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Keywords:

  • diabetes mellitus;
  • prediabetic state;
  • primary prevention;
  • lifestyle intervention;
  • pharmacological intervention

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Diabetes prevention – effectiveness of life style modification
  5. Diabetes prevention – effectiveness of pharmacological treatment
  6. Cost economics of lifestyle intervention and pharmacological intervention
  7. Proposed strategic approach for prediabetic populations
  8. Conflicts of interest
  9. References

The ‘diabetes epidemic’ is an important health and socioeconomic problem worldwide. Type 2 diabetes is a chronic disease with gradual deterioration in glucose metabolism which causes multiple systemic complications. Therefore, early intervention in the prediabetic stage is a valuable approach to reduce diabetes development and related complications. Many clinical trials have suggested that lifestyle intervention, including moderate-intensity exercise and diet control, and pharmacologic intervention using metformin, α-glucosidase inhibitors, thiazolidinediones, anti-obesity drugs and incretin mimics, are effective in preventing diabetes development. However, an individualized approach with careful consideration of the patient’s risk status and health economics is needed to perform a successful intervention programmes. In this review, we will summarize the known evidence on treatment- and cost-effectiveness of drug and lifestyle treatment. Additionally, we will propose a strategic approach algorithm that is applicable to clinical practice.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Diabetes prevention – effectiveness of life style modification
  5. Diabetes prevention – effectiveness of pharmacological treatment
  6. Cost economics of lifestyle intervention and pharmacological intervention
  7. Proposed strategic approach for prediabetic populations
  8. Conflicts of interest
  9. References

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease which is rapidly increasing in populations worldwide. The number of patients with diabetes mellitus is projected to rise from an estimated 171 million in 2000 to 366 million in 2030 [1], and recent increases are remarkable in developing regions, including Asia [2]. Diabetic patients suffer from various microvascular and macrovascular complications and therefore show significantly increased mortality and morbidity. For prevention of development and progression of various complications, it is very important that blood glucose levels are as close to normal ranges as possible. However, many patients have suboptimal glucose control status [3]. Consequently, T2DM is an important national public health problem due to substantial financial loss for appropriate disease control and management of chronic complications [4].

The percentage of population who are prediabetic, with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) is much greater than that of diabetic patients and is persistently increasing [5,6]. The majority of prediabetes progresses to diabetes eventually, although the natural history is variable and ethnic differences exist from a pathophysiological perspective [7]. Additionally, subjects with prediabetes have an increased risk for cardiovascular diseases, like diabetic patients [8–10]. Therefore, early detection and intervention of prediabetes are absolutely indispensable for diabetes prevention.

In several clinical trials, life style intervention and early pharmacologic intervention in high-risk individuals were effective in preventing T2DM [11–18]. Further, a certain amount of evidence exists for the long-term benefit and cost-effectiveness of these interventions [19,20]. However, both insufficient data and practical guidelines are not available to for the appropriate treatment of patients in a real clinical setting because most of the studies have been performed for research purposes.

In this article, evidence about diabetes prevention will be explained related to treatment effectiveness. And the economic viewpoint of diabetes prevention will be described. Finally, we will propose a new strategic approach algorithm to be available in clinical practice for prediabetic patients.

Diabetes prevention – effectiveness of life style modification

  1. Top of page
  2. Summary
  3. Introduction
  4. Diabetes prevention – effectiveness of life style modification
  5. Diabetes prevention – effectiveness of pharmacological treatment
  6. Cost economics of lifestyle intervention and pharmacological intervention
  7. Proposed strategic approach for prediabetic populations
  8. Conflicts of interest
  9. References

Weight gain and physical inactivity are established risk factors of T2DM [21]. Obesity can lead to aggravated insulin resistance and beta-cell dysfunction caused by changes in adipokines, ectopic fat deposition and mitochondrial dysfunction [21,22]. Many clinical studies established that life style modification, including weight reduction and exercise, reduces the risk of type 2 diabetes (Table 1).

