Update and Next Steps for Real-World Translation of ... · estimated 415 million adults worldwide (8.8% of the global population) have dia-betesda number that is projected to increase

Update and Next Steps for Real-WorldTranslation of Interventionsfor Type 2 Diabetes Prevention:Reflections From a Diabetes CareEditors’ Expert ForumDiabetes Care 2016;39:1186–1201 | DOI: 10.2337/dc16-0873

The International Diabetes Federation estimates that 415 million adults world-wide now have diabetes and 318 million have impaired glucose tolerance. Thesenumbers are expected to increase to 642 million and 482 million, respectively, by2040. This burgeoning pandemic places an enormous burden on countriesworldwide, particularly resource-poor regions. Numerous landmark trials evalu-ating both intensive lifestyle modification and pharmacological interventionshave persuasively demonstrated that type 2 diabetes can be prevented or itsonset can be delayed in high-risk individuals with impaired glucose tolerance.However, key challenges remain, including how to scale up such approaches forwidespread translation and implementation, how to select appropriately fromvarious interventions and tailor them for different populations and settings, andhow to ensure that preventive interventions yield clinically meaningful, cost-effective outcomes. In June 2015, a Diabetes Care Editors’ Expert Forum convenedto discuss these issues. This article, an outgrowth of the forum, begins with asummary of seminal prevention trials, followed by a discussion of considerationsfor selecting appropriate populations for intervention and the clinical implicationsof the various diagnostic criteria for prediabetes. The authors outline knowledgegaps in need of elucidation and explore a possible new avenue for securing reg-ulatory approval of a prevention-related indication for metformin, as well asspecific considerations for future pharmacological interventions to delay the on-set of type 2 diabetes. They conclude with descriptions of some innovative, prag-matic translational initiatives already under way around the world.

According to the latest International Diabetes Federation (IDF) calculations, anestimated 415 million adults worldwide (8.8% of the global population) have dia-betesda number that is projected to increase to 642 million (10.4%) by 2040. Thevast majority of diabetes cases are attributable to type 2 diabetes. Furthermore, anestimated 318 million adults have impaired glucose tolerance (IGT). That number isexpected to climb to 482 million in the next 25 years (1). In the U.S. alone, anestimated 86 million adults have prediabetes (2).The toll of diabetes and its complications on patients’ health and quality of life is

enormous. The burgeoning diabetes pandemic also places a great burden on coun-tries throughout the world, particularly in resource-poor regions. The IDF estimatesthat global spending to treat diabetes ranged between $673 billion and $1.2 trillion

1Pennington Biomedical Research Center, Louisi-ana State University, Baton Rouge, LA2University of North Carolina School of Medicine,Chapel Hill, NC3Chronic Disease Prevention Unit, National Insti-tute for Health and Welfare, Helsinki, Finland;Dasman Diabetes Institute, Dasman, Kuwait;Saudi Diabetes Research Group, King AbdulazizUniversity, Jeddah, Saudi Arabia; and Center forVascular Prevention, Danube University Krems,Krems, Austria4Kinexum, Harpers Ferry, WV5CNR Institute of Clinical Physiology, Pisa, Italy6McMaster University and Hamilton Health Sci-ences, Hamilton, Canada7National Institutes of Health, Phoenix, AZ8India Diabetes Research Foundation andDr. A. Ramachandran’s Diabetes Hospitals,Chennai, India9Diabetes Unit, Department of Internal Medi-cine, Hadassah Hebrew University Hospital,Jerusalem, Israel10Dallas Diabetes and Endocrine Center at Med-ical City and The University of Texas Southwest-ern Medical Center, Dallas, TX11VA Puget Sound Health Care System and Uni-versity of Washington, Seattle, WA

Corresponding author: William T. Cefalu, [email protected].

© 2016 by the American Diabetes Association.Readersmayuse this article as longas thework isproperly cited, the use is educational and not forprofit, and the work is not altered.

William T. Cefalu,1 John B. Buse,2

Jaakko Tuomilehto,3

G. Alexander Fleming,4 Ele Ferrannini,5

Hertzel C. Gerstein,6 Peter H. Bennett,7

Ambady Ramachandran,8 Itamar Raz,9

Julio Rosenstock,10 and Steven E. Kahn11

1186 Diabetes Care Volume 39, July 2016

DIABETES

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USD in 2015 (1). A recent global analysisfound that a substantial portion of thisburden falls on patients in low- andmiddle-income countries as out-of-pocket costs(3). In concert with the predicted in-crease in new cases of diabetes, globalexpenditures are projected to rise to be-tween $802 billion and nearly $1.5 tril-lion USD by 2040 (1).Diabetes is also a leading cause of

death. High blood glucose has beenidentified as the third largest risk factorfor premature mortality worldwide, af-ter high blood pressure and tobacco use.Approximately 5 million deaths were at-tributable to diabetes in 2015dmorethan those from HIV/AIDS, tuberculosis,and malaria combined (1,4).Numerous landmark trials in the past

quarter-century have demonstratedconclusively that preventive strategies(i.e., lifestyle modification and variouspharmacological interventions) can de-lay or prevent the development oftype 2 diabetes in high-risk individualswith IGT (5–22). Despite the clarity ofthese findings and large reported effectsizes, translational prevention programshave faced numerous real-world imped-iments, and none of the tested interven-tions have been widely adopted ascomponents of routine clinical care.There are encouraging signs that this

may soon change. An independent expertpanel recently confirmed that the expan-sion of the National Diabetes PreventionProgram (NDPP) (23), a public-private ini-tiative funded by the Affordable Care Actand launched in 2010 to encourage theprovision of evidence-based interven-tions in communities across the country,would reduce spending and improve thequality of patient care (24). This certifica-tion is a crucial step toward expandingNDPP for Medicare beneficiaries withprediabetes.Despite this encouraging news, key

challenges remain, including identifyingthose interventions most suitable forwidespread implementation, selectingappropriately from and tailoring thesetools for various populations and set-tings, and measuring the impact of theirimplementation on disease progressionand on micro- and macrovascular com-plications (23,25,26). To consider theseissues, a Diabetes Care Editors’ ExpertForum was convened in June 2015. Pan-elists reviewed the prevention evidenceto date, discussed areas of controversy,

identified unanswered research ques-tions, and explored innovative ap-proaches to translating this research toreduce the incidence of type 2 diabetes.This article summarizes the proceedingsof that forum.We use the term “preven-tion” throughout the article to refer todelaying the progression to type 2 dia-betes in a proportion of a population atrisk. Ascertaining which individuals willprogress from prediabetes to diabetes(and when) is not possible currently.Therefore, it is not feasible to demon-strate that an intervention has pre-vented the lifelong occurrence ofdiabetes in an individual or a populationof individuals who are otherwise certainto progress. For now, intervention trialscan only determine the fraction of thestudied population that progresses todiabetes. The number of cases thathave been prevented during a trial canbe derived from positive results, but thiscalculation has to be qualified by thelimited observation period and the like-lihood that treatment must be contin-ued indefinitely to preserve some or allof the prevented cases.

TYPE 2 DIABETES PREVENTIONSTUDIES: PROGRESS TO DATE

Charting the future of diabetes preven-tion and suggesting logical next stepsrequires a critical review of the key stud-ies. Different interventions and ap-proaches carried out in a variety ofsettings in diverse populations haveyielded nearly uniform evidence in sup-port of both lifestyle modification andpharmacotherapy as viable means fordelaying or preventing diabetes in high-risk individuals (5–22) (Table 1).

The groundbreaking Da Qing IGT andDiabetes Study (5) was the first large-scale prevention trial to test the efficacyof lifestyle intervention and has pro-vided the longest follow-up data. Itcompared the effects of dietary modifi-cation, exercise, or both to a controlgroup given no intervention in high-risk Chinese adults with IGT. After 6years, the cumulative incidence of dia-betes by 1985 World Health Organiza-tion (WHO) criteria (fasting plasmaglucose [FPG] .140 mg/dL [7.8 mmol/L]or 2-h postload plasma glucose .200mg/dL [11.1 mmol/L]) was significantlyreduced by 31–46% in all interven-tion groups. Evaluation studies involv-ing 94% of the original cohort at the

20- and 23-year follow-ups (27,28)showed a durable 43% lower diabetesincidence rate, a 47% reduction in severediabetic retinopathy (29), and, by year 23,significant reductions in cardiovascular(41%) and all-cause (29%) mortality.

The Finnish Diabetes PreventionStudy (DPS) (6,30) examined the effectsof lifestyle intervention in middle-aged,overweight adults with IGT. Participantswere individually randomized to eitheran intervention group that received on-going individualized counseling aimed atreducing weight, making healthy dietarymodifications, and increasing physicalactivity or a control group receiving gen-eral diet and exercise advice but no in-dividualized counseling. After 4 years,diabetes risk was reduced by 58% inthe intervention group, which also hadgreater improvements in all parametersof the metabolic syndrome. No cases ofdiabetes developed among people whoreached at least four of the study’s fivelifestyle intervention targets for diet andphysical activity (6). Long-term follow-up found a sustained relative risk reduc-tion in diabetes incidence of 43% after7 years and 38% after 13 years, while theabsolute risk difference between groupscontinued to increase through 13 years(31,32).

