Download Preventing Diabetes: Early Versus Late Preventive Interventions

Preventing Diabetes: Early Versus
Late Preventive Interventions
S115
Jaakko Tuomilehto1,2,3,4 and
Peter E.H. Schwarz5,6
Diabetes Care 2016;39(Suppl. 2):S115–S120 | DOI: 10.2337/dcS15-3000
There are a number of arguments in support of early measures for the prevention
of type 2 diabetes (T2D), as well as for concepts and strategies at later intervention
stages. Diabetes prevention is achievable when implemented in a sustainable
manner. Sustainability within a T2D prevention program is more important than
the actual point in time or disease process at which prevention activities may
start. The quality of intervention, as well as its intensity, should vary with the
degree of the identified T2D risk. Nevertheless, preventive interventions should
start as early as possible in order to allow a wide variety of relatively low- and
moderate-intensity programs. The later the disease risk is identified, the more
intensive the intervention should be. Public health interventions for diabetes
prevention represent an optimal model for early intervention. Late interventions
will be targeted at people who already have significant pathophysiological
derangements that can be considered steps leading to the development of T2D.
These derangements may be difficult to reverse, but the worsening of dysglycemia
may be halted, and thus the clinical onset of T2D can be delayed.
Primary prevention of chronic noncommunicable diseases such as type 2 diabetes
(T2D) must be based upon the alteration of the natural history of the disease by
influencing known modifiable risk factors. A large number of risk factors for T2D are
well known: some operating through insulin resistance, some through insulin secretion, and some through both. Many prevention strategies can be implemented
early on in the disease’s life, while some strategies can only be introduced at a later
stage. Controlled lifestyle intervention trials have provided convincing evidence
that T2D can be prevented in different populations and cultural settings (1–4).
The main objective of interventions applied in such “proof-of-concept” studies
was to correct unhealthy lifestyle patterns among the study participants by providing individual and/or group counseling. The implementation of the interventions
varied among these studies. The target groups in these intervention trials were
people at a high risk of T2D. There are, however, many ways to define “high risk.”
Although the high-risk approach is certainly a suitable strategy for late interventions
to prevent T2D, interventions may also be applied early for some high-risk target
groups. The high-risk strategy is a typical approach to be carried out within the
health sector, but it can also be implemented by stakeholders in other sectors, e.g.,
sports, nutrition, and education.
There is controversy about the right time to start interventions for T2D prevention from the medical perspective. Risk factor modification can also be done through
the population approach, in which the entire population, rather than a high-risk
group alone, will be the target (5). The population approach is well suited for early
interventions aiming at promoting healthy diet and physical activity at any age.
Since health promotion interventions are safe and can also result in prevention of
other noncommunicable diseases, the population approach can be the most desired
1
Dasman Diabetes Institute, Dasman, Kuwait
Chronic Disease Prevention Unit, National Institute
for Health and Welfare, Helsinki, Finland
3
Center for Vascular Prevention, Danube University
Krems, Krems, Austria
4
Saudi Diabetes Research Group, King Abdulaziz
University, Jeddah, Saudi Arabia
5
Department for Prevention and Care of Diabetes, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
6
German Center for Diabetes Research, Paul
Langerhans Institute Dresden, Dresden, Germany
2
Corresponding author: Jaakko Tuomilehto,
[email protected].
This publication is based on the presentations
at the 5th World Congress on Controversies to
Consensus in Diabetes, Obesity and Hypertension (CODHy). The Congress and the publication
of this supplement were made possible in
part by unrestricted educational grants from
AstraZeneca.
© 2016 by the American Diabetes Association.
Readers may use this article as long as the work is
properly cited, the use is educational and not for
profit, and the work is not altered.
