Update on postprandial hyperglycemia: The pathophysiology, prevalence, consequences and implications of treating diabetes

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(1) Valorar añadir metformina, si no la tomaba previamente, y no existe contraindicación. (2) Preferencia por arGLP-1 si IMC >30kg/m2. (3) Empagliflozina y canagliflozina pueden usarse a dosis bajas (10 y 100mg respectivamente) hasta FGe de 45ml/min; dapagliflozina 10mg puede usarse hasta FGe de 60ml/min. (4) Liraglutide y dulaglutide pueden usarse hasta FGe de 15ml/min; lixisenatide hasta 30ml/min y exenatide LAR hasta 50ml/min. (5) iDPP4: sitagliptina, saxagliptina y alogliptina son seguros desde el punto de vista CV; saxagliptina aumenta el riesgo de IC, y alogliptina tiene una tendencia no significativa a aumentarla; iSGLT2: empagliflozina y canagliflozina han demostrado beneficio cardiovascular (MACE) y disminución de la hospitalización por insuficiencia cardiaca; arGLP1: liraglutide ha demostrado beneficio cardiovascular (MACE), lixisenatide y exenatide LAR son neutros; insulinas: glargina y degludec son seguras desde el punto de vista cardiovascular. Degludec ha demostrado frente a glargina U100 descenso de hipoglucemias graves en pacientes de alto riesgo cardiovascular. ADOs: antidiabéticos orales; IMC: índice de masa corporal; IR: insuficiencia renal; MACE: mace adverse cardiovascular events." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "P.J. Pinés Corrales, V. Bellido Castañeda, F.J. Ampudia-Blasco" "autores" => array:3 [ 0 => array:2 [ "nombre" => "P.J." "apellidos" => "Pinés Corrales" ] 1 => array:2 [ "nombre" => "V." "apellidos" => "Bellido Castañeda" ] 2 => array:2 [ "nombre" => "F.J." 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Modified from Monnier et al.<a class="elsevierStyleCrossRef" href="#bib0460">3</a>" ] ] ] "textoCompleto" => "BackgroundIncreased postprandial blood glucose (PBG) is the first detectable abnormality in glycemic control. Subsequently, the increase in fasting blood glucose, in PBG and/or in glycated hemoglobin (HbA1c) leads to the diagnosis of diabetes. Controlling PBG is relevant for achieving the therapeutic objectives of treating diabetes. Treatment for type 2 diabetes mellitus (DM2) is started with nutritional therapy, increasing physical activity and, generally, administering metformin.When the disease progresses, we need to use various combinations of oral drugs and/or glucagon-like peptide-1 receptor agonists (GLP-1 RA) and, lastly, basal insulin. In this situation, when appropriate titration of basal insulin does not achieve an appropriate HbA1c level, the postprandial hyperglycemia will need to be assessed and reduced.This document is not a systematic review of postprandial hyperglycemia but rather seeks to impart to clinicians the concept of postprandial hyperglycemia, reflecting on its causes, assessment, prevalence, consequences, and the specific therapeutic strategies for its proper control.Pathophysiology of baseline and postprandial hyperglycemiaIn healthy individuals, insulin and glucagon secretion occurs in a synchronized and inverted manner, which allows the body to maintain stable plasma glucose levels during the interprandial period. Soon after food is consumed, insulin secretion is increased, which suppresses glucagon secretion and, with it, its stimulus on the hepatic production of glucose. This increase in plasma insulin levels also stimulates glucose uptake by the peripheral tissues, thereby preventing the PBG from increasing above 140mg/dL, maintaining a stable blood glucose within a narrow range. However, in prediabetic conditions and in the initial phases of DM2, there is a loss of the initial phase of insulin secretion after the intake, which results in postprandial hyperglycemia. The progressive nature of DM2 results in a loss over time of fasting blood glucose control (baseline hyperglycemia).<a class="elsevierStyleCrossRefs" href="#bib0450">1,2</a>Baseline and postprandial hyperglycemia contribute, to a greater or lesser extent, to the total hyperglycemic burden. The classic study by Monnier et al. revealed that the greater relative contribution of postprandial hyperglycemia occurs with HbA1c values close to the objective (up to 70% with HbA1c values less than 7.3%), with baseline hyperglycemia, conversely, of greater relevance with higher HbA1c values (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0460">3</a> A subsequent study by the same group showed that, in patients with HbA1c levels <8%, postprandial hyperglycemia after breakfast was primarily responsible for the increase in HbA1c levels.<a class="elsevierStyleCrossRef" href="#bib0465">4</a> Likewise, a recently published meta-analysis confirmed that HbA1c values showed a greater association with postprandial blood glucose levels than with fasting blood glucose levels and that the reduction in postprandial hyperglycemia was associated with a greater reduction in HbA1c levels than the reduction in baseline hyperglycemia.<a class="elsevierStyleCrossRef" href="#bib0470">5</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Lastly, achieving fasting blood glucose objectives does not always enable us to reach the HbA1c objectives.<a class="elsevierStyleCrossRef" href="#bib0475">6</a> Between 24% and 54% of patients with DM2 who start treatment with basal insulin do not achieve the HbA1c objectives.<a class="elsevierStyleCrossRef" href="#bib0480">7</a>Postprandial hyperglycemia and oxidative stressPostprandial hyperglycemia is associated with greater glycemic variability, and it has been suggested that hyperglycemic fluctuations can contribute to the development of chronic diabetes complications.<a class="elsevierStyleCrossRef" href="#bib0485">8</a> Oxidative stress and increased superoxide anion production in the mitochondria in hyperglycemia is known to contribute to the development of chronic diabetes complications.<a class="elsevierStyleCrossRef" href="#bib0490">9</a>The issue is whether hyperglycemic fluctuations are more deleterious than the hyperglycemia itself. It has been shown that postprandial hyperglycemic fluctuations affect oxidative stress more than sustained hyperglycemia<a class="elsevierStyleCrossRef" href="#bib0495">10</a> and the association between increased oxidative stress and proinflammatory cytokines during hyperglycemic crises.<a class="elsevierStyleCrossRef" href="#bib0500">11</a> Other authors have reported that the impact of hyperglycemia on endothelial cell apoptosis is more pronounced in cells exposed to intermittent hyperglycemia.<a class="elsevierStyleCrossRefs" href="#bib0505">12,13</a> Studies have also confirmed the impact of postprandial hyperglycemia on the plasma levels of various adhesion molecules, such as the intracellular adhesion molecule, vascular adhesion molecule and E-Selectin, and these changes have been related to the risk of cardiovascular disease (CVD).<a class="elsevierStyleCrossRef" href="#bib0515">14</a> In summary, there is sufficient experimental evidence to relate hyperglycemic fluctuations with oxidative stress, inflammation markers, endothelial dysfunction and the increase in adhesion molecules.There also appears to be a relationship between postprandial hyperglycemia and increased indirect clinical markers of atherosclerosis such as the carotid intima-media thickness (IMT). Various authors have observed that hyperglycemia after an oral glucose tolerance test (OGTT) is associated with increased IMT in healthy individuals with a family history of diabetes.<a class="elsevierStyleCrossRef" href="#bib0520">15</a> Furthermore, in patients with DM2, there is a relationship between hyperglycemic fluctuations 1h after eating and IMT.<a class="elsevierStyleCrossRef" href="#bib0525">16</a>Measuring postprandial hyperglycemiaGlycemic control is currently assessed by measuring HbA1c levels, which reflect the mean plasma glucose level for the last 8–12 weeks.<a class="elsevierStyleCrossRef" href="#bib0530">17</a> HbA1c levels are also a predictor of the risk of developing diabetes-associated complications and reducing HbA1c levels is considered necessary to reduce the risk of the onset/progression of complications, both in type 1 diabetes mellitus (DM1) and DM2.<a class="elsevierStyleCrossRefs" href="#bib0535">18–23</a>However, HbA1c levels do not provide information on blood glucose fluctuations, which occur throughout the day and at the same time on different days (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>) and are known as glycemic variability. The presence of these hyperglycemic peaks and hypoglycemic troughs could explain the contradictory results regarding the cardiovascular benefit with reducing HbA1c levels.<a class="elsevierStyleCrossRefs" href="#bib0895">24,25,26</a> For a proper assessment of glycemic variability and postprandial hyperglycemia, outpatient capillary blood glucose monitoring (OBGM) or continuous blood glucose monitoring (CBGM) is needed. CBGM systems help continuously control glucose levels in the interstitial fluid, offering the possibility of improving glycemic control by increasing the time that the patient spends in the interval objective. There is also a hybrid system called Flash that helps clinicians determine the interstitial glucose value and its increasing or decreasing tendency when the sensor is read with a device. A considerable variety of methods to assess glycemic variability have been described: standard deviation (SD), coefficient of variation (CoV), mean amplitude of glycemic excursion (MAGE) and the mean of daily differences in blood glucose at the same time on different days, among many others. However, some of the measures require that the patient use CBGM (which is not always available, especially for patients with DM2), and there is no consensus on which method to use. The reason for this lack of consensus is that the various methods assess different aspects. Therefore, the method employed cannot be applied to all patients, and, in many cases, several methods need to be applied to obtain complete information.<a class="elsevierStyleCrossRef" href="#bib0575">27</a><elsevierMultimedia ident="fig0010"></elsevierMultimedia>To assess postprandial hyperglycemia, an OBGM needs to be performed between 90 and 120 and/or 180min after the consumption of food, but there is no consensus on the type of consumption that should be done or on the control objectives. The International Diabetes Federation defines postprandial hyperglycemia as values >160mg/dL 1–2h postmeal,<a class="elsevierStyleCrossRef" href="#bib0580">28</a> while the American Association of Clinical Endocrinologists and the American College of Endocrinology uses the value of 140mg/d.<a class="elsevierStyleCrossRef" href="#bib0585">29</a> The American Diabetes Association defined a glucose objective <180mg/dL 2h postmeal.<a class="elsevierStyleCrossRef" href="#bib0590">30</a>If our objective is to determine the degree of glycemic fluctuation during the day, we need at least 7-point OBGM (3 premeal, 3 postmeal and 1 prior to sleep) or CBGM profiles for several days.<a class="elsevierStyleCrossRef" href="#bib0595">31</a> The analysis helps obtain a mean (and SD) blood glucose value that will be our first approximation to the glycemic variability. The limitation of the SD is that it depends on the mean blood glucose value and is higher with higher mean values. We also assume a normal distribution, which is not usually the case.A method for improving some of the limitations of SD is the CoV calculation ([SD/mean]×100).<a class="elsevierStyleCrossRef" href="#bib0585">29</a> The CoV helps assess the need for therapeutic changes and assess their results (a CoV value >36% would be indicative of unstable blood glucose levels).<a class="elsevierStyleCrossRef" href="#bib0600">32</a> MAGE, another glycemic assessment method, represents the mean differences between consecutive hyperglycemia and hypoglycemia peaks. To calculate MAGE, hourly values are needed for 48h. Lastly, if the objective of the assessment is to determine glycemic variability at the same time on different days, the mean of daily differences can be employed, which indicates the mean of the absolute differences between glucose values at the same time on consecutive days. Another easier approximation consists of calculating CoV based on the mean and SD of the values obtained over several days at the same time of day. The calculation based on the first OBGM check performed during the day after the night-time fasting is especially useful.<a class="elsevierStyleCrossRefs" href="#bib0605">33,34</a>In summary, appropriate and tailored recommendations as to when to perform OBGM or CBGM and the regular downloading of data and their correct interpretation are essential to assessing the quality of the glycemic control and variability and to performing appropriate therapeutic adjustments.Consequences of postprandial hyperglycemia: glycemic variability and risk of hypoglycemiaThe concept of glycemic variability includes glycemic fluctuations that occur throughout the day and glycemic variations that occur at the same time on different days. A classic study, based on OBGM data from patients with DM1, revealed that the presence of mild hypoglycemia and glycemic variability were better predictors of the risk of severe hypoglycemia than HbA1c levels. An analysis based on data from the Diabetes Control and Complications Trial also confirmed that the mean and SD of OBGM values enabled a better calculation of the risk of severe hypoglycemia than HbA1c levels in isolation.<a class="elsevierStyleCrossRef" href="#bib0615">35</a>The HbA1c level has an adequate correlation with the mean blood glucose level but offers no information on the glycemic fluctuations throughout the day and between different days. Thus, a patient with fasting blood glucose levels within the objectives can present inadequate HbA1c levels secondary to the presence of postprandial hyperglycemia. Moreover, any HbA1c level can be associated with the continuous presence of marked hyperglycemia and hypoglycemia because a single HbA1c value associated with increased glycemic variability would imply an increased percentage of blood glucose values measured in hyperglycemia and in hypoglycemia.The Verona Diabetes Study of patients with DM2 observed that CoV, calculated with fasting plasma glucose values, was an independent predictor of mortality.