The American Diabetes PreventionProgram (DPP) (7) demonstrated thatlifestyle modification and, to a lesser ex-tent, metformin therapy can reduce theincidence of diabetes in high-risk indi-viduals. Overweight adults with IGTand an FPG .95 mg/dL (5.3 mmol/L)were randomized to either intensivelifestyle intervention focusing on weightloss and exercise, metformin therapy, orplacebo. After a mean 2.8 years, the life-style intervention reduced the cumula-tive incidence of diabetes by 58% (areduction identical to that noted in theDPS), and the reduction with metforminwas 31%, compared with placebo. Afourth DPP arm using the thiazolidine-dione (TZD) troglitazonewas discontinuedearly because of the drug’s hepatotoxic-ity. After amean 0.9 year of therapy in thetroglitazone arm, diabetes incidence wasreduced by 75% compared with placebo.However, 3 years after troglitazone with-drawal, the diabetes incidence rate wasalmost identical to that of the placebogroup (33). The DPP lifestyle interventionalso yielded improvements in all tradi-tional, as well as many nontraditional,

care.diabetesjournals.org Cefalu and Associates 1187

cardiovascular risk factors (34). In the follow-up DPP Outcomes Study, cumulative di-abetes incidence rates still differedsignificantly 10 years (34 and 18% forlifestyle and metformin compared withplacebo, respectively) and 15 years (27and 17%, respectively) after initial ran-domization into the DPP (34,35). A pro-jection of the DPP interventions’ effectsover a lifetime yielded estimates that thelifestyle and metformin interventionsdelayed diabetes by 11 and 3 years, re-spectively, but also reduced the absoluteincidence of diabetes by 20 and 8%, re-spectively (36). However, no differencesin aggregate microvascular or cardiovas-cular outcomes by randomized arm havebecome evident in the DPP, although theexpected lower prevalence of microvas-cular complications in those who did notdevelop diabetes was reported (35).

Two Indian Diabetes Prevention Pro-gramme studies (IDPP-1 and IDPP-2)(8,9) focused on developing practical,translatable lifestyle interventions andcontributed important insights regard-ing potential ethnicity-based variationsin both the pathophysiology of diabetesand responses to lifestyle and pharma-cological interventions. In the IDPP-1,Asian Indian adults with IGTdwhowere younger and leaner than the sub-jects in the Finnish and American studies(6–8)dwere assigned to either a sim-ple lifestyle intervention encouraginghealthy dietary changes and increasedexercise, low-dose metformin therapy(500 mg daily), a combination of lifestylemodification plus metformin, or no in-tervention (control). After 3 years, dia-betes risk was reduced by 28.5, 26.4,and 28.2% in the lifestyle, metformin,

and combination groups, respectively.Both interventions also had positive ef-fects on LDL cholesterol but not onblood pressure (37). The IDPP-2 (9)tested whether adding the TZD pioglita-zone would enhance the efficacy of theIDPP-1 lifestyle intervention. In starkcontrast to a 72% diabetes risk reduc-tion found with pioglitazone in the U.S.ACT NOW (Actos Now for Prevention ofDiabetes) study (10) (discussed below),pioglitazone had no significant effectbeyond that of lifestyle intervention inthe IDPP-2 population. The potentialethnic differences in responses to phar-macological preventive therapy identi-fied in these studies require furtherinvestigation. If substantiated, they rep-resent an important additional issue tobe addressed in any global preventionstrategy.

Table 1—Major type 2 diabetes prevention trials

Location n Intervention Reference

Da Qing IGT and Diabetes Study China 577 Lifestyle modification Pan et al., 1997 (5)

Finnish Diabetes Prevention Study (DPS) Finland 522 Lifestyle modification Tuomilehto et al., 2001 (6)

Diabetes Prevention Program (DPP) U.S. 3,234 Lifestyle modification,metformin

Diabetes Prevention Program ResearchGroup, 2002 (7)

Indian Diabetes PreventionProgramme-1 (IDPP-1) India 531

Lifestyle modification,metformin Ramachandran et al., 2006 (8)

Indian Diabetes PreventionProgramme-2 (IDPP-2) India 407

Lifestyle modification pluspioglitazone Ramachandran et al., 2009 (9)

Zensharen Study for Prevention ofLifestyle Diseases Japan 641 Lifestyle modification Saito et al., 2011 (11)

Prevention of type 2 diabetes bylifestyle intervention Japan 458 Lifestyle modification Kosaka et al., 2005 (12)

TRIPOD (Troglitazone in the Preventionof Diabetes) U.S. 266 Troglitazone Buchanan et al., 2002 (13)

DREAM (Diabetes Reduction Assessmentwith Ramipril and RosiglitazoneMedication) International 5,269 Rosiglitazone DREAM Trial Investigators, 2006 (14)

ACT NOW (Actos Now for Prevention ofDiabetes) U.S. 602 Pioglitazone DeFronzo et al., 2011 (10)

CANOE (Canadian NormoglycemiaOutcomes Evaluation) Canada 207 Rosiglitazone plus metformin Zinman et al., 2010 (15)

ORIGIN (Outcome Reduction With InitialGlargine Intervention) International 12,537 Insulin glargine ORIGIN Trial Investigators, 2012 (16)

STOP-NIDDM (Study to Prevent Non-Insulin-Dependent Diabetes Mellitus) International 1,429 Acarbose Chiasson et al., 2002 (17)

Voglibose for prevention of type 2diabetes mellitus Japan 1,780 Voglibose Kawamori et al., 2009 (18)

EDIT (Early Diabetes Intervention Trial) U.K. 631 Acarbose, metformin Holman et al., 2000 (19)

NAVIGATOR (Nateglinide and Valsartan inImpaired Glucose Tolerance OutcomesResearch) International 9,306 Nateglinide, valsartan NAVIGATOR Study Group, 2010 (20)

XENDOS (Xenical in the Prevention ofDiabetes in Obese Subjects) Sweden 3,305 Orlistat Torgerson et al., 2004 (21)

SCALE (Satiety and ClinicalAdipositydLiraglutide Evidence) International 3,731 Liraglutide Pi-Sunyer et al., 2015 (22)

1188 Diabetes Prevention Update and Future Directions Diabetes Care Volume 39, July 2016

The Japanese Zensharen Study forPrevention of Lifestyle Diseases (11)evaluated overweight Japanese adultswith FPG levels of 100–125 mg/dL(5.6–6.9 mmol/L) who were randomlyassigned to either a frequent or less fre-quent (control) lifestyle interventionprogram for 3 years. The frequent inter-vention resulted in an overall 44% re-duction in diabetes incidence, althoughsubgroup analyses revealed that it waseffective in participants with combinedimpaired fasting glucose (IFG) and IGT(59% relative risk reduction) or highbaseline A1C (76% relative risk reduc-tion) but had no effect in those withisolated IFG or lower baseline A1C. Inanother, smaller Japanese lifestyle in-tervention study, men with IGT wererandomly assigned to a standard inter-vention group (control) or an intensiveintervention group (12). Subjects inthe control group and in the intensiveintervention group were advised tomaintain a BMI of ,24.0 and ,22.0kg/m2, respectively, through diet andexercise. In the intensive group, detailedinstructions on lifestyle modificationwere repeated every 3–4 months. Thecumulative 4-year incidence of diabeteswas 9.3% in the control group and 3.0%in the intensive intervention group; re-duction in diabetes risk from the inten-sive intervention was 67.4%.Because virtually all of the early dia-

betes prevention research suggestedthat the success of an intervention liespartly in its ability to improve insulinsensitivity and because TZDs wereknown to reduce insulin resistance, anumber of studies have examined theeffect of this class of agents. The TRIPOD(Troglitazone in the Prevention of Dia-betes) study (13) demonstrated thattroglitazone could reduce the risk of de-veloping diabetes by 55% in Hispanicwomen with a history of gestational di-abetes mellitus (GDM). The DREAM (Di-abetes Reduction Assessment withRamipril and Rosiglitazone Medication)trial (14) examined the preventive valueof rosiglitazone, and ACT NOW (10) didthe same with pioglitazone. In theDREAM trial, adults with IFG (FPG 110to ,126 mg/dL [6.1 to ,7.0 mmol/L]),IGT, or both were randomly assigned toeither rosiglitazone 8 mg daily or pla-cebo. After 3 years, the composite out-come of incident diabetes or death wasreduced by 60% in the rosiglitazone

group, most of which was due to a re-duction in incident diabetes. Rosiglita-zone was also shown to increase thelikelihood of reversion to normal glu-cose tolerance (NGT) by ;70–80%. InACT NOW, overweight adults with IGTwere randomly assigned to either pio-glitazone titrated to 45 mg daily orplacebo. During a median follow-upof 2.4 years, the pioglitazone grouphad a 72% reduction in diabetes riskcompared with placebo. In addition, theCANOE (Canadian Normoglycemia Out-comes Evaluation) trial (15) found thatlow-dose combination therapy with rosi-glitazone 2 mg plus metformin 500 mgtwice daily in adults with IGT reduced therelative risk of diabetes by 66% during amedian 3.9 years of treatment with sig-nificantly fewer adverse events than inthe DREAM trial. Longer-term passivefollow-up of the DREAM cohort showedthat at a median 1.6 years after the endof the trial and 4.3 years after randomi-zation the rosiglitazone group retaineda 39% lower incidence of the compos-ite outcome but had only 17% more re-version to normoglycemia than theplacebo group (38). Thus, limited expo-sure to a TZD (in this case, rosiglitazone,but also troglitazone in the DPP [33]and pioglitazone in ACT NOW [39]) ap-pears to reduce the long-term inci-dence of diabetes by delaying, ratherthan reversing, the underlying diseaseprocess.

