ORIGINAL RESEARCH published: 10 January 2022 doi: 10.3389/fendo.2021.810757 Trends in the Degree of Control and Treatment of Cardiovascular Risk Factors in People With Type 2 Diabetes in a Primary Care Setting in Catalonia During 2007–2018 Manel Mata-Cases 1,2,3†, Bogdan Vlacho 1†, Jordi Real 1,3, Ramon Puig-Treserra 1, Magdalena Bundó 1,4, Josep Franch-Nadal 1,3,5* and Didac Mauricio 1,3,6,7 1 Grup de Recerca Epidemiològica en Diabetis des de l'Atenció Primària (DAP-CAT), Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la Recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain, 2 Centre d’Atenció Primària La Mina, Gerència d’Àmbit d’Atenció Primària de Barcelona, Institut Català Edited by: de la Salut, Barcelona, Spain, 3 Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Dianjianyi Sun, Asociadas, (CIBERDEM), Barcelona, Spain, 4 Centre d’Atenció Primària Ronda Prim, Gerència d’Àmbit d’Atenció Primària Peking University, China Metropolitana Nord de Barcelona, Institut Català de la Salut, Mataro, Spain, 5 Primary Health Care Center Raval Sud, Reviewed by: Gerència d’Atenció Primaria, Institut Català de la Salut, Barcelona, Spain, 6 Department of Endocrinology & Nutrition, Hospital Ernesto Maddaloni, de la Santa Creu i Sant Pau, IIB Sant Pau, Spain, 7 Departament of Medicine, University of Vic, Central University of Sapienza University of Rome, Italy Catalonia, Vic, Spain Ichiro Sakuma, Hokko Memorial Hospital, Japan Objective: To assess the trends in cardiovascular risk factor control and drug therapy *Correspondence: Josep Franch-Nadal from 2007 to 2018 in subjects with type 2 diabetes mellitus (T2DM). josep.franch@gmail.com Materials and Methods: Cross-sectional analysis using yearly clinical data and † These authors have contributed treatment obtained from the SIDIAP database. Patients aged ≥18 years with a equally to this work and share first authorship diagnosis of T2DM seen in primary care in Catalonia, Spain. Results: The number of T2DM patients increased from 299,855 in 2007 to 394,266 in Specialty section: This article was submitted to 2018. We also found an increasing prevalence of cardiovascular disease, heart failure, and Clinical Diabetes, chronic kidney disease (from 18.4 to 24.4%, from 4.5 to 7.3%, and from 20.2 to 31.3%, a section of the journal respectively). The achievement of glycemic targets (HbA1c<7%) scarcely changed (54.9% Frontiers in Endocrinology to 55.9%). Major improvements were seen in blood pressure (≤140/90 mmHg: from 55% Received: 07 November 2021 Accepted: 16 December 2021 to 71.8%), and in lipid control (low-density lipoprotein cholesterol <100 mg/dl: 33.4% to Published: 10 January 2022 48.4%), especially in people with established cardiovascular disease (48.8 to 69.7%). Citation: Simultaneous achievement of all three targets improved from 12.5% to 20.1% in the Mata-Cases M, Vlacho B, Real J, Puig-Treserra R, Bundó M, overall population and from 24.5% to 32.2% in those with cardiovascular disease but Franch-Nadal J and Mauricio D (2022) plateaued after 2013. There was an increase in the percentage of patients treated with any Trends in the Degree of Control and antidiabetic drug (70.1% to 81.0%), especially metformin (47.7% to 67.7%), and DPP4i (0 Treatment of Cardiovascular Risk Factors in People With Type 2 to 22.6%). The use of SGLT-2 and GLP-1ra increased over the years, but remained very Diabetes in a Primary Care Setting in low in 2018 (5.5% and 2.1% of subjects, respectively). There were also relevant increases Catalonia During 2007–2018. Front. Endocrinol. 12:810757. in the use of statins (38.0% to 49.2%), renin-angiotensin system (RAS) drugs (52.5% to doi: 10.3389/fendo.2021.810757 57.2%), and beta-blockers (14.3% to 22.7%). Frontiers in Endocrinology | www.frontiersin.org 1 January 2022 | Volume 12 | Article 810757 Mata-Cases et al. T2DM Control and Treatments Trends Conclusions: During the 2007-2018 period, relevant improvements in blood pressure and lipid control occurred, especially in people with cardiovascular disease. Despite the increase in the use of antidiabetic and cardiovascular drugs, the proportion of patients in which the three objectives were simultaneously achieved is still insufficient and plateaued after 2013. The use of antidiabetic drugs with demonstrated cardio renal benefits (SGLT-2 and GLP-1ra) increased over the years, but their use remained quite low. Keywords: Type 2 dabetes, antidiabetic drugs, glycemic concrol, epidemiology, observational study INTRODUCTION The healthcare system in Catalonia (Spain) is public and universal, where the primary care centers provide first contact Type 2 diabetes mellitus (T2DM) is a global health problem due and continuing care for persons with any health concerns, and to its high worldwide prevalence, high cost of management, they are usually the principal place where T2DM is diagnosed associated chronic complications, disability, and premature and managed. The antidiabetic treatment is free of charge for deaths (1). Tight glycemic, blood pressure, and lipid control retired and severely ill people, while active subjects pay