Proton Pump Inhibitor Use and the Risk of Cardiovascular Complications and Death in Older Adults with Diabetes: A Population-Based Cohort Study.

BACKGROUND: The unfavorable effect of proton pump inhibitors (PPIs) on cardiovascular (CV) outcomes and mortality was reported in the general population. We investigated the impact of PPIs on CV outcomes and total mortality in older people with diabetes mellitus (DM) for whom evidence is missing. METHODS: Using administrative health databases of the Lombardy Region, we analyzed the risk of myocardial infarction (MI), ischemic stroke and total mortality in individuals with DM (≥65 years of age) exposed to PPIs in 2015 and followed up to 2021. The outcomes were analyzed using a multivariable-adjusted Cox proportional hazards model to compute hazard ratios (HRs) with 95% confidence intervals (CIs). HRs between PPI users and non-users were also estimated in selected subgroups. A sensitivity analysis was also performed in a 1:1 propensity score matching population. RESULTS: A total of 284,068 patients were included in the analysis (49.4% PPI users, 50.6% non-PPI users). A higher prevalence of comorbidities and medications was reported in PPI users as compared with non-users. During a median follow-up of 6.7 years, the use of PPIs was associated with a higher risk for ischemic stroke (HR 1.14, 95% CI 95% 1.08-1.20), MI (HR 1.36, 95% CI 1.31-1.41) and total mortality (HR 1.24, 95% CI 1.22-1.26). These risks were higher in PPI users regardless of the PPI type. Among sexes, previous CV diseases, and insulin subgroups, the use of PPIs was correlated with a statistically significant increased risk of ischemic stroke in men, in individuals without a history of CV disease, and in those who were not treated with insulin. A significantly higher risk of MI was associated with PPIs for all subgroups, as well as for total mortality, with the exception of patients with a previous history of CV diseases. The sensitivity analysis confirmed the results of the unmatched cohort. CONCLUSIONS: Our findings confirmed an increased risk of CV events and all-cause mortality in a large population of older adults with DM exposed to PPIs. This could have an important impact on public health and costs for National Health Service, therefore a regular assessment of PPI appropriateness is recommended, particularly in this population.

Prevalence and Predictors of Post-Acute COVID-19 Symptoms in Italian Primary Care Patients.

BACKGROUND: Despite all the progress in the management of acute COVID-19, it is still not clear why some people continue to experience symptoms after recovery. Using data from a self-administered online survey, we assessed the prevalence and predictors of post-acute COVID-19 in an unselected population followed by GPs. METHODS: Patients ≥18 years with a confirmed COVID-19 diagnosis were included. The survey collected information on demographics, risk factors, COVID-19 course and symptomatology. Fatigue and Quality of Life questionnaires were also administered. Descriptive statistics were used to describe patients' characteristics, stratified as acute and post-acute COVID-19. Logistic regression models were used to assess the association between clinical characteristics and post-acute COVID-19. RESULTS: A total of 1108 surveys were analyzed. Nearly 29% of patients reported post-acute COVID-19. The more persistent symptoms were fatigue, memory and concentration impairment. Adjusted Odds Ratio (OR) showed a significantly higher probability of post-acute COVID-19 for women compared to men (OR 1.9, 95% CI 1.4-2.5), for age >50 years than ≤50 years (OR 1.6, 95% CI 1.2-2.2), for BMI > 25 compared to BMI ≤ 25 (OR 1.6, 95% CI 1.1-2.1) and those with autoimmune diseases, compared to those without (OR 1.8 95% CI 1.1-2.9). In addition, a significant association was found with COVID-19 hospitalization, anxiety and allergies. We found that post-acute COVID-19 patients showed a higher fatigue and a worst quality of life. CONCLUSIONS: These findings suggest the need for tailored personalized strategies to improve the management of patients with post-acute COVID-19.

Impact of first and second/third wave of COVID-19 pandemic on post-acute cardiovascular outcomes in Lombardy.

