Treatment of type 2 diabetes mellitus in elderly patients

Gómez-Huelgas, R.; Gómez Peralta, F.; Rodríguez Mañas, L.; Formiga, F.; Puig Domingo, M.; Mediavilla Bravo, J.J.; Miranda, C.; Ena, J.

doi:10.1016/j.rceng.2017.12.004

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Abbreviations: DPP4i: dipeptidyl peptidase-4 inhibitors; GLP-1RA: glucagon-like peptide-1 receptor agonists; SGLT2i: sodium-glucose cotransporter 2 inhibitors. a Repaglinide and pioglitazone can be used in patients with GFR <30mL/min, but their use is not recommended due to the risk of adverse effects: hypoglycemia (repaglinide); salt and fluid retention, heart failure and fractures (pioglitazone). b Empagliflozin, canagliflozin and liraglutide have shown reduced cardiovascular morbidity and mortality in patients with high vascular risk type 2 diabetes. c Saxagliptin should be avoided for patients with heart failure. d Pioglitazone is contraindicated for patients with heart failure or at risk for fractures." ] ] ] "textoCompleto" => "BackgroundAging is characterized by a progressive loss of an individual's functional capacity. The elderly population is biologically heterogeneous, thereby necessitating a comprehensive assessment, one that includes functional aspects in the decision-making process.<a class="elsevierStyleCrossRef" href="#bib0930">1</a> Although there is no consensus on the definition of an individual as elderly, this document uses the operational definition of having an age greater than 75 years or presenting frailty.<a class="elsevierStyleCrossRef" href="#bib0935">2</a>Demographic predictions put Spain as one of the most aged countries in the world. In 2050, 12% of the Spanish population will be 80 years of age or older.<a class="elsevierStyleCrossRef" href="#bib0940">3</a>Type 2 diabetes mellitus (DM2) is a disease closely linked to aging, and its prevalence increases markedly with age. This situation is due to the combination of insulin secretion deficiency, insulin resistance (related to the increase in visceral, intermuscular and intramuscular adiposity), sarcopenia and physical inactivity in elderly patients. In Spain, 63% of patients with diabetes (of whom more than 90% have DM2) are older than 65 years,<a class="elsevierStyleCrossRef" href="#bib0945">4</a> and more than a third of the population older than 75 years has diabetes.<a class="elsevierStyleCrossRef" href="#bib0950">5</a> It has been predicted that the number of patients with diabetes older than 70 years will quadruple worldwide in the next 3 decades due to the increase in DM2.<a class="elsevierStyleCrossRef" href="#bib0955">6</a>Antidiabetic treatment and the objectives of glycemic control in elderly patients with DM2 should be individualized according to their biopsychosocial characteristics. In elderly patients for whom the benefits of intensive antidiabetic treatment are limited, the basic objectives should be to improve the quality of life, preserve functionality and prevent adverse effects, especially hypoglycemia.<a class="elsevierStyleCrossRef" href="#bib0960">7</a>Treatment of DM2 in the elderly was the subject of a consensus document published in 2012 and endorsed by several Spanish scientific societies.<a class="elsevierStyleCrossRef" href="#bib0965">8</a> Since then, new therapeutic groups and evidence have emerged that warrant an update to this consensus document. The present document focuses on the therapeutic aspects of DM2 in elderly patients.Functional capacity, frailty and diabetesFrailty is a clinical syndrome associated with aging, characterized by the presence of at least 3 of the following criteria: involuntary weight loss, exhaustion, muscle weakness, slowness of gait and physical hypoactivity (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0935">2</a> Frailty is the main predictor of disability, dependence and mortality in the elderly,<a class="elsevierStyleCrossRef" href="#bib0970">9</a> including those with diabetes,<a class="elsevierStyleCrossRef" href="#bib0975">10</a> and is a more potent prognostic marker than the comorbidity burden.<a class="elsevierStyleCrossRef" href="#bib0980">11</a> Diabetes is a risk factor for the development of frailty,<a class="elsevierStyleCrossRef" href="#bib0985">12</a> both for predisposing patients to sarcopenia and cognitive dysfunction and for microvascular and macrovascular complications (retinopathy, polyneuropathy, dysautonomia, renal failure and cardiovascular disease).<a class="elsevierStyleCrossRef" href="#bib0930">1</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Early detection of frailty and sarcopenia are key aspects in the management of elderly patients in general<a class="elsevierStyleCrossRefs" href="#bib0990">13,14</a> and in those who have diabetes in particular.<a class="elsevierStyleCrossRef" href="#bib0930">1</a> The objectives of glycemic control should be based on the patient's functional status, because neither frail elderly patients nor those with established functional impairment will benefit from strict glycemic control,<a class="elsevierStyleCrossRef" href="#bib1000">15</a> which can simultaneously increase the risk of hypoglycemia.<a class="elsevierStyleCrossRef" href="#bib1005">16</a> A recent study concluded that the degree of glycemic control in institutionalized elderly patients was not related to persistent functional impairment or death, which highlighted the need to be conservative when managing diabetes in this population.<a class="elsevierStyleCrossRef" href="#bib1010">17</a>The early implementation of multimodal and multidisciplinary interventions in elderly patients with DM2, based on nutritional education and promoting physical activity, has been shown effective for maintaining functional autonomy.<a class="elsevierStyleCrossRef" href="#bib1015">18</a>Hypoglycemia in elderly patientsThe risk of severe hypoglycemia increases exponentially with age. A recent epidemiological study, performed on a Spanish population, reported that more than two-thirds of cases of severe hypoglycemia treated in emergency departments occurred in individuals older than 60 years, and 46% occurred in those older than 76 years.<a class="elsevierStyleCrossRef" href="#bib1020">19</a>In Spain, the mean age of patients with diabetes hospitalized for severe hypoglycemia exceeded 70 years.<a class="elsevierStyleCrossRef" href="#bib1025">20</a> Even so, overtreatment of hyperglycemia remains the rule, as demonstrated by published data from the United States<a class="elsevierStyleCrossRef" href="#bib1030">21</a> and Spain.<a class="elsevierStyleCrossRef" href="#bib1035">22</a>Elderly patients are more exposed to polypharmacy, drug interactions and adverse drug effects. Hypoglycemia secondary to the use of antidiabetic agents (insulin, sulfonylureas) represents the second leading cause of hospitalization in emergency departments due to adverse drug effects.<a class="elsevierStyleCrossRef" href="#bib1040">23</a>The higher rate of severe hypoglycemia is partly explained by the fact that, due to the lack of adrenergic alarm symptoms, asymptomatic hypoglycemia is more common in the elderly,<a class="elsevierStyleCrossRef" href="#bib1045">24</a> even in those who have poor glycemic control.<a class="elsevierStyleCrossRef" href="#bib1050">25</a> Elderly patients with cognitive disorder are a special risk group for severe hypoglycemia.<a class="elsevierStyleCrossRef" href="#bib1055">26</a> Hypoglycemia in the elderly is associated with delirium, cognitive impairment, falls and fractures, stroke, cardiac arrhythmia and increased mortality.<a class="elsevierStyleCrossRefs" href="#bib1060">27–29</a> Preventing hypoglycemia should therefore be a therapeutic priority.As a general rule for elderly patients, it is recommended that treatment be started with antidiabetic agents with low hypoglycemic risk (especially metformin and dipeptidyl peptidase-4 inhibitors [DPP-4i]) at low doses, with a progressive increase in dose, monitoring the response after each increase).<a class="elsevierStyleCrossRef" href="#bib1075">30</a> As much as possible, drugs associated with a high risk of hypoglycemia (sulfonylureas and insulin, especially prandial and mixtures) should be avoided.<a class="elsevierStyleCrossRef" href="#bib0965">8</a>General principles in the treatment of elderly patients with type 2 diabetesThe general principles that should govern the treatment of elderly patients with DM2 are as follows:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1.The therapeutic plan and glycemic control objectives should be based on a comprehensive patient assessment that accounts for the comorbidities, functional and cognitive capacity, affective disorders (with special emphasis on depressive conditions) and social support, which together help estimate the patient's total and active life expectancy.</li><li class="elsevierStyleListItem" id="lsti0010">2.It is essential to establish a shared decision-making process with the patient and their caregiver(s) that includes their wishes, expectations, preferences and capabilities.</li><li class="elsevierStyleListItem" id="lsti0015">3.The antidiabetic treatment objectives should be to preserve functional capacity and improve the quality of life.</li><li class="elsevierStyleListItem" id="lsti0020">4.Special attention should be paid to the contraindications, adverse effects and potential drug interactions of antidiabetic drugs.</li></ul>Glycemic control objectives for elderly patientsThe glycemic control objectives for elderly patients should be adapted to the patients’ functional and cognitive status, comorbidities and life expectancy.<a class="elsevierStyleCrossRef" href="#bib0965">8</a>Based on the individual assessment, 3 possibilities should be considered: 1) healthy elderly individuals with good functional and cognitive status, low comorbidity burden and good life expectancy: the therapeutic interventions and objectives may be similar to those of young adults with diabetes (HbA1c, 7–7.5%)<a class="elsevierStyleCrossRef" href="#bib1080">31</a>; 2) frail elderly with functional disability, dementia and/or limited life expectancy: Symptomatic hypoglycemia and hyperglycemia should be prevented. A reasonable objective would be to maintain an HbA1c level of 7.5–8.5%<a class="elsevierStyleCrossRefs" href="#bib0965">8,32</a>; and 3) elderly patients undergoing palliative care: The priority should be to preserve the quality of life, prevent symptomatic hyperglycemia and hypoglycemia and reduce the burden associated with antidiabetic treatment. In this context, measuring HbA1c is not relevant. Blood sugar should be kept below the renal threshold for glucose (<200mg/dL). The treatment should be simplified, avoiding drugs that induce hypoglycemia and those associated with gastrointestinal symptoms and hyporexia. Prandial insulin can be discontinued or substituted by oral drugs. The number of capillary blood sugar checks should be decreased or even eliminated.<a class="elsevierStyleCrossRef" href="#bib1090">33</a>Nonpharmacological treatment: nutrition and physical activityThere is little evidence of the benefits of lifestyle changes (therapeutic education, nutrition counseling, individualized physical activity) for elderly or frail patients with DM2.<a class="elsevierStyleCrossRef" href="#bib1080">31</a> A study is currently underway to analyze the impact of lifestyle changes on the functional capacity and quality of life of frail and “prefrail” elderly patients with DM2.<a class="elsevierStyleCrossRef" href="#bib1095">34</a>The Look AHEAD study included patients younger than 75 years (mean age, 59 years) with DM2 and obesity and found that although an intensive multifactorial intervention aimed at weight loss did not manage to reduce cardiovascular events,<a class="elsevierStyleCrossRef" href="#bib1100">35</a> it did improve the achievement of the objectives of metabolic control, cardiovascular risk factors, functional status and quality of life.<a class="elsevierStyleCrossRef" href="#bib1105">36</a> This benefit was greater in the older subgroup (65–75 years).<a class="elsevierStyleCrossRef" href="#bib1110">37</a> Nutrition education programs have shown improved metabolic control in the elderly.<a class="elsevierStyleCrossRef" href="#bib1115">38</a>Excessively low-calorie diets should be avoided in elderly patients due to increased risk of hypoglycemia and malnutrition, as these diets typically provide few proteins. This fact is important because sarcopenic obesity is frequent in the elderly and is characterized by a high body mass index (BMI) and low muscle mass. Highly restrictive diets can therefore worsen sarcopenia, which is associated with functional impairment, a risk of falls and institutionalization.<a class="elsevierStyleCrossRefs" href="#bib1120">39,40</a> Elderly patients might also need calcium and vitamin D and B12 supplements.The elderly are often believed not to benefit from variable-intensity physical exercise programs, not being able to perform them or not having good adherence. However, physical activity, especially multicomponent activity (aerobic, resistance, flexibility and balance), has shown its efficacy in the elderly with diabetes, improving not only glycemic control but also functional independence, self-esteem and quality of life. Its practice should therefore be recommended.<a class="elsevierStyleCrossRef" href="#bib1130">41</a>The prescription of physical activity should be adapted to the patient's limitations and preferences. Before implementing a physical activity program, the presence of potential contraindications, geriatric syndromes and limitations resulting from drug treatment should be ruled out. When starting a program, it is important to prevent orthostatic hypotension, dehydration and hypoglycemia (especially in patients treated with insulin or secretagogues).<a class="elsevierStyleCrossRef" href="#bib1130">41</a>Aerobic activities should be preferably indicated, although they are often limited by the associated comorbidity (e.g., cardiovascular and muscle-skeletal diseases). Aerobic exercises prevent falls, sarcopenia and functional impairment in patients with diabetes<a class="elsevierStyleCrossRef" href="#bib1135">42</a> and improves the cardiovascular risk profile.<a class="elsevierStyleCrossRef" href="#bib1140">43</a> Even a simple program of regular strolls decreases glycemia under fasting conditions, HbA1c and triglyceride levels in elderly patients with DM2.<a class="elsevierStyleCrossRef" href="#bib1145">44</a>Resistance training to increase muscle mass is considered an essential component for preventing and treating DM2 in the elderly and is the program of choice for frail elderly patients. Moderate to high-intensity exercises are, in contrast to previous assumptions, more effective for glycemic control and are generally safe for the elderly population. Exercises reaching 60–70% of the maximum load are usually considered sufficient (in weight training, the maximum weight that can be lifted in a certain exercise to perform one repetition is called a one-repetition maximum). Resistance training has shown metabolic benefits in elderly patients with DM2 (improved insulin sensitivity, reduced blood glucose under fasting conditions and reduced visceral adiposity)<a class="elsevierStyleCrossRef" href="#bib1150">45</a> and is associated with improved muscle strength and mobility and reduced falls.<a class="elsevierStyleCrossRef" href="#bib1155">46</a> However, to maintain the benefits of resistance training, continuous supervision is usually required.<a class="elsevierStyleCrossRef" href="#bib1160">47</a> Lastly, balance training reduces falls in the elderly with DM2.<a class="elsevierStyleCrossRef" href="#bib1165">48</a>PharmacotherapyMetforminAlthough no specific clinical trials have evaluated the safety and efficacy of metformin in the elderly, clinical experience supports its use as the basis of DM2 therapy in any age group,<a class="elsevierStyleCrossRefs" href="#bib1170">49–51</a> especially for patients with a high BMI,<a class="elsevierStyleCrossRef" href="#bib1185">52</a> although it is also effective in those with normal weight. Metformin acts through numerous mechanisms, although the main mechanism appears to be the activation of adenosine monophosphate-kinase, which leads to a reduction in the release of glucose by the liver.Metformin does not usually cause hypoglycemia and has been shown to be useful in patients with cardiovascular disease or stable heart failure.