REVERsal to Normoglycemia by Treating PREDIABETES: The REVERT-PREDIABETES Trial
Phase: PHASE3
Conditions: Prediabetes, Chronic Coronary Syndrome
Sponsor: Michael Mæng

Trial protocol 
REVERsal to normoglycemia by Treating PREDIABETES: the REVERT-PREDIABETES trial 
 
November 2025 
Version 4.0 
 
 
 
The trial will be carried out in accordance with the protocol, current statutory legislation and the 
principles of good clinical practice. 
 
 
Time schedule 
Start of trial: November 1, 2025 
Estimated completion: October 31, 2029 
 
 
 
 

2 
 
Table of contents 
ABBREVIATIONS............................................................................................................................................................. 3 
INTRODUCTION .............................................................................................................................................................. 4 
BACKGROUND .................................................................................................................................................................. 4 
AIMS ................................................................................................................................................................................ 5 
STUDY POPULATIONS ........................................................................................................................................................ 6 
INVESTIGATIONAL MEDICINAL PRODUCTS ........................................................................................................................ 6 
RISK-BENEFIT ASSESSMENT .............................................................................................................................................. 7 
TRIAL PLAN AND DESIGN ............................................................................................................................................ 8 
PRIMARY AND SECONDARY ENDPOINTS ............................................................................................................................ 8 
DESIGN ........................................................................................................................................................................... 11 
RANDOMIZATION ............................................................................................................................................................ 14 
TRIAL DURATION ............................................................................................................................................................ 14 
TRIAL PERIOD ................................................................................................................................................................. 14 
INVESTIGATIONAL MEDICINAL PRODUCTS ................................................................................................................... 14 
ACCOUNTABILITY AND ADMINISTRATION ....................................................................................................................... 15 
TRIAL SUBJECTS......................................................................................................................................................... 16 
INCLUSION AND EXCLUSION CRITERIA ........................................................................................................................... 16 
WITHDRAWAL OF CONSENT ............................................................................................................................................ 17 
DISCONTINUATION OF STUDY TREATMENT ..................................................................................................................... 17 
TREATMENT OF TRIAL SUBJECTS ...................................................................................................................... 18 
INVESTIGATIONAL MEDICINAL PRODUCTS ................................................................................................................... 18 
CONCOMITANT TREATMENT ........................................................................................................................................... 18 
EFFICACY ASSESSMENT ............................................................................................................................................ 18 
SAFETY EVALUATION ................................................................................................................................................. 20 
REPORTING PROCEDURE ................................................................................................................................................. 20 
STATISTICS ..................................................................................................................................................................... 21 
SAMPLE SIZE DETERMINATION ....................................................................................................................................... 21 
ANALYSIS POPULATION .................................................................................................................................................. 21 
BASELINE CHARACTERISTICS ......................................................................................................................................... 21 
STUDY I........................................................................................................................................................................ 21 
STUDY II ...................................................................................................................................................................... 22 
STUDY III ..................................................................................................................................................................... 23 
ETHICAL CONSIDERATIONS AND DATA MANAGEMENT ................................................................................ 24 
PERSPECTIVES ................................................................................................................................................................ 25 
DATA MANAGEMENT ...................................................................................................................................................... 25 
QUALITY OF DATA .......................................................................................................................................................... 25 
FINANCING AND INSURANCE................................................................................................................................... 25 
FINANCING ..................................................................................................................................................................... 25 
CONFLICTS OF INTERESTS............................................................................................................................................... 25 
INSURANCE .................................................................................................................................................................... 25 
REFERENCES ................................................................................................................................................................. 27 
 
 
 

3 
 
Abbreviations 
ASCVD – Atherosclerotic cardiovascular disease 
ACS – acute coronary syndrome  
ADA – American Diabetes Association 
BMI – body mass index 
CAD – coronary artery disease 
CAP – controlled attenuation parameter 
CCS – chronic coronary syndrome 
eGFR – estimated glomerular filtration rate 
GCP – Good Clinical Practice 
GDPR – General Data Protection Regulation 
GLP-1 – glucagon-like peptide 1 
GLP-1 RA – glucagon-like peptide 1 receptor agonist 
HbA1c – hemoglobin A1c 
IEC – International Expert Committee 
MASLD – metabolic dysfunction-associated steatotic liver disease 
MI – myocardial infarction 
OCT – Optical Coherence Tomography 
RVA – Retinal Vessel Analyzer 
SGLT-2i – sodium glucose cotransporter 2 inhibitor 
T2D – Type 2 Diabetes 
 
 

4 
 
Introduction 
 
Background 
Prediabetes, a major risk factor for progression to type 2 diabetes (T2D), is far less investigated than 
T2D. Prediabetes is defined as hemoglobin A1c (HbA1c) 39-47 mmol/mol according to the 
American Diabetes Association (ADA), whereas the International Expert Committee (IEC) has 
considered HbA1c 42-47 mmol/mol a particular high-risk prediabetes-equivalent state. In the 
Danish adult population, the prevalence of prediabetes has been estimated at 7%, with 20% of 
individuals with prediabetes progressing to T2D within 5 years, using the IEC criterion [1]. In the 
USA, the prevalence of prediabetes among the adult population is estimated to 34% and, in people 
aged 65 years or older, as high as 48% when using the ADA criterion. Prediabetes, and its 
progression to T2D, thereby represents a substantial worldwide issue with expected growth in the 
future [2].  
 
T2D is associated with micro- and macrovascular complications. In a Danish T2D cohort, 35% of 
patients already had diabetes-related complications at the time of T2D diagnosis [3]. Thus, 
microvascular diseases, comprising retinopathy, nephropathy, and neuropathy, which traditionally 
are thought to develop after years of diabetes-related hyperglycemia, may already be present in 
persons with prediabetes, challenging the current conventional diagnostic cut-point for T2D, which 
is based on the risk of developing diabetes-related retinopathy [4, 5]. Accordingly, it has been 
suggested that intervening before the development of manifest diabetes might be warranted in 
certain individuals with complications usually considered diabetes-related or whom are at a 
particular high risk of developing T2D, although efforts must be made to identify the appropriate 
individuals and treatment approaches [6]. 
 
The transition from normoglycemia to prediabetes is associated with increasing body weight, 
insulin resistance, declining endogenous insulin secretion, decreased endogenous levels of 
glucagon-like peptide 1 (GLP-1), and increased lipolysis [7]. Interestingly, prediabetes may also be 
associated with an increased prevalence of metabolic dysfunction-associated steatotic liver disease 
(MASLD), and, as the two conditions are highly intertwined by mechanisms such as insulin 
resistance, pursuing reversion of prediabetes to normoglycemia could potentially improve MASLD 
[8, 9].  
 
Most patients with prediabetes show features of the metabolic syndrome, e.g. dyslipidemia, 
hypertension, and abdominal obesity [10]. These metabolic risk factors are also strongly associated 
with the risk of cardiovascular disease. Thus, patients with prediabetes and cardiovascular disease 
serve as an interesting cohort to examine. Importantly, the prevalence of microvascular diseases in 
patients with prediabetes and established coronary artery disease (CAD) remains unknown. In 
patients with cardiovascular disease, a HbA1c within the prediabetes range is highly prevalent and 
in not yet published data we found that more than one in two with a HbA1c 42-47 mmol/mol, recent 
MI and BMI ≥27 developed T2D within 5 years. Thus, these individuals potentially represent a 
high-risk subpopulation of patients which may benefit from early intervention, for example with 
intensive prophylactic actions on dyslipidemia, hypertension, and lifestyle [11]. Moreover, the use 
of glucose-lowering agents such as GLP-1 receptor agonists (GLP-1 RA) and sodium glucose 
cotransporter 2 inhibitors (SGLT-2i), both with a known cardioprotective effect in patients without 
diabetes, is of particular interest when trying to pursue normoglycemia.  
 

5 
 
In the SELECT (Semaglutide Effects on Cardiovascular Outcomes in Patients With Overweight or 
Obesity) trial, patients with preexisting cardiovascular disease (previous myocardial infarction [MI] 
or stroke >60 days prior, or symptomatic peripheral artery disease) and a body mass index (BMI) of 
27 kg/m2 or greater without a history of diabetes were randomized to receive the GLP-1 RA 
semaglutide or placebo [11]. 66% had prediabetes according to the ADA criterion. The SELECT 
trial found that semaglutide reduced the risk of a composite of cardiovascular death, nonfatal 
myocardial infarction, and nonfatal stroke by 20 %. However, based on not yet published results 
from the Western Denmark Heart Registry, three out of four patients with CAD did not meet the 
SELECT eligibility criteria. Thus, we want to investigate patients with prediabetes and chronic 
coronary syndrome (CCS) with documented CAD, irrespective of BMI.  
 
