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Metformin is the drug recommended as the first therapeutic step&#44; along with the adoption of hygienic and dietary measures&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> When the patient&#39;s glycemic control is not sufficient with monotherapy&#44; the addition of a second drug is recommended&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> The most common acute complication in patients with diabetes is hypoglycemia&#44; especially in those treated with insulin and&#47;or sulfonylureas&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;9&#8211;11</span></a> In this respect&#44; the new therapeutic class of dipeptidyl peptidase-4 inhibitors &#40;DPP-4i&#41; has the advantage&#44; when compared with traditional secretagogues&#44; of considerably reducing hypoglycemia&#44; given that its stimulator mechanism for insulin secretion is glucose-dependent&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;12</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Data on the clinical and economic consequences of double drug therapy with antidiabetic agents in a population in Spain are limited or nonexistent&#46; We have described the clinical &#40;treatment compliance&#44; metabolic control&#44; hypoglycemia and macrovascular complications&#41; and economic &#40;use of resources and their costs&#41; consequences of combining metformin with dipeptidyl peptidase inhibitors in patients with type 2 diabetes&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Patients and methods</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Study design and population</span><p id="par0035" class="elsevierStylePara elsevierViewall">We conducted an observational&#44; multicenter&#44; longitudinal study based on a review of medical registries &#40;computer databases&#41; of patients treated with metformin and monitored in outpatient and hospital settings&#46; The study population consisted of individuals attending 6 remodeled primary care centers managed by Badalona Serveis Assistencials SA&#46; Information was obtained on the resources consumed by this reference population from 2 hospital centers&#58; Municipal Hospital of Badalona and Hospital Germans Tr&#237;as i Pujol &#40;<span class="elsevierStyleItalic">hospital admissions</span>&#41;&#46; The population assigned to the centers was mostly urban&#44; with a low to medium socioeconomic level&#44; predominantly industrial&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Inclusion and exclusion criteria</span><p id="par0040" class="elsevierStylePara elsevierViewall">We included all patients who started a second antidiabetic treatment between 1&#47;January&#47;2008 and 31&#47;December&#47;2009 and who had the following characteristics&#58; &#40;a&#41; men and women aged &#8805;30 years&#59; &#40;b&#41; diagnosis of type 2 DM for a minimum of 12 months before the start of the study&#59; &#40;c&#41; those regularly following the protocol&#47;guidelines of cardiovascular risk established in the centers&#59; &#40;d&#41; those who were part of the long-term prescription program to obtain prescriptions &#40;with a confirmed record of the daily dosage&#44; the time interval and duration of each treatment administered&#41;&#59; &#40;e&#41; on current therapy with metformin as the first therapeutic option &#40;monotherapy&#41;&#59; and &#40;f&#41; those who could participate in follow-up for a period of 2 years&#46; We excluded those who were transferred to other municipalities&#44; those who were displaced or outside the area and those who only visited specialists&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Measure of type 2 diabetes and complications</span><p id="par0045" class="elsevierStylePara elsevierViewall">The diagnosis of type 2 DM was determined based on the international classification of primary care &#40;ICPC-2&#41;&#44; component 7 of diseases and health problems&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> and on the coding of hospital discharges and emergency department visits&#44; according to the international classification of diseases &#40;9th edition&#44; clinical modification &#91;ICD-9-CM&#93;&#41;&#46; We obtained information on microvascular complications&#58; &#40;a&#41; diabetic retinopathy&#59; &#40;b&#41; diabetic nephropathy&#59; &#40;c&#41; diabetic neuropathy&#59; and &#40;d&#41; diabetic vasculopathy&#46; We also identified all cases of symptomatic hypoglycemia&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Macrovascular complications and cardiovascular diseases &#40;CVD&#41;</span><p id="par0050" class="elsevierStylePara elsevierViewall">These included &#40;a&#41; heart disease&#44; such as cardiac ischemia&#44; acute myocardial infarction and heart failure&#44; according to the definition of the diagnostic criteria of the World Health Organization&#59; &#40;b&#41; cerebrovascular disease&#44; including stroke &#40;ischemic or hemorrhagic&#59; according to the American Heart Association&#41;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and transient ischemic attack&#59; &#40;c&#41; peripheral arterial disease &#40;all types&#41;&#59; and &#40;d&#41; kidney disease &#40;diabetic nephropathy and renal function impairment &#91;serum creatinine&#58; men<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>133&#59; women<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>124<span class="elsevierStyleHsp" style=""></span>mmol or glomerular filtration rate<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>60<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#93;&#41;&#46; The cumulative incidence rate was defined as the proportion of healthy individuals who developed the complication &#40;number of new cases&#41;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Compliance&#44; treatment persistence and metabolic control</span><p id="par0055" class="elsevierStylePara elsevierViewall">We obtained information on the following antidiabetic agents according to the Anatomical Therapeutic Chemical Classification System &#40;ATC&#41;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#58; &#40;a&#41; metformin &#40;A10BA&#42;&#41;&#59; &#40;b&#41; insulin release stimulants&#58; sulfonylureas &#40;A10BB&#42;&#41; and glinides &#40;A10BX&#42;&#41;&#59; &#40;c&#41; glitazones &#40;A10BG&#42;&#41;&#59; &#40;d&#41; DPP-4i &#40;A10BH&#42;&#41;&#59; and &#40;e&#41; insulin &#40;all types&#41; in monotherapy or in combination &#40;A10BD&#42;&#41;&#46; Patients taking alpha-glucosidase inhibitors were not included due to the insufficient sample size&#46; Compliance for the period was calculated using the ratio between the total number of tablets dispensed and those recommended or prescribed&#46; Treatment