<a class="elsevierStyleCrossRef" href="#bib1190">53</a> Nevertheless, the use of metformin in the elderly can be associated with adverse events such as gastrointestinal intolerance, dysgeusia, hyporexia and vitamin B12 deficiency,<a class="elsevierStyleCrossRef" href="#bib1195">54</a> the latter of which should be periodically monitored.<a class="elsevierStyleCrossRef" href="#bib1200">55</a> Metformin is contraindicated for patients with glomerular filtration rates <30mL/min.<a class="elsevierStyleCrossRefs" href="#bib1205">56,57</a> Although lactic acidosis is uncommon, half of patients older than 65 years present undiagnosed renal function.<a class="elsevierStyleCrossRef" href="#bib1215">58</a> It is therefore important to periodically monitor the renal function and reduce the dosage if the glomerular filtration rate is <45mL/min or discontinue it if <30mL/min.<a class="elsevierStyleCrossRefs" href="#bib1220">59,60</a>The use of metformin should be avoided in conditions of tissue hypoxia, respiratory failure, acute heart failure, hepatic impairment and when there is acute intercurrent disease, when iodinated contrast media is administered or when there is a risk of functional renal failure (vomiting, diarrhea). The usefulness of metformin is highly limited in patients with anorexia and low weight.Treatment should be started with a progressive titration from 425mg/day (half of an 850-mg tablet) to 1700mg/day. Higher dosages are not recommended because they increase the adverse effects without improving the efficacy.Five percent of patients have to discontinue using the drug due to poor gastrointestinal tolerance, a rate that can be higher in elderly patients.<a class="elsevierStyleCrossRef" href="#bib1230">61</a>SulfonylureasThese are low-cost and widely used drugs. They reduce the microvascular complications of DM2<a class="elsevierStyleCrossRef" href="#bib1235">62</a> and increase the release of insulin by blocking the adenosine triphosphate-sensitive potassium channels in pancreatic beta cells. Sulfonylureas should be used with caution given that the risk of severe hypoglycemia increases exponentially with age, especially with glibenclamide,<a class="elsevierStyleCrossRef" href="#bib1240">63</a> which is contraindicated for elderly patients,<a class="elsevierStyleCrossRef" href="#bib1245">64</a> with glimepiride<a class="elsevierStyleCrossRef" href="#bib1250">65</a> or especially gliclazide being preferable,<a class="elsevierStyleCrossRef" href="#bib1255">66</a> which produces the least hypoglycemia.<a class="elsevierStyleCrossRefs" href="#bib1260">67,68</a> Sulfonylureas also induce weight gain and are not recommended for patients with renal failure or high cardiovascular risk. Hypoglycemia is boosted in the presence of renal or hepatic failure, the concomitant administration of other oral diabetes drugs or insulin, a recent hospital discharge, advanced age, reduced dietary intake and the use of 5 or more drugs.<a class="elsevierStyleCrossRef" href="#bib1270">69</a> Sulfonylureas have multiple drug interactions (salicylates, dicoumarin agents, sulfonamides, ﬁbrates, allopurinol, methotrexate, diuretics, beta-blockers, corticosteroids), which complicate their use in polymedicated patients.Meglitinides (repaglinide, nateglinide)These are secretagogues, as are sulfonylureas, but with faster and shorter action and a higher cost. They act preferentially on postprandial hyperglycemia. Their more limited pharmacokinetic profile reduces the risk of hypoglycemia compared with sulfonylureas,<a class="elsevierStyleCrossRef" href="#bib1275">70</a> especially in elderly patients with erratic eating patterns.<a class="elsevierStyleCrossRef" href="#bib1280">71</a> Repaglinide, due to its mainly biliary elimination, can be used for patients with moderate to advanced renal failure.<a class="elsevierStyleCrossRef" href="#bib1285">72</a> Combining the drug with gemfibrozil<a class="elsevierStyleCrossRef" href="#bib1290">73</a> or other drugs that activate or inhibit cytochrome P450 is contraindicated. The drug should be administered approximately 15min before meals.Alpha-glucosidase inhibitors (acarbose, miglitol)These drugs inhibit intestinal alpha-glucosidase, slowing digestion and intestinal absorption of carbohydrates. These inhibitors are especially aimed at controlling postprandial glycemia, especially in patients who have carbohydrate-rich diets. The drugs have systemic effects and can reduce the risk of cardiovascular events and arterial hypertension.<a class="elsevierStyleCrossRef" href="#bib1295">74</a> Although the drugs do not induce hypoglycemia and can be potentially useful for some elderly patients with diabetes,<a class="elsevierStyleCrossRefs" href="#bib1300">75,76</a> their use can be limited by their low efficacy and high rate of adverse gastrointestinal effects (flatulence, diarrhea), both in monotherapy and especially in combination with metformin. These inhibitors can change digoxin and acenocoumarol levels.Thiazolidinediones (pioglitazone)These agents act by increasing peripheral insulin sensitivity. Thiazolidinediones provide longer-lasting glycemic control than metformin and sulfonylureas.<a class="elsevierStyleCrossRef" href="#bib1310">77</a> Pioglitazone does not produce hypoglycemia and acts favorably on the lipid profile (increased HDL-cholesterol and reduced triglyceride levels). Pioglitazone can be beneficial in the secondary prevention of cardiovascular events (proACTIVE study),<a class="elsevierStyleCrossRef" href="#bib1315">78</a> with reduced all-cause mortality.<a class="elsevierStyleCrossRef" href="#bib1320">79</a> The drug has also been shown to histologically improve nonalcoholic steatohepatitis in patients with prediabetes or DM2.<a class="elsevierStyleCrossRef" href="#bib1325">80</a> However, pioglitazone has various adverse effects that limit its use in the elderly,<a class="elsevierStyleCrossRefs" href="#bib1330">81,82</a> such as weight gain, salt and fluid retention, dilutional anemia, increased risk of heart failure,<a class="elsevierStyleCrossRef" href="#bib1340">83</a> increased risk of fractures (especially in postmenopausal women)<a class="elsevierStyleCrossRef" href="#bib1345">84</a> and the possibility of accelerating cognitive impairment.<a class="elsevierStyleCrossRef" href="#bib1350">85</a> The increased risk of bladder cancer with the long-term use of pioglitazone is a subject of debate.<a class="elsevierStyleCrossRefs" href="#bib1355">86,87</a>Dipeptidyl peptidase-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin)These drugs act by inhibiting the proteolytic dipeptidyl peptidase-4 (DPP-4) enzyme, which degrades the incretin hormones, increasing the availability and action of endogenous glucagon-like peptide-1 (GLP-1). DPP4i have been shown to be useful in monotherapy, in combination with other hypoglycemic agents and in triple therapy.These oral drugs are well tolerated, effective and safe in the short<a class="elsevierStyleCrossRefs" href="#bib1365">88,89</a> and long term,<a class="elsevierStyleCrossRefs" href="#bib1375">90,91</a> in elderly and young patients with diabetes.<a class="elsevierStyleCrossRef" href="#bib1385">92</a> The drugs have no effect on gastric emptying, do not induce reduced central intake and do not cause gastrointestinal intolerance or weight loss.DPP4i do not induce hypoglycemia (glucose-dependent mechanism), do not change body weight and have no significant drug interactions, which makes them an attractive therapeutic option for treating DM2 in the elderly. These inhibitors do not require dose adjustments in elderly patients. Several studies have shown the safety and efficacy of vildagliptin,<a class="elsevierStyleCrossRefs" href="#bib1390">93–95</a> sitagliptin,<a class="elsevierStyleCrossRefs" href="#bib1405">96,97</a> saxagliptin,<a class="elsevierStyleCrossRefs" href="#bib1405">96–101</a> linagliptin<a class="elsevierStyleCrossRefs" href="#bib1435">102–104</a> and alogliptin<a class="elsevierStyleCrossRef" href="#bib1450">105</a> in elderly patients.DPP4i have shown their cardiovascular safety in clinical trials performed on patients with high cardiovascular risk,<a class="elsevierStyleCrossRefs" href="#bib1455">106–108</a> including patients older than 75 years.<a class="elsevierStyleCrossRef" href="#bib1470">109</a> In the SAVOR-TIMI 53 study,<a class="elsevierStyleCrossRef" href="#bib1455">106</a> the use of saxagliptin was associated with a significant increase in hospitalizations for heart failure, especially among patients with high baseline levels of B-type natriuretic peptide (BNP) or with a prior history of heart failure or chronic renal failure.<a class="elsevierStyleCrossRefs" href="#bib1475">110,111</a> The EXAMINE study<a class="elsevierStyleCrossRef" href="#bib1460">107</a> also observed a greater tendency (although not significant) to develop heart failure among patients treated with alogliptin.However, extensive observational studies in standard clinical practice<a class="elsevierStyleCrossRef" href="#bib1485">112</a> and the TECOS study with sitagliptin<a class="elsevierStyleCrossRef" href="#bib1490">113</a> could not confirm an association between these drugs and an increased rate of heart failure. Furthermore, separate meta-analyses of patients with DM2 treated with vildagliptin<a class="elsevierStyleCrossRef" href="#bib1495">114</a> or linagliptin<a class="elsevierStyleCrossRef" href="#bib1500">115</a> support its cardiovascular safety and the absence of heart failure risk.Vildagliptin is the only DPP4i that has had a clinical trial with patients with DM2 and chronic heart failure (NYHA functional class I–III) with a left ventricular ejection fraction <40%.<a class="elsevierStyleCrossRef" href="#bib1505">116</a> Treatment with vildagliptin, compared with placebo, was not associated with significant changes in the latter, thereby meeting the objective of noninferiority.<a class="elsevierStyleCrossRef" href="#bib1505">116</a>DPP4i can be used safely, without the risk of hypoglycemia, at any stage of chronic renal failure. All of these inhibitors require dose adjustments in cases of moderate to severe renal failure, except for linagliptin, which is eliminated by the bile duct.DPP4i have few drug interactions, an important advantage for elderly patients, for whom polypharmacy is common.<a class="elsevierStyleCrossRef" href="#bib1510">117</a> Vildagliptin is not metabolized by cytochrome P450 and therefore has a lower risk of interactions.Glucagon-like peptide-1 receptor agonists (exenatide, liraglutide, lixisenatide, exenatide-LAR, dulaglutide)GLP-1 receptor agonists (GLP-1 RA) act by activating GLP-1 receptors, which results in increased insulin secretion and reduced glucagon secretion, depending on the blood glucose level. The agonists also slow gastric emptying and increase the feeling of central satiety.These drugs induce significant weight loss and are therefore an option when weight loss is a priority (e.g., elderly with advanced gonarthrosis, sleep apnea syndrome, hypoventilation, steatohepatitis and metabolic syndrome). However, weight loss and reduced appetite can have undesirable effects in frail elderly patients, for whom hyporexia and malnutrition are common. The presence of sarcopenic obesity is common among elderly patients (excess adiposity with little lean mass due to loss of muscle mass). Sarcopenia is a marker of a poor functional and vital prognosis. Weight loss (a desirable objective in most patients with DM2) at the cost of lean mass can therefore be counterproductive.GLP-1 RAs do not induce hypoglycemia but are associated with frequent gastrointestinal discomfort (nausea, vomiting and diarrhea). In addition to their high cost, the agonists require subcutaneous administration (daily in 2 doses in the case of exenatide; daily in 1 dose for liraglutide and lixisenatide; and weekly with exenatide-LAR and dulaglutide). We should therefore ensure that the patient or caregiver have an appropriate level of dexterity before prescribing these drugs. Although there is controversy on the possible onset of pancreatitis with the use of GLP-1 RAs, various studies have not confirmed this association, considering that the higher incidence of pancreatitis is the result of having diabetes.<a class="elsevierStyleCrossRef" href="#bib1515">118</a>GLP-1 RAs have shown a good cardiovascular safety profile in patients with DM2 of high vascular risk. Compared with placebo, lixisenatide<a class="elsevierStyleCrossRef" href="#bib1520">119</a> and exenatide LAR<a class="elsevierStyleCrossRef" href="#bib1525">120</a> have shown noninferiority, while liraglutide<a class="elsevierStyleCrossRef" href="#bib1530">121</a> and semaglutide (an unmarketed GLP-1 RA that is administered weekly)<a class="elsevierStyleCrossRef" href="#bib1535">122</a> showed a reduction in cardiovascular events.There have been no specific studies with GLP-1 RA in elderly individuals. All analyses by subgroups in patients 65 years of age or older achieved a greater reduction in HbA1c, fewer hypoglycemic events and greater weight loss, although with more gastrointestinal effects than the comparator (glimepiride,<a class="elsevierStyleCrossRef" href="#bib1540">123</a> sitagliptin,<a class="elsevierStyleCrossRefs" href="#bib1545">124,125</a> insulin glargine<a class="elsevierStyleCrossRefs" href="#bib1555">126–128</a> or placebo).<a class="elsevierStyleCrossRef" href="#bib1570">129</a> Significant differences have not been observed in terms of safety and efficacy compared with younger patients.<a class="elsevierStyleCrossRef" href="#bib1575">130</a> In a meta-analysis with lixisenatide<a class="elsevierStyleCrossRef" href="#bib1570">129</a> and in a grouped analysis with liraglutide,<a class="elsevierStyleCrossRef" href="#bib1575">130</a> the results for patients older than 65 years were similar to those observed in other age groups. Nevertheless, none of these studies included vulnerable or frail elderly individuals.In conclusion, GLP-1 RAs can be used with caution in elderly patients, customizing their indication (e.g., elderly patients with obesity and good functional status).<a class="elsevierStyleCrossRef" href="#bib1580">131</a> These drugs should not be administered to frail elderly patients<a class="elsevierStyleCrossRef" href="#bib1075">30</a> or those with a history of pancreatitis and/or glomerular filtration rates <30mL/min.<a class="elsevierStyleCrossRef" href="#bib1585">132</a>Sodium-glucose cotransporter 2 inhibitors (dapagliflozin, canagliflozin, empagliflozin)These drugs inhibit the sodium-glucose cotransporter 2 (SGLT2) in the renal tubule, preventing the reabsorption of glucose and inducing glycosuria. Given that their mechanism of action is independent of insulin,<a class="elsevierStyleCrossRef" href="#bib1590">133</a> SGLT2 inhibitors are effective in all stages of DM2 and do not produce hypoglycemia. Due to their glycosuric effect, SGLT2 inhibitors induce a mean weight loss of 1.8–2kg, at the expense especially of fat mass, and have a hypotensive effect that causes a mean reduction in systolic blood pressure of −4.45mmHg.<a class="elsevierStyleCrossRefs" href="#bib1595">134,135</a> Glycosuria causes osmotic diuresis and polyuria.These are effective drugs that have shown superiority in glycemic control against sulfonylureas<a class="elsevierStyleCrossRefs" href="#bib1605">136,137</a> and sitagliptin.<a class="elsevierStyleCrossRef" href="#bib1615">138</a> The expected reduction in HbA1c levels varies between 0.7% and 1%, sustained up to 3 years of follow-up.SGLT2 inhibitors are administered in a single daily dose orally, are effective in monotherapy<a class="elsevierStyleCrossRef" href="#bib1620">139</a> (if there is a contraindication or intolerance to metformin), as a second hypoglycemic agent and in triple therapy. Hypoglycemia can occur when combining these inhibitors with sulfonylureas or insulin. Therefore, the dosage needs to be reduced or the discontinuation of the sulfonylureas needs to be assessed.