Implementation of Sodium-Glucose Cotransporter (SGLT)-2 Inhibitors in Patients With Heart Failure Through a New Digital Strategy
Phase: NA
Conditions: Heart Failure
Sponsor: Morten Schou

 
 
 
 
 
 
Last updated: May 2023 
Implementation of Sodium-Glucose Cotransporter (SGLT)-2 Inhibitors in 
Patients with Heart Failure through a New Digital Strategy (EMAIL HF):  
A Randomized Clinical Trial 
Investigators 
 
Morten Schou, Professor, Cardiologist, PhD, Principal investigator, Department of Cardiology, Herlev-Gentofte Hospital, 
Copenhagen, DK, member of the steering committee (Voting) 
 
Lars Køber, Professor, Cardiologist, Chairman, Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen, DK, 
member of the steering committee (Voting) 
 
Mariam Elmegaard Malik, Medical Doctor, Daily Leader, Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen, DK, 
member of the steering committee (Voting) 
 
Trine Kiilerich Lauridsen, Cardiologist, PhD, Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen, DK, member of 
the steering committee (Voting) 
 
Jesper Jensen, Medical Doctor, PhD, Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen, DK, member of the steering 
committee (Voting) 
 
Emil Wolsk, Cardiologist, PhD, Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen, DK, member of the steering 
committee (Voting) 
 
Charlotte Andersson, Medical Doctor, PhD, Department of Medicine, Section of Cardiovascular Medicine, Boston Medical Center, 
Boston University School of Medicine, Boston, MA, USA, member of the steering committee (Voting) 
 
Jens Jakob Thune, Cardiologist, PhD, Department of Cardiology, Bispebjerg-Frederiksberg Hospital, Copenhagen, DK, member of 
the steering committee (Voting) 
 
Christian Ditlev Tuxen, Cardiologist, PhD, Department of Cardiology, Bispebjerg-Frederiksberg Hospital, Copenhagen, DK, 
member of the steering committee (Voting) 
 
Emil Fosbøl, Cardiologist, PhD, Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen, DK, member of the 
steering committee (Voting)  
 
Mads Kristian Ersbøll, Cardiologist, PhD, Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen, DK, member 
of the steering committee (Voting)  
 
Nadia Dridi, Cardiologist, PhD, Department of Cardiology, Roskilde University Hospital, Roskilde, DK, member of the steering 
committee (Voting) 
 
Morten Petersen, Cardiologist, PhD, Department of Cardiology, Amager-Hvidovre Hospital, Copenhagen, DK, member of the 
steering committee (Voting) 
 
Nis Ottesen Stride, Cardiologist, PhD, Department of Cardiology, Nordsjællands Hospital, Hillerød, DK, member of the steering 
committee (Voting) 
 
Anders Barasa, Cardiologist, PhD, Department of Cardiology, Glostrup Hospital, Copenhagen, DK, member of the steering 
committee (Voting) 
 
John McMurray, Cardiologist, Experienced Trialist, Department of Cardiology, University of Glasgow, Scotland, member of the 
steering committee (Voting) 
 
Mark Petrie, Cardiologist, Experienced Trialist, Department of Cardiology, University of Glasgow, Scotland, member of the 
steering committee (Voting) 
 
Patient representative (anonymous), followed in the Heart Failure Clinic, Herlev-Gentofte Hospital, Copenhagen, DK, member of 
the steering committee (Voting) 
 
Peter Bonfils, Medical Doctor, General Practitioner, member of the steering committee (Voting) 

 
 
 
 
 
 
Last updated: May 2023 
Objectives 
 
Primary objective 
The primary objective of the study is to investigate whether it is possible to implement novel medical 
therapies, in this case a sodium-glucose co-transporter-2 (SGLT-2) inhibitor to heart failure patients, 
through a new digital strategy and hereby increase the number of eligible patients initiating therapy 
and shorten the time to initiation compared to the process today.  
 
Secondary objectives 
Secondary objectives include developing a digital message system linked to an outpatient clinic that 
can be implemented and used across the healthcare system in Denmark and abroad when new 
scientific discoveries or therapies need to be implemented effectively.  
 
As we are investigating the implementation of a SGLT-2 inhibitor in heart failure patients, we also 
intend to prevent all-cause death and hospitalizations for heart failure as a secondary objective. 
Further, we will evaluate whether subgroups like elderly patients and patients with lower 
socioeconomic status have the same effect of the digital platform intervention. And finally, relevant 
health economic analyses, including cost-benefit analyses, will be conducted.  
 
