Journal of Clinical Medicine Article Potential Risk of Overtreatment in Patients with Type 2 Diabetes Aged 75 Years or Older: Data from a Population Database in Catalonia, Spain Manel Mata-Cases 1,2,3, * , Didac Mauricio 1,2,4,5 , Jordi Real 1 , Bogdan Vlacho 1 , Laura Romera-Liebana 1,6 , Núria Molist-Brunet 7,8 , Marta Cedenilla 9 and Josep Franch-Nadal 1,2,10, * 1 DAP-Cat Group, Unitat de Suport a la Recerca Barcelona Ciutat, Institut Universitari d’Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), 08025 Barcelona, Spain 2 CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM CB15/00071), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain 3 Primary Health Care Center La Mina, Gerència d’Àmbit d’Atenció Primària Barcelona Ciutat, Institut Català de la Salut, Sant Adrià de Besòs, 08930 Barcelona, Spain 4 Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain 5 Departament of Medicine, University of Vic-Central University of Catalonia (UVIC-UCC), 08500 Vic, Spain 6 Primary Healthcare Centre Raval Nord, Institut Català de la Salut, 08001 Barcelona, Spain 7 Hospital Universitari de la Santa Creu de Vic, 08500 Vic, Spain 8 Central Catalonia Chronicity Research Group (C3RG), Centre for Health and Social Care Research (CESS), University of Vic-Central University of Catalonia (UVIC-UCC), 08500 Vic, Spain 9 Medical Affairs Department, MSD Spain, 28027 Madrid, Spain 10 Primary Health Care Center Raval Sud, Gerència d’Àmbit d’Atenció Primària Barcelona Ciutat, Institut Català de la Salut, 08001 Barcelona, Spain * Correspondence: manelmatacases@gmail.com (M.M.-C.); josep.franch@gmail.com (J.F.-N.); Citation: Mata-Cases, M.; Mauricio, Tel.: +34-93-2075-752 (J.F.-N.) D.; Real, J.; Vlacho, B.; Romera-Liebana, L.; Molist-Brunet, Abstract: Aim: To assess the potential risk of overtreatment in patients with type 2 diabetes (T2DM) N.; Cedenilla, M.; Franch-Nadal, J. Potential Risk of Overtreatment in aged 75 years or older in primary care. Methods: Electronic health records retrieved from the Patients with Type 2 Diabetes Aged SIDIAP database (Catalonia, Spain) in 2016. Variables: age, gender, body mass index, registered 75 Years or Older: Data from a hypoglycemia, last HbA1c and glomerular filtration rates, and prescriptions for antidiabetic drugs. Population Database in Catalonia, Potential overtreatment was defined as having HbA1c < 7% or HbA1c < 6.5% in older patients Spain. J. Clin. Med. 2022, 11, 5134. treated with insulin, sulfonylureas, or glinides. Results: From a total population of 138,374 T2DM https://doi.org/10.3390/ patients aged 75 years or older, 123,515 had at least one HbA1c available. An HbA1c below 7.0% was jcm11175134 present in 59.1% of patients, and below 6.5% in 37.7%. Overall, 23.0% of patients were treated with Academic Editor: Brian T. Tomlinson insulin, 17.8% with sulfonylureas, and 6.6% with glinides. Potential overtreatment (HbA1c < 7%) was suspected in 26.6% of patients treated with any high-risk drug, 47.8% with sulfonylureas, 43.5% with Received: 14 July 2022 glinides, and 28.1% with insulin. Using the threshold of HbA1c < 6.5%, these figures were: 21.6%, Accepted: 26 August 2022 24.4%, 17.9%, and 12.3%, respectively. Conclusion: One in four older adults with T2DM treated with Published: 31 August 2022 antidiabetic drugs associated with a high risk of hypoglycemia might be at risk of overtreatment. Publisher’s Note: MDPI stays neutral This risk is higher in those treated with sulfonylureas or glinides than with insulin. with regard to jurisdictional claims in published maps and institutional affil- Keywords: type 2 diabetes; treatment; overtreatment; older diabetes adults iations. 