<a class="elsevierStyleCrossRef" href="#bib1625">140</a>In the EMPA-REG study, performed on patients with DM2, cardiovascular disease and a glomerular filtration rate >30mL/min/1.72m2, empagliflozin decreased overall mortality by 32%, hospitalizations for heart failure by 35% and mortality due to cardiovascular causes by 38%.<a class="elsevierStyleCrossRef" href="#bib1630">141</a> In this study, empagliflozin showed a nephroprotective effect, delaying the progression of renal failure and the need for dialysis.<a class="elsevierStyleCrossRef" href="#bib1635">142</a> Based on these results, the latest guidelines from the European Society of Cardiology recommend considering the use of the SGLT2 inhibitor empagliflozin in patients with heart failure and DM2.<a class="elsevierStyleCrossRef" href="#bib1640">143</a>More recently, the results of the study on equivalent cardiovascular safety with canagliflozin have been published.<a class="elsevierStyleCrossRef" href="#bib1645">144</a> This study involved a grouped analysis of the CANVAS and CANVAS-R studies, which included 10,142 patients with DM2 and high cardiovascular risk. The patients treated with canagliflozin had a 14% reduction (hazard ratio [HR], 0.8; 95% confidence interval [95% CI] 0.75–0.97) in the risk of events included globally in the primary endpoint (a composite of death by cardiovascular cause, nonfatal myocardial infarction and nonfatal stroke). Statistical significance was not reached, however, in reducing each of these events separately. Hospitalization for heart failure was reduced by 33% (HR, 0.67; 95% CI 0.52–0.87). The results showed renal benefits with canagliflozin, reducing both the progression of albuminuria (HR, 0.73; 95% CI 0.67–0.79) and the composite result of a sustained reduction of 40% in the estimated glomerular filtration rate and death by renal causes (HR, 0.60; 95% CI 0.47–0.77). A more detailed analysis of these results is being performed, which has still not been incorporated in the international recommendations.The most common adverse effect of these drugs is genital mycoses, especially in women. A slight increase has also been reported in urinary tract infections.<a class="elsevierStyleCrossRef" href="#bib1645">144</a> In elderly individuals, we should consider the potential adverse effects related to volume depletion secondary to osmotic diuresis (dehydration, electrolyte disorders, hypotension and renal failure).<a class="elsevierStyleCrossRef" href="#bib1650">145</a> Given the drugs’ hypotensive effect, it is important to rule out the presence of orthostatic hypotension, which is common in elderly patients with diabetes.<a class="elsevierStyleCrossRef" href="#bib1655">146</a> Although a study with canagliflozin observed an increased number of fractures (extremities but not hip),<a class="elsevierStyleCrossRef" href="#bib1660">147</a> possibly related to an increased risk of falls, this association was not confirmed in a subsequent study.<a class="elsevierStyleCrossRef" href="#bib1665">148</a> The CANVAS study confirmed a greater tendency for fractures in patients treated with canagliflozin versus placebo (HR, 1.23; 95% CI 0.99–1.52). In this study, treatment with canagliflozin was associated with a higher risk of amputation, mainly of toes and the metatarsal (6.3 vs. 3.4 participants with amputation per 1000 patient-years, which corresponds to a risk ratio of 1.97; 95% CI 1.41–2.75).<a class="elsevierStyleCrossRef" href="#bib1645">144</a> Finally, rare cases of normoglycemic ketoacidosis have been reported (with only slightly elevated blood glucose readings), especially in long-standing DM2 in conditions of insulinopenia or latent autoimmune diabetes in adults in which an insulin dose reduction was performed. Normoglycemic ketoacidosis has also been reported in fasting conditions, with excessive alcohol consumption, extreme physical exercise and intercurrent acute processes.<a class="elsevierStyleCrossRef" href="#bib1670">149</a>The action of these drugs depends on the renal function, such that their efficacy decreases when the glomerular filtration rate is <60mL/min/1.72m2. Dapagliflozin should not be administered below this filtration rate; however, empagliflozin and canagliflozin may be used, with reduced dosages,<a class="elsevierStyleCrossRefs" href="#bib1675">150,151</a> for GFRs between 45 and 60mL/min/1.72m2 and discontinued for GFRs <30mL/min/1.72m2.There is little experience on the use of SGLT2 inhibitors in the elderly population and should therefore be indicated with caution and individually in selected patients.<a class="elsevierStyleCrossRef" href="#bib1685">152</a> Canagliflozin has had a number of studies with elderly patients of up to 80 years of age, which has shown a safety and efficacy comparable to that with younger patients.<a class="elsevierStyleCrossRefs" href="#bib1650">145,147,148,153–155</a> Furthermore, the analysis by age subgroup with empagliflozin<a class="elsevierStyleCrossRef" href="#bib1620">139</a> and dapagliflozin<a class="elsevierStyleCrossRefs" href="#bib1705">156–158</a> has shown similar results to those obtained in younger patients.InsulinInsulin is the most potent hypoglycemic agent and acts by activating the insulin receptors, decreasing glucose production by the liver and promoting the peripheral use of glucose. In Spain, 20% of patients with diabetes older than 75 years were treated with insulin in monotherapy or combined with other antidiabetic agents.<a class="elsevierStyleCrossRef" href="#bib1720">159</a>Patients older than 80 years treated with insulin have a greater risk of severe hypoglycemia,<a class="elsevierStyleCrossRef" href="#bib1060">27</a> falls and fractures.<a class="elsevierStyleCrossRef" href="#bib1725">160</a> To minimize these risks, insulin therapy for the elderly should be individualized, emphasizing patient safety. It is worth remembering that HbA1c levels are not a reliable predictor of the risk of hypoglycemia.<a class="elsevierStyleCrossRef" href="#bib1730">161</a>Basal insulinizationThe starting daily dose should be lower (0.1–0.2IU/kg) than for younger patients with DM2, especially for frail elderly patients, those with low weight and those with renal failure. Dose adjustments should be performed gradually and progressively.When treatment is started with a basal insulin, it is recommended that the treatment with metformin be maintained to reduce the insulin requirements.<a class="elsevierStyleCrossRef" href="#bib1735">162</a> The combination of basal insulin and oral secretagogues (sulfonylureas, glinides) is not safe for elderly patients due to the high risk of hypoglycemia. The maintenance or discontinuation of other noninsulin antidiabetic drugs should be individually assessed, considering the complexity of the treatment and its costs.<a class="elsevierStyleCrossRef" href="#bib1735">162</a>Although they have not demonstrated superiority in glycemic control, basal insulin analogs (glargine 100U and 300U, detemir, degludec) have a lower risk of hypoglycemia (especially nocturnal) than human neutral protamine Hagedorn insulin,<a class="elsevierStyleCrossRefs" href="#bib1740">163–165</a> and can therefore be preferable for elderly patients despite the drugs’ higher cost. Compared with insulin glargine 100U, both insulin glargine 300U<a class="elsevierStyleCrossRef" href="#bib1755">166</a> and insulin degludec<a class="elsevierStyleCrossRefs" href="#bib1760">167,168</a> have shown a lower rate of hypoglycemia (especially nocturnal) and greater flexibility in the administration schedule, due to their lower variability and longer drug action. These characteristics favorably place these new insulins for the management of elderly institutionalized patients, although studies are needed on this population.<a class="elsevierStyleCrossRef" href="#bib1770">169</a>Basal insulin intensificationWhen the glycemic control objectives are not met with a basal insulin regimen, the insulin therapy needs to be intensified, either by adding a dose of prandial insulin in the main meal (basal-plus), in the 3 main meals (basal-bolus) or transitioning to a regimen of 2 or 3 daily doses of premixed insulin. These complex insulin therapy regimens are associated with a significant risk of hypoglycemia<a class="elsevierStyleCrossRefs" href="#bib1740">163,170,171</a> and represent a significant burden of care, including the need for repeated capillary blood glucose checks.If prandial insulin is required, rapid-acting insulin analogs are preferable to regular insulin due the former's lower rate of hypoglycemia.<a class="elsevierStyleCrossRef" href="#bib1785">172</a> Biphasic or premixed insulins, such as insulin aspart and insulin glulisine, can be administered after meals<a class="elsevierStyleCrossRefs" href="#bib1775">170,173,174</a> and improve glycemic control in patients poorly controlled with basal insulin but are associated with a higher risk of hypoglycemia and weight gain.<a class="elsevierStyleCrossRefs" href="#bib1780">171,175</a> Premixed insulins have an inflexible pharmacokinetic profile and are therefore only indicated for elderly patients with regular schedules and patterns of dietary intake and physical activity. In these cases, premixed insulins can provide glycemic control similar to that of the more complex basal-bolus regimen.<a class="elsevierStyleCrossRef" href="#bib1805">176</a>In elderly patients with difficult-to-control or highly progressed DM2 with insulinopenia and a good capacity for self-care, the basal-bolus regimen can provide appropriate glycemic control with a good safety profile and patient satisfaction.<a class="elsevierStyleCrossRef" href="#bib1810">177</a>Insulin devicesAnother issue to consider is the various devices for administering insulin and choosing that which best fits the patient's abilities and capabilities. By far, the most widely used is the pen type. To detect elderly patients with problems in self-administering insulin, a test known as the “clock-drawing test” is employed to assess cognitive impairment and the presence of constructional apraxia.<a class="elsevierStyleCrossRef" href="#bib1815">178</a> The test consists of having the patient draw (on a blank sheet of paper) a clock indicating ten past eleven.Combined therapiesIn the elderly, it is essential to simplify insulin therapy as much as possible to reduce the risk of hypoglycemia and minimize the burden of care associated with the complex insulin regimens.<a class="elsevierStyleCrossRef" href="#bib1730">161</a> As has been mentioned, oral diabetes drugs should be maintained (except for sulfonylureas/glinides) with the basal insulin to reduce the insulin requirements and risks of hypoglycemia.<a class="elsevierStyleCrossRefs" href="#bib1735">162,179</a> DPP4i have an especially appropriate profile in this population due to their low risk of hypoglycemia and broad experience with their use in elderly patients with frailty and renal failure. Their combination with basal insulin allows for the insulin dosage to be reduced and minimizes the adverse effects of the insulin (hypoglycemia, weight gain).<a class="elsevierStyleCrossRef" href="#bib1825">180</a>The combined therapy of basal insulin and GLP-1 RA provides excellent glycemic control and a lower risk of hypoglycemia than the complex insulin regimens.<a class="elsevierStyleCrossRef" href="#bib1830">181</a> There have been studies with fixed-dose combinations of basal insulin and GLP-1 RA (degludec and liraglutide; glargine and lixisenatide) that facilitate the posology and improve the gastrointestinal tolerance to GLP-1 RA. These combinations can therefore play a role in treating DM2 in the elderly. Nevertheless, the lesser experience with using these combinations in the elderly, a lack of specific studies and the combinations’ higher cost make careful patient selection a necessity.Therapy deintensificationElderly patients with diabetes are frequently overtreated.<a class="elsevierStyleCrossRefs" href="#bib1030">21,22</a> Antidiabetic therapy deintensification is therefore appropriate after a comprehensive geriatric assessment has been conducted, indicating less complex and safer regimens (with a lower risk of hypoglycemia, lower burden of care, better tolerance and no drug interactions).<a class="elsevierStyleCrossRef" href="#bib1835">182</a> The simplification of complex insulin regimens in elderly patients reduces the risk of hypoglycemia and the burden of care, without compromising glycemic control.<a class="elsevierStyleCrossRef" href="#bib1730">161</a> In this respect, it is worth remembering that a high HbA1c level does not rule out the risk of hypoglycemia in the elderly.<a class="elsevierStyleCrossRefs" href="#bib1050">25,161</a>Therapeutic algorithm for type 2 diabetes in elderly patients (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) The planning of DM2 therapy for elderly patients should be based on a comprehensive geriatric assessment. If the elderly patient is frail, dependent or has moderate to severe dementia, the priority objective is to prevent symptomatic hypoglycemia and hyperglycemia. The antidiabetic agents recommended in these cases would be metformin and DPP4i. Other antidiabetic drugs not associated with a significant risk of hypoglycemia have adverse effects that limit their use in this population, effects such as hypotension, dehydration and renal failure (with SGLT2i) and nausea, vomiting, diarrhea and weight loss (with GLP-1 RA) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Renal failure is a prevalent comorbidity in elderly patients with diabetes and affects the treatment options.<a class="elsevierStyleCrossRef" href="#bib1840">183</a> In Spain, the prevalence of stage 4 and 5 chronic kidney disease (glomerular filtration rate <30mL/min/1.73m2) in patients with DM2 aged 70–79 years and ≥80 years is approximately 30% and 50%, respectively.<a class="elsevierStyleCrossRef" href="#bib1845">184</a> In these circumstances, the preferred therapeutic options are DPP4i and insulin. Although repaglinide and pioglitazone may be used from a pharmacokinetic standpoint, their adverse effects profile (hypoglycemia with repaglinide; heart failure and fractures with pioglitazone) make them an inadvisable option.