just a lower the risk of diabetes-related complications and death, small part of the cost of the drugs. Since 2006, a system of especially when attained concomitantly. Consequently, electronic medical records (EMR), called e-CAP, was fully multifactorial risk-factor control forms the foundation of implemented in primary care, which allowed the creation of clinical care for patients with T2DM (2–7). There has been the SIDIAP population database (19, 20). To date, it is not consensus regarding several major goals of diabetes treatment for known whether there has been progress in the degree of control over two decades: achieving treatment targets for hemoglobin of the three primary objectives (HbA1c, BP, and LDL-C) in our A1c (HbA1c) levels, blood pressure (BP), and low-density primary care environment. lipoprotein cholesterol (LDL-C) levels, as well as promoting Due to important changes in the therapeutic guidelines, we smoking cessation (2–7). Previous studies reported that hypothesized that there would be changes in the control of achievement of the three diabetes treatment goals had cardiovascular risk factors (CVRFs) and pattern of use of improved from the late 1990s to 2018 in the United States antidiabetic drugs in our T2DM population. Our study aimed (US) (8–10), mainly from 1999 to 2010 (8), but recent analyses to describe the degree of control and treatment pattern related suggest that progress may have stalled or reversed in later periods to CVRFs during 2007-2018 in primary care centers in (9, 10). Furthermore, a study in the United Kingdom (UK) Catalonia (Spain). showed that control of cardiovascular risk factors (CVRFs) remained suboptimal among both sexes (11), while another study reported that CVRFs had worsened especially among the overweight and obese adults (12). MATERIALS AND METHODS Several studies have been published showing changes in the prescription of antidiabetic drugs (13–18). In the UK, an Design and Settings observational study reported an increase in metformin We obtained annual cross-sectional data from 2007 to 2018 using prescriptions and a decrease in sulphonylureas prescriptions the primary health care SIDIAP database. This database includes between 2000 and 2017 (13). A study from Austria between secondary pseudo-anonymized routinely collected health data 2012 and 2018 reported that metformin (alone or in from subjects attended in the primary health care centers combination) was the most frequently prescribed drug, and its (PHCCs) of the leading health care provider in Catalonia use increased over the years; the prescriptions of SGLT-2i and (Spain), the Catalan Institute of Health (Institut Català de la GLP-1ra also increased, while prescriptions of sulphonylureas Salut, ICS). The SIDIAP database is a well-recognized and valid decreased (14). Several studies showed similar trends in the database for the study of diabetes, including EMR, clinical and prescription of antidiabetic drugs in the United States (US): laboratory parameters, and medicine prescription and dispensation metformin remains the dominantly prescribed drug, together data. In 2018, the ICS managed 288 PHCCs that served 5,672,956 with insulins and sulfonylureas, while increased use has been registered citizens, 75.2% of the Catalan population. observed mainly for Dipeptidyl peptidase-4 inhibitors (DPP-4i) and Glucagon-like peptide-1 receptor agonist (GLP-1ra) (15– Eligibility Criteria 17). In Catalonia, using the SIDIAP (Sistema per el We included all subjects 18 years or older with a diagnosis of Desenvolupament de la Investigació en Atenció Primària) T2DM in the database defined by the International Statistical population database, our group reported that despite the Classification of Diseases and Related Health Problems (ICD-10) increasing use of new antidiabetic drugs, no clinically relevant diagnostic codes (E11 or E14 and sub-codes). We excluded all changes were observed in glycemic control from 2007 to subjects with diagnostic codes of other types of diabetes such as 2013 (18). type 1, gestational, or other (E10, O24, E13, respectively). Frontiers in Endocrinology | www.frontiersin.org 2 January 2022 | Volume 12 | Article 810757 Mata-Cases et al. T2DM Control and Treatments Trends Study Variables (2007-2018). For categorical variables, we used the For each year evaluated, the “cut-off” date was defined as “prop_trend_test” function of the R Package rstatix (version December 31st. We collected variables related to the social- 0.7.0). This function performs chi-squared test to assess the trend demographic characteristics (age, sex, smoking status, and in proportions. Data management and all analyses were alcohol consumption) and duration of T2DM. Comorbidities, performed using R statistical software, version 3.6.3. (2020/ such as hypertension and hypercholesterolemia, were defined on 02/29). the base of the specific diagnostic code and/or drug treatment for any of these conditions. Peripheral artery disease, Institutional Review Board Statement cerebrovascular disease, heart failure, ischemic heart disease, The studies involving human