1. Introduction Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. The rising prevalence of type 2 diabetes mellitus (T2DM) in most parts of the world is This article is an open access article likely to increase the incidence of the chronic complications associated with the disease [1]. distributed under the terms and This calls for the improved treatment of hyperglycemia and other risk factors associated conditions of the Creative Commons with T2DM to lower the risk of both micro- and macrovascular complications, as all interna- Attribution (CC BY) license (https:// tional and national consensus documents and guidelines propose [2–4]. However, in older creativecommons.org/licenses/by/ patients with multimorbidity or those who are frail, the benefits of tight glycemic control 4.0/). J. Clin. Med. 2022, 11, 5134. https://doi.org/10.3390/jcm11175134 https://www.mdpi.com/journal/jcm J. Clin. Med. 2022, 11, 5134 2 of 13 decline and the risk and burden of antidiabetic treatments increase [5–7]. Moreover, obser- vational studies of people with T2DM who are older or have high clinical complexity have found an association between tight blood glucose control (HbA1c < 7% (53 mmol/mol)) and higher risk of falls, severe hypoglycemia, emergency department visits, hospitaliza- tions, and death [7–11]. Trying to achieve tight glycemic levels could be detrimental in older patients, particularly those with complications and serious comorbidities, because of their high likelihood of severe hypoglycemia [5–7]. Such episodes in older adults have implications for both short-term (e.g., risk of falls, accidents, hospitalizations, and death) and long-term negative outcomes (e.g., lower quality of life, decreased cognitive function, and increased risk of cardiovascular mortality) [7]. Some real-world population studies on older adults with T2DM have consistently shown that, despite the fact that they are well controlled (HbA1c < 7%), they are treated with antidiabetic drugs associated with a high risk of hypoglycemia (insulin, sulfonylureas, and glinides) and, thus, they might be at risk of overtreatment [12–18]. Primary healthcare professionals face the challenge of implementing increasingly complex treatment algorithms and overcoming therapeutic inertia in daily practice, which results not only in delayed treatment intensification but also in delayed treatment deinten- sification among the old and frail [19]. Deintensification has been incorporated into some therapeutic guidelines [20–22] and has been shown to be safe and effective in a metanaly- sis [23]. However, deintensification is relatively infrequent in clinical practice [24–26]. The failure to deintensify therapy raises safety concerns and may contribute to overtreatment; in turn, it may lead to avoidable direct and indirect health costs [6]. Several reports on the management and treatment of patients with T2DM in Catalonia (Spain), based on the SIDIAP population database, have consistently shown that older adults have better control than other age subgroups [27–30]. For instance, 59.2% of T2DM patients over 75 had HbA1c < 7% and 37.7% HbA1c < 6.5% in 2016 [30], which leads us to suspect the existence of potential overtreatment. We undertook this study to specifically analyze the potential risk of overtreatment defined as an HbA1c < 7% or an HbA1c < 6.5% in patients aged 75 years or older treated with drugs associated with a higher risk of hypoglycemia (insulin, sulfonylureas, or glinides). Moreover, we evaluated the use of high-risk antidiabetic drugs, potential overtreatment, and the presence of hypoglycemia in cardiovascular and renal comorbidities. 