<a class="elsevierStyleCrossRef" href="#bib1850">185</a>Finally, for elderly patients with a high cardiovascular risk and none of the previously mentioned clinical limitations (moderate–severe renal failure, frailty, dementia), the priority should be to select antidiabetic drugs that have shown cardiovascular benefits, such as empagliflozin and liraglutide. Other drugs that have shown cardiovascular safety include metformin, pioglitazone and DPP4i.Conflict of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres991073" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec954991" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres991072" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec954992" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Functional capacity, frailty and diabetes" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Hypoglycemia in elderly patients" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "General principles in the treatment of elderly patients with type 2 diabetes" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Glycemic control objectives for elderly patients" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Nonpharmacological treatment: nutrition and physical activity" ] 10 => array:3 [ "identificador" => "sec0035" "titulo" => "Pharmacotherapy" "secciones" => array:14 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Metformin" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Sulfonylureas" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Meglitinides (repaglinide, nateglinide)" ] 3 => array:2 [ "identificador" => "sec0055" "titulo" => "Alpha-glucosidase inhibitors (acarbose, miglitol)" ] 4 => array:2 [ "identificador" => "sec0060" "titulo" => "Thiazolidinediones (pioglitazone)" ] 5 => array:2 [ "identificador" => "sec0065" "titulo" => "Dipeptidyl peptidase-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin)" ] 6 => array:2 [ "identificador" => "sec0070" "titulo" => "Glucagon-like peptide-1 receptor agonists (exenatide, liraglutide, lixisenatide, exenatide-LAR, dulaglutide)" ] 7 => array:2 [ "identificador" => "sec0075" "titulo" => "Sodium-glucose cotransporter 2 inhibitors (dapagliflozin, canagliflozin, empagliflozin)" ] 8 => array:2 [ "identificador" => "sec0080" "titulo" => "Insulin" ] 9 => array:2 [ "identificador" => "sec0085" "titulo" => "Basal insulinization" ] 10 => array:2 [ "identificador" => "sec0090" "titulo" => "Basal insulin intensification" ] 11 => array:2 [ "identificador" => "sec0095" "titulo" => "Insulin devices" ] 12 => array:2 [ "identificador" => "sec0100" "titulo" => "Combined therapies" ] 13 => array:2 [ "identificador" => "sec0105" "titulo" => "Therapy deintensification" ] ] ] 11 => array:2 [ "identificador" => "sec0110" "titulo" => "Therapeutic algorithm for type 2 diabetes in elderly patients (Fig. 1)" ] 12 => array:2 [ "identificador" => "sec0115" "titulo" => "Conflict of interest" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-10-11" "fechaAceptado" => "2017-12-03" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec954991" "palabras" => array:3 [ 0 => "Type 2 diabetes mellitus" 1 => "Elderly" 2 => "Antidiabetic treatment" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec954992" "palabras" => array:3 [ 0 => "Diabetes mellitus tipo 2" 1 => "Anciano" 2 => "Tratamiento antidiabético" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The prevalence of type 2 diabetes mellitus (DM2) increases markedly with age. Antidiabetic treatment and the objectives of glycaemic control in elderly patients with DM2 should be individualized according to their biopsychosocial characteristics. In elderly patients for whom the benefits of intensive antidiabetic treatment are limited, the basic objectives should be to improve the quality of life, preserve functionality and avoid adverse effects, especially hypoglycaemia. Treatment of DM2 in the elderly was the subject of a consensus document published in 2012 and endorsed by several Spanish scientific societies. Since then, new therapeutic groups and evidence have emerged that warrant an update to this consensus document. The present document focuses on the therapeutic aspects of DM2 in elderly patients, understood as being older than 75 years or frail." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La prevalencia de la diabetes mellitus tipo 2 (DM2) se incrementa marcadamente con la edad. El tratamiento antidiabético y los objetivos de control glucémico en el anciano con DM2 deben individualizarse en función de sus características biopsicosociales. En los pacientes de edad avanzada, en los que los beneficios de un tratamiento antidiabético intensivo son limitados, los objetivos básicos deben ser mejorar la calidad de vida, preservar la funcionalidad y evitar los efectos adversos, muy especialmente las hipoglucemias. El tratamiento de la DM2 en el anciano fue objeto de un consenso, publicado en 2012 y avalado por varias sociedades científicas españolas. Desde entonces, han aparecido nuevos grupos terapéuticos y evidencias que hacen recomendable su actualización. El presente documento se centrará en los aspectos terapéuticos de la DM2 en el paciente anciano, entendiendo como tal el tener una edad mayor de 75 años o presentar fragilidad." ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Gómez-Huelgas R, Gómez Peralta F, Rodríguez Mañas L, Formiga F, Puig Domingo M, Mediavilla Bravo JJ, et al. Tratamiento de la diabetes mellitus tipo 2 en el paciente anciano. Rev Clin Esp. 2018;218:74–88." ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "This article is published simultaneously in https://doi.org/10.1016/j.regg.2017.12.003, with the consent of the authors and editors." ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1519 "Ancho" => 2506 "Tamanyo" => 258442 ] ] "descripcion" => array:1 [ "en" => "Treatment algorithm for type 2 diabetes mellitus in elderly patients. Abbreviations: DPP4i: dipeptidyl peptidase-4 inhibitors; GLP-1RA: glucagon-like peptide-1 receptor agonists; SGLT2i: sodium-glucose cotransporter 2 inhibitors. a Repaglinide and pioglitazone can be used in patients with GFR <30mL/min, but their use is not recommended due to the risk of adverse effects: hypoglycemia (repaglinide); salt and fluid retention, heart failure and fractures (pioglitazone). b Empagliflozin, canagliflozin and liraglutide have shown reduced cardiovascular morbidity and mortality in patients with high vascular risk type 2 diabetes. c Saxagliptin should be avoided for patients with heart failure. d Pioglitazone is contraindicated for patients with heart failure or at risk for fractures." ] ] 1 => 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:2 [ "leyenda" => "We considered the presence of the frailty phenotype when the patient met 3 or more criteria and the prefrailty phenotype when 1 or 2 criteria were met.Abbreviation: BMI, body mass index.Taken from Fried et al.<a class="elsevierStyleCrossRef" href="#bib0935">2</a>" "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="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Marker \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Assessment tool \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Spontaneous weight loss \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unexplained loss >4.5kg or >5% of the weight in the last year \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Fatigue \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Self-reported fatigue, identified by a score >2 on the Center Epidemiological Studies-Depression scale (0–8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Muscle weakness \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Grip strength (dynamometer) <20% of normal, adjusted for BMI and sex \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Motor retardation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Gait speed for covering 4.5m <20% of normal, adjusted for sex and height (>6–7s) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypoactivity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Weekly calorie expenditure below the lower quintile, adjusted for sex (men <383kcal/week, women <270kcal/week) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1678923.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Fried frailty criteria." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:185 [ 0 => array:3 [ "identificador" => "bib0930" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetes in older people: new insights and remaining challenges" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S2213-8587(14)70176-7" "Revista" => array:6 [ …6] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0935" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Frailty in older adults: evidence for a phenotype" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0940" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available from: www.unpopulation.org [accessed 06.11.17]" "contribucion" => array:1 [ 0 => array:1 [ "titulo" => "Population ageing and development" ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:1 [ …1] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0945" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evolución de los indicadores de calidad asistencial al diabético tipo 2 en atención primaria (1996–2007)" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0950" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevalence of diabetes mellitus and impaired glucose regulation in Spain: the Di@bet.es study" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => 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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Treatment algorithm for type 2 diabetes mellitus in elderly patients&#46;</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; DPP4i&#58; dipeptidyl peptidase-4 inhibitors&#59; GLP-1RA&#58; glucagon-like peptide-1 receptor agonists&#59; SGLT2i&#58; sodium-glucose cotransporter 2 inhibitors&#46;</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">a</span> Repaglinide and pioglitazone can be used in patients with GFR &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#44; but their use is not recommended due to the risk of adverse effects&#58; hypoglycemia &#40;repaglinide&#41;&#59; salt and fluid retention&#44; heart failure and fractures &#40;pioglitazone&#41;&#46;</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">b</span> Empagliflozin&#44; canagliflozin and liraglutide have shown reduced cardiovascular morbidity and mortality in patients with high vascular risk type 2 diabetes&#46;</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">c</span> Saxagliptin should be avoided for patients with heart failure&#46;</p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">d</span> Pioglitazone is contraindicated for patients with heart failure or at risk for fractures&#46;</p>"
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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">Aging is characterized by a progressive loss of an individual&#39;s functional capacity&#46; The elderly population is biologically heterogeneous&#44; thereby necessitating a comprehensive assessment&#44; one that includes functional aspects in the decision-making process&#46;<a class="elsevierStyleCrossRef" href="#bib0930"><span class="elsevierStyleSup">1</span></a> Although there is no consensus on the definition of an individual as elderly&#44; this document uses the operational definition of having an age greater than 75 years or presenting frailty&#46;<a class="elsevierStyleCrossRef" href="#bib0935"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Demographic predictions put Spain as one of the most aged countries in the world&#46; In 2050&#44; 12&#37; of the Spanish population will be 80 years of age or older&#46;<a class="elsevierStyleCrossRef" href="#bib0940"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Type 2 diabetes mellitus &#40;DM2&#41; is a disease closely linked to aging&#44; and its prevalence increases markedly with age&#46; This situation is due to the combination of insulin secretion deficiency&#44; insulin resistance &#40;related to the increase in visceral&#44; intermuscular and intramuscular adiposity&#41;&#44; sarcopenia and physical inactivity in elderly patients&#46; In Spain&#44; 63&#37; of patients with diabetes &#40;of whom more than 90&#37; have DM2&#41; are older than 65 years&#44;<a class="elsevierStyleCrossRef" href="#bib0945"><span class="elsevierStyleSup">4</span></a> and more than a third of the population older than 75 years has diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0950"><span class="elsevierStyleSup">5</span></a> It has been predicted that the number of patients with diabetes older than 70 years will quadruple worldwide in the next 3 decades due to the increase in DM2&#46;<a class="elsevierStyleCrossRef" href="#bib0955"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Antidiabetic treatment and the objectives of glycemic control in elderly patients with DM2 should be individualized according to their biopsychosocial characteristics&#46; In elderly patients for whom the benefits of intensive antidiabetic treatment are limited&#44; the basic objectives should be to improve the quality of life&#44; preserve functionality and prevent adverse effects&#44; especially hypoglycemia&#46;<a class="elsevierStyleCrossRef" href="#bib0960"><span class="elsevierStyleSup">7</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Treatment of DM2 in the elderly was the subject of a consensus document published in 2012 and endorsed by several Spanish scientific societies&#46;<a class="elsevierStyleCrossRef" href="#bib0965"><span class="elsevierStyleSup">8</span></a> Since then&#44; new therapeutic groups and evidence have emerged that warrant an update to this consensus document&#46; The present document focuses on the therapeutic aspects of DM2 in elderly patients&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Functional capacity&#44; frailty and diabetes</span><p id="par0030" class="elsevierStylePara elsevierViewall">Frailty is a clinical syndrome associated with aging&#44; characterized by the presence of at least 3 of the following criteria&#58; involuntary weight loss&#44; exhaustion&#44; muscle weakness&#44; slowness of gait and physical hypoactivity &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0935"><span class="elsevierStyleSup">2</span></a> Frailty is the main predictor of disability&#44; dependence and mortality in the elderly&#44;<a class="elsevierStyleCrossRef" href="#bib0970"><span class="elsevierStyleSup">9</span></a> including those with diabetes&#44;<a class="elsevierStyleCrossRef" href="#bib0975"><span class="elsevierStyleSup">10</span></a> and is a more potent prognostic marker than the comorbidity burden&#46;<a class="elsevierStyleCrossRef" href="#bib0980"><span class="elsevierStyleSup">11</span></a> Diabetes is a risk factor for the development of frailty&#44;<a class="elsevierStyleCrossRef" href="#bib0985"><span class="elsevierStyleSup">12</span></a> both for predisposing patients to sarcopenia and cognitive dysfunction and for microvascular and macrovascular complications &#40;retinopathy&#44; polyneuropathy&#44; dysautonomia&#44; renal failure and cardiovascular disease&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0930"><span class="elsevierStyleSup">1</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Early detection of frailty and sarcopenia are key aspects in the management of elderly patients in general<a class="elsevierStyleCrossRefs" href="#bib0990"><span class="elsevierStyleSup">13&#44;14</span></a> and in those who have diabetes in particular&#46;<a class="elsevierStyleCrossRef" href="#bib0930"><span class="elsevierStyleSup">1</span></a> The objectives of glycemic control should be based on the patient&#39;s functional status&#44; because neither frail elderly patients nor those with established functional impairment will benefit from strict glycemic control&#44;<a class="elsevierStyleCrossRef" href="#bib1000"><span class="elsevierStyleSup">15</span></a> which can simultaneously increase the risk of hypoglycemia&#46;<a class="elsevierStyleCrossRef" href="#bib1005"><span class="elsevierStyleSup">16</span></a> A recent study concluded that the degree of glycemic control in institutionalized elderly patients was not related to persistent functional impairment or death&#44; which highlighted the need to be conservative when managing diabetes in this population&#46;<a class="elsevierStyleCrossRef" href="#bib1010"><span class="elsevierStyleSup">17</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The early implementation of multimodal and multidisciplinary interventions in elderly patients with DM2&#44; based on nutritional education and promoting physical activity&#44; has been shown effective for maintaining functional autonomy&#46;<a class="elsevierStyleCrossRef" href="#bib1015"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Hypoglycemia in elderly patients</span><p id="par0045" class="elsevierStylePara elsevierViewall">The risk of severe hypoglycemia increases exponentially with age&#46; A recent epidemiological study&#44; performed on a Spanish population&#44; reported that more than two-thirds of cases of severe hypoglycemia treated in emergency departments occurred in individuals older than 60 years&#44; and 46&#37; occurred in those older than 76 years&#46;<a class="elsevierStyleCrossRef" href="#bib1020"><span class="elsevierStyleSup">19</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In Spain&#44; the mean age of patients with diabetes hospitalized for severe hypoglycemia exceeded 70 years&#46;<a class="elsevierStyleCrossRef" href="#bib1025"><span class="elsevierStyleSup">20</span></a> Even so&#44; overtreatment of hyperglycemia remains the rule&#44; as demonstrated by published data from the United States<a class="elsevierStyleCrossRef" href="#bib1030"><span