participants were reviewed and peripheral neuropathy, retinopathy as well as composite approved by Institutional Review Board (or Ethics Committee) variables for microvascular and macrovascular complications of IDIAP Jordi Gol i Gurina Foundation (protocol code 21/111-P were defined by the diagnostic codes of these conditions. and date of approval 04/05/2021). Written informed consent for Chronic kidney disease (CKD) was defined by the specific participation was not required for this study in accordance with diagnostic code and/or the combination of CKD-EPI the national legislation and the institutional requirements. glomerular filtration rate <60 ml/min/1,73m2 and/or an albumin/creatinine ratio >30mg/g. The closest measurement to the “cut-off” date for clinical variables (systolic and diastolic blood pressure and body mass index -BMI) and laboratory RESULTS parameters (HbA1c, lipid profile, renal profile) were considered. Drug treatment dispensations during the whole Characteristics of the Subjects year (antidiabetic, antithrombotic, antihypertensive, and lipid- Characteristics of the study subjects at each time-point of the lowering drugs) were collected. Six steps of antidiabetic study are presented in Table 1. During the 12 years of treatment were considered: non-pharmacological therapy (no observation, the population identified with T2DM in our drugs), non-insulin antidiabetic drug (NIAD) monotherapy, database increased from 299,855 in 2007 to 394,266 subjects in NIAD double therapy, NIAD triple therapy, insulin alone and 2018. The mean age increased from 68.4 to 70.3 years, and the insulin in combination. The non-pharmacological therapy was proportion of males was from 51.9% to 55%. Regarding toxic defined if there were no records for dispensing antidiabetic drugs habits, smokers decreased from 18.1% in 2007 to 14.4% in 2018, during the previous year. Monotherapy was defined for NIADs and high-risk alcohol consumption decreased from 2.9% to 1.2%. and insulin separately. Dual therapy was defined as a An increase in the prevalence of cardiovascular disease, heart combination of two NIADs, while triple therapy was a failure, and chronic kidney disease was observed (from 18.4 to combination of three NIADs. Insulin in combination included 24.4%, from 4.5 to 7.3% and from 20.2 to 31.3%, respectively). all subjects with insulin in combination with any NIAD. Concerning comorbidities, hypertension and dyslipidemia were highly prevalent among T2DM subjects; both increased Statistical Methods over the years. The prevalence of chronic diabetic complications Descriptive analysis for study variables was done for each year also increased progressively. We observed a progressive decrease of observation. We calculated mean and standard deviation for in BP and LDL-C mean values while BMI and HbA1c did not all quantitative variables, and frequencies and percentages for show any relevant changes. qualitative variables. We calculated the degree of glycemic, blood pressure, and lipid control and the use of antihypertensive, lipid- Use of Antidiabetic Treatment lowering, antithrombotic, and glucose-lowering therapies. Figure 1A and Supplementary Table 1 show the proportion of According to local and international guidelines, glycemic patients in each treatment step (no drugs, NIAD monotherapy, control was defined at an HbA1c level below 7%; we also used NIAD dual therapy, NIAD triple therapy, insulin alone, and an HbA1c threshold below 8%, which is the pay-for-performance insulin in combination). We observed a considerable decrease goal at our institution (ICS). We used the mean of all available (12.1%) in people without pharmacological antidiabetic BP measurements (usually 3-4 readings) to estimate each treatment, from 29.9% to 19.0% at the end of the observation patient’s systolic and diastolic BP. BP control was defined as a period. NIAD monotherapy increased from 29.9% to 34.2%. The systolic/diastolic BP level equal or less than 140/90 mm Hg. use of double NIAD therapy and insulin alone slightly decreased, Cholesterol control was defined as having an LDL-C level less while triple NIAD therapy and insulin in combination with than 100 mg/dL. We further defined a composite indicator using NIAD increased over the years. the three outcomes (HbA1c, BP, and LDL-C). LDL-C control Figure 1B and Supplementary Table 1 show the frequencies and the combined indicator were analyzed globally and of antidiabetic drug use. The use of metformin increased from separately in people with and without cardiovascular disease 47.7% to 67.7%, as was the case for DPP-4i: from 0 to 22.6%. The (CVD). Additionally, we performed trend tests to analyze use of sodium-glucose co-transporter 2 inhibitors (SGLT-2i) and whether the reported changes were statistically significant. For GLP-1ra increased over the years, but their use remained low the continuous variables, we applied one-factor ANOVA, where (5.5% and 2.1% of patients, respectively, in 2018). The use of the factors were the different year periods we wanted to compare thiazolidinediones, alpha-glucosidase inhibitors, and especially Frontiers in Endocrinology | www.frontiersin.org 3 January 2022 | Volume 12 | Article 810757 Mata-Cases et al. T2DM Control and Treatments Trends TABLE 1 | Characteristics of the subjects during the study period. 