Digital, blended lifestyle intervention program for remission and improved management of type 2 diabetes

Prevalence T2DM
The world is facing multiple pandemics, from zoonoses to chronic diseases. Some
can be prevented by encouraging social distancing, limited contact, isolation,
and ultimately vaccines. While others, like diabetes, thrive under these
circumstances due to poor adherence to healthy diets and reduced physical
activity. It is estimated that one in eleven individuals suffer from diabetes
(T2DM), according to the International Diabetes Federation. Unfortunately, it
is also estimated that by the year 2030, there will be an estimated 552 million
cases of T2D.

Economic burden T2DM
There is a substantial intangible cost to diabetes, the pain and suffering of
these patients is, unfortunately, difficult to quantify. In the Netherlands,
the estimated cost of diabetes per patient per year is ¤9500 when indirect
costs are also considered. These extra consists include the costs directly
associated with diabetes, such as the diagnosis, disease management as well as
T2DM triggered complications. While indirect costs include management of
common commodities such as hypertension, elevated body mass index (BMI),
cardiovascular disease, etc., loss of productivity such as sick days,
inefficiency, etc. as well as other costs like welfare payments to patients
suffering from diabetes related disability5. However, the overall total
economic burden of T2DM in the Netherland was an estimated ¤5.9 billion as of
2016. This figure is expected to continue to rise due to the general ageing of
the population as well as inactive and poor dietary behaviours.

This cost rose 26% between 2012 and 2017, and may increase more substantially
due to current circumstances, as well as the ageing population In addition to
the financial costs.
.

Reversibility of T2DM
However, there is ever-increasing awareness that the tied can be turned, that
impaired blood glucose tolerance and fasting glucose tolerance can be
effectively treated with lifestyle interventions, thus preventing progression
to T2DM. Studies have shown that early T2DM can be reversed using a number of
different dietary strategies, so long as they achieve substantial weight loss.
The reversibility of diabetes was first observed in bariatric patients
undergoing gastric bypass surgery; patients* blood glucose levels completely
normalised, have been observed to remain so for up to 10 years in 90% of
patients. More recent studies have suggested that lifestyle interventions can
achieve similar results. In one of the premier studies on the topic, Lim et.
al. 2011 showed that diabetes could be reversed. Individuals following a
600kcal diet reduced their liver fat content by 30% and to have their blood
glucose levels normalise within the first seven days of the study, while weight
loss was on average 13 kilograms and insulin became supranormal (1.37*±*0.27 vs
controls 1.15*±*0.18 nmol min*1 m*2) within 8 weeks. However, such a study is
difficult to perform in larger settings and or real-world conditions due to the
severe restrictions placed on the participants, making less strict and virtual
interventions interesting alternatives.

The Look AHEAD study considered this and examined the influence of a diet and
exercise intervention on individuals aged 45 years and older with T2DM.
Individuals reduced caloric (1200 - 1800kcal; <30% calories from fat, and >15%
protein) intake and increased physical activity (< 175 minutes per week) in
order to achieve an approximate 7% weight loss. It observed significant
improvement of T2DM status, as much as 11.5% of patients achieved (partial)
T2DM remission within the first year. On the other hand, recent improvements in
technology have led to the rise in digital-based interventions. Patients
participating in the Virta programme, an intensive digital diabetes, ketogenic
diet programme, significantly improved body weight and HBA1c. Specifically, 94%
of patients on insulin were able to reduce or eliminate their dosages.
Sulfonylureas were entirely eliminated, patients lost on average 12% of their
body weight, and HBA1c values reduced from 7.6 ± 0.09% to 6.3 ± 0.07% within
one year. Similarly, other studies such TeLiPro, Low Carb Program, and Better
Therapeutics observed improvements in TDM2 related outcomes (reduction in
HbA1c > .5%, weight loss > 5%, and/or diabetes medication cessation) between
three months to one year after program initiation, while other programmes like
u-Healthcare, Our Path, GlycoLeap, Noom Coach were able to consistently show
improvements in HBA1c and weight loss in participants between three and six
months, while reports of harm were sparse. Taken together, this suggests a
well-designed digital intensive lifestyle intervention has to potential to
significantly improve healthcare outcomes in T2DM.

Primary Objective:
1. To determine the effectiveness of a personalised, holistic 24-week digital
lifestyle programme in achieving diabetes type 2 (T2DM) remission independence
from blood glucose-lowering medications, in a Dutch population, in comparison
with usual care.

