COVID-19 and Diabetes.

The prevalence of diabetes in people with coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has varied worldwide. Most of the available evidence suggests a significant increase in severity and mortality of COVID-19 in people with either type 1 (T1DM) or type 2 diabetes mellitus (T2DM), especially in association with poor glycemic control. While new-onset hyperglycemia and new-onset diabetes (both T1DM and T2DM) have been increasingly recognized in the context of COVID-19 and have been associated with worse outcome, no conclusive evidence yet suggests direct tropism of SARS-CoV-2 on the ß cells of pancreatic islets. While all approved oral antidiabetic agents appear to be safe in people with T2DM having COVID-19, no conclusive data are yet available to indicate a mortality benefit with any class of these drugs, in the absence of large randomized controlled trials.

Noninsulin-based antihyperglycemic medications in patients with diabetes and COVID-19: A systematic review and meta-analysis.

BACKGROUND: Patients with diabetes are more likely to suffer COVID-19 complications. Using noninsulin antihyperglycemic medications (AGMs) during COVID-19 infection has proved challenging. In this study, we evaluate different noninsulin AGMs in patients with COVID-19. METHODS: We searched Medline, Embase, Web of Science, and Cochrane on 24 January 2022. We used the following keywords (COVID-19) AND (diabetes mellitus) AND (antihyperglycemic agent). The inclusion criteria were studies reporting one or more of the outcomes. We excluded non-English articles, case reports, and literature reviews. Study outcomes were mortality, hospitalization, and intensive care unit (ICU) admission. RESULTS: The use of metformin rather than other glucose-lowering medications was associated with statistically significant lower mortality (risk ratio [RR]: 0.60, 95% confidence interval [CI]: 0.47, 0.77, p < .001). Dipeptidyl peptidase-4 inhibitor (DPP-4i) use was associated with statistically significantly higher hospitalization risk (RR: 1.44, 95% CI: 1.23, 1.68, p < .001) and higher risk of ICU admissions and/or mechanical ventilation vs nonusers (RR: 1.24, 95% CI: 1.04, 1.48, p < .02). There was a statistically significant decrease in hospitalization for SGLT-2i users vs nonusers (RR: 0.89, 95% CI: 0.84-0.95, p < .001). Glucagon-like peptide-1 receptor agonist (GLP-1RA) use was associated with a statistically significant decrease in mortality (RR: 0.56, 95% CI: 0.42, 073, p < 0.001), ICU admission, and/or mechanical ventilation (RR: 0.79, 95% CI: 0.69-0.89, p < .001), and hospitalization (RR: 0.73, 95% CI: 0.54, 0.98, p = .04). CONCLUSIONS: AGM use was not associated with increased mortality. However, metformin and GLP-1RA use reduced mortality risk statistically significantly. DPP-4i use was associated with a statistically significant increase in the risk of hospitalization and admission to the ICU.

Metabolic and cardiovascular benefits with combination therapy of SGLT-2 inhibitors and GLP-1 receptor agonists in type 2 diabetes.

Both GLP-1 receptor agonists (GLP-1RA) and SGLT-2 inhibitors (SGLT-2I) are newer classes of anti-diabetic agents that lower HbA1c moderately and decrease body weight and systolic blood pressure (SBP) modestly. Combination therapy with GLP-1RA plus SGLT-2I have shown a greater reduction in HbA1c, body weight, and SBP compared to either agent alone without any significant increase in hypoglycemia or other side effects. Since several agents from each class of these drugs have shown an improvement in cardiovascular (CV) and renal outcomes in their respective cardiovascular outcome trials (CVOT), combination therapy is theoretically expected to have additional CV and renal benefits. In this comprehensive opinion review, we found HbA1c lowering with GLP-1RA plus SGLT-2I to be less than additive compared to the sum of HbA1c lowering with either agent alone, although body weight lowering was nearly additive and the SBP lowering was more than additive. Our additional meta-analysis of CV outcomes with GLP-1RA plus SGLT-2I combination therapy from the pooled data of five CVOT found a similar reduction in three-point major adverse cardiovascular events compared to GLP-1RA or SGLT-2I alone, against placebo. Interestingly, a greater benefit in reduction of heart failure hospitalization with GLP-1RA plus SGLT-2I combination therapy was noted in the pooled meta-analysis of two randomized controlled trials. Future adequately powered trials can confirm whether additional CV or renal benefit is truly exerted by GLP-1RA plus SGLT-2I combination therapy.