persistence was defined as the time &#40;in months&#41; without withdrawing from the initial therapy or without changing to another medication for at least 30 days after the initial prescription&#46; Metabolic control was established based on glycated hemoglobin levels &#40;HbA1c&#41; &#60;7&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Demographic and comorbidity variables</span><p id="par0060" class="elsevierStylePara elsevierViewall">As a summary variable for overall comorbidity for each treated patient&#44; we used &#40;a&#41; the Charlson comorbidity index<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> as an approximation of patient severity and &#40;b&#41; the individual case-mix index&#44; obtained based on the Adjusted Clinical Groups &#40;ACG&#41;&#44; which is a patient classification system by isoresource consumption&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> The applied ACG provides resource utilization bands &#40;RUBs&#41;&#44; whereby each patient is grouped&#44; according to their overall morbidity&#44; into 1 of 5 mutually exclusive categories &#40;1&#58; healthy or very low morbidity&#59; 2&#58; low morbidity&#59; 3&#58; moderate morbidity&#59; 4&#58; high morbidity&#59; and 5&#58; very high morbidity&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Use of resources and cost model</span><p id="par0065" class="elsevierStylePara elsevierViewall">We considered direct healthcare costs to be those related to the health care activities conducted by professionals&#46; The nonhealthcare or indirect costs were those related to the loss of work productivity &#40;number of people on disability and sick days&#41;&#46; The various study concepts and their economic assessments are detailed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> &#40;corresponding to 2011&#41;&#46; The various fees were obtained from the centers&#8217; accounting analysis&#44; except for the medication and sick leave&#46; The work disability days or loss of productivity were considered nonhealthcare costs &#40;indirect costs&#41;&#46; The cost was quantified according to the minimum interprofessional wage &#40;source&#58; National Statistics Institute of Spain&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Statistical analysis</span><p id="par0070" class="elsevierStylePara elsevierViewall">We performed a descriptive-univariate statistical analysis with values for the mean&#44; standard&#47;typical deviation &#40;SD&#41; and 95&#37; confidence intervals &#40;CI&#41;&#46; We determined the normality of the distribution with the Kolmogorov&#8211;Smirnov test for quantitative variables&#46; In the bivariate analysis&#44; we used ANOVA&#44; chi-squared&#44; or Pearson&#39;s linear correlation and the nonparametric Mann&#8211;Whitney&#8211;Wilcoxon tests&#46; We performed a logistic regression analysis to determine the comorbidities associated with the DPP-4i group and another to define the variables associated with CVD &#40;presence&#47;absence&#41;&#44; with the enter procedure &#40;statistic&#58; Wald&#41;&#46; Comparisons of the outpatient and hospital costs were performed according to the recommendations of Thompson and Barber<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> using analysis of covariance &#40;ANCOVA&#41;&#44; with gender&#44; age&#44; RUBs&#44; Charlson index and progression time of the diagnosis as covariates&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Results</span><p id="par0075" class="elsevierStylePara elsevierViewall">From a selection of 62&#44;370 patients&#44; 6620 patients were diagnosed with type 2 DM &#40;prevalence&#58; 10&#46;6&#37;&#59; 95&#37; CI&#58; 10&#46;4&#8211;10&#46;8&#37;&#41;&#46; A total of 4553 patients were excluded from the study&#58; 978 were not undergoing a drug treatment&#44; 464 were being treated with other drug therapies&#44; 241 discontinued the therapy&#44; 1887 modified the therapy during follow-up&#44; 655 were considered lost to follow-up and 328 were excluded for unknown or other causes&#46; The percentage distribution of the excluded patients in the 2 study groups was similar&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">We selected 2067 patients on therapy with antidiabetic agents &#40;double therapy&#41;&#46; The mean age was 66&#46;6 &#40;SD&#58; 10&#46;9&#41; years and 53&#46;1&#37; were male&#46; Some 25&#46;1&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>519&#41; were being treated with metformin and a DPP-4i&#44; and 74&#46;9&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1548&#41; were being treated with metformin and other non-DPP-4i hypoglycemic drugs&#46; The distribution of second-line drugs in this group was as follows&#58; 42&#46;9&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>886&#41; were treated with sulfonylureas&#44; 14&#46;0&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>290&#41; with glitazones and 18&#46;0&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>372&#41; with insulin &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; The patients on therapy with DPP-4i had a lower mean age than the reference group &#40;65&#46;8 vs&#46; 67&#46;3 years&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;007&#41; and had similar overall comorbidity &#40;5&#46;3 vs&#46; 5&#46;5 diagnoses&#44; respectively&#41;&#46; The patients in the reference group had a higher proportion of strokes &#40;18&#46;7&#37; vs&#46; 13&#46;1&#37;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;004&#41; and retinopathy &#40;23&#46;8&#37; vs&#46; 17&#46;0&#37;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">The patients treated with DPP-4i&#44; in comparison with those that received other hypoglycemic agents&#44; showed better treatment compliance &#40;70&#46;3&#37; vs&#46; 59&#46;6&#37;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; and treatment persistence &#40;63&#46;4&#37; vs&#46; 51&#46;0&#37;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; We achieved an acceptable correlation between the degree of compliance and the treatment time &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;481&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; The metabolic control &#40;HbA1c<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>7&#37;&#41; in the DPP-4i group at the completion of the 2-year follow-up was higher than in those treated with other hypoglycemic agents &#40;64&#46;3&#37; vs&#46; 59&#46;6&#37;&#44; respectively&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; Therapy with DPP-4i was associated with higher therapeutic compliance &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;3&#59; 95&#37; CI&#58; 1&#46;1&#8211;1&#46;5&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; treatment