Background: COVID-19 has been associated with a higher risk of post-acute complications. Our aim was to analyze and compare post-acute cardiovascular complications of COVID-19 survivors of the first and second/third pandemic waves in Lombardy, in both hospitalized and non-hospitalized COVID-19 patients. Methods and results: We included adults aged ≥40 years infected during the first and second/third waves of COVID-19 pandemic. The follow-up initiated 30 days after COVID-19 diagnosis and continued up to 9 months. Hazard ratios (HRs) and 95% confidence intervals (CIs) of the post-acute cardiovascular outcomes were calculated against an inverse probability treatment weighted control group. Subgroup analysis were performed by age classes, sex, previous cardiovascular disease and stratified by COVID-19 hospitalization status to explore the impact of COVID-19 severity on outcomes. Compared to the control group, COVID-19 patients had an increased risk of hospitalization for any cardiovascular complications (HR 1st wave 1.53 95% CI: 1.38-1.69; HR 2nd/3rd wave 1.25 95% CI: 1.19-1.31) and for individual cardiovascular outcomes, although HRs were higher in COVID-19 group from the 1st pandemic wave. The results were confirmed in the subgroup analyses. Of note, the risk for any cardiovascular disease was also evident even among individuals who were not hospitalized during the acute phase of the infection. Conclusion: Our results provide evidence that COVID-19 is a risk factor for post-acute cardiovascular complications among different pandemic waves regardless of COVID-19 severity, age, sex and a history of cardiovascular diseases. Care strategies of people with COVID-19 should include cardiac monitoring.

The Moli-sani risk score, a new algorithm for measuring the global impact of modifiable cardiovascular risk factors.

BACKGROUND: Cardiovascular (CV) disease is preventable through interventions targeting modifiable factors. Most algorithms based on modifiable CV risk factors (CV-rf) have been developed in US populations and do not account for the role of diet. We aimed to assess an algorithm based on modifiable CV-rf including diet, using data from an Italian population. METHODS: To derive the Moli-sani Risk Score (MRS), we used data on 16,656 men and women (age ≥ 35 y) from the population of the Moli-sani Study. The Risk-and-Prevention-Study, Italy (N = 8606) acted as external validation cohort and the Life's-Simple-7 score was used as benchmark. The MRS targeted at fatal or non-fatal CV events and included 9 common modifiable CV-rf. RESULTS: After 8.1 years (median) of follow-up, 816 events occurred in the derivation cohort. The MRS was calculated as a weighted sum of its 9 components, with weights reflecting the strength of the association. In comparison with individuals in the first, those in the fourth quartile of the score had hazard ratio (HR) for CV events equal to 3.18 (95%CI: 2.54-3.97). One more point in the score was associated with 7% (6%-8%) and 4% (3%-5%) higher hazard of events in the derivation and validation cohort, respectively. The MRS performed better than the Life's Simple-7 for discrimination. CONCLUSION: We propose the Moli-sani Risk Score, a validated, performing algorithm able to measure the combined impact that modifiable CV-rf have on CV risk. The score can be used to design preventive interventions, quantify the effectiveness of interventions, and compare different preventive strategies.

Rationale and design of the CV-PREVITAL study: an Italian multiple cohort randomised controlled trial investigating innovative digital strategies in primary cardiovascular prevention.

INTRODUCTION: Prevention of cardiovascular disease (CVD) is of key importance in reducing morbidity, disability and mortality worldwide. Observational studies suggest that digital health interventions can be an effective strategy to reduce cardiovascular (CV) risk. However, evidence from large randomised clinical trials is lacking. METHODS AND ANALYSIS: The CV-PREVITAL study is a multicentre, prospective, randomised, controlled, open-label interventional trial designed to compare the effectiveness of an educational and motivational mobile health (mHealth) intervention versus usual care in reducing CV risk. The intervention aims at improving diet, physical activity, sleep quality, psycho-behavioural aspects, as well as promoting smoking cessation and adherence to pharmacological treatment for CV risk factors. The trial aims to enrol approximately 80 000 subjects without overt CVDs referring to general practitioners' offices, community pharmacies or clinics of Scientific Institute for Research, Hospitalization and Health Care (Italian acronym IRCCS) affiliated with the Italian Cardiology Network. All participants are evaluated at baseline and after 12 months to assess the effectiveness of the intervention on short-term endpoints, namely improvement in CV risk score and reduction of major CV risk factors. Beyond the funded life of the study, a long-term (7 years) follow-up is also planned to assess the effectiveness of the intervention on the incidence of major adverse CV events. A series of ancillary studies designed to evaluate the effect of the mHealth intervention on additional risk biomarkers are also performed. ETHICS AND DISSEMINATION: This study received ethics approval from the ethics committee of the coordinating centre (Monzino Cardiology Center; R1256/20-CCM 1319) and from all other relevant IRBs and ethics committees. Findings are disseminated through scientific meetings and peer-reviewed journals and via social media. Partners are informed about the study's course and findings through regular meetings. TRIAL REGISTRATION NUMBER: NCT05339841.