Background 
In the last few decades, we have witnessed a great proliferation of new medical breakthroughs and 
discoveries across various medical fields, that have had great impact on the public health. At the same 
time, the recent and still ongoing COVID-19 pandemic has also revealed how vulnerable the health 
care system is to sudden and major challenges and its urgent need for structural and digital 
transformation.  
Today, literature states that when new scientific discoveries are published, it takes 10 years in average 
from the publication process of new guidelines to implementation in the health care system. 
Furthermore, it is stated that the complete process from research to clinical practice takes an average 
of 17 years. (1-3) Despite the continuous improvements in science, this loss of potential patient 
benefit remains one of the biggest challenges in the health care systems across the world.  
The explanation for the prolonged process is multifactorial. However, the most important factor 
seems to be the complexity of cross-institutional patient care involving several links, including out-
patient clinics, general practitioners, patient associations etc.  

 
 
 
 
 
 
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With this randomized clinical trial, we wish to address this issue by developing a digital strategy 
based on a simple e-mail system, where uniform information regarding new scientific discoveries 
including new therapy options, are sent directly from the healthcare experts to the patients in real 
time, bypassing the existing and delaying links as illustrated in Figure 1.  Also, in a world where 
patients continue to take more control of their own health, this becomes even more important. 
 
Today, a large patient group that is experiencing the issues stated above is the patients diagnosed with 
heart failure - a severe and continuously growing public health issue that is associated with substantial 
patient morbidity and mortality. As many as 1 in 5 people are expected to develop heart failure during 
their lifetime and only a quarter of the patients admitted to hospital for the first time will survive 
longer than 5 years. Researchers around the world have continuously been focusing on improving 
existing therapies and on finding new ways to treat this complex group of patients. Since 2019, strong 
and consistent evidence has accrued from clinical trials that a new heart failure therapy can reduce 
mortality risk and prevent admission for heart failure – the SGLT-2 inhibitors, dapagliflozin and 
empagliflozin. (4-6) Less than two years after, the therapy was already approved for clinical use in 
the treatment of heart failure by the U.S. Food and Drug Administration (FDA) and the European 
Medicines Agency (EMA), and clinical guidelines have also been updated accordingly. 
Despite the approval for clinical use, studies in the population have shown that the majority of eligible 
heart failure patients are not started on therapy, mainly due to the issues stated above, where some 
patients are followed by their general practitioner, some at the department of cardiology and some 
patients at the department of internal medicine due to coexisting comorbidities (7). 
 
To increase the number of eligible patients with heart failure initiating therapy with a SGLT2 
inhibitor, we plan to use the digital strategy to provide evidence-based and uniform information from 
clinical experts directly to the patients. In this way, we are evaluating in a randomized clinical trial 
design whether a new scientific discovery can be implemented faster by a digital strategy and direct 
involvement of the patients than by usual care in patients with chronic heart failure followed in a 
public healthcare system.  
 
Methods 
Study design 
The study is a pragmatic two-armed, multicentre, randomised clinical trial, that will be coordinated 
from the Department of Cardiology, Herlev-Gentofte University Hospital. All patients with a 

 
 
 
 
 
 
Last updated: May 2023 
registered diagnosis of heart failure living in The Capital Region of Denmark and Roskilde, who have 
not yet been started on therapy with SGLT-2 inhibitors will be identified and recruited from Danish 
nationwide registries through their personal identification number (CPR-number). In Denmark, the 
CPR-number is also linked to a personal secure mailbox, Digital Post, where all government letters 
including healthcare related letters are sent to the Danish citizens. These heart failure patients will be 
randomized 1:1 to receive a government e-mail from heart failure specialists, with information about 
the novel heart failure therapy, SGLT-2 inhibitors.  Beside information, the patients will be offered a 
consultation (phone or in person at a heart failure clinic) where a heart failure specialist will prescribe 
and initiate the therapy if the patient is eligible. Depending on the patients’ residential address and 
postal code, he or she will be referred to one of the following heart failure clinics: Herlev-Gentofte 
Hospital, 
Amager-Hvidovre 
Hospital, 
Bispebjerg-Frederiksberg 
Hospital, 
Rigshospitalet 
Blegdamsvej-Glostrup, Nordsjællands Hospital, or Zealand University Hospital, Roskilde. 
 
