Evidence Based Prevention of Type 2 Diabetes : Role of Lifestyle Intervention as Compared to Pharmacological Agents

Background: The global epidemic of type 2 Diabetes Mellitus (T2DM) presents significant challenges to world health both in terms of financial costs as well as morbidity. Thus, considerable research has been focussed on the prevention or delay of the onset of T2DM. Aim: The aim of this article is to review published studies that evaluate lifestyle and pharmacological interventions aimed at preventing T2DM and to compare both these interventions. Methods: We undertook an electronic search of MEDLINE, PubMed, EMBASE and Cochrane Register of Controlled Trials, with the English language restriction and published until May 2015. Five major diabetes prevention trials using lifestyle intervention (LSI) and five using pharmacological intervention were identified. We reviewed the study design, key components, and outcomes for each study aimed to delay T2DM. Results: Both LSI and pharmacological intervention were found to be effective to reduce the risk of developing T2DM in at risk population. LSI with modest goals of weight loss and physical activity is safe, cost saving and prevents or delays the onset of diabetes, even after discontinuation of the treatment providing long term benefits. A Considerable effort from well-trained, multidisciplinary staff is needed to achieve these modest goals. For patients who are unable to achieve the lifestyle goals or those who progress to T2DM despite being on LSI, pharmacological intervention has shown to be effective, especially in younger obese patients. Adverse effects with pharmacological intervention were common. Conclusion: Strong evidence exists for the prevention or delay of type 2 diabetes through lifestyle and pharmacological intervention. LSI with weight loss and increased physical activity are safe, costeffective and are currently recommended for the prevention of diabetes.


Introduction
Type 2 Diabetes Mellitus (T2DM) is one of the most costly and burdensome of chronic diseases and is a global epidemic.Estimates by the International Diabetes Federation indicate that 387 million people have diabetes, and that this figure is expected to rise to 592 million by 2035 with an additional 175 million cases currently undiagnosed [1].
Individuals with T2DM are at a significantly higher risk of co-morbidities particularly cardiovascular disease (CVD) [2,3].Additionally, pre-diabetes independently increases the risk of CVD and death [4].Furthermore, micro vascular disease is already present in many individuals with undiagnosed or newly diagnosed T2DM.The onset of retinopathy has been observed to occur around 4-7 years before a clinical diagnosis of diabetes [5].
The considerable economic burden of diabetes is shared by patients and countries (developed and developing).It is estimated that subjects with diabetes account for an average of nearly $85,500 in treatment costs over their lifetime [6].Thus, the focus of recent research is toward prevention or delaying the onset of T2DM.

Candidates for prevention of T2dm
The focus of diabetes prevention is mainly recommended for individuals at high-risk of developing diabetes, particularly those with Impaired Glucose Tolerance (IGT) or Impaired Fasting Glucose (IFG).In fact, the National Institute for Health and Care Excellence guidelines [7] recommends risk assessment to be done using validated tools for all eligible adults aged 40 and above, except pregnant women; people aged 25-39 years of South Asian, Chinese, African-Caribbean, black African and other high-risk black and minority ethnic groups, except pregnant women; and adults with conditions that increase the risk of type 2 diabetes.

Methods
Source articles were identified in PubMed Central (including MEDLINE); EMBASE; Cochrane Central Register of Controlled Trials (CENTRAL), up to May 2015.We searched the English language literature using the keywords: impaired glucose tolerance, type 2 diabetes prevention, lifestyle intervention, pharmacological intervention.Primary focus was on large scale outcome trials, which are generally considered the best to guide evidence-based decisions; in addition, specific emphasis was placed on studies having a follow-up time period of at least 2 years, allowing assessment of the durability of any treatment effect and more complete safety evaluation.Five prevention studies utilizing lifestyle changes (Da Qing [8,9], FDPS: Finnish Diabetes Prevention Study [10] , USDPP: United States Diabetes Prevention Program [11], IDPP: Indian Diabetes Prevention Program [12] and Swedish Malmo Study [13]), and five utilizing pharmacological agents to prevent diabetes (USDPP: Unites States Diabetes Prevention Program [11]; DREAM: Diabetes Reduction Assessment with ramipril and rosiglitazone medication [14]; NAVIGATOR: Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research trial [15]; ORIGIN: Outcome Reduction with Initial Glargine Intervention [16] and, STOP-NIDDM: Study to Prevent Non-insulin-dependent Diabetes Mellitus) [17,18] were identified.

