Int J Diabetes Clin Res ISSN: 2377-3634

• Abstract
• Keywords
• Introduction
• Methods
• Discussion
• Conclusion
• Acknowledgements
• Table 1
• Table 2
• Table 3
• Table 4
• Table 5
• Table 6
• References

Download PDF
    

International Journal of Diabetes and Clinical Research

¹Department of Medicine, BAPS Yogiji Maharaj Hospital, Ahmedabad, Gujarat, India
²Dietician/Diabetes Educator, Chowpatty Medical Centre, 3 Baig Mansion, Mumbai, Maharashtra, India
³Professor of Diabetes, Diabetes Research Group, Swansea University Medical School, Swansea, SA2 8PP, UK
⁴Consultant Endocrinologist, University Hospital of Wales, Cardiff, UK

Abstract

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, cost-effective and are currently recommended for the prevention of diabetes.

Keywords

Type 2 Diabetes Mellitus, Prevention, Lifestyle management, Pharmacotherapy, Cost effectiveness.

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.

Those at high-risk on risk scoring should undergo venous blood tests (fasting plasma glucose (FPG) or HbA1c). A FPG of 5.5-6.9 mmol/L or HbA1c level of 42-47 mmol/mol (6.0-6.4%) indicates high risk [7].

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)

2. Pharmacological Interventions

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].

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

The LSI interventions have been observed to be successful in preventing or delaying the onset of T2DM in high risk individuals. Findings of the Da Qing study suggest that LSI interventions continue to prove beneficial for a long time [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 high-risk 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 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.

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.

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 long-term 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 weight-loss 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 well-trained 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.

Acknowledgements

• University of South Wales

• Caroline McPhillips

• Dudu Ndebele

• Gaafar Abdalla

• Hisham Seid Ahmed

• Julien Charles

• Mohamed Alsohli

• Obaid Reedy

• Sairabanu Sokwalla

References

1. (2014) IDF Diabetes Atlas Sixth Edition Update, International Diabetes Federation.
   


2. Laakso M (2010) Cardiovascular disease in type 2 diabetes from population to man to mechanisms: the Kelly West Award Lecture 2008. Diabetes Care 33: 442-449.
   


3. Lorber D (2014) Importance of cardiovascular disease risk management in patients with type 2 diabetes mellitus. Diabetes Metab Syndr Obes 7: 169-183.
   


4. Saydah SH, Loria CM, Eberhardt M, Brancati FL (2001) Subclinical states of glucose intolerance and risk of death in the US. Diabetes Care 24- 447-453.
   


5. Martin-Merino E, Fortuny J, Rivero-Ferrer E, Garcia-Rodriguez LA (2014) Incidence of Retinal Complications in a Cohort of Newly Diagnosed Diabetic Patients. PLoS ONE 9: e100283.
   


6. Zhuo X, Zhang P, Hoerger TJ (2013) Lifetime direct medical costs of treating type 2 diabetes and diabetic complications. Am J Prev Med 45: 253-261.
   


7. NICE guidelines (2012) Preventing type 2 diabetes: risk identification and interventions for individuals at high risk.
   


8. Li G, Zhang P, Wang J, Gregg EW, Yang W, et al. (2008) The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet 371: 1783-1789.
   


9. Pan XR, Li GW, Hu YH, Wang JX, Yang WY, et al. (1997) Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 20: 537-544.
   


10. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, et al. (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344: 1343-1350.
    


11. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, et al. (2002) Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin. N Engl J Med 346: 393-403.
    


12. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, et al. (2006) The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia, 49: 289-297.
    


13. Eriksson KF, Lindgarde F (1991) Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise. The 6-year Malmo feasibility study. Diabetologia 34: 891-898.
    


14. Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, et al. (2006) Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 368: 1096-1105.
    


15. Holman RR, Haffner SM, McMurray JJ, Bethel MA, Holzhauer B, et al. (2010) Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med 362: 1463-1476.
    


