitors of ACE or DPP-4 could simultaneously inhibit the activities of both DPP-4 and ACE. METHODS: Forty Sprague Dawley rats were used. The control group received only saline. The other three groups were treated with anagliptin, ramipril, or lisinopril. Two different doses were tested separated with a 6-day drug-free interval. Angiotensin II (Ang II) levels and the activities of ACE and DPP-4 were measured from blood samples at baseline and days 1, 10, and 14. After the oral glucose challenge test, levels of the active form of glucagon-like peptide-1 (GLP-1) were measured. RESULTS: Regardless of the dose, anagliptin did not show any inhibitory effect on the activity of ACE or Ang II levels. Concerning ramipril and lisinopril, only a high dose of lisinopril was able to produce a modest reduction of the DPP-4 activity but not enough to inhibit the inactivation of GLP-1. CONCLUSION: It seems that while most of the ACE inhibitors cannot affect DPP-4 activity, inhibitors of DPP-4 vary in their effects on ACE activity. The selection of DPP-4 inhibitors under different clinical situations should take into account the action of these drugs on ACE.

Once-Weekly Semaglutide in Adults with Overweight or Obesity.

BACKGROUND: Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed. METHODS: In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions. RESULTS: The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]). CONCLUSIONS: In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

Are glucagon-like peptide 1 analogues effective and safe in severe COVID-19 patients with type 2 diabetes?-a case report.

Many cases of novel coronavirus 2019 (COVID-19) have confirmed in many countries around the world. Due to the disorders of the immune system, diabetic patients are more likely to suffer from severe COVID-19. Glucagon-like peptide 1 analogues (GLP-1 analogues) commonly can be used to reduce blood sugar. There is no clear evidence that it can be safely and effectively used in patients with diabetes merged severe COVID-19. In this case, we described A 65-year-old male with hypertension and diabetes was diagnosed with severe COVID-19, he took liraglutide at doses ranging from 0.8 to 1.8 mg. Before admission, liraglutide was not used to reduce blood glucose. Hydroxychloroquine sulfate and abidol were used to antivirus and supportive treatment were used simultaneously during hospitalization. During treatment, the patient's own state was paid attention to, and blood glucose, liver function, kidney function, white blood cells, lymphocytes and other indicators were checked and chest CT was reviewed regularly, which could reflect changes in disease. After treatment, the patient's blood glucose was under control, and his liver function, renal function, white blood cells, lymphocytes and other indicators were normal and chest CT also improved. The case showed that liraglutide may be effective and safe used in patients with severe COVID-19 combined with type 2 diabetes, but more clinical trials are needed.

Dipeptidyl peptidase 4 inhibitors: Applications in innate immunity?

Dipeptidyl peptidase (DPP)-4 inhibitors are a class of orally available, small molecule inhibitors that prolong the insulinotropic activity of the incretin hormone glucagon-like peptide-1 (GLP-1) and are highly effective for the treatment of Type-2 diabetes. DPP4 can also cleave several immunoregulatory peptides including chemokines. Emerging evidence continues to implicate DPP4 inhibitors as immunomodulators, with recent findings suggesting DPP4 inhibitors modify specific aspects of innate immunity. This review summarises recent insights into how DPP4 inhibitors could be implicated in endothelial, neutrophil and monocyte/macrophage mediated immunity. Additionally, this review highlights additional avenues of research with DPP4 inhibitors in the context of the COVID-19 pandemic.

The active GLP-1 analogue liraglutide alleviates H9N2 influenza virus-induced acute lung injury in mice.

Influenza virus is responsible for significant morbidity and mortality worldwide. Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is the major cause of death in influenza virus infected patients. Recent studies indicated that active glucagon like peptide-1 (GLP-1) encoded by glucagon (GCG) gene exerts anti-inflammatory functions. The aim of this study was to determine the potential role of active GLP-1 in H9N2 influenza virus-induced ALI/ARDS in mice. First, we uncovered that GCG mRNA expression levels and GCG precursor protein levels were significantly increased, but total GLP-1 and active GLP-1 levels were decreased in the lungs of H9N2-infected mice. Next, liraglutide, an active GLP-1 analogue, was used to treat infected mice and to observe its effects on H9N2 virus-induced ALI. Liraglutide treatment ameliorated the declined body weight, decreased food intake and mortality observed in infected mice. It also alleviated the severity of lung injury, including lowering lung index, decreasing inflammatory cell infiltration and lowing total protein levels in bronchoalveolar lavage fluid (BALF). In addition, liraglutide did not influence viral titers in infected lungs, but decreased the levels of interleukin-1ß, interleukin-6 and tumor necrosis factor-α in BALF. These results indicated that liraglutide alleviated H9N2 virus-induced ALI in mice most likely due to lower levels of pro-inflammatory cytokines.

Stabilizing Cellular Barriers: Raising the Shields Against COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its clinical manifestation (COVID-19; coronavirus disease 2019) have caused a worldwide health crisis. Disruption of epithelial and endothelial barriers is a key clinical turning point that differentiates patients who are likely to develop severe COVID-19 outcomes: it marks a significant escalation in respiratory symptoms, loss of viral containment and a progression toward multi-organ dysfunction. These barrier mechanisms are independently compromised by known COVID-19 risk factors, including diabetes, obesity and aging: thus, a synergism between these underlying conditions and SARS-CoV-2 mechanisms may explain why these risk factors correlate with more severe outcomes. This review examines the key cellular mechanisms that SARS-CoV-2 and its underlying risk factors utilize to disrupt barrier function. As an outlook, we propose that glucagon-like peptide 1 (GLP-1) may be a therapeutic intervention that can slow COVID-19 progression and improve clinical outcome following SARS-CoV-2 infection. GLP-1 signaling activates barrier-promoting processes that directly oppose the pro-inflammatory mechanisms commandeered by SARS-CoV-2 and its underlying risk factors.

Currently prescribed drugs in the UK that could upregulate or downregulate ACE2 in COVID-19 disease: a systematic review.

OBJECTIVE: To review evidence on routinely prescribed drugs in the UK that could upregulate or downregulate ACE2 and potentially affect COVID-19 disease. DESIGN: Systematic review. DATA SOURCE: MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science. STUDY SELECTION: Any design with animal or human models examining a currently prescribed UK drug compared with a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. DATA EXTRACTION AND SYNTHESIS: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1 April 2020. Methodological quality was assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool for animal studies and Cochrane risk-of-bias tool for human studies. RESULTS: We screened 3360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and one hundred and two were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were angiotensin receptor blockers (ARBs) (n=55) and ACE inhibitors (ACE-I) (n=22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel blockers (n=3) glucagon-like peptide 1 (GLP-1) agonists (n=2) and Non-steroidal anti-inflammatory drugs (NSAIDs) (n=2). CONCLUSIONS: There is an abundance of the academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty among patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.