Approach to prevention of T2dm
Two major approaches are adopted for prevention of T2DM: 1. Lifestyle Intervention (LSI)

Evidence of lifestyle interventions:
LSI is a comprehensive approach to correct several risk factors for T2DM in those at risk.The targets for LSI in the FDPS study were: (i) Weight loss more than 5% (ii) To reduce the intake of fat to less than 30% of total energy intake, and that of saturated fats to less than 10% of total energy (iii) To increase of dietary fibres to more or equal 15 gram per 1000 kilocalorie, and (iv) To increase the level of physical activity to at least 150 minutes per week [10].[8,9].A reduction in the incidence of diabetes observed during the active phase continued for 14 years post active intervention.The authors conclude that in absence of active intervention the risk of developing diabetes remains high in this population.This reflects the challenges of maintaining patients on LSI over prolonged periods of time [8,9].
Interestingly the Indian Diabetes Prevention Program (IDDP) study [12] found that the rate of progression of diabetes in highrisk individuals of Indian origin was much faster compared to other populations.It was suggested that small doses of metformin be used prophylactically in order to slow the progression of IGT to T2DM

years
The subjects were randomised into 2 groups

Control Life Style Modification
To test the feasibility aspect of long-term intervention with an emphasis on life-style changes.

Improvement in glucose tolerance was correlated to weight reduction and increased fitness
Incidence of diabetes: Reference group: 29% Intervention group: 11% The incidence in the intervention group was less than half that of the other group.as the effects of LSI and metformin intervention were the same [12].This finding is applicable only to the Indian population which may be important in the overall approach of care in real settings.

Abbreviations
The United States Diabetes Prevention Program (USDPP) study describes use of LSI mediated weight reduction to be effective across age, gender, racial and ethnic groups [11,19] while the Finnish Diabetes Prevention Study (FDPS) documented an overall reduction in the incidence of diabetes by 58% suggesting that primary prevention of T2DM is possible in the primary care setting using non pharmacologic interventions [10,20].The Swedish Malmo study not only documented normalised glucose tolerance in the intervention group but also documented a reduction in blood pressure, lipids and hyperinsulinemia.These metabolic benefits were correlated with weight reduction and increased fitness.The Swedish Malmo study included subjects with early diabetes.More than 50% subjects with diabetes were in remission at the 6 year follow-up, showing the LSI benefits carry on for a significant duration in patients with existing diabetes as well and may be used to reverse diabetes in early diagnosis [13,21].
The LSI benefits seem to long lasting across varied populations, gender and age.They not only reduce the incidence of diabetes but also seem to delay and prevent in onset of diabetes while being cost effective and can be used easily in primary health care setting.The real challenge is however to achieve compliance and keep the subjects motivated enough to continue following the rigorous regime.

Evidence for pharmacological interventions in prevention of T2DM:
Pharmacological therapies have also been proven to be effective in preventing or delaying the onset of T2DM (Table 3).The risk reduction in diabetes is the most evident with rosiglitazone (62% risk reduction), followed by metformin (31%), insulin glargine (30%), acarbose (25%) valsartan (14%), Nateglinide (0%) [22].Reduction in CVD outcomes were studied in Study to Prevent NIDDM (STOP-NIDDM) study and was reported to be lowered by 49% [17,18].One should be cautious given the differing glucose and cardiovascular end-point criteria, as well as adverse effect profile (Table 4) [22].It is important that the risk benefit ratio of every treatment option and modality is weighed before initiation.

Other notable studies
The Troglitazone in Prevention of Diabetes (TRIPOD) study randomised 266 Hispanic women with prior gestational diabetes to troglitazone or placebo [23].The study showed a reduction in T2DM incidence of > 50% after 1.5 years in the troglitazone group.However, troglitazone was withdrawn in 2000 due to reports of fatal liver toxicity.
The XENical in the prevention of Diabetes in Obese Subjects (XENDOS) study compared orlistat to LSI [24].It was a multicentre, randomized, double blind, placebo-controlled parallel group prospective study performed in Sweden over a period of 4 years, and showed that patients with IGT showed a significant reduction of progression to diabetes of 18.8% in the orlistat group, compared to 28.8% in the placebo group (p < 0.005), along with a favourable and sustainable cardio-metabolic risk profile.Gastrointestinal adverse effects, such as steatorrhoea, faecal incontinence and frequent bowel movements were commonly reported.