PREVENTION AND PROGRESSION OF DIABETES
Diabetes Care Volume 39, Supplement 2, August 2016
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Early Versus Late Prevention Interventions
way to implement early intervention for
T2D prevention. In addition to the participation of people in the health sector,
the population approach requires the participation of other stakeholders from
sectors such as taxation, city planning,
education, agriculture, etc.
Definition of “High Risk” for
Developing Interventions to
Prevent T2D
The high risk of developing T2D can be
identified in different ways. For early and
late interventions, the following risk stratification may be used.
Fetal Life and Infancy
It has been known that characteristics of
fetal growth retardation are associated
with an increased risk of T2D during
adult life (6,7). In addition, babies born
small who experience the so-called
catch-up growth during early infancy,
which leads to a rapid increase in body
weight (and thus fat mass), are at particularly high risk of T2D (8). Also, the
probability of developing T2D seems to
be higher in children who were born
small but are the heaviest during prepubertal years. In principle, such information
could be used to initiate early prevention
of T2D. However, intervention studies in
which children and adolescents at high
risk based on their characteristics at birth
and infancy are selected for the study do
not exist.
Diabetes Care Volume 39, Supplement 2, August 2016
intervention was beneficial in both
positive– and negative–family history
groups (15).
Adults With High Estimated T2D Risk
For prediction of T2D, several multivariable models that combine risk factor
profiles and sometimes also measures
of glucose disturbances with other biochemical or clinical variables have been
published (16). Such algorithms are appropriate for etiologic investigations to
search for underlying causes of T2D.
However, due to their complexity they
may not be practical for public health
screening efforts aimed at identifying
individuals at a high risk of T2D or other
forms of glucose disturbances (16).
During the past decade, there has
been a lot of interest on the development and validation of simple risk scores
for T2D, based on either nonlaboratory
parameters alone or combining such information with biochemical parameters
(17–21). With use of a T2D risk score, it is
possible to identify people at high risk
who can then be invited to join lifestyle
intervention programs. This approach
has been used in the follow-up of the
Finnish National Diabetes Prevention
Program (FIN-D2D) (22) and the European
DE-PLAN (Diabetes in Europe–Prevention
Using Lifestyle, Physical Activity and Nutritional Intervention) project (23).
Genetic Predisposition
Women With History of Gestational
Diabetes Mellitus
At present, .80 genetic T2D susceptibility loci have been identified, but each
has only a small effect on T2D risk (8).
On the basis of these loci, it is possible to
generate a genetic risk score to predict
the development of T2D. Such a score
can be applied at any age, even at birth
or in childhood, and thus may offer an
opportunity to select high-risk individuals for early interventions to prevent the
development of the disease (9,10). Such
intervention studies initiated from a genetic risk assessment have not been conducted thus far. Post hoc analyses of the
Finnish Diabetes Prevention Study (DPS)
and the U.S. Diabetes Prevention Program
(DPP) applying the genotype data of selected known susceptibility loci have unequivocally demonstrated that carriers of
high-risk alleles benefit significantly from
lifestyle intervention (11–15). The DPS results also showed both that people with a
high and low genetic risk score benefited
from lifestyle intervention and that the
Gestational diabetes mellitus (GDM) is
defined as any degree of glucose intolerance with signs or first recognition
occurring during pregnancy (24). After
delivery, glucose levels return to the
nondiabetes range. The prevalence of
GDM may range from 1 to 14% of all
pregnancies depending on the population studied and diagnostic criteria used
in defining GDM (25). Women with GDM
are likely to develop impaired glucose
tolerance (IGT) or T2D during the postnatal period (26) or later in life (27–29).
Subgroup analyses among women with
previous GDM participating in the large
lifestyle intervention and pharmacological T2D prevention trials have yielded
substantial reductions in the risk of T2D,
making such relatively young women an
attractive clientele for early intervention
to prevent the development of T2D. The
Tianjin Gestational Diabetes Mellitus Prevention Program (29) is currently testing
the efficacy of the prevention of T2D in
women with a history of GDM in China.