<a class="elsevierStyleCrossRef" href="#bib0620">36</a> Another study conducted with patients with DM2 also observed that OBGM data was more useful in predicting the risk of severe hypoglycemia than isolated HbA1c values.<a class="elsevierStyleCrossRef" href="#bib0625">37</a> Jin et al. indicated that greater glycemic variability in patients with DM1 and DM2 could be associated with the type of treatment employed (premixed insulins) and to the patient's characteristics, such as residual insulin secretion.<a class="elsevierStyleCrossRef" href="#bib0630">38</a>A recently published secondary analysis of the DEVOTE study data assessed the relationship between glycemic variability and the risk of severe hypoglycemia. The study analyzed the SD based on 3 consecutive OBGM checks, performed before breakfast every month during the study (glycemic variability at the same time of day between different days), revealing a relationship between glycemic variability (before breakfast) and the risk of severe hypoglycemia (HR, 4.11; 95% CI 3.15–5.35).<a class="elsevierStyleCrossRef" href="#bib0635">39</a>In summary, an appropriate download and analysis of OBGM and CBGM data (in search of excessive glycemic variability and unintentional hypoglycemia and hyperglycemia) helps detect patients at a greater risk of severe hypoglycemia and thereby helps establish preventive therapeutic strategies to reduce the risk of these conditions.Prevalence of postprandial hyperglycemiaPostprandial hyperglycemia is frequent, even when the metabolic control is apparently appropriate according to the HbA1c value. However, determining the actual prevalence of postprandial hyperglycemia is difficult because there are few studies that have evaluated this condition and there is no consensus on its definition. A study that assessed the capillary blood glucose profiles of patients with DM2 untreated with insulin observed postprandial hyperglycemia in 84% of the patients.<a class="elsevierStyleCrossRef" href="#bib0640">40</a> The TranSTAR study, conducted with patients with DM2 in Spain, observed poor glycemic control (according to postprandial blood glucose levels) in 88.4% of the patients.<a class="elsevierStyleCrossRef" href="#bib0645">41</a> Studies conducted with CBGM showed similar results for patients with DM1.<a class="elsevierStyleCrossRef" href="#bib0650">42</a> A recently published survey of patients with DM1 and DM2 undergoing treatment with insulin found that 61.9% of the patients reported experiencing postprandial hyperglycemia in the previous week.<a class="elsevierStyleCrossRef" href="#bib0655">43</a> Twenty-four percent to 54% of patients with DM2 undergoing treatment with basal insulin do not achieve the HbA1c objective, despite achieving appropriate fasting blood glucose levels, which indicates poor control caused by postprandial hyperglycemia.<a class="elsevierStyleCrossRef" href="#bib0480">7</a>The results of these studies demonstrate that postprandial hyperglycemia is a frequent metabolic disorder in individuals with diabetes and that often goes unnoticed due to its limited monitoring. A greater use of CBGM systems, including flash glucose monitoring, could facilitate the detection of postprandial hyperglycemia.Consequences of postprandial hyperglycemia: associated mortality and cardiovascular diseaseThe definition of PBG objectives is backed by the fact that postprandial hyperglycemia can play an important role in the development of macrovascular complications.Epidemiological evidence of postprandial hyperglycemia and mortality (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>)The Honolulu Heart Program observed a linear relationship between blood glucose values after the OGTT and CVD, regardless of other cardiovascular risk factors.<a class="elsevierStyleCrossRef" href="#bib0660">44</a> The Diabetes Intervention Study studied the risk factors associated with coronary artery disease and mortality in individuals recently diagnosed with DM2, confirming the relationship between postprandial hyperglycemia and the risk of death.<a class="elsevierStyleCrossRef" href="#bib0665">45</a> The Chicago Heart Association Detection Project in Industry Study confirmed the relationship between mortality and the presence of hyperglycemia after OGTT in asymptomatic individuals.<a class="elsevierStyleCrossRef" href="#bib0670">46</a> Other studies such as the Whitehall Study, the Paris Prospective Study and the Helsinki Policemen Study also verified the relationship between hyperglycemia after OGTT and mortality.<a class="elsevierStyleCrossRef" href="#bib0675">47</a> The Hoorn Study reaffirmed the relationship between postprandial hyperglycemia and mortality.<a class="elsevierStyleCrossRef" href="#bib0680">48</a> Lastly, the DECODE Study established that the implementation of the OGTT can provide additional information to that provided by fasting glucose levels by identifying patients with a greater mortality risk.<a class="elsevierStyleCrossRef" href="#bib0685">49</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The Baltimore Longitudinal Study of Aging strengthened the predictive value of OGTT over fasting glucose readings,<a class="elsevierStyleCrossRef" href="#bib0690">50</a> and the San Luigi Gonzaga Diabetes Study observed that postprandial blood glucose was, along with HbA1c, an independent risk factor for developing CVD and for all-cause mortality.<a class="elsevierStyleCrossRef" href="#bib0695">51</a>Lastly, a study conducted in a Chinese population also verified a closer relationship between CVD and postprandial blood glucose levels than between CVD and fasting blood glucose levels.<a class="elsevierStyleCrossRef" href="#bib0700">52</a>In summary, the various analyzed epidemiological studies agree that postprandial hyperglycemia is an independent risk factor of CVD and of mortality for healthy individuals and patients with diabetes.<a class="elsevierStyleCrossRefs" href="#bib0705">53,54</a>Intervention studies on postprandial hyperglycemia (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>)The Acarbose for the Prevention of Type 2 Diabetes Mellitus (STOP-NIDDM) trial showed that, for individuals with impaired glucose tolerance, treatment with acarbose is associated with a reduction in cardiovascular events, particularly silent acute myocardial infarction (AMI).<a class="elsevierStyleCrossRef" href="#bib0715">55</a> These results agree with a subsequent meta-analysis performed on 7 randomized, double-blind, placebo-controlled trials in which treatment with acarbose was associated with a reduction in the risk of AMI and CVD in patients with DM2.<a class="elsevierStyleCrossRef" href="#bib0720">56</a> However, the results of the Acarbose Cardiovascular Evaluation study showed no benefit in the treatment with acarbose in a population with CVD and impaired glucose tolerance.<a class="elsevierStyleCrossRef" href="#bib0725">57</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>The Effects of Prandial Versus Fasting Glycemia on Cardiovascular Outcomes in Type 2 Diabetes (HEART2D) study was designed to compare the effects of the preferential control of baseline hyperglycemia (using 2 doses of neutral protamine Hagedorn insulin or one dose of insulin glargine) versus postprandial control (using 3 doses of insulin lispro) in patients with DM2 in the 3 weeks following an AMI. The study was suspended at 2.7 years due to a lack of objective differences between the 2 treatments. However, the difference in postprandial blood glucose levels at the end of the study between the groups was only 14mg/dL, too low a reading to affect the primary cardiovascular objective.<a class="elsevierStyleCrossRef" href="#bib0730">58</a> The Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study showed no benefit with nateglinide versus placebo in reducing CVD in individuals with impaired glucose tolerance.<a class="elsevierStyleCrossRef" href="#bib0735">59</a>Other intervention studies have acted on indirect clinical markers of CVD such as IMT. Esposito et al. showed a significant reduction in IMT in more patients when using repaglinide than with glibenclamide.<a class="elsevierStyleCrossRef" href="#bib0740">60</a> Hanefeld et al. also demonstrated less IMT progression with acarbose than with placebo in patients with carbohydrate intolerance.<a class="elsevierStyleCrossRef" href="#bib0745">61</a> The use of rapid-acting insulin analogs (lispro and aspart) versus regular insulin appears to produce a benefit in the surrogate biochemical markers of CVD (increase in nitrotyrosine and in methylglyoxal and 3-deoxyglucosone), and this benefit appears to be related with better postprandial control.<a class="elsevierStyleCrossRefs" href="#bib0750">62,63</a>In summary, despite the experimental basis described and the evidence of epidemiological studies that show the association between CVD and postprandial hyperglycemia, the intervention studies have not managed to uniformly and definitively demonstrate a cardiovascular benefit for the treatments directed at controlling PBG. This lack of apparent benefit could be due to various factors: (1) the drug used in the NAVIGATOR study was an insulin secretor (the active treatment branch had greater progression to diabetes and more hypoglycemia), and the results are probably not applicable to drugs with other mechanisms of action. (2) The HEART2D study failed to achieve the difference specified in the study's design in postprandial control between the 2 treatment branches and could therefore find no benefits. (3) The potential cardiovascular benefits observed in the STOP-NIDDM study could not be confirmed when conducting the Acarbose Cardiovascular Evaluation study; however, there were significant differences between the 2 studies (different ethnic groups, patient ages and different acarbose dosages), which could explain this difference.Therapeutic strategies for reducing postprandial hyperglycemia versus baseline hyperglycemiaIndividual management of diabetes is currently recommended.<a class="elsevierStyleCrossRef" href="#bib0760">64</a> In general, the recommendation is to keep HbA1c levels <7%, if this can be reached safely and without hypoglycemic events.<a class="elsevierStyleCrossRef" href="#bib0590">30</a> This review has confirmed that baseline hyperglycemia and postprandial hyperglycemia contribute to impaired glycemic control. The importance of postprandial hyperglycemia becomes more apparent when treatment with a basal insulin is intensified, with HbA1c values remaining above the control objectives despite titrating the insulin dosage.This information is relevant when selecting the treatment, given that its effect on postprandial control can be different (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). A treatment or combination of treatments should be chosen based on each patient's needs and characteristics.<a class="elsevierStyleCrossRef" href="#bib0765">65</a> The main therapeutic strategies for controlling postprandial hyperglycemia are described below.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Carbohydrates in the dietStudies that have evaluated the ideal quantity of carbohydrates for individuals with diabetes have not been conclusive. The glycemic index (GI) categorizes food by its capacity to increase blood glucose levels, measuring the relationship between the area under the curve of the postprandial glycemic response produced by the ingestion of 50g of carbohydrates supplied by a specific food and a food pattern (glucose or white bread) and multiplied by 100 (considering that the GI is low if ≤55, medium if 56–69 and high if ≥70). The glycemic load is the product of GI and the carbohydrate content of a standard portion of food. Studies have observed that lowering the glycemic load can reduce HbA1c levels between 0.2% and 0.5%.<a class="elsevierStyleCrossRefs" href="#bib0770">66,67</a> The consumption of carbohydrates based on whole grain cereals, vegetables, fruits, legumes and milk products is therefore recommended.<a class="elsevierStyleCrossRef" href="#bib0590">30</a>GlinidesRepaglinide is a rapid-acting secretagogue that can serve as an alternative to sulfonylureas for patients with allergies to sulfamides, patients with irregular schedules and for delayed postprandial hypoglycemia in patients who use sulfonylureas. Repaglinide should be taken before each main meal and is associated with reduced postprandial blood glucose levels.<a class="elsevierStyleCrossRef" href="#bib0780">68</a> The drug is eliminated in the bile and is therefore an option for patients with renal failure.DPP-4 inhibitorsDipeptidyl peptidase-4 inhibitors (DPP4i) block GLP-1 degradation, increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent manner. All DDP4i have been shown to reduce postprandial blood glucose levels. For example, sitagliptin showed a greater reduction in postprandial blood glucose levels compared with placebo. Other studies have shown a greater effect on postprandial blood glucose levels with sitagliptin and vildagliptin compared with rosiglitazone or glimepiride.<a class="elsevierStyleCrossRef" href="#bib0785">69</a> DPP4i are well tolerated, neutral with respect to weight and have a low risk of hypoglycemia.<a class="elsevierStyleCrossRef" href="#bib0790">70</a>GLP-1 receptor agonistsAs with the previous group, GLP-1 RA have an incretin action. Furthermore, GLP-1 RA slow gastric emptying and increase satiety, promoting weight loss.<a class="elsevierStyleCrossRef" href="#bib0795">71</a> GLP-1 RA can be classified by their origin (exendin derivatives such as exenatide and lixisenatide or GLP-1 derivatives such as liraglutide and dulaglutide) and by their action as short-acting or prandial (exenatide, lixisenatide) and long-acting (liraglutide, exenatide LAR and dulaglutide).