CCS refers to the clinical presentation of CAD during stable periods, thus also following an acute 
coronary syndrome (ACS). We have found that >30 days after an ACS, as exemplified by primary 
percutaneous coronary intervention treated ST-elevation myocardial infarction, the excess risk of 
mortality is very limited when compared to a matched general population [12]. Therefore, we seek 
to examine patients with CCS with or without a previous MI and with or without a BMI ≥27 kg/m2; 
while for patients with MI study initiation will be delayed for at least 30 days.  
 
In this study we aim i) to compare the prevalence of microvascular diseases and MASLD in patients 
with established CAD and prediabetes versus normoglycemia; ii) to show that it is possible to revert 
prediabetes to normoglycemia in most patients by the use of glucose-lowering medications with 
documented cardiovascular protective effects; and iii) to examine the incidence of progression to 
prediabetes/T2D one year after termination of intervention. 
To answer these questions, we have established a collaboration with expert national researchers 
within epidemiology, T2D, retinopathy, MASLD, and coronary heart disease. 
 
Aims 
STUDY I 
Working title: Prevalence of microvascular diabetes-related diseases and MASLD in patients with 
CCS and prediabetes undergoing coronary angiography.  
Aim: To compare the prevalence of retinopathy, nephropathy, neuropathy, and MASLD in patients 
with CCS and prediabetes versus normoglycemia. 
Hypothesis: Microvascular diseases and MASLD are more common in patients with CCS and 
prediabetes compared with normoglycemia. 
 
STUDY II 
Working title: Prediabetes, CCS, and medically induced reversal to normoglycemia: a randomized 
trial. 
Aim: To examine effects of intensified medical follow-up and treatment including cardioprotective 
glucose-lowering drugs on the proportion of patients with angiographically documented CAD that 
can be reverted from prediabetes to normoglycemia. 
Hypothesis: In a randomized setting, it is possible to induce a significantly higher incidence of 
reversal from prediabetes to normoglycemia in the interventional therapy arm compared with the 
conventional therapy arm. 
 
STUDY III 

6 
 
Working title: Incidence of recurrence of prediabetes or progression to T2D one year after 
termination of glucose-lowering medical intervention in patients with CCS and prediabetes at 
baseline. 
Aim: To examine the 2-year effects of intensified medical follow-up and treatment on recurrence of 
prediabetes or progression to T2D in patients with CCS and prediabetes. 
Hypothesis: The prevalence of patients with prediabetes or T2D (HbA1c ≥42 mmol/mol) is no 
longer substantially different in the interventional and conventional therapy arm at 2-year follow-up 
due to recurrence of prediabetes or progression to T2D following termination of glucose-lowering 
medications. 
 
Study populations 
The randomized cohort (108 patients; used for Study 1-3) 
Patients with angiographically documented CAD and prediabetes as defined by IEC are identified 
in relation to examination or treatment at the Department of Cardiology at Aarhus University 
Hospital by staff in the Department (nurses or physicians). These will assess patient files to ensure 
that patients are eligible for study enrolment.  
 
The baseline comparison cohort (50 patients; Study 1 only) 
For study I, patients with angiographically documented CAD with normoglycemia (HbA1c <39 
mmol/mol) are identified in relation to examination or treatment at the Department of Cardiology at 
Aarhus University Hospital by staff in the Department (nurses or physicians).  
 
Potentially eligible patients will either receive oral and written information by an investigator; or be 
asked by the staff at the Department of Cardiology if they accept to be contacted at a later time 
regarding study participation, which will be noted in the patient files. Everyone assessed who meet 
our inclusion and exclusion criteria are invited to participate at a screening visit (Table 4), where 
informed consent is obtained by an investigator. Patients will be given a sufficient amount of time 
to consider their participation and discuss with relatives if needed. All patients need to be capable of 
giving informed consent as assessed by the investigator in order to be eligible, thus, patients must 
speak the national language to participate. 
 
After collection of informed consent to study participation, a HbA1c measurement is repeated to 
confirm a HbA1c of 42-47 mmol/mol or <39 mmol/mol. If eligibility is confirmed, the participant 
will be invited for the baseline visit. At the baseline visit 108 trial subjects with HbA1c 42-47 
mmol/mol will be randomized 1:1 to either the interventional therapy arm or conventional therapy 
arm. Patients deemed not eligible after visit 1 will be registered as screen failure, and the reason 
will be registered. An additional comparison cohort of 50 patients with normoglycemia will undergo 
evaluation of baseline microvascular diabetes-related diseases and MASLD and will be compared 
with the randomized cohort.  
 
Investigational medicinal products 
GLP-1 RA: semaglutide subcutaneous once-weekly titrated to a maximum of 2.4 mg or the 
maximum tolerable dose. Needles will be provided. 
The dose of a maximum of 2.4 mg per week is in accordance with the current recommended 
maximum dose for the treatment of overweight or obesity. 
 
SGLT-2i: dapagliflozin 10 mg oral tablet daily. This is in accordance with the generally 
recommended dose. 

7 
 
 
Treatment of dyslipidemia and hypertension will be conducted according to guidelines, and will 
thus not be further explained in this section. 
 
Risk-benefit assessment 
Risks 
The examinations are further described below. Blood samples will provide much information and 
are rarely linked to prolonged discomfort. The eye examination requires administration of mydriatic 
eye drops (duration 3-4 hours), which might lead to a burning sensation (seconds) and blurred 
vision (hours). Very rarely an allergic reaction to the preservative in the eye drops occurs, which can 
be treated unproblematically by anti-allergic eye drops. 
 
For trial subjects randomized to the interventional arm, treatment optimization regarding 
hypertension and dyslipidemia will be conducted according to guidelines. The potential adverse 
effects, generally associated with the specific therapeutic choices, will be considered as part of the 
treatment strategy.  
 
Risks regarding treatment with semaglutide: 
- 
Gastrointestinal disorders: Such as diarrhea, nausea, and vomiting. This is the most 
frequently reported adverse reaction in clinical trials, generally of mild or moderate severity 
[11, 13]. The risk is minimized by starting at a low dose followed by gradual escalation of 
dose. 
- 
Cholelithiasis/gallbladder-related disorders: In some studies, with overweight patients 
without T2D, the risks of cholelithiasis or cholecystitis are marginally higher compared to 
placebo. In other studies, however, there is not found an increased risk of gallbladder-related 
disorders or cholelithiasis [11, 13, 14]. 
- 
Allergic reactions: As for all medications, participants are at risk of developing allergic 
reactions. 
- 
Pregnancy: Animal studies have shown reproductive toxicity. Only limited data exist from 
the use of the medication in pregnant women. In pregnant patients with T2D, 
periconceptional use of GLP-1 RA is associated with a significantly higher risk of major 
congenital malformations as compared to non-exposure to antidiabetic medications [15]. 
Thus, semaglutide should not be used while pregnant. Consequently, females who are 
pregnant, breast-feeding, intends to become pregnant, or is of child-bearing potential and not 
using a highly effective contraceptive method will be excluded from the trial.  
- 
Hypoglycemia: No significantly increased risk of hypoglycemia in patients without diabetes 
[16]. 
- 
Cancer: Pancreatic cancer has been classified as a potential class risk for all marketed GLP-
1 RA, however, there has not been established a causal association with semaglutide. In a 
number of trials, there were found no significant differences between rates of neoplasms in 
patients treated with semaglutide or placebo [11, 14]. 
- 
Acute pancreatitis: Has been observed with the use of drugs from the GLP-1 RA. For this 
reason, subjects with a history of pancreatitis will not be enrolled. Further, in the case of 
suspicion of pancreatitis, semaglutide will be discontinued.  
 
Risks regarding treatment with dapagliflozin: 

8 
 
- 
Genital mycotic infection: For patients with diabetes, treatment with a SGLT-2i is associated 
with an increased risk of genital mycotic infection. The risk for patients without diabetes 
remains less clarified but is described to be lower than for those with diabetes [17]. 
- 
Urinary tract infections: Is an expected adverse effect, however, data from large, randomized 
clinical studies have not yet found evidence of an elevated risk hereof [18, 19]. 
- 
Ketoacidosis: In patients without T2D there is a minimal risk of ketoacidosis as there has 
been reported a very few numbers of cases [17]. 
- 
Pregnancy: Only limited data exist from the use of the medication in pregnant women. 
However, in a study of pregnant patients with T2D, periconceptional use of SGLT-2i was 
associated with a higher risk of major congenital malformations as compared to non-
exposure to antidiabetic medications, although not significant [15].Consequently, females 
who are pregnant, breast-feeding, intends to become pregnant, or is of child-bearing 
potential and not using a highly effective contraceptive method will be excluded from the 
trial.  
- 
Allergic reactions: As for all medications, participants are at risk of developing allergic 
reactions. 
 
