Importance The efficacy of vitamin D3supplementation in coronavirus disease 2019 (COVID-19) remains unclear. Objective To investigate the effect of a single high dose of vitamin D3on hospital length of stay in patients with COVID-19. Design, Setting, and Participants This was a multicenter, double-blind, randomized, placebo-controlled trial conducted in 2 sites in Sao Paulo, Brazil. The study included 240 hospitalized patients with COVID-19 who were moderately to severely ill at the time of enrollment from June 2, 2020, to August 27, 2020. The final follow-up was on October 7, 2020. Interventions Patients were randomly assigned to receive a single oral dose of 200 000 IU of vitamin D3(n = 120) or placebo (n = 120). Main Outcomes and Measures The primary outcome was length of stay, defined as the time from the date of randomization to hospital discharge. Prespecified secondary outcomes included mortality during hospitalization; the number of patients admitted to the intensive care unit; the number of patients who required mechanical ventilation and the duration of mechanical ventilation; and serum levels of 25-hydroxyvitamin D, total calcium, creatinine, and C-reactive protein. Results Of 240 randomized patients, 237 were included in the primary analysis (mean [SD] age, 56.2 [14.4] years; 104 [43.9%] women; mean [SD] baseline 25-hydroxyvitamin D level, 20.9 [9.2] ng/mL). Median (interquartile range) length of stay was not significantly different between the vitamin D3(7.0 [4.0-10.0] days) and placebo groups (7.0 [5.0-13.0] days) (log-rankP = .59; unadjusted hazard ratio for hospital discharge, 1.07 [95% CI, 0.82-1.39];P = .62). The difference between the vitamin D3 group and the placebo group was not significant for in-hospital mortality (7.6% vs 5.1%; difference, 2.5% [95% CI, –4.1% to 9.2%];P = .43), admission to the intensive care unit (16.0% vs 21.2%; difference, –5.2% [95% CI, –15.1% to 4.7%];P = .30), or need for mechanical ventilation (7.6% vs 14.4%; difference, –6.8% [95% CI, –15.1% to 1.2%];P = .09). Mean serum levels of 25-hydroxyvitamin D significantly increased after a single dose of vitamin D3vs placebo (44.4 ng/mL vs 19.8 ng/mL; difference, 24.1 ng/mL [95% CI, 19.5-28.7];P  Conclusions and Relevance Among hospitalized patients with COVID-19, a single high dose of vitamin D3, compared with placebo, did not significantly reduce hospital length of stay. The findings do not support the use of a high dose of vitamin D3for treatment of moderate to severe COVID-19. Trial Registration ClinicalTrials.gov Identifier:NCT04449718

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Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial.

BACKGROUND: Disease severity and mortality rates due to COVID-19 infection are greater in the elderly and chronically ill patients, populations at high risk for vitamin D deficiency. Vitamin D plays an important role in immune function and inflammation. This systematic review and meta-analysis assesses the impact of vitamin D status and supplementation on COVID-19 related mortality and health outcomes. METHODS: We searched four databases until December 18th 2020, and trial registries until January 20th 2021. Two reviewers screened the studies, collected data, assessed the risk of bias, and graded the evidence for each outcome across studies, independently and in duplicate. Pre-specified outcomes of interest were mortality, ICU admission, invasive and non-invasive ventilation, hospitalization, time of hospital stay, disease severity and SARS-CoV-2 positivity. We only included data from peer-reviewed articles in our primary analyses. RESULTS: We identified 31 peer-reviewed observational studies. In our primary analysis, there was a positive trend between serum 25(OH)D level <20â¯ng/ml and an increased risk of mortality, ICU admission, invasive ventilation, non-invasive ventilation or SARS-CoV-2 positivity. However, these associations were not statistically significant. Mean 25(OH)D levels was 5.9â¯ng/ml (95% CI [-9.5, -2.3]) significantly lower in COVID-19 positive, compared to negative patients. The certainty of the evidence was very low. We identified 32 clinical trial protocols, but only three have published results to-date. The trials administer vitamin D doses of 357 to 60,000â¯IU/day, from one week to 12â¯months. Eight megatrials investigate the efficacy of vitamin D in outpatient populations. A pilot trial revealed a significant decrease in ICU admission with calcifediol, compared to placebo (ORâ¯=â¯0.003), but the certainty of the evidence was unclear. Another small trial showed that supplementation with cholecalciferol, 60,000â¯IU/day, decreased fibrinogen levels, but did not have an effect on D-dimer, procalcitonin and CRP levels, compared to placebo. The third trial did not find any effect of vitamin D supplementation on COVID-19 related health outcomes. CONCLUSION: While the available evidence to-date, from largely poor-quality observational studies, may be viewed as showing a trend for an association between low serum 25(OH)D levels and COVID-19 related health outcomes, this relationship was not found to be statistically significant. Calcifediol supplementation may have a protective effect on COVID-19 related ICU admissions. The current use of high doses of vitamin D in COVID-19 patients is not based on solid evidence. It awaits results from ongoing trials to determine the efficacy, desirable doses, and safety, of vitamin D supplementation to prevent and treat COVID-19 related health outcomes.