16. ORIGIN Trial Investigators, Gerstein HC, Bosch J, Dagenais GR, Diaz R, et al. (2012) Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 367: 319-328.
    


17. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, et al. (2002) Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 359: 2072-2077.
    


18. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, et al. (2003) Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA290: 486-494.
    


19. Hamman RF, Wing RR, Edelstein SL, Lachin JM, Bray GA, et al. (2006) Effect of weight loss with lifestyle intervention on risk of diabetes. Diabetes Care 29: 2102-2107.
    


20. Lindstrom J, Peltonen M, Eriksson JG, Aunola S, Hamalainen H, et al. (2008) Determinants for the effectiveness of lifestyle intervention in the Finnish Diabetes Prevention Study. Diabetes Care 31: 857-862.
    


21. Knowler WC, Narayan KM, Hanson RL, Nelson RG, Bennett PH, et al. (1995) Preventing non-insulin-dependent diabetes. Diabetes 44: 483-488.
    


22. Bethel MA, Xu W, Theodorakis MJ (2015) Pharmacological interventions for preventing or delaying onset of type 2 diabetes mellitus. Diabetes Obes Metab 17: 231-244.
    


23. Buchanon T, Xiang A, Peters R, Kjus S, Mamoquin A, et al. (2002) Preservation of pancreatic beta cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 51: 2796-2803.
    


24. Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L (2004) XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 27: 155-161.
    


25. Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, Hamman RF, Christophi CA, et al. (2009) 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 374: 1677-1686.
    


26. Herman WH, Hoerger TJ, Brandle M, Hicks K, Sorensen S, et al. (2005) The cost-effectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance. Ann Intern Med 142: 323-332.
    


27. Lindstrom J, Ilanne-Parikka P, Peltonen M, Aunola S, Eriksson JG, et al. (2006) Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: the follow-up results of the Finnish Diabetes Prevention Study. Lancet 368: 1673-1679.
    


28. (2014) International Diabetes Federation. Health Economics of Diabetes Prevention.
    


29. Sherwin S (2003) Prevention or Delay of type 2 Diabetes. Diabetes Care 26: Suppl 1:S62-69.
    


30. Ratner RE, Sathasivam A (2011) Treatment recommendations for prediabetes. Med Clin North Am 95: 385-395.
    


31. Ahmad L, Crandall J (2010) Type 2 Diabetes Prevention: A Review. Clinical Diabetes 28: 53-59.
    


32. Quilici S, Chancellor J, Maclaine G, McGuire A, Andersson D, Chiasson JL. (2005) Cost-effectiveness of acarbose for the management of impaired glucose tolerance in Sweden. Int J Clin Pract 59: 1143-1152.
    


33. Caro JJ, Getsios D, Caro I, Klittich WS, O'Brien JA. (2004) Economic evaluation of therapeutic interventions to prevent Type 2 diabetes in Canada. Diabetic Medicine 21: 1229-1236.
    


34. Palmer AJ, Roze S, Valentine WJ, Spinas GA, Shaw JE, Zimmet PZ (2004) Intensive lifestyle changes or metformin in patients with impaired glucose tolerance: modeling the long-term health economic implications of the diabetes prevention program in Australia, France, Germany, Switzerland, and the United Kingdom. Clin Ther 26: 304-21.
    


35. Mantavani L, Palmer AJ, Morgutti M, Valentine WJ, Renaudin C, et al. (2004) Long-term cost-effectiveness of the Diabetes Prevention Program in an Italian setting. 40th Annual Meeting of the European Association for the Study of Diabetes, A955.
    


36. Palmer AJ, Roze S, Valentine WJ, Renaudin C (2004) Cost-effectiveness analysis of the Diabetes Prevention Program in a Spanish setting. Value in Health 7: 741.
    


37. Eddy DM, Schlessinger L, Kahn R (2005) Clinical outcomes and cost-effectiveness of strategies for managing people at high risk for diabetes. Ann Intern Med 143: 251-264.