Empagliflozin cardiovascular and renal effectiveness and safety compared to dipeptidyl peptidase-4 inhibitors across 11 countries in Europe and Asia : Results from the EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study

Background: Continued expansion of indications for sodium-glucose cotransporter-2 inhibitors increases importance of evaluating cardiovascular and kidney efficacy and safety of empagliflozin in patients with type 2 diabetes compared to similar therapies. Methods: The EMPRISE Europe and Asia study is a non-interventional cohort study using data from 2014 -2019 in seven European (Denmark, Finland, Germany, Norway, Spain, Sweden, United Kingdom) and four Asian (Israel, Japan, South Korea, Taiwan) countries. Patients with type 2 diabetes initiating empagliflozin were 1:1 propensity score matched to patients initiating dipeptidyl peptidase-4 inhibitors. Primary end-points included hospitalization for heart failure, all-cause mortality, myocardial infarction and stroke. Other cardiovascular, renal, and safety outcomes were examined.Findings: Among 83,946 matched patient pairs, (0.7 years overall mean follow-up time), initiation of empagli-flozin was associated with lower risk of hospitalization for heart failure compared to dipeptidyl peptidase-4 inhibitors (Hazard Ratio 0.70; 95% CI 0.60 to 0.83). Risks of all-cause mortality (0.55; 0.48 to 0.63), stroke (0. 82; 0.71 to 0.96), and end-stage renal disease (0.43; 0.30 to 0.63) were lower and risk for myocardial infarc-tion, bone fracture, severe hypoglycemia, and lower-limb amputation were similar between initiators of empagliflozin and dipeptidyl peptidase-4 inhibitors. Initiation of empagliflozin was associated with higher risk for diabetic ketoacidosis (1.97; 1.28 to 3.03) compared to dipeptidyl peptidase-4 inhibitors. Results were consistent across continents and regions.Interpretation: Results from this EMPRISE Europe and Asia study complements previous clinical trials and real-world studies by providing further evidence of the beneficial cardiorenal effects and overall safety of empagliflozin compared to dipeptidyl peptidase-4 inhibitors.(c) 2023 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)Peer reviewe

Association of symptoms with prior suspected or confirmed COVID-19, or prior viral or respiratory illness.

Hazard ratios for association of symptoms with previous infection after 12 weeks, by case category. Hazard ratios were adjusted for age, sex, age/sex interaction, number of consultations in the year before the index date, number of symptom days 1–3 months before the index date, recording of the specific symptom 1–3 months before the index date, ethnicity, smoking, body mass index and a generated propensity score for acquiring COVID-19 infection, with the baseline hazard function stratified by general practice.</p

Read terms for viral or respiratory illnesses.

BackgroundLong Covid is a widely recognised consequence of COVID-19 infection, but little is known about the burden of symptoms that patients present with in primary care, as these are typically recorded only in free text clinical notes.AimsTo compare symptoms in patients with and without a history of COVID-19, and investigate symptoms associated with a Long Covid diagnosis.MethodsWe used primary care electronic health record data until the end of December 2020 from The Health Improvement Network (THIN), a Cegedim database. We included adults registered with participating practices in England, Scotland or Wales. We extracted information about 89 symptoms and ‘Long Covid’ diagnoses from free text using natural language processing. We calculated hazard ratios (adjusted for age, sex, baseline medical conditions and prior symptoms) for each symptom from 12 weeks after the COVID-19 diagnosis.ResultsWe compared 11,015 patients with confirmed COVID-19 and 18,098 unexposed controls. Only 20% of symptom records were coded, with 80% in free text. A wide range of symptoms were associated with COVID-19 at least 12 weeks post-infection, with strongest associations for fatigue (adjusted hazard ratio (aHR) 3.46, 95% confidence interval (CI) 2.87, 4.17), shortness of breath (aHR 2.89, 95% CI 2.48, 3.36), palpitations (aHR 2.59, 95% CI 1.86, 3.60), and phlegm (aHR 2.43, 95% CI 1.65, 3.59). However, a limited subset of symptoms were recorded within 7 days prior to a Long Covid diagnosis in more than 20% of cases: shortness of breath, chest pain, pain, fatigue, cough, and anxiety / depression.ConclusionsNumerous symptoms are reported to primary care at least 12 weeks after COVID-19 infection, but only a subset are commonly associated with a GP diagnosis of Long Covid.</div

CONSORT diagram showing selection of patients in each category.