Benefits 
All patients will be examined for presence of microvascular diseases and MASLD at baseline. 
These examinations are not routinely performed in individuals with prediabetes or normoglycemia 
and might serve a potential benefit for the patients. 
 
For patients randomized to the interventional arm, their medical treatment of dyslipidemia and 
hypertension will be monitored beyond the conventional ≈ 3 months cardiac rehabilitation program 
in Denmark and they may thus have a greater chance of reaching target goals. They will also be 
provided sustained counseling on diet, alcohol intake, smoking cessation, and exercise on top of the 
cardiac rehabilitation program beyond the standard ≈ 3-month rehabilitation program. Further, by 
initiating treatment with semaglutide and potentially dapagliflozin, we aim to achieve 
normoglycemia in patients, which in the SELECT-eligible patients were beneficial and may thus 
also be of benefit in the approximately three-quarters of patients with prediabetes in this study who 
would not fulfill the SELECT inclusion criteria. The glucose-lowering drugs, in particular GLP-1 
RA, used in this study have documented cardiovascular risk reduction and, further, have 
documented secondary benefits including, but not limited to, improvements of high-sensitivity C-
reactive protein (hs-CRP), LDL cholesterol, triglycerides, renal function, and body weight [11, 20-
22]. All glucose-lowering treatments will be supplied free of charge for the patients. 
 
Trial participants within the conventional therapy arm will receive the current practice at their local 
hospital or general practitioner, therefore their participation in this trial will not in any way 
negatively impact their management. 
 
Risk-benefit conclusion 
We conclude that the abovementioned risks do not outweigh the potential benefits of this study in 
trial subjects with established cardiovascular disease and prediabetes, considering the established 
exclusion criteria. 
 
Trial plan and design 
Primary and secondary endpoints 

9 
 
To compare the effect of glucose-lowering treatment, optimization of blood pressure and lipids, and 
lifestyle counseling as compared with conventional follow-up and medical intervention in trial 
subjects with CCS and established CAD as well as prediabetes. 
 
 
 
Figure 1. Overview of study design. 
 
At baseline, all randomized trial subjects will be examined for the presence of potential 
microvascular diseases commonly associated with diabetes, i.e., retinopathy (eye examination), 
nephropathy (urine and blood samples), and neuropathy (monofilament test and Vagus device test) 
(Table 1); nephropathy also assessed at 1-year follow-up. Further, a fibroscan with transient 
elastography with controlled attenuation parameter (CAP) will be conducted at baseline and 1-year 
follow-up for MASLD severity (liver steatosis and fibrosis). The examinations are further described 
below. 
 
Blood samples at baseline, 1-year, and 2-year follow-up will elucidate levels of HbA1c, 
hemoglobin, creatinine, cystatin-C, sodium, potassium, hs-CRP, lipids (LDL, HDL, triglycerides, 
cholesterol, non-HDL), c-peptide, fasting insulin and glucose, amylase, alanine aminotransferase, 
FIB-4, ADAPT-score, PRO-C3, and CD163. Insulin resistance will be estimated by the homeostasis 
model assessment of insulin resistance (HOMA-IR).  
 
In the cases of PRO-C3, CD163, c-peptide and insulin, blood samples are stored in a biobank for 
later batch analyses. PRO-C3 is analyzed by a third party. All other samples are analyzed within the 
clinical laboratory.  
 
A maximum of 33 ml blood will be collected per visit. At baseline and 1-year follow-up, this 
amount will be collected. At 2-year follow-up, a maximum of 23 ml will be collected. At other visits 
a maximum of 13 ml will be collected. All randomized participants are expected to undergo study 
related blood collection four times, for those in the interventional arm at least one additional 
sampling is expected. Further blood samples may be conducted at the discretion of the investigator. 
 
Those with normoglycemia and CCS are seen only at screening and baseline. They will undergo 
blood sampling (two collections), urine sampling, interview, vital measures, body metrics and 
composition, nerve examination, eye examinations, and fibroscan. 
 
 

10 
 
 
Table 1 
Outcomes 
STUDY I (Baseline) 
 
Primary  
- 
Presence of a composite of retinopathy, 
nephropathy, neuropathy, and MASLD 
Secondary 
Presence of  
- 
Retinopathy  
- 
Nephropathy  
- 
Neuropathy 
- 
MASLD  
Presence of a composite of retinopathy, 
nephropathy, and neuropathy. 
STUDY II (1-year follow-up) 
 
Primary 
- 
Incidence of normoglycemia defined as 
HbA1c <39 mmol/mol 
Secondary 
- 
Incidence of normoglycemia defined as 
HbA1c <42 mmol/mol 
- 
Change in HbA1c 
- 
Change in eGFR 
- 
Change in cystatin-C 
- 
Change in hs-CRP 
- 
Change in lipid parameters 
- 
Change in c-peptide 
- 
Change in HOMA-IR 
- 
Change in Fib-4 
- 
Change in CD163 
- 
Change in PRO-C3 
- 
Change in MASLD severity 
- 
Change in urine albumin-creatinine 
ratio 
- 
Change in weight 
- 
Change in waist circumference 
STUDY III (2-year follow-up) 
 
Main outcome of interest 
- 
Prevalence of HbA1c ≥42 mmol/mol 
Secondary 
- 
Incidence of T2D 
- 
Prevalence of prediabetes defined as 
HbA1c 42-47 mmol/mol 
- 
Prevalence of prediabetes defined as 
HbA1c 39-47 mmol/mol 
- 
Change in HbA1c 
- 
Change in eGFR 
- 
Change in cystatin-C 
- 
Change in hs-CRP 
- 
Change in lipid parameters 
- 
Change in c-peptide 
- 
Change in HOMA-IR 
- 
Change in Fib-4 
- 
Change in CD163 

11 
 
- 
Change in PRO-C3 
- 
Change in weight 
- 
Change in waist circumference 
All secondary outcomes are considered exploratory. 
 
Design 
The trial will be conducted as a non-blinded randomized controlled trial and the conventional 
therapy arm adheres to current practice at the subject’s local hospital or general practitioner without 
any study visits after screening apart from baseline, 1-year, and 2-year follow-up examinations. For 
this reason, there will be no placebo treatment. 
 
Baseline blood samples will be obtained from all trial subjects. 
Within the interventional therapy arm, trial subjects will through monthly visits be treated to 
optimal levels of glycemia, blood pressure, and lipids, hereafter visits every 3 months according to 
Table 2. Regarding hypertension and dyslipidemia, treatment will be according to current 
guidelines. 
 
Hyperglycemia: 
- 
Semaglutide titration according to the recommended dose titration for semaglutide to a 
maximum maintenance dose of 2.4 mg once-weekly or maximum tolerable dose (Table 2). 
HbA1c is measured at visit 5. If normoglycemia is not reached, it will be possible to add 
dapagliflozin. 
In case of significant gastrointestinal side effects at a specific dose, postponement of dose 
escalation as well as a dose reduction should be discussed.  
 
Table 2 
Week 
1-4 
5-8  
9-12 
13-16  
17- 
Dose 
0.25 mg 
0.5 mg 
1.0 mg 
1.7 mg 
2.4 mg 
 
Due to the varying definitions of prediabetes, we will consider normoglycemia at HbA1c <39 
mmol/mol, which is according to ADA, despite alone including patients with HbA1c 42-47 
mmol/mol, which is prediabetes according to IEC, as this is considered a particular high-risk 
subgroup.  
 
Optimization of medical therapy (individualized treatment strategy according to current guidelines): 
- 
Dyslipidemia: goal non-HDL<2.2 mmol/l and/or LDL ≤1.4 mmol/l and at least 50% 
reduction of LDL. 
- 
Hypertension: goal clinical blood pressure at 125-135/75-85 mmHg, as optimally measured 
blood pressure in a clinical situation generally lies 5/5 mmHg higher than home 
measurements. 
 
When medical treatment is fully titrated according to the mentioned goals and sufficient 
lifestyle counseling is provided, intervention period visits will be replaced by visits every 3 
months for the remainder of the 1-year intervention period. Overview of expected study visits 
and examinations are presented in Table 3, although visit numbers depend on when the goals 
are reached, thus number and timing of visits might vary. A safety telephone visit (visit 10) is 
scheduled for the interventional therapy group five weeks after end of treatment to allow for 
registration of adverse events. 