class="elsevierStyleSup">21</span></a> and Spain&#46;<a class="elsevierStyleCrossRef" href="#bib1035"><span class="elsevierStyleSup">22</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Elderly patients are more exposed to polypharmacy&#44; drug interactions and adverse drug effects&#46; Hypoglycemia secondary to the use of antidiabetic agents &#40;insulin&#44; sulfonylureas&#41; represents the second leading cause of hospitalization in emergency departments due to adverse drug effects&#46;<a class="elsevierStyleCrossRef" href="#bib1040"><span class="elsevierStyleSup">23</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The higher rate of severe hypoglycemia is partly explained by the fact that&#44; due to the lack of adrenergic alarm symptoms&#44; asymptomatic hypoglycemia is more common in the elderly&#44;<a class="elsevierStyleCrossRef" href="#bib1045"><span class="elsevierStyleSup">24</span></a> even in those who have poor glycemic control&#46;<a class="elsevierStyleCrossRef" href="#bib1050"><span class="elsevierStyleSup">25</span></a> Elderly patients with cognitive disorder are a special risk group for severe hypoglycemia&#46;<a class="elsevierStyleCrossRef" href="#bib1055"><span class="elsevierStyleSup">26</span></a> Hypoglycemia in the elderly is associated with delirium&#44; cognitive impairment&#44; falls and fractures&#44; stroke&#44; cardiac arrhythmia and increased mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib1060"><span class="elsevierStyleSup">27&#8211;29</span></a> Preventing hypoglycemia should therefore be a therapeutic priority&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">As a general rule for elderly patients&#44; it is recommended that treatment be started with antidiabetic agents with low hypoglycemic risk &#40;especially metformin and dipeptidyl peptidase-4 inhibitors &#91;DPP-4i&#93;&#41; at low doses&#44; with a progressive increase in dose&#44; monitoring the response after each increase&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1075"><span class="elsevierStyleSup">30</span></a> As much as possible&#44; drugs associated with a high risk of hypoglycemia &#40;sulfonylureas and insulin&#44; especially prandial and mixtures&#41; should be avoided&#46;<a class="elsevierStyleCrossRef" href="#bib0965"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">General principles in the treatment of elderly patients with type 2 diabetes</span><p id="par0070" class="elsevierStylePara elsevierViewall">The general principles that should govern the treatment of elderly patients with DM2 are as follows&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0075" class="elsevierStylePara elsevierViewall">The therapeutic plan and glycemic control objectives should be based on a comprehensive patient assessment that accounts for the comorbidities&#44; functional and cognitive capacity&#44; affective disorders &#40;with special emphasis on depressive conditions&#41; and social support&#44; which together help estimate the patient&#39;s total and active life expectancy&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0080" class="elsevierStylePara elsevierViewall">It is essential to establish a shared decision-making process with the patient and their caregiver&#40;s&#41; that includes their wishes&#44; expectations&#44; preferences and capabilities&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3&#46;</span><p id="par0085" class="elsevierStylePara elsevierViewall">The antidiabetic treatment objectives should be to preserve functional capacity and improve the quality of life&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4&#46;</span><p id="par0090" class="elsevierStylePara elsevierViewall">Special attention should be paid to the contraindications&#44; adverse effects and potential drug interactions of antidiabetic drugs&#46;</p></li></ul></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Glycemic control objectives for elderly patients</span><p id="par0095" class="elsevierStylePara elsevierViewall">The glycemic control objectives for elderly patients should be adapted to the patients&#8217; functional and cognitive status&#44; comorbidities and life expectancy&#46;<a class="elsevierStyleCrossRef" href="#bib0965"><span class="elsevierStyleSup">8</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Based on the individual assessment&#44; 3 possibilities should be considered&#58; 1&#41; healthy elderly individuals with good functional and cognitive status&#44; low comorbidity burden and good life expectancy&#58; the therapeutic interventions and objectives may be similar to those of young adults with diabetes &#40;HbA1c&#44; 7&#8211;7&#46;5&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib1080"><span class="elsevierStyleSup">31</span></a>&#59; 2&#41; frail elderly with functional disability&#44; dementia and&#47;or limited life expectancy&#58; Symptomatic hypoglycemia and hyperglycemia should be prevented&#46; A reasonable objective would be to maintain an HbA1c level of 7&#46;5&#8211;8&#46;5&#37;<a class="elsevierStyleCrossRefs" href="#bib0965"><span class="elsevierStyleSup">8&#44;32</span></a>&#59; and 3&#41; elderly patients undergoing palliative care&#58; The priority should be to preserve the quality of life&#44; prevent symptomatic hyperglycemia and hypoglycemia and reduce the burden associated with antidiabetic treatment&#46; In this context&#44; measuring HbA1c is not relevant&#46; Blood sugar should be kept below the renal threshold for glucose &#40;&#60;200<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;&#46; The treatment should be simplified&#44; avoiding drugs that induce hypoglycemia and those associated with gastrointestinal symptoms and hyporexia&#46; Prandial insulin can be discontinued or substituted by oral drugs&#46; The number of capillary blood sugar checks should be decreased or even eliminated&#46;<a class="elsevierStyleCrossRef" href="#bib1090"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Nonpharmacological treatment&#58; nutrition and physical activity</span><p id="par0105" class="elsevierStylePara elsevierViewall">There is little evidence of the benefits of lifestyle changes &#40;therapeutic education&#44; nutrition counseling&#44; individualized physical activity&#41; for elderly or frail patients with DM2&#46;<a class="elsevierStyleCrossRef" href="#bib1080"><span class="elsevierStyleSup">31</span></a> A study is currently underway to analyze the impact of lifestyle changes on the functional capacity and quality of life of frail and &#8220;prefrail&#8221; elderly patients with DM2&#46;<a class="elsevierStyleCrossRef" href="#bib1095"><span class="elsevierStyleSup">34</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">The Look AHEAD study included patients younger than 75 years &#40;mean age&#44; 59 years&#41; with DM2 and obesity and found that although an intensive multifactorial intervention aimed at weight loss did not manage to reduce cardiovascular events&#44;<a class="elsevierStyleCrossRef" href="#bib1100"><span class="elsevierStyleSup">35</span></a> it did improve the achievement of the objectives of metabolic control&#44; cardiovascular risk factors&#44; functional status and quality of life&#46;<a class="elsevierStyleCrossRef" href="#bib1105"><span class="elsevierStyleSup">36</span></a> This benefit was greater in the older subgroup &#40;65&#8211;75 years&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1110"><span class="elsevierStyleSup">37</span></a> Nutrition education programs have shown improved metabolic control in the elderly&#46;<a class="elsevierStyleCrossRef" href="#bib1115"><span class="elsevierStyleSup">38</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Excessively low-calorie diets should be avoided in elderly patients due to increased risk of hypoglycemia and malnutrition&#44; as these diets typically provide few proteins&#46; This fact is important because sarcopenic obesity is frequent in the elderly and is characterized by a high body mass index &#40;BMI&#41; and low muscle mass&#46; Highly restrictive diets can therefore worsen sarcopenia&#44; which is associated with functional impairment&#44; a risk of falls and institutionalization&#46;<a class="elsevierStyleCrossRefs" href="#bib1120"><span class="elsevierStyleSup">39&#44;40</span></a> Elderly patients might also need calcium and vitamin D and B12 supplements&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The elderly are often believed not to benefit from variable-intensity physical exercise programs&#44; not being able to perform them or not having good adherence&#46; However&#44; physical activity&#44; especially multicomponent activity &#40;aerobic&#44; resistance&#44; flexibility and balance&#41;&#44; has shown its efficacy in the elderly with diabetes&#44; improving not only glycemic control but also functional independence&#44; self-esteem and quality of life&#46; Its practice should therefore be recommended&#46;<a class="elsevierStyleCrossRef" href="#bib1130"><span class="elsevierStyleSup">41</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The prescription of physical activity should be adapted to the patient&#39;s limitations and preferences&#46; Before implementing a physical activity program&#44; the presence of potential contraindications&#44; geriatric syndromes and limitations resulting from drug treatment should be ruled out&#46; When starting a program&#44; it is important to prevent orthostatic hypotension&#44; dehydration and hypoglycemia &#40;especially in patients treated with insulin or secretagogues&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1130"><span class="elsevierStyleSup">41</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Aerobic activities should be preferably indicated&#44; although they are often limited by the associated comorbidity &#40;e&#46;g&#46;&#44; cardiovascular and muscle-skeletal diseases&#41;&#46; Aerobic exercises prevent falls&#44; sarcopenia and functional impairment in patients with diabetes<a class="elsevierStyleCrossRef" href="#bib1135"><span class="elsevierStyleSup">42</span></a> and improves the cardiovascular risk profile&#46;<a class="elsevierStyleCrossRef" href="#bib1140"><span class="elsevierStyleSup">43</span></a> Even a simple program of regular strolls decreases glycemia under fasting conditions&#44; HbA1c and triglyceride levels in elderly patients with DM2&#46;<a class="elsevierStyleCrossRef" href="#bib1145"><span class="elsevierStyleSup">44</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Resistance training to increase muscle mass is considered an essential component for preventing and treating DM2 in the elderly and is the program of choice for frail elderly patients&#46; Moderate to high-intensity exercises are&#44; in contrast to previous assumptions&#44; more effective for glycemic control and are generally safe for the elderly population&#46; Exercises reaching 60&#8211;70&#37; of the maximum load are usually considered sufficient &#40;in weight training&#44; the maximum weight that can be lifted in a certain exercise to perform one repetition is called a one-repetition maximum&#41;&#46; Resistance training has shown metabolic benefits in elderly patients with DM2 &#40;improved insulin sensitivity&#44; reduced blood glucose under fasting conditions and reduced visceral adiposity&#41;<a class="elsevierStyleCrossRef" href="#bib1150"><span class="elsevierStyleSup">45</span></a> and is associated with improved muscle strength and mobility and reduced falls&#46;<a class="elsevierStyleCrossRef" href="#bib1155"><span class="elsevierStyleSup">46</span></a> However&#44; to maintain the benefits of resistance training&#44; continuous supervision is usually required&#46;<a class="elsevierStyleCrossRef" href="#bib1160"><span class="elsevierStyleSup">47</span></a> Lastly&#44; balance training reduces falls in the elderly with DM2&#46;<a class="elsevierStyleCrossRef" href="#bib1165"><span class="elsevierStyleSup">48</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Pharmacotherapy</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Metformin</span><p id="par0140" class="elsevierStylePara elsevierViewall">Although no specific clinical trials have evaluated the safety and efficacy of metformin in the elderly&#44; clinical experience supports its use as the basis of DM2 therapy in any age group&#44;<a class="elsevierStyleCrossRefs" href="#bib1170"><span class="elsevierStyleSup">49&#8211;51</span></a> especially for patients with a high BMI&#44;<a class="elsevierStyleCrossRef" href="#bib1185"><span class="elsevierStyleSup">52</span></a> although it is also effective in those with normal weight&#46; Metformin acts through numerous mechanisms&#44; although the main mechanism appears to be the activation of adenosine monophosphate-kinase&#44; which leads to a reduction in the release of glucose by the liver&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Metformin does not usually cause hypoglycemia and has been shown to be useful in patients with cardiovascular disease or stable heart failure&#46;<a class="elsevierStyleCrossRef" href="#bib1190"><span class="elsevierStyleSup">53</span></a> Nevertheless&#44; the use of metformin in the elderly can be associated with adverse events such as gastrointestinal intolerance&#44; dysgeusia&#44; hyporexia and vitamin B12 deficiency&#44;<a class="elsevierStyleCrossRef" href="#bib1195"><span class="elsevierStyleSup">54</span></a> the latter of which should be periodically monitored&#46;<a class="elsevierStyleCrossRef" href="#bib1200"><span class="elsevierStyleSup">55</span></a> Metformin is contraindicated for patients with glomerular filtration rates &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46;<a class="elsevierStyleCrossRefs" href="#bib1205"><span class="elsevierStyleSup">56&#44;57</span></a> Although lactic acidosis is uncommon&#44; half of patients older than 65 years present undiagnosed renal function&#46;<a class="elsevierStyleCrossRef" href="#bib1215"><span class="elsevierStyleSup">58</span></a> It is therefore important to periodically monitor the renal function and reduce the dosage if the glomerular filtration rate is &#60;45<span class="elsevierStyleHsp" style=""></span>mL&#47;min or discontinue it if &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46;<a class="elsevierStyleCrossRefs" href="#bib1220"><span class="elsevierStyleSup">59&#44;60</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The use of metformin should be avoided in conditions of tissue hypoxia&#44; respiratory failure&#44; acute heart failure&#44; hepatic impairment and when there is acute intercurrent disease&#44; when iodinated contrast media is administered or when there is a risk of functional renal failure &#40;vomiting&#44; diarrhea&#41;&#46; The usefulness of metformin is highly limited in patients with anorexia and low weight&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Treatment should be started with a progressive titration from 425<span class="elsevierStyleHsp" style=""></span>mg&#47;day &#40;half of an 850-mg tablet&#41; to 1700<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46; Higher dosages are not recommended because they increase the adverse effects without improving the efficacy&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Five percent of patients have to discontinue using the drug due to poor gastrointestinal tolerance&#44; a rate that can be higher in elderly patients&#46;<a class="elsevierStyleCrossRef" href="#bib1230"><span class="elsevierStyleSup">61</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Sulfonylureas</span><p id="par0165" class="elsevierStylePara elsevierViewall">These are low-cost and widely used drugs&#46; They reduce the microvascular complications of DM2<a class="elsevierStyleCrossRef" href="#bib1235"><span class="elsevierStyleSup">62</span></a> and increase the release of insulin by blocking the adenosine triphosphate-sensitive potassium channels in pancreatic beta cells&#46; Sulfonylureas should be used with caution given that the risk of severe hypoglycemia increases exponentially with age&#44; especially with glibenclamide&#44;<a