The impact of obesity on severe disease and mortality in people with SARS-CoV-2: A systematic review and meta-analysis.

Background: Obesity accompanied by excess ectopic fat storage has been postulated as a risk factor for severe disease in people with SARS-CoV-2 through the stimulation of inflammation, functional immunologic deficit and a pro-thrombotic disseminated intravascular coagulation with associated high rates of venous thromboembolism. Methods: Observational studies in COVID-19 patients reporting data on raised body mass index at admission and associated clinical outcomes were identified from MEDLINE, Embase, Web of Science and the Cochrane Library up to 16 May 2020. Mean differences and relative risks (RR) with 95% confidence intervals (CIs) were aggregated using random effects models. Results: Eight retrospective cohort studies and one cohort prospective cohort study with data on of 4,920 patients with COVID-19 were eligible. Comparing BMI ≥ 25 vs <25 kg/m2, the RRs (95% CIs) of severe illness and mortality were 2.35 (1.43-3.86) and 3.52 (1.32-9.42), respectively. In a pooled analysis of three studies, the RR (95% CI) of severe illness comparing BMI > 35 vs <25 kg/m2 was 7.04 (2.72-18.20). High levels of statistical heterogeneity were partly explained by age; BMI ≥ 25 kg/m2 was associated with an increased risk of severe illness in older age groups (≥60 years), whereas the association was weaker in younger age groups (<60 years). Conclusions: Excess adiposity is a risk factor for severe disease and mortality in people with SARS-CoV-2 infection. This was particularly pronounced in people 60 and older. The increased risk of worse outcomes from SARS-CoV-2 infection in people with excess adiposity should be taken into account when considering individual and population risks and when deciding on which groups to target for public health messaging on prevention and detection measures. Systematic review registration: PROSPERO 2020: CRD42020179783.

Humoral antibody kinetics with ChAdOx1-nCOV (Covishield™) and BBV-152 (Covaxin™) vaccine among Indian Healthcare workers: A 6-month longitudinal cross-sectional Coronavirus Vaccine-induced antibody titre (COVAT) study.

BACKGROUND AND AIMS: There is limited data available on longitudinal humoral antibody dynamics following two doses of ChAdOx1-nCOV (Covishield™) and BBV-152 (Covaxin™) vaccine against SARS-CoV-2 among Indians. METHODS: We conducted a 6-month longitudinal study in vaccinated healthcare workers by serially measuring quantitative anti-spike antibody at 3-weeks, 3-months and 6-months after the completion of second dose. Geometric mean titer (GMT) and linear mixed models were used to assess the dynamics of antibody levels at 6 months. RESULTS: Of the 481 participants, GMT of anti-spike antibody decreased by 56% at 6-months regardless of age, gender, blood group, body-mass index and comorbidities in 360 SARS-CoV-2 naive individuals but significantly more in hypertensives. Participants with past infection had significantly higher GMT at all time points compared to the naive individuals. Among SARS-CoV-2 naive cohorts, a significantly higher GMT was noted amongst the Covishield recipients at all time points, but there was a 44% decline in GMT at 6-month compared to the peak titer period. Decline in GMT was insignificant (8%) in Covaxin recipients at 6-month despite a lower GMT at all time points vs. Covishield. There was 5.6-fold decrease in seropositivity rate at 6-month with both vaccines. Participants with type 2 diabetes mellitus have a lower seropositivity rate at all the time points. Seropositivity rate was significantly higher with Covishield vs. Covaxin at all time points except at 6-month where Covaxin recipients had a higher seropositivity rate but no difference noted in propensity-matched analysis. CONCLUSIONS: There is waning humoral antibody response following two doses of either vaccine at six months. Covishield recipients had a higher anti-spike antibody GMT compared with Covaxin at all-time points, however a significant decline in antibody titers was seen with Covishield but not with Covaxin at 6-months.