Comparison: lifestyle or medication?
Table 5 compares the diabetes and CVD risk reduction observed in studies of lifestyle and pharmacological intervention.As shown, both LSI and pharmacological agents show short-term risk reduction in incidence of diabetes.However, none of the studies using pharmacological agents have been able to demonstrate a continued reduction in diabetes risk after drug discontinuation.On the other hand, results from the follow-up of LSI studies reveal that LSI was successful in reducing diabetes incidence even after several years of follow up without any active intervention [8,25] LSI was also associated with reduction in the CVD mortality [8,20] not seen with pharmacological agents.• The reduction in diabetes incidence seen during the 6-year period of active intervention persisted for two decades.
• Participants with impaired glucose tolerance randomised to lifestyle intervention groups had a 43% lower diabetes incidence for up to 14 years after the active intervention ceased, and diabetes onset was delayed an average of 3.6 years.
• The risk of eventually developing diabetes in people with impaired glucose tolerance in the absence of intervention remains high for many years, since 93% of the controls developed diabetes over 20 years

IDDP [12]
• The rate of progression in the Indian subjects was much higher that other populations in whom similar studies have been conducted.The rates in the Indian population were found to be 18.3%/year as opposed to 6%/year in the Finnish study.
• Metformin in doses as low as 500mg/day effectively reduced the progression of IGT to Diabetes in Indian populations • In Indian Populations effectiveness of LSM and metformin were found to be similar whereas in all other populations LSM was found to be a superior intervention

US DPP [11,19]
• 50% of the participants in the lifestyle intervention group achieved the goal of weight loss of 7% or more by the end of the 24 weeks,and 74% met the goal of at least 150 minutes of physical activity per week.The daily energy intake decreased by a mean of 249 ± 27 kcal in the placebo group, 296 ± 23 kcal in the metformin group, and 450 ± 26 kcal in the lifestyleintervention group (P < 0.001).
• The participants assigned to the lifestyle intervention had much greater weight loss and a greater increase in leisure physical activity than did participants assigned to receive metformin or placebo.The average weight loss was 0.1, 2.1, and 5.6 kg in the placebo, metformin, and lifestyle-intervention groups, respectively (P < 0.001).
• The effects of reduction in the incidence of diabetes were similar in men and women and in all racial and ethnic groups.The intensive lifestyle intervention was at least as effective in older participants as it was in younger participants.
• These findings suggest that dietary composition and physical activity are important in diabetes prevention, but their effect on diabetes risk is primarily mediated through resulting weight reduction [23].

FDPS [10,20]
• The mean (± SD) amount of weight lost between base line and the end of year 1 was 4.2 ± 5.1 kg in the intervention group and 0.8 ± 3.7 kg in the control group; the net loss by the end of year 2 was 3.5 ± 5.5 kg in the intervention group and 0.8 ± 4.4 kg in the control group.
• Weight change was significantly associated with the achievement of each of the four lifestyle goals, consequently, success score was strongly and inversely correlated with weight reduction [24].

Swedish Malmo Feasibility Study [13,21]
• There was significant weight loss in the intervention group: body weight was reduced by 2.3-3.7%.Weight increased in the reference group by 0.5-1.7%(p ˂ 0.0001).
• In ˃ 50% of the participants' glucose tolerance was normalized.
• In the intervention group, after completing the trial, blood pressure, lipids, and hyperinsulinaemia were reduced.
• More than 50% of the diabetic patients were in remission at 6-year follow-up.

Cost effectiveness
The DPP investigators analyzed the cost per quality-adjusted life year (QALY), comparing the lifestyle and metformin interventions to placebo.The cost per QALY for the LSI was approximately $1,100 compared to $31,300 for the metformin intervention [26].Hence LSI was not only the most effective treatment for diabetes prevention, but also the most cost-efficient.They also concluded that both DPP interventions would be cost-effective from societal and health system perspectives.
The follow-up data from the Finnish DPS shows that after the intensive lifestyle intervention that was provided to the intensive intervention group for 4 years, additional benefits in terms of a lower risk of T2DM were still obtained during at least 3 years without any effort from health personnel [27].This will improve the longterm cost-effectiveness estimates markedly.With pharmacologic intervention, such long-term effects after stopping the treatment are unlikely, and if treatment is continued for the long term, it will require efforts from health care providers in addition to the cost of the drug itself.Table 6 illustrates the various studies that analysed the cost-effectiveness of T2DM prevention [28].