The ORIGIN (Outcome ReductionWith Initial Glargine Intervention) trial(16,40) explored the same question ofpreventing diabetes by reducing b-cellload, in this case with insulin therapy.Adults with cardiovascular risk factorswho either had or were at risk for de-veloping diabetes were randomized toreceive either insulin glargine or stan-dard care. Although the study’s primaryfocus was on cardiovascular outcomes,incident diabetes among at-risk partici-pants was also examined. After a meanfollow-up of 6.2 years, glargine reducedthe risk of diabetes by 28% comparedwith standard care based on oral glu-cose tolerance tests (OGTTs) performed;1 month after insulin was stopped.When participants were identifiedthrough a second OGTT performed;3 months later and those with uncer-tain new diabetes diagnoses were in-cluded, the total risk reduction was31%. A 2-year passive follow-up study

of 4,718 of the original 12,537 ORIGINparticipants was consistent with a leg-acy effect, with new diabetes cases oc-curring in 41 and 48% of the glargine andstandard care groups, respectively,when both confirmed and unconfirmedcases were included (41).

Additional prevention studies havebeen conducted with other pharmacolog-ical agents. The international STOP-NIDDM(Study to Prevent Non-Insulin-DependentDiabetes Mellitus) trial (17), a 2009 Japa-nese study (18), and the U.K. Early Diabe-tes Intervention Trial (EDIT) (19) allinvestigated the preventive effects ofa-glucosidase inhibitors in individualswith IGT. In STOP-NIDDM, participants re-ceiving 100 mg of acarbose three timesdaily for 3 years had a 25% reduction inrelative risk of diabetes compared withplacebo. Acarbose therapy also signifi-cantly increased the rate of reversion toNGT (17). In the Japanese study, partici-pants receiving 0.2 mg of voglibose threetimes daily for 4 years had a 40% reductionin the relative risk of diabetes comparedwith placebo and were significantly morelikely to achieve normoglycemia (18). EDITrandomized 631 U.K. participants at riskfor diabetes based on two FPG levels of99–139 mg/dL (5.5–7.7 mmol/L) to acar-bose 50 mg, metformin 500 mg, ormatched placebo three times dailyin a 23 2 factorial study. After 3 years,no statistical risk reductions with wereobserved with acarbose or metformin(8 and 37%, respectively) comparedwith placebo (19). Although the finalEDIT results have not been fully report-ed, no differences were seen in the rel-ative risk for diabetes by 6 years foracarbose (1.04, P = 0.81), metformin(0.99, P = 0.94), or their combination(1.02, P = 0.91). Interestingly, for thosewith IGT at baseline, the relative risk ofdiabetes was reduced by acarbose (0.66,P = 0.046) but not by metformin (1.09,P = 0.70), perhaps because the fastingglucose level and BMI in this study werelower than in the DPP. The investigatorsconcluded that the ability of therapiesto reduce the risk of diabetes may differfor those with IGT versus those with IFG(42).

TheinternationalNAVIGATOR(Nateglinideand Valsartan in Impaired Glucose Toler-ance Outcomes Research) trial (20) testedwhether treatment with themeglitinidenateglinide reduces the risk of diabetesand cardiovascular events in adults with

care.diabetesjournals.org Cefalu and Associates 1189

IGT and cardiovascular disease or car-diovascular risk factors. The study com-pared nateglinide up to 60 mg threetimes daily or valsartan therapy to pla-cebo. During a median follow-up of 5years, nateglinide did not significantlyreduce the cumulative incidence of dia-betes compared with placebo (36 vs.34%, respectively). There was no reduc-tion in the nateglinide group in a corecardiovascular composite outcomethat included death from cardiovascu-lar causes, nonfatal myocardial infarc-tion, nonfatal stroke, or hospitalizationfor heart failure (7.9 vs. 8.3%, respec-tively), and there was no reduction inan extended cardiovascular compositeoutcome that included the individualcomponents of the core composite out-come as well as hospitalization forunstable angina and arterial revascular-ization (14.2 vs. 15.2%, respectively).Furthermore, nateglinide therapy in-creased the risk of hypoglycemia.In the Swedish XENDOS (Xenical in the

Prevention of Diabetes in Obese Sub-jects) trial (21), obese adults with eitherNGT or IGT were randomly assigned tolifestyle modification plus either orlistat120 mg or placebo three times daily.After 4 years, the cumulative incidenceof diabetes was 9.0% with placebo and6.2% with orlistat, corresponding to anoverall risk reduction of 37.3%. Analysesindicated that the preventive effect oforlistat was explained by its effect onparticipants with IGT at baseline, inwhom orlistat yielded a risk reductionof 52%. Participants receiving orlistatalso had significantly greater meanweight loss (5.8 vs. 3.0 kg with placebo),which was not dependent on their glu-cose tolerance status.The international SCALE (Satiety and

Clinical AdipositydLiraglutide Evidence)trial (22) investigated the effects ofthe glucagon-like peptide 1 recep-tor agonist liraglutide on weight andcardiometabolic risk factors in obeseadults without diabetes. Participantswere randomly assigned to receive eitherliraglutide 3.0 mg in once-daily injectionsor placebo in addition to counseling onlifestyle modification. After 56 weeks,those receiving liraglutide lost signifi-cantly more weight (difference –5.6 kg).Weight loss of at least 5% body weightwas achieved in 63.2 and 27.1% ofthe participants in the liraglutide andplacebo groups, respectively, and 33.1

and 10.6%, respectively, lost .10%body weight. A1C, fasting glucose, andfasting insulin levels decreased morewith liraglutide than with placebo, andthe liraglutide group also had lower glu-cose and higher insulin and C-peptidelevels during OGTT. Insulin resistanceand b-cell function also improved withliraglutide. The prevalence of prediabe-tes at week 56 was significantly lowerwith liraglutide (7.2 vs. 20.7% amongparticipants with baseline normoglycemiaand 30.8 vs. 67.3% among those withbaseline prediabetes), and type 2 diabe-tes developed in fewer patients receiv-ing liraglutide than with placebo (4 vs. 14cases).

Taken together, these studies con-vincingly support lifestyle modificationfocusing on healthful eating and in-creased physical activity and variouspharmacological therapies as viablestrategies for preventing type 2 diabe-tes. However, they also raise importantnew questions, such as 1) how best toidentify the most appropriate targetpopulations for intervention, 2) how todisseminate lifestyle interventions inthe most cost-effective manner, and 3)how expanding preventive pharmaco-therapy options might further the goalof reducing diabetes rates worldwide.

TYPE 2 DIABETES PREVENTIONSTUDIES: CHALLENGINGQUESTIONS

Identifying Appropriate TargetPopulationsMany longitudinal studies have outlinedthe trajectories of the metabolic factors(i.e., insulin secretion, insulin sensitivity,and 2-h glucose levels) preceding diag-nosis. For example, Tabak et al. (43)showed that insulin secretion and insu-lin actionmay be considered to be in thenormal range until 2–6 years before diag-nosis, when abruptmetabolic changes re-sult in deterioration of fasting and 2-hpostload glucose levels. Each of the threeclinical categories used to identify theprediabetic state (isolated IFG, isolatedIGT, and combined IFG and IGT) mayrepresent a distinctive pathophysiology(44). Individuals in each of these cate-gories have an elevated diabetes risk,and responses to interventionsmay differbased on the category and severity of theabnormality. Thus, attempts to curb theprevalence of diabetes must focus oneffectively screening, identifying, and

treating people who are at increasedrisk by virtue of being in one of thesecategories.

However, there is not uniform agree-ment on the specific approach to take.Given the different trajectories of fast-ing glucose, postprandial glucose, andinsulin levels before diagnosis, whatspecific point would be the most appro-priate at which to intervene?