Table 1.   Randomized controlled trials with the aim of preventing diabetes by lifestyle modification
StudiesTarget populationsInterventionResults
Diabetes Prevention Program (DPP) [11]IFG or IGT subjects over age 25 with BMI ≥24 (≥22 in Asians) (n = 3234)Lifestyle intervention (≥7% weight reduction, diet control and ≥150 min/week, moderate intensity exercise) or drug intervention (metformin 850 mg b.i.d.)58% reduction of diabetes development in lifestyle intervention group and 31% reduction in metformin treatment group during mean 2.8-year follow-up period
Finnish Diabetes Prevention study (DPS) [16]Middle aged, overweight subjects with IGT (n = 522)Lifestyle intervention (≥5% weight reduction, diet control and exercise ≥30 min/day)58% reduction of diabetes development during mean 3.2-year follow-up period
China Da Qing Diabetes Prevention study (CDQDP) [17] IGT subjects (n = 577)Four groups: Control versus diet versus exercise versus diet plus exercise interventionCumulative incidence of diabetes: 67.7% in control, 43.8% in diet, 41.1% in exercise, 46.0% in both diet and exercise during mean 6-year follow-up period
Japanese Trial in IGT males [18]IGT subjects (n = 458)Lifestyle intervention (daily 30 min exercise), target BMI: control below 24 kg/m2versus intervention below 22 kg/m267.4% reduction of diabetes development during mean 4-year follow-up period
Indian Diabetes Prevention Programme study (IDPP) [25]Asian Indians with IGT (n = 531)Four groups: Control versus lifestyle intervention versus metformin treatment (500 mg/day) versus lifestyle intervention plus metformin treatmentRisk reduction of diabetes development: 28.5% with lifestyle intervention, 26.4% with metformin treatment, and 28.2% with lifestyle intervention plus metformin treatment during mean 3-year follow-up period

In the Diabetes Prevention Program (DPP) research, development of T2DM successfully decreased for IFG and IGT subjects with body mass indexes (BMIs) more than 24 kg/m2 after diet control and regular exercise [11]. Participants were maintained on moderate-intensity exercise of more than 150 min per week and weight reduction of more than 7% for the study period. In the lifestyle-intervention group, the incidence of diabetes was 58% lower than in the control group. In the Finnish Diabetes Prevention (DPS) study, overweight, middle-aged persons (with BMIs of more than 25 kg/m2) who had IGT performed moderate-intensity exercise for more than 30 min per day, lost 5% or more of their body weight, reduced the amount of dietary saturated fat, and increased fibre intake [16]. The cumulative incidence of diabetes was 58% lower in the intervention group for a 3.2-year observational period. The China Da Qing Diabetes Prevention Study (CDQDPS) participants with IGT were assigned to dietary intervention only, exercise intervention only, diet plus exercise intervention, and control groups [17]. For a 6-year observational period, the incidence of T2DM was lower in the three groups (diet alone, 48%; exercise alone, 41%; diet and exercise, 46%) compared with the control group.

Effects for prevention of diabetes were sustained after the endpoint of studies in all the above three trials. During a 10-year follow-up for DPP participants, incidence rates of diabetes remained 34% lower in the lifestyle group despite regaining about 5 kg in body weight [23]. In the DPS study, lifestyle intervention resulted in absolute risk reduction of 15% for an overall follow-up of 7 years. The effects were sustained after individual lifestyle counselling was stopped [24]. Additionally, the prevention effect persisted for up to 14 years after active intervention in CDQDPS [20].

The treatment effect was similar among diabetes prevention studies of non-white ethnicities other than CDQDPS. The Indian Diabetes Prevention Programme (IDPP-1) targeting 531 native Asian Indians with IGT showed very high progression rate from IGT to diabetes in the control group compared with the previous DPP study, DPS study and CDQDPS study. In the lifestyle modification group, a 15.7% reduction of cumulative incidences over a 3-year period was observed [25]. The Japanese trial of relatively lean, male subjects with IGT resulted in a 67.4% reduction in diabetes risk during a 4-year follow-up period [18].