2. Methods This was a cross-sectional study using the SIDIAP database (Information System for the Development of Research in Primary Care) (www.sidiap.org, accessed on 7 August 2022) [28], which contains pseudo-anonymized longitudinal patient information obtained from the electronic health records (EHR) of patients attended by 286 primary care teams at the Institut Català de la Salut (Catalan Health Institute), which covered 74% of the total population in Catalonia in 2016 [29]. In brief, SIDIAP contains sociodemographic characteristics, morbidity (International Classification of Diseases, Tenth Revision; ICD- 10), clinical and lifestyle variables, specialist referrals, laboratory tests, and treatments (prescription and pharmacy invoicing data) since 2006. All primary care health centers use the same EHR, called the Primary Care Clinical Station (in Catalan: Estació Clínica d’Atenció Primària, ECAP). Catalonia is a Mediterranean region in northeastern Spain, with a public health system in which every citizen is registered with a general practitioner and a nurse in a publicly funded primary care health center. Healthcare and all diagnostic procedures are free of charge to patients. Antidiabetic medications are free for retired people, severely ill people, and people with disabilities and at a very small cost for active patients. 2.1. Study Eligibility Criteria The study population consisted of patients aged 75 years or older with a diagnosis of T2DM (ICD-10 codes E11 and E14 and subcodes) on 31 December 2016. Patients with any other type of diabetes were excluded from the analysis. J. Clin. Med. 2022, 11, 5134 3 of 13 2.2. Study Variables Variables collected were age, sex, time since diagnosis, body mass index (BMI), blood pressure, lipid profile, estimated Glomerular Filtration Rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Equation, the urine albumin to creatinine ratio (UACR), and the most recent HbA1c value of the preceding 24 months. ICD- 10 codes and data pertaining to other cardiovascular risk factors and chronic complications and comorbidities were also available and have been extensively described elsewhere [29]. To identify hypoglycemia, we used ICD-10 diagnostic code E16.2. Data on glucose-lowering medication were obtained from the CatSalut drug pharmacy invoice database. 2.3. Statistical Methods Descriptive analysis consisted of summary statistics, mean and standard deviation for continuous variables, and percentages for categorical variables. Three subgroups of age were considered: 75–80, 81–85, and >85 years old. Glycemic control was stratified into four categories by HbA1c intervals (<6.5%, 6.5% to 6.9%, 7.0% to 7.9%, 8.0 to 8.9%, and ≥9%). According to renal function, patients were classified in three groups: normal/mild (eGFR ≥ 60 mL/min), moderate chronic renal failure (CRF) (eGFR 30–59 mL/min), and severe CRF (eGFR < 30 mL/min). Potential overtreatment was defined as having an HbA1c < 7% or HbA1c < 6.5% in patients aged 75 years or older treated with drugs associated with a high risk of hypoglycemia (insulin, sulfonylureas, or glinides). Steps of treatment and potential overtreatment were analyzed according to sex and age sub- groups and the presence of other comorbidities: cardiovascular disease (CVD), chronic kidney disease (CKD), heart failure (HF), and severe CRF. Four antidiabetic steps of treatment—lifestyle modification only, non-insulin antidiabetic drug (NIAD) monotherapy, a combination of NIADS, and insulin alone or in combination with any NIAD—were considered. Antidiabetic drugs were classified in two groups: high risk of hypoglycemia (sulfonylureas, glinides, and insulin) and low risk of hypoglycemia (other NIADs). 2.4. Ethics Committee Approval The study was approved by the Ethics Committee of the Primary Health Care Univer- sity Research Institute (IDIAP) Jordi Gol (approval number: P17/015). In accordance with the Spanish regulations on observational studies, this retrospective study using pseudo- anonymized data did not require obtaining informed consent from the patient. 