Determining Appropriate Diagnostic

Criteria for Prediabetes

The current diagnostic recommendationsfor diabetes are an FPG level$126mg/dL(7.0 mmol/L) or a 2-h plasma glucose dur-ing an OGTT $200 mg/dL (11.1 mmol/L)(Fig. 1). These criteria historically werebased on thresholds for the risk of reti-nopathy (45–48). The term “impaired glu-cose tolerance,” comprising people athigh risk to progress to diabetes, was es-tablished in 1979, and its definition (2-hOGTT glucose levels between the normaland diabetic values) essentially has notchanged since then (46). Inmost diabetesprevention studies to date, subjects havehad IGT (i.e., a 2-h OGTT glucose level of140–199 mg/dL [7.8–11.0 mmol/L]).

The controversy regarding appropri-ately diagnosing prediabetes and target-ing interventions relates to the use ofother suggested criteria (FPG and A1C).For example, in 2003, an American Diabe-tes Association (ADA) Expert Committeesuggested that the FPG threshold for IFGbe reduced from 110mg/dL (6.1 mmol/L)to 100mg/dL (5.6mmol/L) (48). The com-mittee suggested that this lower cut pointmay improve the sensitivity of the predic-tion of diabetes risk, but this change hasnot been universally accepted becausethe specificity is markedly reduced bylowering the threshold; thus, many peo-ple whomay not progress to diabetes arebeing labeled as having prediabetes (49).In 2009, an A1C cut point of $6.5% (48mmol/mol) was introduced to diag-nose diabetes, and this was later en-dorsed by a WHO consultation committee(50,51). Since 2010, ADA has recom-mended that an A1C range of 5.7–6.4%(39–46mmol/mol) be considered indica-tive of prediabetes (45). However, otherorganizations have not agreed with theseFPG and A1C cut points (51–53). A recentmeta-analysis evaluated progressionrates by prediabetes definition. It wasfound that A1C values of 6.0–6.4% (42–46 mmol/mol) might identify individuals

1190 Diabetes Prevention Update and Future Directions Diabetes Care Volume 39, July 2016

at lower risk than other prediabetes def-initions, butmore research is needed (54).The success of any broad-based pre-

vention strategy will hinge on attainingconsensus regarding the most appropri-ate diagnostic test and the glycemic cutpoint at which to begin intervention. Thecurrent lack of concordance on this issueis not a trivial matter and has tremendousclinical implications (55). At present, life-style intervention has been shown to beunequivocally effective in reducing diabe-tes incidence only in subjects with iso-lated IGT or combined IGT and IFG andin subjects with A1C levels of 6.0 to,6.5% (42 to ,48 mmol/mol). Withoutintervention, these individuals have amuch higher incidence of diabetes thando individualswho are classified as havingprediabetes by other criteria. Existingdata are not sufficient to make evi-dence-based recommendations for thosewith prediabetes classified by other crite-ria; targeted studies are needed to pro-vide more specific information.

Clinical Implications of the Prediabetes

Diagnosis

More general agreement exists regardingthe clinical implications of the prediabeticstate. First and foremost, prediabetes islinked to microvascular complications (56–59). For example, using data from the Na-tional Health and Nutrition ExaminationSurvey (NHANES) and defining “prediabe-tes” as an FPG $100 mg/dL (5.6 mmol/L)but ,126 mg/dL (7.0 mmol/L), Plantingaet al. (56) reported that the prevalenceof chronic kidney disease was 17.7% in

individuals with prediabetes comparedwith 10.6% in those with no diabetesand 39.6% and 41.7% in individuals withdiagnosed or undiagnosed diabetes, re-spectively. Second, each category of pre-diabetes (i.e., IFG, IGT, or a combinationof both) increases the relative risk andincident rate of progression to diabetes,although isolated IFG has less predictivevalue (60). Although previous studies pri-marily usedan IFGcutpoint of$110mg/dL(6.1 mmol/L), there is evidence that lower(but still elevated) 2-h glucose and A1C val-ues also confer risk (61–63), although dataon FPG are less clear.

Onemajor factor to consider is whetherthe ADA-recommended lower thresholdsfor A1C and IFG are associated with highercardiovascular risk. Understanding thatrisk is a graded continuum, one would ex-pect these values to confer some level ofincreased risk, and there is evidence tosupport this (64–66), although some stud-ies have demonstrated less excess riskthan others. For example, in the U.S.MESA (Multi-Ethnic Study of Atheroscle-rosis) trial (64), IFG was defined as notype 2 diabetes and a fasting glucose of100–125 mg/dL (5.6–6.9 mmol/L) andwas associated with an increased inci-dence of cardiovascular events in univar-iate, but not multivariate, analysiscompared with those with normal fast-ing glucose. Data from the Emerging RiskFactors Collaboration (ERFC) (65) sug-gested that “there are generally contin-uous associations between fastingglucose levels greater than 100 mg per

deciliter and risk of death, supportingthe view that hyperglycemia (or some fac-tor closely related to it) may be directlyrelevant.” In addition, Xu et al. (66) per-formed a meta-analysis on the risk ofcoronary heart disease (CHD) using differ-ent IFG criteria. They found an increasedrisk of CHD when FPG was as low as100 mg/dLdthe lower ADA cut pointfor IFGdand concluded that “these re-sults reaffirm the importanceof screeningfor prediabetes using the ADA criteria.”

Collectively, these studies indicate theclinical implications of the continuum ofexcess risk for microvascular complica-tions, macrovascular complications, mor-tality, and type 2 diabetes even at thelower values within the glycemic rangethat defines prediabetes (67).

Disseminating Lifestyle InterventionsCost-EffectivelyNumerous efforts have been made totranslate lifestyle interventions into real-world practice, although risk reductionsgenerally have not matched the levelsachieved in proof-of-concept researchstudies (68–79). This is not surprising inthat clinical practices face different chal-lenges from those in research settings,including personnel training, fundingand reimbursement schemes, competingneeds in clinics, and compliance and ad-herence barriers (80).

Clearly, more work is needed to makewidespread practical use of the lessonslearned thus far, to tailor simple and prac-tical interventions to specific populationsand individuals, and to identify patientsfor whom lifestyle modification may notbe enough. A great deal of information isnow available about the predictors of inci-dent diabetes and of successful risk reduc-tion through lifestyle intervention (Table 2)(5,7,11,12,27–29,34,35,76,81–97). Thesefindings will help to guide future effortsto determine the most appropriate candi-dates for widespread translation initiativesamong high-risk individuals. Other remain-ing questions regarding lifestyle interven-tion include the following:

c How much do the dietary and exercisecomponents contribute individually toreducing diabetes risk and delaying orpreventing the onset of the disease, orare the two inextricably linked? Howmuch weight loss maintained overhow many years is required for sus-tained prevention of type 2 diabetes?

Figure 1—Criteria for diagnosing diabetes and prediabetes. Diagnosis of diabetes is made on thebasis of an FPG level$126mg/dL (7.0 mmol/L), a 2-h plasma glucose level during an OGTT$200mg/dL (11.1 mmol/L), or an A1C $6.5% (48 mmol/mol). When using A1C for diagnosis, it isimportant to take the patient’s age, race/ethnicity, and anemia/hemoglobinopathy status intoconsideration. Diabetes can also be diagnosed based on unequivocal symptoms and a randomplasma glucose value$200 mg/dL (11.1 mmol/L). Any abnormality by any testing method mustbe repeated and confirmed on a separate day. For the diagnosis of prediabetes, cut points arenot as well established. A 2-h plasma glucose during an OGTT of 140–199mg/dL (7.8–11.0mmol/L)is known as IGT and considered indicative of prediabetes, but recommended FPG and A1C cutpoints for prediabetes have varied (FPG $100–125 or $110–125 mg/dL [5.6–6.9 or 6.1–6.9mmol/L] andA1C$5.7–6.4 or$6.0–6.4% [39–46or 42–46mmol/mol]). Adaptedwith permissionfrom American Diabetes Association (45).

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Table 2—Predictors of diabetes risk reduction through lifestyle intervention

Study Relevant findings

Da Qing IGT and Diabetes Study (5,27–29,81) c Diet, exercise, and a combination of diet and exercise intervention for 6 years inChinese adults with IGT were equally effective in reducing diabetes incidence.

c Interventions were effective in people with a BMI higher or lower than 25 kg/m2.c Benefit could not be wholly ascribed to changes in BMI.c Interventions were most effective in those with less insulin resistance andgreater insulin secretion at baseline.

c Reduced cumulative diabetes incidence persisted for at least 17 years after thetermination of the active intervention.

c Lifestyle intervention was associated with a subsequent lower incidence ofsevere retinopathy and lower mortality.