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 p-value N 299855 318065 335771 355019 369600 384826 395470 402312 401175 404252 400209 394266 – Age, mean (SD), years 68.4 68.6 68.8 68.9 69.1 69.3 69.5 69.7 69.9 70.1 70.2 70.3 <0.001* (12.2) (12.3) (12.4) (12.5) (12.6) (12.6) (12.7) (12.7) (12.6) (12.6) (12.6) (12.5) Age >75 years, n (%) 98104 107607 115629 124675 132801 140657 144226 145462 147890 149950 148749 148385 <0.001** (32.7) (33.8) (34.4) (35.1) (35.9) (36.6) (36.5) (36.2) (36.9) (37.1) (37.2) (37.6) Diabetes duration, (years) 5.72 6.17 6.56 6.93 7.32 7.68 8.04 8.46 8.89 9.33 9.76 10.2 <0.001* (5.58) (5.59) (5.63) (5.71) (5.80) (5.92) (6.03) (6.08) (6.17) (6.30) (6.42) (6.57) Sex (male), n (%) 155534 166499 177329 188809 197641 206793 213202 217706 218271 220818 219289 216708 <0.001** (51.9) (52.3) (52.8) (53.2) (53.5) (53.7) (53.9) (54.1) (54.4) (54.6) (54.8) (55.0) Smoking habit, n (%) No smoker 151906 169301 186097 212027 224377 233993 233957 230948 224317 221448 216008 209774 <0.001** (64.5) (64.3) (64.0) (64.7) (64.3) (63.7) (61.4) (59.2) (57.3) (55.9) (54.8) (53.8) Ex-smoker 42554 46441 49119 50377 50347 51658 54518 56625 56756 57323 57457 56060 <0.001** (18.1) (17.6) (16.9) (15.4) (14.4) (14.1) (14.3) (14.5) (14.5) (14.5) (14.6) (14.4) Current smoker 40926 47488 55656 65449 74050 81493 92541 102432 110433 117462 120801 124391 <0.001** (17.4) (18.0) (19.1) (20.0) (21.2) (22.2) (24.3) (26.3) (28.2) (29.6) (30.6) (31.9) Alcohol consumption, n (%) No alcohol consumption 82147 93138 108256 129886 137741 151994 169619 159519 160084 166452 161344 167135 <0.001** (70.0) (70.9) (70.7) (70.5) (71.0) (71.6) (69.5) (65.5) (64.4) (64.2) (63.7) (63.9) Low risk alcohol consumption 31721 34600 41045 50310 52133 56258 70112 79852 84434 88968 88419 91182 <0.001** (27.0) (26.3) (26.8) (27.3) (26.9) (26.5) (28.7) (32.8) (34.0) (34.3) (34.9) (34.8) High risk alcohol 3492 3578 3781 4069 4021 4038 4328 4303 3977 3803 3525 3335 <0.001** consumption (2.98) (2.72) (2.47) (2.21) (2.07) (1.90) (1.77) (1.77) (1.60) (1.47) (1.39) (1.27) Comorbidities, n (%) Hypertension 222302 237453 253054 269075 281742 294236 304925 311876 312206 315212 312336 308599 <0.001** (74.1) (74.7) (75.4) (75.8) (76.2) (76.5) (77.1) (77.5) (77.8) (78.0) (78.0) (78.3) Hypercholesterolemia 169551 185959 205119 224327 239694 253181 266431 274067 275969 278764 277187 274519 <0.001** (56.5) (58.5) (61.1) (63.2) (64.9) (65.8) (67.4) (68.1) (68.8) (69.0) (69.3) (69.6) Obesity 75824 77715 81900 89403 91969 97538 112956 119249 121540 125400 123006 122075 <0.001** (45.2) (45.1) (45.4) (45.6) (45.5) (45.4) (46.3) (46.4) (46.1) (46.0) (45.3) (44.8) Retinopathy 14466 16976 19892 22930 25440 28177 31020 34166 36446 38403 39175 40676 <0.001** (4.8) (5.3) (5.9) (6.5) (6.9) (7.3) (7.8) (8.5) (9.1) (9.5%) (9.79) (10.3) Chronic kidney Disease 60473 68120 77217 84019 87471 96813 103750 111530 116389 117985 121388 124078 <0.001** (20.2) (21.4) (23.0) (23.7) (23.7) (25.2) (26.2) (27.7) (29.0) (29.2) (30.3) (31.5) Cardiovascular disease 55035 61252 67826 74674 80154 85780 90173 93578 94779 97136 97202 96379 <0.001** (18.4) (19.3) (20.2) (21.0) (21.7) (22.3) (22.8) (23.3) (23.6) (24.0) (24.3) (24.4) Heart failure 13498 15275 17176 19653 21852 24623 27012 28664 29331 30218 29777 28870 <0.001** (4.5) (4.8) (5.1) (5.5) (5.9) (6.4) (6.8) (7.1) (7.3) (7.5) (7.4) (7.3) Clinical variables, mean, (SD) Systolic blood pressure 138 137 136 135 135 134 133 133 133 133 133 133 <0.001* (mm Hg) (16.9) (16.5) (16.1) (15.6) (15.3) (14.8) (14.4) (14.2) (13.9) (13.6) (13.8) (13.7) Diastolic blood pressure 76.4 76.1 75.8 75.5 75.2 74.7 74.4 74.5 74.7 74.9 75.0 75.1 <0.001* (mm Hg) (9.79) (9.78) (9.81) (9.82) (9.84) (9.74) (9.77) (9.77) (9.73) (9.68) (9.77) (9.74) BMI >30 kg/m2 75824 77715 81900 89403 91969 97538 112956 119249 121540 125400 123006 122075 <0.001* (45.2) (45.1) (45.4) (45.6) (45.5) (45.4) (46.3) (46.4) (46.1) (46.0) (45.3) (44.8) BMI, (kg/m2) 30.1 30.1 30.1 30.1 30.1 30.1 30.2 30.2 30.2 30.2 30.1 30.0 <0.001* (5.02) (5.01) (5.05) (5.07) (5.08) (5.11) (5.18) (5.19) (5.20) (5.22) (5.21) (5.21) HbA1c, (%) 7.16 7.23 7.25 7.17 7.25 7.22 7.09 7.07 7.10 7.10 7.07 7.09 <0.001* (1.46) (1.48) (1.47) (1.36) (1.36) (1.33) (1.31) (1.29) (1.29) (1.31) (1.29) (1.29) Cholesterol Total,(mg/dL) 194 192 193 190 188 187 184 184 183 182 183 182 <0.001* (39.5) (39.9) (39.9) (39.8) (39.3) (39.4) (39.4) (39.2) (39.7) (39.8) (40.5) (40.4) Cholesterol HDL,(mg/dL) 50.0 49.9 49.1 48.6 48.9 49.0 49.4 49.0 48.9 48.9 49.3 48.7 <0.001* (13.3) (13.3) (13.2) (12.9) (13.2) (13.2) (13.2) (13.1) (13.0) (13.0) (13.1) (12.7) Cholesterol LDL,(mg/dL) 115 113 114 112 109 109 105 105 105 103 103 103 <0.001* (33.0) (33.3) (33.3) (33.0) (32.8) (32.8) (32.7) (32.5) (32.7) (32.5) (33.1) (33.3) Triglycerides, (mg/dL) 153 155 157 153 155 154 156 157 158 159 162 159 <0.001* (110) (108) (107) (103) (104) (103) (102) (103) (103) (105) (106) (104) Estimated