Another ongoing study is the GIFTS (Genomic and Lifestyle Predictors of Foetal
Outcome Relevant to Diabetes and Obesity
and Their Relevance to Prevention Strategies in South Asian Peoples) project in
Bangladesh, Pakistan, and India (30).
GDM is a pathophysiological state identified in an increasing number of young
and middle-aged women that can be a
starting point for early interventions to
improve insulin sensitivity and thereby
prevent the development of T2D.
Prediabetes
Several studies have taken the approach
of only inviting individuals with IGT and/
or impaired fasting glucose (IFG) to interventions (1–4,31). These people, by
definition, have significant pathophysiological disturbances and thus should be
considered targets for later interventions. Thus far, no clinical trial evidence
exists to show that the development of
T2D can be prevented by lifestyle intervention in people with isolated IFG.
There is only one lifestyle intervention
trial that recruited people with IFG (31).
This trial showed a 59% relative risk reduction of T2D in people who had IFG
combined with IGT, an effect similar to
that in other trials in people with IGT
(1,2), but no beneficial effect in people
with isolated IFG. Reasons for the lack of
response to lifestyle intervention in
people with isolated IFG are not known,
but what is known is that pathophysiology between IFG and IGT is different
(32). This question needs to be addressed in future studies. The American
Diabetes Association is recommending
lifestyle intervention and even metformin for people with IFG and “high-risk
HbA1c” (5.7–6.4%) (33) and states that
this recommendation is based on “expert consensus.” Healthy lifestyle can
be recommended to everyone, but without evidence that the intervention provided was efficient, the use of health
care resources may be difficult to justify.
Thus far, no T2D prevention studies
have been carried out specifically recruiting people with HbA1c ,6.5%.
Older People
During aging, several pathophysiological
processes can promote the development of T2D. In particular, the pancreatic b-cell mass and insulin production
capacity decrease, muscles develop sarcopenia, and physical fitness reduces. As
care.diabetesjournals.org
is typical for endocrine cells, the b-cell loss
with aging may not be reversible, although
the functioning of existing b-cells might be
improvable (34). A progressive loss of muscle mass and strength with aging called
“sarcopenia” has a complex etiology involving neuronal, hormonal, immunological, nutritional, and physical activity
mechanisms (35,36) and is associated
with an increased fat mass infiltration.
Sarcopenia is associated with worsening
insulin sensitivity (37), and there is a
strong inverse association between insulin resistance and relative muscle mass
(38). The results from T2D prevention trials in people with IGT in both DPS and DPP
were most pronounced among the oldest
people (34). Thus, late interventions targeted to elderly people at risk for T2D are
warranted.
Obesity
Weight gain in adults is associated with
increased T2D risk. In the Health Professionals Follow-Up Study (HPFS), in people
aged 40–75 years at baseline, a weight
gain of .10–15 kg was associated
with a significantly increased risk of T2D
and also all-cause mortality (39). These
results are in agreement with those
from other studies that have also detected some ethnicity-specific differences
in this association (40–44). A working
group of experts in the fields of pathophysiology, genetics, clinical trials, and
clinical care of obesity and/or T2D
prepared a summary and made recommendations based on published literature
and their own data (45) at a conference in
2011. The impact of obesity on T2D risk is
determined not only by BMI but also by
the location where fat accumulates in the
body. Increased upper-body fat, indicating visceral adiposity, reflected as increased waist size or waist-to-hip ratio,
is strongly associated with T2D (46), although the underlying mechanisms remain uncertain. Whether subcutaneous
fat lacks the pathological effects of
visceral fat or is simply a more neutral
storage location remains unclear (47). Visceral obesity especially and, probably
even more so, the amount of liver fat
define the pathophysiological background for the causal role of obesity in
the development of T2D (35). The difference between obese people at risk for
T2D and those who are obese but do
not develop diabetes risk is probably
due to body fat composition, including
Tuomilehto and Schwarz
visceral and hepatic fat. Overweight/obesity
is an underlying risk factor for T2D with
epidemic dimensions, but weight alone is
not a sufficient indicator or sole target for
diabetes prevention. Visceral obesity and a
high amount of hepatic fat can be directly
translated into increased T2D risk, highlighting the relevance of waist circumference
as a surrogate for increased T2D risk
(36,37). While obesity prevention obviously
deals with early intervention to prevent T2D,
too, reduction of obesity is one of the most
common late T2D prevention strategies.