12 
 
 
Conventional therapy will be conducted according to current practice at the trial subject’s 
hometown hospital or general practitioner. These trial subjects are seen only at screening, baseline, 
1-year and 2-year follow-up with no additional visits. At inclusion, it will be discussed that 
initiation of a GLP-1 RA during the first year is discouraged in the case another equal medication or 
management can be initiated instead. 
 
Table 3. Trial overview for participants with prediabetes and CCS. 
Baseline 
                      
Screening 
Intervention period 
1-year 
follow-up 
Safety 
2-year 
follow-up 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Timing of visit 
(weeks) 
 
0 
4  
 
8  
 
12 
16  
 
28 
40 
52 
57 
104 
Visit window 
(days) 
 
 
±7 
±7 
±7 
±7 
±7 
±7 
±14 
±7 
±14 
Medical history 
x 
X 
 
 
 
 
 
 
 
 
 
Evaluation/ 
adjustment of 
medical treatment 
 
X 
x 
x 
x 
x 
x 
x 
X 
 
 
Blood samples A 
 
X 
 
 
 
 
 
 
X 
 
x 
Blood samples B 
x 
 
(x) 
(x) 
x 
(x) 
(x) 
(x) 
 
 
 
Urine sample 
 
X 
 
 
 
 
 
 
x 
 
 
Vital measures 
 
X 
x 
x 
x 
x 
x 
x 
x 
 
x 
Body metrics and 
composition  
 
X 
 
 
 
 
 
 
x 
 
x 
Eye examinations 
 
X 
 
 
 
 
 
 
 
 
 
Nerve 
examination 
 
X 
 
 
 
 
 
 
 
 
 
Fibroscan 
 
X 
 
 
 
 
 
 
x 
 
 
Lifestyle 
counseling 
 
 
x 
x 
x 
x 
 
 
 
 
 
Adverse events 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
Dispensing of 
medication 
 
X 
x 
x 
x 
x 
x 
x 
 
 
 
Discontinuation 
criteria 
 
X 
x 
x 
x 
x 
x 
x 
 
 
 
Concomitant 
medication 
 
X 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Medical history: at screening/baseline patients are interviewed on their health status and 
previous or current concomitant diseases, supplemented by information from patient files. 
Information on average alcohol use and smoking habits are reported. 
 
Blood samples A: HbA1c, hemoglobin, creatinine, cystatin-C, sodium, potassium, hs-CRP, 
lipids (LDL, HDL, triglycerides, cholesterol, non-HDL), c-peptide, fasting insulin and glucose 
(HOMA-IR), amylase, alanine aminotransferase, FIB-4, ADAPT-score, PRO-C3, and CD163.  
 

13 
 
Blood samples B:  
When clinically relevant, for instance: 
- 
At screening/if treatment of hyperglycemia has been adjusted (after 12 weeks): HbA1c, 
hemoglobin. 
- 
If treatment of hypertension has been adjusted (primarily ARB or thiazide): creatinine, 
sodium, and potassium. 
- 
If treatment of dyslipidemia has been adjusted: alanine aminotransferase and lipids. 
- 
Further blood samples may be conducted at the discretion of the treating physician. 
 
Urine sample: albumin and creatinine for calculation of albumin-creatinine ratio. Two samples 
from two different days are analyzed at both baseline and 1-year follow-up. A sample kit will be 
provided before the visit. 
 
Vital measures: blood pressure and pulse.  
 
Body metrics and composition assessment: Height, weight and waist circumference are measured in 
centimeter and kilograms. Further, a non-invasive bioelectrical impedance analysis is conducted to 
estimate body composition.  
 
Eye examinations: Visual acuity is measured by reading letters on a visual acuity chart. 
Subsequently, the pupils are dilated using mydriatic eye drops (Mydriacyl 1% and Metaoxedrin 
10%) used routinely for imaging of the retina. The retinal morphology will be documented by 
fundus photography and the thickness by Optical Coherence Tomography (OCT) scanning. Retinal 
reactivity (changes in vessel diameter) is assessed using the Retinal Vessel Analyzer (RVA). 
 
Nerve examination: Firstly, a monofilament test, where the subject’s sensitivity to the touch of a 
monofilament on the skin of the feet is evaluated. Secondly, using a handheld Vagus Device, which 
evaluates the heart rate and variability by guiding the subject through standardized tests to assess 
for cardiac autonomic neuropathy [23]. 
 
FibroScan: Liver transient elastography with Controlled Attenuation Parameter (CAP) is a non-
invasive diagnostic tool that uses ultrasound technology, which is conducted to assess liver steatosis 
and fibrosis. Trial subjects should remain fasting 3 hours before the scan is conducted. 
 
Lifestyle counseling: Counseling on diet, alcohol intake, smoking cessation, and exercise will be 
provided when relevant.  
 
Dispensing of medication: Medication will be dispensed until next study visit. Further, compliance 
to study medication will be assessed. 
 
Interview: During visits, trial subjects will be asked to provide information on potential adverse 
effects and events, which might have occurred since their last visit. Further, they will be asked 
about any concomitant medication. It will be ensured that no discontinuation criteria are present. 
 
Data will be reported in an electronical Case Report Forms (eCRFs) in REDCap. Data not 
previously written down or elsewhere electronically registered will be recorded directly into 
REDCap and considered to be source data. This could be vital measures, height, weight, waist 
circumference, as well as the results of nerve examination, and fibroscan.  

14 
 
 
Randomization 
Trial subjects with prediabetes will be randomized 1:1 to the interventional therapy arm or the 
conventional therapy arm. Randomization will be non-blinded due to the trial design as previously 
described. However, statistical analyses and evaluation of the results are performed blinded to the 
randomization group. 
 
The randomization will be performed with the use of the eCRFs system REDCap. To ensure 
balanced sex distribution between arms, randomization will be stratified by sex. Further, 
randomization will be done in permuted blocks of varying size (4, 6 or 8), to avoid any 
predictability of the randomization. The allocation lists will be uploaded in REDCap by the 
Research Data Management at Institute for Clinical Medicine, Aarhus University, an independent 
party. To ensure allocation concealment, the randomization sequence will be concealed from 
investigators and study personnel involved in participant enrolment and assignment until the point 
of allocation. This process safeguards against selection bias and maintains the integrity of the 
randomization. 
 
Trial duration 
The intervention period will terminate at 1 year, where glucose-lowering treatments are 
discontinued. Afterwards, follow-up without further interventions will continue until 2 years after 
inclusion. 
 
Neither temporary nor permanent discontinuation of medical treatment will lead to withdrawal from 
the trial. A trial subject may withdraw consent at any time. Indications for discontinuation of study 
products will be discussed below. 
 
Trial period 
Trial period completion is defined as 
- 
When the trial subject has completed the final scheduled visit at year 2, at baseline for those 
with normoglycemia 
Or 
- 
When the trial subject has died during trial. 
 
End of trial is defined as the date of the last visit of the last trial subject. 
 
Investigational medicinal products 
Semaglutide 
Is authorized for clinical use in the European Union. The current authorized indications for once-
weekly subcutaneous use in the European Union is 
- 
As Wegovy: along with diet and physical activity to help people lose weight and keep it 
under control. Either in patients with a BMI of 30 or greater or a BMI of at least 27 mg/kg2 
with concomitant weight-related health problems such as diabetes, hypertension, abnormal 
lipids, obstructive sleep apnea, documented CCS, previous MI, stroke or peripheral artery 
disease. 
- 
As Ozempic: treatment in adults whose T2D is not satisfactorily controlled. Either as add-on 
to other diabetes medications or on its own in patients who cannot take metformin. 
In our cohort, the medication is not used at an authorized indication per se when the BMI is <27 
mg/kg2. Further, the glucose-lowering medications are expensive and currently not eligible for 

15 
 
subsidies in Denmark unless you have T2D. However, it has been shown to reduce the risk of 
cardiovascular outcomes in patients with BMI ≥27 mg/kg2 without diabetes and is used in patients 
with T2D with a BMI <27 mg/kg2. Due to the large amount of safety data in these cohorts, we find 
it reasonable to use it in a prediabetes and CCS cohort when using the IEC criteria for prediabetes, 
as the current diabetes diagnosis threshold is defined according to the risk of retinopathy. Further, it 
has been proposed to intervene before the development of manifest diabetes in certain individuals 
with diabetes-related complications or at a particular high risk of developing T2D. 
 
The target dose of a maximum of 2.4 mg subcutaneously once-weekly is chosen based on the 
current maximum dose to treat patients for overweight or obesity, and previously used in clinical 
trials such as SELECT. To minimize gastrointestinal side effects, gradual dose escalation is 
conducted as previously described. 
 
Trial subjects will be instructed to inject the medication once-weekly (preferably the same day of 
the week), by a pre-filled pen-injector. Injections may be administered in the upper arm, abdomen 
or thigh at any time of the day, with or without meals. Needles will be provided. 
 