<a class="elsevierStyleCrossRef" href="#bib0800">72</a> Numerous studies have shown that these drugs improve postprandial blood glucose levels.Short-acting GLP-1 RA exert a more potent effect on postprandial blood glucose in the meal in which they are administered, by increasing the delay in gastric emptying. Long-acting GLP-1 RA have a lesser effect on gastric emptying but reduce fasting blood glucose and HbA1c levels more than short-acting GLP-1 RA.<a class="elsevierStyleCrossRef" href="#bib0805">73</a> These data were confirmed in a study that compared the pharmacodynamic characteristics of lixisenatide and liraglutide. Lixisenatide showed an increased reduction of blood glucose levels after breakfast (70mg/dL vs. 25mg/dL), while liraglutide had a greater effect on baseline blood glucose levels (23mg/dL vs. 5mg/dL) and the glycemic profile for the rest of the day.<a class="elsevierStyleCrossRef" href="#bib0810">74</a>In general, GLP-1 RA are well-tolerated drugs with a low risk of hypoglycemia. Their most common adverse effects are gastrointestinal. GLP-1 RA promote weight loss and improve the lipid profile and blood pressure.<a class="elsevierStyleCrossRef" href="#bib0815">75</a> Liraglutide has also been shown to provide a cardiovascular benefit for high-risk patients.<a class="elsevierStyleCrossRef" href="#bib0820">76</a>Sodium-dependent glucose cotransporter 2 inhibitorsSodium-dependent glucose cotransporter 2 inhibitors (SGLT2i) inhibit the renal reabsorption of glucose, producing glycosuria, thereby reducing hyperglycemia. The reduction in postprandial blood glucose levels with these drugs is due to the greater renal excretion of glucose.<a class="elsevierStyleCrossRef" href="#bib0825">77</a> In the specific case of the 300-mg dose of canagliflozin, this reduction is more pronounced due to the delay in intestinal glucose absorption by the local inhibition of the intestinal SGLT-1.<a class="elsevierStyleCrossRef" href="#bib0830">78</a>SGLT2i have a low risk of hypoglycemia, promote weight loss and improve blood pressure.<a class="elsevierStyleCrossRef" href="#bib0835">79</a> Empagliflozin and canagliflozin have shown cardiovascular benefits and reduced risk of hospitalization due to heart failure.<a class="elsevierStyleCrossRefs" href="#bib0840">80,81</a> In general, these drugs are well tolerated, with the main adverse effect being genitourinary infections.<a class="elsevierStyleCrossRef" href="#bib0850">82</a>Prandial insulinThe addition of prandial insulin for patients undergoing basal insulin therapy is considered when they have persistently high HbA1c levels while their baseline blood glucose levels are within the objectives.<a class="elsevierStyleCrossRef" href="#bib0855">83</a> The available rapid-acting insulin analogs have shown better control of postprandial blood glucose levels compared with regular human insulin.<a class="elsevierStyleCrossRef" href="#bib0860">84</a>Although these analogs start to act quickly, the physiological secretion starts sooner, and its effect takes longer to disappear. This situation sometimes results in the premeal administration of these analogs not achieving control over the postprandial blood glucose peak and can cause hypoglycemic values before the next meal.To better reproduce physiological insulin secretion, new strategies are being developed such as the addition of excipients different from already known rapid-acting insulin analogs or their combination with oligomers and small organic components designed to speed absorption and bioavailability.<a class="elsevierStyleCrossRef" href="#bib0865">85</a> Faster-acting insulin aspart is a new insulin aspart formulation that contains 2 additional excipients: nicotinamide (vitamin B3) and arginine. The addition of these 2 excipients enables an earlier hypoglycemic effect than insulin aspart. The onset of action is therefore twice as fast, with a quicker and more powerful hypoglycemic action in the first hour.<a class="elsevierStyleCrossRefs" href="#bib0870">86,87</a> Studies have shown the noninferiority of faster-acting insulin aspart in achieving HbA1c objectives compared with insulin aspart, as well as a greater reduction in postprandial blood glucose levels in the first hour.<a class="elsevierStyleCrossRefs" href="#bib0880">88–90</a>There are therefore various alternatives for reducing postprandial hyperglycemia.To this end, it is important to detect the presence and magnitude of the postprandial hyperglycemia, either with OBGM or CBGM, and to individually select the most appropriate treatment for each patient (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<elsevierMultimedia ident="fig0015"></elsevierMultimedia>ConclusionsAppropriate control of postprandial blood glucose levels is a mainstay in the evaluation of patients with diabetes. Achieving the fasting blood glucose objectives does not always help achieve the HbA1c objectives if the patient presents postprandial hyperglycemia.To evaluate postprandial blood glucose, we need to use OBGM or CBGM, but there is no consensus on the control objectives for postprandial blood glucose. This requires clinicians to personalize the recommendations as to when to perform OBGM or CBGM and on what tools to use to interpret their results.Hyperglycemic fluctuations have been related to oxidative stress, inflammatory markers, endothelial dysfunction and increased numbers of adhesion molecules. There is also a consistent association between postprandial hyperglycemia, the increase in indirect clinical markers of atherosclerosis and cardiovascular disease. However, intervention studies directed at controlling PBG have not demonstrated the cardiovascular benefit uniformly and definitively.Postprandial hyperglycemia usually goes unnoticed by patients and practitioners due to its limited monitoring. A greater use of CBGM, including flash glucose monitoring, has shown that postprandial hyperglycemia is a frequent disorder that is difficult to control in certain patients with the current drugs. The proper download and analysis of OBGM and CBGM data can also help detect excessive glycemic variability and/or inadvertent hypoglycemia, which has been related to a greater risk of severe hypoglycemia.The various available drug options act differently on PBG and in controlling glycemic variability. As a result, detecting the presence of postprandial hyperglycemia or excessive glycemic variability is necessary when selecting the most appropriate drug treatment for each patient.FundingThe authors received financial assistance from Novo Nordisk to subsidize the cost of publishing this article. Novo Nordisk has had no influence over the article's content nor have they participated in designing the study, collecting and/or analyzing the data nor presenting the article.Conflicts of interestDr. Ampudia, Bellido and Pinés declare that they have received fees for lectures and/or consulting from Novo Nordisk." "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres1306144" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1206270" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1306145" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1206271" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Background" "secciones" => array:15 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Pathophysiology of baseline and postprandial hyperglycemia" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Postprandial hyperglycemia and oxidative stress" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "Measuring postprandial hyperglycemia" ] 3 => array:2 [ "identificador" => "sec0025" "titulo" => "Consequences of postprandial hyperglycemia: glycemic variability and risk of hypoglycemia" ] 4 => array:2 [ "identificador" => "sec0030" "titulo" => "Prevalence of postprandial hyperglycemia" ] 5 => array:2 [ "identificador" => "sec0035" "titulo" => "Consequences of postprandial hyperglycemia: associated mortality and cardiovascular disease" ] 6 => array:2 [ "identificador" => "sec0040" "titulo" => "Epidemiological evidence of postprandial hyperglycemia and mortality (Table 1)" ] 7 => array:2 [ "identificador" => "sec0045" "titulo" => "Intervention studies on postprandial hyperglycemia (Table 2)" ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Therapeutic strategies for reducing postprandial hyperglycemia versus baseline hyperglycemia" ] 9 => array:2 [ "identificador" => "sec0055" "titulo" => "Carbohydrates in the diet" ] 10 => array:2 [ "identificador" => "sec0060" "titulo" => "Glinides" ] 11 => array:2 [ "identificador" => "sec0065" "titulo" => "DPP-4 inhibitors" ] 12 => array:2 [ "identificador" => "sec0070" "titulo" => "GLP-1 receptor agonists" ] 13 => array:2 [ "identificador" => "sec0075" "titulo" => "Sodium-dependent glucose cotransporter 2 inhibitors" ] 14 => array:2 [ "identificador" => "sec0080" "titulo" => "Prandial insulin" ] ] ] 5 => array:2 [ "identificador" => "sec0085" "titulo" => "Conclusions" ] 6 => array:2 [ "identificador" => "sec0090" "titulo" => "Funding" ] 7 => array:2 [ "identificador" => "sec0095" "titulo" => "Conflicts of interest" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1206270" "palabras" => array:4 [ 0 => "Diabetes mellitus" 1 => "Postprandial hyperglycemia" 2 => "Baseline hyperglycemia" 3 => "Cardiovascular risk" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1206271" "palabras" => array:4 [ 0 => "Diabetes mellitus" 1 => "Hiperglucemia posprandial" 2 => "Hiperglucemia basal" 3 => "Riesgo cardiovascular" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "To achieve appropriate glycaemic control, postprandial and baseline hyperglycemia should be reduced. Various epidemiological studies have suggested an association between fluctuations in postprandial blood glucose and cardiovascular risk. However, studies of interventions performed to date have not shown that selective control of postprandial hyperglycemia is associated with cardiovascular benefits. Accordingly, an appropriate combination of drugs that control both baseline and postprandial hyperglycemia (individually based on each patient's characteristics) is the best strategy for achieving good glycaemic control. This review seeks to impart to clinicians the concept of postprandial hyperglycemia, analysing its causes, how to measure it, its prevalence, its consequences and, ultimately, the available therapeutic strategies for the preferential control of the postprandial hyperglycemia along with baseline hyperglycemia." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Para alcanzar un control glucémico adecuado, la hiperglucemia posprandial y basal debe reducirse. Diversos estudios epidemiológicos sugieren una asociación de las fluctuaciones de glucemia posprandial con el riesgo cardiovascular. Sin embargo, los estudios de intervención realizados hasta el momento no demuestran que el control selectivo de la hiperglucemia posprandial se asocie con beneficios cardiovasculares. En consecuencia, una adecuada combinación de fármacos, que controlen tanto la hiperglucemia basal como la posprandial, de forma individualizada según las características de cada paciente, es la mejor estrategia para alcanzar un buen control glucémico. Esta revisión pretende acercar a los clínicos el concepto de hiperglucemia posprandial, analizando las causas, cómo puede medirse, su prevalencia, sus consecuencias y, finalmente, qué estrategias terapéuticas existen para el control preferente de la misma junto a la hiperglucemia basal." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Pinés Corrales PJ, Bellido Castañeda V, Ampudia-Blasco FJ. Actualización sobre hiperglucemia posprandial: fisiopatología, prevalencia, consecuencias e implicaciones para el tratamiento de la diabetes. Rev Clin Esp. 2020;220:57–68." ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1248 "Ancho" => 1495 "Tamanyo" => 103237 ] ] "descripcion" => array:1 [ "en" => "Relative contribution (%) of baseline and postprandial hyperglycemia according to the HbA1c level. Modified from Monnier et al.<a class="elsevierStyleCrossRef" href="#bib0460">3</a>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1420 "Ancho" => 2118 "Tamanyo" => 160607 ] ] "descripcion" => array:1 [ "en" => "Continuous blood glucose monitoring of 2 theoretical patients with the same HbA1c level, one with unstable glycemic control or high variability (in blue) and the other with stable glycemic control or adequate variability (in red). This figure's color can only be observed in the electronic version of this article." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1128 "Ancho" => 2559 "Tamanyo" => 260446 ] ] "descripcion" => array:1 [ "en" => "Algorithm for treating postprandial hyperglycemia in patients undergoing basal insulin therapy. (1) Assess the addition of metformin, if the patient has not previously taken it and there is no contraindication. (2) Preference for GLP-1 RA if BMI>30kg/m2. (3) Empagliflozin and canagliflozin may be used at low doses (10 and 100mg, respectively) up to an eGFR of 45mL/min; 10-mg Dapagliflozin may be used up to an eGFR of 60mL/min. (4) Liraglutide and Dulaglutide may be used up to an eGFR of 15mL/min; lixisenatide up to 30mL/min; and exenatide LAR up to 50mL/min. (5) DPP4i: sitagliptin, saxagliptin and alogliptin are safe from the CV standpoint, saxagliptin increases the risk of heart failure, and alogliptin has a nonsignificant tendency to increase heart failure; SGLT2-i: Empagliflozin and canagliflozin have shown cardiovascular benefits (MACE) and reduced hospitalization for heart failure; GLP-1RA: Liraglutide has shown cardiovascular benefits (MACE); lixisenatide and exenatide LAR are neutral; Insulins: glargine and degludec are safe from the CV standpoint. Degludec has shown a reduction in severe hypoglycemia compared with glargine U100 in patients with high cardiovascular risk. Abbreviations: BMI, body mass index; DPP4i, dipeptidyl peptidase-4 inhibitors; GLP-1 RA, glucagon-like peptide-1 receptor agonists; HbA1c, glycated hemoglobin; MACE, major adverse cardiovascular events; ODAs, oral diabetes drugs; RF, renal failure; SGLT2i, sodium-dependent glucose cotransporter 2 inhibitors." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "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"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Epidemiological evidence of postprandial hyperglycemia and mortality</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Honolulu Heart Program<a class="elsevierStyleCrossRef" href="#bib0660">44</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">Blood glucose levels 1h after meals as a predictor of coronary artery disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diabetes Intervention Study<a class="elsevierStyleCrossRef" href="#bib0665">45</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">Postprandial hyperglycemia as a risk factor for mortality \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chicago Heart Study<a class="elsevierStyleCrossRef" href="#bib0670">46</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">Blood glucose levels 2h after an oral glucose overload as a predictor of overall mortality \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Paris Prospective Study and Helsinki Policemen Study<a class="elsevierStyleCrossRef" href="#bib0675">47</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">Blood glucose levels 2h after an oral glucose overload as a predictor of overall mortality and cardiovascular disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hoorn Study<a class="elsevierStyleCrossRef" href="#bib0680">48</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">Blood glucose levels 2h after meals as a better predictor of mortality than HbA1c levels \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DECODE Study<a class="elsevierStyleCrossRef" href="#bib0685">49</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">High blood glucose levels 2h after an oral glucose overload associated with a greater risk of death, regardless of blood glucose levels under fasting conditions \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">San Luigi Gonzaga Diabetes Study<a class="elsevierStyleCrossRef" href="#bib0695">51</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">Blood glucose levels 2h after meals is an independent risk factor of cardiovascular disease \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2237773.png" ] ] ] ] "descripcion" => array:1 [ "en" => "The most relevant epidemiological studies that observed an association between postprandial hyperglycemia and the risk of cardiovascular disease." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: CVD, cardiovascular disease; IMT, intima-media thickness." "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"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Intervention studies on postprandial hyperglycemia</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">STOP-NIDDM<a class="elsevierStyleCrossRef" href="#bib0715">55</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">Treatment with acarbose is associated with a reduction in cardiovascular events in individuals with impaired glucose tolerance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Acarbose Cardiovascular Evaluation<a class="elsevierStyleCrossRef" href="#bib0725">57</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">A reduction in cardiovascular events was not shown with acarbose treatment in a Chinese population with cardiovascular disease and impaired glucose tolerance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HEART2D<a class="elsevierStyleCrossRef" href="#bib0730">58</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">There were no differences with postprandial blood glucose control versus baseline in the 3 weeks after an acute myocardial infarction \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NAVIGATOR<a class="elsevierStyleCrossRef" href="#bib0735">59</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">No benefit was shown with nateglinide versus placebo in reducing cardiovascular disease in individuals with impaired glucose tolerance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Esposito et al.<a class="elsevierStyleCrossRef" href="#bib0740">60</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">Reduced intima-media thickness with the use of repaglinide versus glyburide \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hanefeld et al.<a class="elsevierStyleCrossRef" href="#bib0745">61</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">Reduced intima-media thickness with the use of acarbose versus placebo \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2237771.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Intervention studies on postprandial hyperglycemia." ] ] 5 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: FPG, fasting plasma glucose; GLP-1 RA, glucagon-like peptide-1 receptor agonists; HbA1c, glycated hemoglobin; PBG, postprandial blood glucose; SGLT2i, sodium-dependent glucose cotransporter 2 inhibitors." "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"><th 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" scope="col" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Concomitant treatment \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Change in HbA1c, % \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Change in FPG, mg/dL \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Change in 2-h PBG, mg/dL \t\t\t\t\t\t\n \t\t\t\t\t\t</th></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 " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DPP-4i</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sitagliptin 100mg \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">Monotherapy, metformin, pioglitazone, glimepiride or combination \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">−0.3 to −2.4 \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">−1 to −64 \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">−49 to −117 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Linagliptin 2.5mg \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">Monotherapy, metformin, pioglitazone or sulfonylurea \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">−0.4 to −1.6 \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">−5 to −49 \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">−34 to −49 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Saxagliptin 2.5 or 5mg \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">Monotherapy, metformin, thiazolidinedione or glyburide \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">−0.4 to −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">−1 to −64 \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">−49 to −117 \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 " colspan="5" align="left" valign="\n \t\t\t\t\ttop\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 " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GLP-1 RA</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Exenatide 10μg (breakfast and dinner) \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">Monotherapy, metformin, sulfonylurea, thiazolidinedione or combination \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">−0.9 \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">−10 to −19 \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">−71 to −126 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lixisenatide 20μg \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">Metformin, sulfonylurea, pioglitazone, basal insulin or combination \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">−0.6 to −0.9 \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">−8 to −21 \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">−81 to −143 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Liraglutide 1.2 or 1.8mg \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">Monotherapy, metformin, sulfonylurea, pioglitazone, or combination \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">−0.8 to −1.5 \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">−15 to −44 \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">−33 to −49 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Exenatide LAR \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">Monotherapy, metformin, sulfonylurea, pioglitazone, or combination \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">−1.3 to −1.6 \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">−25 to −41 \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">−96 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dulaglutide \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">Monotherapy, metformin, sulfonylurea, pioglitazone, or combination \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">−0.7 to −1.5 \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">−16 to −42 \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">−30 to −35 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Albiglutide \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">Monotherapy, metformin, sulfonylurea, pioglitazone, or combination \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">−0.6 to −0.9 \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">−12 to −25 \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">−64 \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 " colspan="5" align="left" valign="\n \t\t\t\t\ttop\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 " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SGLT2i</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dapagliflozin 5mg or 10mg \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">Monotherapy, metformin, sulfonylurea, pioglitazone, sitagliptin or combination \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">−0.5 to −2.1 \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">−21 to −61 \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">−55 to −68 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Canagliflozin 100mg or 300mg \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">Monotherapy, metformin, sulfonylurea, pioglitazone, sitagliptin or combination \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">−0.8 to −1.1 \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">−18 to −38 \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">−43 to −59 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Empagliflozin 10mg or 25mg \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">Monotherapy, metformin, sulfonylurea, pioglitazone, or combination \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">−0.6 to −0.8 \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">−17 to v25 \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">−23 to −44 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2237772.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Efficacy of various treatments on HbA1c, fasting plasma glucose and Postprandial blood glucose levels." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:90 [ 0 => array:3 [ "identificador" => "bib0450" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The role of impaired early insulin secretion in the pathogenesis of type II diabetes mellitus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s001250100580" "Revista" => array:6 [ "tituloSerie" => "Diabetologia" "fecha" => "2001" "volumen" => "44" "paginaInicial" => "929" "paginaFinal" => "945" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0455" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The glucose triad and its role in comprehensive glycaemic control: current status, future management" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1742-1241.2010.02517.x" "Revista" => array:6 [ "tituloSerie" => "Int J Clin Pract" "fecha" => "2010" "volumen" => "64" "paginaInicial" => "1705" "paginaFinal" => "1711" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0460" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients. Variations with the increasing levels of HbA1c" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/diacare.26.3.881" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2003" "volumen" => "26" "paginaInicial" => "881" "paginaFinal" => "885" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0465" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The loss of postprandial glycemic control precedes stepwise deterioration of fasting with worsening diabetes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/dc06-1612" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2007" "volumen" => "30" "paginaInicial" => "263" "paginaFinal" => "269" "link" => array:1 [ 0 => array:2 [ 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"etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.diabres.2006.11.011" "Revista" => array:6 [ "tituloSerie" => "Diabetes Res Clin Pract" "fecha" => "2007" "volumen" => "77" "paginaInicial" => "280" "paginaFinal" => "285" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0480" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A global study of the unmet need for glycemic control and predictor factors among patients with type 2 diabetes mellitus who have achieved optimal fasting plasma glucose control on basal insulin" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/dmrr.2858" "Revista" => array:3 [ "tituloSerie" => "Diabetes Metab Res Rev" "fecha" => "2017" "paginaInicial" => "33" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0485" 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Update on postprandial hyperglycemia: The pathophysiology, prevalence, consequences and implications of treating diabetes

Actualización sobre hiperglucemia posprandial: fisiopatología, prevalencia, consecuencias e implicaciones para el tratamiento de la diabetes

P.J. Pinés Corralesa, V. Bellido Castañedab, F.J. Ampudia-Blascoc,

Corresponding author

Francisco.J.Ampudia@uv.es

Corresponding author.