Discussion
The available reported evidence suggests that there is much greater benefit for LSI as compared to pharmacological agents.LSI is cost saving and appears to be very safe as no untoward effects of LSI were noted in either the Finnish [10] or DPP study [11].Both the Finnish study and the DPP reduced the magnitude of some CVD risk factors, suggesting that LSI may have additional health benefits.
Drug therapy to prevent or delay diabetes appears to be much less beneficial for a variety of reasons [29].(i) As shown in the DPP, metformin was half as effective as lifestyle modifications (31% vs 58%) in prevention of diabetes.The advantage of lifestyle modification was even greater in older or less overweight patients.The relative risk reduction using acarbose (36%) appears similar to that of metformin.(ii) All glucose-lowering drugs require monitoring, have been associated with significant adverse side effects, and are contraindicated in some individuals.(iii) Most of the hypoglycemic agents available have not been studied with regard to protection against CVD or have any other clinical benefit to non diabetic individuals.(iv) Medications used for delaying the onset of diabetes are already used for treatment of diabetes.Prescribing such medications will increase a patient's total years of drug exposure and may increase the likelihood of untoward drug effects.
None of the pharmacological agent has been able to show a durable effect after discontinuation.This highlights that these medications simply delays the diagnosis of diabetes rather than alter the underlying pathophysiology and begs the question: Are we treating early T2DM or are we preventing it?
In contrast, the lifestyle interventions appeared to prevent or delay the onset of diabetes, even after discontinuation of therapy, as shown in the follow-up studies (34% Risk Reduction (RR) in DPP and 43% RR in Da Quing study).
It is also necessary to bear in mind the limitations associated with the studies included in the review.One of the main limitations of the studies was a high or unclear risk of bias largely due to inability to blind patients in the treatment group and lack of consistency and precision among studies.This led to low or insufficient strength evidence for most outcomes.
Another limitation includes the group of patients that were identified as being at increased risk for diabetes.This is a controversial area, with various definitions and diagnostic cut points having been proposed over the past few years [30].Furthermore, there is no evidence of benefit in all-cause mortality and insufficient evidence to suggest benefit on cardiovascular and microvascular outcomes (a non-significant 17% reduction in CVD mortality, in the Finnish study) [10].Improvement was seen for some secondary outcomes, but it generally did not persist beyond the intervention phase, and the clinical significance is unclear.
Even though the lifestyle goals set were modest, and the participants were already motivated, there was only partial success in achieving the desired objectives.In the Finnish study, only 43% achieved the weight reduction goal, and 36% of subjects increased their physical activity [10].In the DPP, only 50% reached the weightloss goal, and 74% reached the exercise goal [11].In both studies, some weight was regained despite the continuation of intensive strategies.
Another potential limitation is the interpretation of the LSI achievements beyond the confines of a trial.Although in the LSI studies, diabetes could be delayed or prevented with only modest changes in weight and activity, considerable effort from welltrained staff was needed to achieve these behavioural changes.A multidisciplinary care team consisting of nurses, clinicians, dietitians, psychologist, physiotherapists and health educators is needed.The prevention programs have to be culturally adaptive for office-based counselling which may be challenging in diverse communities.

Conclusion
Recent studies have convincingly shown that lifestyle modification is the most effective tool in the prevention or delay of T2DM.A modest weight-loss goal of 5-10% and moderate-intensity physical activity such as brisk walking for at least 150 minutes per week plays an important role in reducing diabetes risk [31].
For patients who are unable to achieve the lifestyle goals or those who progress to T2DM despite being on LSI, metformin has also been proven effective, especially in younger obese patients.Acarbose may also confer a moderate risk reduction.The reports of cardiovascular and fracture risk make thiazolidinediones less attractive as a prevention strategy.However, none of these medications are as effective in diabetes prevention as the lifestyle intervention strategies, and cost-effectiveness analyses suggest that pharmacotherapy may have greater financial costs.

Table 1
illustrates the major studies conducted comparing LSI and pharmacotherapy.Relevant and significant findings have been listed in table 2.

Table 2 :
Conclusions of lifestyle intervention studies

Table 3 :
Pharmacologic interventions for the prevention of diabetes [22] BMI: Body mass index, DREAM: Diabetes REduction Assessment with ramipril and rosiglitazone Medication, DPP: Diabetes Prevention Program, FPG: Fasting plasma glucose, IGT: Impaired glucose tolerance, IFG: Impaired fasting glucose, NAVIGATOR: Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research trial, ORIGIN: Outcome Reduction with Initial Glargine Intervention, OGTT: Oral glucose tolerance test, OR: Odds ratio, STOP-NIDDM: Study to Prevent Non-insulin-dependent Diabetes Mellitus.

Table 5 :
Comparison of Studies of Lifestyle Intervention vs Pharmacological Agents Markov model, DPP and UKPDS data adapted to US setting, projected LE, QALE and total direct medical costs, lifetime time horizon, healthcare payer and societal perspectives taken.ILC dominant versus metformin, metformin not cost-effective for over 65 years of age, outcomes sensitive to the pricing of treatments.Markov model, based on DPP, projected LE, years free of diabetes and total direct costs, lifetime time horizon, extensive sensitivity analyses and sub-group analyses on age and BMI.ILC and metformin dominant versus control except UK (ICER €6,381 and 5,400 per life year gained, respectively) Markov model, based on DPP, adapted to italian setting, projected LE,years free of diabetes and total direct costs,lifetime time horizon.ILC and metformin cost effective vs control (ICER € 11,234 and 11,556 per life year gained,respectively) Markov model, based on DPP, adapted to Spanish setting, projected LE, years free of diabetes and total direct costs, lifetime time horizon.Metformin cost-effective versus control (ICER €5,080 per life year gained), IILC costs prohibitive due to personnel costs.