Prevention of Diabetes Mellitus in Subjects with Impaired Glucose Tolerance in the Finnish Diabetes Prevention Study: Results From a Randomized Clinical Trial
Jaana Lindström*,
Johan G. Eriksson*,
Timo T. Valle*,
Sirkka Aunola,
Zygimantas Cepaitis*,
Martti Hakumäki,
Helena Hämäläinen,
Pirjo Ilanne-Parikka,
Sirkka Keinänen-Kiukaanniemi¶,
Mauri Laakso**,
Anne Louheranta,
Marjo Mannelin**,
Vesa Martikkala*,
Vladislav Moltchanov**,
Merja Rastas,
Virpi Salminen,,
Jouko Sundvall,
Matti Uusitupa and
Jaakko Tuomilehto*,
*National Public Health Institute, Department of Epidemiology and Health Promotion, Diabetes and Genetic Epidemiology Unit, Helsinki; Social Insurance Institution, Research Department, Turku; University of Kuopio, Department of Clinical Nutrition, Kuopio; Finnish Diabetes Association, The Diabetes Centre, Tampere; ¶University of Oulu, Department of Public Health Science and General Practice, Oulu; **Oulu Deaconess Institute, Department of Sports Medicine, Oulu; Institute of Nursing and Health Care, Tampere; National Public Health Institute, Department of Health and Functional Capacity, Helsinki; and University of Helsinki, Department of Public Health, Helsinki, Finland.
Correspondence to Jaakko Tuomilehto, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland. Phone: 358-9-4744-8635; Fax: 358-9-4744-8338;
ABSTRACT. Type 2 diabetes mellitus is increasing worldwide largelyas a result from increasing obesity and sedentary lifestyle.The Finnish Diabetes Prevention Study (DPS) is the first individuallyrandomized controlled clinical trial to test the feasibilityand efficacy of lifestyle modification in high-risk subjects.We randomly assigned 522 (172 men, 350 women) middle-aged (meanage 55 yr), overweight (mean body mass index 31 kg/m2) subjectswith impaired glucose tolerance either to the lifestyle interventionor control group. Each subject in the intervention group receivedindividualized counseling aimed at reducing weight and intakeof total and saturated fat, and increasing intake of fiber andphysical activity. An oral glucose tolerance test was performedannually to detect incident cases of diabetes and to measurechanges in metabolic parameters. The mean (± SD) weightreduction from baseline to year 1 and to year 2, respectively,was 4.2 ± 5.1 kg and 3.5 ± 5.5 in the interventiongroup and 0.8 ± 3.7 kg and 0.8 ± 4.4 in the controlgroup (P < 0.001 between the groups). At the time of firstanalysis of the outcome data the mean duration of follow-upwas 3.2 yr. The risk of diabetes was reduced by 58% (P <0.001) in the intervention group compared with the control group.The reduction in the incidence of diabetes was directly associatedwith number and magnitude of lifestyle changes made. In conclusion,the DPS is the first controlled trial demonstrating that type2 diabetes can be prevented by changes in lifestyle in high-risksubjects. E-mail: jaakko.tuomilehto@ktl.fi
Type 2 diabetes (T2DM) results from the exposure to environmentalrisk factors in genetically predisposed subjects (1) and itsincidence is increasing worldwide. Although the genetic basisof T2DM diabetes has still to be identified, unequivocal evidenceshows that obesity and physical inactivity are the main environmentaldeterminants of the disease (2–9). Subjects with impairedglucose tolerance (IGT) have an increased risk for T2DM andcardiovascular complications of hyperglycemia (10), and thereforeform an important high-risk group for actions aimed at preventingdiabetes (2–5). Approximately 10 to 15% of the adult populationsin developed countries have IGT (2–5). Chronic hyperglycemiais a necessary condition for microvascular complications suchas nephropathy and retinopathy, but it has been recently shownthat hyperglycemia is also an independent risk factor for cardiovasculardisease (CVD). Once clinical symptoms of diabetes occur, thenatural history of the process leading to T2DM has progressedfar, and approximately 50% of the function of the pancreaticB cells has already been lost (2–5). This process is likelyto progress further, even when intensive anti-diabetic treatmentis applied. There is no doubt that the primary prevention ofT2DM would be the most powerful way to prevent the devastatingmultiple complications resulted from hyperglycemia in the majorityof T2DM patients. However, until recently no data existed fromcontrolled clinical trials to estimate the potential for preventionof T2DM. The Finnish Diabetes Prevention Study (DPS) is thefirst randomized controlled trial carried out to determine thefeasibility and effects of a lifestyle intervention programdesigned to prevent or delay the onset of T2DM in subjects withIGT (11). Recently, results from other studies on preventionof T2DM in IGT subjects have also been reported (12,13).
Design of the Finnish Diabetes Prevention Study
The design of the DPS has been described in detail elsewhere(11,14). Overweight subjects, i.e., body mass index (BMI) >25kg/m2 with IGT aged 40 to 65 yr, were eligible for the study.The study subjects were recruited through various methods. Peoplewho in earlier epidemiologic surveys had been found eligiblewere contacted. Subjects were also recruited through advertisingin local newspapers and by opportunistic population screeningswith special emphasis on the high risk groups such as obesesubjects and first-degree relatives of type 2 diabetic patients.