a Servicio de Endocrinología y Nutrición, Complejo Hospitalario Universitario de Albacete, Albacete, Spain

b Servicio de Endocrinología y Nutrición, Hospital Universitario Cruces, Bilbao, Spain

c Unidad de Referencia de Diabetes, Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, Valencia, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Increased postprandial blood glucose &#40;PBG&#41; is the first detectable abnormality in glycemic control&#46; Subsequently&#44; the increase in fasting blood glucose&#44; in PBG and&#47;or in glycated hemoglobin &#40;HbA1c&#41; leads to the diagnosis of diabetes&#46; Controlling PBG is relevant for achieving the therapeutic objectives of treating diabetes&#46; Treatment for type 2 diabetes mellitus &#40;DM2&#41; is started with nutritional therapy&#44; increasing physical activity and&#44; generally&#44; administering metformin&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">When the disease progresses&#44; we need to use various combinations of oral drugs and&#47;or glucagon-like peptide-1 receptor agonists &#40;GLP-1 RA&#41; and&#44; lastly&#44; basal insulin&#46; In this situation&#44; when appropriate titration of basal insulin does not achieve an appropriate HbA1c level&#44; the postprandial hyperglycemia will need to be assessed and reduced&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">This document is not a systematic review of postprandial hyperglycemia but rather seeks to impart to clinicians the concept of postprandial hyperglycemia&#44; reflecting on its causes&#44; assessment&#44; prevalence&#44; consequences&#44; and the specific therapeutic strategies for its proper control&#46;</p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Pathophysiology of baseline and postprandial hyperglycemia</span><p id="par0020" class="elsevierStylePara elsevierViewall">In healthy individuals&#44; insulin and glucagon secretion occurs in a synchronized and inverted manner&#44; which allows the body to maintain stable plasma glucose levels during the interprandial period&#46; Soon after food is consumed&#44; insulin secretion is increased&#44; which suppresses glucagon secretion and&#44; with it&#44; its stimulus on the hepatic production of glucose&#46; This increase in plasma insulin levels also stimulates glucose uptake by the peripheral tissues&#44; thereby preventing the PBG from increasing above 140<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44; maintaining a stable blood glucose within a narrow range&#46; However&#44; in prediabetic conditions and in the initial phases of DM2&#44; there is a loss of the initial phase of insulin secretion after the intake&#44; which results in postprandial hyperglycemia&#46; The progressive nature of DM2 results in a loss over time of fasting blood glucose control &#40;baseline hyperglycemia&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Baseline and postprandial hyperglycemia contribute&#44; to a greater or lesser extent&#44; to the total hyperglycemic burden&#46; The classic study by Monnier et al&#46; revealed that the greater relative contribution of postprandial hyperglycemia occurs with HbA1c values close to the objective &#40;up to 70&#37; with HbA1c values less than 7&#46;3&#37;&#41;&#44; with baseline hyperglycemia&#44; conversely&#44; of greater relevance with higher HbA1c values &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">3</span></a> A subsequent study by the same group showed that&#44; in patients with HbA1c levels &#60;8&#37;&#44; postprandial hyperglycemia after breakfast was primarily responsible for the increase in HbA1c levels&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">4</span></a> Likewise&#44; a recently published meta-analysis confirmed that HbA1c values showed a greater association with postprandial blood glucose levels than with fasting blood glucose levels and that the reduction in postprandial hyperglycemia was associated with a greater reduction in HbA1c levels than the reduction in baseline hyperglycemia&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">5</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Lastly&#44; achieving fasting blood glucose objectives does not always enable us to reach the HbA1c objectives&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">6</span></a> Between 24&#37; and 54&#37; of patients with DM2 who start treatment with basal insulin do not achieve the HbA1c objectives&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">7</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Postprandial hyperglycemia and oxidative stress</span><p id="par0035" class="elsevierStylePara elsevierViewall">Postprandial hyperglycemia is associated with greater glycemic variability&#44; and it has been suggested that hyperglycemic fluctuations can contribute to the development of chronic diabetes complications&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">8</span></a> Oxidative stress and increased superoxide anion production in the mitochondria in hyperglycemia is known to contribute to the development of chronic diabetes complications&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">9</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The issue is whether hyperglycemic fluctuations are more deleterious than the hyperglycemia itself&#46; It has been shown that postprandial hyperglycemic fluctuations affect oxidative stress more than sustained hyperglycemia<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">10</span></a> and the association between increased oxidative stress and proinflammatory cytokines during hyperglycemic crises&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">11</span></a> Other authors have reported that the impact of hyperglycemia on endothelial cell apoptosis is more pronounced in cells exposed to intermittent hyperglycemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">12&#44;13</span></a> Studies have also confirmed the impact of postprandial hyperglycemia on the plasma levels of various adhesion molecules&#44; such as the intracellular adhesion molecule&#44; vascular adhesion molecule and E-Selectin&#44; and these changes have been related to the risk of cardiovascular disease &#40;CVD&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">14</span></a> In summary&#44; there is sufficient experimental evidence to relate hyperglycemic fluctuations with oxidative stress&#44; inflammation markers&#44; endothelial dysfunction and the increase in adhesion molecules&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">There also appears to be a relationship between postprandial hyperglycemia and increased indirect clinical markers of atherosclerosis such as the carotid intima-media thickness &#40;IMT&#41;&#46; Various authors have observed that hyperglycemia after an oral glucose tolerance test &#40;OGTT&#41; is associated with increased IMT in healthy individuals with a family history of diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">15</span></a> Furthermore&#44; in patients with DM2&#44; there is a relationship between hyperglycemic fluctuations 1<span class="elsevierStyleHsp" style=""></span>h after eating and IMT&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Measuring postprandial hyperglycemia</span><p id="par0050" class="elsevierStylePara elsevierViewall">Glycemic control is currently assessed by measuring HbA1c levels&#44; which reflect the mean plasma glucose level for the last 8&#8211;12 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">17</span></a> HbA1c levels are also a predictor of the risk of developing diabetes-associated complications and reducing HbA1c levels is considered necessary to reduce the risk of the onset&#47;progression of complications&#44; both in type 1 diabetes mellitus &#40;DM1&#41; and DM2&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">18&#8211;23</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">However&#44; HbA1c levels do not provide information on blood glucose fluctuations&#44; which occur throughout the day and at the same time on different days &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41; and are known as glycemic variability&#46; The presence of these hyperglycemic peaks and hypoglycemic troughs could explain the contradictory results regarding the cardiovascular benefit with reducing HbA1c levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0895"><span class="elsevierStyleSup">24&#44;25&#44;26</span></a> For a proper assessment of glycemic variability and postprandial hyperglycemia&#44; outpatient capillary blood glucose monitoring &#40;OBGM&#41; or continuous blood glucose monitoring &#40;CBGM&#41; is needed&#46; CBGM systems help continuously control glucose levels in the interstitial fluid&#44; offering the possibility of improving glycemic control by increasing the time that the patient spends in the interval objective&#46; There is also a hybrid system called Flash that helps clinicians determine the interstitial glucose value and its increasing or decreasing tendency when the sensor is read with a device&#46; A considerable variety of methods to assess glycemic variability have been described&#58; standard deviation &#40;SD&#41;&#44; coefficient of variation &#40;CoV&#41;&#44; mean amplitude of glycemic excursion &#40;MAGE&#41; and the mean of daily differences in blood glucose at the same time on different days&#44; among many others&#46; However&#44; some of the measures require that the patient use CBGM &#40;which is not always available&#44; especially for patients with DM2&#41;&#44; and there is no consensus on which method to use&#46; The reason for this lack of consensus is that the various methods assess different aspects&#46; Therefore&#44; the method employed cannot be applied to all patients&#44; and&#44; in many cases&#44; several methods need to be applied to obtain complete information&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">27</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">To assess postprandial hyperglycemia&#44; an OBGM needs to be performed between 90 and 120 and&#47;or 180<span class="elsevierStyleHsp" style=""></span>min after the consumption of food&#44; but there is no consensus on the type of consumption that should be done or on the control objectives&#46; The International Diabetes Federation defines postprandial hyperglycemia as values &#62;160<span class="elsevierStyleHsp" style=""></span>mg&#47;dL 1&#8211;2<span class="elsevierStyleHsp" style=""></span>h postmeal&#44;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">28</span></a> while the American Association of Clinical Endocrinologists and the American College of Endocrinology uses the value of 140<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">29</span></a> The American Diabetes Association defined a glucose objective &#60;180<span class="elsevierStyleHsp" style=""></span>mg&#47;dL 2<span class="elsevierStyleHsp" style=""></span>h postmeal&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">30</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">If our objective is to determine the degree of glycemic fluctuation during the day&#44; we need at least 7-point OBGM &#40;3 premeal&#44; 3 postmeal and 1 prior to sleep&#41; or CBGM profiles for several days&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">31</span></a> The analysis helps obtain a mean &#40;and SD&#41; blood glucose value that will be our first approximation to the glycemic variability&#46; The limitation of the SD is that it depends on the mean blood glucose value and is higher with higher mean values&#46; We also assume a normal distribution&#44; which is not usually the case&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">A method for improving some of the limitations of SD is the CoV calculation &#40;&#91;SD&#47;mean&#93;<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>100&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">29</span></a> The CoV helps assess the need for therapeutic changes and assess their results &#40;a CoV value &#62;36&#37; would be indicative of unstable blood glucose levels&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">32</span></a> MAGE&#44; another glycemic assessment method&#44; represents the mean differences between consecutive hyperglycemia and hypoglycemia peaks&#46; To calculate MAGE&#44; hourly values are needed for 48<span class="elsevierStyleHsp" style=""></span>h&#46; Lastly&#44; if the objective of the assessment is to determine glycemic variability at the same time on different days&#44; the mean of daily differences can be employed&#44; which indicates the mean of the absolute differences between glucose values at the same time on consecutive days&#46; Another easier approximation consists of calculating CoV based on the mean and SD of the values obtained over several days at the same time of day&#46; The calculation based on the first OBGM check performed during the day after the night-time fasting is especially useful&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">33&#44;34</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">In summary&#44; appropriate and tailored recommendations as to when to perform OBGM or CBGM and the regular downloading of data and their correct interpretation are essential to assessing the quality of the glycemic control and variability and to performing appropriate therapeutic adjustments&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Consequences of postprandial hyperglycemia&#58; glycemic variability and risk of hypoglycemia</span><p id="par0080" class="elsevierStylePara elsevierViewall">The concept of glycemic variability includes glycemic fluctuations that occur throughout the day and glycemic variations that occur at the same time on different days&#46; A classic study&#44; based on OBGM data from patients with DM1&#44; revealed that the presence of mild hypoglycemia and glycemic variability were better predictors of the risk of severe hypoglycemia than HbA1c levels&#46; An analysis based on data from the Diabetes Control and Complications Trial also confirmed that the mean and SD of OBGM values enabled a better calculation of the risk of severe hypoglycemia than HbA1c levels in