duration &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;2&#59; 95&#37; CI&#58; 1&#46;1&#8211;1&#46;3&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;032&#41; and better metabolic control &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;4&#59; 95&#37; CI&#58; 1&#46;2&#8211;1&#46;6&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;015&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The patients treated with DPP-4i&#44; in comparison with those who received other hypoglycemic agents&#44; attended fewer primary care medical visits &#40;21&#46;6&#37; vs&#46; 29&#46;4&#37;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; shorter hospital stays &#40;0&#46;1 vs&#46; 0&#46;2 days&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;039&#41; and fewer specialist care visits &#40;1&#46;8 vs&#46; 2&#46;6&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The total cost of care for patients with type 2 DM rose to 5&#46;3 million euros&#44; of which 96&#46;6&#37; corresponded to direct healthcare costs and 3&#46;4&#37; to indirect nonhealthcare costs &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; The average&#47;unit total costs &#40;healthcare and nonhealthcare&#41; of the subjects treated with DPP-4i was less than that calculated for patients who were treated with other hypoglycemic agents &#40;2242 &#8364; vs&#46; 2666 &#8364;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; In the adjusted model &#40;ANCOVA&#41;&#44; these costs were 2347 &#8364; &#40;95&#37; CI&#58; 2&#46;150&#8211;2&#46;633 &#8364;&#41; vs&#46; 2682 &#8364; &#40;95&#37; CI&#58; 2&#46;573&#8211;2&#46;793 &#8364;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; All components of the healthcare costs showed these differences &#40;primary care and specialized&#41;&#46; The nonhealthcare costs were not conclusive&#46; The healthcare cost showed a moderate correlation with age &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;335&#41; and general comorbidity &#40;RUBs&#59; <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;348&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">A total of 136 patients had some CVD &#40;rate&#58; 6&#46;6&#37;&#59; 95&#37; CI&#58; 5&#46;5&#37;-7&#46;7&#37;&#41;&#46; The rate of CVD in the group treated with DPP-4i&#44; in comparison with those that were treated with other hypoglycemic agents&#44; was lower &#40;3&#46;7&#37; vs&#46; 7&#46;6&#37;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;002&#41;&#46; The group treated with DPP-4i had a lower proportion of new cases of ischemic heart disease &#40;1&#46;0&#37; vs&#46; 2&#46;1&#37;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;036&#41;&#44; strokes &#40;1&#46;9&#37; vs&#46; 3&#46;7&#37;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;042&#41; and renal failure &#40;0&#46;8&#37; vs&#46; 2&#46;2&#37;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;045&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; In the logistic regression model&#44; the presence of CVD was associated with treatment non-compliance &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;1&#59; 95&#37; CI&#58; 1&#46;0&#8211;1&#46;8&#41;&#44; poor control of the disease &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;2&#59; 95&#37; CI&#58; 1&#46;1&#8211;1&#46;7&#41;&#44; overall comorbidity &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;1&#59; 95&#37; CI&#58; 1&#46;6&#8211;2&#46;9&#41;&#44; male gender &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;5&#59; 95&#37; CI&#58; 1&#46;1&#8211;2&#46;2&#41; and age &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;1&#59; 95&#37; CI&#58; 1&#46;0&#8211;1&#46;2&#41; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41;&#46; The percentage of patients with hypoglycemia was 36&#46;7&#37;&#46; The patients of the DPP-4i group had a lower proportion of hypoglycemia than those who were treated with other hypoglycemic agents &#40;13&#46;9&#37; vs&#46; 44&#46;3&#37;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; Some 0&#46;5&#37; of the patients required hospitalization&#59; 1&#46;1&#37; were treated in hospital emergency departments&#44; and 35&#46;7&#37; were treated in Primary Care&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">The possible heterogeneity of the group treated with metformin with other hypoglycemic agents motivated a subanalysis of all drug groups &#40;DPP-4i vs&#46; sulfonylureas&#44; glitazones and insulin&#41;&#46; At the 2-year follow-up&#44; the patients treated with DPP-4i had greater treatment compliance &#40;70&#46;3&#37; vs&#46; 59&#46;9&#37;&#44; 60&#46;3&#37; and 58&#46;4&#37;&#44; respectively&#41;&#59; better control of the disease &#40;64&#46;3&#37; vs&#46; 62&#46;6&#37;&#44; 62&#46;8&#37; and 50&#46;5&#37;&#44; respectively&#41; and a lower proportion of hypoglycemia &#40;13&#46;9&#37; vs&#46; 40&#46;4&#37;&#44; 37&#46;6&#37; and 58&#46;9&#37;&#44; respectively&#41; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; The average&#47;unit total costs were 2&#46;242 &#8364; vs&#46; 2&#46;475 &#8364;&#44; 2&#46;724 &#8364; and 3&#46;164 &#8364;&#44; respectively &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; The rates of CVD were 3&#46;7&#37; vs&#46; 6&#46;4&#37;&#44; 7&#46;6 and 10&#46;2&#37;&#44; respectively&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discussion</span><p id="par0110" class="elsevierStylePara elsevierViewall">Our study shows that patients treated with &#40;double therapy&#41; metformin and DPP-4i&#44; when compared with those who were treated with metformin and other hypoglycemic agents including insulin&#44; have a lower probability of experiencing hypoglycemia and&#44; as a whole&#44; are associated with lower healthcare costs&#46; To a certain degree&#44; it is possible that patients on insulin can interfere with the comparability of the group treated with metformin and other hypoglycemic agents &#40;a study limitation&#41;&#46; This is because they can be patients with more micro-macrovascular complications and&#47;or with poorer metabolic control&#44; probably due to presenting a type 2 DM that has progressed more or to being patients with greater genetic susceptibility&#46; Nevertheless&#44; their contribution to the full group of patients treated with metformin and other hypoglycemic agents is limited &#40;18&#37; of the total&#41; and is in consistent with routine clinical practice&#44; with these data consistent with those from other studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;20</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">DPP-4i was the second therapeutic option in this study population &#40;25&#46;1&#37; of the total&#41;&#46; Our results show that&#44; at