CONSORT diagram showing selection of patients in each category.</p

Association of symptoms with prior COVID-19 infection by time.

Hazard ratios for association of symptoms with previous COVID infection by time. Hazard ratios were adjusted for age, sex, age/sex interaction, number of consultations in the year before the index date, number of symptom days 1–3 months before the index date, recording of the specific symptom 1–3 months before the index date, ethnicity, smoking, body mass index and a generated propensity score for acquiring COVID-19 infection, with the baseline hazard function stratified by general practice.</p

Three class latent class model for symptoms among patients with Long Covid.

‘Long Covid’ was defined as either (a) presence of any symptom included in the WHO case definition of post COVID condition at least 12 weeks after the initial COVID-19 diagnosis, or (b) a symptom included in the secondary outcome of the study by Subramanian et al. (Nat Med 2022, doi: 10.1038/s41591-022-01909-w, S3 Table), for comparison with that study. For (a), symptoms in the 3 months after the WHO symptom were used in the latent class analysis; for (b) symptom records at any time were used. Cluster descriptions for (a): Class 1 (50.8%): Anxiety / depression (26%), Fatigue / asthenia (19%), Abdominal pain (17%), Headache (13%), Nausea / vomiting (12%), Joint pain (11%), Diarrhoea (10%), Constipation (10%). Class 2 (35.2%): Shortness of breath (67%), Cough (34%), Fatigue / asthenia (28%), Chest pain (20%), Anxiety / depression (17%), Wheezing (13%). Class 3 (13.9%): Shortness of breath (64%), Anxiety / depression (49%), Nausea / vomiting (47%), Cough (42%), Chest pain (37%), Fatigue / asthenia (34%), Abdominal pain (34%), Constipation (28%), Diarrhoea (25%), Purpura / rash (24%), Wheezing (24%), Palpitations / tachycardia (22%), Chills and fever (21%), Headache (18%), Limb swelling (17%), Presyncope / dizziness (16%), Phlegm (16%), Gastric reflux (14%), Weight loss (14%), Paraesthesia (13%), Joint pain (13%), Bloating (12%), Allergies / angioedema (11%). Cluster descriptions for (b): Class 1 (68.8%): Anxiety / depression (17%), Purpura / rash (15%), Fatigue / asthenia (12%), Nausea / vomiting (10%), Shortness of breath (10%). Class 2 (19.0%): Shortness of breath (74%), Cough (56%), Chest pain (29%), Fatigue / asthenia (27%), Wheezing (27%), Anxiety / depression (21%), Phlegm (16%). Class 3 (12.3%): Shortness of breath (53%), Nausea / vomiting (53%), Anxiety / depression (50%), Fatigue / asthenia (47%), Abdominal pain (43%), Cough (41%), Diarrhoea (32%), Constipation (31%), Chest pain (30%), Purpura / rash (29%), Headache (26%), Chills and fever (24%), Presyncope / dizziness (22%), Palpitations / tachycardia (21%), Paraesthesia (20%), Joint pain (18%), Weight loss (18%), Limb swelling (18%), Gastric reflux (18%), Bloating (15%), Wheezing (14%), Phlegm (12%). (PDF)</p

Long Covid symptoms and diagnosis in primary care: a cohort study using structured and unstructured data in The Health Improvement Network primary care database

