Reversal to Normoglycemia by Treating Prediabetes

Prediabetes is a precursor to diabetes, but compared with diabetes, much less is known about prediabetes. Prediabetes is defined based on a blood sample measuring long-term average glucose levels. In the Danish population, about 7% have prediabetes, and roughly one in five will develop diabetes within five years. In the US, significantly more people have this condition - about 38% of the adult population - and it is reasonable to expect a growing global prevalence over the years.

Diabetes is associated with various microvascular diseases, traditionally referred to as diabetic complications, such as diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. However, it has been shown that some of these conditions are already present in some individuals with prediabetes, even though this condition does not meet the diagnostic criteria for diabetes. Several metabolic changes are often seen in people with prediabetes, including high cholesterol, hypertension, increased inflammatory markers, and obesity. Additionally, there is a possible link between prediabetes and the occurrence of fat accumulation in the liver. These risk factors are also believed to be associated with the development of coronary atherosclerosis. In individuals with coronary atherosclerosis there is an overrepresentation of prediabetes. Therefore, the investigators would like to investigate whether this group of people might benefit from having their long-term average glucose levels reduced to normal from prediabetes using glucose-lowering medication, which is approved for use in people with diabetes and has also shown a cardioprotective effect in individuals without diabetes.

The medications that will be used for this purpose are:

Semaglutide, administered once weekly as a subcutaneous injection. The dose will be gradually increased at 4-week intervals up to a maximum of 2.4 mg. If this is insufficient, it may be considered to start Dapagliflozin (Forxiga), 10 mg tablet daily. Both treatments are approved for use in Europe but are not currently used to treat prediabetes.

A total of 108 individuals with prediabetes and coronary atherosclerosis who consent to participate in the trial will be randomly assigned (1:1) to two groups:

1. Interventional therapy arm: Participants will attend visits at Aarhus University Hospital and begin glucose-lowering treatment. Additionally, any hypertension or high cholesterol will be optimized according to current guidelines. They will be offered lifestyle counselling. Participants will have their blood pressure measured regularly and, if necessary, blood samples are drawn to optimize the above. 2. Conventional therapy arm: Participants will receive standard treatment either at the hospital or from their general practitioner, without any influence from the trial and without starting trial-related medication.

Furthermore, a third group of 50 participants with coronary atherosclerosis and normal long-term average glucose levels will be included.

All trial participants will, at inclusion, be examined for the presence of diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, and liver fat accumulation. This will be done through blood samples, urine samples, nerve examinations, and liver ultrasound. In addition, height, weight, waist circumference, body muscle and fat composition, pulse, and blood pressure will be measured. The third group will then conclude their participation.

The interventional therapy arm will begin the described intervention, which lasts for one year. After one year, the intervention period will end. Both randomized groups will then be examined by blood samples, urine samples, liver ultrasound, height, weight, waist circumference, body muscle and fat composition, pulse, and blood pressure. One year later, the above examinations will be repeated, except for the liver ultrasound. This will mark the end of the trial.