glomerular filtration 73.9 73.5 73.0 73.6 74.3 73.8 73.4 72.8 72.7 73.7 73.5 73.4 <0.001* rate (mL/min/1.73m2) (17.0) (17.3) (17.6) (17.5) (17.6) (17.8) (17.9) (18.2) (18.4) (18.4) (18.5) (18.5) Albumin/creatinine rat (mg/g) 38.0 39.3 39.7 41.6 40.7 42.6 44.1 48.7 54.3 58.2 62.3 64.4 <0.001* (138) (141) (149) (158) (153) (158) (165) (181) (202) (211) (223) (227) Drug treatments, n (%) Antidiabetic drugs 206701 222751 238624 257162 271761 284746 292978 300237 305678 312368 316072 319272 <0.001** (68.9) (70.0) (71.1) (72.4) (73.5) (74.0) (74.1) (74.6) (76.2) (77.3) (79.0) (81.0) Antithrombotic drugs 113108 121593 132746 140210 145230 141294 148350 148959 147561 147479 144272 139478 <0.001** (37.7) (38.3) (68.2) (39.5) (39.3) (36.7) (37.5) (37.0) (36.8) (36.5) (36.1) (35.4) (Continued) Frontiers in Endocrinology | www.frontiersin.org 4 January 2022 | Volume 12 | Article 810757 Mata-Cases et al. T2DM Control and Treatments Trends TABLE 1 | Continued 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 p-value Lipid-lowering drugs 124280 136850 155808 173200 186254 189858 203642 207653 208937 209943 208987 208840 <0.001** (41.4) (43.0) (46.4) (48.8) (50.4) (49.3) (51.5) (51.6) (52.1) (51.9) (52.2) (53.0) Antihypertensive 189348 200707 215455 229767 240860 247106 261151 268779 271849 276935 278346 278356 <0.001** (63.1) (63.1) (64.2) (64.7) (65.2) (64.2) (66.0) (66.8) (67.8) (68.5) (69.6) (70.6) BMI, body mass index; HbA1c, glycated hemoglobin A1c; SD, standard deviation; *Anova 1 Factor; **Chi-square trend test. sulphonylureas decreased notably (the latter from 31.7% to from 79% to 81.1% for HbA1c<8% (Figure 2A). At the end of the 18.8%), while the use of glinides remained stable (5.5% in 2018). observational period, more than a third of subjects (34.9%) had Trends in HbA1c levels are presented in Figure 2 and an HbA1c<6.5% (47.5 mmol/mol) while 18.9% were poorly Supplementary Tables 2, 3. Small changes were observed controlled (HbA1c>8%, 64 mmol/mol). When we analyzed the throughout the study period for the different categories of mean HbA1c for each step of treatment (i.e., no drugs, NIAD HbA1c: from 54.9% to 55.9% for the HbA1c<7% threshold and monotherapy, NIAD dual therapy, NIAD triple therapy, insulin A B FIGURE 1 | Trends in the proportion of subjects by different steps of antidiabetic treatment and using non-insulin antidiabetic drugs. (A) Annual trends in the proportion of subjects by steps of antidiabetic treatment. (B) Annual trends in the proportion of subjects treated with non-insulin antidiabetice drugs. Frontiers in Endocrinology | www.frontiersin.org 5 January 2022 | Volume 12 | Article 810757 Mata-Cases et al. T2DM Control and Treatments Trends A B FIGURE 2 | Trends in glycemic control by HbA1c categories and by step of treatment. (A) Annual trends in distribution of subjects according to HbA1c categories. (B) Annual trends in the mean HbA1c for each step of treatmet. alone and insulin in combination), in general, glycemic control 2018, the use of lipid-lowering drugs increased from 41.4% to worsened with the more complex treatments, but a trend to 53.0%, while the use of antithrombotic drugs slightly decreased improvement was observed for all drug strategies from 2013 to (from 37.7% to 35.4%) (Table 1). The use of antiplatelet drugs 2018 (Figure 2B). The more pronounced reductions of mean slightly decreased over the years (from 32.5% to 29.2%), while the HbA1c were observed in those subjects receiving double NIAD use of anticoagulants increased (5.2% to 6.2%) (Figure 3A). who experienced a reduction of mean HbA1c of -0.33% (from Among the antihypertensive drugs, renin-angiotensin system 7.5% to 7.2%) and in those under monotherapy treatment with a (RAS) drugs (Angiotensin-converting-enzyme inhibitors-ACEI reduction of -0.28% (from 6.9% to 6.6%), while non- or Angiotensin II receptor blocker-ARB) and diuretics were pharmacological treatment (no drugs) remained stable (6.3%). principally used and gradually increased (from 52.5% to 57.2% and from 38.7% to 42.3%, respectively) (Figure 3B). There was Use of Antithrombotic, Antihypertensive, an increase in the use of ACEI, ARB, and especially beta-blockers and Lipid-Lowering Agents (1.3%, 3.4%, and 8.4%, respectively). Regarding the lipid- Figure 3 and Supplementary Table 4 show the use of lowering agents, statins were by far the most widely used lipid- antithrombotic, antihypertensive, and lipid-lowering drugs lowering drugs in all years, and their use greatly increased over the years. During the study period, the use of (11.2%), from 38.0% to 49.2%, at the end of the study antihypertensive increased from 63.1% in 2007 to 70.6% in period (Figure 3C). Frontiers in Endocrinology | www.frontiersin.org 6 January 2022 | Volume 12 | Article 810757 Mata-Cases et al. T2DM Control and Treatments Trends A B C FIGURE 3 | Trends in the proportion of subjects treated with antithrombotic, antihypertensive, and lipid-lowering drugs. (A) Annual trends in the proportion of subjects treated with antithrombotic drugs. (B) Annual trends in the proportion of subjects treated