class="elsevierStyleCrossRef" href="#bib1240"><span class="elsevierStyleSup">63</span></a> which is contraindicated for elderly patients&#44;<a class="elsevierStyleCrossRef" href="#bib1245"><span class="elsevierStyleSup">64</span></a> with glimepiride<a class="elsevierStyleCrossRef" href="#bib1250"><span class="elsevierStyleSup">65</span></a> or especially gliclazide being preferable&#44;<a class="elsevierStyleCrossRef" href="#bib1255"><span class="elsevierStyleSup">66</span></a> which produces the least hypoglycemia&#46;<a class="elsevierStyleCrossRefs" href="#bib1260"><span class="elsevierStyleSup">67&#44;68</span></a> Sulfonylureas also induce weight gain and are not recommended for patients with renal failure or high cardiovascular risk&#46; Hypoglycemia is boosted in the presence of renal or hepatic failure&#44; the concomitant administration of other oral diabetes drugs or insulin&#44; a recent hospital discharge&#44; advanced age&#44; reduced dietary intake and the use of 5 or more drugs&#46;<a class="elsevierStyleCrossRef" href="#bib1270"><span class="elsevierStyleSup">69</span></a> Sulfonylureas have multiple drug interactions &#40;salicylates&#44; dicoumarin agents&#44; sulfonamides&#44; &#64257;brates&#44; allopurinol&#44; methotrexate&#44; diuretics&#44; beta-blockers&#44; corticosteroids&#41;&#44; which complicate their use in polymedicated patients&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Meglitinides &#40;repaglinide&#44; nateglinide&#41;</span><p id="par0170" class="elsevierStylePara elsevierViewall">These are secretagogues&#44; as are sulfonylureas&#44; but with faster and shorter action and a higher cost&#46; They act preferentially on postprandial hyperglycemia&#46; Their more limited pharmacokinetic profile reduces the risk of hypoglycemia compared with sulfonylureas&#44;<a class="elsevierStyleCrossRef" href="#bib1275"><span class="elsevierStyleSup">70</span></a> especially in elderly patients with erratic eating patterns&#46;<a class="elsevierStyleCrossRef" href="#bib1280"><span class="elsevierStyleSup">71</span></a> Repaglinide&#44; due to its mainly biliary elimination&#44; can be used for patients with moderate to advanced renal failure&#46;<a class="elsevierStyleCrossRef" href="#bib1285"><span class="elsevierStyleSup">72</span></a> Combining the drug with gemfibrozil<a class="elsevierStyleCrossRef" href="#bib1290"><span class="elsevierStyleSup">73</span></a> or other drugs that activate or inhibit cytochrome P450 is contraindicated&#46; The drug should be administered approximately 15<span class="elsevierStyleHsp" style=""></span>min before meals&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Alpha-glucosidase inhibitors &#40;acarbose&#44; miglitol&#41;</span><p id="par0175" class="elsevierStylePara elsevierViewall">These drugs inhibit intestinal alpha-glucosidase&#44; slowing digestion and intestinal absorption of carbohydrates&#46; These inhibitors are especially aimed at controlling postprandial glycemia&#44; especially in patients who have carbohydrate-rich diets&#46; The drugs have systemic effects and can reduce the risk of cardiovascular events and arterial hypertension&#46;<a class="elsevierStyleCrossRef" href="#bib1295"><span class="elsevierStyleSup">74</span></a> Although the drugs do not induce hypoglycemia and can be potentially useful for some elderly patients with diabetes&#44;<a class="elsevierStyleCrossRefs" href="#bib1300"><span class="elsevierStyleSup">75&#44;76</span></a> their use can be limited by their low efficacy and high rate of adverse gastrointestinal effects &#40;flatulence&#44; diarrhea&#41;&#44; both in monotherapy and especially in combination with metformin&#46; These inhibitors can change digoxin and acenocoumarol levels&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Thiazolidinediones &#40;pioglitazone&#41;</span><p id="par0180" class="elsevierStylePara elsevierViewall">These agents act by increasing peripheral insulin sensitivity&#46; Thiazolidinediones provide longer-lasting glycemic control than metformin and sulfonylureas&#46;<a class="elsevierStyleCrossRef" href="#bib1310"><span class="elsevierStyleSup">77</span></a> Pioglitazone does not produce hypoglycemia and acts favorably on the lipid profile &#40;increased HDL-cholesterol and reduced triglyceride levels&#41;&#46; Pioglitazone can be beneficial in the secondary prevention of cardiovascular events &#40;proACTIVE study&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib1315"><span class="elsevierStyleSup">78</span></a> with reduced all-cause mortality&#46;<a class="elsevierStyleCrossRef" href="#bib1320"><span class="elsevierStyleSup">79</span></a> The drug has also been shown to histologically improve nonalcoholic steatohepatitis in patients with prediabetes or DM2&#46;<a class="elsevierStyleCrossRef" href="#bib1325"><span class="elsevierStyleSup">80</span></a> However&#44; pioglitazone has various adverse effects that limit its use in the elderly&#44;<a class="elsevierStyleCrossRefs" href="#bib1330"><span class="elsevierStyleSup">81&#44;82</span></a> such as weight gain&#44; salt and fluid retention&#44; dilutional anemia&#44; increased risk of heart failure&#44;<a class="elsevierStyleCrossRef" href="#bib1340"><span class="elsevierStyleSup">83</span></a> increased risk of fractures &#40;especially in postmenopausal women&#41;<a class="elsevierStyleCrossRef" href="#bib1345"><span class="elsevierStyleSup">84</span></a> and the possibility of accelerating cognitive impairment&#46;<a class="elsevierStyleCrossRef" href="#bib1350"><span class="elsevierStyleSup">85</span></a> The increased risk of bladder cancer with the long-term use of pioglitazone is a subject of debate&#46;<a class="elsevierStyleCrossRefs" href="#bib1355"><span class="elsevierStyleSup">86&#44;87</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Dipeptidyl peptidase-4 inhibitors &#40;sitagliptin&#44; vildagliptin&#44; saxagliptin&#44; linagliptin&#44; alogliptin&#41;</span><p id="par0185" class="elsevierStylePara elsevierViewall">These drugs act by inhibiting the proteolytic dipeptidyl peptidase-4 &#40;DPP-4&#41; enzyme&#44; which degrades the incretin hormones&#44; increasing the availability and action of endogenous glucagon-like peptide-1 &#40;GLP-1&#41;&#46; DPP4i have been shown to be useful in monotherapy&#44; in combination with other hypoglycemic agents and in triple therapy&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">These oral drugs are well tolerated&#44; effective and safe in the short<a class="elsevierStyleCrossRefs" href="#bib1365"><span class="elsevierStyleSup">88&#44;89</span></a> and long term&#44;<a class="elsevierStyleCrossRefs" href="#bib1375"><span class="elsevierStyleSup">90&#44;91</span></a> in elderly and young patients with diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib1385"><span class="elsevierStyleSup">92</span></a> The drugs have no effect on gastric emptying&#44; do not induce reduced central intake and do not cause gastrointestinal intolerance or weight loss&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">DPP4i do not induce hypoglycemia &#40;glucose-dependent mechanism&#41;&#44; do not change body weight and have no significant drug interactions&#44; which makes them an attractive therapeutic option for treating DM2 in the elderly&#46; These inhibitors do not require dose adjustments in elderly patients&#46; Several studies have shown the safety and efficacy of vildagliptin&#44;<a class="elsevierStyleCrossRefs" href="#bib1390"><span class="elsevierStyleSup">93&#8211;95</span></a> sitagliptin&#44;<a class="elsevierStyleCrossRefs" href="#bib1405"><span class="elsevierStyleSup">96&#44;97</span></a> saxagliptin&#44;<a class="elsevierStyleCrossRefs" href="#bib1405"><span class="elsevierStyleSup">96&#8211;101</span></a> linagliptin<a class="elsevierStyleCrossRefs" href="#bib1435"><span class="elsevierStyleSup">102&#8211;104</span></a> and alogliptin<a class="elsevierStyleCrossRef" href="#bib1450"><span class="elsevierStyleSup">105</span></a> in elderly patients&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">DPP4i have shown their cardiovascular safety in clinical trials performed on patients with high cardiovascular risk&#44;<a class="elsevierStyleCrossRefs" href="#bib1455"><span class="elsevierStyleSup">106&#8211;108</span></a> including patients older than 75 years&#46;<a class="elsevierStyleCrossRef" href="#bib1470"><span class="elsevierStyleSup">109</span></a> In the SAVOR-TIMI 53 study&#44;<a class="elsevierStyleCrossRef" href="#bib1455"><span class="elsevierStyleSup">106</span></a> the use of saxagliptin was associated with a significant increase in hospitalizations for heart failure&#44; especially among patients with high baseline levels of B-type natriuretic peptide &#40;BNP&#41; or with a prior history of heart failure or chronic renal failure&#46;<a class="elsevierStyleCrossRefs" href="#bib1475"><span class="elsevierStyleSup">110&#44;111</span></a> The EXAMINE study<a class="elsevierStyleCrossRef" href="#bib1460"><span class="elsevierStyleSup">107</span></a> also observed a greater tendency &#40;although not significant&#41; to develop heart failure among patients treated with alogliptin&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">However&#44; extensive observational studies in standard clinical practice<a class="elsevierStyleCrossRef" href="#bib1485"><span class="elsevierStyleSup">112</span></a> and the TECOS study with sitagliptin<a class="elsevierStyleCrossRef" href="#bib1490"><span class="elsevierStyleSup">113</span></a> could not confirm an association between these drugs and an increased rate of heart failure&#46; Furthermore&#44; separate meta-analyses of patients with DM2 treated with vildagliptin<a class="elsevierStyleCrossRef" href="#bib1495"><span class="elsevierStyleSup">114</span></a> or linagliptin<a class="elsevierStyleCrossRef" href="#bib1500"><span class="elsevierStyleSup">115</span></a> support its cardiovascular safety and the absence of heart failure risk&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Vildagliptin is the only DPP4i that has had a clinical trial with patients with DM2 and chronic heart failure &#40;NYHA functional class <span class="elsevierStyleSmallCaps">I&#8211;III</span>&#41; with a left ventricular ejection fraction &#60;40&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib1505"><span class="elsevierStyleSup">116</span></a> Treatment with vildagliptin&#44; compared with placebo&#44; was not associated with significant changes in the latter&#44; thereby meeting the objective of noninferiority&#46;<a class="elsevierStyleCrossRef" href="#bib1505"><span class="elsevierStyleSup">116</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">DPP4i can be used safely&#44; without the risk of hypoglycemia&#44; at any stage of chronic renal failure&#46; All of these inhibitors require dose adjustments in cases of moderate to severe renal failure&#44; except for linagliptin&#44; which is eliminated by the bile duct&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">DPP4i have few drug interactions&#44; an important advantage for elderly patients&#44; for whom polypharmacy is common&#46;<a class="elsevierStyleCrossRef" href="#bib1510"><span class="elsevierStyleSup">117</span></a> Vildagliptin is not metabolized by cytochrome P450 and therefore has a lower risk of interactions&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Glucagon-like peptide-1 receptor agonists &#40;exenatide&#44; liraglutide&#44; lixisenatide&#44; exenatide-LAR&#44; dulaglutide&#41;</span><p id="par0225" class="elsevierStylePara elsevierViewall">GLP-1 receptor agonists &#40;GLP-1 RA&#41; act by activating GLP-1 receptors&#44; which results in increased insulin secretion and reduced glucagon secretion&#44; depending on the blood glucose level&#46; The agonists also slow gastric emptying and increase the feeling of central satiety&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">These drugs induce significant weight loss and are therefore an option when weight loss is a priority &#40;e&#46;g&#46;&#44; elderly with advanced gonarthrosis&#44; sleep apnea syndrome&#44; hypoventilation&#44; steatohepatitis and metabolic syndrome&#41;&#46; However&#44; weight loss and reduced appetite can have undesirable effects in frail elderly patients&#44; for whom hyporexia and malnutrition are common&#46; The presence of sarcopenic obesity is common among elderly patients &#40;excess adiposity with little lean mass due to loss of muscle mass&#41;&#46; Sarcopenia is a marker of a poor functional and vital prognosis&#46; Weight loss &#40;a desirable objective in most patients with DM2&#41; at the cost of lean mass can therefore be counterproductive&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">GLP-1 RAs do not induce hypoglycemia but are associated with frequent gastrointestinal discomfort &#40;nausea&#44; vomiting and diarrhea&#41;&#46; In addition to their high cost&#44; the agonists require subcutaneous administration &#40;daily in 2 doses in the case of exenatide&#59; daily in 1 dose for liraglutide and lixisenatide&#59; and weekly with exenatide-LAR and dulaglutide&#41;&#46; We should therefore ensure that the patient or caregiver have an appropriate level of dexterity before prescribing these drugs&#46; Although there is controversy on the possible onset of pancreatitis with the use of GLP-1 RAs&#44; various studies have not confirmed this association&#44; considering that the higher incidence of pancreatitis is the result of having diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib1515"><span class="elsevierStyleSup">118</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">GLP-1 RAs have shown a good cardiovascular safety profile in patients with DM2 of high vascular risk&#46; Compared with placebo&#44; lixisenatide<a class="elsevierStyleCrossRef" href="#bib1520"><span class="elsevierStyleSup">119</span></a> and exenatide LAR<a class="elsevierStyleCrossRef" href="#bib1525"><span class="elsevierStyleSup">120</span></a> have shown noninferiority&#44; while liraglutide<a class="elsevierStyleCrossRef" href="#bib1530"><span class="elsevierStyleSup">121</span></a> and semaglutide &#40;an unmarketed GLP-1 RA that is administered weekly&#41;<a class="elsevierStyleCrossRef" href="#bib1535"><span class="elsevierStyleSup">122</span></a> showed a reduction in cardiovascular events&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">There have been no specific studies with GLP-1 RA in elderly individuals&#46; All analyses by subgroups in patients 65 years of age or older achieved a greater reduction in HbA1c&#44; fewer hypoglycemic events and greater weight loss&#44; although with more gastrointestinal effects than the comparator &#40;glimepiride&#44;<a class="elsevierStyleCrossRef" href="#bib1540"><span class="elsevierStyleSup">123</span></a> sitagliptin&#44;<a class="elsevierStyleCrossRefs" href="#bib1545"><span class="elsevierStyleSup">124&#44;125</span></a> insulin glargine<a class="elsevierStyleCrossRefs" href="#bib1555"><span class="elsevierStyleSup">126&#8211;128</span></a> or placebo&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1570"><span class="elsevierStyleSup">129</span></a> Significant differences have not been observed in terms of safety and efficacy compared with younger patients&#46;<a class="elsevierStyleCrossRef" href="#bib1575"><span class="elsevierStyleSup">130</span></a> In a meta-analysis with lixisenatide<a class="elsevierStyleCrossRef" href="#bib1570"><span class="elsevierStyleSup">129</span></a> and in a grouped analysis with liraglutide&#44;<a class="elsevierStyleCrossRef" href="#bib1575"><span class="elsevierStyleSup">130</span></a> the results for patients older than 65 years were similar to those observed in other age groups&#46; Nevertheless&#44; none of these studies included vulnerable or frail elderly individuals&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">In conclusion&#44; GLP-1 RAs can be used with caution in elderly patients&#44; customizing their indication &#40;e&#46;g&#46;&#44; elderly patients with obesity and good functional status&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1580"><span