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.

Impact of chronic GLP-1 RA and SGLT-2I therapy on in-hospital outcome of diabetic patients with acute myocardial infarction.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter-2 inhibitors (SGLT-2i) demonstrated cardiovascular and renal protection. Whether their benefits occur also during hospitalization for acute myocardial infarction (AMI) in patients with diabetes mellitus (DM) is not known. We evaluated in-hospital outcomes of patients hospitalized with AMI according to their chronic use of GLP-1 RA and/or SGLT-2i. METHODS: Using the health administrative databases of Lombardy, patients hospitalized with AMI from 2010 to 2019 were included. They were stratified according to DM status, then grouped into three cohorts using a propensity score matching: non-DM patients; DM patients treated with GLP-1 RA and/or SGLT-2i; DM patients not treated with GLP-1 RA/SGLT-2i. The primary endpoint of the study was the composite of in-hospital mortality, acute heart failure, and acute kidney injury requiring renal replacement therapy. RESULTS: We identified 146,798 patients hospitalized with AMI (mean age 71 ± 13 years, 34% females, 47% STEMI; 26% with DM). After matching, 3,090 AMI patients (1030 in each group) were included in the analysis. Overall, the primary endpoint rate was 16% (n = 502) and progressively increased from non-DM patients to DM patients treated with and without GLP-1 RA/SGLT-2i (13%, 16%, and 20%, respectively; P < 0.0001). Compared with non-DM patients, DM patients with GLP-1 RA/SGLT-2i had a 30% higher risk of the primary endpoint, while those not treated with GLP-1 RA/SGLT-2i had a 60% higher risk (P < 0.0001). CONCLUSION: Chronic therapy with GLP-1 RA and/or SGLT-2i has a favorable impact on the clinical outcome of DM patients hospitalized with AMI.

Diabetes mellitus duration and mortality in patients hospitalized with acute myocardial infarction.

BACKGROUND: Diabetes mellitus (DM) is associated with an increased mortality risk in patients hospitalized with acute myocardial infarction (AMI); however, no studies have investigated the impact of the duration of DM on in-hospital mortality. In this study, we evaluated in-hospital mortality in AMI patients according to DM status and its duration. METHODS: Using health administrative databases of Lombardy, DM patients≥50 years hospitalized with AMI from 2010 to 2019 were included in the analysis and were stratified according to the duration of DM: <5, 5-10, and > 10 years. The primary endpoint was mortality during AMI hospitalization and the secondary endpoint was 1-year mortality in comparison with No-DM patients. Logistic and Cox regressions analyses were used to estimate odds ratios (ORs, CI 95%) and hazard ratios (HRs, CI 95%) for the outcomes, according to DM status and duration and AMI type (STEMI and NSTEMI). RESULTS: Our study cohort comprised 29,566 and 109,247 DM and No-DM patients, respectively. Adjusted ORs and HRs showed a significantly higher risk of in-hospital mortality (OR 1.50, 95% CI 1.43-1.58) and 1-year mortality (HR 1.51, 95% CI 1.46-1.55) in DM patients in comparison with those without. These risks increased progressively with the duration of DM, with the highest risk observed in patients with DM duration ≥ 10 years (OR 1.59, 95% CI 1.50-1.69 for in-hospital mortality and HR 1.59, 95% CI 1.53-1.64 for 1-year mortality). These findings were similar in STEMI and in NSTEMI patients. CONCLUSIONS: Our study demonstrates that the duration of DM parallels mortality risk in patients hospitalized with AMI, highlighting that DM duration should be considered as an important early prognostic risk factor in patients with AMI.

Lifetime risk, life expectancy, and years of life lost to type 2 diabetes in 23 high-income jurisdictions: a multinational, population-based study.