Finnish Diabetes Prevention Study (DPS) (82–89) c Lifestyle intervention was most effective among the oldest participants andthose scoring highest on a composite risk assessment at baseline. This scoringinstrument or others like it may be useful for identifying individuals most likely tobenefit from intensive lifestyle intervention.

c Participants who had greater insulin sensitivity and better insulin secretionduring the study were less likely to progress to diabetes during a mean follow-upof 6 years. Regression to NGT was more strongly associated with greater insulinsecretion than with better insulin sensitivity.

c Participants with greater improvements in weight and BMI during the first yearwere less likely to develop diabetes. Thus, BMI reduction may be a key goal toimprove insulin sensitivity, preserve insulin secretion, and ultimately prevent ordelay diabetes.

c Achievement of each of the study’s five lifestyle goals significantly decreasedrisk. None of the participants who achieved at least four of the five goalsdeveloped diabetes by year 4.

c Participants with longer typical sleep durations had a higher risk of developingdiabetes in the control group but not in the intervention group; lifestyleintervention was similarly effective regardless of participants’ sleep habits. Thus,lifestyle intervention may reduce the excess risk conferred by longer sleepduration.

c Several genetic variants conferred higher diabetes risk. Post hoc analysesshowed that although lifestyle intervention was effective regardless of familyhistory of diabetes its effectiveness varied markedly according to participants’genetic variant status. This demonstrates the potential role of genotype indiabetes prevention efforts.

Diabetes Prevention Program (DPP) (7,34,35,90–94) c Short- and long-term effects of intensive lifestyle intervention were greatestamong older participants, those with greater baseline insulin sensitivity andinsulin secretion, and those with greater improvements in each during the activestudy period.

c For women with a history of GDM, lifestyle modification and metformin weresimilarly effective, whereas for women without previous GDM, only lifestyleintervention reduced diabetes risk.

c Lifestyle intervention was similarly effective in those with and without highergenetic risk.

c The presence or absence of diabetes-related antibodies did not affect diabetesrisk or predict responses to intervention.

c Individuals from any group who regained NGT at least once during activeintervention reduced their diabetes risk by 56% during long-term follow-upcomparedwith those with persistent prediabetes. Thus, even transient reversionto NGT by any means appears to lower future diabetes risk. Reversion was morecommon in the lifestyle group and was more likely in participants who achievedgreater weight loss, were younger, and had lower glucose levels and betterb-cellfunction at baseline. Paradoxically, lifestyle group members who did not revertto NGT during the study were actually at higher risk during follow-up, perhapsbecause of a particularly strong susceptibility (genetic or environmental) todiabetes. Thus, a combination of interventions may be needed for individualswhose dysglycemia is not reversed through lifestyle modification alone.

Indian Diabetes Prevention Programme-1 (IDPP-1) (95) c Baseline A1Cwas themost significant predictor of diabetes; however, preventiveinterventions were similarly effective across A1C subgroups.

c Lifestyle intervention reduced diabetes risk in this population independent ofweight loss.

Continued on p. 1193

1192 Diabetes Prevention Update and Future Directions Diabetes Care Volume 39, July 2016

c Are the beneficial effects of exerciseor increased leisure-time activity ef-fective independent of weight lossamong people who are overweight/obese and those who are of normalweight? Is delay or prevention of di-abetes possible in the absence ofweight loss in some populations?

c Is it appropriate to group individualswith isolated IFG together with thosewho have IGT or a combination ofboth as the target for preventive in-terventions? If not, what strategiesmight be necessary to reduce diabe-tes risk in people with each typeof metabolic dysregulation (or, forthat matter, with higher or lowerA1C values)?

c Howmight lifestyle interventions thathave proven effective in structuredresearch settings be implementedsuccessfully through large-scale pub-lic health initiatives?

Expanding PharmacotherapeuticOptions: Moving Toward aPrevention-Related Indicationfor MetforminRelying on diet and physical activity is notenough to delay progression for some at-risk individuals because long-term adher-ence to healthy lifestyle behaviors can bedifficult (26). Furthermore, as previouslynoted, interventions implemented in re-search studies can be prohibitively laborintensive and expensive to deliver in real-world settings, where they face differentobstacles (80). In addition, the costs ofprevention services, suchas lifestylemod-ification programs and health coaching,typically have not been reimbursed bypayers (25). The recently announced

findings supporting the cost-effectivenessof the NDPP (23,24) are encouraging, asis a recent recommendation from theU.S.Preventive Services Task Force that obeseadults aged 40–70 years who do not havesymptomsofdiabetes should be screenedfor abnormal blood glucose in the primarycare setting (98). Although these andother public health initiatives (99–103)could soon improve this situation, currentreimbursement structures and a shortageof qualified lifestyle coaches in primarycare and nonmedical settings remainproblematic.

For these reasons, preventive pharma-cotherapy has been proposed as an ad-junct to lifestyle modification (39). Asreviewed above, strong evidence fromrandomized controlled trials has shownthe potential of various pharmacologicaltherapies to prevent progression totype 2 diabetes in people with IGT (7–10,13–22,33,104). The preventive effects ofthese agents, although not fully under-stood, appear to be related primarily totheir ability to lower blood glucose and topreserve or delay the deterioration ofb-cell function and thereby modify thedisease progression (105), as demon-strated in the DPP (90). TZDs improve in-sulin sensitivity and glucose utilizationand also have direct, positive effects onthe b-cells; a-glucosidase inhibitors re-tard carbohydrate absorption and lowerpostprandial hyperglycemia, reducing theb-cell load; and metformin, a biguanide,suppresses hepatic glucose production.Each of these mechanisms potentiallycould modulate factors related to preser-vation of b-cell function by reducing thedemand for insulin secretion.

As preventive monotherapy, onlymetformin has been studied for longerthan ;3 years, and reductions in diabe-tes incidence have generally dissipatedafter discontinuation of glucose-loweringdrugs (26). In addition, TZDs have beenplagued with concerns regarding seriousadverse events, and acarbose is associ-atedwith gastrointestinal (GI) symptomsand greater adherence problems(17,104,106). Some newer obesity anddiabetes medications (e.g., orlistat andglucagon-like peptide 1 receptor ago-nists) (21,22,107) have the potential fordiabetes prevention based on their pos-itive effects on weight and cardiovascu-lar risk factors and possibly also b-cellfunction and protection. However, suchagents are costly, some are injectables(which may pose a barrier for somepeople), and all require further studyin the population with prediabetes(26,108).

Metformin, with proven effective-ness, long-term safety (109), and cost-effectiveness as the first-line type 2diabetes treatment (110), is the mostlikely candidate for widespread use indiabetes prevention (100). Althoughless effective overall than lifestyle inter-vention in the DPP, it was as effective aslifestyle modification for younger partic-ipants, very obese participants ($35kg/m2), and women with a history of GDM.However, it was no more effective thanplacebo in older participants (.60 yearsof age) (7,111). A recent risk-based re-analysis of the DPP (112) found that thebenefit of metformin was unevenly dis-tributed within the study population suchthat only subjects in the highest-risk

Table 2—Continued

Study Relevant findings

Indian text-messaging intervention study (76,96,97) c Participants who regained NGT by 6 months reduced their risk of progression todiabetes by 75%by year 2 comparedwith thosewho did not return to NGTwithinthe first 6 months. Better b-cell function at baseline and its improvement duringthe study were associated with reversion to NGT by 2 years.

c Progression to diabetes was associated with declining b-cell function throughoutthe study period.

Zensharen Study for Prevention of LifestyleDiseases (11)

c Lifestyle intervention was highly effective in participants with combined IGT andIFG and in those with a baseline A1C $5.6% (Japan Diabetes Society method).

c Lifestyle intervention was ineffective in participants with isolated IFG and inthose with a baseline A1C ,5.6%.

Japanese study on prevention of type 2 diabetes bylifestyle intervention (12)

c The cumulative 4-year incidence of diabetes, based on confirmed diagnostic FPGlevels of 140mg/dL (7.8 mmol/L) or higher, was 3.0% in the intensive and 9.3% inthe conventional group.

c Changes in BMI only partially accounted for the lower incidence in the intensivegroup.

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quartile experienced marked risk re-duction, whereas the remaining sub-jects received little or no benefit. Since2008, ADA has recommended consid-eration of metformin therapy for indi-viduals who are at very high risk fordiabetes (currently including individualswho are ,60 years of age, are veryobese, have a history of GDM, or haveIGT, IFG, or an A1C of 5.7–6.4% [39–46mmol/mol]) (113).Despite this recommendation, met-

formin use for diabetes prevention hasbeen minimal in many countries. Costmay not be a major issue, but GI sideeffects and the lack of perceived benefitwith no measurable targets may play arole in the low rate of metformin use inprediabetes. For example, a recent eval-uation of metformin prescription ratesin a nationwide sample of .17,000 in-sured adults aged 19–58 years with pre-diabetes in the U.S. found that only 3.7%were prescribedmetformin in the 2010–2012 period. Even within a subgroup ofindividuals with a BMI .35 kg/m2 or ahistory of GDMdcharacteristics specif-ically identified in ADA guidelinesdonly7.8% received a metformin prescrip-tion (114). Although more research isneeded to pinpoint the reasons for thislack of uptake for metformin use in pre-diabetes, the authors suggested thatproviders’ lack of knowledge about DPPand the natural course of prediabetes,reluctance on the part of patients andproviders to “medicalize” prediabetes,and the lack of a metformin prediabe-tes indication approved by the U.S.Food and Drug Administration (FDA)and similar agencies in other countriesall may play a role. That said, a prediabe-tes indication for acarbose has been ap-proved in several countries (115), but itis uncertain how often that agent is pre-scribed for this use.The lack of a prevention-related indi-

cation for metformin poses a significantbarrier to more widespread use, butperhaps not an insurmountable one. Al-though conventional wisdom holds thatthe FDA is reluctant to approve such anindication for any drug, the agency’s2008 draft guidance for industry on de-veloping diabetes drugs seems to sug-gest otherwise (116). This document,although never finalized, outlines theFDA’s expectations for “products in-tended to prevent the development ofdiabetes” (116). These expectations

include that supporting research studiesneed to 1) be conducted in populationsof high-risk individuals (e.g., thosewith IGT, IFG, or a history of GDM); 2)include a washout period to confirmthat the drug truly delays, rather thanmerely masks, progression of the under-lying disease process; 3) be of substan-tial duration and size; and 4) include aspossible end points either delay intype 2 diabetes diagnosis or reductionin the proportion of patients diagnosedwith type 2 diabetes relative to placebo.