An updated practical guideline on use of molnupiravir and comparison with agents having emergency use authorization for treatment of COVID-19.

BACKGROUND AND AIMS: Molnupiravir is a newer oral antiviral drug that has recently received emergency use authorization (EUA) in USA, UK and India. We aim to conduct an update on our previous systematic review to provide practical clinical guideline for using molnupiravir in patients with COVID-19. METHODS: We systematically searched the electronic database of PubMed, MedRxiv and Google Scholar until January 5, 2022, using key MeSH keywords. RESULTS: Final result of phase 3 study in 1433 non-hospitalized COVID-19 patients showed a significant reduction in composite risk of hospital admission or death (absolute risk difference, -3.0% [95% confidence interval {CI}, -5.9 to -0.1%]; 1-sided P = 0.02) although with a non-significant 31% relative risk reduction (RRR). RRR for death alone was 89% (95% CI, 14 to 99; P-value not reported). Number needed to treat to prevent 1 death or 1 hospitalization or death composite appears to be closely competitive to other agents having EUA in people with COVID-19. However, cost-wise molnupiravir is comparatively cheaper compared to all other agents. CONCLUSION: Molnupiravir could be a useful agent in non-pregnant unvaccinated adults with COVID-19 who are at increased risk of severity including hospitalization. However, it is effective only when used within 5-days of onset of symptoms. A 5-days course seems to be safe without any obvious short-term side effects.

Molnupiravir in COVID-19: A systematic review of literature.

BACKGROUND AND AIMS: Molnupiravir is a newer oral antiviral drug that has recently been tested in COVID-19. We aim to conduct a systematic review of literature to find out the efficacy and safety of molnupiravir in patients with COVID-19. METHODS: We systematically searched the electronic database of PubMed, MedRxiv and Google Scholar from inception until October 15, 2021, using MeSH keywords. Ongoing trials of molnupiravir in COVID-19 were additionally searched from the ClinicalTrials.Gov and ctri.nic.in/Clinicaltrials. We retrieved all the available granular details of phase 1 to 3 studies of molnupiravir in COVID-19. Subsequently we reviewed the results narratively. RESULTS: Two phase 1 double-blind, randomized, placebo-controlled (DBRPC) studies of molnupiravir showed that 1600 mg daily dose is safe and tolerable, without any serious adverse events up to 5.5 days. One phase 2 DBPRC study found significantly lower time to clearance (RNA negativity) with molnupiravir 800 mg twice daily compared to the placebo (log-rank p value = 0.013) in mild to moderate COVID-19. Interim report of one phase 3 DBRPC study in non-hospitalized COVID-19 found a significant reduction in the risk of hospital admission or death by 50% (p = 0.0012). However, no significant benefit was observed with molnupiravir in the later stage of moderate to severe COVID-19. CONCLUSION: Molnupiravir is first oral antiviral drug to demonstrate a significant benefit in reducing hospitalization or death in mild COVID-19 and could be an important weapon in the battle against SARS-CoV-2. However, its role in moderate to severe COVID-19 is questionable and more studies are needed.

Antibody response after first and second-dose of ChAdOx1-nCOV (CovishieldTM®) and BBV-152 (CovaxinTM®) among health care workers in India: The final results of cross-sectional coronavirus vaccine-induced antibody titre (COVAT) study.