isolation&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">35</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The HbA1c level has an adequate correlation with the mean blood glucose level but offers no information on the glycemic fluctuations throughout the day and between different days&#46; Thus&#44; a patient with fasting blood glucose levels within the objectives can present inadequate HbA1c levels secondary to the presence of postprandial hyperglycemia&#46; Moreover&#44; any HbA1c level can be associated with the continuous presence of marked hyperglycemia and hypoglycemia because a single HbA1c value associated with increased glycemic variability would imply an increased percentage of blood glucose values measured in hyperglycemia and in hypoglycemia&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The Verona Diabetes Study of patients with DM2 observed that CoV&#44; calculated with fasting plasma glucose values&#44; was an independent predictor of mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">36</span></a> Another study conducted with patients with DM2 also observed that OBGM data was more useful in predicting the risk of severe hypoglycemia than isolated HbA1c values&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">37</span></a> Jin et al&#46; indicated that greater glycemic variability in patients with DM1 and DM2 could be associated with the type of treatment employed &#40;premixed insulins&#41; and to the patient&#39;s characteristics&#44; such as residual insulin secretion&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">38</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">A recently published secondary analysis of the DEVOTE study data assessed the relationship between glycemic variability and the risk of severe hypoglycemia&#46; The study analyzed the SD based on 3 consecutive OBGM checks&#44; performed before breakfast every month during the study &#40;glycemic variability at the same time of day between different days&#41;&#44; revealing a relationship between glycemic variability &#40;before breakfast&#41; and the risk of severe hypoglycemia &#40;HR&#44; 4&#46;11&#59; 95&#37; CI 3&#46;15&#8211;5&#46;35&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">39</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">In summary&#44; an appropriate download and analysis of OBGM and CBGM data &#40;in search of excessive glycemic variability and unintentional hypoglycemia and hyperglycemia&#41; helps detect patients at a greater risk of severe hypoglycemia and thereby helps establish preventive therapeutic strategies to reduce the risk of these conditions&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Prevalence of postprandial hyperglycemia</span><p id="par0105" class="elsevierStylePara elsevierViewall">Postprandial hyperglycemia is frequent&#44; even when the metabolic control is apparently appropriate according to the HbA1c value&#46; However&#44; determining the actual prevalence of postprandial hyperglycemia is difficult because there are few studies that have evaluated this condition and there is no consensus on its definition&#46; A study that assessed the capillary blood glucose profiles of patients with DM2 untreated with insulin observed postprandial hyperglycemia in 84&#37; of the patients&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">40</span></a> The TranSTAR study&#44; conducted with patients with DM2 in Spain&#44; observed poor glycemic control &#40;according to postprandial blood glucose levels&#41; in 88&#46;4&#37; of the patients&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">41</span></a> Studies conducted with CBGM showed similar results for patients with DM1&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">42</span></a> A recently published survey of patients with DM1 and DM2 undergoing treatment with insulin found that 61&#46;9&#37; of the patients reported experiencing postprandial hyperglycemia in the previous week&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">43</span></a> Twenty-four percent to 54&#37; of patients with DM2 undergoing treatment with basal insulin do not achieve the HbA1c objective&#44; despite achieving appropriate fasting blood glucose levels&#44; which indicates poor control caused by postprandial hyperglycemia&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">7</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">The results of these studies demonstrate that postprandial hyperglycemia is a frequent metabolic disorder in individuals with diabetes and that often goes unnoticed due to its limited monitoring&#46; A greater use of CBGM systems&#44; including flash glucose monitoring&#44; could facilitate the detection of postprandial hyperglycemia&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Consequences of postprandial hyperglycemia&#58; associated mortality and cardiovascular disease</span><p id="par0115" class="elsevierStylePara elsevierViewall">The definition of PBG objectives is backed by the fact that postprandial hyperglycemia can play an important role in the development of macrovascular complications&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Epidemiological evidence of postprandial hyperglycemia and mortality &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;</span><p id="par0120" class="elsevierStylePara elsevierViewall">The Honolulu Heart Program observed a linear relationship between blood glucose values after the OGTT and CVD&#44; regardless of other cardiovascular risk factors&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">44</span></a> The Diabetes Intervention Study studied the risk factors associated with coronary artery disease and mortality in individuals recently diagnosed with DM2&#44; confirming the relationship between postprandial hyperglycemia and the risk of death&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">45</span></a> The Chicago Heart Association Detection Project in Industry Study confirmed the relationship between mortality and the presence of hyperglycemia after OGTT in asymptomatic individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">46</span></a> Other studies such as the Whitehall Study&#44; the Paris Prospective Study and the Helsinki Policemen Study also verified the relationship between hyperglycemia after OGTT and mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">47</span></a> The Hoorn Study reaffirmed the relationship between postprandial hyperglycemia and mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">48</span></a> Lastly&#44; the DECODE Study established that the implementation of the OGTT can provide additional information to that provided by fasting glucose levels by identifying patients with a greater mortality risk&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">49</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">The Baltimore Longitudinal Study of Aging strengthened the predictive value of OGTT over fasting glucose readings&#44;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">50</span></a> and the San Luigi Gonzaga Diabetes Study observed that postprandial blood glucose was&#44; along with HbA1c&#44; an independent risk factor for developing CVD and for all-cause mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">51</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Lastly&#44; a study conducted in a Chinese population also verified a closer relationship between CVD and postprandial blood glucose levels than between CVD and fasting blood glucose levels&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">52</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">In summary&#44; the various analyzed epidemiological studies agree that postprandial hyperglycemia is an independent risk factor of CVD and of mortality for healthy individuals and patients with diabetes&#46;<a class="elsevierStyleCrossRefs" href="#bib0705"><span class="elsevierStyleSup">53&#44;54</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Intervention studies on postprandial hyperglycemia &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;</span><p id="par0140" class="elsevierStylePara elsevierViewall">The Acarbose for the Prevention of Type 2 Diabetes Mellitus &#40;STOP-NIDDM&#41; trial showed that&#44; for individuals with impaired glucose tolerance&#44; treatment with acarbose is associated with a reduction in cardiovascular events&#44; particularly silent acute myocardial infarction &#40;AMI&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">55</span></a> These results agree with a subsequent meta-analysis performed on 7 randomized&#44; double-blind&#44; placebo-controlled trials in which treatment with acarbose was associated with a reduction in the risk of AMI and CVD in patients with DM2&#46;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">56</span></a> However&#44; the results of the Acarbose Cardiovascular Evaluation study showed no benefit in the treatment with acarbose in a population with CVD and impaired glucose tolerance&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">57</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0145" class="elsevierStylePara elsevierViewall">The Effects of Prandial Versus Fasting Glycemia on Cardiovascular Outcomes in Type 2 Diabetes &#40;HEART2D&#41; study was designed to compare the effects of the preferential control of baseline hyperglycemia &#40;using 2 doses of neutral protamine Hagedorn insulin or one dose of insulin glargine&#41; versus postprandial control &#40;using 3 doses of insulin lispro&#41; in patients with DM2 in the 3 weeks following an AMI&#46; The study was suspended at 2&#46;7 years due to a lack of objective differences between the 2 treatments&#46; However&#44; the difference in postprandial blood glucose levels at the end of the study between the groups was only 14<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44; too low a reading to affect the primary cardiovascular objective&#46;<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">58</span></a> The Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research &#40;NAVIGATOR&#41; study showed no benefit with nateglinide versus placebo in reducing CVD in individuals with impaired glucose tolerance&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">59</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Other intervention studies have acted on indirect clinical markers of CVD such as IMT&#46; Esposito et al&#46; showed a significant reduction in IMT in more patients when using repaglinide than with glibenclamide&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">60</span></a> Hanefeld et al&#46; also demonstrated less IMT progression with acarbose than with placebo in patients with carbohydrate intolerance&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">61</span></a> The use of rapid-acting insulin analogs &#40;lispro and aspart&#41; versus regular insulin appears to produce a benefit in the surrogate biochemical markers of CVD &#40;increase in nitrotyrosine and in methylglyoxal and 3-deoxyglucosone&#41;&#44; and this benefit appears to be related with better postprandial control&#46;<a class="elsevierStyleCrossRefs" href="#bib0750"><span class="elsevierStyleSup">62&#44;63</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">In summary&#44; despite the experimental basis described and the evidence of epidemiological studies that show the association between CVD and postprandial hyperglycemia&#44; the intervention studies have not managed to uniformly and definitively demonstrate a cardiovascular benefit for the treatments directed at controlling PBG&#46; This lack of apparent benefit could be due to various factors&#58; &#40;1&#41; the drug used in the NAVIGATOR study was an insulin secretor &#40;the active treatment branch had greater progression to diabetes and more hypoglycemia&#41;&#44; and the results are probably not applicable to drugs with other mechanisms of action&#46; &#40;2&#41; The HEART2D study failed to achieve the difference specified in the study&#39;s design in postprandial control between the 2 treatment branches and could therefore find no benefits&#46; &#40;3&#41; The potential cardiovascular benefits observed in the STOP-NIDDM study could not be confirmed when conducting the Acarbose Cardiovascular Evaluation study&#59; however&#44; there were significant differences between the 2 studies &#40;different ethnic groups&#44; patient ages and different acarbose dosages&#41;&#44; which could explain this difference&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Therapeutic strategies for reducing postprandial hyperglycemia versus baseline hyperglycemia</span><p id="par0160" class="elsevierStylePara elsevierViewall">Individual management of diabetes is currently recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">64</span></a> In general&#44; the recommendation is to keep HbA1c levels &#60;7&#37;&#44; if this can be reached safely and without hypoglycemic events&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">30</span></a> This review has confirmed that baseline hyperglycemia and postprandial hyperglycemia contribute to impaired glycemic control&#46; The importance of postprandial hyperglycemia becomes more apparent when treatment with a basal insulin is intensified&#44; with HbA1c values remaining above the control objectives despite titrating the insulin dosage&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">This information is relevant when selecting the treatment&#44; given that its effect on postprandial control can be different &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; A treatment or combination of treatments should be chosen based on each patient&#39;s needs and characteristics&#46;<a class="elsevierStyleCrossRef" href="#bib0765"><span class="elsevierStyleSup">65</span></a> The main therapeutic strategies for controlling postprandial hyperglycemia are described below&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Carbohydrates in the diet</span><p id="par0170" class="elsevierStylePara elsevierViewall">Studies that have evaluated the ideal quantity of carbohydrates for individuals with diabetes have not been conclusive&#46; The glycemic index &#40;GI&#41; categorizes food by its capacity