Editorial
Primary prevention of type 2 diabetes by lifestyle intervention in primary care setting
Prevención de diabetes mellitus tipo 2 por intervenciones de estilo de vida en un ámbito de asistencia primaria
G.E. Umpierrez, Francisco J. Pasquel
Department of Medicine, Emory University, Atlanta, GA, United States
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Umpierrez, Francisco J. Pasquel" "autores" => array:2 [ 0 => array:3 [ "nombre" => "G.E." "apellidos" => "Umpierrez" "email" => array:1 [ 0 => "geumpie@emory.edu" ] ] 1 => array:2 [ "nombre" => "Francisco J." "apellidos" => "Pasquel" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Department of Medicine, Emory University, Atlanta, GA, United States" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Prevención de diabetes mellitus tipo 2 por intervenciones de estilo de vida en un ámbito de asistencia primaria" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The prevalence of diabetes around the world is alarmingly high and it is only growing. The World Health Organization estimates that 347 million people worldwide have diabetes and by 2030, that number is expected to rise to 552 million.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Many more people have prediabetes, a high-risk state for diabetes developing defined by blood glucose concentrations higher than normal, but lower than established diabetes thresholds.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Data from the population-based US National Health and Nutrition Examination Survey (NHANES) indicates that 35% of US adults older than 20 years and 50% of those older than 65 years had prediabetes, with an estimated 79 million adults with prediabetes.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Worldwide, the number of people with prediabetes is expected to reach 472 million by 2030.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> About 5–10% of people with prediabetes will reach the clinical criteria for diabetes every year, and as many as 70% of individuals with prediabetes will progress to diabetes during their lifespan.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Prediabetes is characterized by fasting and/or postprandial blood glucose concentrations higher than normal, but lower than established thresholds for diabetes. As per World Health Organization, people with prediabetes have impaired fasting glucose (IFG) if their fasting plasma glucose (FPG) concentration is between 6.1 and 7.0<span class="elsevierStyleHsp" style=""></span>mmol/L (110 and 126<span class="elsevierStyleHsp" style=""></span>mg/dL); and impaired glucose tolerance (IGT), if the FPG concentration is <7.0<span class="elsevierStyleHsp" style=""></span>mmol/L (126<span class="elsevierStyleHsp" style=""></span>mg/dL) and a 2<span class="elsevierStyleHsp" style=""></span>h post-load plasma glucose concentration ≥7.8 and <11.1<span class="elsevierStyleHsp" style=""></span>mmol/L (140 and 200<span class="elsevierStyleHsp" style=""></span>mg/dL), during a 75<span class="elsevierStyleHsp" style=""></span>g oral glucose tolerance test.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The American Diabetes Association (ADA) applies the same thresholds for IGT, but uses a lower cutoff value for IFG of 5.6–6.9<span class="elsevierStyleHsp" style=""></span>mmol/L (100–125<span class="elsevierStyleHsp" style=""></span>mg/dL). In addition, the ADA recently recommended the use of glycated hemoglobin A1c (HbA1c) with a value of 5.7–6.4% to identify this category for high diabetes risk.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Several lifestyle intervention studies based on diet and exercise have unequivocally shown that progression to diabetes is possible in high-risk individuals with prediabetes (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). These trials have shown to be effective in all ethnic groups and various social and cultural settings worldwide.