IGT was defined as a 2-h plasma glucose concentration of 140to 200 mg/dl in subjects whose fasting plasma glucose concentrationwas less than 140 mg/dl (15). The test was repeated after thefirst positive test and the mean of the two 2-h plasma glucosevalues had to be within the IGT range for inclusion into thestudy. Altogether, 522 subjects in five study centers were randomlyallocated to one of the two treatment groups.
The subjects in the control group were given general verbaland written diet and exercise information at baseline and atsubsequent annual visits but no specific individual tailoringwas performed.
The subjects in the intervention group were given detailed adviceabout how to achieve the intervention goals, which were reductionin weight of 5% or more, total fat intake less than 30% of energyconsumed, saturated fat intake less than 10% of energy consumed,fiber intake of 15 g/1000 kcal, and moderate exercise for 30min/d or more. Frequent ingestion of wholemeal products, vegetables,berries and fruit, low-fat milk and meat products, soft margarines,and vegetable oils rich in monounsaturated fatty acids wererecommended. The dietary advice was based on 3-d food recordscompleted four times per year. The subjects had seven sessionswith a nutritionist during the first year of the study and every3 mo thereafter. They were also individually guided to increasetheir level of physical activity. Endurance exercise (walking,jogging, swimming, aerobic ball games, skiing) was recommendedto increase aerobic capacity and cardiorespiratory fitness.Supervised, progressive, individually tailored circuit-typeresistance training sessions to improve the functional capacityand strength of the large muscle groups were also offered.
Assessment of the Endpoints
T2DM was the primary endpoint. It was defined according to theWorld Health Organization 1985 criteria (15), i.e., either afasting plasma glucose concentration over 140 mg/dl or 2-h post-challengeplasma glucose concentration 200 mg/dl. The diagnosisof diabetes had to be confirmed by a repeat OGTT; if the diagnosiswas not confirmed in the second test, the subject followed theprogram according to the original randomization. The independentEndpoint Committee confirmed all incident cases of diabetes.
Statistical Analysis
We estimated a cumulative incidence of T2DM of 35% in the studysubjects with IGT during a 6-yr period. The reduction in incidencein the intervention group compared with the control group wasassumed to be 35%. The DPS was designed to have 160 cases ofT2DM during the 6-yr study period. At a midpoint when 80 caseshad been accumulated, an interim analysis of the data by randomizationgroup was planned. An independent statistician completed thisanalysis, and, based on the results of this the Endpoint Committee,recommended that the trial be closed prematurely.
Survival curves were calculated to estimate the cumulative incidenceof diabetes. The difference in incidence of diabetes in thegroups was tested using the two-sided log-rank test. All analysesof endpoints were based on the intention-to-treat principle.To estimate how the incidence of diabetes was related to thetarget lifestyle changes, each intervention goal was graded(0 = not achieved, 1 = achieved) at the 1-yr visit and the "successscore" was computed as the sum of the grades.
At the time of study closure, 90% of the study subjects hadbeen in the trial for at least 2 yr, and the mean follow-uptime was 3.2 yr. The baseline characteristics of the two groupswere similar, demonstrating successful randomization (Table 1).During the first year, the mean (± SD) body weightdecreased by 4.2 ± 5.1 kg (4.7 ± 5.4%) in theintervention group and by 0.8 ± 3.7 kg (0.9 ±4.2%) in the control group (P < 0.001) (Table 2). Waist circumference,fasting plasma glucose, 2-h post-challenge plasma glucose, andserum insulin concentrations decreased significantly more inthe intervention group than in the control group. At 2 yr theweight reduction remained significantly greater in the interventiongroup (3.5 ± 5.5 kg) than in the control group (0.8 ±4.4 kg). Reductions in 2-h serum insulin, serum triglyceride,and BP were also significantly greater in the intervention groupthan in the control group.
Table 2. Changes in some clinical and metabolic variables during the interventiona
A total of 86 incident cases of diabetes were diagnosed; 27in the intervention group and 59 in the control group. The cumulativeincidence of diabetes was lower in the intervention group thanin the control group (Table 3). The difference was statisticallysignificant after only 2 yr, 6% in the intervention group (95%confidence interval (CI), 3 to 9%) and 14% in the control group(95% CI, 10 to 19%) and at 4 yr, 11% (95% CI, 6 to 15%) and23% (95% CI, 17 to 29%). Based on the Cox regression analysisusing all person-years accumulated, the cumulative incidencein the intervention group was 58% lower (hazard ratio 0.4; 95%CI, 0.3 to 0.7; P < 0.001) than in the control group. Inmen, the incidence of diabetes was reduced by 63% (95% CI, 18to 79%; P = 0.01) and in women by 54% (95% CI, 26 to 81%; P= 0.008).