the 2-year follow-up&#44; patients treated with DPP-4i show greater treatment compliance&#47;persistence and better metabolic control&#46; The studies on compliance and persistence with oral antidiabetic agents and insulin are scarce and difficult to compare with each other due to the different methodologies used&#46; These studies show a compliance of 40&#37;-80&#37;&#46; On this issue&#44; M&#225;rquez Contreras et al&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> highlighted in a recent study that a quarter of diabetic patients do not comply with insulin therapy&#46; Cramer et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> in a review conducted on 139 studies&#44; reported that at 12 months&#44; the treatment persistence rate was 63&#37; and the compliance with oral antidiabetic agents was 58&#37;&#44; which was similar in all analyzed therapeutic classes&#46; Jermendy et al&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> in a series of patients in combination therapy with metformin and sulfonylureas&#44; observed a 56&#37; persistence rate at 1 year&#46; Although these results are consistent with those found in our study&#44; these variables were slightly higher in the patients treated with metformin and DPP-4i&#46; This situation might be due to a random event &#40;individual variability&#41; or to the presence of a number of unidentified confounding factors&#46; Nevertheless&#44; a plausible explanation might be found in the presence of a better tolerance and safety profile and especially by a significantly lower rate of hypoglycemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;8</span></a> It seems clear that the role of DPP-4i in the therapeutic arsenal for type 2 DM is evolving swiftly&#44; even though we lack long-term data to evaluate its effect on metabolic control&#46; The available evidence about the direct association between compliance and metabolic control seems beyond all doubt&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;21&#44;23</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">The second most relevant finding of this study is that the patients treated with metformin and DPP-4i had lower healthcare costs&#44; with a reduction in the use of specialized care resources and fewer hospital admissions&#46; The limited existing studies show that as compliance and metabolic control of these patients increase&#44; the lower the risk of hospitalization&#46; As an example&#44; the review by Breitscheidel et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> concluded that improvements in compliance can lead to reduced total healthcare costs in type 2 DM&#46; In 7 studies&#44; compliance was inversely associated with total healthcare costs&#59; the studies showed a lower cost due to a lower proportion of hospital days&#46; Nevertheless&#44; the variability of these studies is high&#46; In general&#44; our results are consistent with these studies&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> highlighting in particular the direct relationship between hypoglycemic episodes and a lower consumption of healthcare resources&#46; Although the cost of DPP-4i agents is greater than that of alternative drugs&#44; this cost seems offset by the lower costs of follow-up&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Our data show lower rates of CVD and renal failure in patients treated with DPP-4i&#46; In this respect&#44; evidence<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#8211;8&#44;19&#44;20</span></a> on both type 1 and type 2 DM has shown that good metabolic control results in significant improvements in the rate and outcomes of microangiopathic complications&#44; a benefit that persists for years although it worsens metabolic control&#46; The evolution of macrovascular complications&#44; however&#44; does not seem to depend as much on reaching an acceptable level of HbA1c&#44; but rather on the type of treatment employed and the onset or not of hypoglycemic episodes&#46; Given the close relationship between some microangiopathies &#40;mainly nephropathy&#41; and CVD&#44; it is logical to consider that good metabolic control has a positively influence&#44; but with a lower intensity than the control of other risk factors&#44; such as dyslipidemia and high blood pressure&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;8&#44;26</span></a> Currently&#44; DPP-4i agents can have a cardiovascular benefit&#44; but we have to wait for the results of various ongoing clinical trials&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">The main limitation of this study is the possible selection bias by the attending physician when administering one or another hypoglycemic drug&#59; the interpretation of the results should therefore be performed prudently&#46; Similarly&#44; it is possible that the patients who progress from metformin to insulin present higher complications&#46; This situation&#44; not measured exactly in our study&#44; could be due to faster evolutionary forms of the disease and&#47;or to the fact that patients treated with insulin present a greater degree of complexity&#46; Another limitation of the study is due to the measurement of hypoglycemia&#44; given that we only identified episodes in which the patient required medical care and in which this care was documented&#59; episodes of hypoglycemia could therefore have been underdiagnosed&#46; Additionally&#44; the slight differences observed of greater age and progression time of the diabetes in the group treated with metformin and other hypoglycemic agents could partly explain the increased comorbidity and consumption of healthcare resources&#46; Future research will be necessary in order to provide studies on cost-effectiveness and studies on diagnostic delay and treatment&#44; and to collect data from other healthcare organizations&#46; Despite the limitations of this study&#44; the patients on treatment with DPP-4i &#40;double therapy&#41; showed an increased likelihood of greater compliance&#44; metabolic control and lower rates of hypoglycemia&#44; which resulted in lower healthcare costs&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Contribution of the authors</span><p id="par0135" class="elsevierStylePara elsevierViewall">Concept and design of the manuscript&#58; A&#46; Sicras&#44; C&#46; Rold&#225;n and B&#46; Font&#46; Data collection&#58; A&#46; Sicras and R&#46; Navarro&#46; Interpretation of the data&#44; drafting&#44; review and approval of the submitted manuscript by all authors&#58; A&#46; Sicras&#44; C&#46; Rold&#225;n&#44; B&#46; Font&#44; R&#46; Navarro and J&#46; Ib&#225;&#241;ez&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Funding</span><p id="par0140" class="elsevierStylePara elsevierViewall">The study was funded by Novartis Farmac&#233;utica SA&#44; who did not interfere in the final results&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflicts of interest</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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            1 => "Antecedentes y objetivo"