BACKGROUND: We assessed the humoral immune response of both ChAdOx1-nCOV (CovishieldTM) and BBV-152 (CovaxinTM) vaccines in Indian health care workers (HCW). METHODS: A Pan-India, Cross-sectional, Coronavirus Vaccine-induced Antibody Titre (COVAT) study was conducted that measured SARS-CoV-2 anti-spike binding antibody quantitatively, 21 days or more after the first and second dose of two vaccines in both severe acute respiratory syndrome (SARS-CoV-2) naïve and recovered HCW. Primary aim was to analyze antibody response (seropositivity rate, Geometric Mean Titre [GMT] and 95% Confidence Interval [CI]) following each dose of both vaccines and its correlation to age, sex, blood group, body mass index (BMI) and comorbidities. Here we report the results of anti-spike antibody response after first and two completed doses. RESULTS: Among the 515 HCW (305 Male, 210 Female) who took two doses of both vaccines, 95.0% showed seropositivity to anti-spike antibody. However, both seropositivity rate and GMT (95% CI) of anti-spike antibody was significantly higher in Covishield vs. Covaxin recipients (98.1 vs. 80.0%; 129.3 vs. 48.3 AU/mL; both p < 0.001). This difference persisted in 457 SARS-CoV-2 naïve and propensity-matched (age, sex and BMI) analysis of 116 participants. Age > 60-years, males, people with any comorbidities, and history of hypertension (HTN) had a significantly less anti-spike antibody GMT compared to age ≤ 60 years, females, no comorbidities and no HTN respectively, after the completion of two doses of either vaccine. Gender, presence of comorbidities, and vaccine type were independent predictors of antibody seropositivity rate and anti-spike antibody titre levels in multiple logistic and log transformed linear regression analysis. Both vaccine recipients had similar solicited mild to moderate adverse events and none had severe or unsolicited side effects. CONCLUSIONS: Both vaccines elicited good immune response after two doses, although seropositivity rates and GMT of anti-spike antibody titre was significantly higher in Covishield compared to Covaxin recipients.

Mucormycosis in COVID-19: A systematic review of cases reported worldwide and in India.

BACKGROUND AND AIMS: There are increasing case reports of rhino-orbital mucormycosis in people with coronavirus disease 2019 (COVID-19), especially from India. Diabetes mellitus (DM) is an independent risk factor for both severe COVID-19 and mucormycosis. We aim to conduct a systematic review of literature to find out the patient's characteristics having mucormycosis and COVID-19. METHODS: We searched the electronic database of PubMed and Google Scholar from inception until May 13, 2021 using keywords. We retrieved all the granular details of case reports/series of patients with mucormycosis, and COVID-19 reported world-wide. Subsequently we analyzed the patient characteristics, associated comorbidities, location of mucormycosis, use of steroids and its outcome in people with COVID-19. RESULTS: Overall, 101 cases of mucormycosis in people with COVID-19 have been reported, of which 82 cases were from India and 19 from the rest of the world. Mucormycosis was predominantly seen in males (78.9%), both in people who were active (59.4%) or recovered (40.6%) from COVID-19. Pre-existing diabetes mellitus (DM) was present in 80% of cases, while concomitant diabetic ketoacidosis (DKA) was present in 14.9%. Corticosteroid intake for the treatment of COVID-19 was recorded in 76.3% of cases. Mucormycosis involving nose and sinuses (88.9%) was most common followed by rhino-orbital (56.7%). Mortality was noted in 30.7% of the cases. CONCLUSION: An unholy trinity of diabetes, rampant use of corticosteroid in a background of COVID-19 appears to increase mucormycosis. All efforts should be made to maintain optimal glucose and only judicious use of corticosteroids in patients with COVID-19.

Impact of COVID-19 and comorbidities on health and economics: Focus on developing countries and India.