Hypothesis 
The main hypothesis of this study is that through a new digital strategy where patients with a certain 
registered diagnosis are contacted via e-mail (Digital Post) and informed about novel and approved 
therapy, in this case SGLT-2 inhibitors for heart failure patients, we can increase the number of 
eligible patients initiated on therapy significantly and shorten the time to initiation compared to a 
control group.  It is expected that the strategy will be highly cost effective, and that elderly and 
patients with a lower socioeconomic level, also will benefit from the digital implementation of SGLT-
2 inhibitors. 
 
Study population 
The study population consists of all registered patients with heart failure living in the Capital Region 
of Denmark and in Roskilde who have not yet initiated therapy with SGLT-2 inhibitors. Patients with 
and without type 2 diabetes will be included, and it is expected that approximately 20% of the patients 
with heart failure will have co-existing type 2 diabetes (10). 
 
Inclusion and exclusion criteria 
Eligible participants should fulfil all the following criteria:  
(1) Registered diagnosis of heart failure (ICD-10 code: DI50) within the last 10 years 
(2) Living in the Capital Region of Denmark or Roskilde 

 
 
 
 
 
 
Last updated: May 2023 
(3) Age >=20 years (adults)  
 
Patients matching any of the following criteria will be excluded:  
(1) Redeemed prescription of a SGLT-2 inhibitor after 2015 
(2) Type 1 diabetes mellitus 
(3) History of ketoacidosis 
(4) Chronic kidney disease in long-term dialysis 
(5) Living in a nursing home 
(6) Dementia 
(7) Cancer diagnosis within the last year (except prostate cancer and non-melonoma skin cancer).  
(8) Exemption from the public digital mailbox system 
 
Endpoints 
Primary endpoint  
1. Proportion of patients initiating therapy with a SGLT-2 inhibitor between the control and 
intervention group (from randomisation up to six months).  
 
 Secondary endpoint 
2. Time to first occurrence of a composite heart failure endpoint consisting of all-cause death or heart 
failure hospitalisation, with examination of the components of this composite (from randomisation to 
study end) 
Other outcome measures 
3. Number of all-cause deaths and heart failure hospitalisations, with examination of the components 
of this composite (from randomisation to study end) 
4. Time to first occurrence of a 3-point expanded composite heart failure endpoint consisting of all-
cause death, heart failure hospitalisation, or renal failure (from randomisation to study end) 

 
 
 
 
 
 
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5. Time to first occurrence of a 4-point expanded composite heart failure endpoint consisting of all-
cause death, heart failure hospitalisation, non-fatal myocardial infarction, non-fatal stroke (from 
randomisation to study end) 
6. Time to initiation of therapy with a SGLT-2 inhibitor (from randomisation to study end) 
7. Adherence to therapy (from randomisation to study end) 
8. Proportion of elderly (>75 years) initiating therapy with SGLT-2 inhibitors (from randomisation to 
study end) 
9. Proportion of patients with lower educational level initiating therapy with SGLT-2 inhibitors (from 
randomisation to study end) 
10. Proportion of patients with lower socioeconomic level initiating therapy with SGLT-2 inhibitors 
(from randomisation to study end) 
11. Proportion of immigrants initiating therapy with SGLT-2 inhibitors (from randomisation to study 
end) 
12. Proportion of patients with type 2 diabetes initiating therapy with SGLT-2 inhibitors (from 
randomisation to study end) 
13. Proportion of male and female patients initiating therapy with SGLT-2 inhibitors (from 
randomisation to study end) 
 
Randomisation, blinding, the intervention, and schedule of enrolment 
The setup of enrolment is illustrated in figure 2 and 3. All patients with heart failure living in the 
Capital Region of Denmark and Roskilde are identified through nationwide health care registers and 
randomised 1:1 (simple randomisation) to receive an e-mail via Digital Post regarding the novel 
therapy with SGLT-2 inhibitors (figure 4). The patients receiving an e-mail are encouraged to follow 
a weblink where they can register to be contacted by their local Heart Failure Clinic if they are 
interested in the therapy. A reminder is sent to those who have not responded or registered within 14 

 
 
 
 
 
 
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days. A heart failure specialist will then contact the patients and inform them about the therapy, 
evaluate their medical history through their medical record and obtain informed consent. When the 
cardiologist has confirmed eligibility with fulfilment of all inclusion criteria and no exclusion criteria 
the patients are then started on therapy with follow up at the Heart Failure Clinic or via the patient’s 
general practitioner. Due to the trial design, it is not possible to blind the patients nor the investigators. 
SGLT-2 inhibitors that are approved by the EMA (empagliflozin and dapagliflozin) and are in 
accordance with heart failure guidelines will be used equally. It is planned that n≈5,000 patients will 
receive an e-mail with information on SGLT-2 inhibitor therapy and n≈5,000 will not.  The patients 
will be randomized in blocks of approximately 200-400 patients each month except for July and 
December, which corresponds to ≈10,000 during the study period.  
 