If one dose is missed, it should be administered as soon as possible, except if the time to next dose 
is <48 hours. In the last case, the missed dose should not be administered. The regular dosing day of 
the week should not be changed due to a missed dose. 
 
Dapagliflozin 
Is authorized for clinical use in the European Union. 
The current authorized indications for dapagliflozin use in the European Union are: 
- 
T2D: Individuals from 10 years of age whose diabetes is not satisfactorily controlled 
- 
Chronic heart failure: in symptomatic patients with a reduced ejection fraction 
- 
Chronic kidney disease: in adult patients 
In our study cohort, the medication is not used at an authorized indication. However, as for 
semaglutide, there is a large amount of safety data in patients with T2D, renal disease, or heart 
failure, and we find that it is reasonable to use in a prediabetes and CCS cohort without expecting 
safety issues beyond that of the established indications. Again, the current diabetes diagnosis 
threshold is defined according to the risk of retinopathy. Further, it has been proposed to intervene 
before the development of manifest diabetes in certain individuals with diabetes-related 
complications or at a particular high risk of developing T2D. 
 
Generally, the recommended dose is 10 mg once daily. Therefore, we have chosen this dose as 
standard in the current trial. The dose is taken orally as a tablet. 
 
Accountability and administration 
Only trial subjects that are enrolled may use and self-administer the trial products. Further, only 
authorized site staff may supply or administer trial product. Both semaglutide and dapagliflozin are 
acquired especially for the current trial. Products will be provided at each visit for the period until 
next visit. 
 
The investigator is responsible for drug accountability and record maintenance, which should be 
done at pen level. Any returned, expired, or damaged products must be stored separately from non-
allocated trial products. 
 

16 
 
Trial subjects 
Inclusion and exclusion criteria 
We will include patients aged 18 to 80 years, CCS, and prediabetes (HbA1c 42-47 mmol/mol) or 
normoglycemia (HbA1c <39 mmol/mol). Patients with a recent MI are seen at baseline minimum 
30 days after MI. Prediabetes or normoglycemia is ensured by a measurement within six months 
before screening and repeated at screening. Both measurements must be within the indicated range. 
HbA1c is not valid if a person has anemia or a recent blood transfusion, therefore such persons are 
excluded. Anemia is defined as a hemoglobin <7.3 mmol/l for women and <8.3 mmol/l for men. 
We want to examine persons without diabetes, the latter defined as any HbA1c >47 mmol/mol, a 
previous diabetes diagnosis, or current/previous usage of any diabetes medications; thus, these are 
excluded. 
The following exclusion criteria are due to (relative) contraindications to initiation of treatment with 
either semaglutide or dapagliflozin: previous pancreatitis, current pregnancy, breastfeeding or fertile 
women who do not use birth control, or strongly reduced liver function. For women with 
childbearing potential (following menarche and until becoming post-menopausal unless 
permanently sterile), a negative pregnancy test must be performed prior to inclusion. Highly 
effective contraception must be used until 5 weeks after discontinuation of medical treatment and 
appropriate methods include combined hormonal contraception or progestogen-only hormonal 
contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-
releasing system, bilateral tubal occlusion, vasectomized partner, or sexual abstinence. 
Due to a potential indication for initiation of SGLT-2i and a potential influence on the validity of the 
HbA1c measurement, patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 
m2 are excluded. Owing to a potential influence on the validity of the HbA1c measurement, patients 
with chronic alcohol abuse, known hemoglobinopathy, or intake of mediations known to affect 
HbA1c, will be excluded. Finally, patients with heart failure and NYHA class III or IV are excluded 
due to unreliability of the fibroscan in these patients. 
 
Table 4 
Inclusion criteria 
Exclusion criteria 
- 
Chronic coronary syndrome with 
documented coronary artery disease. In 
the case of previous MI, at least 30 days 
between the event and randomization is 
required. 
- 
Prediabetes defined as HbA1c 42-47 
mmol/mol (IEC criteria) OR 
normoglycemia defined as HbA1c <39 
mmol/mol 
- 
Age 18 to 80 years 
- 
eGFR <30 mL/min/1.73 m2 
- 
Previous diabetes diagnosis, previous 
HbA1c >47 mmol/mol, or 
current/previous usage of diabetes 
medication  
- 
Anemia, recent bleeding or blood 
transfusion (<3 months) 
- 
Previous pancreatitis 
- 
Pregnancy, breastfeeding, or fertile 
women who do not use highly effective 
contraception 
- 
Strongly reduced liver function 
- 
Chronic alcohol abuse 
- 
Known hemoglobinopathy and other 
conditions with effect on erythrocyte 
lifespan 
- 
Intake of medications with known 
effect on HbA1c validity such as: 
antiretroviral medications, 

17 
 
trimethoprim, sulfamethoxazole, 
sulfasalazine hydroxyurea, dapsone, 
acetylsalicylic acid (>3 g/daily), high 
dose vitamin C and E. 
- 
Heart failure with NYHA class III or IV 
 
Trial subjects must be capable of giving informed consent as assessed by the investigator. 
Patients with BMI<25 kg/m2 will be assessed individually by an investigator for eligibility (e.g., 
whether initiation of a GLP-1 RA with potential weight loss is clinically justifiable).  
 
Withdrawal of consent 
A trial subject may withdraw consent at any time.  
If withdrawal is considered, the subject will as an alternative be offered a more flexible 
participation in the trial, such as fewer visits or conversion to phone contacts if possible. 
Alternatively, treatment pause could be suggested. Nonetheless, completing the baseline, 1-year and 
2-year visit should always be encouraged.  
 
There is no obligation to give a reason for withdrawal, however the investigator should make a 
reasonable effort to try to uncover the reason(s), as the primary reason for withdrawal in such case 
should be sought specified, while respecting the trial subject’s rights. 
 
Trial subjects leaving the study will not be replaced by new subjects. 
 
Discontinuation of study treatment 
Semaglutide 
Temporarily/permanent in case of 
1) Suspected pancreatitis 
2) Pregnancy or breastfeeding 
3) Intention to become pregnant (discontinuation at least 5 weeks before end of contraceptive 
method) 
4) Treatment with another GLP-1 RA 
5) Diagnosis of type 1 diabetes 
6) Diabetic ketoacidosis 
7) Other safety concerns, at the discretion of the investigator 
For re-initiation of medication, the start dose should be considered at a reduced dose if at least 4 
consecutive doses are missed. 
 
Dapagliflozin 
Temporarily/permanent in case of 
1) Recurrent cystitis or genital mycosis 
2) Diabetic ketoacidosis 
3) Diagnosis of type 1 diabetes 
4) Pregnancy or breastfeeding 
5) Intention to become pregnant 
6) Hypovolemia, dehydration or hypotension 
7) Other safety concerns, at the discretion of the investigator 
 

18 
 
Neither temporary nor permanent discontinuation of medicinal treatment will lead to withdrawal 
from the trial. 
 
Treatment of trial subjects 
Investigational medicinal products 
Wegovy active substance: semaglutide. 
Forxiga active substance: dapagliflozin propanediol monohydrate (international common name: 
dapagliflozin) 
 
After the end of trial, trial subjects are to be treated at the discretion of the investigator. Generally, 
glucose-lowering medications will be discontinued, whereas any initiated treatments for 
dyslipidemia and hypertension should be continued. 
 
The delivery of products to the trial site, the inventory at the site, the use of medicine by each 
subject, and the return of used/unused products will be recorded continuously. Records will include 
dates, quantities, batch/serial numbers, expiration dates, and the unique code number of the 
investigational product and trial subjects. 
 
Patient compliance to semaglutide will be assessed by tracking delivery of medication to each trial 
subject as well as any returned medicine and packaging.  
 
Semaglutide 
During the intervention period, the medication is administered once-weekly subcutaneously at a 
maximum dose of 2.4 mg. Needles used must be authorized. 
Trial product must be stored in a refrigerator (2-8 °C) until use of each pen is initiated. The pen 
under current use may be stored for a maximum of 6 weeks at room temperature (below 30 °C), or 
in a refrigerator (2-8 °C). Medication should be protected from light and not let to freeze.  
 
Dapagliflozin 
During the intervention period, the medication is administered daily orally as a tablet at a maximum 
dose of 10 mg if indicated. There are no requirements for trial product storage.  
 
Concomitant treatment 
Medical treatment initiated before and during the trial is recorded in eCRFs upon study visits. 
 