3. Results By 31 December 2016, the SIDIAP database contained records from 138,374 patients with T2DM aged 75 years or older. The mean age was 82.6 (5.1) years, and 55% were women. In total, 123,515 (89.3%) patients had at least one HbA1c available. The mean HbA1c was 7.0% (Table 1); an HbA1c below 7.0% was present in 59.1% of patients and below 6.5% in 37.7% (Figure 1a). The degree of glycemic control stratified using HbA1c intervals (<6.5%, 6.5% to 6.9%, 7.0% to 7.9%, 8.0% to 8.9%, and ≥9%) for sex, age groups, and the considered comorbidities is shown in Figure 1a. Figure 1b shows the distribution of HbA1c intervals, displaying three subcategories in patients with HbA1c < 7%: treated with antidiabetic drugs with a high risk of hypoglycemia (26.7%), treated with low-risk antidiabetic drugs (16.9%), and treated only with lifestyle modification (15.6%). CKD was present in 51.9% of subjects, and severe CRF (eGFR < 30 mL/min) was present in 7.6% of 124,748 (90.15%) patients with at least one eGFR measurement available (Table 1). J. Clin. Med. 2022, 11, 5134 4 of 13 Table 1. Clinical characteristics of patients by sex and age subgroups and the presence of comorbidities. Women 75–80 81–85 >85 Severe Overall Men CVD HF CKD Variables n= Years Old Years Old Years Old CRF n = 138,374 n = 61,449 n = 44,668 n = 17,986 n = 71,848 76,925 n = 48,951 n = 47,278 n = 42,145 n = 5272 Mean age, years (SD) 82.6 (5.1) 81.9 (4.8) 83.2 (5.3) 77.5 (1.5) 82.9 (1.1) 88.9 (3.1) 83.1 (5.1) 84.2 (5.3) 83.5 (5.2) 84.7 (5.4) Gender (female), % 55.6 0 100 49.2 55.1 63.5 44.3 59.6 57.1 59.8 Mean diabetes 11.2 (6.8) 11.1 (6.6) 11.3 (7.0) 10.7 (6.4) 11.4 (6.8) 11.7 (7.1) 12.0 (7.1) 11.7 (7.1) 11.8 (6.9) 12.9 (7.2) duration, years (SD) Mean HbA1c, % (SD) 7.0 (1.1) 7.0 (1.1) 7.0 (1.1) 7.0 (1.1) 7.0 (1.1) 7.0 (1.1) 7.1 (1.1) 7.1 (1.2) 7.1 (1.1) 7.1 (1.2) (n = 123,515) Current smoker, % 4.8 9.1 1.3 6.9 4.5 2.6 5.6 3.3 4.5 3.7 Mean BMI, kg/m2 (SD) 28.9 (3.9) 28.2 (3.9) 29.5 (5.2) 29.6 (4.8) 28.9(4.7) 27.9 (4.5) 28.5 (4.5) 30.0 (5.4) 29.1 (4.8) 29.4 (5.2) (n = 117,212) Obesity (BMI > 30 kg/m2 ), % (n = 36.1 29.2 41.9 41.1 36.7 28.5 33.0 16.9 37.9 41.2 117,212) Hypertension, % 84.4 80.3 87.7 82.5 84.9 86.1 85.9 89.2 89.5 91.6 Hyperlipidemia, % 60.4 56.3 63.7 63.8 61.1 55.7 63.0 60.4 61.8 60.9 CVD, % 32.3 40.5 25.7 29.2 32.6 35.6 - 49.4 37.1 45.3 HF, % 13.0 11.8 13.9 8.9 12.6 18.2 19.9 - 17.8 33.2 Retinopathy, % 15.8 15.0 16.4 15.4 16.2 15.8 18.8 19.6 17.8 22.1 Neuropathy, % 10.0 8.4 11.3 10.5 10.45 8.8 11.4 11.8 10.8 9.0 CKD (eGFR < 60 mL/min/1.73 m2 or 51.9 50.2 53.3 42.1 53.8 62.5 59.7 71.1 - - albuminuria > 30 mg/g), % Severe chronic renal failure (eGFR < 30 7.6 7.0 8.2 4.6 7.1 11.8 10.7 19.3 - - mL/min/1.73 m2 ), % (n = 124,748) Antidiabetic Treatment Only lifestyle 19.4 18.0 20.6 15.6 18.5 25.0 17.0 18.9 17.9 20.1 modification, % Non-insulin antidiabetic drug 37.9 38.6 37.4 38.4 37.8 37.5 34.3 31.8 35.2 25.7 monotherapy, % Non-insulin antidiabetic drug 19.7 21.7 18.0 23.1 20.0 15.3 18 13.7 18.6 7.8 combination, % Insulin (alone or in 23.0 21.7 24.0 22.9 23.7 22.3 30.6 35.7 28.3 46.5 combination), % Sulfonylureas, % 17.8 18.8 17.8 19.9 17.8 15.3 16.4 13.8 16.9 17.2 Glinides, % 6.7 6.8 6.6 6.0 6.9 7.4 7.6 8.9 8.6 4.6 High-risk 43.5 43.3 43.6 44.5 44.1 41.6 49.8 53.1 49.0 66.0 antidiabetics, % Only low-risk 37.6 38.7 35.8 39.9 37.4 33.4 33.2 28.0 33.1 13.1 antidiabetics, % CVD: cardiovascular disease; HF: heart failure; CKD: chronic kidney disease; CRF: chronic renal failure; eGFR: J. Clin. Med. 2022, 11, x FOR PEER REVIEW 5 of 15 estimated Glomerular Filtration Rate. High-risk antidiabetic drugs: sulfonylureas, glinides, insulin; low-risk ADs: metformin, SGLT-2 inhibitors, GLP-1 receptor agonists, DPP4 inhibitors, alfa-glucosidase inhibitors, pioglitazone. 