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Can J Diabetes 37 (2013) S16eS19

Canadian Journal of Diabetesjournal homepage:

www.canadianjournalofdiabetes.com

Clinical Practice Guidelines

Reducing the Risk of Developing Diabetes

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee

The initial draft of this chapter was prepared by Thomas Ransom MD, MSc, FRCPC,Ronald Goldenberg MD, FRCPC, FACE, Amanda Mikalachki RN, CDE,Ally P.H. Prebtani BScPhm, MD, FRCPC, Zubin Punthakee MD, MSc, FRCPC

KEY MESSAGES

� As safe and effective preventive therapies for type 1 diabetes have not yetbeen identified, any attempts to prevent type 1 diabetes should beundertaken only within the confines of formal research protocols.

� Intensive and structured lifestyle modification that results in loss ofapproximately 5% of initial body weight can reduce the risk of progressionfrom impaired fasting glucose or impaired glucose tolerance to type 2diabetes by almost 60%.

� Progression from prediabetes to type 2 diabetes can also be reduced bypharmacological therapy with metformin (w30% reduction), acarbose(w30% reduction) and thiazolidinediones (w60% reduction).

Introduction

Ideal preventive strategies for both type 1 and type 2 diabetesshould range from focusing efforts on individuals identified asbeing at risk for developing diabetes to broader, more group- orpopulation-based strategies. For the practicing healthcare profes-sional, it is the individualized strategies that are sought. Theprevention or delay of diabetes not only would alleviate the indi-vidual of the burden of disease but also could decrease associatedmorbidity and mortality. Preventive strategies would differdepending on the type of diabetes. Given the increasing incidenceand prevalence of diabetes, development of safe and cost-effectiveinterventions to reduce the risk of diabetes are needed to helpdecrease the burden of diabetes on individuals and the healthcaresystem.

Reducing the Risk of Developing Type 1 Diabetes

Type 1 diabetes is a chronic autoimmune condition character-ized by destruction of pancreatic beta cells. The causes are multi-factorial, with both genetic and environmental factors playinga part. There is a long preclinical period before the onset of overtsymptoms, which may be amenable to therapeutic intervention toprevent disease. The exact nature of causative environmentalfactors continues to be debated. Immunotherapeutic interventionscontinue to be the main focus of disease prevention. Enhancementof “regulatory” immune mechanisms currently shows the mostpromise in terms of slowing the progression of the disease andpreserving beta cell mass (secondary prevention).

1499-2671/$ e see front matter � 2013 Canadian Diabetes Associationhttp://dx.doi.org/10.1016/j.jcjd.2013.01.013

Twomajor trials of interventions to prevent or delay the onset oftype 1 diabetes have been completed. The European NicotinamideDiabetes Intervention Trial (ENDIT), a randomized, double-blind,placebo-controlled trial of high-dose nicotinamide therapy,recruited first-degree relatives of people who were <20 years oldwhen diagnosed with type 1 diabetes, were islet cell antibodypositive, were <40 years of age and had a normal oral glucosetolerance test (OGTT) result. Although nicotinamide had provedprotective in animal studies, no effect was observed in ENDITduring the 5-year trial period (1). The Diabetes Prevention Trial-Type 1 (DPT-1) studied the efficacy of low-dose insulin injectionsin high-risk (projected 5-year risk of >50%) first-degree relatives ofsubjects with type 1 diabetes. Overall, the insulin treatments hadno effect (2), but in a subset of participants with high levels ofinsulin autoantibodies, a delay, and perhaps a reduction, in theincidence of type 1 diabetes was observed (3). A third large trial, theongoing Trial to Reduce IDDM in the Genetically at Risk (TRIGR)study, is investigating the effect of excluding cow’s milk protein andreplacing it with hydrolyzed formula milk in genetically at-riskinfants until 6 to 8 months of age. Preliminary data suggest therewere fewer autoantibody-positive children at 10 years (4), but dataon the overt development of diabetes by age 10will not be availableuntil 2017.

A second strategy is to try and halt, at the time of diagnosis, theimmune-mediated destruction of beta cells so as to preserve anyresidual capacity to produce insulin. Progress in the field has beenappropriately slow due to important ethical considerations.Namely, side effects from excessive immunosuppression/modula-tion cannot be tolerated because of the reasonable life expectancywith insulin substitution therapy.