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          "titulo" => "Patients and methods"
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              "titulo" => "Study design and population"
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              "titulo" => "Inclusion and exclusion criteria"
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              "identificador" => "sec0035"
              "titulo" => "Measure of type 2 diabetes and complications"
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              "titulo" => "Macrovascular complications and cardiovascular diseases &#40;CVD&#41;"
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              "titulo" => "Compliance&#44; treatment persistence and metabolic control"
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              "titulo" => "Demographic and comorbidity variables"
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    "fechaRecibido" => "2013-03-18"
    "fechaAceptado" => "2013-06-02"
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          "clase" => "keyword"
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            0 => "DPPIV"
            1 => "Diabetes"
            2 => "Metabolic control"
            3 => "Hypoglycemia"
            4 => "Cardiovascular disease"
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          "palabras" => array:6 [
            0 => "IDPP4"
            1 => "Diabetes"
            2 => "Control metab&#243;lico"
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        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Backgrounds and objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">There are different second line glucose lowering drugs whose efficacy&#44; safety and economic profile have not been established in our setting&#46; We have analyzed the clinical &#40;diabetic treatment adherence&#44; metabolic control&#44; hypoglycemia and macrovascular complications&#41; and economic &#40;resource use and costs&#41; consequences of the combination of metformin with dipeptidyl peptidase inhibitors &#40;DPPIV&#41; in patients with type 2 diabetes&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We conducted a multicenter&#44; observational and retrospective study&#46; Patients &#8805;30 years treated with metformin who initiated a second antidiabetic treatment during 2008&#8211;2009 were enrolled in the study&#46; Two groups of patients were established&#58; metformin with DPPIV and metformin with other diabetic drugs&#46; The main measurements were comorbidity&#44; compliance&#47;persistence&#44; metabolic control &#40;glycosylated hemoglobin &#60;7&#37;&#41;&#44; complications &#40;hypoglycemia&#44; macrovascular&#41; and total costs&#46; Patients were followed-up for 2 years&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A total of 2067 patients were enrolled &#40;mean age&#58; 66&#46;6 years&#44; 53&#46;1&#37; male&#41;&#46; Of these&#44; 519 patients &#40;25&#46;1&#37;&#41; were analyzed in the metformin<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>DPPIV group and 1548 patients &#40;74&#46;9&#37;&#41; in the group metformin<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>other antidiabetic drug&#46; The DPPIV group patients showed better compliance &#40;70&#46;3 vs&#46; 59&#46;6&#37;&#41;&#44; persistence &#40;63&#46;4 vs&#46; 51&#46;0&#37;&#41; and metabolic control &#40;64&#46;3 vs&#46; 59&#46;6&#37;&#41;&#44; respectively &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; compared to the other group&#46; They also showed a lower proportion of hypoglycemia &#40;13&#46;9 vs&#46; 44&#46;3&#37;&#41;&#44; cardiovascular events &#40;3&#46;7 vs&#46; 7&#46;6&#37;&#41; and total costs &#40;2347 vs&#46; &#8364; 2682&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Despite the limitations of the study&#44; patients treated with metformin associated to DPPIV were more likely to show increased adherence&#44; metabolic control and lower rates of hypoglycemia than those treated with metformin associated to other antidiabetics&#46;</p>"
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        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes y objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Existen diversos tratamientos farmacol&#243;gicos hipoglucemiantes de segunda l&#237;nea cuya eficacia&#44; seguridad y perfil econ&#243;mico no se ha precisado en nuestro medio&#46; Hemos analizado las consecuencias cl&#237;nicas &#40;adherencia al tratamiento antidiab&#233;tico&#44; control metab&#243;lico&#44; hipoglucemias y complicaciones macrovasculares&#41; y econ&#243;micas &#40;uso de recursos y costes&#41; de la combinaci&#243;n de metformina con inhibidores de la dipeptidilpeptidasa &#40;IDPP4&#41; en pacientes con diabetes tipo 2 en comparaci&#243;n con metformina y otros f&#225;rmacos hipoglucemiantes&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio observacional multic&#233;ntrico de car&#225;cter retrospectivo&#46; Se incluyeron pacientes de &#8805;<span class="elsevierStyleHsp" style=""></span>30 a&#241;os tratados con metformina que iniciaron un segundo tratamiento antidiab&#233;tico durante los a&#241;os 2008-2009&#46; Se establecieron 2 grupos de pacientes&#58; metformina con IDPP4 y metformina con otros f&#225;rmacos antidiab&#233;ticos&#46; Las principales medidas fueron&#58; la comorbilidad&#44; el cumplimiento&#47;persistencia&#44; el control metab&#243;lico &#40;hemoglobina glicosilada<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>7&#37;&#41;&#44; complicaciones &#40;hipoglucemias&#44; macrovasculares&#41; y costes totales&#46; El seguimiento se realiz&#243; durante 2 a&#241;os&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se reclutaron 2&#46;067 pacientes &#40;edad media&#58; 66&#44;6 a&#241;os&#59; 53&#44;1&#37; varones&#41;&#46; En el grupo metformina<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IDPP4 se analizaron 519 pacientes &#40;25&#44;1&#37;&#41; y en el grupo metformina<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>otros f&#225;rmacos antidiab&#233;ticos&#58; 1&#46;548 pacientes &#40;74&#44;9&#37;&#41;&#46; Los enfermos tratados con IDPP4&#44; en comparaci&#243;n con los que recibieron metformina asociada a otros antidiab&#233;ticos&#44; mostraron un mejor cumplimiento &#40;70&#44;3 vs&#46; 59&#44;6&#37;&#41;&#44; persistencia &#40;63&#44;4 