Table 3. Cumulative incidence of diabetes during the lifestyle intervention in intervention and control groups
Success in achieving the intervention goals was estimated fromthe food records and exercise questionnaires collected at the1-yr examination (Table 4). The proportion of subjects in theintervention group who succeeded in achieving a specific goalvaried from 25% ("fiber intake") to 86% ("exercise"). The studysubjects were ranked according to their success in achievingthe five intervention targets (a "success score" from 0 to 5)at the 1-yr examination (Table 5). The association between thesuccess score and the risk of diabetes, including the 95% CI,was estimated using logistic regression analysis applied tothe observed data. There was a strong and graded inverse correlationbetween the "success score" and the incidence of diabetes. Ofthe subjects who did not achieve any of the targets, 38% and31% of the intervention and control groups, respectively developeddiabetes during follow-up. Of those who reached four or allfive targets (49 subjects in the intervention group and 15 subjectsin the control group), none developed diabetes.
The DPS has now provided direct and unequivocal evidence thatT2DM can be prevented by lifestyle intervention in middle-agedhigh-risk men and women. The 58% overall reduction in incidenceof T2DM was larger than expected. Nevertheless, the estimateof the effect of the intervention can be considered conservativefor two reasons. First, the results were analyzed using theintention-to-treat principle, although some subjects in theintervention group did not follow the recommendations aboutdiet and exercise. Second, due to ethical reasons, all subjectsallocated to the control group also received general healthadvice at baseline and at annual follow-up visits. Thus, subjectsin the control group may have benefited from the advice provided.More recently, the US Diabetes Prevention Program (DPP) wasalso stopped prematurely after an interim analysis that wascarried out after the publication of the results from the DPS.Interestingly, the reduction in the incidence of T2DM in theDPP was also 58% (13).
The results from previous Swedish (16) and Chinese (17) studiesalso suggested that a lifestyle intervention is efficient inpreventing diabetes, and the magnitude of the benefits was inthe same range as that observed in the DPS and DPP. In thesetwo studies, the subjects were not randomly assigned to theintervention and control groups. In the Chinese study (17),an attempt to determine whether an intervention of diet or exercisewas more effective revealed no difference in outcome betweenthe two interventions. We did not try to separate these interventions,but tried to achieve as large a lifestyle change as possibleon an individual basis.
The effect of the intervention on the incidence of diabeteswas most pronounced in those subjects who made multiple lifestylechanges and who managed to reach most of the lifestyle targets.On the other hand, inability to make any changes in lifestylewas associated with a 35% incidence of T2DM as predicted. Theaverage weight reduction achieved was modest yet the decreasein the incidence of diabetes in the intervention group was substantial.
Our physical exercise counseling included components that improveboth cardiorespiratory fitness and muscle strength. It is likelythat any type of physical activity, whether sports, householdwork, gardening, or occupational tasks, is similarly beneficialin preventing diabetes. Many subjects with impaired glucosetolerance are both obese and inactive and therefore the findingof a "dose-response" in correcting these multiple risk behaviorswould be expected.
The main justification for the prevention of T2DM in high-risksubjects is that it may prevent or postpone the onset of andcomplications related to T2DM, and it may decrease the costsof the treatment. Both asymptomatic and symptomatic diabeticpatients have an increased prevalence of both macrovascularand microvascular complications at the time of diagnosis ofdiabetes. Many also have an atherogenic serum lipid profileand hypertension (18–21). The lifestyle intervention inthe DPS not only improved glucose tolerance, but also reducedthe levels of several other cardiovascular risk factors. Itis commonly argued that it is difficult to change the lifestylein obese and sedentary people, but we think such a pessimismmay not be justified. The effect of the intervention was rapid:already after 2 yr of intervention the risk of T2DM had reducedsignificantly more in the intervention group compared with thecontrol group.
In conclusion, primary prevention of T2DM is possible by a nonpharmacologicintervention that can be implemented in a primary health caresetting. Based on our study, 22 subjects with impaired glucosetolerance need to be treated for 1 yr or five people for 5 yrwith a lifestyle intervention to prevent one case of diabetes.
Acknowledgments
This study was supported by the Finnish Academy (grants 8473/2298,40758/5767, 38387/54175), Ministry of Education, Novo NordiskFoundation, Yrjö Jahnsson Foundation, Juho Vainio Foundation,and Finnish Diabetes Research Foundation. We are indebted toOlli Heinonen, Katri Hemiö, Pirjo Härkönen, PiaHögström, Anja Ilmanen, Kaija Kettunen, Pirjo Lehto,Liisa Mikkola, Paula Nyholm, and Arja Putila for their skillfulassistance in performing the study; to Dr. Timo Lakka and Prof.Jukka T. Salonen for their expert advice concerning exerciseassessment; and to Prof. Marja-Riitta Taskinen and Prof. AnttiAro for their participation in the Endpoint Committee.
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Abstract
Introduction
200 mg/dl. The diagnosis of diabetes had to be confirmed by a repeat OGTT; if the diagnosis was not confirmed in the second test, the subject followed the program according to the original randomization. The independent Endpoint Committee confirmed all incident cases of diabetes. 