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">The Swedish Malmo feasibility study<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">8</span></a> determined the effect of increased physical exercise and weight control as major intervention strategies to prevent or delay type 2 diabetes in 181 men with impaired glucose tolerance (IGT) and 79 non-randomized subjects with IGT, who received no specific diabetes prevention treatment. At the 5-year treatment follow-up, mean weight reduction was 2.0–3.3<span class="elsevierStyleHsp" style=""></span>kg in the intervention group, whereas there was an increase of 0.2–2<span class="elsevierStyleHsp" style=""></span>kg in control group. In the intervention group, glucose tolerance improved in 75.8% of cases and 10.6% developed diabetes during follow-up. In the non-intervention group, glucose tolerance worsened in 67.1%, and diabetes was found in 28.6%. The relative risk of diabetes development in intervention compared to control group was 0.37 (95% confidence interval of 0.20–0.68, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.003).<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">8</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The Chinese Da Qing Study,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">9</span></a> randomized people with IGT into one of four groups: exercise only, diet only, diet plus exercise, and no intervention (control group). The cumulative incidence of diabetes during 6 years was lower in the intervention groups compared with the control group (41% in the exercise group, 44% in the diet group, 46% in the diet plus exercise group, and 68% in the control group). A 20-year follow-up report of this trial reported that subjects in the diet and exercise groups continue to benefit having a similar risk reduction during the post intervention period.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">10</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The Finnish Diabetes Prevention Study (DPS)<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">11</span></a> randomized middle-aged overweight subjects with IGT to an intervention group of diet and exercise or to a control group. The goals of the lifestyle interventions were to achieve a >5% reduction in body weight, reduce all fat intake to <30% of energy consumption, and a program of moderate physical activity for >30<span class="elsevierStyleHsp" style=""></span>min/day. They reported that an intensive diet and exercise program was associated with a 58% reduction in the risk of developing type 2 diabetes. An extended follow-up observation of the DPS trial revealed that subjects in the intervention group continued to show a sustained reduction in the cumulative incidence of diabetes after a median of 7 years.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">12</span></a> The relative risk reduction during the total follow-up was 43%.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">12</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The U.S. Diabetes Prevention Program (DPP)<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">13</span></a> randomized 3234 adults with prediabetes to a standard lifestyle recommendations plus placebo or 850<span class="elsevierStyleHsp" style=""></span>mg metformin twice daily or to an intensive lifestyle modification program. The goal of the program was to achieve and maintain >7% reduction in body weight through a low-calorie, low fat diet plus physical activity of moderate intensity for at least 150<span class="elsevierStyleHsp" style=""></span>min/week. The lifestyle modification reduced the incidence of type 2 diabetes by 58%. The cumulative incidence of diabetes during the follow-up period was lower in the lifestyle intervention and metformin groups than in the placebo group, with incidence rates of 4.8, 7.8, and 11.0 cases per 100 person-years, respectively. The reduction in incidence can be translated to one case of diabetes prevented for every 7 individuals with IGT treated for 3 years in the lifestyle intervention group. During an extension follow-up of 10 years after completion of the trial, the Diabetes Prevention Program outcomes Study<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">14</span></a> reported continuous benefits with reduction in the cumulative incidence of type 2 diabetes incidence by 34% compared with the control group.</p><p id="par0050" class="elsevierStylePara elsevierViewall">A Japanese lifestyle intervention study in Tokyo randomized a total of 458 men with IGT to an intensive lifestyle intervention (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>102) and standard intervention group (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>356). The subjects were seen in an ordinary outpatient clinic.