BACKGROUND: Diabetes is a major public health issue. Because lifetime risk, life expectancy, and years of life lost are meaningful metrics for clinical decision making, we aimed to estimate these measures for type 2 diabetes in the high-income setting. METHODS: For this multinational, population-based study, we sourced data from 24 databases for 23 jurisdictions (either whole countries or regions of a country): Australia; Austria; Canada; Denmark; Finland; France; Germany; Hong Kong; Hungary; Israel; Italy; Japan; Latvia; Lithuania; the Netherlands; Norway; Scotland; Singapore; South Korea; Spain; Taiwan; the UK; and the USA. Our main outcomes were lifetime risk of type 2 diabetes, life expectancy in people with and without type 2 diabetes, and years of life lost to type 2 diabetes. We modelled the incidence and mortality of type 2 diabetes in people with and without type 2 diabetes in sex-stratified, age-adjusted, and calendar year-adjusted Poisson models for each jurisdiction. Using incidence and mortality, we constructed life tables for people of both sexes aged 20-100 years for each jurisdiction and at two timepoints 5 years apart in the period 2005-19 where possible. Life expectancy from a given age was computed as the area under the survival curves and lifetime lost was calculated as the difference between the expected lifetime of people with versus without type 2 diabetes at a given age. Lifetime risk was calculated as the proportion of each cohort who developed type 2 diabetes between the ages of 20 years and 100 years. We estimated 95% CIs using parametric bootstrapping. FINDINGS: Across all study cohorts from the 23 jurisdictions (total person-years 1 577 234 194), there were 5 119 585 incident cases of type 2 diabetes, 4 007 064 deaths in those with type 2 diabetes, and 11 854 043 deaths in those without type 2 diabetes. The lifetime risk of type 2 diabetes ranged from 16·3% (95% CI 15·6-17·0) for Scottish women to 59·6% (58·5-60·8) for Singaporean men. Lifetime risk declined with time in 11 of the 15 jurisdictions for which two timepoints were studied. Among people with type 2 diabetes, the highest life expectancies were found for both sexes in Japan in 2017-18, where life expectancy at age 20 years was 59·2 years (95% CI 59·2-59·3) for men and 64·1 years (64·0-64·2) for women. The lowest life expectancy at age 20 years with type 2 diabetes was observed in 2013-14 in Lithuania (43·7 years [42·7-44·6]) for men and in 2010-11 in Latvia (54·2 years [53·4-54·9]) for women. Life expectancy in people with type 2 diabetes increased with time for both sexes in all jurisdictions, except for Spain and Scotland. The life expectancy gap between those with and without type 2 diabetes declined substantially in Latvia from 2010-11 to 2015-16 and in the USA from 2009-10 to 2014-15. Years of life lost to type 2 diabetes ranged from 2·5 years (Latvia; 2015-16) to 12·9 years (Israel Clalit Health Services; 2015-16) for 20-year-old men and from 3·1 years (Finland; 2011-12) to 11·2 years (Israel Clalit Health Services; 2010-11 and 2015-16) for 20-year-old women. With time, the expected number of years of life lost to type 2 diabetes decreased in some jurisdictions and increased in others. The greatest decrease in years of life lost to type 2 diabetes occurred in the USA between 2009-10 and 2014-15 for 20-year-old men (a decrease of 2·7 years). INTERPRETATION: Despite declining lifetime risk and improvements in life expectancy for those with type 2 diabetes in many high-income jurisdictions, the burden of type 2 diabetes remains substantial. Public health strategies might benefit from tailored approaches to continue to improve health outcomes for people with diabetes. FUNDING: US Centers for Disease Control and Prevention and Diabetes Australia.

Effectiveness and safety of GLP-1 receptor agonists versus SGLT-2 inhibitors in type 2 diabetes: an Italian cohort study.