Theguidancenotes that, in theabsenceof a clearly defined “clinically meaningfuleffect size,”merely delaying a diagnosis ofdiabetesmay not bea sufficiently tangiblebenefit againstwhich to judge risks. It sug-gests, however, that certain supportingoutcomes, such as demonstration of a du-rable delay indiabetesonset after therapyends or evidence of delay or reduction ofmicro- or macrovascular complications,could strengthen a candidate drug’sclaim. In addition, the guidance statesthat the FDA’s expectations for the safetyof prevention-related products are likelyto behigher than for drugs aimed at treat-ing type 2 diabetes.

Notably, the FDA guidance does notsuggest that a candidate agent must besupported by evidence that it actually“prevents” type 2 diabetes but ratherthat it durably delays disease onsetand thereby can be expected to reducelong-term complications. Some wouldreserve the term “prevention” for inter-ventions that, at least in a significantproportion of individuals, forestall theonset of diabetes for decades or longer.Others may take a more pragmatic per-spective and hold that the terms “reduc-tion,” “prevention,” and “delay”may beconsidered close enough on the samespectrum to be used interchangeably(117). The distinction may be importantto the FDA, which likely would set ahigher evidence bar for a “prevention”indication than it would for an indication“for the treatment of prediabetes” or“for reducing the risk of developingtype 2 diabetes.” To date, the only evi-dence in support of strictly defined “pre-vention” has come from the previouslymentioned DPP cost-effectiveness anal-ysis (36) showing that the effects of themetformin intervention, projected overa lifetime, would not only delay diabe-tes but also reduce its absolute incidenceby 8%.

Consistent with the FDA guidance,however, the evidence base for metfor-min may already be substantial enoughto support approval of some form ofprevention-related indication. Somework may be necessary to develop ex-pert consensus with regard to whatconstitutes a clinically meaningful delayin the development of diabetes in thecontext of metformin’s known benefitsand risks; this would be analogous to aprevious successful initiative to estab-lish measures of C-peptide as the pri-mary efficacy end point for new type 1diabetes drugs (118). Notably, the FDAhas awarded cardiovascular preventionindications for statins on the basis ofresults from a single robust trial showingsignificant reductions in tangible cardio-vascular events (119).

Admittedly, the DPP did not evaluateparticipants’ diabetes status off therapyby including a metformin washout pe-riod. In its guidance, the FDA reasonablyasks for confirmation that normal glu-cose regulation persists after washoutto exclude the possibility that a glu-cose-lowering agent is not simply main-taining normoglycemia in those whoactually have progressed to diabetes.Evaluating diabetes status after washoutmust be distinguished from demonstrat-ing the durability of the diabetes-delayingeffect. The latter is determined by restart-ing treatment and determining at subse-quent time points (each after treatmentwashout) what proportion of the popula-tion retains normal glucose regulationstatus. This distinction is less importantfor trials of long duration with a singlewashout evaluation at the end andmore important for shorter trials witha single end point, for which durabilityremains an open question, and for longtrials with intermediate end points. Mea-suringdurability becomesmore importantwhen the safety profile of a candidatedrug is not so benign. Here, weighing thedurability of benefit against cumulativeadversity would be an important aspectof estimating theoverall benefit-to-risk re-lationship of what for some could be alifelong therapy.

In the case of metformin, the long-term safety profile is well established,making the drug suitable for lifelonguse once it is started for prevention, al-though there have been associated GItolerability issues and concerns aboutvitamin B12 deficiency and anemia, as

1194 Diabetes Prevention Update and Future Directions Diabetes Care Volume 39, July 2016

well as neuropathy in those with lowvitamin B12 levels (120). Similar to cur-rent ADA recommendations, the indica-tion for metformin should limit its use tosubpopulations found in the DPP to beat high risk (i.e., those with a history ofGDM, who are very obese, or who havemore severe or progressive hyperglyce-mia) until additional evidence supportsexpansion of the indicated population.Of interest in this regard, metformin re-duced IGT progression to diabetes in theIDPP’s lean Indian population about aswell as it did in the DPP’s obese popula-tion (7,8).Key practical questions are: how

could approval of a new metformin in-dication be achieved, and who will leadthis effort? The conventional mecha-nism would be for one or more of thecompanies marketing metformin in theU.S. to compile and submit a supple-mentary new drug application contain-ing the data and other necessaryinformation to allow the FDA to approvethe indication. However, these compa-nies may not wish to spend the signifi-cant resources required for such anapplication given that metformin is al-ready available in generic form. Realiz-ing the long-term societal benefits oftype 2 diabetes prevention may requireother avenues for FDA approval (25).One approach could be for the FDA toreceive a comprehensive package of ev-idence and other relevant material andcall an advisory committee for a full pub-lic discussion. With a positive vote of itsadvisory committee, the FDA could con-clude that the indication should begranted and allow companies with ap-proved metformin new drug applicationsto add the new indication to their labels.An organization such as ADA could veryappropriately lead the effort to compilethe briefing package for the FDA and fa-cilitate other supportive actions.

UNMET RESEARCH NEEDS

We need to learn more about racial andethnic differences in responses to life-style and, particularly, pharmacologicalinterventions. Are there meaningful dif-ferences, or are they more perceivedthan real because different populationswere not compared in the same study?The similar effectiveness of the DPP in-terventions in five ethnic groups sug-gests that this may be more theoreticalthan real (7).

Much remains to be learned aboutthe genetics of diabetes risk, the effectsof genetics as a modifier of preventioninterventions, and the potential role ofgenetic testing to identify appropriatesubjects for future research. In this re-gard, genetics has been somewhat dis-appointing to date. Compilation ofgenetic risk scores has demonstratedthat greater genetic risk is associatedwith a greater likelihood of progressionto diabetes. However, this work has alsodemonstrated that a high genetic riskscore in adults is typically also associ-atedwith elevated glucose levels, mean-ing that glucose itself is as good apredictor and certainly less expensive.Thus, the true utility of genetic riskscores may be in identifying young indi-viduals who are at the greatest risk andinitiating preventive therapy in themwell before their glucose levels start toincrease substantially.

More detailed evidence is needed toinform efforts to tailor preventive mea-sures based on patients’ phenotype, ge-notype, composite diabetes risk scores,personal characteristics, socioeconomicfactors, and other relevant parameters.

THE FUTURE IS NOW:TRANSLATION THROUGHNATIONAL AND COMMUNITYCAMPAIGNS

Carefully conducted landmark preven-tion trials have provided more thanenough evidence that prevention or de-lay of type 2 diabetes is possible in high-risk individuals. Clearly, the next step isto implement these strategies, and newtechnologies and innovations offerpromising ways to reduce the laborand costs associated with scaling up pre-vention initiatives on a population level.Individuals can be screened for predia-betes in numerous low-cost ways for en-rollment in an intervention. Communityor workplace health screenings, pro-vider referrals, and reviews of electronicmedical records all can be leveraged toscreen for diabetes risk. Individuals canalso self-screen using one of the manyavailable risk scoring instruments. Suchrisk questionnaires, originating frommany sources in various populations,are available on the Internet and canbe publicized through traditional adver-tising and social media (82,121–125).

Throughout the world, countries arenow developing practical, affordable

population-based programs that canbe tailored for individual and culturaldifferences and implemented relativelyinexpensively. Some of these programsare described below, and their reportedresults, where available, are summa-rized in Table 3 (24,68,76–78,126–129).

Taking advantage of new technolo-gies can aid in the translational effortby reducing costs and expanding reachto a wide audience. For example, an In-dian study assessed the effectivenessof a text-messaging lifestyle interven-tion and convincingly demonstratedthat a low-cost, low-labor program of-fering lifestyle modification supportthrough a widely available mediumcan produce clinically meaningful out-comes (76). Similar approaches are be-ing implemented in other countries,some under the auspices of the WHO/International Telecommunication UnionBe He@lthy, Be Mobile program (130).