Diabetes prevention – effectiveness of pharmacological treatment

  1. Top of page
  2. Summary
  3. Introduction
  4. Diabetes prevention – effectiveness of life style modification
  5. Diabetes prevention – effectiveness of pharmacological treatment
  6. Cost economics of lifestyle intervention and pharmacological intervention
  7. Proposed strategic approach for prediabetic populations
  8. Conflicts of interest
  9. References

Many clinical trials concluded that drug treatment was effective for the prevention of diabetes (Table 2). However, drug use in a real clinical practice for diabetes prevention is currently limited due to the insufficiency of evidence about cost-effectiveness.

Table 2.   Randomized controlled trials aimed at preventing diabetes by pharmacological intervention
StudiesDrugsTarget populationsResults
Diabetes Prevention Program (DPP) [11] Metformin (850 mg b.i.d.)IFG or IGT subjects over age 25 with BMI ≥24 (≥22 in Asians) (n = 3234)31% reduction in treatment group during mean 2.8-year follow-up period
Indian Diabetes Prevention Program (IDPP) [25] Metformin (500 mg/day)Asian Indians with IGT (n = 531)26.4% reduction in treatment group during mean 3-year follow-up period
STOP-NIDDM trial [13] Acarbose (100 mg t.i.d.)IGT subjects (n = 1419)25% reduction in acarbose treatment group during mean 3.3 year follow-up period
Japanese voglibose trial [14]Voglibose (0.2 mg t.i.d.)Japanese IGT subjects (n = 1780)40.5% risk reduction in voglibose treatment group during an average 48.1 week treatment period
DREAM study [12] Rosiglitazone (8 mg/day)IGT and/or IFG subjects (n = 5269)62% reduction of diabetes development during mean 3 year follow-up period
ACT NOW study [29]Pioglitazone (30–45 mg/day)IGT subjects (n = 602)Hazards ratio for conversion to diabetes: 0.28 in the pioglitazone-treated group for 2.4 years
XENDOS study [15]Orlistat (120 mg t.i.d.)Obese IGT subjects (BMI >30 kg/m2) (n = 3277)37% reduction in all treatment groups (45% in treated group with IGT) during mean 4-year follow-up period

Metformin

Metformin is a widely used oral hypoglycaemic agent as a glucose sensitizer and suppressor of hepatic gluconeogenesis and glucose production [26]. It has also no long-term serious adverse effects. Metformin treatment of 850 mg b.i.d. reduced diabetes risk by 31% compared with the control group in prediabetes subjects [11]. However, it was less effective compared with the lifestyle intervention group. In the IDDP study of Asian Indian subjects with IGT, a 26.4% risk reduction was observed in the metformin group, although only small doses of metformin (500 mg/day) were prescribed [25]. There was no synergistic benefit by combining metformin with lifestyle intervention.

α-Glucosidase inhibitors

Both acarbose and voglibose are effective for diabetes prevention. The STOP-NIDDM trial with 1419 IGT patients showed that the acarbose group had a reduced diabetes risk of 25% more than the placebo group during a mean 3.3-year follow-up period [13]. Patients with acarbose treatment also had higher reverted rates from IGT to normal glucose tolerance (NGT). In addition, acarbose reduced the relative risk of new cases of hypertension by 34%, and 49% of any cardiovascular events in individuals with prediabetes [27].

For 1780 Japanese patients with IGT, voglibose significantly reduced the development of type 2 diabetes by 40.5% compared with placebo during a treatment period of an average of 48.1 weeks [14]. Despite this effectiveness, its use for diabetes prevention is still controversial because it is relatively costly and many patients cannot tolerate this medication due to gastrointestinal side effects.

Thiazolidinediones

Thiazolidinediones reduce insulin resistance as a PPAR-γ agonist. The DREAM study concluded that rosiglitazone (8 mg/day) reduced the incidence of type 2 diabetes by 62% for a 3-year treatment period [12]. However, experts did not recommend its use for diabetes prevention because it increases the risk of congestive heart failure, fractures and weight gain [12,28]. It is no longer used in clinical practice due to concerns of cardiovascular safety.