Efficacy assessment 
Blood samples: HbA1c, hemoglobin, creatinine, cystatin-C, sodium, potassium, hs-CRP, lipids 
(LDL, HDL, triglycerides, cholesterol, non-HDL), c-peptide, fasting insulin and glucose 
(HOMA-IR), amylase, alanine aminotransferase, FIB-4, ADAPT-score, PRO-C3, and CD163. 
Samples of plasma and serum for a biobank, for batch analyses of PRO-C3, CD163, c-peptide 
and insulin. 
The samples will be analyzed at baseline, 1-year and 2-year follow-up, and changes will be 
assessed statistically. Apart from HbA1c ˗ our primary outcome in STUDIES II and III ˗ blood 
samples are generally indicated due to potential medications for the interventional arm, or used 
as secondary study outcomes to elucidate changes and differences between the two cohorts. 
 

19 
 
Urine sample: albumin and creatinine for calculation of albumin-creatinine ratio. A ratio of 30-300 
mg/g creatinine indicates moderate albuminuria and a ratio >300 mg/g creatinine indicates severe 
albuminuria. 
 
Vital measures: blood pressure and pulse. These will be measured by conducting three 
measurements, whereof the mean of the second and third measurement is recorded. The information 
is used to adjust the medical treatment in the case of hypertension in the intervention group. At 
baseline, 1-year and 2-year follow-up it provides information on prevalence of participants reaching 
treatment goals. 
 
Body metrics and composition assessment: Height is measured without shoes (centimeters). Body 
weight is measured without shoes and wearing light clothing only (kilograms). Waist circumference 
is measured midway between the lower rib margin and the iliac crest in standing position while 
breathing normally (centimeters). The measuring tape should touch the skin but not compress 
tissue. Information is obtained to gain knowledge on any weight loss or gain, crude and as BMI, as 
well as related changes in waist circumference. Body composition is assessed non-invasively using 
a bioelectrical impedance analysis at 50 kHz conducted with a stand-on multi-frequency stand-on 
body composition analyzer (Seca mBCA 515, Seca GmbH, Hamburg, Germany). 
 
Eye examinations: visual acuity, fundus photographs and OCT scans are assessed by experienced 
specialists regarding grade of diabetic retinopathy according to International Clinical Disease 
Severity Scale for diabetic retinopathy, and presence of diabetic macular edema. Grade 0 denotes no 
diabetic retinopathy. Grade 1-3 involves different stages of non-proliferative diabetic retinopathy. 
Grade 4 represents proliferative diabetic retinopathy [24]. Retinal reactivity (changes in vessel 
diameter) as examined by RVA is evaluated by experienced specialists. 
 
Nerve examination: We will conduct a monofilament test, which is a sensory test where the 
examiner applies a 10 g monofilament perpendicular until it bends to the skin of the feet in 
predefined locations. Wounds and hyperkeratotic areas are to be avoided. If the touch is not 
registered in one location, the tactile sensation is considered reduced. The number of touches that 
the participant sense and correctly locate will be registered. 
Further, cardiac autonomic neuropathy will be assessed using a handheld VagusTM Device (Medicus 
Engineering), which evaluates the heart rate and the heart rate variability via the palm of the hands 
as the device measures electrical signals generated by each heartbeat. First, a 5-minute baseline 
heart rate measurement during rest is done. Subsequently, the device guides the subject through 
standardized tests of three situations lasting one minute each: changing position from supine to 
upright, expiration and inspiration, and during forced expiration (Valsalva) [25]. Test results are 
compared with available reference values from Medicus Engineering. One abnormal test result 
indicates early signs of cardiac autonomic neuropathy categorized borderline, whereas at least two 
abnormal test results confirm cardiac autonomic neuropathy. 
 
FibroScan: Liver transient elastography with CAP simultaneously assess liver steatosis and fibrosis 
by combining two key parameters: CAP, which quantifies the level of liver steatosis, and the Liver 
Stiffness, which evaluates liver fibrosis, as indicators of MASLD severity. Steatosis will be graded 
as S0-S3, fibrosis as F0-F4. 
 

20 
 
Safety evaluation 
The safety of all randomized trial subjects is continuously monitored based on information recorded 
at each visit from the initiation of medication to the end of treatment (five weeks after 
discontinuation of semaglutide). In this information, potential adverse events (AE) and serious 
adverse events (SAE) are identified. 
 
An AE is any untoward medical event (symptom or illness) of a trial subject after initiation of study 
medication. There is not necessarily a connection between the AE and the trial treatment. 
 
A SAE is defined as an adverse event that fulfill at least one of the following criteria: results in 
death, is life threatening, require inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent disability/incapacity or results in a congenital anomaly/birth 
defect. 
 
The investigator will assess the severity and likely causality between the trial medication and the 
incident. To judge the latter, the latest product resumé will be consulted. In case of a likely causality 
with a SAE this is defined as a serious adverse reaction (SAR). Whether it is a suspected or 
unexpected serious adverse reaction (SUSAR) is assessed by product resumé consultation. 
All adverse reactions will be followed up by the investigator until resolution or stabilization. The 
type of follow-up will depend on the nature and severity of the adverse reaction and may include 
physical examination, laboratory testing, or specialist evaluation. 
Concomitant illness is any illness present at the start of the trial. Only significant worsening of such 
will lead to recording. Outpatient visits will generally not be recorded if related to a known 
concomitant illness. 
 
Reporting procedure 
All SAE, SAR and SUSAR must be reported to the sponsor by the investigator within 24 hours of 
first gaining knowledge about the event. 
 
The sponsor is obliged to immediately report suspected serious unexpected adverse reactions 
(SUSARs) that occur in connection with the clinical trial. 
The deadline for the sponsor's reporting of SUSARs must consider the seriousness of the side effect, 
and must be as follows: 
a) in the case of fatal or life-threatening suspected serious unexpected side effects, as 
soon as possible and in any case no later than seven days after the sponsor has become aware of the 
side effect. 
b) in the case of suspected serious unexpected side effects that are not fatal or life-
threatening, no later than 15 days after the sponsor has become aware of the side effect. 
Sponsor must report SUSARs to the Eudravigilance database.  
 
In Central Denmark Region/Aarhus University, the GCP unit at Aarhus University Hospital has the 
correct user access and training in reporting SUSARS to Eudravigilance database and will take care 
of reporting SUSARs in collaboration with the sponsor. 
 
Once a year an annual safety report will be submitted to CTIS. 
 

21 
 
The sponsor shall via CTIS notify about serious breaches. A ‘serious breach’ means a breach likely 
to affect to a significant degree the safety and rights of a subject or the reliability and robustness of 
the data generated in the clinical trial. 
 
Statistics 
Sample size determination 
We estimated a reversal rate from prediabetes to normoglycemia of 62% in the intervention therapy 
arm and 30% in the conventional therapy arm. Semaglutide has previously demonstrated an ability 
to induce reversal to normoglycemia in 70.8 % of patients with BMI ≥ 27 kg/m2 and HbA1c 42-47 
mmol/mol at three years, with the lowest HbA1c observed within the first year [26]. In the present 
trial, participants with a lower BMI are also eligible for inclusion. Accordingly, the estimated 
reversal rate in the intervention arm has been conservatively set, despite the potential addition of 
Forxiga to the treatment regimen. In the same reference trial, a reversal rate of 19% was observed in 
a comparable placebo group. This has been used to set a conservative estimate for the conventional 
therapy arm in the current study. 
 
Assuming an alpha cut-off of 5% and power of 90%, 49 trial subjects are needed in each arm. To 
account for withdrawal of consent or a fatal event prior to end of 1-year follow-up, a total of 108 
trial subjects will be randomized. 
 
Analysis population 
The intention-to-treat population will consist of all participants randomized and examined at 
baseline. The as-treated population will examine the treatment actually received by the participant. 
We intent to primarily use the intention-to-treat population for our analyses, secondarily the as-
treated population. 
 
The trial will be terminated after 2 years of follow-up for all trial subjects. 
Analyses for STUDY I will be conducted after all participants have completed the baseline 
examination, for STUDY II after all participants have completed 1 year of follow-up, and STUDY 
III after all participants have completed 2 years of follow-up. 
Missing information of any of the variables included the multivariable Poisson regression analysis 
(sex, smoking, hypertension, alcohol intake, peripheral artery disease, and BMI) will be handled 
through multiple imputations using chained equations assuming data are missing at random[27, 28] 
The number of imputations will be determined according to the proportion of participants with 
missing information. We will include all prespecified covariates intended for the multivariable 
regression analysis in the multiple imputation model, as well as the primary outcome variable in the 
model to reduce bias.  
In case of loss to follow up due to emigration, death or withdrawal, participants will be censored. 
 