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">15</span></a> The cumulative 4-year incidence of diabetes was 9.3% in the control group, versus 3.0% in the intervention group, and the reduction in risk of diabetes was 67.4% (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001).</p><p id="par0055" class="elsevierStylePara elsevierViewall">The Indian Diabetes Prevention Program,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">16</span></a> randomized 531 individuals with IGT into four groups: metformin, lifestyle modification, both lifestyle modification and metformin, or a control group. The cumulative incidence of type 2 diabetes during the median follow-up period of 30 months was significantly lower in the lifestyle modification group (39%), the metformin group (41%), and the lifestyle modification plus metformin group (40%) compared with the control group (55%). The relative risk reduction was 28.5% with lifestyle modification (95% CI 20.5–37.3, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.018), 26.4% with metformin (95% CI 19.1–35.1, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.029) and 28.2% with lifestyle plus metformin (95% CI 20.3–37.0, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.022), as compared with the control group.</p><p id="par0060" class="elsevierStylePara elsevierViewall">More recently, Costa et al.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">17</span></a> reported the results of the DE-PLAN Project (Diabetes in Europe – Prevention using Lifestyle, Physical Activity and Nutritional intervention), a real-life primary care lifestyle intervention in preventing type 2 diabetes in a high-risk population in Catalonia. Patients were screened using the Finnish Diabetes Risk Score (FINDRISC) and a 2-hour oral glucose tolerance test (OGTT). The protocol consisted of two interventions standard care or intensive lifestyle intervention delivered individually or in groups. The intensive group intervention consisted of a 6<span class="elsevierStyleHsp" style=""></span>h educational program scheduled in two to four sessions with five to 15 participants, who also received specific training materials. Targets for lifestyle intervention included less than 30% of daily energy from fat, no more than 10% of energy from saturated fat, at least 3.6<span class="elsevierStyleHsp" style=""></span>g/1000<span class="elsevierStyleHsp" style=""></span>kJ (15<span class="elsevierStyleHsp" style=""></span>g/1000<span class="elsevierStyleHsp" style=""></span>kcal) of fiber, and at least 30<span class="elsevierStyleHsp" style=""></span>min/day of moderate physical activity to achieve a 3% weight reduction. Among patients allocated to standard care (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>219) and intensive intervention (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>333) groups, diabetes was diagnosed in 124 individuals: 63 (28.8%) in the standard care group and 61 (18.3%) in the intensive intervention group. During a 4.2-year median follow-up, the incidences of diabetes were 7.2 and 4.6 cases per 100 person-years, respectively (36.5% relative risk reduction). The number of participants needed to treat with intensive intervention for 4 years to reduce one case of diabetes was 9.5. The success was slighted lower than other lifestyle intervention trials; however, DE-PLAN was a real-life intervention conducted in a primary care setting.</p><p id="par0065" class="elsevierStylePara elsevierViewall">In this issue of the journal, Sagarra et al.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">18</span></a> reports an analysis cost-effectiveness of the DE-PLAN study. The median cost was 752€ in the group and 656€ in the individual intervention. After 4.2-year median follow-up, the 36.5% relative-risk-reduction with intensive intervention was associated with an incremental cost of 106€ per participant in the individual level and 10€ in the group-based compared to the standard intervention. The median cost per participant in the standard and lifestyle intensive intervention was 646€ and 686€, respectively. Thus, the cost of the intensive intervention was 40€ over the standard intervention (106€ for the group and 10€ for the individual intervention). The cost per case for each case of diabetes prevention was estimated to be 746€ and 108€ in the individual and group intervention, respectively, because the probability of developing diabetes was lower in the group intervention (28.9%) compared to individual intervention (34.4%).