In the ACT NOW study using 30–45 mg doses of pioglitazone in 602 patients with IGT, pioglitazone was effective in the prevention of diabetes during a median follow-up period of 2.4 years and had higher rate of conversion from IGT to NGT [29]. However, oedema and weight gain were more common in the pioglitazone group than in the placebo group.

Anti-obesity drugs

In the XENDOS study, orlistat, a gastrointestinal lipase inhibitor, was administered to obese populations with BMIs over 30 kg/m2 for 4 years [15]. Orlistat decreased the risk of developing diabetes by 37.3% for all study participants and 45% for IGT subjects. However, the cost-effectiveness of this treatment has not been shown.

Incretins

Incretins are gastrointestinal hormones that are secreted in a glucose-dependent manner. Glucagon-like peptide-1 (GLP-1) released by L-cells is a well-known incretin hormone. GLP-1 stimulates endogenous insulin secretion in pancreatic β-cells, suppresses glucagon secretion in α-cells, controls gastrointestinal motility and induces weight loss [30]. Many studies demonstrated that IGT and type 2 diabetic patients have impaired GLP-1 response [31–33]. Thus, incretin mimics are considered to be potential drug therapies for prediabetic patients.

Currently, there is no randomized controlled trial targeting only IGT or IFG patients to confirm the effectiveness of incretin for prevention of diabetes development. In a study of 564 obese people which included about 30% of prediabetic subjects, liraglutide, a GLP-1 analogue, reduced fasting plasma glucose, mean HbA1c and plasma glucose during an oral glucose tolerance test compared with placebo and orlistat [34]. However, further studies will be required to confirm the effect for diabetes prevention.

Cost economics of lifestyle intervention and pharmacological intervention

  1. Top of page
  2. Summary
  3. Introduction
  4. Diabetes prevention – effectiveness of life style modification
  5. Diabetes prevention – effectiveness of pharmacological treatment
  6. Cost economics of lifestyle intervention and pharmacological intervention
  7. Proposed strategic approach for prediabetic populations
  8. Conflicts of interest
  9. References

For long-term and wide applications of intervention programmes, consideration for cost-effectiveness is another important factor, as well as the efficacy of treatment itself. In an evaluation of within-trial cost-effectiveness for the DPP study, lifestyle intervention increased total medical costs compared with the placebo group [35] (Table 3). However, lifestyle intervention was cost-effective compared with the medical costs of other preventive or palliative intervention such as models for newly diagnosed type 2 diabetes patients to perform intensive glucose control, patients with dyslipidaemia using HMG-CoA reductase inhibitors and hypertension patients [36]. Also, lifestyle modification was cost-saving for all age groups [37]. A simulation model using a population-based sample in Sweden proved that lifestyle intervention programmes saved a mean total cost of €1853 in 2003 (1€ = $0.94) per patient [38]. In the IDPP study, the cost for lifestyle modification was much lower than the costs for the DPP study because of lower personnel expenses and cost-effectiveness [39]. Accordingly, lifestyle modification will be a useful healthcare model in both developed countries and other developing countries.