As safe and effective preventive therapies for type 1 diabeteshave not yet been identified, any attempts to prevent type 1 dia-betes should be undertaken only within the confines of formalresearch protocols.

Reducing the Risk of Developing Type 2 Diabetes

Preventing type 2 diabetes may result in significant publichealth benefits, including lower rates of cardiovascular disease(CVD), renal failure, blindness and premature mortality. An epide-miological analysis projected that if all diabetes could be avoided inwhite American males through effective primary prevention, the

T. Ransom et al. / Can J Diabetes 37 (2013) S16eS19 S17

risk of all-cause and cardiovascular mortality in the entire pop-ulation could be reduced by up to 6.2% and 9.0%, respectively (5).Data from the US indicate that 28% of cardiovascular expendituresare attributable to diabetes (6). Primary approaches to preventingdiabetes in a population include the following: 1) programs tar-geting high-risk individuals in the community (such as those withimpaired glucose tolerance [IGT] or obesity); 2) programs targetinghigh-risk subgroups of the population, such as high-risk ethnicgroups; and 3) programs for the general population, such as thosedesigned to promote physical activity and healthy eating in adultsor children (7e9). Prospective cohort studies have identifiedhistorical, physical and biochemical variables associated with thesubsequent development of type 2 diabetes. These include olderage, certain ethnic backgrounds, obesity (especially abdominalobesity), physical inactivity, history of gestational diabetes mellitus,overt coronary artery disease, high fasting insulin levels and IGT(10e12). Results of large, well-designed studies assessing lifestyleand pharmacological interventions in adults to prevent theprogression from IGT to diabetes have been published. No phar-macological agent is approved for diabetes prevention in Canada.

Lifestyle

Changes in lifestyle were assessed in the Finnish DiabetesPrevention Study (DPS) (13) and the Diabetes Prevention Program(DPP) (14). Dietary modification that targeted a low-calorie, low-fat, low-saturated fat, high-fibre diet and moderate-intensityphysical activity of at least 150 minutes per week resulted ina moderate weight loss of approximately 5% of initial body weight.In both studies, the risk reduction for diabetes was 58% at 4 years.These studies included comprehensive, sustained programs toachieve these outcomes. On the basis of the observed benefits oflifestyle in the DPP, all participants were offered further lifestyleinterventions for a median of 5.7 more years and benefits weresustained for up to 10 years (15).

In another lifestyle intervention trial, 458 Japanese males withIGT were randomly assigned in a 4:1 ratio to a standard interven-tion (n¼356) or an intensive intervention (n¼102) and followed for4 years (16). Intensive treatment was associated with a 67.4%reduction in risk of diabetes (p<0.001). IGT and diabetes werediagnosed using a 100 g OGTT and the following diagnostic criteria:IGT ¼2-hour plasma glucose (2hPG) 8.8 to 13.1 mmol/L; diabetes ¼2hPG �13.2 mmol/L (16). These levels corresponded to the 1980World Health Organization (WHO) diagnostic criteria using a 75 gOGTT (17,18).

In a more recent trial, 641 overweight Japanese men (aged 30 to60 years) with impaired fasting glucose (IFG) were randomized toeither a frequent intervention group (n¼311) or a control group(n¼330) for 36 months. The frequent intervention group receivedindividual instructions and follow-up support for lifestyle modifi-cation frommedical staff 9 times. The control group received similarindividual instructions 4 times at 12-month intervals during thesameperiod. Results showedan incidence of type2diabetes of 12.2%in the frequent intervention group and 16.6% in the control group,with an adjusted hazard ratio (HR) in the frequent interventiongroup of 0.56 (95% confidence interval [CI] 0.36e0.87). Post hocsubgroup analyses showed the HR reduced to 0.41 (95% CI0.24e0.69) among participantswith IGTat baseline and to 0.24 (95%CI 0.12e0.48) among those with a baseline A1C level >5.6% (19).