BACKGROUND: GLP-1 receptor agonists (GLP-1 RA) and SGLT-2 inhibitors (SGLT-2i) have shown to reduce the risk of major adverse cardiovascular events (MACE), death and worsening nephropathy when added to standard of care. However, these two dug classes differ in efficacy and safety. We compared the effectiveness and safety profile of GLP-1 RA and SGLT-2i in a large and unselected cohort of patients with type 2 diabetes resident in Lombardy from 2015 to 2020. METHODS: Using linkable administrative health databases, we included patients aged 50 years and older initiating GLP-1 RA or SGLT-2i. Clinical events were: death, hospital admission for myocardial infarction (MI), stroke, heart failure (HF), and renal disease as individual and composite outcomes (MACE-3: all cause-death, non-fatal MI, non-fatal stroke; MACE-4: MACE-3 plus unstable angina). Outcomes were evaluated separately in subjects with and without previous cardiovascular (CV) diseases. Treatments were compared using Cox proportional hazards regression model after Propensity Score Matching (PSM) in both intention-to-treat (ITT) and per protocol (PP) analyses. Serious adverse events were also evaluated. RESULTS: The analysis comprised 20,762 patients per cohort. The ITT analysis showed a significant risk reduction for non-fatal MI (HR 0.77; CI 95% 0.66-0.90), MACE-3 (HR 0.91; CI 95% 0.84-0.98), and MACE-4 (HR 0.92; CI 95% 0.86-0.99) in GLP-1RA compared with SGLT-2i users, while no difference was reported in the incidence of HF hospitalization and stroke between the two cohorts. Similar benefits were found in the subgroup of patients without previous CV diseases only. PP analysis largely confirmed the main results. The incidence of serious adverse events was low in both cohorts (< 1%). CONCLUSIONS: GLP-1RA showed to be equally safe and more effective than SGLT-2i in reducing the risk of MACE-3, MACE-4 and MI. This study adds to the growing body of real-world evidence addressing the specific clinical properties of GLP-1RA and SGLT-2i in everyday practice to tailor treatment to the individual patient.

Insulin treatment in patients with diabetes mellitus and heart failure in the era of new antidiabetic medications.

BACKGROUND: Coexistent heart failure (HF) and diabetes mellitus (DM) are associated with marked morbidity and mortality. Optimizing treatment strategies can reduce the number and severity of events. Insulin is frequently used in these patients, but its benefit/risk ratio is still not clear, particularly since new antidiabetic drugs that reduce major adverse cardiac events (MACEs) and renal failure have recently come into use. Our aim is to compare the clinical effects of insulin in a real-world setting of first-time users, with sodium-glucose cotransporter-2 inhibitor (SGLT-2i), glucagon-like peptide-1 receptor agonist (GLP-1RA) and the other antihyperglycemic agents (other-AHAs). METHODS: We used the administrative databases of two Italian regions, during the years 2010-2018. Outcomes in whole and propensity-matched cohorts were examined using Cox models. A meta-analysis was also conducted combining the data from both regions. RESULTS: We identified 34 376 individuals ≥50 years old with DM and HF; 42.0% were aged >80 years and 46.7% were women. SGLT-2i and GLP-1RA significantly reduced MACE compared with insulin and particularly death from any cause (SGLT-2i, hazard ratio (95% CI) 0.29 (0.23 to 0.36); GLP-1RA, 0.482 (0.51 to 0.42)) and first hospitalization for HF (0.57 (0.40 to 0.81) and 0.67 (0.59 to 0.76)). CONCLUSIONS: In patients with DM and HF, SGLT-2i and GLP-1RA significantly reduced MACE compared with insulin, and particularly any cause of death and first hospitalization for HF. These groups of medications had high safety profiles compared with other-AHAs and particularly with insulin. The inadequate optimization of HF and DM cotreatment in the insulin cohort is noteworthy.

Trends in all-cause mortality among people with diagnosed diabetes in high-income settings: a multicountry analysis of aggregate data.