BACKGROUND AND AIMS: Presence of comorbidities in patients with Coronavirus disease 2019 (COVID-19) have often been associated with increased in-hospital complications and mortality. Intriguingly, several developed countries with a higher quality of life have relatively higher mortality with COVID-19, compared to the middle- or low-income countries. Moreover, certain ethnic groups have shown a higher predilection to contract COVID-19, with heightened mortality. We sought to review the available literature with regards to impact of COVID-19 and comorbidities on the health and economics, especially in context to the developing countries including India. METHODS: A Boolean search was carried out in PubMed, MedRxiv and Google Scholar databases up till August 23, 2020 using the specific keywords, to find the prevalence of comorbidities and its outcome in patients with COVID-19. RESULTS: All available evidence consistently suggests that presence of comorbidities is associated with a poor outcome in patients with COVID-19. Diabetes prevalence is highest in Indian COVID-19 patients, compared to other countries. Majority of the patients with COVID-19 are asymptomatic ranging from 26 to 76%. CONCLUSIONS: Universal masking is the need of hour during unlock period. Low-income countries such as India, Brazil and Africa with less resources and an average socio-economic background, must adopt a strict policy for an affordable testing programs to trace, test, identify and home quarantine of asymptomatic cases. Despite the huge number of COVID-19 patients, India still has low volume research at the moment.

At-admission hyperglycemia is consistently associated with poor prognosis and early intervention can improve outcomes in patients with COVID-19.

BACKGROUND & AIMS: At-admission hyperglycemia have been associated with poorer outcome during critical illnesses. At-admission hyperglycemia in previously unknown diabetes is not uncommonly encountered entity in patients with COVID-19. We sought to find out the outcomes of at-admission hyperglycemia and effect of early intervention to achieve optimal glycemic control in relation to COVID-19 patients. METHODS: We searched the PubMed and Google Scholar database up till August 20, 2020 using specific keywords related to our aims and objectives. RESULTS: All currently available evidences clearly hint that at-admission hyperglycemia in patients with COVID-19 is associated with a poorer outcome, compared with normoglycemic individuals. Fortunately, early intervention by achieving an optimal glycemic control has also been associated with a significant improvement in the outcomes in patients with COVID-19. CONCLUSION: At-admission hyperglycemia should be taken seriously by all clinicians treating patients with COVID-19. All efforts should be made towards an optimal glycemic control in patients with COVID-19, even in absence of pre-existing diabetes.

Non-insulin anti-diabetic agents in patients with type 2 diabetes and COVID-19: A Critical Appraisal of Literature.

BACKGROUND & AIMS: Several observational studies have recently reported the outcomes of non-insulin anti-diabetic agents (ADA) in patients with T2DM and coronavirus disease 2019 (COVID-19). We sought to review the literature to appraise the clinicians on these outcomes. METHODS: A literature search using the specific keywords was carried out in the database of PubMed, MedRxiv and Google Scholar up till December 11, 2020 applying Boolean method. Full text of all the relevant articles that reported the outcomes of ADA in patients with T2DM and COVID-19 were retrieved. Subsequently, an appraisal of literature report was narratively presented. RESULTS: Available studies that reported the outcomes of ADA are either case series or retrospective cohorts or prospective observational studies, in absence of the randomized controlled trials (RCTs). Results from these observational studies suggest that amongst all the non-insulin ADA, metformin users prior to the hospitalization had improved outcomes compared to the non-users. Data for dipeptidyl-peptidase-4 inhibitors (DPP-4i) are encouraging although inconsistent. No documentation of any harm or benefit has been observed for sulfonylureas (SUs), sodium glucose co-transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide receptor agonists (GLP-1RAs). No data is yet available for pioglitazone. CONCLUSION: Metformin and DPP-4i should be continued in patients with T2DM until hospitalization or unless contraindicated. No evidence of harm suggests that SUs, SGLT-2i or GLP-1RAs may not be stopped unless very sick, hospitalized or contraindicated. The results from RCTs are needed to claim any meaningful benefit with either metformin or DPP-4i in patients with T2DM and COVID-19.

Assessment of risk, severity, mortality, glycemic control and antidiabetic agents in patients with diabetes and COVID-19: A narrative review.