Elsewhere, numerous public healthinitiatives have begun translating preven-tion research into effective community-based, or even nationwide, interventions.The Finnish National Diabetes PreventionProgram (FIN-D2D) (77,131,132) was thefirst of these efforts. Implemented in2003 in five districts covering a popula-tion of 1.5 million, it encompasses threeconcurrent strategies: a high-risk strategyaimed at incorporating diabetes preven-tion and cardiovascular risk reduction intoroutine primary care using existingresources, a population strategy focusedon raising awareness, and an early treat-ment strategy for individuals identifiedthrough screening as having diabetes.The ultimate goal of FIN-D2D is to refineand expand this multistrategy approachto serve all of Finland. The Finnish expe-rience also has been used in the largeEuropean effort DE-PLAN (Diabetes inEurope: Prevention Using Lifestyle, Phy-sical Activity andNutritional Intervention)to develop screening for type 2 diabetesrisk followed by lifestyle programs in sev-eral local settings, mainly in primary care(133). This has been further elaboratedwithin the IMAGE (Development and Im-plementation of a European Guidelineand Training Standards for Diabetes Pre-vention) network, which has developedtools for the implementation of preven-tion in practice (134).

The second large-scale preventionprogram reported was Victoria, Aus-tralia’s Life! Taking Action on Diabetes

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Table 3—Sample translational prevention initiatives and their reported outcomes

Study or initiative Findings/results

Indian text-messaging intervention study (76) After 2 years, participants receiving twice-weeklymotivational textmessages had a36% relative reduction in diabetes risk compared with those receiving standardadvice but no text messages.

Finnish National Diabetes Prevention Program(FIN-D2D) (77)

After 1 year, average weight loss in this high-risk population was 1.3 kg in men and1.1 kg in women, with a 1.3-cm reduction in waist circumference. Decreasesin blood pressure were 0.8 mmHg systolic and 1.5 diastolic in men, and 1.9 and1.6 mmHg, respectively, in women. Total cholesterol, LDL cholesterol, andtriglyceride levels decreased by 5–8% inmenand 2–5% inwomen.Overall, 17.5%of subjects lost $5% of their body weight, 16.8% lost 2.5–4.9% weight, 46.1%maintained their baseline weight, and 19.6% gained$2.5% weight. The relativerisk of diabetes was 0.31 in the group who lost $5% weight, 0.72 in the groupwho lost 2.5– 4.9% weight, and 1.10 in the group who gained$2.5% comparedwith the group who maintained weight.

Australian Life! Taking Action on Diabetes program (78) Between 2007 and mid-2011, there were .14,800 referrals to the program, and.8,400 individuals started the program. Participants who attended the first 5sessions (offered every 2 weeks) lost amean 1.4 kg in weight and 2.5 cm in waistcircumference; those who also attended the sixth session (offered 8 monthsafter the first) lost a mean 2.4 kg in weight (2.7% weight) and 3.8 cm in waistcircumference, for an imputed potential diabetes risk reduction of 21–39%.

VA MOVE! Weight Management Program (68) Retrospective, observational analysis found a significant, dose-dependent, inverseassociation between incident diabetes and participation. Compared withnonparticipation, intense and sustained participation (at least eight sessions within6 months over at least a 4-month span) was associated with a 33% reduction indiabetes incidence, and lower-intensity participation yielded a 20% reduction indiabetes incidence. Those who participated intensively also lost more weight thanlow-intensity participants (–2.2 vs. –0.64%over 3 years). However, the programhasnot reached a substantial proportion of the eligible population; only 13%participated in at least one session between 2005 and 2012.

Special Diabetes Program for Indians–DiabetesPrevention (SPDI-DP) (126)

More than 2,500 participants started the 16-session program by 31 July 2008, withclinical assessments performed at baseline, soon after completing the program,and annually for up to 3 years. Crude incidence of diabetes was;3.5% per yearamong those who finished all 16 sessions, whereas it more than doubled (7.5%per year) among those who did not finish the program. Participants on averagelost 9.6 lb immediately after completing the program, representing a 4.4%weight loss. This attenuated over the three annual visits but still differedsignificantly from no weight loss. By the end of the program sessions, 22.5% ofparticipants had achieved the 7% weight loss goal; at the 3-year follow-up,17.5% had achieved this goal. The percentage of participants achieving the 150min/week exercise goal increased from 22% at baseline to 56% after theprogram and was $38% at each of the annual assessments. Participants alsohad significant improvements in blood glucose, blood pressure, and lipidparameters throughout the follow-up period.

DEPLOY (Diabetes Education & Prevention with a LifestyleIntervention Offered at the YMCA) pilot study (127,128)and YMCA Diabetes Prevention Program (129)

In the DEPLOY pilot study, body weight at 6 months decreased by a mean 5.7 kg or6.0% in intervention participants and 1.8 kg or 2.0% in control subjects; thisdifference persisted through 12 months, with no racial or sex differences. Also,significant between-group differences in total cholesterol levels at both follow-up points were observed. At 4 and 12 months, the intervention group hadsignificant decreases in 10-year coronary heart disease risk of 3.28 and 2.23%,respectively, comparedwith control subjects, who had a decrease in 10-year riskof 0.78% at 4 months and an increase in risk of 1.88% at 12 months.

As of December 2015, 39,435 individuals had attended at least one programsession at one of 202 YMCA centers in 43 states. The average weight loss amongparticipants was 4.7% at the end of the 16 sessions and 5.4% by 1 year. Onaverage, participants undertook 157.5 min/week of physical activity.

NDPP/Medicare/YMCA demonstration program (24) Throughthisprogram, fundedbyCMSunder theAffordableCareAct, eligibleMedicarebeneficiaries at high risk for diabetes attended initial weeklymeetings andmonthlyfollow-up sessions with a lifestyle coach to address long-term dietary and lifestylemodification to reduce their risk for diabetes.Meanweight loss was 4.7% for thosewhoattendedat least fourweekly sessions and5.2%for thosewhoattendedat leastnine sessions. More than 80% of recruited participants attended at least foursessions. When compared with similar Medicare beneficiaries not in the program,CMSestimateda savings of $2,650 for each enrollee over a 15-monthperiod,whichwas more than enough to cover the cost of the program.

1196 Diabetes Prevention Update and Future Directions Diabetes Care Volume 39, July 2016

program (78). Established in 2007 andbuilt in part on the Finnish experience, thisstatewide program has been implementedin a systematic approach featuring a struc-tured group intervention, standardizedfacilitator training and accreditation, afacilitator payment process linked to returnof data, a participant manual, a continuousquality improvement process, and ongoingevaluation. TheprogramusesanAustralianrisk tool to screen potential participantsand a multifaceted social marketing andcommunications plan to raise awarenessand facilitate recruitment.In Singapore, several initiatives have

been launched as part of the govern-ment’s Healthy LivingMaster Plan to en-courage the population in general, andindividuals with prediabetes specifically,to adopt lifestyle changes to reducetheir diabetes risk (135–138). A low-cost, nurse educator–led prediabetes in-tervention program offers participantsthree individual counseling sessions atcommunity centers or primary care clin-ics and telephone follow-up after 6, 9,and 12 months. OGTTs are performedafter 1 year to determine whether par-ticipants’ dysglycemia has improved. Inaddition, the Healthier Dining Pro-gramme encourages food and beveragecompanies to improve the nutritionalquality of their offerings, and the Work-place Health Programme encouragesand provides resources to Singaporeanemployers to provide an integrated ap-proach to workplace health.Israel recently launchedan innovativeap-

proach to prevention funded through a so-cial impact bond. Under this arrangement,private donors finance a 1-year intensiveintervention program in high-risk individu-als. Health maintenance organizations andthe Israeli National Insurance Institute willrepay donors their original investmentplus a dividend based on cost reductionsrealized through health improvements re-sulting from the program (139).In the U.S., numerous small DPP trans-

lational interventions have been imple-mented in diverse settings using a varietyof innovative formats (69–75). On a largerscale, the most promising programs todate have been implemented in the vet-eran population (68) and American Indian/Alaska Native (AI/AN) communities (126)and throughYMCAcenters throughout thecountry (129).The U.S. Department of Veterans Af-

fairs (VA) MOVE! Weight Management

Program (68) offers interactive educa-tion sessions on nutrition, physical activ-ity, self-management, and goal settingfor veterans who are overweight orobese and have a weight-related disor-der. Since 2005, .500,000 veteranshave participated, making MOVE! thelargest such program in the U.S.

The Special Diabetes Program for In-dians–Diabetes Prevention (SPDI-DP)(126) targets the AI/ANpopulation, whichhas the highest diabetes prevalence rateof any segment of the U.S. population (2).Since 2006, the SPDI-DP has tested thefeasibility and impact of an adapted DPPlifestyle intervention offered in nativecommunities that lack essential resourcesand have diverse health care settings andmobile populations, all of which posechallenges to recruitment, retention,and effectiveness. The program is beingoffered through 36 health care programsserving 80 AI/AN tribes in 18 states.