A 20-year follow-up of the Chinese Da Qing Diabetes PreventionTrial showed that after 6 years of active lifestyle interventions vs. notreatmentandanadditional 14years of passive follow-up, a 43% (95%CI 19e59) relative risk reduction for incident diabetes persisted,and vision-threatening retinopathy was reduced by 47% (95% CI1e71). There were, however, no identified reductions in nephrop-athy, neuropathy, cardiovascular events or mortality (20,21).

Pharmacotherapy

MetforminMetforminwas used in a second arm of the DPP (14). A dosage of

850 mg bid for an average of 2.8 years significantly decreasedprogression to diabetes by 31%. In the DPP population, metformindid not have any significant effect in the older age group (�60 years)and in less obese subjects (body mass index [BMI] <35 kg/m2).To determine whether the observed benefit was a transient phar-macological effect or was more sustained, a repeat OGTT wasundertaken after a short washout period. The results of this studysuggested that 26% of the diabetes prevention effect could beaccounted for by the pharmacological action of metformin (whichdid not persist when the drug was stopped). After the washout, theincidence of diabetes was still reduced by 25% (22). The benefitspersisted for up to 10 years (15).

ThiazolidinedionesThe DPP Research Group published the results from the trogli-

tazone arm, which was part of the original protocol (23). The drugwas discontinued after a mean follow-up of 0.9 years due to livertoxicity. Troglitazone 400 mg once daily resulted in a relative riskreduction of 75% (p¼0.02) during the short period of time. Thiseffect was not sustained after discontinuation of troglitazone.

The Diabetes Reduction Assessment with Ramipril and Rosigli-tazone Medication (DREAM) trial randomized 5269 subjects withIGT and/or IFG, in a 2 � 2 factorial fashion, to ramipril (up to 15 mg/day) and/or rosiglitazone (8 mg/day) vs. placebo (24,25). Eligiblesubjects were 30 years old and not known to have CVD. Theprimary outcome of DREAM was a composite of development ofdiabetes or death. The conclusion of the DREAM investigators wasthat the results suggest that ramipril may have favourable effectson glucose metabolism, a finding that is consistent with otherreports. However, not all trials have found such an association. Fornow, the routine use of ramipril for the express purpose of pre-venting diabetes is not indicated.” Treatment with rosiglitazoneresulted in a 60% reduction in the primary composite outcome ofdiabetes or death (HR 0.40, 95% CI 0.35e0.46), primarily due toa 62% relative reduction in the risk of progression to diabetes (HR0.38, 95% CI 0.33e0.44). Although the trial was not powered toprovide a definitive estimate of the effect of rosiglitazone on CVoutcomes, there was a trend toward an increase in risk of the CVcomposite outcome with rosiglitazone (HR 1.37, 95% CI 0.97e1.94)driven primarily by a significant increase in nonfatal congestiveheart failure (HR 7.03, 95% CI 1.60e30.9; p¼0.01).

In theActosNow for the Prevention ofDiabetes (ACTNOW) study,602 high-risk IGT subjects were randomized to receive pioglitazoneor placebo and were followed for 2.4 years. Pioglitazone decreasedthe conversion of IGT to type 2 diabetes by 72% (p<0.00001) (26).

Despite the favourable effects of thiazolidinediones on delayingthe development of type 2 diabetes, the multiple potential adverseeffects of this class of medication makes it difficult to recommendtheir widespread use in IFG or IGT.

Combination therapyThe combination of metformin 500 mg twice daily and rosiglita-

zone 2 mg twice daily was found to reduce the progression to dia-betes by 66% (95%CI 41e80) among 103peoplewith IGTcompared to104 people randomized to placebo over a median of 3.9 years (27).

Alpha-glucosidase inhibitorsThe Study to Prevent Non-Insulin Dependent Diabetes (STOP-

NIDDM) used acarbose at a dosage of 100 mg tid in a 5-year studywith a mean follow-up of 3.3 years (28). Overall, there was a 25%reduction in the risk of progression to diabetes when the diagnosiswas based on 1 OGGT and a 36% reduction in the risk of progression