with antihypertensive drugs. (C) Annual trends in the proportion of subjects treated with lipid lowering drugs. Frontiers in Endocrinology | www.frontiersin.org 7 January 2022 | Volume 12 | Article 810757 Mata-Cases et al. T2DM Control and Treatments Trends A B C D FIGURE 4 | Trends in the proportion of subjects achieving different therapeutic goals. (A) Annual trends in the proportion of subjects reaching HbA1c <7%. (B) Annual trends in the proportion of subjects reaching blood pressure ≤140/90 mmHg. (C) Annual trends in the proportion of subjects reaching LDL-C<100 mg/dl, global,with and without cardiovascular disease. (D) Annual trends in the proportion of subjects reaching all three goals, global, with and without cardiocvascular disease. Therapeutic Goals DISCUSSION Trends in achieving the therapeutic goals are presented in Figure 4 and Supplementary Tables 5, 6. The percentage of subjects This cross-sectional study shows the trends in the degree of achieving an HbA1c target <7% (53.0 mmol/mol) remained cardiovascular risk factor control and prescribing practices fairly stable over the years, with some smooth oscillations: the between 2007 and 2018 in primary care in a Mediterranean percentage of subjects meeting this goal was lowest in 2011 (50.9%) area. During this period, a 31% increase (94,411 subjects) was and highest in 2014 (57.5%), and at the end of the observation observed in the registered T2DM population, and in the period it was 55.9% (Figure 4A). According to the threshold of our prevalence of cardiovascular disease, heart failure, and chronic institution (HbA1c<8%), there was a 2% increase, from 79.0% to kidney disease (from 18.4 to 24.4%, from 4.5 to 7.3% and from 81.1%. These results are presented in the Supplementary Table 5. 20.2 to 31.3%, respectively). This could be probably due to an Major improvements were seen in the proportion of people improvement in registration and the aging population. In fact, with blood pressure control (≤140/90 mm Hg), from 55% to there was an increase in the mean age (from 68.4 to 70.3 years) 71.8% (Figure 4B). The same trend was seen with lipid control and in the percentage of patients older than 75 (from 32.7% to (low-density lipoprotein cholesterol <100 mg/dl): from 33.4% to 37.6%). The unexpected low diabetes duration could be 48.4%, especially in people with CVD: 48.8 to 69.7% (Figure 4C). explained by the EMR system (eCAP), which was widely Finally, achievement of all three targets (combined indicator) introduced in 2006 in Catalonia. The accuracy of patients’ improved from 12.5% to 20.1% in the whole population and diagnosis dates reported in the first years could be affected from 18.7% to 28.3% in those with CVD (Figure 4D). by memory, while further diagnoses based on laboratory Improvements in all indicators, except LDL-C in patients results were probably more accurately registered after the with CVD, plateaued after 2013. The percentage of patients with implementation of the eCAP. There was also an increase in the CVD with LDL-C control continued increasing from 64.6% in records of chronic complications, especially chronic kidney 2013 to 69.7% in 2018. disease (CKD), retinopathy, and heart failure. At the end of the study, nearly a quarter of patients (24.4%) had CVD and 31% Trend Tests Analysis CKD. These figures align with those of other studies on the We observed significant p values for trend test for nearly all of prevalence of chronic complications (21, 22). the variables over the years, except for the distribution of subjects Concerning the control of CVRFs, greater improvements according to HbA1c categories and the use of angiotensin have been observed for cholesterol and BP than for glycemic receptor blockers. control, as described in previous reports in the US and the UK Frontiers in Endocrinology | www.frontiersin.org 8 January 2022 | Volume 12 | Article 810757 Mata-Cases et al. T2DM Control and Treatments Trends (8–12). In our database, glycemic control slightly improved from the prescription of SGLT-2i and GLP-1ra that may have 54.9% to 55.9% for the HbA1c<7% threshold and from 79 to contributed to their limited use. In addition, in Spain, GLP-1ra 81.1% for HbA1c<8%, which is the pay-for-performance goal of are only reimbursed, after administrative validation, in our institution (ICS). These changes do not seem to be combination with other antidiabetic drugs for subjects with a outstanding, but at least they have not decreased as recently BMI>30. This was not the case for SGLT-2i despite a more recent described in the US (10), in Germany and Austria (15), and in an introduction in our country (from 2013 on). The increase after international collaboration study of 49 countries (16). Moreover, 2015 was very impressive, quickly surpassing the GLP-1ra regarding the treatment steps, a slight trend in the reduction in prescription rate in 2018 (5.5% vs. 2.1%, respectively). DPP4i the mean HbA1c was seen in all pharmacological steps, the had the greatest increase in use, in agreement with other reports greatest seen with one or two NIAD starting in 2013, with a 0.3% conducted