BACKGROUND: Population-level trends in mortality among people with diabetes are inadequately described. We aimed to examine the magnitude and trends in excess all-cause mortality in people with diabetes. METHODS: In this retrospective, multicountry analysis, we collected aggregate data from 19 data sources in 16 high-income countries or jurisdictions (in six data sources in Asia, eight in Europe, one from Australia, and four from North America) for the period from Jan 1, 1995, to Dec 31, 2016, (or a subset of this period) on all-cause mortality in people with diagnosed total or type 2 diabetes. We collected data from administrative sources, health insurance records, registries, and a health survey. We estimated excess mortality using the standardised mortality ratio (SMR). FINDINGS: In our dataset, there were approximately 21 million deaths during 0·5 billion person-years of follow-up among people with diagnosed diabetes. 17 of 19 data sources showed decreases in the age-standardised and sex-standardised mortality in people with diabetes, among which the annual percentage change in mortality ranged from -0·5% (95% CI -0·7 to -0·3) in Hungary to -4·2% (-4·3 to -4·1) in Hong Kong. The largest decreases in mortality were observed in east and southeast Asia, with a change of -4·2% (95% CI -4·3 to -4·1) in Hong Kong, -4·0% (-4·8 to -3·2) in South Korea, -3·5% (-4·0 to -3·0) in Taiwan, and -3·6% (-4·2 to -2·9) in Singapore. The annual estimated change in SMR between people with and without diabetes ranged from -3·0% (95% CI -3·0 to -2·9; US Medicare) to 1·6% (1·4 to 1·7; Lombardy, Italy). Among the 17 data sources with decreasing mortality among people with diabetes, we found a significant SMR increase in five data sources, no significant SMR change in four data sources, and a significant SMR decrease in eight data sources. INTERPRETATION: All-cause mortality in diabetes has decreased in most of the high-income countries we assessed. In eight of 19 data sources analysed, mortality decreased more rapidly in people with diabetes than in those without diabetes. Further longevity gains will require continued improvement in prevention and management of diabetes. FUNDING: US Centers for Disease Control and Prevention, Diabetes Australia Research Program, and Victoria State Government Operational Infrastructure Support Program.

Metformin use is associated with a decrease in the risk of hospitalization and mortality in COVID-19 patients with diabetes: A population-based study in Lombardy.

AIM: To compare the association of metformin use and coronavirus disease 2019 (COVID-19) outcomes in a cohort of 31 966 patients with diabetes in Lombardy. METHODS: We used a COVID-19 linkable administrative regional database to select patients with diabetes who were aged 40 years or older. They had at least two prescriptions of antidiabetic drugs in 2019 and a positive test for severe acute respiratory syndrome coronavirus-2 from 15 February 2020 to 15 March 2021. The association of metformin use and clinical outcomes was assessed by multivariable logistic regression analyses and after propensity score matching (PSM). Clinical outcomes were all-cause mortality, in-hospital mortality, hospitalization for COVID-19, and admission to an intensive care unit (ICU). RESULTS: In multivariable models, metformin use was associated with a significantly lower risk of total mortality (OR 0.70; 95% CI 0.66-0.75), in-hospital mortality (OR 0.68; 95% CI 0.63-0.73), hospitalization for COVID-19 (OR 0.86; 95% CI 0.81-0.91), and ICU admission (OR 0.81; 95% CI 0.69-0.94) compared with metformin non-users. Results were similar after PSM; metformin was associated with a significantly lower risk of total mortality (OR 0.79; 95% CI 0.73-0.86), in-hospital mortality (OR 0.74; 95% CI 0.67-0.81), and ICU admission (OR 0.77; 95% CI 0.63-0.95). CONCLUSIONS: In this large cohort, metformin use was associated with a protective effect in COVID-19 clinical outcomes, suggesting that it might be a potentially useful drug to prevent severe COVID-19 disease, although randomized controlled trials (RCTs) are needed to confirm this. While awaiting the results of RCTs, we suggest continuing prescribing metformin to COVID-19 patients with diabetes.

High-dose ivermectin for early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial.

High concentrations of ivermectin demonstrated antiviral activity against SARS-CoV-2 in vitro. The aim of this study was to assess the safety and efficacy of high-dose ivermectin in reducing viral load in individuals with early SARS-CoV-2 infection. This was a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial. Participants were adults recently diagnosed with asymptomatic/oligosymptomatic SARS-CoV-2 infection. Exclusion criteria were: pregnant or lactating women; CNS disease; dialysis; severe medical condition with prognosis <6 months; warfarin treatment; and antiviral/chloroquine phosphate/hydroxychloroquine treatment. Participants were assigned (ratio 1:1:1) according to a randomised permuted block procedure to one of the following arms: placebo (arm A); single-dose ivermectin 600 µg/kg plus placebo for 5 days (arm B); and single-dose ivermectin 1200 µg/kg for 5 days (arm C). Primary outcomes were serious adverse drug reactions (SADRs) and change in viral load at Day 7. From 31 July 2020 to 26 May 2021, 32 participants were randomised to arm A, 29 to arm B and 32 to arm C. Recruitment was stopped on 10 June because of a dramatic drop in cases. The safety analysis included 89 participants and the change in viral load was calculated in 87 participants. No SADRs were registered. Mean (S.D.) log10 viral load reduction was 2.9 (1.6) in arm C, 2.5 (2.2) in arm B and 2.0 (2.1) in arm A, with no significant differences (P = 0.099 and 0.122 for C vs. A and B vs. A, respectively). High-dose ivermectin was safe but did not show efficacy to reduce viral load.