The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis.

BACKGROUND: The role of vitamin D supplementation as a treatment for COVID-19 has been a subject of considerable discussion. A thorough understanding of the current evidence regarding the effectiveness and safety of vitamin D supplementation for COVID-19 based on randomised controlled trials is required. OBJECTIVES: To assess whether vitamin D supplementation is effective and safe for the treatment of COVID-19 in comparison to an active comparator, placebo, or standard of care alone, and to maintain the currency of the evidence, using a living systematic review approach. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, Web of Science and the WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions to 11 March 2021. SELECTION CRITERIA: We followed standard Cochrane methodology. We included randomised controlled trials (RCTs) evaluating vitamin D supplementation for people with COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies investigating preventive effects, or studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)). DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane risk of bias tool (ROB 2) for RCTs. We rated the certainty of evidence using the GRADE approach for the following prioritised outcome categories: individuals with moderate or severe COVID-19: all-cause mortality, clinical status, quality of life, adverse events, serious adverse events, and for individuals with asymptomatic or mild disease: all-cause mortality, development of severe clinical COVID-19 symptoms, quality of life, adverse events, serious adverse events. MAIN RESULTS: We identified three RCTs with 356 participants, of whom 183 received vitamin D. In accordance with the World Health Organization (WHO) clinical progression scale, two studies investigated participants with moderate or severe disease, and one study individuals with mild or asymptomatic disease. The control groups consisted of placebo treatment or standard of care alone. Effectiveness of vitamin D supplementation for people with COVID-19 and moderate to severe disease We included two studies with 313 participants. Due to substantial clinical and methodological diversity of both studies, we were not able to pool data. Vitamin D status was unknown in one study, whereas the other study reported data for vitamin D deficient participants. One study administered multiple doses of oral calcifediol at days 1, 3 and 7,  whereas the other study gave a single high dose of oral cholecalciferol at baseline. We assessed one study with low risk of bias for effectiveness outcomes, and the other with some concerns about randomisation and selective reporting. All-cause mortality at hospital discharge (313 participants) We found two studies reporting data for this outcome. One study reported no deaths when treated with vitamin D out of 50 participants, compared to two deaths out of 26 participants in the control group (Risk ratio (RR) 0.11, 95% confidence interval (CI) 0.01 to 2.13). The other study reported nine deaths out of 119 individuals in the vitamin D group, whereas six participants out of 118 died in the placebo group (RR 1.49, 95% CI 0.55 to 4.04]. We are very uncertain whether vitamin D has an effect on all-cause mortality at hospital discharge (very low-certainty evidence). Clinical status assessed by the need for invasive mechanical ventilation (237 participants) We found one study reporting data for this outcome. Nine out of 119 participants needed invasive mechanical ventilation when treated with vitamin D, compared to 17 out of 118 participants in the placebo group (RR 0.52, 95% CI 0.24 to 1.13). Vitamin D supplementation may decrease need for invasive mechanical ventilation, but the evidence is uncertain (low-certainty evidence). Quality of life We did not find data for quality of life. Safety of vitamin D supplementation for people with COVID-19 and moderate to severe disease We did not include data from one study, because assessment of serious adverse events was not described and we are concerned that data might have been inconsistently measured. This study reported vomiting in one out of 119 participants immediately after vitamin D intake (RR 2.98, 95% CI 0.12 to 72.30). We are very uncertain whether vitamin D supplementation is associated with higher risk for adverse events (very low-certainty). Effectiveness and safety of vitamin D supplementation for people with COVID-19 and asymptomatic or mild disease We found one study including 40 individuals, which did not report our prioritised outcomes, but instead data for viral clearance, inflammatory markers, and vitamin D serum levels. The authors reported no events of hypercalcaemia, but recording and assessment of further adverse events remains unclear. Authors administered oral cholecalciferol in daily doses for at least 14 days, and continued with weekly doses if vitamin D blood levels were > 50 ng/mL. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to determine the benefits and harms of vitamin D supplementation as a treatment of COVID-19. The evidence for the effectiveness of vitamin D supplementation for the treatment of COVID-19 is very uncertain. Moreover, we found only limited safety information, and were concerned about consistency in measurement and recording of these outcomes. There was substantial clinical and methodological heterogeneity of included studies, mainly because of different supplementation strategies, formulations, vitamin D status of participants, and reported outcomes. There is an urgent need for well-designed and adequately powered randomised controlled trials (RCTs) with an appropriate randomisation procedure, comparability of study arms and preferably double-blinding. We identified 21 ongoing and three completed studies without published results, which indicates that these needs will be addressed and that our findings are subject to change in the future. Due to the living approach of this work, we will update the review periodically.

Vitamin D supplementation for the treatment of COVID-19: a living systematic review.