vs&#46; 51&#44;0&#37;&#41; y control metab&#243;lico &#40;64&#44;3 vs&#46; 59&#44;6&#37;&#41; &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; Tambi&#233;n presentaron una menor proporci&#243;n de hipoglucemias &#40;13&#44;9 vs&#46; 44&#44;3&#37;&#41;&#44; eventos cardiovasculares &#40;3&#44;7 vs&#46; 7&#44;6&#37;&#41; y costes totales &#40;2&#46;347 vs&#46; 2&#46;682&#8364;&#41; &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41; durante los 2 a&#241;os del estudio&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A pesar de las limitaciones del estudio&#44; los pacientes en tratamiento con metformina asociada a IDPP4 mostraron un mayor cumplimiento terap&#233;utico&#44; control metab&#243;lico y menores tasas de hipoglucemias que los enfermos tratados con metformina asociada a otros antidiab&#233;ticos&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Sicras Mainar A&#44; et al&#46; Consecuencias cl&#237;nicas y econ&#243;micas de la combinaci&#243;n de metformina con inhibidores de la dipeptidilpeptidasa en pacientes con diabetes tipo 2&#46; Rev Clin Esp&#46; 2013&#59;213&#58;377&#8211;384&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Distribution of cardiovascular events according to the study groups during the 2-year follow-up&#46; Reference group&#58; patients treated with metformin and another hypoglycemic drug &#40;sulfonylurea&#44; glitazone or insulin&#41;&#46; DPP-4i group&#58; patients treated with metformin and inhibitors of the dipeptidyl peptidase-4&#46; Relationship of events&#58; ischemic heart disease &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>38&#41;&#44; stroke &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>67&#41; and renal failure &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>38&#41;&#46; The total number of events by group was <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>107 and <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>19 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; respectively&#46; A patient could have more than one event&#46; Renal failure&#58; corresponds to a glomerular filtration rate &#60;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; Statistically significant differences in the comparisons by pairs &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41;&#46;</p>"
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Specialized Care Medical Visit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">104&#46;41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Additional examinations</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Laboratory Tests&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22&#46;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Conventional radiology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#46;50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Diagnostic tests&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Drug prescription</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PVP<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>VAT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Indirect work productivity costs</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cost per day NOT worked&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">101&#46;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; RUBs&#44; resource utilization bands&#59; COPD&#44; chronic obstructive pulmonary disease&#59; DPP-4i&#44; dipeptidyl peptidase-4 inhibitors&#59; NS&#44; not significant&#59; other hypoglycemic agents&#58; including sulfonylureas&#44; glitazones and insulin&#59; <span class="elsevierStyleItalic">P</span>&#58; statistical significance&#59; SS&#58; social security&#46;</p><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Values expressed in percentages or mean &#40;standard deviation&#41;&#46;</p>"
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Study groups&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Total&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Metformin<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>other hypoglycemic agents&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Number of patients&#44; &#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2067&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1548&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>519&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Mean age&#44; years</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">66&#46;6 &#40;10&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">67&#46;3 &#40;11&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">65&#46;8 &#40;10&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#46;007&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t">53&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">52&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&#46;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Pensioner scheme&#44; SS</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">77&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80&#46;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">69&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">General comorbidity</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Mean number of diagnoses</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;5 &#40;2&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;5 &#40;2&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;3 &#40;2&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Charlson index mean</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;0 &#40;0&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;0 &#40;0&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;0 &#40;0&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Mean RUB</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;0 &#40;0&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;0 &#40;0&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;9 &#40;0&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;047&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">RUB-1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">RUB-4</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">RUB-5</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#46;035&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="5" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Associated comorbidities</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">High blood pressure</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Dyslipidemia</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Obesity</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Active