100% 6.3 6.0 6.6 6.3 6.4 6.3 7.4 8.5 7.4 9.7 90% 9.8 9.5 10.0 9.7 10.1 9.6 11.1 11.7 10.7 12.1 80% 70% 24.7 24.8 24.7 25.7 25.2 23.0 25.5 25.0 25.1 24.1 ≥9% 60% 20.3 8-8.9% 50% 21.4 22.1 21.0 22.4 21.4 20.8 21.9 17.2 19.7 7-7.9% 40% 30% 6.5-6.9% 20% 40.8 <6.5% 37.7 37.6 37.7 35.9 36.9 35.2 35.1 34.9 36.9 10% 0% All Men Women 75-80 81-85 >85 yrs. CVD HF CKD Severe yrs. old yrs. old old CRF n = 123,515 patients with available HbA1c. CVD: cardiovascular disease; HF: Heart Failure; CKD: Chronic Kidney Disease; CRF: Chronic Renal failure (a) 100% 1. Cont. Figure 6.3 6.0 6.6 6.0 6.5 6.3 7.4 8.5 7.4 9.7 90% 9.8 9.5 10.0 9.5 10.5 9.5 11.1 11.7 10.7 12.1 80% 24.7 24.8 24.7 26.2 23.0 70% 24.7 25.5 25.1 25.0 24.1 ≥9% 60% 8-8.9% 20% 40.8 <6.5% 37.7 37.6 37.7 35.9 36.9 35.2 35.1 34.9 36.9 10% 0% All Men Women 75-80 81-85 >85 yrs. CVD HF CKD Severe yrs. old yrs. old old CRF J. Clin. Med. 2022, 11, 5134 5 of 13 n = 123,515 patients with available HbA1c. CVD: cardiovascular disease; HF: Heart Failure; CKD: Chronic Kidney Disease; CRF: Chronic Renal failure (a) 100% 6.3 6.0 6.6 6.0 6.5 6.3 7.4 8.5 7.4 9.7 90% 9.8 9.5 10.0 9.5 10.5 9.5 11.1 11.7 10.7 12.1 80% 24.7 24.8 24.7 26.2 23.0 70% 24.7 25.5 25.1 25.0 24.1 ≥9% 60% 8-8.9% 50% 26.7 7-7.9% 26.7 27.3 26.1 26.4 26.9 40% 31.6 30.6 24.7 <7% High risk AD 34.8 30% <7% Low risk AD 14.9 16.9 17.9 16.3 16.2 13.5 <7% without AD 19.1 20% 12.2 11.9 6.9 10% 15.6 16.3 15.2 19.6 15.9 14.5 12.8 12.2 13.1 14.3 0% All Men Women 75-80 81-85 >85 yrs. CVD HF CKD Severe yrs. old yrs. old old CRF n = 123,515 patients with available HbA1c. Potential overtreatment (HbA1c < 7% using any high-risk AD drug) corresponds to the red area of each column. AD: Antidiabetic Drug; CVD: cardiovascular disease; HF: Heart Failure; CKD: Chronic Kidney Disease; CRF: Chronic Renal failure. (b) Figure 1. Degree of glycemic control. (a) Degree of glycemic control (HbA1c categories) by sex, age Figure 1. Degree of glycemic control. subgroups, and (a) Degree comorbidities; (b) Degreeof of glycemic control glycemic control (HbA1c (HbA1c categories) categories) by sex, age sub- by sex, groups, and comorbidities considering the use of antidiabetic drugs in patients with HbA1c < 7%. age subgroups, and comorbidities; (b) Degree of glycemic control (HbA1c categories) by sex, age subgroups, and comorbidities considering the use of antidiabetic drugs in patients with HbA1c < 7%. 3.1. Antidiabetic Treatment J. Clin. Med. 2022, 11, x FOR PEER REVIEW 6 of 15 Overall, 19.4% of patients were treated with only lifestyle changes, 43.5 with antidi- abetics with a high risk of hypoglycemia (23.0% with insulin, 17.8% with sulfonylureas, 3.1. Antidiabetic Treatment 6.7% with glinides), and 37.6% with antidiabetic drugs with a low risk of hypoglycemia Overall, 19.4% of patients were treated with only lifestyle changes, 43.5 with antidi- (Table 1). The distribution abetics by withtreatment a high risk ofsteps for each hypoglycemia category (23.0% of HbA1c with insulin, showed 17.8% with that, in sulfonylureas, patients with HbA1c <6.7% 6.5%, with81.2% were glinides), and treated 37.6% withwith only lifestyle antidiabetic drugs withchanges a low riskor monotherapy. of hypoglycemia (Table 1). The distribution by treatment steps for each category of HbA1c showed that, in Conversely, in patients with HbA1c ≥ 9%, 88.8% of them were treated with a NIAD com- patients with HbA1c < 6.5%, 81.2% were treated with only lifestyle changes or monother- bination or insulin (Figure 2a). The apy. Conversely, in use of with patients high-risk HbA1c ≥drugs increased 9%, 88.8% of them wereastreated HbA1c withincreased: a NIAD in patients with HbA1c < 6.5%, combination or their insulin use was (Figure 2a).21.6%, while The use of in those high-risk as HbA1c≥in-9%, with HbA1c drugs increased it was 86.9% (Figure creased: in patients with HbA1c < 6.5%, their use was 21.6%, while in those with HbA1c ≥ 2b). Comparing the use of insulin in patients with HbA1c < 6.5% 9%, it was 86.9% (Figure 2b). Comparing the use of insulin in patients with HbA1c < 6.5% to those with HbA1cto≥those 9%, the with percentages HbA1c were 7.6% ≥ 9%, the percentages andand were 7.6% 67.3%, respectively. 