To provide a precise summary and collate the hitherto available clinical evidence on the effect of vitamin D supplementation on clinical outcomes in COVID-19 patients. PubMed/MEDLINE, Scopus, and Web of Science databases were systematically searched using appropriate keywords till June 8, 2021, to identify observational studies and randomized controlled trials (RCTs) reporting adverse clinical outcomes (ICU admission and/or mortality) in COVID-19 patients receiving vitamin D supplementation vs. those not receiving the same. Both prior use and use of vitamin D after COVID-19 diagnosis were considered. Unadjusted/adjusted pooled odds ratio (OR) with 95% confidence intervals (CI) were calculated (PROSPERO registration number CRD42021248488). We identified 13 studies (10 observational, 3 RCTs) pooling data retrieved from 2933 COVID-19 patients. Pooled analysis of unadjusted data showed that vitamin D use in COVID-19 was significantly associated with reduced ICU admission/mortality (OR 0.41, 95% CI: 0.20, 0.81, p = 0.01, I2 = 66%, random-effects model). Similarly, on pooling adjusted risk estimates, vitamin D was also found to reduce the risk of adverse outcomes (pooled OR 0.27, 95% CI: 0.08, 0.91, p = 0.03, I2 = 80%, random-effects model). Subgroup analysis showed that vitamin D supplementation was associated with improved clinical outcomes only in patients receiving the drug post-COVID-19 diagnosis and not in those who had received vitamin D before diagnosis. Vitamin D supplementation might be associated with improved clinical outcomes, especially when administered after the diagnosis of COVID-19. However, issues regarding the appropriate dose, duration, and mode of administration of vitamin D remain unanswered and need further research.

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Vitamin D supplementation and clinical outcomes in COVID-19: a systematic review and meta-analysis.

COVID-19 has completely changed our daily clinical practice as well as our social relations. Many organs and biological systems are involved in SARS-Cov-2 infection, either due to direct virus-induced damage or to indirect effects that can have systemic consequences. Endocrine system is not only an exception but its involvement in COVID-19 is so relevant that an “endocrine phenotype” of COVID-19 has progressively acquired clinical relevance. We have been appointed by the European Society of Endocrinology (ESE) to update with the current statement ESE members and the whole endocrine community on the emerging endocrine phenotype of COVID-19 and its implication for the prevention and management of the disease. Diabetes has a major role in this phenotype since it is one of the most frequent comorbidities associated with severity and mortality of COVID-19. Careful management including treatment modifications may be required for protecting our patients rather with known diabetes from the most dangerous consequences of COVID-19 or hospitalized with COVID-19, but also in patients with SARS-CoV-2 induced newly onset diabetes. Obesity increases susceptibility to SARS-CoV-2 and the risk for COVID-19 adverse outcome. Adequate nutritional management needs to be granted to patients with obesity or undernourishment in order to limit their increased susceptibility and severity of COVID-19 infection. Lack of vitamin D, hypocalcemia and vertebral fractures have also emerged as frequent findings in the hospitalized COVID-19 population and may negatively impact on the outcome of such patients. Also, in patients with adrenal insufficiency prompt adaptation of glucocorticoid doses may be needed. Moreover, in this updated statement role of sex hormones as well as peculiar pituitary and thyroid aspects of COVID-19 have been included. Finally, in view of the mass vaccination, potential implications for endocrine patients should be considered.

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COVID-19 and endocrine and metabolic diseases. An updated statement from the European Society of Endocrinology.

The SARS-CoV-2 virus responsible for the COVID-19 pandemic has generated an explosion of interest both in the mechanisms of infection leading to dissemination and expression of this disease, and in potential risk factors that may have a mechanistic basis for disease propagation or control. Vitamin D has emerged as a factor that may be involved in these two areas. The focus of this article is to apply our current understanding of vitamin D as a facilitator of immunocompetence both with regard to innate and adaptive immunity and to consider how this may relate to COVID-19 disease. There are also intriguing potential links to vitamin D as a factor in the cytokine storm that portends some of the most serious consequences of SARS-CoV-2 infection, such as the acute respiratory distress syndrome. Moreover, cardiac and coagulopathic features of COVID-19 disease deserve attention as they may also be related to vitamin D. Finally, we review the current clinical data associating vitamin D with SARS-CoV-2 infection, a putative clinical link that at this time must still be considered hypothetical.

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MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19.

Various embodiments relate to a compound (represented by Formula I) or a pharmaceutically acceptable salt or tautomer thereof. The compound may selectively inhibit a Forkhead Box O1 (FOXO1) transcription factor. Various embodiments relate to methods comprising administering to a mammal having a disease or disorder associated with impaired pancreatic endocrine function, a therapeutically effective amount of the compound or a pharmaceutically acceptable salt or tautomer thereof. Various embodiments relate to methods for producing enteroendocrine cells that make and secrete insulin in a mammal, comprising administering to the mammal an effective amount of the compound or a pharmaceutically acceptable salt or tautomer thereof.

Accili Domenico

Papers

MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19.

Selective foxo inhibitors for treatment of diabetes and other disorders related to impaired pancreatic function