class="elsevierStyleSup">131</span></a> These drugs should not be administered to frail elderly patients<a class="elsevierStyleCrossRef" href="#bib1075"><span class="elsevierStyleSup">30</span></a> or those with a history of pancreatitis and&#47;or glomerular filtration rates &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46;<a class="elsevierStyleCrossRef" href="#bib1585"><span class="elsevierStyleSup">132</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Sodium-glucose cotransporter 2 inhibitors &#40;dapagliflozin&#44; canagliflozin&#44; empagliflozin&#41;</span><p id="par0255" class="elsevierStylePara elsevierViewall">These drugs inhibit the sodium-glucose cotransporter 2 &#40;SGLT2&#41; in the renal tubule&#44; preventing the reabsorption of glucose and inducing glycosuria&#46; Given that their mechanism of action is independent of insulin&#44;<a class="elsevierStyleCrossRef" href="#bib1590"><span class="elsevierStyleSup">133</span></a> SGLT2 inhibitors are effective in all stages of DM2 and do not produce hypoglycemia&#46; Due to their glycosuric effect&#44; SGLT2 inhibitors induce a mean weight loss of 1&#46;8&#8211;2<span class="elsevierStyleHsp" style=""></span>kg&#44; at the expense especially of fat mass&#44; and have a hypotensive effect that causes a mean reduction in systolic blood pressure of &#8722;4&#46;45<span class="elsevierStyleHsp" style=""></span>mmHg&#46;<a class="elsevierStyleCrossRefs" href="#bib1595"><span class="elsevierStyleSup">134&#44;135</span></a> Glycosuria causes osmotic diuresis and polyuria&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">These are effective drugs that have shown superiority in glycemic control against sulfonylureas<a class="elsevierStyleCrossRefs" href="#bib1605"><span class="elsevierStyleSup">136&#44;137</span></a> and sitagliptin&#46;<a class="elsevierStyleCrossRef" href="#bib1615"><span class="elsevierStyleSup">138</span></a> The expected reduction in HbA1c levels varies between 0&#46;7&#37; and 1&#37;&#44; sustained up to 3 years of follow-up&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">SGLT2 inhibitors are administered in a single daily dose orally&#44; are effective in monotherapy<a class="elsevierStyleCrossRef" href="#bib1620"><span class="elsevierStyleSup">139</span></a> &#40;if there is a contraindication or intolerance to metformin&#41;&#44; as a second hypoglycemic agent and in triple therapy&#46; Hypoglycemia can occur when combining these inhibitors with sulfonylureas or insulin&#46; Therefore&#44; the dosage needs to be reduced or the discontinuation of the sulfonylureas needs to be assessed&#46;<a class="elsevierStyleCrossRef" href="#bib1625"><span class="elsevierStyleSup">140</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">In the EMPA-REG study&#44; performed on patients with DM2&#44; cardiovascular disease and a glomerular filtration rate &#62;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;72<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; empagliflozin decreased overall mortality by 32&#37;&#44; hospitalizations for heart failure by 35&#37; and mortality due to cardiovascular causes by 38&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib1630"><span class="elsevierStyleSup">141</span></a> In this study&#44; empagliflozin showed a nephroprotective effect&#44; delaying the progression of renal failure and the need for dialysis&#46;<a class="elsevierStyleCrossRef" href="#bib1635"><span class="elsevierStyleSup">142</span></a> Based on these results&#44; the latest guidelines from the European Society of Cardiology recommend considering the use of the SGLT2 inhibitor empagliflozin in patients with heart failure and DM2&#46;<a class="elsevierStyleCrossRef" href="#bib1640"><span class="elsevierStyleSup">143</span></a></p><p id="par0275" class="elsevierStylePara elsevierViewall">More recently&#44; the results of the study on equivalent cardiovascular safety with canagliflozin have been published&#46;<a class="elsevierStyleCrossRef" href="#bib1645"><span class="elsevierStyleSup">144</span></a> This study involved a grouped analysis of the CANVAS and CANVAS-R studies&#44; which included 10&#44;142 patients with DM2 and high cardiovascular risk&#46; The patients treated with canagliflozin had a 14&#37; reduction &#40;hazard ratio &#91;HR&#93;&#44; 0&#46;8&#59; 95&#37; confidence interval &#91;95&#37; CI&#93; 0&#46;75&#8211;0&#46;97&#41; in the risk of events included globally in the primary endpoint &#40;a composite of death by cardiovascular cause&#44; nonfatal myocardial infarction and nonfatal stroke&#41;&#46; Statistical significance was not reached&#44; however&#44; in reducing each of these events separately&#46; Hospitalization for heart failure was reduced by 33&#37; &#40;HR&#44; 0&#46;67&#59; 95&#37; CI 0&#46;52&#8211;0&#46;87&#41;&#46; The results showed renal benefits with canagliflozin&#44; reducing both the progression of albuminuria &#40;HR&#44; 0&#46;73&#59; 95&#37; CI 0&#46;67&#8211;0&#46;79&#41; and the composite result of a sustained reduction of 40&#37; in the estimated glomerular filtration rate and death by renal causes &#40;HR&#44; 0&#46;60&#59; 95&#37; CI 0&#46;47&#8211;0&#46;77&#41;&#46; A more detailed analysis of these results is being performed&#44; which has still not been incorporated in the international recommendations&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">The most common adverse effect of these drugs is genital mycoses&#44; especially in women&#46; A slight increase has also been reported in urinary tract infections&#46;<a class="elsevierStyleCrossRef" href="#bib1645"><span class="elsevierStyleSup">144</span></a> In elderly individuals&#44; we should consider the potential adverse effects related to volume depletion secondary to osmotic diuresis &#40;dehydration&#44; electrolyte disorders&#44; hypotension and renal failure&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1650"><span class="elsevierStyleSup">145</span></a> Given the drugs&#8217; hypotensive effect&#44; it is important to rule out the presence of orthostatic hypotension&#44; which is common in elderly patients with diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib1655"><span class="elsevierStyleSup">146</span></a> Although a study with canagliflozin observed an increased number of fractures &#40;extremities but not hip&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib1660"><span class="elsevierStyleSup">147</span></a> possibly related to an increased risk of falls&#44; this association was not confirmed in a subsequent study&#46;<a class="elsevierStyleCrossRef" href="#bib1665"><span class="elsevierStyleSup">148</span></a> The CANVAS study confirmed a greater tendency for fractures in patients treated with canagliflozin versus placebo &#40;HR&#44; 1&#46;23&#59; 95&#37; CI 0&#46;99&#8211;1&#46;52&#41;&#46; In this study&#44; treatment with canagliflozin was associated with a higher risk of amputation&#44; mainly of toes and the metatarsal &#40;6&#46;3 vs&#46; 3&#46;4 participants with amputation per 1000 patient-years&#44; which corresponds to a risk ratio of 1&#46;97&#59; 95&#37; CI 1&#46;41&#8211;2&#46;75&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1645"><span class="elsevierStyleSup">144</span></a> Finally&#44; rare cases of normoglycemic ketoacidosis have been reported &#40;with only slightly elevated blood glucose readings&#41;&#44; especially in long-standing DM2 in conditions of insulinopenia or latent autoimmune diabetes in adults in which an insulin dose reduction was performed&#46; Normoglycemic ketoacidosis has also been reported in fasting conditions&#44; with excessive alcohol consumption&#44; extreme physical exercise and intercurrent acute processes&#46;<a class="elsevierStyleCrossRef" href="#bib1670"><span class="elsevierStyleSup">149</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">The action of these drugs depends on the renal function&#44; such that their efficacy decreases when the glomerular filtration rate is &#60;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;72<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46; Dapagliflozin should not be administered below this filtration rate&#59; however&#44; empagliflozin and canagliflozin may be used&#44; with reduced dosages&#44;<a class="elsevierStyleCrossRefs" href="#bib1675"><span class="elsevierStyleSup">150&#44;151</span></a> for GFRs between 45 and 60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;72<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> and discontinued for GFRs &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;72<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">There is little experience on the use of SGLT2 inhibitors in the elderly population and should therefore be indicated with caution and individually in selected patients&#46;<a class="elsevierStyleCrossRef" href="#bib1685"><span class="elsevierStyleSup">152</span></a> Canagliflozin has had a number of studies with elderly patients of up to 80 years of age&#44; which has shown a safety and efficacy comparable to that with younger patients&#46;<a class="elsevierStyleCrossRefs" href="#bib1650"><span class="elsevierStyleSup">145&#44;147&#44;148&#44;153&#8211;155</span></a> Furthermore&#44; the analysis by age subgroup with empagliflozin<a class="elsevierStyleCrossRef" href="#bib1620"><span class="elsevierStyleSup">139</span></a> and dapagliflozin<a class="elsevierStyleCrossRefs" href="#bib1705"><span class="elsevierStyleSup">156&#8211;158</span></a> has shown similar results to those obtained in younger patients&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Insulin</span><p id="par0295" class="elsevierStylePara elsevierViewall">Insulin is the most potent hypoglycemic agent and acts by activating the insulin receptors&#44; decreasing glucose production by the liver and promoting the peripheral use of glucose&#46; In Spain&#44; 20&#37; of patients with diabetes older than 75 years were treated with insulin in monotherapy or combined with other antidiabetic agents&#46;<a class="elsevierStyleCrossRef" href="#bib1720"><span class="elsevierStyleSup">159</span></a></p><p id="par0300" class="elsevierStylePara elsevierViewall">Patients older than 80 years treated with insulin have a greater risk of severe hypoglycemia&#44;<a class="elsevierStyleCrossRef" href="#bib1060"><span class="elsevierStyleSup">27</span></a> falls and fractures&#46;<a class="elsevierStyleCrossRef" href="#bib1725"><span class="elsevierStyleSup">160</span></a> To minimize these risks&#44; insulin therapy for the elderly should be individualized&#44; emphasizing patient safety&#46; It is worth remembering that HbA1c levels are not a reliable predictor of the risk of hypoglycemia&#46;<a class="elsevierStyleCrossRef" href="#bib1730"><span class="elsevierStyleSup">161</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Basal insulinization</span><p id="par0305" class="elsevierStylePara elsevierViewall">The starting daily dose should be lower &#40;0&#46;1&#8211;0&#46;2<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#41; than for younger patients with DM2&#44; especially for frail elderly patients&#44; those with low weight and those with renal failure&#46; Dose adjustments should be performed gradually and progressively&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">When treatment is started with a basal insulin&#44; it is recommended that the treatment with metformin be maintained to reduce the insulin requirements&#46;<a class="elsevierStyleCrossRef" href="#bib1735"><span class="elsevierStyleSup">162</span></a> The combination of basal insulin and oral secretagogues &#40;sulfonylureas&#44; glinides&#41; is not safe for elderly patients due to the high risk of hypoglycemia&#46; The maintenance or discontinuation of other noninsulin antidiabetic drugs should be individually assessed&#44; considering the complexity of the treatment and its costs&#46;<a class="elsevierStyleCrossRef" href="#bib1735"><span class="elsevierStyleSup">162</span></a></p><p id="par0315" class="elsevierStylePara elsevierViewall">Although they have not demonstrated superiority in glycemic control&#44; basal insulin analogs &#40;glargine 100<span class="elsevierStyleHsp" style=""></span>U and 300<span class="elsevierStyleHsp" style=""></span>U&#44; detemir&#44; degludec&#41; have a lower risk of hypoglycemia &#40;especially nocturnal&#41; than human neutral protamine Hagedorn insulin&#44;<a class="elsevierStyleCrossRefs" href="#bib1740"><span class="elsevierStyleSup">163&#8211;165</span></a> and can therefore be preferable for elderly patients despite the drugs&#8217; higher cost&#46; Compared with insulin glargine 100<span class="elsevierStyleHsp" style=""></span>U&#44; both insulin glargine 300U<a class="elsevierStyleCrossRef" href="#bib1755"><span class="elsevierStyleSup">166</span></a> and insulin degludec<a class="elsevierStyleCrossRefs" href="#bib1760"><span class="elsevierStyleSup">167&#44;168</span></a> have shown a lower rate of hypoglycemia &#40;especially nocturnal&#41; and greater flexibility in the administration schedule&#44; due to their lower variability and longer drug action&#46; These characteristics favorably place these new insulins for the management of elderly institutionalized patients&#44; although studies are needed on this population&#46;<a class="elsevierStyleCrossRef" href="#bib1770"><span class="elsevierStyleSup">169</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Basal insulin intensification</span><p id="par0320" class="elsevierStylePara elsevierViewall">When the glycemic control objectives are not met with a basal insulin regimen&#44; the insulin therapy needs to be intensified&#44; either by adding a dose of prandial insulin in the main meal &#40;basal-plus&#41;&#44; in the 3 main meals &#40;basal-bolus&#41; or transitioning to a regimen of 2 or 3 daily doses of premixed insulin&#46; These complex insulin therapy regimens are associated with a significant risk of hypoglycemia<a class="elsevierStyleCrossRefs" href="#bib1740"><span class="elsevierStyleSup">163&#44;170&#44;171</span></a> and represent a significant burden of care&#44; including the need for repeated capillary blood glucose checks&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">If prandial insulin is required&#44; rapid-acting insulin analogs are preferable to regular insulin due the former&#39;s lower rate of hypoglycemia&#46;<a class="elsevierStyleCrossRef" href="#bib1785"><span class="elsevierStyleSup">172</span></a> Biphasic or premixed insulins&#44; such as insulin aspart and insulin glulisine&#44; can be administered after meals<a class="elsevierStyleCrossRefs" href="#bib1775"><span class="elsevierStyleSup">170&#44;173&#44;174</span></a> and improve glycemic control in patients poorly controlled with basal insulin but are associated with a higher risk of hypoglycemia and weight gain&#46;<a class="elsevierStyleCrossRefs" href="#bib1780"><span class="elsevierStyleSup">171&#44;175</span></a> Premixed insulins have an inflexible pharmacokinetic profile and are therefore only indicated for elderly patients with regular schedules and patterns of dietary intake and physical activity&#46; In these cases&#44; premixed insulins can provide glycemic control similar to that of the more complex basal-bolus regimen&#46;<a class="elsevierStyleCrossRef" href="#bib1805"><span class="elsevierStyleSup">176</span></a></p><p id="par0330" class="elsevierStylePara elsevierViewall">In elderly patients with difficult-to-control or highly progressed DM2 with insulinopenia and a good capacity for self-care&#44; the basal-bolus regimen can provide appropriate glycemic control with a good safety profile and patient satisfaction&#46;<a class="elsevierStyleCrossRef" href="#bib1810"><span class="elsevierStyleSup">177</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Insulin devices</span><p id="par0335" class="elsevierStylePara elsevierViewall">Another issue to consider is the various devices for administering insulin and choosing that which best fits the patient&#39;s abilities and capabilities&#46; By far&#44; the most widely used is the pen type&#46; To detect elderly