67.3%, respectively. These These pro- progressive increasesgressive were increases less marked were lessfor other marked high-risk for other high-riskantidiabetic drugs: antidiabetic drugs: 10.8% 10.8% to 15.9% to for sulfonylureas and 3.2% to 3.6% for glinides (Figure 2b). 15.9% for sulfonylureas and 3.2% to 3.6% for glinides (Figure 2b). 100% 7.6 13.2 90% 25.1 23.0 Insulin 11.1 29.8 80% 18.8 70% 55.8 67.3 15.1 19.7 60% NIAD combi 48.5 30.0 50% 40% 49.0 33.0 37.9 NIAD mono 30% 28.3 20% 33.6 21.5 32.7 26.2 10% 19.1 13.8 19.4 Only lifestyle 8.9 0% 6.5 2.1 2.2 modification <6.5% 6.5-6.9% 7-7.9% 8-8.9% ≥9% Missing All HbA1c n = 138,374 T2DM patients older than 75; 123,515 of them with available HbA1c. NIAD: Noninsulin Antidiabetic Drug (a) Figure 2. Cont. J. Clin. Med. 2022, 11, 5134 6 of 13 J. Clin. Med. 2022, 11, x FOR PEER REVIEW 7 of 15 90 86.9 82.0 80 70 67.3 58.8 60 55.8 Sulfonylureas 50 45.7 47.4 41.5 43.0 Glinides 37.2 37.6 40 33.5 34.7 Insulin 29.8 30 23.5 25.1 23.0 High Risk AD 21.6 20.8 16.2 15.8 15.9 17.8 20 13.2 14.1 Low Risk AD 10.8 10.9 7.6 5.5 5.5 6.7 10 3.2 4.1 3.6 4.7 0 <6.5% 6.5-6.9% 7-7.9% 8-8.9% ≥9% Missing All HbA1c n = 138,374 T2DM patients older than 75; 123,515 of them with available HbA1c. AD: Antidiabetic Drug (b) Figure 2. Antidiabetic treatment. (a) Steps of antidiabetic treatment by HbA1c categories; (b) Use Figure 2. Antidiabetic treatment. (a) Steps of antidiabetic treatment by HbA1c categories; (b) Use of of high-risk antidiabetic drugs by HbA1c categories. high-risk antidiabetic drugs by HbA1c categories. Table 2 shows the steps of treatment and the use of antidiabetic drugs by age sub- groups for each comorbidity. Patterns of use were quite similar among CKD, CVD, and Table 2 shows the steps of treatment and the use of antidiabetic drugs by age subgroups HF patients in which insulin was more frequently prescribed (28.3%, 30.6%, and 35.7%, for each comorbidity. Patterns of use respectively) and,were quite similar consequently, among the percentage CKD, CVD, of high-risk and HF antidiabetic drugspatients (49.0%, in which insulin was more 49.8%,frequently prescribed and 53.1%, respectively) (28.3%, (Table 30.6%, 1). These and 35.7%, percentages respectively) decreased progressively when age increased, being lower in people older than 85 in all comorbidities but HF (Table and, consequently, the percentage of high-risk antidiabetic drugs (49.0%, 49.8%, and 53.1%, 2). For instance: insulin in patients with severe CRF decreased from 59.8% in the 75–80- respectively) (Table 1).year-old Thesegrouppercentages decreased to 41.5% in the >85-year-oldprogressively group. In a similarwhen age way, the use increased, of high-risk being lower in people antidiabetic older than 85decreased drugs in all comorbidities but from 72.2% to 58.2% HF age in these (Table 2). For subgroups. instance: Conversely, in patients with HF, the use of insulin increased from 30.6% to 36.1% in subjects older than insulin in patients with85severe CRF decreased from 59.8% in the 75–80-year-old group to (Table 2). 