Trends in the incidence of diagnosed diabetes: a multicountry analysis of aggregate data from 22 million diagnoses in high-income and middle-income settings.

BACKGROUND: Diabetes prevalence is increasing in most places in the world, but prevalence is affected by both risk of developing diabetes and survival of those with diabetes. Diabetes incidence is a better metric to understand the trends in population risk of diabetes. Using a multicountry analysis, we aimed to ascertain whether the incidence of clinically diagnosed diabetes has changed over time. METHODS: In this multicountry data analysis, we assembled aggregated data describing trends in diagnosed total or type 2 diabetes incidence from 24 population-based data sources in 21 countries or jurisdictions. Data were from administrative sources, health insurance records, registries, and a health survey. We modelled incidence rates with Poisson regression, using age and calendar time (1995-2018) as variables, describing the effects with restricted cubic splines with six knots for age and calendar time. FINDINGS: Our data included about 22 million diabetes diagnoses from 5 billion person-years of follow-up. Data were from 19 high-income and two middle-income countries or jurisdictions. 23 data sources had data from 2010 onwards, among which 19 had a downward or stable trend, with an annual estimated change in incidence ranging from -1·1% to -10·8%. Among the four data sources with an increasing trend from 2010 onwards, the annual estimated change ranged from 0·9% to 5·6%. The findings were robust to sensitivity analyses excluding data sources in which the data quality was lower and were consistent in analyses stratified by different diabetes definitions. INTERPRETATION: The incidence of diagnosed diabetes is stabilising or declining in many high-income countries. The reasons for the declines in the incidence of diagnosed diabetes warrant further investigation with appropriate data sources. FUNDING: US Centers for Disease Control and Prevention, Diabetes Australia Research Program, and Victoria State Government Operational Infrastructure Support Program.

Temporal trends from 2005 to 2018 in deaths and cardiovascular events in subjects with newly diagnosed rheumatoid arthritis.

Although rheumatoid arthritis (RA) is associated with an increased risk of death and cardiovascular (CV) disease, the excess of these risks is expected to have diminished over time, in more recent incident cohorts with RA. We analysed the risk of all-cause death, stroke, and myocardial infarction as primary outcomes and all CV events as secondary outcomes in RA subjects compared to the general population, from 2005 to 2018. The risk outcomes were also evaluated in relation to the time since RA diagnosis. We conducted a cohort study using linkable administrative healthcare databases of the Lombardy Region, Northern Italy. Analyses included subjects newly diagnosed RA subjects and a random sample of No-RA subjects. An adjusted Cox proportional hazard regression model was used to calculate hazard ratios and 95% CIs for all outcomes. The study population comprised 16,047 RA subjects and 500,000 without RA. The risks of dying (HR 1.22, 95% CI 1.15-1.30), stroke (HR 1.39, 95% CI 1.22-1.58), myocardial infarction (HR 2.00, 95% CI 1.78-2.26) were significantly higher in the RA cohort, as were those that for secondary outcomes. Differences between RA and No-RA already emerged during the first five years after diagnosis. Risk patterns remained statistically significant during the next 5 years or more. Subjects with RA still have a higher risk of death and worse CV outcomes than the general population, appearing early and not decreasing with time. Preventive interventions are urgently needed.

Impact of liver disease on oral anticoagulant prescription and major adverse events in patients with atrial fibrillation: analysis from a population-based cohort study.