</p><p id="par0070" class="elsevierStylePara elsevierViewall">The cost of the intervention of the Spanish Trial was significant lower than the DPP study in the United States. Over 3 years, including the cost of identifying persons with IGT, the direct medical cost of the US DPP lifestyle intervention was $2919 per participant.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">19</span></a> The lifestyle intervention was more expensive in year 1 ($1399) than in year 2 ($679) or 3 ($702). Similarly, the cost was lower than the direct medical cost of about 2614€ spent in the Finish Diabetes prevention study.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">10</span></a> These studies demonstrate that lifestyle intervention programs aimed to prevent type 2 diabetes in populations at risk are cost effective.</p><p id="par0075" class="elsevierStylePara elsevierViewall">In summary, diabetes is projected to be one of the five leading causes of death in high-income countries by 2030 and one of the ten leading causes of death worldwide, which emphasizes the public health importance of reducing diabetes risk at the population level.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Lifestyle change is the cornerstone for diabetes prevention. The primary aim of lifestyle interventions is to prevent or delay development of type 2 diabetes by targeting obesity and physical inactivity, the two most important modifiable risk factors of diabetes development.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">11,13</span></a> The results of the American, Finish and Spanish preventive interventions indicate that intensive lifestyle interventions are successful in preventing the progression to diabetes in populations at risk, and such interventions are cost-effective.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">19</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">The fundamental question is how the results from these clinical trials can be translated to clinical settings in real life. Population strategies focusing on raising awareness of diabetes, screening high-risk individuals and implementing appropriate and cultural sensitive lifestyle interventions may reduce the risk of developing diabetes and its complications. A large-scale nationwide diabetes prevention program to be conducted in primary care setting, the National Program for the Prevention of Type 2 Diabetes (FIN-D2D), was recently implemented in Finland, and will cover a population of 1.5 million.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">20</span></a> The DE-PLAN Spanish trial clearly shows that safe and cost effective diabetes prevention programs can be successfully delivery by primary care professionals.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">LSI: lifestyle intervention based on diet and exercise; DPS: Diabetes Prevention Study; DPP, US: Diabetes Prevention Study, United States; IDPP-1: Indian Diabetes Prevention Program; DE-PLAN: Diabetes in Europe – Prevention using Lifestyle, Physical Activity and Nutritional intervention.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Type of intervention \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Participants, number \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Duration of intervention, years<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Risk reduction, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Total duration of follow-up, years* \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Risk reduction during follow-up, % \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Malmo, Sweden<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">8</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LSIControl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18179 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Da-Qing, China<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">9,10</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DietExerciseDiet & exerciseControl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">130141126133 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">314642 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DPS, Finland<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">11,12</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LSIControl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">265257 