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

Baseline characteristics.

<p>Baseline characteristics.</p

Rate-ratios for incidence of events of adherence to medication.

<p>Rate-ratios for Age (per 5 years), Diabetes duration (per 5 years), Country of origin with Denmark as reference, Medication Complexity score (per 1 unit), and Number of transitions out of state (per 1 transition). Panel A: For first initiation of treatment. For implementation: Panel B1: For running out of supply into a supply gap; Panel B2: For resuming supply of medicine after a supply gap. Panel C: For first discontinuation of treatment. Panels A–D show rate-ratios for metformin, sulfonylureas, acetylsalicylic acid, thiazide diuretics, ACEs & ARBs, and statins. DM, Diabetes Mellitus. MC score, Medication Complexity score. ACEs, Angiotensin Converting Enzyme inhibitors. ARBs, Angiotensin Receptor Blockers.</p

Time course of adherence to metformin, sulfonylureas, acetylsalicylic acid, thiazide diuretics, ACEs & ARBs, and statins.

<p>Patients are categorized in one of five different states during follow-up: Waiting and not having initiated treatment yet is represented by the blue area in the figure; having filled prescriptions and having sufficient supply of medication to cover the daily prescribed dose (green area); being without supplies for a maximum of 50 days (yellow area); having discontinued treatment after a gap of 50 days without supplies of medication (red area), whereas the purple area represents patients who do not initiate treatment by filling a prescription within the first 360 days and hence have not accepted the treatment. Patients will move between the 5 states during follow-up according to their adherence behavior. The proportion of patients in each of the 5 states at any given time is shown on the vertical axis. Further details are described by Jensen et al.[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0179546#pone.0179546.ref019" target="_blank">19</a>].</p

Use of 13 most commonly prescribed medicines.

<p>Use of 13 most commonly prescribed medicines.</p

Linear associations between birth weight and measures of adult adiposity.

<p>Estimates for men (black) and women (grey) with 95% CI. • Model 1: Unadjusted. ▴ Model 2: Adjusted for age, birthplace, ancestry and family history of obesity. ▪ Model 3: Adjusted for as model 2 incl. waist circumference.</p

Characteristics of the study population (n = 1473).

a<p>Mean ± SD (all such values).</p>b<p>n (%) (all such values).</p><p>Characteristics of the study population (n = 1473).</p

Associations between birth weight and measures of adiposity stratified by sex.

a<p>Model 1. Unadjusted model.</p>b<p>Model 2. Adjusted for age, birthplace, ancestry and family history of obesity.</p>c<p>Model 3. Adjusted for age, birthplace, ancestry, family history of obesity and waist circumference (left column).</p>d<p>Model 3. Adjusted for age, birthplace, ancestry, family history of obesity and birth weight (right column).</p><p>Associations between birth weight and measures of adiposity stratified by sex.</p

Splines showing the relations between birth weight and measures of adult adiposity for women.

<p>Quadratic splines of the relation between birth weight and (a) body mass index (BMI), (b) waist circumference, (c) fat mass index (FMI), (d) fat-free mass index (FFMI), (e) visceral adipose tissue (VAT) and (f) subcutaneous adipose tissue (SAT). The thick lines represent the relations predicted for a person aged 33, being full Inuit, born in a town, and reported family history of obesity. The full thin lines show the 95% CI and dotted lines show the 95% prediction interval.</p

Splines showing the relations between birth weight and measure of adult adiposity for men.

<p>Quadratic splines of the relation between birth weight and (a) body mass index (BMI), (b) waist circumference, (c) fat mass index (FMI), (d) fat-free mass index (FFMI), (e) visceral adipose tissue (VAT) and (f) subcutaneous adipose tissue (SAT). The thick lines represent the relations are predicted for a person aged 33, being full Inuit, born in a town, and reported family history of obesity. The full thin lines show the 95% CI and dotted lines show the 95% prediction interval.</p