AIMS: Rising prevalence of non-communicable diseases world-wide has made diabetes an important comorbidity in patients with coronavirus disease-19 (COVID-19). We sought to review the risk, severity and mortality in COVID-19 and its relation to the glycemic control, and role of anti-diabetic agents in patients with diabetes. METHODS: A Boolean search was made in PubMed, MedRxiv and Google Scholar database until May 10, 2020 and full articles with supplementary appendix were retrieved using the specific key words related to the topic. RESULTS: There is a high prevalence of diabetes in patients with COVID-19. Patients with diabetes had a significantly more severe variety of COVID-19 and increased mortality, compared to the groups without diabetes. Moreover, poor glycemic control is associated with a significantly higher severe COVID-19 and increased mortality, compared to the well-controlled glycemic groups. No data currently available for or against any anti-diabetic agents in COVID-19. CONCLUSIONS: Diabetes, in particular poorly-controlled group is associated with a significantly higher risk of severe COVID-19 and mortality. This calls for an optimal glycemic control and an increased emphasis on future preventative therapies including the vaccination programs for these groups in addition to the traditional risk prevention such as social distancing and self-isolation.

Hyperglycemia without diabetes and new-onset diabetes are both associated with poorer outcomes in COVID-19.

Hyperglycemia with or without blood glucose in diabetes range is an emerging finding not uncommonly encountered in patients with COVID-19. Increasingly, all evidence currently available hints that both new-onset hyperglycemia without diabetes and new-onset diabetes in COVID-19 is associated with a poorer outcome compared with normoglycemic individuals and people with pre-existing diabetes.

Diabetes in COVID-19: Prevalence, pathophysiology, prognosis and practical considerations.

BACKGROUND AND AIMS: High prevalence of diabetes makes it an important comorbidity in patients with COVID-19. We sought to review and analyze the data regarding the association between diabetes and COVID-19, pathophysiology of the disease in diabetes and management of patients with diabetes who develop COVID-19 infection. METHODS: PubMed database and Google Scholar were searched using the key terms 'COVID-19', 'SARS-CoV-2', 'diabetes', 'antidiabetic therapy' up to April 2, 2020. Full texts of the retrieved articles were accessed. RESULTS: There is evidence of increased incidence and severity of COVID-19 in patients with diabetes. COVID-19 could have effect on the pathophysiology of diabetes. Blood glucose control is important not only for patients who are infected with COVID-19, but also for those without the disease. Innovations like telemedicine are useful to treat patients with diabetes in today's times.

Role of corticosteroid in the management of COVID-19: A systemic review and a Clinician's perspective.

BACKGROUND AND AIMS: Interest in corticosteroid therapy in COVID-19 has been rekindled after the results from Randomized Evaluation of COVid-19 thERapY (RECOVERY) Trial. However, the World health Organization has not recommended corticosteroid in the treatment of COVID-19. We sought to conduct a systematic review on the role of corticosteroid in the management of patients of COVID-19. METHODS: A systematic electronic search of PubMed, Cochrane and MedRxiv database using specific keywords was made up till June 17, 2020. Full text of all the original articles with supplementary appendix that fulfilled the inclusion criteria were retrieved and a detailed analysis of results were represented. RESULTS: Of the 5 studies (4 retrospective studies and 1 quasi-prospective study) conducted for evaluating the role of corticosteroids, 3 studies have shown benefit, while 2 studies shown no benefit and there was a suggestion of significant harm in critical cases in one sub-study. RECOVERY trial is the only randomized controlled trial that has shown a significant reduction of death by 35% in ventilated patients and by 20% amongst patients on supplemental oxygen therapy with the dexamethasone, although no benefit was observed in mild cases. CONCLUSIONS: While the results from retrospective studies are heterogenous and difficult to infer of a definitive protective benefit with corticosteroids, RECOVERY trial found a significantly better outcome with dexamethasone, mostly in severe cases. Nonetheless, more studies are needed to replicate the outcome shown in RECOVERY trial for a substantial conclusion.