Background: Long Covid is a widely recognised consequence of COVID-19 infection, but little is known about the burden of symptoms that patients present with in primary care, as these are typically recorded only in free text clinical notes.Aims: to compare symptoms in patients with and without a history of COVID-19, and investigate symptoms associated with a Long Covid diagnosis.Method: we used primary care electronic health record data until the end of December 2020 from The Health Improvement Network (THIN), a Cegedim database. We included adults registered with participating practices in England, Scotland or Wales. We extracted information about 89 symptoms and ‘Long Covid’ diagnoses from free text using natural language processing. We calculated hazard ratios (adjusted for age, sex, baseline medical conditions and prior symptoms) for each symptom from 12 weeks after the COVID-19 diagnosis.Results: we compared 11,015 patients with confirmed COVID-19 and 18,098 unexposed controls. Only 20% of symptom records were coded, with 80% in free text. A wide range of symptoms were associated with COVID-19 at least 12 weeks post-infection, with strongest associations for fatigue (adjusted hazard ratio (aHR) 3.46, 95% confidence interval (CI) 2.87, 4.17), shortness of breath (aHR 2.89, 95% CI 2.48, 3.36), palpitations (aHR 2.59, 95% CI 1.86, 3.60), and phlegm (aHR 2.43, 95% CI 1.65, 3.59). However, a limited subset of symptoms were recorded within 7 days prior to a Long Covid diagnosis in more than 20% of cases: shortness of breath, chest pain, pain, fatigue, cough, and anxiety / depression.Conclusions: numerous symptoms are reported to primary care at least 12 weeks after COVID-19 infection, but only a subset are commonly associated with a GP diagnosis of Long Covid.</p

Elbow plot for latent class analysis.

Elbow plot from latent class analysis for symptoms occurring within 3 months of a WHO Long Covid symptom, among patients at least 12 weeks after a COVID infection. The inflexion point at 2 classes shows that additional classes do not improve the fit of the model. AIC, Akaike Information Criterion; BIC, Bayesian Information Criterion; SABIC, sample size adjusted Bayesian Information Criterion; CAIC, Corrected Akaike Information Criterion. (PDF)</p

Baseline characteristics of patients by cohort.

BackgroundLong Covid is a widely recognised consequence of COVID-19 infection, but little is known about the burden of symptoms that patients present with in primary care, as these are typically recorded only in free text clinical notes.AimsTo compare symptoms in patients with and without a history of COVID-19, and investigate symptoms associated with a Long Covid diagnosis.MethodsWe used primary care electronic health record data until the end of December 2020 from The Health Improvement Network (THIN), a Cegedim database. We included adults registered with participating practices in England, Scotland or Wales. We extracted information about 89 symptoms and ‘Long Covid’ diagnoses from free text using natural language processing. We calculated hazard ratios (adjusted for age, sex, baseline medical conditions and prior symptoms) for each symptom from 12 weeks after the COVID-19 diagnosis.ResultsWe compared 11,015 patients with confirmed COVID-19 and 18,098 unexposed controls. Only 20% of symptom records were coded, with 80% in free text. A wide range of symptoms were associated with COVID-19 at least 12 weeks post-infection, with strongest associations for fatigue (adjusted hazard ratio (aHR) 3.46, 95% confidence interval (CI) 2.87, 4.17), shortness of breath (aHR 2.89, 95% CI 2.48, 3.36), palpitations (aHR 2.59, 95% CI 1.86, 3.60), and phlegm (aHR 2.43, 95% CI 1.65, 3.59). However, a limited subset of symptoms were recorded within 7 days prior to a Long Covid diagnosis in more than 20% of cases: shortness of breath, chest pain, pain, fatigue, cough, and anxiety / depression.ConclusionsNumerous symptoms are reported to primary care at least 12 weeks after COVID-19 infection, but only a subset are commonly associated with a GP diagnosis of Long Covid.</div

Hazard ratios by level of adjustment.

Association of symptoms with previous COVID infection after 12 weeks, by level of adjustment. ‘Fully adjusted hazard ratios’ were adjusted for age, sex, age/sex interaction, number of consultations in the year before the index date, number of symptom days 1–3 months before the index date, recording of the specific symptom 1–3 months before the index date, ethnicity, smoking, body mass index and a generated propensity score for acquiring COVID-19 infection, and stratified by general practice. (PDF)</p