T. Ransom et al. / Can J Diabetes 37 (2013) S16eS19S18

to diabetes when the diagnosis was based on 2 consecutive OGTTs.This beneficial effect was not affected by age or BMI. However,when the drug was discontinued, the effect of acarbose did notpersist (28). In this IGT population, acarbose treatment was alsoassociated with a 49% reduction in CV events (p¼0.032) and a 50%reduction in the progression of carotid intima-media thickness(29,30). In another trial, 1780 Japanese patients with IGT wererandomly assigned to oral voglibose 0.2 mg three times per day(n¼897) or placebo (n¼883). Results showed that, over a mean of48.1 weeks, voglibose was better than placebo at reducing theprogression to type 2 diabetes (5.6% vs. 11.9%; HR 0.595, 95% CI0.433e0.818; (p¼0.0014). More subjects in the voglibose groupachieved normoglycemia than in the placebo group (66.8% vs.51.5%; HR 1.539, 95% CI 1.357e1.746; p<0.0001).

OrlistatThe Xenical in the Prevention of Diabetes in Obese Subjects

(XENDOS) study examined the effect of orlistat in combinationwithan intensive lifestyle modification program (diet and exercise) onthe prevention of diabetes in 3305 obese individuals (31). Subjectswere randomized to orlistat 120 mg or placebo tid with meals for 4years. Weight loss was observed in both groups, but the orlistatgroup lost significantly more (5.8 vs. 3 kg; p<0.001). Compared toplacebo, orlistat treatment was associated with a further 37%reduction in the incidence of diabetes. However, 2 importantmethodological limitations affect the interpretation of theseresults. First, therewas a very high dropout rated48% in the orlistatgroup and 66% in the placebo group. Second, the last observationcarried forward was used for analysis, which is generally not fav-oured for prevention or survival studies. Nonetheless, the signifi-cant weight loss would be expected to decrease the risk of diabetesas already shown in the DPS and the DPP.

Incretin-based therapiesLiraglutide has been shown to effectively prevent IGT conver-

sion to type 2 diabetes and cause reversion to normoglycemia(32). In a 20-week study, liraglutide was administered to 564obese individuals who did not have diabetes, 31% of whom hadIGT. Subjects were randomized to 1 of 4 liraglutide doses (1.2 mg,1.8 mg, 2.4 mg, or 3.0 mg; n¼90e95) or to placebo (n¼98), or toorlistat (120 mg; n¼95) three times daily. A1C was reduced by0.14% to 0.24%. The prevalence of prediabetes decreased by 84% to96% with liraglutide 1.8 mg, 2.4 mg and 3.0 mg doses.

Diabetes prevention in high-risk ethnicities

Ethnic groups, such as South Asians, Hispanics and Aboriginals,are at very high risk for and have a high prevalence of type 2 dia-betes (12%e15% in the Western world) (33,34).

RECOMMENDATIONS

1. A structured program of lifestyle modification that includes moderateweight loss and regular physical activity should be implemented to reducethe risk of type 2 diabetes in individuals with IGT [Grade A, Level 1A (13,14)]and IFG [Grade B, Level 2 (18)] and A1C 6.0%e6.4% [Grade D, Consensus].

2. In individuals with IGT, pharmacological therapy with metformin [Grade A,Level 1A (14)] or acarbose [Grade A, Level 1A (27)] may be used to reducethe risk of type 2 diabetes.

Abbreviations:A1C, glycated hemoglobin; IFG, impaired fasting glucose; IGT, impairedglucose tolerance.

The reasons for this are multifactorial and include geneticsusceptibility, altered fat distribution (more visceral fat withgreater insulin resistance) and higher prevalence of metabolicsyndrome. Many of them develop diabetes at a younger age andoften have complications at the time of diagnosis due to long-standing, preexistent diabetes. As a result, there may be a benefitof delaying the onset of diabetes in this population. The IndianDiabetes Prevention Programme showed similar results in pre-venting diabetes with both lifestyle and pharmacological inter-ventions where the progression to diabetes from IGTwas quite high(55%) over 3 years (35). The Indian Diabetes Prevention Programmeshows that lifestyle modification and metformin prevent type 2diabetes in Asian subjects with IGT (IDPP-1).

This approach of prevention may lead to cost savings, fewercomplications and lower morbidity, but it remains to be provenwith hard clinical endpoints. Lifestyle measures not only reduce therisk of diabetes but have other health benefits, so the overall benefitis positive with little harm. One must keep in mind that themeasures of prevention must be delivered in a culturally sensitivemanner to these populations.

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