patients with problems in self-administering insulin&#44; a test known as the &#8220;clock-drawing test&#8221; is employed to assess cognitive impairment and the presence of constructional apraxia&#46;<a class="elsevierStyleCrossRef" href="#bib1815"><span class="elsevierStyleSup">178</span></a> The test consists of having the patient draw &#40;on a blank sheet of paper&#41; a clock indicating ten past eleven&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Combined therapies</span><p id="par0340" class="elsevierStylePara elsevierViewall">In the elderly&#44; it is essential to simplify insulin therapy as much as possible to reduce the risk of hypoglycemia and minimize the burden of care associated with the complex insulin regimens&#46;<a class="elsevierStyleCrossRef" href="#bib1730"><span class="elsevierStyleSup">161</span></a> As has been mentioned&#44; oral diabetes drugs should be maintained &#40;except for sulfonylureas&#47;glinides&#41; with the basal insulin to reduce the insulin requirements and risks of hypoglycemia&#46;<a class="elsevierStyleCrossRefs" href="#bib1735"><span class="elsevierStyleSup">162&#44;179</span></a> DPP4i have an especially appropriate profile in this population due to their low risk of hypoglycemia and broad experience with their use in elderly patients with frailty and renal failure&#46; Their combination with basal insulin allows for the insulin dosage to be reduced and minimizes the adverse effects of the insulin &#40;hypoglycemia&#44; weight gain&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1825"><span class="elsevierStyleSup">180</span></a></p><p id="par0345" class="elsevierStylePara elsevierViewall">The combined therapy of basal insulin and GLP-1 RA provides excellent glycemic control and a lower risk of hypoglycemia than the complex insulin regimens&#46;<a class="elsevierStyleCrossRef" href="#bib1830"><span class="elsevierStyleSup">181</span></a> There have been studies with fixed-dose combinations of basal insulin and GLP-1 RA &#40;degludec and liraglutide&#59; glargine and lixisenatide&#41; that facilitate the posology and improve the gastrointestinal tolerance to GLP-1 RA&#46; These combinations can therefore play a role in treating DM2 in the elderly&#46; Nevertheless&#44; the lesser experience with using these combinations in the elderly&#44; a lack of specific studies and the combinations&#8217; higher cost make careful patient selection a necessity&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Therapy deintensification</span><p id="par0350" class="elsevierStylePara elsevierViewall">Elderly patients with diabetes are frequently overtreated&#46;<a class="elsevierStyleCrossRefs" href="#bib1030"><span class="elsevierStyleSup">21&#44;22</span></a> Antidiabetic therapy deintensification is therefore appropriate after a comprehensive geriatric assessment has been conducted&#44; indicating less complex and safer regimens &#40;with a lower risk of hypoglycemia&#44; lower burden of care&#44; better tolerance and no drug interactions&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1835"><span class="elsevierStyleSup">182</span></a> The simplification of complex insulin regimens in elderly patients reduces the risk of hypoglycemia and the burden of care&#44; without compromising glycemic control&#46;<a class="elsevierStyleCrossRef" href="#bib1730"><span class="elsevierStyleSup">161</span></a> In this respect&#44; it is worth remembering that a high HbA1c level does not rule out the risk of hypoglycemia in the elderly&#46;<a class="elsevierStyleCrossRefs" href="#bib1050"><span class="elsevierStyleSup">25&#44;161</span></a></p></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Therapeutic algorithm for type 2 diabetes in elderly patients &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;</span><p id="par0355" class="elsevierStylePara elsevierViewall"> The planning of DM2 therapy for elderly patients should be based on a comprehensive geriatric assessment&#46; If the elderly patient is frail&#44; dependent or has moderate to severe dementia&#44; the priority objective is to prevent symptomatic hypoglycemia and hyperglycemia&#46; The antidiabetic agents recommended in these cases would be metformin and DPP4i&#46; Other antidiabetic drugs not associated with a significant risk of hypoglycemia have adverse effects that limit their use in this population&#44; effects such as hypotension&#44; dehydration and renal failure &#40;with SGLT2i&#41; and nausea&#44; vomiting&#44; diarrhea and weight loss &#40;with GLP-1 RA&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0360" class="elsevierStylePara elsevierViewall">Renal failure is a prevalent comorbidity in elderly patients with diabetes and affects the treatment options&#46;<a class="elsevierStyleCrossRef" href="#bib1840"><span class="elsevierStyleSup">183</span></a> In Spain&#44; the prevalence of stage 4 and 5 chronic kidney disease &#40;glomerular filtration rate &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41; in patients with DM2 aged 70&#8211;79 years and &#8805;80 years is approximately 30&#37; and 50&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib1845"><span class="elsevierStyleSup">184</span></a> In these circumstances&#44; the preferred therapeutic options are DPP4i and insulin&#46; Although repaglinide and pioglitazone may be used from a pharmacokinetic standpoint&#44; their adverse effects profile &#40;hypoglycemia with repaglinide&#59; heart failure and fractures with pioglitazone&#41; make them an inadvisable option&#46;<a class="elsevierStyleCrossRef" href="#bib1850"><span class="elsevierStyleSup">185</span></a></p><p id="par0365" class="elsevierStylePara elsevierViewall">Finally&#44; for elderly patients with a high cardiovascular risk and none of the previously mentioned clinical limitations &#40;moderate&#8211;severe renal failure&#44; frailty&#44; dementia&#41;&#44; the priority should be to select antidiabetic drugs that have shown cardiovascular benefits&#44; such as empagliflozin and liraglutide&#46; Other drugs that have shown cardiovascular safety include metformin&#44; pioglitazone and DPP4i&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflict of interest</span><p id="par0370" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "xpalclavsec954991"
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          "titulo" => "Background"
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          "titulo" => "Functional capacity&#44; frailty and diabetes"
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          "titulo" => "Hypoglycemia in elderly patients"
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          "titulo" => "General principles in the treatment of elderly patients with type 2 diabetes"
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          "titulo" => "Glycemic control objectives for elderly patients"
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              "titulo" => "Metformin"
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              "identificador" => "sec0080"
              "titulo" => "Insulin"
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              "identificador" => "sec0085"
              "titulo" => "Basal insulinization"
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              "identificador" => "sec0090"
              "titulo" => "Basal insulin intensification"
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              "identificador" => "sec0095"
              "titulo" => "Insulin devices"
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              "identificador" => "sec0100"
              "titulo" => "Combined therapies"
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              "identificador" => "sec0105"
              "titulo" => "Therapy deintensification"
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          ]
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          "identificador" => "sec0110"
          "titulo" => "Therapeutic algorithm for type 2 diabetes in elderly patients &#40;Fig&#46; 1&#41;"
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          "titulo" => "Conflict of interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2017-10-11"
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          "clase" => "keyword"
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            0 => "Type 2 diabetes mellitus"
            1 => "Elderly"
            2 => "Antidiabetic treatment"
          ]
        ]
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          "clase" => "keyword"
          "titulo" => "Palabras clave"
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          "palabras" => array:3 [
            0 => "Diabetes mellitus tipo 2"
            1 => "Anciano"
            2 => "Tratamiento antidiab&#233;tico"
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      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The prevalence of type 2 diabetes mellitus &#40;DM2&#41; increases markedly with age&#46; Antidiabetic treatment and the objectives of glycaemic control in elderly patients with DM2 should be individualized according to their biopsychosocial characteristics&#46; In elderly patients for whom the benefits of intensive antidiabetic treatment are limited&#44; the basic objectives should be to improve the quality of life&#44; preserve functionality and avoid adverse effects&#44; especially hypoglycaemia&#46; Treatment of DM2 in the elderly was the subject of a consensus document published in 2012 and endorsed by several Spanish scientific societies&#46; Since then&#44; new therapeutic groups and evidence have emerged that warrant an update to this consensus document&#46; The present document focuses on the therapeutic aspects of DM2 in elderly patients&#44; understood as being older than 75 years or frail&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La prevalencia de la diabetes mellitus tipo 2 &#40;DM2&#41; se incrementa marcadamente con la edad&#46; El tratamiento antidiab&#233;tico y los objetivos de control gluc&#233;mico en el anciano con DM2 deben individualizarse en funci&#243;n de sus caracter&#237;sticas biopsicosociales&#46; En los pacientes de edad avanzada&#44; en los que los beneficios de un tratamiento antidiab&#233;tico intensivo son limitados&#44; los objetivos b&#225;sicos deben ser mejorar la calidad de vida&#44; preservar la funcionalidad y evitar los efectos adversos&#44; muy especialmente las hipoglucemias&#46; El tratamiento de la DM2 en el anciano fue objeto de un consenso&#44; publicado en 2012 y avalado por varias sociedades cient&#237;ficas espa&#241;olas&#46; Desde entonces&#44; han aparecido nuevos grupos terap&#233;uticos y evidencias que hacen recomendable su actualizaci&#243;n&#46; El presente documento se centrar&#225; en los aspectos terap&#233;uticos de la DM2 en el paciente anciano&#44; entendiendo como tal el tener una edad mayor de 75 a&#241;os o presentar fragilidad&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; G&#243;mez-Huelgas R&#44; G&#243;mez Peralta F&#44; Rodr&#237;guez Ma&#241;as L&#44; Formiga F&#44; Puig Domingo M&#44; Mediavilla Bravo JJ&#44; et al&#46; Tratamiento de la diabetes mellitus tipo 2 en el paciente anciano&#46; Rev Clin Esp&#46; 2018&#59;218&#58;74&#8211;88&#46;</p>"
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        "etiqueta" => "&#9734;&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">This article is published simultaneously in <span class="elsevierStyleInterRef" id="intr0010" href="https://doi.org/10.1016/j.regg.2017.12.003">https&#58;&#47;&#47;doi&#46;org&#47;10&#46;1016&#47;j&#46;regg&#46;2017&#46;12&#46;003</span>&#44; with the consent of the authors and editors&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Treatment algorithm for type 2 diabetes mellitus in elderly patients&#46;</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; DPP4i&#58; dipeptidyl peptidase-4 inhibitors&#59; GLP-1RA&#58; glucagon-like peptide-1 receptor agonists&#59; SGLT2i&#58; sodium-glucose cotransporter 2 inhibitors&#46;</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">a</span> Repaglinide and pioglitazone can be used in patients with GFR &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#44; but their use is not recommended due to the risk of adverse effects&#58; hypoglycemia &#40;repaglinide&#41;&#59; salt and fluid retention&#44; heart failure and fractures &#40;pioglitazone&#41;&#46;</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">b</span> Empagliflozin&#44; canagliflozin and liraglutide have shown reduced cardiovascular morbidity and mortality in patients with high vascular risk type 2 diabetes&#46;</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">c</span> Saxagliptin should be avoided for patients with heart failure&#46;</p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">d</span> Pioglitazone is contraindicated for patients with heart failure or at risk for fractures&#46;</p>"
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypoactivity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Weekly calorie expenditure below the lower quintile&#44; adjusted for sex &#40;men &#60;383<span class="elsevierStyleHsp" style=""></span>kcal&#47;week&#44; women &#60;270<span class="elsevierStyleHsp" style=""></span>kcal&#47;week&#41;&nbsp;\t\t\t\t\t\t\n
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                    0 => array:2 [
                      "titulo" => "Diabetes in older people&#58; new insights and remaining challenges"
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                    0 => array:2 [
                      "doi" => "10.1016/S2213-8587(14)70176-7"
                      "Revista" => array:6 [ …6]
                    ]
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                    0 => array:2 [
                      "titulo" => "Frailty in older adults&#58; evidence for a phenotype"
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                    0 => array:1 [
                      "titulo" => "Population ageing and development"
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                      "titulo" => "Evoluci&#243;n de los indicadores de calidad asistencial al diab&#233;tico tipo 2 en atenci&#243;n primaria &#40;1996&#8211;2007&#41;"
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                    0 => array:2 [
                      "titulo" => "Prevalence of diabetes mellitus and impaired glucose regulation in Spain&#58; the Di&#64;bet&#46;es study"
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                    0 => array:2 [
                      "doi" => "10.1007/s00125-011-2336-9"
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                  "referenciaCompleta" => "Federaci&#243;n Internacional de la Diabetes&#46; Atlas de la diabetes&#46; 6&#46;&#170; ed&#46; Actualizaci&#243;n&#59; 2014 &#91;accessed 11&#46;10&#46;17&#93;&#46; Available from&#58; <a href="http://www.idf.org/diabetesatlas">www&#46;idf&#46;org&#47;diabetesatlas</a>&#46;"
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                      "titulo" => "A call for action in diabetes care for older people"
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                      "titulo" => "Frailty as a major factor in the increased risk of death and disability in older people with diabetes"
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                      "titulo" => "Diabetes and risk of frailty and its potential mechanisms&#58; a prospective cohort study of older adults"
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                      "doi" => "10.1016/j.jamda.2015.04.008"
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                      "titulo" => "The third transition&#58; the clinical evolution oriented to the contemporary older patient"
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                      "titulo" => "The risks and benefits of implementing glycemic control guidelines in frail older adults with diabetes mellitus"
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