Table 3.   Cost economics of diabetes prevention
StudiesMethodsResults
Cost in DPP study [35]Direct medical cost Direct nonmedical cost Indirect medical costTotal direct medical cost: $79 versus$2780 versus$2542 (placebo versus life style intervention versus metformin) Total direct nonmedical cost: $15 692 versus$17 137 versus$15 683 Total indirect medical cost: $2604 versus$2430 versus$2834
Within-trial cost-effectiveness in DPP study [36]QALYs (quality-adjusted life-years) gained Cost per case of diabetes prevented Cost per QALYs gainedQALYs gained: 0.072 versus 0.022 (lifestyle and placebo versus metformin and placebo) Cost per case of diabetes prevented: $24 400 versus$34 500 (lifestyle versus metformin) in DPP, $13 200 versus$14 300 in routine clinical practice Cost per QALYs gained: $51 600 versus$99 200 in DPP, $27 100 versus$35 000 in routine clinical practice
Lifetime cost-utility in DPP study [37]Direct medical cost Direct nonmedical cost QALYs Cost per QALYCost per QALY: $1100 versus$31 300 (lifestyle versus metformin) Cost per QALY from a societal perspective: $8800 versus$29 900
Cost-effectiveness in DPS study [38]Cost of intervention Direct cost Indirect cost QALYsMean cost of intervention: 2614 (2003€) Mean direct cost: 16 157 versus 17 099 (prevention versus no prevention, 2003€) Mean indirect cost: 2055 versus 2966 (2003€) Mean QALY: 12.5 versus 12.3
Cost-effectiveness in IDPP study [39]Direct medical cost Indirect medical cost Cost-effectiveness ratio (CER): Incremental cost (IC) × number needed to prevent one case of diabetes (NNT)Total cost: 2739 versus 10 136 versus 9881 versus 12 144 (control versus lifestyle versus metformin versus lifestyle + metformin) CER: 47 341 versus 49 280 versus 61 133 (lifestyle versus metformin versus lifestyle + metformin)

While lifestyle intervention has relatively well-established evidence from an economic viewpoint, there are few studies about the cost-effectiveness for pharmacological treatment in diabetes prevention except metformin. Metformin is the only drug with proven cost economics, although its cost-effectiveness is less than that of lifestyle intervention [36,39]. In the DPP study, metformin intervention was cost-effective in younger participants but not in participants older than 65 years of age [37]. The cost for metformin intervention was much lower in the IDPP study due to relatively lower dosage and lower cost in India [39]. To reduce economic burden for long-term metformin treatment, consideration about drug dosage and generic medication use are required. Further studies about the cost-effectiveness of other drugs with proven treatment-effectiveness are needed.

Proposed strategic approach for prediabetic populations

  1. Top of page
  2. Summary
  3. Introduction
  4. Diabetes prevention – effectiveness of life style modification
  5. Diabetes prevention – effectiveness of pharmacological treatment
  6. Cost economics of lifestyle intervention and pharmacological intervention
  7. Proposed strategic approach for prediabetic populations
  8. Conflicts of interest
  9. References

The appropriate selection of target patients and early intervention in individuals with prediabetes is important to reduce the socioeconomic burden for diabetes. The fasting plasma glucose measure is a commonly used method to diagnose prediabetes and diabetes. However, in Asian patients, isolated IGT is more common than isolated IFG and combined IFG/IGT compared with Caucasian patients [40,41]. Therefore, alternative methods such as postchallenge plasma glucose or glycated haemoglobin should be considered as a screening test in Asian patients with high risk of diabetes. Non-white ethnics are more vulnerable to diabetes development than white ethnics at lower BMI ranges [42]. Thus, the BMI cut-off point for obesity and overweight in non-white ethnicities should be lower than for white individuals.

Lifestyle modification is the first choice of intervention for diabetes prevention because it has good cost- and treatment-effectiveness. Subjects with a poor response to lifestyle intervention, weight reduction using moderate-intensity exercise and diet control during a period of 6–12 months should be considered for a more aggressive lifestyle intervention programme. If the patients have additional cardiovascular risk factors, such as hypertension, current smoking, dyslipidaemia, obesity and a family history of cardiovascular diseases, pharmacological intervention using drugs with proven cost-effectiveness could be added to lifestyle treatment. Metformin and α-glucosidase inhibitors are suitable choices for initial pharmacological intervention. If disease progression continues, other effective drugs with proven treatment-effectiveness could be used, depending on the status of the individual patients (Figure 1).

image

Figure 1.  Algorithm of strategic approach for diabetes prevention

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References

  1. Top of page
  2. Summary
  3. Introduction
  4. Diabetes prevention – effectiveness of life style modification
  5. Diabetes prevention – effectiveness of pharmacological treatment
  6. Cost economics of lifestyle intervention and pharmacological intervention
  7. Proposed strategic approach for prediabetic populations
  8. Conflicts of interest
  9. References
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