to increase blood glucose levels&#44; measuring the relationship between the area under the curve of the postprandial glycemic response produced by the ingestion of 50<span class="elsevierStyleHsp" style=""></span>g of carbohydrates supplied by a specific food and a food pattern &#40;glucose or white bread&#41; and multiplied by 100 &#40;considering that the GI is low if &#8804;55&#44; medium if 56&#8211;69 and high if &#8805;70&#41;&#46; The glycemic load is the product of GI and the carbohydrate content of a standard portion of food&#46; Studies have observed that lowering the glycemic load can reduce HbA1c levels between 0&#46;2&#37; and 0&#46;5&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0770"><span class="elsevierStyleSup">66&#44;67</span></a> The consumption of carbohydrates based on whole grain cereals&#44; vegetables&#44; fruits&#44; legumes and milk products is therefore recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">30</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Glinides</span><p id="par0175" class="elsevierStylePara elsevierViewall">Repaglinide is a rapid-acting secretagogue that can serve as an alternative to sulfonylureas for patients with allergies to sulfamides&#44; patients with irregular schedules and for delayed postprandial hypoglycemia in patients who use sulfonylureas&#46; Repaglinide should be taken before each main meal and is associated with reduced postprandial blood glucose levels&#46;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">68</span></a> The drug is eliminated in the bile and is therefore an option for patients with renal failure&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">DPP-4 inhibitors</span><p id="par0180" class="elsevierStylePara elsevierViewall">Dipeptidyl peptidase-4 inhibitors &#40;DPP4i&#41; block GLP-1 degradation&#44; increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent manner&#46; All DDP4i have been shown to reduce postprandial blood glucose levels&#46; For example&#44; sitagliptin showed a greater reduction in postprandial blood glucose levels compared with placebo&#46; Other studies have shown a greater effect on postprandial blood glucose levels with sitagliptin and vildagliptin compared with rosiglitazone or glimepiride&#46;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">69</span></a> DPP4i are well tolerated&#44; neutral with respect to weight and have a low risk of hypoglycemia&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">70</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">GLP-1 receptor agonists</span><p id="par0185" class="elsevierStylePara elsevierViewall">As with the previous group&#44; GLP-1 RA have an incretin action&#46; Furthermore&#44; GLP-1 RA slow gastric emptying and increase satiety&#44; promoting weight loss&#46;<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">71</span></a> GLP-1 RA can be classified by their origin &#40;exendin derivatives such as exenatide and lixisenatide or GLP-1 derivatives such as liraglutide and dulaglutide&#41; and by their action as short-acting or prandial &#40;exenatide&#44; lixisenatide&#41; and long-acting &#40;liraglutide&#44; exenatide LAR and dulaglutide&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">72</span></a> Numerous studies have shown that these drugs improve postprandial blood glucose levels&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Short-acting GLP-1 RA exert a more potent effect on postprandial blood glucose in the meal in which they are administered&#44; by increasing the delay in gastric emptying&#46; Long-acting GLP-1 RA have a lesser effect on gastric emptying but reduce fasting blood glucose and HbA1c levels more than short-acting GLP-1 RA&#46;<a class="elsevierStyleCrossRef" href="#bib0805"><span class="elsevierStyleSup">73</span></a> These data were confirmed in a study that compared the pharmacodynamic characteristics of lixisenatide and liraglutide&#46; Lixisenatide showed an increased reduction of blood glucose levels after breakfast &#40;70<span class="elsevierStyleHsp" style=""></span>mg&#47;dL vs&#46; 25<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;&#44; while liraglutide had a greater effect on baseline blood glucose levels &#40;23<span class="elsevierStyleHsp" style=""></span>mg&#47;dL vs&#46; 5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41; and the glycemic profile for the rest of the day&#46;<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">74</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">In general&#44; GLP-1 RA are well-tolerated drugs with a low risk of hypoglycemia&#46; Their most common adverse effects are gastrointestinal&#46; GLP-1 RA promote weight loss and improve the lipid profile and blood pressure&#46;<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">75</span></a> Liraglutide has also been shown to provide a cardiovascular benefit for high-risk patients&#46;<a class="elsevierStyleCrossRef" href="#bib0820"><span class="elsevierStyleSup">76</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Sodium-dependent glucose cotransporter 2 inhibitors</span><p id="par0200" class="elsevierStylePara elsevierViewall">Sodium-dependent glucose cotransporter 2 inhibitors &#40;SGLT2i&#41; inhibit the renal reabsorption of glucose&#44; producing glycosuria&#44; thereby reducing hyperglycemia&#46; The reduction in postprandial blood glucose levels with these drugs is due to the greater renal excretion of glucose&#46;<a class="elsevierStyleCrossRef" href="#bib0825"><span class="elsevierStyleSup">77</span></a> In the specific case of the 300-mg dose of canagliflozin&#44; this reduction is more pronounced due to the delay in intestinal glucose absorption by the local inhibition of the intestinal SGLT-1&#46;<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">78</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">SGLT2i have a low risk of hypoglycemia&#44; promote weight loss and improve blood pressure&#46;<a class="elsevierStyleCrossRef" href="#bib0835"><span class="elsevierStyleSup">79</span></a> Empagliflozin and canagliflozin have shown cardiovascular benefits and reduced risk of hospitalization due to heart failure&#46;<a class="elsevierStyleCrossRefs" href="#bib0840"><span class="elsevierStyleSup">80&#44;81</span></a> In general&#44; these drugs are well tolerated&#44; with the main adverse effect being genitourinary infections&#46;<a class="elsevierStyleCrossRef" href="#bib0850"><span class="elsevierStyleSup">82</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Prandial insulin</span><p id="par0210" class="elsevierStylePara elsevierViewall">The addition of prandial insulin for patients undergoing basal insulin therapy is considered when they have persistently high HbA1c levels while their baseline blood glucose levels are within the objectives&#46;<a class="elsevierStyleCrossRef" href="#bib0855"><span class="elsevierStyleSup">83</span></a> The available rapid-acting insulin analogs have shown better control of postprandial blood glucose levels compared with regular human insulin&#46;<a class="elsevierStyleCrossRef" href="#bib0860"><span class="elsevierStyleSup">84</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Although these analogs start to act quickly&#44; the physiological secretion starts sooner&#44; and its effect takes longer to disappear&#46; This situation sometimes results in the premeal administration of these analogs not achieving control over the postprandial blood glucose peak and can cause hypoglycemic values before the next meal&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">To better reproduce physiological insulin secretion&#44; new strategies are being developed such as the addition of excipients different from already known rapid-acting insulin analogs or their combination with oligomers and small organic components designed to speed absorption and bioavailability&#46;<a class="elsevierStyleCrossRef" href="#bib0865"><span class="elsevierStyleSup">85</span></a> Faster-acting insulin aspart is a new insulin aspart formulation that contains 2 additional excipients&#58; nicotinamide &#40;vitamin B3&#41; and arginine&#46; The addition of these 2 excipients enables an earlier hypoglycemic effect than insulin aspart&#46; The onset of action is therefore twice as fast&#44; with a quicker and more powerful hypoglycemic action in the first hour&#46;<a class="elsevierStyleCrossRefs" href="#bib0870"><span class="elsevierStyleSup">86&#44;87</span></a> Studies have shown the noninferiority of faster-acting insulin aspart in achieving HbA1c objectives compared with insulin aspart&#44; as well as a greater reduction in postprandial blood glucose levels in the first hour&#46;<a class="elsevierStyleCrossRefs" href="#bib0880"><span class="elsevierStyleSup">88&#8211;90</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">There are therefore various alternatives for reducing postprandial hyperglycemia&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">To this end&#44; it is important to detect the presence and magnitude of the postprandial hyperglycemia&#44; either with OBGM or CBGM&#44; and to individually select the most appropriate treatment for each patient &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conclusions</span><p id="par0235" class="elsevierStylePara elsevierViewall">Appropriate control of postprandial blood glucose levels is a mainstay in the evaluation of patients with diabetes&#46; Achieving the fasting blood glucose objectives does not always help achieve the HbA1c objectives if the patient presents postprandial hyperglycemia&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">To evaluate postprandial blood glucose&#44; we need to use OBGM or CBGM&#44; but there is no consensus on the control objectives for postprandial blood glucose&#46; This requires clinicians to personalize the recommendations as to when to perform OBGM or CBGM and on what tools to use to interpret their results&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">Hyperglycemic fluctuations have been related to oxidative stress&#44; inflammatory markers&#44; endothelial dysfunction and increased numbers of adhesion molecules&#46; There is also a consistent association between postprandial hyperglycemia&#44; the increase in indirect clinical markers of atherosclerosis and cardiovascular disease&#46; However&#44; intervention studies directed at controlling PBG have not demonstrated the cardiovascular benefit uniformly and definitively&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Postprandial hyperglycemia usually goes unnoticed by patients and practitioners due to its limited monitoring&#46; A greater use of CBGM&#44; including flash glucose monitoring&#44; has shown that postprandial hyperglycemia is a frequent disorder that is difficult to control in certain patients with the current drugs&#46; The proper download and analysis of OBGM and CBGM data can also help detect excessive glycemic variability and&#47;or inadvertent hypoglycemia&#44; which has been related to a greater risk of severe hypoglycemia&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">The various available drug options act differently on PBG and in controlling glycemic variability&#46; As a result&#44; detecting the presence of postprandial hyperglycemia or excessive glycemic variability is necessary when selecting the most appropriate drug treatment for each patient&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Funding</span><p id="par0260" class="elsevierStylePara elsevierViewall">The authors received financial assistance from Novo Nordisk to subsidize the cost of publishing this article&#46; Novo Nordisk has had no influence over the article&#39;s content nor have they participated in designing the study&#44; collecting and&#47;or analyzing the data nor presenting the article&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflicts of interest</span><p id="par0265" class="elsevierStylePara elsevierViewall">Dr&#46; Ampudia&#44; Bellido and Pin&#233;s declare that they have received fees for lectures and&#47;or consulting from Novo Nordisk&#46;</p></span></span>"
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              "titulo" => "Pathophysiology of baseline and postprandial hyperglycemia"
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              "titulo" => "Measuring postprandial hyperglycemia"
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              "titulo" => "Prevalence of postprandial hyperglycemia"
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              "titulo" => "Epidemiological evidence of postprandial hyperglycemia and mortality &#40;Table 1&#41;"
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              "titulo" => "Intervention studies on postprandial hyperglycemia &#40;Table 2&#41;"
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              "titulo" => "Therapeutic strategies for reducing postprandial hyperglycemia versus baseline hyperglycemia"
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            0 => "Diabetes mellitus"
            1 => "Postprandial hyperglycemia"
            2 => "Baseline hyperglycemia"
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          "palabras" => array:4 [
            0 => "Diabetes mellitus"
            1 => "Hiperglucemia posprandial"
            2 => "Hiperglucemia basal"