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DPP, US<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">13,14</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LSIMetforminPlacebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">107910731082 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5831 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Japanese Lifestyle Intervention Trial, Japan<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">15</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LSIControl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">102356 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">67.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IDPP, India<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">16</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LSIMetforminLSI & MetforminControl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">133133129136 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28.526.428.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DE-PLAN, Spain<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">17</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LSIControl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">333219 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 4 | 0 | 4 |
| 2024 Octubre | 19 | 12 | 31 |
| 2024 Septiembre | 27 | 2 | 29 |
| 2024 Agosto | 21 | 6 | 27 |
| 2024 Julio | 20 | 3 | 23 |
| 2024 Junio | 11 | 1 | 12 |
| 2024 Mayo | 21 | 1 | 22 |
| 2024 Abril | 12 | 9 | 21 |
| 2024 Marzo | 18 | 6 | 24 |
| 2024 Febrero | 13 | 0 | 13 |
| 2024 Enero | 15 | 4 | 19 |
| 2023 Diciembre | 11 | 1 | 12 |
| 2023 Noviembre | 15 | 3 | 18 |
| 2023 Octubre | 9 | 10 | 19 |
| 2023 Septiembre | 10 | 2 | 12 |
| 2023 Agosto | 10 | 6 | 16 |
| 2023 Julio | 11 | 9 | 20 |
| 2023 Junio | 13 | 2 | 15 |
| 2023 Mayo | 12 | 18 | 30 |
| 2023 Abril | 11 | 12 | 23 |
| 2023 Marzo | 17 | 14 | 31 |
| 2023 Febrero | 7 | 7 | 14 |
| 2023 Enero | 9 | 4 | 13 |
| 2022 Diciembre | 11 | 2 | 13 |
| 2022 Noviembre | 13 | 5 | 18 |
| 2022 Octubre | 12 | 4 | 16 |
| 2022 Septiembre | 9 | 5 | 14 |
| 2022 Agosto | 12 | 10 | 22 |
| 2022 Julio | 22 | 11 | 33 |
| 2022 Junio | 7 | 3 | 10 |
| 2022 Mayo | 13 | 3 | 16 |
| 2022 Abril | 11 | 10 | 21 |
| 2022 Marzo | 17 | 8 | 25 |
| 2022 Febrero | 8 | 9 | 17 |
| 2022 Enero | 10 | 0 | 10 |
| 2021 Diciembre | 6 | 1 | 7 |
| 2021 Noviembre | 4 | 2 | 6 |
| 2021 Octubre | 0 | 5 | 5 |
| 2021 Septiembre | 0 | 6 | 6 |
| 2021 Agosto | 0 | 10 | 10 |
| 2021 Julio | 0 | 8 | 8 |
| 2021 Junio | 0 | 9 | 9 |
| 2021 Mayo | 0 | 6 | 6 |
| 2021 Abril | 0 | 7 | 7 |
| 2021 Marzo | 0 | 14 | 14 |
| 2021 Febrero | 0 | 3 | 3 |
| 2021 Enero | 0 | 7 | 7 |
| 2020 Noviembre | 0 | 4 | 4 |
| 2020 Octubre | 0 | 1 | 1 |
| 2020 Agosto | 0 | 3 | 3 |
| 2020 Julio | 0 | 1 | 1 |
| 2020 Junio | 0 | 2 | 2 |
| 2020 Mayo | 0 | 4 | 4 |
| 2020 Abril | 0 | 2 | 2 |
| 2020 Marzo | 0 | 6 | 6 |
| 2020 Febrero | 0 | 5 | 5 |
| 2020 Enero | 0 | 1 | 1 |
| 2019 Diciembre | 0 | 2 | 2 |
| 2019 Octubre | 0 | 3 | 3 |
| 2019 Septiembre | 0 | 6 | 6 |
| 2019 Agosto | 0 | 6 | 6 |
| 2019 Julio | 0 | 2 | 2 |
| 2019 Junio | 1 | 9 | 10 |
| 2019 Mayo | 0 | 12 | 12 |
| 2019 Abril | 0 | 20 | 20 |
| 2019 Febrero | 0 | 5 | 5 |
| 2019 Enero | 0 | 1 | 1 |
| 2018 Diciembre | 0 | 6 | 6 |
| 2018 Noviembre | 0 | 5 | 5 |
| 2018 Agosto | 0 | 1 | 1 |
| 2018 Julio | 0 | 5 | 5 |
| 2018 Junio | 0 | 1 | 1 |
| 2018 Marzo | 4 | 0 | 4 |
| 2018 Febrero | 117 | 5 | 122 |
| 2018 Enero | 31 | 8 | 39 |
| 2017 Diciembre | 89 | 11 | 100 |
| 2017 Noviembre | 33 | 13 | 46 |
| 2017 Octubre | 33 | 7 | 40 |
| 2017 Septiembre | 31 | 15 | 46 |
| 2017 Agosto | 12 | 15 | 27 |
| 2017 Julio | 25 | 12 | 37 |
| 2017 Junio | 25 | 12 | 37 |
| 2017 Mayo | 33 | 6 | 39 |
| 2017 Abril | 46 | 4 | 50 |
| 2017 Marzo | 50 | 60 | 110 |
| 2017 Febrero | 40 | 17 | 57 |
| 2017 Enero | 36 | 10 | 46 |
| 2016 Diciembre | 28 | 12 | 40 |
| 2016 Noviembre | 18 | 12 | 30 |
| 2016 Octubre | 30 | 13 | 43 |
| 2016 Septiembre | 16 | 6 | 22 |
| 2016 Agosto | 21 | 7 | 28 |
| 2016 Julio | 13 | 4 | 17 |
| 2016 Junio | 1 | 10 | 11 |
| 2016 Mayo | 1 | 6 | 7 |
| 2016 Abril | 0 | 4 | 4 |
| 2016 Marzo | 0 | 8 | 8 |
| 2016 Febrero | 0 | 9 | 9 |
| 2016 Enero | 0 | 1 | 1 |
| 2015 Diciembre | 0 | 8 | 8 |
| 2015 Noviembre | 0 | 4 | 4 |
| 2015 Septiembre | 0 | 1 | 1 |
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