41.5% in the >85-year-old group. In a similar way, the use of high-risk antidiabetic drugs decreased from 72.2% to Table 2. Stepsin 58.2% of these treatment and subgroups. age use of antidiabeticConversely, drugs by age subgroups and the presence in patients with HF, of comorbidities. the use of insulin increased from 30.6% to 36.1% in subjects older than 85 (Table 2). Overall CVD HF CKD Severe CRF n= n= n= n= (eGFR < 30 mL/min) Table 2. Steps of treatment 138,374 and use of antidiabetic 39,928 17,986drugs by age subgroups 71,848 and then =presence 5272 of 75–80 81–85 >85 75–80 81–85 >85 75–80 81–85 >85 75–80 81–85 >85 comorbidities. yrs. yrs. yrs. yrs. yrs. yrs. yrs. yrs. yrs. yrs. yrs. yrs. n= n= n= n= n= n= n= n= n= n= n= n= Overall 17,504 15,766HF12,398 5506 5994 6486 CKD 25,716 Severe 24,219 21,193 1379 CRF 2190 1703 CVD n= Only lifestyle modifi- (eGFR < 30 mL/min) n = 39,928 n = 17,986 n = 71,848 138,374 19.4 13.1 15.8 24.1 13.0 17.3 25.3 13.4 17.0 24.1 14.0 n = 17.4 5272 27.9 cation, % 75–80 Non-insulin81–85 antidia- >85 75–80 81–85 >85 75–80 81–85 >85 75–80 81–85 >85 yrs. betic drug yrs. monother- yrs. 37.9 yrs. 34.6 yrs.35.1 33.6 yrs. 30.4 yrs. 31.6 33.1 yrs. 34.2 yrs. 35.2 36.3 yrs.20.6 yrs. 21.0 yrs. 25.1 n= apy,n % = n= n= n= n= n= n= n= n= n= n= 17,504 15,766 Non-insulin antidia- 12,398 5506 5994 6486 25,716 24,219 21,193 1379 1703 2190 Only lifestyle betic drug combina- 19.7 21.0 18.0 13.9 16.0 14.3 11.1 22.2 18.7 14.4 5.6 4.6 5.6 19.4 13.1 15.8 24.1 13.0 17.3 25.3 13.4 17.0 24.1 14.0 17.4 27.9 modification, % tion, % Non-insulin antidiabetic drug 37.9 33.6 34.6 35.1 30.4 31.6 33.1 34.2 35.2 36.3 20.6 21.0 25.1 monotherapy, % Non-insulin antidiabetic drug 19.7 21.0 18.0 13.9 16.0 14.3 11.1 22.2 18.7 14.4 5.6 4.6 5.6 combination, % Insulin (alone or in 23.0 32.3 31.6 26.9 30.6 33.3 36.1 30.2 29.0 25.2 59.8 57.0 41.5 combination), % Sulfonylureas, % 17.8 18.3 15.9 14.3 15.3 13.9 12.3 18.8 16.8 14.7 2.8 4.1 6.3 Glinides, % 6.7 6.9 7.8 8.2 8.1 9.0 9.4 8.0 8.8 9.1 17.0 18.6 16.3 Any high-risk 43.5 52.3 50.4 45.5 57.9 54.2 47.9 51.8 49.6 45.0 72.2 71.1 58.2 antidiabetic drug, % Any low-risk 37.6 34.6 33.8 31.3 29.1 28.5 26.8 34.8 33.4 30.9 13.8 11.5 13.9 antidiabetic drug, % CVD: cardiovascular disease; HF: heart failure; CKD: chronic kidney disease; CRF: chronic renal failure; eGFR: estimated Glomerular Filtration Rate. High-risk antidiabetic drugs: sulfonylureas, glinides, insulin; low-risk ADs: metformin, SGLT-2 inhibitors, GLP-1 receptor agonists, DPP4 inhibitors, alfa-glucosidase inhibitors, pioglitazone. betic drug, % CVD: cardiovascular disease; HF: heart failure; CKD: chronic kidney disease; CRF: chronic renal failure; eGFR: estimated Glomerular Filtration Rate. High‐risk antidiabetic drugs: sulfonylureas, glinides, insulin; low‐risk ADs: metformin, SGLT‐2 inhibitors, GLP‐1 receptor agonists, DPP4 inhib‐ itors, alfa‐glucosidase inhibitors, pioglitazone. J. Clin. Med. 2022, 11, 5134 3.2. Potential Overtreatment 7 of 13 Potential overtreatment in patients with an HbA1c < 7% using any high‐risk antidia‐ betic drug was suspected in 26.6% of them (Figure 3), being higher in those treated with 3.2.sulfonylurea or glinides (47.8% and 43.5%, respectively) than with insulin (28.1%). In Fig‐ Potential Overtreatment ure 1b, overtreatment for patients with an HbA1c < 7% is represented by the red area in Potential overtreatment in patients with an HbA1c < 7% using any high-risk antidia- each column, where its frequency can be visually compared to that of well‐controlled pa‐ betic drug was suspected in 26.6% of them (Figure 3), being higher in those treated with tients not using any antidiabetic drugs (only lifestyle modification) or using only low‐risk sulfonylurea antidiabetic or glinides drugs. Using(47.8% and 43.5%, the threshold respectively) of an HbA1c than < 6.5%, these withwere: figures insulin 21.6%(28.1%). (any In Figure 1b, overtreatment for patients with an HbA1c < 7% is represented high‐risk drug), 24.4% (sulfonylurea), 17.9% (glinides), and 12.3% (insulin). by the red area in eachNo column, where relevant its frequency differences in the sexcan andbeage visually groupscompared were found.toPotential that of well-controlled overtreat‐ patients not using any antidiabetic drugs (only lifestyle modification) ment was more frequent in patients with CVD (31.6%), HF (34.8%), CKD or using onlyand (30.6%), low-risk antidiabetic severe CRF drugs. Using (24.7%) for anthe threshold HbA1c of an HbA1c < 7% (Figures 1b and< 3). 