Secondary Objective(s):
1. To determine if the 24-week digital lifestyle programme leads to improved
glycaemic control in terms of reduced dependence on medications, in terms of
reduced dosage or number of antihypertensive or antidiabetic medications, and/
or improved HbA1c in diabetes type 2 (T2DM) in a Dutch population, in
comparison with usual care.
2. To determine if a digitally administered trial leads to other medical
benefits in Dutch diabetes type two patients, including changes in blood
chemistry and body composition.
3. To evaluate if a digital diabetes remission programme can be effectively
delivered in conjunction with routine primary or secondary care, including the
consideration feasibility of the programme, in terms of patient acceptability
and compliance to the programme (app engagement).
4. To analyse the association between the different diabetyping methods
developed by TNO and Ahlqvist and Udler with respect to genetic and phenotypic
methods.
5. To determine if there is an association between diabetype and remission and
or glycaemic control.
6. To determine the cost-effectiveness of running a digital lifestyle-based
intervention, in comparison to usual care over a 12- and 24-month period.

Open-label, randomised, controlled trial.

Patients will partake in a 24-week intervention followed by a two-year
follow-up period. The intervention will consist of diabetic phenotyping
(diabetyping), and a personalised app-based lifestyle intervention, done in
conjunction with usual care, the so-called blended care model. Individuals
will be allocated to either a high (unsaturated) fat, low-carbohydrate
Mediterranean (50 g) or a Mediterranean wiht limited carbohydrates (120 g) diet
based on their diabetype, insulin use, and personal preference. This will be
given in conjunction with physical activity programme, which will focus more on
aerobic activity or resistance training depending on diabetype. All
participants will be provided with additional coaching, which will include
aspects of diet, physical activity but also aspects of mindfulness, and emotion
regulation. The participants will be assessed at screening, before the start of
the Maintenance phase, and at follow-ups one, two, and three. Control patients
will follow the usual care and will also be followed up, following the same
schedule. The treatment is further clarified below:

Prior to commencing the study, participants in the active intervention group
will receive a home kit, approximately one to two weeks before. This will
contain all the necessary products, information, and instructions (where
applicable) for participating in the study. Moreover, they will be carefully
informed about the types of personalisation*s available to them. The
participants will have either a whole food type diet or a low carbohydrate diet
recommended to them based on their metabolic profiles. In addition, they will
also have specific types of exercise recommended to them, however, they will be
able to choose which of these, and which combination of exercise and diets they
follow. Participants* treating physicians and coaches will be informed about
their choices, and will receive supporting medication adjustment documents,
based on those made in previous studies. It will remain the responsibility of
the treating physicians to adjust any medications the participants are
receiving.

The control group is required to meet the same criteria as the intervention
group. The control group only receives health assessments (with the exception
of the diabetyping, glucose tolerance test, and genetic testing), they will not
receive any health intervention. They will continue to receive standard
diabetes care.

This study will lead to insight as to how a digital health intervention can be
(successfully) carried out within the Netherlands in a type two diabetes
population. Insights here will be used to improve the intervention, such that
treatment efficacy can be further increased. This should translate into
improved quality of life for patients with respect to improved blood glucose
control and or complete diabetes remission. which will likely reduce the risk
of or time to the development of complications associated with type two
diabetes. Improvement of blood glucose control could look like reduced and or
removal from hyperglycaemic medications, reduced frequency of blood glucose
measurements. There is some risk associated with the commencement of this
study. In rare circumstances, a participant could develop a serious condition,
called ketoacidosis, and the complications associated with it.

This risk will be mitigated as much as possible through the careful
introduction of a controlled diet, and gradual, medically supervised reduction
of medication and blood glucose levels. Additionally, hyper or hypoglycaemia
may also be experienced if participants do not carefully follow their
prescribed diets.

Burdens the participants will experience include four clinic visits, 24 weeks
of a digital diet and lifestyle intervention, venepunctures, questionnaires,
and physical tests, as well as two years of follow-up. Additionally,
participants may feel some discomforts or potential injuries from increased
levels of activity and or diet or bruising/discomfort at the site of
venepunctures or fingerpricks. During the active intervention phase of the
study, this will take seven to ten hours per week. This includes (additional)
exercise, meal planning, and interactions with the digital platform Ifood
logging, participation in group sessions, etc). During the follow-up period, no
additional requirements are made on the participants.