Pros and Cons of Lifestyle
Interventions if Implemented Early
Versus Late
Comparing different intervention strategies to prevent T2D reveals differences
in characteristics such as pathophysiology, personalized profiling, acceptance,
and biological and psychological adverse effects, as well as costs. The main
intervention strategies comprise physical
activity, advice on eating behavior, weight
reduction, and behavioral goal setting. For
each of these characteristics and strategies, there are some differences between
when the interventions started early and
when they started late.
Pathophysiology
On a pathophysiological level, the interplay between muscle, fat tissue, gut, and
brain is of relevance (35). By secreting
adipokines and hepatokines, increased
visceral and hepatic fat accumulation is
an important driver for an increased T2D
risk (38). People with a high amount of
visceral and liver fat may profit less from
lifestyle intervention and may thus require intensified lifestyle prevention
strategies or even pharmacological approaches to improve insulin sensitivity
(35). Increased physical activity improves muscle mass and reduces fat
mass, resulting in improved insulin sensitivity. A recent meta-analysis provides
strong evidence for an inverse relationship between physical activity and risk
of T2D, which may partly be mediated
by reducing adiposity (48). Daily physical
activity is a central element of early intervention for T2D prevention. Among
strategies focusing on eating behavior,
reduction of saturated fatty acids and
total fat consumption together with an
increased fiber consumption and reduction of sugar-sweetened beverages are
the most important approaches for preventing T2D (34). Consuming high amounts
of fat and alcohol leads to the accumulation of visceral fat and boosters the development of fatty liver disease. Consuming
soft drinks with artificial sweeteners may
influence gut microbiota and thus increase glucose intolerance (49). Changes
in dietary habits are effective in preventing T2D if started early and performed in a
sustained manner. For the short-term, interventions focusing on weight reduction
can influence T2D risks effectively. They
are also preferable for later interventions,
as mathematic models show (39). The preferred weight-reduction strategies in T2D
prevention are those that effectively reduce visceral and hepatic fat (40).
Personal Profiling: Choosing the Right
Intervention for the Person at Risk
It is challenging to educate people on
healthy eating behavior, especially those
with a low health literacy (41). Finding the
intervention that has the highest probability for success in preventing T2D in an
individual is one of the major challenges.
In design of interventions for T2D prevention, following a behavior change model
improves the success rate (3,42). In the
past, the application of educational programs was mostly driven by disease characteristics. Developing profiles, including
individual dimensions such as the degree
of motivation and personal preferences,
would increase the probability of the success (43). For instance, SweetSmart is a
concept that provides an assessment to
identify the most appropriate intervention applicable to a personal profile and
is applicable to both early and late interventions (43).
Personal profiling also means the efficient identification of people who are
at a high T2D risk. There are several T2D
risk prediction tools that include information on behavioral characteristics,
biomarkers, anthropometric markers,
and genetic markers (34,44). Compared
with clinical risk factors alone, common
genetic variants associated with the risk
of T2D have only a minor effect on the
ability to predict the development of
T2D (45). A combination of clinical, anthropometric, and behavioral parameters offers a better prediction of the
future T2D risk (46,47). Emerging information regarding metabolomics,
lipidomics, and proteomics may help in
the future to elucidate T2D risk increasingly in a personalized manner (50,51). A
recent study showed that history of daily
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Early Versus Late Prevention Interventions
physical activity was a robust proxy indicator of the risk of chronic diseases today
(52). Most personal risk profiles are associated with clinically relevant risk factors
and are therefore most relevant for late
interventions. Goal-setting strategies addressing behavioral stigmata are applicable throughout the whole diabetes risk
journey.