AIMS: Data on the impact of liver disease (LD) in patients with atrial fibrillation (AF) and the role of oral anticoagulant (OAC) drugs for stroke prevention are limited. METHODS AND RESULTS: A retrospective observational population-based cohort study on the administrative health databases of Lombardy region Italy. All AF patients ≥40 years admitted to hospital from 2000 to 2018 were considered. Atrial fibrillation and LD diagnosis were established using ICD9-CM codes. Use of OAC was determined with Anatomical Therapeutic Chemical codes. Primary study outcomes were stroke, major bleeding, and all-cause death. Among 393 507 AF patients, 16 168 (4.1%) had concomitant LD. Liver disease AF patients were significantly less treated with OAC. Concomitant LD was associated with an increased risk in all the study outcomes [hazard ratio (HR): 1.18, 95% confidence interval (CI): 1.11-1.25 for stroke; HR: 1.57, 95% CI: 1.47-1.66 for major bleeding; HR: 1.41, 95% CI: 1.39-1.44 for all-cause death]. Use of OAC in patients with AF and LD resulted in a reduction in stroke (HR: 0.80, 95% CI: 0.70-0.92), major bleeding (HR: 0.86, 95% CI: 0.74-0.99), and all-cause death (HR: 0.77, 95% CI: 0.73-0.80), with similar results according to subgroups. A net clinical benefit (NCB) analysis suggested a positive benefit/risk ratio in using OAC in AF patients with LD (NCB: 0.408, 95% CI: 0.375-0.472). CONCLUSION: In AF patients, concomitant LD carries a significantly higher risk for all clinical outcomes. Use of OAC in AF patients with LD was associated with a significant favourable benefit/risk ratio, even in high-risk patient subgroups.

Sex-related differences in prevalence, treatment and outcomes in patients with atrial fibrillation.

To analyze sex-related differences about AF prevalence, use of OAC and outcomes focusing on the older age classes. We used administrative data of the Lombardy Region, describing period prevalence, use of OAC and outcomes from 2002 to 2014 for all patients diagnosed with AF. AF prevalence over the 2002-2014 period was higher in males than in females (2.7% vs. 2.1%, p < 0.001), increasing with age. From 2003 to 2014, not treated AF patients decreased mostly in males (from 40.3 to 33.7% with respect to 43.7-39.8% in females). Age-stratified adjusted logistic regression analysis found that females were more likely treated with OAC when < 65 years in 2003 (OR 1.51, 95% CI 1.35-1.69) and in 2014 (OR 1.32, 95% CI 1.13-1.53); contrariwise, were less likely treated with OAC when age ≥ 75 years, in 2003 (OR 0.92, 95% CI 0.86-0.98) and in 2014 (OR 0.77, 95% CI 0.72-0.81).Adjusted Cox regression analysis confirmed that female AF patients had a higher risk of stroke (HR 1.18, 95% CI 1.14-1.21) and a lower risk of major bleeding (HR 0.83, 95% CI 0.80-0.86), while, had a lower risk for all-cause death (HR 0.82, 95% CI 0.80-0.83). AF prevalence was higher in male than in female patients, while thromboembolic risk was higher in female. Older female patients were under-treated with OAC particularly in recent years. Over long-term follow-up, female had a higher risk of stroke and a lower risk of major bleeding and all-cause death.

Long-Term Relationship Between Atrial Fibrillation, Multimorbidity and Oral Anticoagulant Drug Use.

OBJECTIVES: To analyze the relationship between atrial fibrillation (AF) and Charlson comorbidity index (CCI) in a population-based cohort study over a long-term follow-up period, in relation to oral anticoagulant (OAC) prescriptions and outcomes. PATIENTS AND METHODS: We used data from the administrative health databases of Lombardy. All patients with AF and age 40 years and older and who were admitted to the hospital in 2002 were considered for analysis and followed up to 2014. AF diagnosis and CCI were established according to codes from the International Classification of Diseases, Ninth Revision. RESULTS: In 2002, 24,040 patients were admitted with a diagnosis of AF. CCI was higher in patients with AF than in those without AF (1.8±2.1 vs 0.2±0.9; P<.001). Over 12 years of follow-up, AF was associated with an increased risk of higher CCI (beta coefficient, 1.69; 95% CI, 1.67-1.70). In patients with AF, CCI was inversely associated with OAC prescription at baseline (P<.001) and at the end of the follow-up (P=.03). Patients with AF and a high CCI (≥4) had a higher cumulative incidence of stroke, major bleeding, and all-cause death (all P<.001), compared with those with low CCI (range, 0-3). Adjusted Cox regression analysis revealed that time-dependent continuous CCI was associated with an increased risk for stroke, major bleeding, and all-cause death (all P<.001). CONCLUSIONS: In hospitalized patients, AF is associated with an increase in CCI that is inversely associated with OAC prescriptions during follow-up. CCI is independently associated with an increased risk of stroke, major bleeding, and all-cause death.