smokers</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Alcoholism</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Ischemic heart disease</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">12&#46;9&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Stroke</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">17&#46;3&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">18&#46;7&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">13&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#46;004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Organ failure&#58;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">18&#46;7&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">19&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">16&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Bronchial asthma</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">5&#46;2&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">4&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">COPD</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Neuropathies</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Dementia &#40;all types&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Diabetic retinopathy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Diabetic neuropathy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Diabetic nephropathy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#46;2&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#46;3&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Microalbuminuria&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">16&#46;9&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">12&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;010&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Metformin<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>other hypoglycemic agents&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Metformin<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>DPP-4i&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t">2472 &#40;1414&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2549 &#40;1481&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">2241 &#40;1162&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Primary Care Costs&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2165 &#40;1210&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2215 &#40;1250&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2017 &#40;1072&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Medical visits&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">637 &#40;368&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">681 &#40;366&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">502 &#40;343&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Laboratory tests&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">64 &#40;43&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">69 &#40;45&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50 &#40;33&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Conventional radiology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19 &#40;23&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18 &#40;23&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20 &#40;23&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Additional tests&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18 &#40;28&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">18 &#40;29&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">17 &#40;25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Medication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1429 &#40;1645&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1428 &#40;1558&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1429 &#40;1742&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Specialized Care Costs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">306 &#40;487&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">334 &#40;537&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">225 &#40;275&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;&#46;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Days in hospital&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28 &#40;283&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">36 &#40;325&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 &#40;52&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;039&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Medical visits&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">248 &#40;363&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">267 &#40;392&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">191 &#40;252&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#60;&#46;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Emergency department visits&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30 &#40;64&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31 &#40;64&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28 &#40;63&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;311&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Nonhealthcare costs &#40;productivity&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">87 &#40;1648&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">117 &#40;1904&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;0&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Total costs</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2560 &#40;2202&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">2666 &#40;2445&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">2242 &#40;1162&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Adjusted Costs Model</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Difference</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Healthcare costs</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;216&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2560&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">2344&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>95&#37; CI&nbsp;\t\t\t\t\t\t\n
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Journal Information
Vol. 213. Issue 8.
Pages 377-384 (November 2013)
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Vol. 213. Issue 8.
Pages 377-384 (November 2013)
Original article
Clinical and economical consequences of the combination of metformin with dipeptidyl peptidase inhibitors in type 2 diabetes patients
Consecuencias clínicas y económicas de la combinación de metformina con inhibidores de la dipeptidilpeptidasa en pacientes con diabetes tipo 2
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A. Sicras Mainara,
Corresponding author
asicras@bsa.cat