Acceptance
Today, we live in a toxic food environment,
which provides us with energy-dense and
cheap food 24 h a day and exposes us to
aggressive marketing campaigns that promote the consumption of unhealthy food
items (53). We are all consumers and
influenced by our peer environment marketing, our own experiences, and educational level. These factors are driven by
cultural, religious, ethnic, and social aspects, all of which influence acceptance
and adherence and also the efficacy of
T2D prevention. Our eating behavior is
reflected in our daily food choices, where
our cognitive knowledge on healthy eating competes with the emotional arguments of marketing campaigns of food
industry. Such marketing campaigns often twist unhealthy food items into images of healthy lifestyle. There might be
an increased acceptance of a healthy eating behavior by applying strategies such
as higher taxes on unhealthy food items,
plain packaging, intuitive food labeling,
or a policy of liability of food and beverage companies for adverse health events
associated with the use of their products.
These strategies would help the consumer to make healthier choices and trigger the acceptance of healthy nutritional
behavioral strategies (54). Goal-setting
strategies are by intentiondindividual
strategies. Goal-setting strategies can
help people at high risk of T2D accept
and adhere to healthier lifestyles, and
they can provide a more useful approach
for sustainable T2D prevention (44).
Biological and Psychological Adverse
Effects
The intensity of sports and physical activity correlates directly with a probability of
adverse effects: injuries, organ failure,
overexhaustion, and psychological resistance. Some studies show that the higher
the disease risk and the better the expected intervention effects, the more
people are willing to accept and endure
potential side effects (55). Daily walking or
similar leisure-time activities may result in
Diabetes Care Volume 39, Supplement 2, August 2016
fewer metabolic effects in the short-term,
but these activities have only minimal side
effects and show a positive dose response
for the prevention of T2D in the long-term
(48). Walking 5 and 7 h per week is relatively easy to achieve and can be applied
as a part of both early and late intervention for diabetes prevention.
In some prevention studies, depression scores increased a little in some of
the participants (56). This effect was related to the feeling of nonadherence to
nutritional intervention, especially in
weight-reduction programs. Changing
dietary behavior requires a supportive
environment, as well as food and nutrition policies and strategies in the community (54). Behavioral goal-setting
strategies are focusing on the assessment
of individual motivation with a model of
understanding the disease risk, developing an action plan, and developing routines to maintain the desired effect (44).
Such strategies translate into a sustained
behavior change and are best when applied as early as possible. Relapse can
happen and needs to be considered to
be part of the iterative goal setting and
not as an adverse effect (44).
Costs of Diabetes Prevention
The cost-effectiveness analysis of T2D prevention programs has shown that the prevention of T2D is cost-efficient (57). The
long-term follow-up data show even
greater benefits, since beneficial effects
of lifestyle intervention on T2D risk reduction seem to remain for many years after
the intervention program is over (4). The
dilemma is that the different stakeholders
(individuals, employers, health plan or insurance, state and society, etc.) often
have different perspectives on the concept of cost efficacy (58). The most direct
cost benefit from T2D prevention can be
seen in the occupational health setting, in
which the employers invest in prevention
programs for their employees in order
to keep them healthy and active in the
workforce (59). It is not clear which intervention can generate the greatest
benefit with least cost. It seems that early
T2D prevention programs are individually
more cost-efficient, since the magnitude
of change in lifestyle habits may be easier
to achieve than during later stages in the
natural history of T2D (Table 1).