Baseline characteristics 
Categorial data will be presented as numbers and proportions. Continuous data will be presented as 
either the arithmetic mean ± standard deviation (SD) in the case of normal distribution, or as the 
median and the interquartile range in the case of non-normality. Q-Q plots and histograms will be 
used to assess normal distribution. 
 
STUDY I  

22 
 
Hypothesis: Microvascular diseases and MASLD are more common in patients with prediabetes 
compared with normoglycemia. 
 
Primary outcome:  
- 
The baseline prevalence of a combined endpoint of nephropathy, neuropathy, retinopathy 
and MASLD will be reported for both those with prediabetes and normoglycemia. Risk 
ratios will be estimated by Poisson regression, both crude and adjusted for sex, smoking, 
hypertension, alcohol intake, PAD, and BMI using normoglycemia as reference. 
 
Secondary outcomes (exploratory):  
- 
The baseline prevalence of nephropathy, neuropathy, retinopathy, or MASLD, respectively, 
will be reported for both cohorts. Further, the risk ratio will be estimated by Poisson 
regression, both crude and adjusted for sex, smoking, hypertension, alcohol intake, PAD and 
BMI. 
- 
The baseline prevalence of a combined endpoint of nephropathy, neuropathy, and 
retinopathy will be reported for both those with prediabetes and normoglycemia. The odds 
ratio will be estimated as described above. 
 
STUDY II  
Hypothesis: In a randomized setting, it is possible to induce a significantly higher incidence of 
reversal from prediabetes to normoglycemia in the interventional arm compared with the 
conventional therapy arm. 
 
Primary outcome: 
- 
The null hypothesis of no difference 1-year incidence of normoglycemia assessed by chi-
square test. P-value <0.05 is considered significant. 
- 
In exploratory analysis, we will estimate risk ratio using Poisson regression model using a 
robust variance covariance estimator with the control arm as reference. 
- 
To account for the competing risk of death during 1-year follow-up, we will use the Fine-
Gray model to estimate the sub-distribution hazard ratio, and the Aalen-Johansen estimator 
to calculate 1-year incidence and 1-year risk difference of normoglycemia in sensitivity 
analysis. 
 
Secondary outcomes (exploratory): 
- 
Secondary outcomes include T2D (defined as HbA1c ≥48 mmol/mol) and normoglycemia 
(here defined as HbA1c<42 mmol/mol). The outcomes will be analyzed as described for the 
primary outcome. 
 
Continuous data: 
- 
Differences from baseline to 1-year follow-up will be estimated in each group. Differences 
will be presented as either the arithmetic mean ± standard deviation (SD) in the case of 
normality, or as the median and the interquartile range in the case of non-normality. 
- 
Normally distributed data: a paired t-test will be used to assess the differences within each 
cohort 
- 
Non-normally distributed data: a Wilcoxon signed-rank test or bootstrapping method will be 
applied  
- 
An ANCOVA model with intervention as the fixed factor and the baseline of the outcome as 
a covariate will be used to investigate the association between the interventional arm and the 

23 
 
specific outcome differences as compared to the control arm in the case of normality. In the 
case of non-normality, a rank-based ANCOVA model will be used. 
 
Other categorical data: 
- 
Differences in prevalence from baseline to 1-year follow-up within groups will be estimated. 
The null-hypothesis will be tested by McNemar’s test within each cohort. 
- 
Risk ratio will be estimated by a Poisson regression model using a robust variance 
covariance estimator with the control arm as reference. 
 
STUDY III 
Hypothesis: The prevalence of patients with prediabetes or T2D (HbA1c ≥42 mmol/mol) is no 
longer substantially different in the interventional and conventional therapy arm at 2-year follow-up 
due to recurrence of prediabetes or progression to T2D following termination of glucose-lowering 
medications. 
 
Main outcome of interest:  
- 
2-year incidence of HbA1c ≥42 mmol/mol. 
- 
The null hypothesis of no difference 2-year incidence of normoglycemia assessed by chi-
square test. P-value <0.05 is considered significant. 
- 
In exploratory analysis, we will estimate risk ratio using Poisson regression model using a 
robust variance covariance estimator with the control arm as reference. 
- 
To account for the competing risk of death during 2-year follow-up, we will use the Fine-
Gray model to estimate the sub-distribution hazard ratio, and the Aalen-Johansen estimator 
to calculate 2-year incidence and 2-year risk difference of HbA1c ≥42 mmol/mol in 
sensitivity analysis. 
 
Secondary outcomes (exploratory): 
- 
Secondary outcomes include 2-year prevalence of T2D (defined as HbA1c ≥48 mmol/mol), 
prediabetes (defined as both HbA1c 42-47 mmol/mol and HbA1c 39-47 mmol/mol) and 
normoglycemia (defined as HbA1c <39 mmol/mol). The outcomes will be analyzed as 
described for the main outcome of interest. 
 
Continuous data: 
- 
Differences from 1-year follow-up to 2-year follow-up will be estimated in each cohort. 
Differences will be presented as either the arithmetic mean ± standard deviation (SD) in the 
case of normality, or as the median and the interquartile range in the case of non-normality. 
- 
Normally distributed data: a paired t-test will be used to assess the differences within each 
cohort 
- 
Non-normally distributed data: a Wilcoxon signed-rank test or bootstrapping method will be 
applied  
- 
An ANCOVA model with intervention as the fixed factor and the baseline of the outcome as 
a covariate will be used to investigate the association between the interventional arm and the 
specific outcome differences as compared with the conventional therapy arm in the case of 
normality. In the case of non-normality, a rank-based ANCOVA model will be used. 
 
General considerations 
Each of the sub-studies have one prespecified primary outcome/main outcome of interest. 
Hypothesis testing for this outcome used a two-sided significance level of 0.05. No multiplicity 

24 
 
adjustment will be applied to the primary analysis. All secondary outcomes are considered 
exploratory, why no adjustments for multiple testing will be applied, as such, p-values should be 
interpreted descriptively and the results are considered hypothesis generating. 
 
 
Two-sided 95 % confidence intervals (CI) and p-values will be presented. P-values of <0.05 will be 
considered indicative of statistical significance. 
 
For studies II and III, analyses will be repeated after stratification for HbA1c at 1-year follow-up in 
4 strata: <39 mmol/mol, 39-41 mmol/mol, 42-47 mmol/mol, or >47 mmol/mol, when appropriate. 
The statistical analyses outlined above will be used. 
 
Any deviations from this statistical analysis plan will be documented as “post hoc” analyses in the 
publications. 
 
Ethical considerations and data management 
The trial will be conducted under monitoring by the local unit of Good Clinical Practice (GCP), to 
ensure the rights of trial subjects, that data are accurate, complete, and verifiable from source 
documents, and in compliance with the approved protocol and applicable regulatory requirements. 
Before initiation of the trial, all necessary approvals will be obtained. 
 
At screening for study participation eligibility, all trial subjects will be identified in relation to 
examination or treatment at the Department of Cardiology at Aarhus University Hospital due to 
suspected or known CAD. The investigators at the Department of Cardiology will screen patient 
files for presence of prediabetes defined by HbA1c 42-47 mmol/mol or normoglycemia defined as 
HbA1c <39 mmol/mol, angiographically verified CAD, age between 18 and 80, or any exclusion 
criteria. Patients who meet the inclusion and exclusion criteria, will receive written and oral 
information on the trial, and informed consent will be collected.  
 
For patients meeting the inclusion criteria, a screening log will be filled out including information 
on initials, sex, age, inclusion (yes/no), screening date, the responsible physician and if not 
included, the reason for exclusion. No additional information will be recorded in the eCRF before 
written consent is obtained. Written consent includes the acceptance of investigator access to the 
trial-relevant information in electronical patient files. As stated in the participant information 
document, the trial subjects’ consent to the access to source documents and relevant medical records 
for trial-related monitoring, audits, Independent Ethics Committee review, and regulatory 
inspection. Patients are informed that their participation is voluntary, and withdrawal is possible at 
any time. Neither decline to participate nor withdrawal will influence the future treatment of the 
patient. 
 
All trial subjects have established CAD, thus optimization of treatment of dyslipidemia and 
hypertension in the interventional therapy arm is indicated and conducted according to guidelines. 
Further, all randomized trial subjects have prediabetes and a potential diabetes-related 
macrovascular complication in the form of CAD, which is the rationale for initiating glucose-
lowering treatment in the interventional therapy arm. Semaglutide is generally considered safe to 
use, although with a higher prevalence of gastrointestinal side effects such as diarrhea, nausea and 
vomiting [11]. Addition of a SGLT-2i is considered safe in patients with T2D [29]. 

25 
 
Besides blood samples, none of the examinations are invasive.  
 
For randomized patients their general practitioner is informed of study participation according to 
the participation information document. 
 