The YMCA Diabetes Prevention Pro-gram is based on DEPLOY (Diabetes Ed-ucation & Prevention with a LifestyleIntervention Offered at the YMCA), a2005–2010 pilot study of a DPP-type in-tervention adapted for community im-plementation through YMCAs (127). Theyear-long course is open to overweightadults whomeet glucose criteria for pre-diabetes, have had GDM, or have a highscore on a qualifying risk test. It providesgroup education and counseling withgoals of 5–7% weight loss and $150min/week of physical activity.

The YMCA program operates as part ofNDPP (23), which offers training for life-style coaches and a formal recognitionprocess for high-quality intervention pro-grams. NDPP has facilitated a partnershipbetween the YMCA and United HealthGroup through which the YMCA receivespay-for-performance reimbursement forthe program from insurers and privateemployers. NDPP is now working to ex-pand that partnership to include moreprograms and payers and to refine amar-keting strategy to increase referrals toand participation in lifestyle interventionprograms nationwide.

In 2011, the U.S. Centers forMedicare& Medicaid Services (CMS) awarded theNational Council of YMCAs of the USA$11.8 million to enroll eligible Medicarebeneficiaries at high risk for diabetes ina prevention program targeting weightloss of$5%. The results of this initiativeled to the recent independent findings

in support of the expansion of the NDPPmodel throughout the Medicare pro-gram (24).

NEXT STEPS

The programs described above have de-veloped innovative, pragmatic methodsof delivering lifestyle change interven-tions; many have made use of the latestinformation and communication tech-nologies; and each has involved the ac-tive cooperation of key stakeholders inthe medical community, nongovern-mental organizations, and public andprivate sector agencies. We are eagerlyawaiting reports of their outcomes andhope that the components deployedwillplay an important role in reducing theprevalence of a disease with such wide-ranging personal, societal, and eco-nomic consequences.

A logical early step in advancing pre-ventive strategies may be for the dia-betes medical community to reachconsensus on how to approach wide-spread translational programs that po-tentially can be implemented on a globallevel. Although lifestyle interventionsare effective, our sole reliance on peo-ple’s adherence to diet and physical ac-tivity recommendations will not beenough to delay progression for a largeportion of the at-risk population. Thus,attention also must be given to recom-mendations for pharmacological ther-apy to yield long-term societal benefitsin the area of type 2 diabetes preventionand reduction in diabetes complica-tions, including cardiovascular disease.Hence, in this Expert Forum, we alsodiscussed a possible alternative avenuefor FDA approval of a new preventionindication for metformin. Specifically,we developed a compelling argumentthat the evidence base for metforminalready may be substantial enough tosupport approval of such an indication.We readily admit that additional workwill be needed, and many hurdles re-main. Still, this is an exciting time fordiabetes prevention, and althoughreal-world translation is the next great-est hurdle, it also represents the biggestopportunity to stem the tide of theglobal diabetes pandemic.

Acknowledgments. Writing and editing sup-port services for this article were provided byDebbie Kendall of Kendall Editorial in Richmond,

care.diabetesjournals.org Cefalu and Associates 1197

VA. The Editorial Committee recognizes that theworkof the journal andcontributions suchas thisExpert Forumwould not be possible without thededicated work and continued support of manyindividuals. Specifically, the planning, logistics,and funding of the meeting and the incredibleeditorial support would not have been possiblewithout the tireless efforts of Chris Kohler andhis staff at the ADAPublishing office. In addition,the Editorial Committee thanks Lyn Reynoldsand her staff in the ADA editorial office forsupport and Anne Gooch at the PenningtonBiomedical Research Center for her valuableassistance in helping to organize the ExpertForum. W.T.C. is supported in part by NationalInstitutes of Health (NIH) grant 1U54-GM-104940, which funds the Louisiana Clinical andTranslational Science Center, and NIH grantP50-AT-002776.Duality of Interest. W.T.C. has served as prin-cipal investigator on clinical research grantsreceived by his institutions from AstraZeneca,Janssen, MannKind Corp., and Sanofi and hasserved as a consultant for Intarcia Therapeutics,Adocia, and Sanofi. J.B.B. has been an investigatorand/or consultant under contracts between hisemployer and the following companies: Adocia,Andromeda, Astellas, AstraZeneca, BoehringerIngelheim,Bristol-MyersSquibb,DanceBiopharm,Elcelyx, Eli Lilly and Co., F. Hoffman-La Roche, GIDynamics, GlaxoSmithKline, Halozyme, IntarciaTherapeutics, Johnson & Johnson, Lexicon,MacroGenics, Medtronic Minimed, Merck Sharp& Dohme, Metavention, Novo Nordisk, Orexigen,Osiris, Quest, Sanofi, Scion NeuroStim, Takeda,Tolerex, and vTv Therapeutics. He is a consultantto and has stock options from PhaseBio. J.T. hasreceived grant support from AstraZeneca,Boehringer Ingelheim, Merck Sharp & Dohme,Merck Serono, Regeneron, and Sanofi. He has re-ceived honoraria for speaking engagements fromAstraZeneca, Eli Lilly and Co., Novo Nordisk, andSanofi and consulting fees from AstraZeneca,Bayer Pharma, and Novo Nordisk. He is a stockshareholder of Orion Pharma. G.A.F. is a panelmember/consultant for Acosti, Adocia, Arisaph,Artemis, Bio-Cancer Treatment International Ltd.,Becton Dickinson, BioCon, Diasome, Dompe,Emperra, Exsulin, Thermo Fisher Scientific, Gilead,Hyperion, IMTherapeutics, Innoneo, Intarcia Ther-apeutics, Islet Sciences, Lexicon, Locemia, Johnson& Johnson, MannKind Corp., Mars, MediWound,Melior, N-Gene, NuSirt, Royalty Pharma, Pfizer,Rhythm, Sanofi, SkyePharma, Strongbridge Bio-pharma, SynAgile, Takeda, Teva, Thermalin, The-tis, ThromboGenics, Tolerion, VeroScience, andVersartis. He is a stock/shareholder of AmmonettPharma, Exsulin Corporation, Locemia, Innoneo,SynAgile, and Thetis. E.F. is an advisory boardmember for Boehringer Ingelheim/Eli Lilly andCo. and Merck Sharp & Dohme. He is a consul-tant for AstraZeneca, GlaxoSmithKline, and Jans-sen and a speaker for AstraZeneca, BoehringerIngelheim, Eli Lilly and Co., Merck Sharp &Dohme, Mitsubishi, Novo Nordisk, Sanofi, andTakeda. He receives research grant supportfrom Eli Lilly and Co. H.C.G. has received grantsupport from AstraZeneca, Eli Lilly and Co.,Merck Sharp & Dohme, and Sanofi; honorariafor speaking engagements from AstraZeneca,Berlin Chemie, Boehringer Ingelheim, NovoNordisk, and Sanofi; and consulting fees from

Abbott Pharmaceuticals, Amgen, AstraZeneca,Boehringer Ingelheim, Eli Lilly and Co., KaneqBioscience, Merck Sharp & Dohme, Novo Nor-disk, and Sanofi. A.R. is an advisory board mem-ber for AstraZeneca andMerck Sharp&Dohme. Hehas received honoraria for speaking engagementsfrom Bayer, Eli Lilly and Co., Merck Sharp &Dohme, Novartis, Novo Nordisk, and Sanofi.The India Diabetes Research Foundation, ofwhichhe is president, has received research funding sup-port fromAstraZeneca andNovartis. I.R. has servedon advisory boards for AstraZeneca/Bristol-MyersSquibb, Boehringer Ingelheim, Eli Lilly and Co., Lab-Style Innovations, Merck Sharp & Dohme, NovoNordisk, Orgenesis, Sanofi, and SmartZyme Innova-tion; has been a consultant for AstraZeneca/Bristol-Myers Squibb, FuturRx, Gili Medical, InsulineMedical, Kamada, and NephroGenex; hasbeen a speaker for AstraZeneca/Bristol-MyersSquibb, Boehringer Ingelheim, Eli Lilly and Co.,Johnson & Johnson, Merck Sharp & Dohme, No-vartis PharmaAG, NovoNordisk, Sanofi, and Teva;and is a stock/shareholder in Glucome, InsulineMedical, LabStyle Innovations, Orgenesis, andSmartZyme Innovation. J.R. has servedonadvisoryboards and received honoraria or consulting feesfrom AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly and Co.,Intarcia Therapeutics, Janssen, Merck Sharp &Dohme, Novo Nordisk, and Sanofi. He has receivedgrants/research support from Asahi, AstraZeneca,Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly andCo., GlaxoSmithKline, Hanmi, Intarcia Therapeu-tics, Janssen, Lexicon, MannKind Corp., MerckSharp & Dohme, Novo Nordisk, Pfizer, Sanofi,and Takeda. S.E.K. is a consultant/advisory boardmember for Boehringer Ingelheim, Elcelyx, Eli Lillyand Co., GlaxoSmithKline, Intarcia Therapeutics,Janssen, Merck Sharp & Dohme, Novo Nordisk,and Receptos and has received grant supportfrom Eli Lilly and Co. No other potential conflictsof interest relevant to this article were reported.

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