How to Implement Early and Late T2D
Prevention in Routine Clinical
Practice
We have obtained a substantial amount
of scientific evidence on T2D prevention
and developed prevention practice recommendations that can be used to define which interventions are effective
among people at high risk (40). A sustainable implementation of intervention programs to reach millions of people at risk
does not require more evidence from
medical research work. Rather, it requires
policy and entrepreneur-like efforts (60).
The perspective in T2D prevention
should be in the implementation of scalable prevention programs. In particular,
it should be in the development of sustainable business models for T2D prevention. This can be reached not only
by building a policy frame to encourage
the development of T2D prevention but
also by developing policies, including tax
on unhealthy foods, food labeling, and
liability for adverse health effects on the
food and beverage industry (61). Additionally, reducing taxes for entrepreneurs
to build up business models in T2D prevention would foster implementation.
Tax exemption for noncommunicable disease prevention initiatives can be bound
to reach a certain number of individuals
or a specified health effect with a documented quality. Another implementation
strategy can be applied in the occupational
health care sector. In some countries, corporations deduct the amount of money
they spend investing in their employees’
Table 1—Schematic representation of intervention strategies by the basis of
intervention for early and late preventive intervention
Basis of
intervention
Pathophysiology
Physical
activity
Advice on eating
behavior
Weight
reduction
Goal-setting
strategies
Early
Early, late
Late
Early, late
Personalized
profiling
Early
Late
Late
Early, late
Acceptance
Early
Late
Late
Early
Early, late
Early
Late
Late
Early
Early
Late
Late
Adverse effects
Costs
care.diabetesjournals.org
health from income tax. This can become
very cost-efficient if the investment in
employees’ health promotion reduces
absenteeism at the workplace. The participation and uptake of prevention activities
are, in most of the cases, very individual
personal decisions. If interventions do not
match individual preferences and needs,
they will not succeed. We have to learn
from the marketing strategies of the big
food companies, as well as accept that
we have to sell and market our prevention
strategy better than they do, in order to
reach our clients who are at risk for developing T2D (53).
Tuomilehto and Schwarz
with environmental public health strategy, including all public health and political tools, is needed in order to build a
friendly environment for T2D prevention.
This may also include the use of T2D prevention as a model for targeting growing
risks for other chronic diseases and developing prevention strategies for noncommunicable diseases in general. Early
versus late prevention may be distinguished by different characteristics of intervention strategies, but all are following
one goal: to develop sustainable prevention approaches in order to halt the pathophysiological process through which T2D
is developing.
Conclusions
There are a number of arguments favoring early activities in the prevention of
T2D, as well as concepts and strategies
of interventions that suit best for later
stages (34). T2D prevention is a success
story if implemented in a sustainable
manner. Sustainability within a T2D prevention program is more important than
the actual point in time or stage in the
natural history in the progression to T2D
at which prevention activities may start.
The quality of intervention, as well as its
intensity, will vary with the degree of
the observed risk. Interventions to prevent T2D should start as early as possible to allow a wide variety of low- and
moderate-intensity programs (40). However, the results from the major T2D prevention trials have shown that the best
relative risk reduction in T2D incidence
was obtained in older participants (1,2)
and in those who had the highest estimated T2D risk (62).
Public health interventions for T2D prevention represent an optimal model for
early intervention. The later the people
at high risk are identified, the more aggressive and more adapted to the pathophysiological stage of T2D development
the intervention should be. This may
also include the use of pharmacological
agents for interventions. Furthermore,
sustainability of the intervention should
be combined with effectiveness, and this
requires quality management. All intervention programs should include an embedded quality-management strategy to
assure the timely and efficient delivery
of interventions. For the implementation
of a variety of T2D prevention programs,
new concepts are needed to achieve a
sustainable program delivery. Business
planning in T2D prevention, together
Funding. This article was partly supported by
grants from the European Commission FP7
(grant agreement numbers Health-2011-F2279074 and Health-2011-278917).
Duality of Interest. No potential conflicts of
interest relevant to this article were reported.
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