Perspectives 
Prediabetes is highly prevalent in the western world. It is strongly associated with obesity and 
progression to T2D, and may be associated with diabetes-related microvascular diseases. The 
increasing global burden of obesity and T2D highlights the importance of preventing disease at an 
early stage and to pursue initiation of timely management. 
 
Our future study results may suggest that the diagnostic cut-point of T2D should be re-defined to a 
lower HbA1c level, or at least that prophylactic intervention in some cohorts should be initiated 
already at the stage of prediabetes, as this could be a window of opportunity to intervene at an early 
stage to prevent further progression to diabetes or development of related complications in high-risk 
patients. 
 
Data management 
Patient data is protected by the General Data Protection Regulation (GDPR). 
The primary investigator is responsible for ensuring the accuracy, completeness and contemporary 
registration of data. According to the European Union regulation, the trial master file will be stored 
for 25 years after the end of the trial. 
 
Quality of data 
In accordance with the ICH-GCP guidelines, the project will be monitored by the local GCP unit. 
The monitor will closely follow the conduct of the trial, this through periodical visits as well as 
telephonically/written contact with the investigator.  
 
Financing and insurance 
Financing 
The study is partly financed by The Novo Nordisk Foundation (grant number NNF22OC0074083).  
 
Conflicts of interests 
Sponsor-Investigator and the current trial is supported by a research grant from the Novo Nordisk 
Foundation (grant number NNF22OC0074083).  
Outside this trial, the Sponsor-Investigator has received lecture and/or advisory board fees from 
Novo Nordisk, has received research grants from Philips, Bayer, and Novo Nordisk, has ongoing 
institutional research contracts with Novo Nordisk, Philips, Janssen, and ResoTher, and has minor 
shareholder equity positions in Eli Lilly & Company and Novo Nordisk. 
 
Insurance 
In case of any injury related to the trial, patients can seek compensation by contacting 
“Patienterstatningen”. All patients will receive a standard letter of information besides the 
participant information.  
 
 

26 
 
Publication policy 
We commit to communicate and disclose the study results regardless of outcome (i.e., whether 
considered positive, neutral, or negative). This includes publication of manuscripts in English in a 
peer-reviewed scientific journal. The results will be reported in an objective and accurate manner, 
and strengths and limitations will be discussed. 
As soon as possible and no later than one year after the trial has ended, the summary of the results 
will be submitted to the CTIS portal. 
 
 

27 
 
References 
 
1. 
Nicolaisen, S.K., et al., HbA1c-defined prediabetes and progression to type 2 diabetes in 
Denmark: A population-based study based on routine clinical care laboratory data. Diabetes 
Res Clin Pract, 2023. 203: p. 110829. 
2. 
Zand, A., K. Ibrahim, and B. Patham, Prediabetes: Why Should We Care? Methodist Debakey 
Cardiovasc J, 2018. 14(4): p. 289-297. 
3. 
Gedebjerg, A., et al., Prevalence of micro- and macrovascular diabetes complications at 
time of type 2 diabetes diagnosis and associated clinical characteristics: A cross-sectional 
baseline study of 6958 patients in the Danish DD2 cohort. J Diabetes Complications, 2018. 
32(1): p. 34-40. 
4. 
Brannick, B., A. Wynn, and S. Dagogo-Jack, Prediabetes as a toxic environment for the 
initiation of microvascular and macrovascular complications. Exp Biol Med (Maywood), 
2016. 241(12): p. 1323-31. 
5. 
Kumar, R., et al., Evidence for current diagnostic criteria of diabetes mellitus. World J 
Diabetes, 2016. 7(17): p. 396-405. 
6. 
Blond, M.B., et al., The prediabetes conundrum: striking the balance between risk and 
resources. Diabetologia, 2023. 66(6): p. 1016-1023. 
7. 
Brannick, B. and S. Dagogo-Jack, Prediabetes and Cardiovascular Disease: Pathophysiology 
and Interventions for Prevention and Risk Reduction. Endocrinol Metab Clin North Am, 
2018. 47(1): p. 33-50. 
8. 
Xie, Y., et al., Association of glycated hemoglobin with non-alcoholic fatty liver disease 
patients and the severity of liver steatosis and fibrosis measured by transient elastography 
in adults without diabetes. BMC Endocr Disord, 2022. 22(1): p. 220. 
9. 
Adeghate, E.A., GLP-1 receptor agonists in the treatment of diabetic non-alcoholic 
steatohepatitis patients. Expert Opin Pharmacother, 2024. 25(3): p. 223-232. 
10. 
Nanavaty, D., et al., Prediabetes is an incremental risk factor for adverse cardiac events: A 
nationwide analysis. Atheroscler Plus, 2023. 54: p. 22-26. 
11. 
Lincoff, A.M., et al., Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. 
N Engl J Med, 2023. 389(24): p. 2221-2232. 
12. 
Thrane, P.G., et al., 10-Year Mortality After ST-Segment Elevation Myocardial Infarction 
Compared to the General Population. J Am Coll Cardiol, 2024. 83(25): p. 2615-2625. 
13. 
Kommu, S. and R.L. Berg, Efficacy and safety of once-weekly subcutaneous semaglutide on 
weight loss in patients with overweight or obesity without diabetes mellitus-A systematic 
review and meta-analysis of randomized controlled trials. Obes Rev, 2024. 25(9): p. e13792. 
14. 
Alkhezi, O.S., et al., Comparative effectiveness of glucagon-like peptide-1 receptor agonists 
for the management of obesity in adults without diabetes: A network meta-analysis of 
randomized clinical trials. Obes Rev, 2023. 24(3): p. e13543. 
15. 
Cesta, C.E., et al., Safety of GLP-1 Receptor Agonists and Other Second-Line Antidiabetics in 
Early Pregnancy. JAMA Intern Med, 2024. 184(2): p. 144-152. 
16. 
Ansari, H.U.H., et al., Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists on 
Body Weight and Cardiometabolic Parameters in Individuals With Obesity and Without 
Diabetes: A Systematic Review and Meta-Analysis. Endocr Pract, 2024. 30(2): p. 160-171. 
17. 
O'Hara, D.V., et al., Applications of SGLT2 inhibitors beyond glycaemic control. Nat Rev 
Nephrol, 2024. 20(8): p. 513-529. 

28 
 
18. 
Wiviott, S.D., I. Raz, and M.S. Sabatine, Dapagliflozin and Cardiovascular Outcomes in Type 
2 Diabetes. Reply. N Engl J Med, 2019. 380(19): p. 1881-1882. 
19. 
Herrington, W.G., et al., Cardiac, renal, and metabolic effects of sodium-glucose co-
transporter 2 inhibitors: a position paper from the European Society of Cardiology ad-hoc 
task force on sodium-glucose co-transporter 2 inhibitors. Eur J Heart Fail, 2021. 23(8): p. 
1260-1275. 
20. 
Perkovic, V., et al., Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 
Diabetes. N Engl J Med, 2024. 391(2): p. 109-121. 
21. 
Heerspink, H.J.L., et al., Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med, 
2020. 383(15): p. 1436-1446. 
22. 
McMurray, J.J.V., et al., Dapagliflozin in Patients with Heart Failure and Reduced Ejection 
Fraction. N Engl J Med, 2019. 381(21): p. 1995-2008. 
23. 
Ejskjaer, N., et al., A Pocket-size Device to Detect Autonomic Neuropathy. J Diabetes Sci 
Technol, 2008. 2(4): p. 692-6. 
24. 
Ciulla, T.A., A.G. Amador, and B. Zinman, Diabetic retinopathy and diabetic macular edema: 
pathophysiology, screening, and novel therapies. Diabetes Care, 2003. 26(9): p. 2653-64. 
25. 
Gulichsen, E., et al., Screening for diabetic cardiac autonomic neuropathy using a new 
handheld device. J Diabetes Sci Technol, 2012. 6(4): p. 965-72. 
26. 
Kahn, S.E., et al., Effect of Semaglutide on Regression and Progression of Glycemia in People 
With Overweight or Obesity but Without Diabetes in the SELECT Trial. Diabetes Care, 2024. 
47(8): p. 1350-1359. 
27. 
White, I.R., P. Royston, and A.M. Wood, Multiple imputation using chained equations: Issues 
and guidance for practice. Stat Med, 2011. 30(4): p. 377-99. 
28. 
Van Buuren, S., Flexible Imputation of Missing Data. 2 ed. 2012: CRC Press. 
29. 
Gorgojo-Martinez, J.J., et al., Real-world effectiveness and safety of dapagliflozin therapy 
added to a GLP1 receptor agonist in patients with type 2 diabetes. Nutr Metab Cardiovasc 
Dis, 2017. 27(2): p. 129-137.