            3 => "Riesgo cardiovascular"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To achieve appropriate glycaemic control&#44; postprandial and baseline hyperglycemia should be reduced&#46; Various epidemiological studies have suggested an association between fluctuations in postprandial blood glucose and cardiovascular risk&#46; However&#44; studies of interventions performed to date have not shown that selective control of postprandial hyperglycemia is associated with cardiovascular benefits&#46; Accordingly&#44; an appropriate combination of drugs that control both baseline and postprandial hyperglycemia &#40;individually based on each patient&#39;s characteristics&#41; is the best strategy for achieving good glycaemic control&#46; This review seeks to impart to clinicians the concept of postprandial hyperglycemia&#44; analysing its causes&#44; how to measure it&#44; its prevalence&#44; its consequences and&#44; ultimately&#44; the available therapeutic strategies for the preferential control of the postprandial hyperglycemia along with baseline hyperglycemia&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Para alcanzar un control gluc&#233;mico adecuado&#44; la hiperglucemia posprandial y basal debe reducirse&#46; Diversos estudios epidemiol&#243;gicos sugieren una asociaci&#243;n de las fluctuaciones de glucemia posprandial con el riesgo cardiovascular&#46; Sin embargo&#44; los estudios de intervenci&#243;n realizados hasta el momento no demuestran que el control selectivo de la hiperglucemia posprandial se asocie con beneficios cardiovasculares&#46; En consecuencia&#44; una adecuada combinaci&#243;n de f&#225;rmacos&#44; que controlen tanto la hiperglucemia basal como la posprandial&#44; de forma individualizada seg&#250;n las caracter&#237;sticas de cada paciente&#44; es la mejor estrategia para alcanzar un buen control gluc&#233;mico&#46; Esta revisi&#243;n pretende acercar a los cl&#237;nicos el concepto de hiperglucemia posprandial&#44; analizando las causas&#44; c&#243;mo puede medirse&#44; su prevalencia&#44; sus consecuencias y&#44; finalmente&#44; qu&#233; estrategias terap&#233;uticas existen para el control preferente de la misma junto a la hiperglucemia basal&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Pin&#233;s Corrales PJ&#44; Bellido Casta&#241;eda V&#44; Ampudia-Blasco FJ&#46; Actualizaci&#243;n sobre hiperglucemia posprandial&#58; fisiopatolog&#237;a&#44; prevalencia&#44; consecuencias e implicaciones para el tratamiento de la diabetes&#46; Rev Clin Esp&#46; 2020&#59;220&#58;57&#8211;68&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Relative contribution &#40;&#37;&#41; of baseline and postprandial hyperglycemia according to the HbA1c level&#46; Modified from Monnier et al&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">3</span></a></p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Continuous blood glucose monitoring of 2 theoretical patients with the same HbA1c level&#44; one with unstable glycemic control or high variability &#40;in blue&#41; and the other with stable glycemic control or adequate variability &#40;in red&#41;&#46; This figure&#39;s color can only be observed in the electronic version of this article&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Algorithm for treating postprandial hyperglycemia in patients undergoing basal insulin therapy&#46; &#40;1&#41; Assess the addition of metformin&#44; if the patient has not previously taken it and there is no contraindication&#46; &#40;2&#41; Preference for GLP-1 RA if BMI<span class="elsevierStyleHsp" style=""></span>&#62;30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#46; &#40;3&#41; Empagliflozin and canagliflozin may be used at low doses &#40;10 and 100<span class="elsevierStyleHsp" style=""></span>mg&#44; respectively&#41; up to an eGFR of 45<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#59; 10-mg Dapagliflozin may be used up to an eGFR of 60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; &#40;4&#41; Liraglutide and Dulaglutide may be used up to an eGFR of 15<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#59; lixisenatide up to 30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#59; and exenatide LAR up to 50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; &#40;5&#41; DPP4i&#58; sitagliptin&#44; saxagliptin and alogliptin are safe from the CV standpoint&#44; saxagliptin increases the risk of heart failure&#44; and alogliptin has a nonsignificant tendency to increase heart failure&#59; SGLT2-i&#58; Empagliflozin and canagliflozin have shown cardiovascular benefits &#40;MACE&#41; and reduced hospitalization for heart failure&#59; GLP-1RA&#58; Liraglutide has shown cardiovascular benefits &#40;MACE&#41;&#59; lixisenatide and exenatide LAR are neutral&#59; Insulins&#58; glargine and degludec are safe from the CV standpoint&#46; Degludec has shown a reduction in severe hypoglycemia compared with glargine U100 in patients with high cardiovascular risk&#46;</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; BMI&#44; body mass index&#59; DPP4i&#44; dipeptidyl peptidase-4 inhibitors&#59; GLP-1 RA&#44; glucagon-like peptide-1 receptor agonists&#59; HbA1c&#44; glycated hemoglobin&#59; MACE&#44; major adverse cardiovascular events&#59; ODAs&#44; oral diabetes drugs&#59; RF&#44; renal failure&#59; SGLT2i&#44; sodium-dependent glucose cotransporter 2 inhibitors&#46;</p>"
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                  \t\t\t\t">Honolulu Heart Program<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">44</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Blood glucose levels 1<span class="elsevierStyleHsp" style=""></span>h after meals as a predictor of coronary artery disease&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Diabetes Intervention Study<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">45</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Postprandial hyperglycemia as a risk factor for mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Chicago Heart Study<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">46</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Blood glucose levels 2<span class="elsevierStyleHsp" style=""></span>h after an oral glucose overload as a predictor of overall mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Paris Prospective Study and Helsinki Policemen Study<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">47</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blood glucose levels 2<span class="elsevierStyleHsp" style=""></span>h after an oral glucose overload as a predictor of overall mortality and cardiovascular disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Hoorn Study<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">48</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Blood glucose levels 2<span class="elsevierStyleHsp" style=""></span>h after meals as a better predictor of mortality than HbA1c levels&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">DECODE Study<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">49</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">High blood glucose levels 2<span class="elsevierStyleHsp" style=""></span>h after an oral glucose overload associated with a greater risk of death&#44; regardless of blood glucose levels under fasting conditions&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">San Luigi Gonzaga Diabetes Study<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">51</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">Blood glucose levels 2<span class="elsevierStyleHsp" style=""></span>h after meals is an independent risk factor of cardiovascular disease&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; CVD&#44; cardiovascular disease&#59; IMT&#44; intima-media thickness&#46;</p>"
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Intervention studies on postprandial hyperglycemia</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">STOP-NIDDM<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">55</span></a>&nbsp;\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">Treatment with acarbose is associated with a reduction in cardiovascular events in individuals with impaired glucose tolerance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Acarbose Cardiovascular Evaluation<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">57</span></a>&nbsp;\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">A reduction in cardiovascular events was not shown with acarbose treatment in a Chinese population with cardiovascular disease and impaired glucose tolerance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HEART2D<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">58</span></a>&nbsp;\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">There were no differences with postprandial blood glucose control versus baseline in the 3 weeks after an acute myocardial infarction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NAVIGATOR<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">59</span></a>&nbsp;\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">No benefit was shown with nateglinide versus placebo in reducing cardiovascular disease in individuals with impaired glucose tolerance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Esposito et al&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">60</span></a>&nbsp;\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">Reduced intima-media thickness with the use of repaglinide versus glyburide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hanefeld et al&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">61</span></a>&nbsp;\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">Reduced intima-media thickness with the use of acarbose versus placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; FPG&#44; fasting plasma glucose&#59; GLP-1 RA&#44; glucagon-like peptide-1 receptor agonists&#59; HbA1c&#44; glycated hemoglobin&#59; PBG&#44; postprandial blood glucose&#59; SGLT2i&#44; sodium-dependent glucose cotransporter 2 inhibitors&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th 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" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Concomitant treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Change in HbA1c&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Change in FPG&#44; mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Change in 2-h PBG&#44; mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></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  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">DPP-4i</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Sitagliptin 100<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\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">Monotherapy&#44; metformin&#44; pioglitazone&#44; glimepiride or combination&nbsp;\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">&#8722;0&#46;3 to &#8722;2&#46;4&nbsp;\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">&#8722;1 to &#8722;64&nbsp;\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">&#8722;49 to &#8722;117&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Linagliptin 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\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">Monotherapy&#44; metformin&#44; pioglitazone or sulfonylurea&nbsp;\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">&#8722;0&#46;4 to &#8722;1&#46;6&nbsp;\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">&#8722;5 to &#8722;49&nbsp;\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">&#8722;34 to &#8722;49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Saxagliptin 2&#46;5 or 5<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\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">Monotherapy&#44; metformin&#44; thiazolidinedione or glyburide&nbsp;\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">&#8722;0&#46;4 to &#8722;2&#46;5&nbsp;\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">&#8722;1 to &#8722;64&nbsp;\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">&#8722;49 to &#8722;117&nbsp;\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  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">GLP-1 RA</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Exenatide 10<span class="elsevierStyleHsp" style=""></span>&#956;g &#40;breakfast and dinner&#41;&nbsp;\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">Monotherapy&#44; metformin&#44; sulfonylurea&#44; thiazolidinedione or combination&nbsp;\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">&#8722;0&#46;9&nbsp;\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">&#8722;10 to &#8722;19&nbsp;\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">&#8722;71 to &#8722;126&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Lixisenatide 20<span class="elsevierStyleHsp" style=""></span>&#956;g&nbsp;\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">Metformin&#44; sulfonylurea&#44; pioglitazone&#44; basal insulin or combination&nbsp;\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">&#8722;0&#46;6 to &#8722;0&#46;9&nbsp;\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">&#8722;8 to &#8722;21&nbsp;\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">&#8722;81 to &#8722;143&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Liraglutide 1&#46;2 or 1&#46;8<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\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">Monotherapy&#44; metformin&#44; sulfonylurea&#44; pioglitazone&#44; or combination&nbsp;\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">&#8722;0&#46;8 to &#8722;1&#46;5&nbsp;\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">&#8722;15 to &#8722;44&nbsp;\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">&#8722;33 to &#8722;49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Exenatide LAR&nbsp;\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">Monotherapy&#44; metformin&#44; sulfonylurea&#44; pioglitazone&#44; or combination&nbsp;\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">&#8722;1&#46;3 to &#8722;1&#46;6&nbsp;\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">&#8722;25 to &#8722;41&nbsp;\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">&#8722;96&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Dulaglutide&nbsp;\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">Monotherapy&#44; metformin&#44; sulfonylurea&#44; pioglitazone&#44; or combination&nbsp;\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">&#8722;0&#46;7 to &#8722;1&#46;5&nbsp;\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
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Monotherapy&#44; metformin&#44; sulfonylurea&#44; pioglitazone&#44; or combination&nbsp;\t\t\t\t\t\t\n
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                          "etal" => true
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2018.12.002

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