Statistical analyses 
Patients allocated to receive an e-mail will be compared to the control group by conventional 
statistical methods (chi2 tests, log rank tests (non-parametric), and Cox proportional hazard regression 
analyses). Clinical information on the patients based on ICD-10 codes (see appendix) and other 
covariates including level of education, socioeconomic position, ethnicity etc. will be obtained by the 
Danish Health Data Authority. Prescriptions of a SGLT-2 inhibitor and other relevant therapies will 
also be obtained from the Danish Health Data Authority (11). 
 
Sample size considerations 
The trial’s primary objective is to evaluate the effect of the digital implementation strategy on SGLT2 
inhibitor uptake. However, powering the study solely for uptake would require a substantially smaller 
sample size and would not allow a meaningful assessment of whether increased uptake translates into 
differences in patient-important clinical outcomes. Therefore, the sample size was determined based 
on the key secondary clinical endpoint, defined as time to first HF hospitalization or all-cause 
mortality, while still ensuring sufficient precision for the primary analysis of uptake. 
Power calculations assume 80% statistical power with a two-sided significance level of 0.05. The 
anticipated intervention effect for the clinical endpoint is a hazard ratio of 0.80 (corresponding to a 
20% relative risk reduction), informed by evidence from large outcome trials of SGLT2 inhibitors in 
HF. Using a Cox proportional hazards model (with the assumed event rate, effect size, and variability 
in the population), the minimum required number of events to detect this difference is 631. The study 
population is expected to have a median time-to-event of approximately 5 years based on historical 

 
 
 
 
 
 
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data, and each participant is expected to be followed for at least 1 year. A 15% censoring rate is 
anticipated, reflecting withdrawal of consent and loss to follow-up (including emigration). Under 
these assumptions, the total required sample size is 5,788 patients to ensure accrual of the target 
number of events. 
 
Health economic analyses 
Health economic consequences of the study will be estimated by determining the annual healthcare 
utilization of HF patients receiving an e-mail via Digital Post compared with the matched controls. 
Data will be obtained from the Danish Health Data Authority. The cost estimates will be divided into 
direct and indirect costs. The direct costs include total cost of inpatient hospital care, total cost of 
outpatient clinic services provided, total drug prescription use and pharmacy costs, inpatient 
hospitalization by length of stay, outpatient clinic and general practitioners’ visits weighted by 
frequency. The indirect costs include reduced labour supply and public transfer payments (sick pay, 
pension, unemployment benefit, etc.) measured on an annual basis.  
 
Study organization  
Research team 
The EMAIL HF trial will be conducted by a highly specialized research team, based on a long-term 
collaboration in heart failure research between six hospitals (Herlev-Gentofte University Hospital, 
Rigshospitalet, 
Amager-Hvidovre-Glostrup 
Hospital, 
Bispebjerg-Frederiksberg 
Hospital, 
Nordsjællands Hospital, Roskilde University Hospital) and the Department of Biostatistics, 
University of Copenhagen in the Capital Region of Denmark.  The research team includes 
epidemiologists, heart failure specialists, professors of cardiology, and a professor in statistics. The 
trial will be conducted in collaboration with experienced trialists and epidemiologists in 
cardiovascular medicine from University of Glasgow, Scotland.  
 
Steering committee  
The executive steering committee consists of Mariam Elmegaard Malik (MEM), Emil Fosbøl (EM), 
Emil Wolsk (EW), Jesper Jensen (JJ), Charlotte Andersson (CA), Lars Køber (LK), Nadia Dridi 
(ND), Morten Petersen (MP), Mads Kristian Ersbøll (MKE), Nis Ottesen Stride (NOS), Anders 
Barasa (AB), Jens Jakob Thune (JJT), Christian Ditlev Tuxen (CDT), John McMurray (JM), Mark 
Petrie (MP) and Morten Schou (MS). The primary investigator is MS from Herlev-Gentofte 

 
 
 
 
 
 
Last updated: May 2023 
University Hospital and LK from Rigshospitalet is chairman. The steering committee is responsible 
for the study design, patient enrollment, reporting, registration at www.clinicaltrials.gov and 
publication of the trial. Members of the steering committee will have full access to the final trial data. 
 