Corresponding author.
, C. Roldán Suárezb, B. Font Ramosb, R. Navarro Artiedac, J. Ibáñez Nollad
a Dirección de planificación, Badalona Serveis Assistencials SA, Badalona, Barcelona, Spain
b Novartis Farmacéutica SA, Barcelona, Spain
c Documentación médica, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
d Dirección médica, Badalona Serveis Assistencials SA, Badalona, Barcelona, Spain
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Figures (1)
Tables (3)
Table 1. Economic assessment of unit costs and losses of work productivity.
Table 2. Study patient characteristics.
Table 3. Model of costs (net and adjusted) according to the study groups (average/unit in euros) during the 2-year follow-up.
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Abstract
Backgrounds and objective

There are different second line glucose lowering drugs whose efficacy, safety and economic profile have not been established in our setting. We have analyzed the clinical (diabetic treatment adherence, metabolic control, hypoglycemia and macrovascular complications) and economic (resource use and costs) consequences of the combination of metformin with dipeptidyl peptidase inhibitors (DPPIV) in patients with type 2 diabetes.

Patients and methods

We conducted a multicenter, observational and retrospective study. Patients ≥30 years treated with metformin who initiated a second antidiabetic treatment during 2008–2009 were enrolled in the study. Two groups of patients were established: metformin with DPPIV and metformin with other diabetic drugs. The main measurements were comorbidity, compliance/persistence, metabolic control (glycosylated hemoglobin <7%), complications (hypoglycemia, macrovascular) and total costs. Patients were followed-up for 2 years.

Results

A total of 2067 patients were enrolled (mean age: 66.6 years, 53.1% male). Of these, 519 patients (25.1%) were analyzed in the metformin+DPPIV group and 1548 patients (74.9%) in the group metformin+other antidiabetic drug. The DPPIV group patients showed better compliance (70.3 vs. 59.6%), persistence (63.4 vs. 51.0%) and metabolic control (64.3 vs. 59.6%), respectively (P<.001) compared to the other group. They also showed a lower proportion of hypoglycemia (13.9 vs. 44.3%), cardiovascular events (3.7 vs. 7.6%) and total costs (2347 vs. € 2682), P<.05.

Conclusions

Despite the limitations of the study, patients treated with metformin associated to DPPIV were more likely to show increased adherence, metabolic control and lower rates of hypoglycemia than those treated with metformin associated to other antidiabetics.

Keywords:
DPPIV
Diabetes
Metabolic control
Hypoglycemia
Cardiovascular disease
Health care costs
Resumen
Antecedentes y objetivo

Existen diversos tratamientos farmacológicos hipoglucemiantes de segunda línea cuya eficacia, seguridad y perfil económico no se ha precisado en nuestro medio. Hemos analizado las consecuencias clínicas (adherencia al tratamiento antidiabético, control metabólico, hipoglucemias y complicaciones macrovasculares) y económicas (uso de recursos y costes) de la combinación de metformina con inhibidores de la dipeptidilpeptidasa (IDPP4) en pacientes con diabetes tipo 2 en comparación con metformina y otros fármacos hipoglucemiantes.

Pacientes y métodos

Estudio observacional multicéntrico de carácter retrospectivo. Se incluyeron pacientes de ≥30 años tratados con metformina que iniciaron un segundo tratamiento antidiabético durante los años 2008-2009. Se establecieron 2 grupos de pacientes: metformina con IDPP4 y metformina con otros fármacos antidiabéticos. Las principales medidas fueron: la comorbilidad, el cumplimiento/persistencia, el control metabólico (hemoglobina glicosilada<7%), complicaciones (hipoglucemias, macrovasculares) y costes totales. El seguimiento se realizó durante 2 años.

Resultados

Se reclutaron 2.067 pacientes (edad media: 66,6 años; 53,1% varones). En el grupo metformina+IDPP4 se analizaron 519 pacientes (25,1%) y en el grupo metformina+otros fármacos antidiabéticos: 1.548 pacientes (74,9%). Los enfermos tratados con IDPP4, en comparación con los que recibieron metformina asociada a otros antidiabéticos, mostraron un mejor cumplimiento (70,3 vs. 59,6%), persistencia (63,4 vs. 51,0%) y control metabólico (64,3 vs. 59,6%) (p<0,001). También presentaron una menor proporción de hipoglucemias (13,9 vs. 44,3%), eventos cardiovasculares (3,7 vs. 7,6%) y costes totales (2.347 vs. 2.682€) (p<0,05) durante los 2 años del estudio.

Conclusiones

A pesar de las limitaciones del estudio, los pacientes en tratamiento con metformina asociada a IDPP4 mostraron un mayor cumplimiento terapéutico, control metabólico y menores tasas de hipoglucemias que los enfermos tratados con metformina asociada a otros antidiabéticos.

Palabras clave:
IDPP4
Diabetes
Control metabólico
Hipoglucemias
Eventos cardiovasculares
Costes sanitarios

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