worldwide (8–10, 13–18). They are an alternative to reduction in both cases. sulfonylureas for their lower risk of hypoglycemia, bodyweight Major improvements were seen in the percentage of people increase, and greater convenience as an oral treatment instead of achieving target blood pressure, from 55% to 71.8%. The same injectable drugs (26). trend was seen for LDL-C targets: 33.4% to 48.4%, especially in The percentage of people treated with statins, beta-blockers, people with CVD: 48.8% to 69.7%. Nevertheless, only one in five and RAS drugs increased notably. Similar figures have been patients achieved all three risk factor control goals, increasing observed in the NHANES (National Health and Nutrition from 12.5% to 20.1% in the whole population, but stagnation Examination Survey) study as mentioned earlier: 56.3% used occurred after 2013. This improvement was greater for those statins, and 60.3% used a RAS antihypertensive (10). Use of with CVD (from 18.7% to 28.3%), probably due to more intense antithrombotic therapies (mainly aspirin) showed a slight treatment with lipid-lowering drugs. Published data from the US, reduction, probably because of the recommendation against based on NHANES surveys from 1999 to 2018, showed a the prescription of aspirin in primary prevention since 2010 (27). worsening of glycemic control (HbA1c<7%) between the 2007– This study has some strengths and limitations. The main 2010 and 2015–2018 surveys: from 57.4% to 50.5% of people strength is that we used a large database to determine trends in achieving this target (10). In the same study, the percentage of primary care. However, this was a retrospective study, and people with blood pressure control (BP <140/90 mmHg) missing data should be noted, especially in the first years of the decreased from 74.2% to 70.4%, and minimal improvements study. For instance, the percentage of missing values for HbA1c were seen in lipid control, while the percentage of people in was 36.9% in 2007, which decreased to 25% in 2018. This was whom all three targets were simultaneously achieved plateaued also the case for the available values for calculating the combined after 2010 at around 22.2% in 2015–2018 (10). This percentage in 3 CVRF indicators: only 48.9% of patients had both three the composite indicator is similar to the 20% observed in our measurements in 2007 but this increased to 62.1% in 2018. database that also plateaued from 2013 to 2018. Lack of data could be explained due to some patients not A matter of concern is the fact that the composite indicator attending their routine visits, incomplete recording of patient plateaued after an initial and progressive improvement. A possible information by some health professionals, and that a small explanation would be a ceiling on glycemic and blood pressure proportion of subjects are under the care of endocrinologists in improvements, beyond which it is difficult to improve since hospitals or private clinics. In studies like the current one that relevant factors such as patient adherence, tolerance to drugs, include a very large sample of participants, even small differences and especially the need for less stringent goals in patients of are statistically significant. Actually, the statistical differences advanced age. More than a third of the subjects were 75 years or found in our study do not add relevant information for the final older, and the benefits of strict glycemic control this population interpretation of the findings. Nevertheless, a large number of has not yet been fully demonstrated (23, 24). Overcoming clinical measurements and the consistency of similar annual results inertia by healthcare professionals, improving adherence to contribute to the validity of our conclusions. medications and healthy lifestyle behaviors in patients, and In conclusion, in our country, during 2007-2018, relevant providing necessary health care access and resources, education, improvements were observed in blood pressure and lipid control, and self-management support by the healthcare system are especially in people with cardiovascular disease. Despite the challenges that need to be tackled (25). increase in the use of antidiabetic and cardiovascular drugs, Regarding pharmacological treatment, there was an increase the proportion of patients in which the three objectives were in the proportion of subjects receiving antidiabetic drugs, simultaneously achieved is still insufficient and plateaued after especially for metformin and DPP4i. The use of newer classes 2013. Finally, the use of antidiabetic drugs with demonstrated of glucose-lowering drugs rose, whereas older classes such as cardio renal benefits like SGLT-2 and GLP-1ra increased over the sulfonylureas, pioglitazone, and alfa glucosidase inhibitors years, but their use remained very low. declined; these findings reflect a shift toward safer or better- tolerated drugs. Although increasing, the use of SGLT-2i and GLP-1ra agents with demonstrated cardiovascular benefits (2–7), DATA AVAILABILITY STATEMENT remained low, probably because they are newer, more expensive, and