Data Safety and Monitoring  
Adverse events will be recorded continuously via the nationwide health registers by the investigators 
(discontinuation of the drug, urinary tract infections, genitalia infections, hypoglycaemic events, 
volume depletion, acute renal failure, diabetic ketoacidosis, thromboembolic events, bone fractures). 
Before initiation of SGLT-2 inhibitor therapy, all patients will be informed to contact their primary 
physician in case of side effects. Information on drug discontinuation will be obtained by the 
nationwide health registries. 
 
Study center and time schedule 
All patients with heart failure are identified from nationwide Danish registers. Patient screening, 
randomization, and all protocol-specified assessments will take place at the Departments of 
Cardiology in each of the five sites/hospitals. It is expected that the trial process will begin in 
November 2021 and end in December 2025: 
2021 Q1-Q4: Application for funding  
2022 Q1-Q3: Approval by Danish authorities, preparation of study start 
2023 Q1: First patient first visit 
2025 Q1: Last patient last visit 
2026 Q2-Q4: Presentation of results and publication 
 
Patient involvement 
Two heart failure patients are involved in the process of formulating the e-mail with the information 
on SGLT-2 inhibitor therapy that will be sent to the heart failure patients during the study. One patient 
will be offered to be a member of the steering committee. The patients have already been introduced 
to the research idea and concept and find the study highly relevant from a patient perspective. 
 
Ethics and severe adverse events 
During the trial, all adverse events (AEs) and severe adverse events (SAEs) related to the study drug 
(i.e., volume depletion, renal events, major hypoglycaemic events, bone fractures, diabetic 

 
 
 
 
 
 
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ketoacidosis, and amputations) will be monitored continuously from the patients’ medical record that 
is linked to the nationwide health registers. Data on other adverse events will not be routinely 
collected 
in 
view 
of 
the 
extensive 
previous 
collection 
of 
safety 
data 
regarding 
dapagliflozin/empagliflozin (4,12). Relevant authorities including the principal investigator will be 
informed in accordance with applicable laws and International Conference of Harmonization Good 
Clinical Practice (ICH-GCP) guidelines (13). Dapagliflozin has been approved for treatment of heart 
failure patients with reduced ejection fraction since 2019 and empagliflozin in 2021. Guidelines have 
been updated accordingly. In the recent phase III trials, dapagliflozin and empagliflozin were very 
well tolerated thus the risk of adverse side effects to both drugs is expected to be low (4). If, however, 
a patient should suffer any harm from study participation, compensation is set by the public Patient 
Compensation Association in Denmark.  
The EMAIL HF trial has been evaluated and approved by The Ethical Committee of the Capital 
Region in Denmark which concluded that the study is ethically justifiable and that it can be initiated 
(F-22035916). The Ethical Committee of Denmark has also previously approved the suggested 
study design where patients are identified by nationwide registries and then contacted by e-mail via 
Digital Post (14,15). 
 
Dissemination of results 
After completion of the trial, the results of the study will be submitted to international peer-reviewed 
scientific journals, irrespective of the outcome. Based on the recommendations of the International 
Committee of Medical Journal Editors (ICMJE), the steering committee will assess authorship 
eligibility for the scientific papers related to the trial. Furthermore, the results will be presented at 
national and international conferences by members of the steering committee. The study will result 
in one main publication and at least five publications of the predefined substudies of interest. 
 
Conclusions and clinical implications 
Based on a simple digital strategy, where scientific information regarding novel therapy options is 
sent directly from clinical experts to the patients via Digital Post, the EMAIL HF trial is expected to 
increase the number of eligible patients initiating therapy and to shorten the time to initiation 
markedly, compared to the process today. The trial will also answer the question whether a digital 
strategy is effective in vulnerable patient subgroups like elderly patients and patients with lower 

 
 
 
 
 
 
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education level. If the study hypotheses are confirmed the results have to potential to change the 
structure and organization of the healthcare system in Denmark and abroad. 
 
Secondary, because the digital strategy will be investigated in patients with heart failure where the 
patients will receive information regarding the new therapy option with SGLT-2 inhibitors, 
dapagliflozin and empagliflozin the trial is also expected to reduce the burden of morbidity and 
increase quality and length of life in this large and vulnerable patient group.   
   
 
 
 
 
 
 
 
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Figure 1.  Study hypothesis 
 
 
 
 
 

 
 
 
 
 
 
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Figure 2.  Study design 
 
 
 
 

 
 
 
 
 
 
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Figure 3.  Patient enrolment 
 
 
*One study year accounts for 44 weeks, with no patient inclusion in July and December. 
 
 
 

 
 
 
 
 
 
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Figure 4. Patient randomisation