have prescription restrictions in our country. For instance, The data analyzed in this study is subject to the following there were negative economic incentives during this period for licenses/restrictions: The data controller for SIDIAP does not Frontiers in Endocrinology | www.frontiersin.org 9 January 2022 | Volume 12 | Article 810757 Mata-Cases et al. T2DM Control and Treatments Trends allow the sharing of raw data. Requests to access these datasets conceived the research and participated in its design. JR and RP- should be directed to JF-N, josep.franch@gmail.com. T performed statistical analysis. MM-C and BV wrote the initial draft of the manuscript, which MM-C, JF-N, JR, RP-T, MB, DM, and BV edited. All authors contributed to the article and approved the submitted version. ETHICS STATEMENT The studies involving human participants were reviewed and approved by Institutional Review Board (or Ethics Committee) ACKNOWLEDGMENTS of IDIAP Jordi Gol i Gurina Foundation (protocol code 21/111-P and date of approval 04/05/2021). Written informed consent for The authors acknowledge Amanda Prowse for providing support participation was not required for this study in accordance with in editing the paper. the national legislation and the institutional requirements. SUPPLEMENTARY MATERIAL AUTHOR CONTRIBUTIONS The Supplementary Material for this article can be found online MM-C and BV have contributed equally to this work and share at: https://www.frontiersin.org/articles/10.3389/fendo.2021. the first authorship. MM-C, JF-N, JR, RP-T, MB, DM, and BV 810757/full#supplementary-material 12. Scholes S, Fat LN, Mindell JS. Trends in Cardiovascular Disease Risk Factors REFERENCES by BMI Category Among Adults in England, 2003-2018. Obesity (2021) 1. Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge 29:1347–62. doi: 10.1002/oby.23184 AW, et al. IDF Diabetes Atlas: Global Estimates of Diabetes Prevalence for 13. Wilkinson S, Douglas I, Stirnadel-Farrant H, Fogarty D, Pokrajac A, Smeeth L, 2017 and Projections for 2045. Diabetes Res Clin Pract (2018) 138:271–81. et al. Changing Use of Antidiabetic Drugs in the UK: Trends in Prescribing doi: 10.1016/j.diabres.2018.02.023 2000–2017. 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Comparative Effectiveness for Glycemic fees from Astra-Zeneca, Ascensia, Boehringer Ingelheim, GSK, Lilly, MSD, Control in Older Adults With Diabetes. Curr Geriatr Rep (2017) 6:175–86. Novartis, Novo Nordisk, and Sanofi; he has received research grants to the doi: 10.1007/s13670-017-0215-z institution from Astra-Zeneca, GSK, Lilly, MSD, Novartis, Novo Nordisk, 25. Hill-Briggs F, Adler NE, Berkowitz SA, Chin MH, Gary-Webb TL, Navas- Sanofi, and Boehringer. MB has received advisory and speaking fees from MSD. Acien A, et al. Social Determinants of Health and Diabetes: A Scientific The remaining authors declare that the research was conducted in the absence of Review. Diabetes Care (2021) 44:258–79. doi: 10.2337/dci20-0053 any commercial or financial relationships that could be construed as a potential 26. von Arx L-B, Kjær T. The Patient Perspective of Diabetes Care: A Systematic conflict of interest. Review of Stated Preference Research. Patient Patient-Centered Outcomes Res (2014) 7:283–300. doi: 10.1007/s40271-014-0057-0 Publisher’s Note: All claims expressed in this article are solely those of the authors 27. Pignone M, Alberts MJ, Colwell JA, Cushman M, Inzucchi SE, Mukherjee D, and do not necessarily represent those of their affiliated organizations, or those of et al. Aspirin for Primary Prevention of Cardiovascular Events in People With the publisher, the editors and the reviewers. Any product that may be evaluated in Diabetes. Circulation (2010) 121:2694–701. doi: 10.1161/CIR. this article, or claim that may be made by its manufacturer, is not guaranteed or 0b013e3181e3b133 endorsed by the publisher. Conflict of Interest: MM-C has received advisory honorarium from Astra- Zeneca, Bayer, Boehringer Ingelheim, GSK, Lilly, MSD, Novartis, Novo Copyright © 2022 Mata-Cases, Vlacho, Real, Puig-Treserra, Bundo,́ Franch-Nadal Nordisk, and Sanofi; he has received speaker honorarium from Astra-Zeneca, and Mauricio. This is an open-access article distributed under the terms of the Bayer, Boehringer Ingelheim, GSK, Lilly, Menarini, MSD, Novartis, Novo Creative Commons Attribution License (CC BY). The use, distribution or Nordisk, and Sanofi; he has received research grants to the institution from reproduction in other forums is permitted, provided the original author(s) and the Astra-Zeneca, GSK, Lilly, MSD, Novartis, Novo Nordisk and Sanofi. JF-N has copyright owner(s) are credited and that the original publication in this journal is received advisory and or speaking fees from Astra-Zeneca, Ascensia, Boehringer cited, in accordance with accepted academic practice. No use, distribution or Ingelheim, GSK, Lilly, MSD, Novartis, Novo Nordisk, and Sanofi; he has received reproduction is permitted which does not comply with these terms. Frontiers in Endocrinology | www.frontiersin.org 11 January 2022 | Volume 12 | Article 810757