6.5%, these These figures figures were: for an 21.6% HbA1c < (any 6.5% were 26.0%, 28.8%, 25.0%, and 20.7%, respectively (Figure 3). high-risk drug), 24.4% (sulfonylurea), 17.9% (glinides), and 12.3% (insulin). 34.8 35 31.6 30.6 30 28.8 26.6 27.3 26.1 26.4 26.9 26.9 26.0 All 24.7 25.0 25 21.6 22.5 20.9 21.0 21.8 22.2 20.7 Men 20 Women 15 75‐80 yrs. 10 old 81‐85 yrs. 5 old 0 HbA1c < 7% HbA1c < 6.5% CVD: cardiovascular disease; HF: Heart Failure; CKD: Chronic Kidney Disease; CRF: Chronic Renal failure. Figure 3. Potential overtreatment according to an HbA1c < 7.0% or an HbA1c < 6.5% criteria by sex Figure 3. Potential overtreatment according to an HbA1c < 7.0% or an HbA1c < 6.5% criteria by sex and age subgroups and comorbidities. CVD: cardiovascular disease; HF: heart failure; CKD: chronic andkidney age subgroups andchronic disease; CRF: comorbidities. renal failure. NoHypoglycemia relevant differences in the as a health sex and problem wasage groupsinwere registered 1.2%found. Potential of patients overtreatment and was higher wasinmore personsfrequent treatedinwith patients with insulin CVD (4.6% (31.6%), HF (34.8%), in monotherapy and 3.1%CKD (30.6%), and in association withsevere CRF (24.7%) for an HbA1c < 7% (Figures 1b and 3). These figures for an HbA1c < 6.5% were 26.0%, 28.8%, 25.0%, and 20.7%, respectively (Figure 3). Hypoglycemia as a health problem was registered in 1.2% of patients and was higher in persons treated with insulin (4.6% in monotherapy and 3.1% in association with NIADs) and glinides (1.5%), and it was lower with sulfonylureas (0.6%) and those treated with diet or low-risk antidiabetic drugs (both 0.3%) (Table 3). The frequency of registered hypoglycemia was slightly greater in women, 1.2 vs. 1.0% in men, and it increased with age (1.4% in older than 85). It also increased progressively as the HbA1c value increased, probably because of the greater use of high-risk antidiabetic drugs, especially insulin, in patients with an HbA1c above 8%: 2.5% between 8 and 8.9% and 2.7% above 9% (Figure 4). According to renal function, the frequency was greater in patients with severe CRF (2.5%) In relation to sulfonylureas, the frequency was quite similar in all subgroups and comorbidities (0.5 to 0.8%), being the greatest (0.8%) in three subgroups: patients older than 85, with an HbA1c < 6.5%, or with severe CRF. Finally, treatment with insulin monotherapy had a higher frequency than insulin in combination with NIADs, especially in patients older than 85, 5.0 vs. 3.8%, respectively, and in patients with moderate CRF (eGFR 30–59 mL/min), 5.6 vs. 3.2%, respectively. J. Clin. Med. 2022, 11, 5134 8 of 13 Table 3. Frequency of registered hypoglycemia in patients treated with drugs associated with a higher risk of hypoglycemia (insulin, sulfonylureas, or glinides) and treatment steps according to sex and age subgroups, the categories of HbA1c, and estimated Glomerular Filtration Rate. eGFR eGFR eGFR 75–80 81–85 >85 HbA1c HbA1c HbA1c HbA1c HbA1c Missing Overall Women Men > 60 30–59 < 30 yrs. yrs. yrs. < 6.5% 6.5–6.9% 7–7.9% 8–8.9% ≥ 9% HbA1c mL/min mL/min mL/min n= n= n= n= n= n= n= n= n= n= n= n = 31,262 n = 12,713 n = 6858 n = 5138 13,8374 76,925 61,449 59,440 44,314 34,620 46,554 21,705 19,282 74,817 43,292 All patients, 1596 958 638 424 589 301 178 446 321 186 164 682 685 466 (1.0) 134 (2.5) n (%) (1.2) (1.2) (1.0) (1.2) (1.4) (0.6) (0.8) (1.4) (2.5) (2.7) (0.9) (0.9) (1.6) Sulfonylurea, 150 90 53 38 49 43 24 38 21 9 15 89 51 2 60 (0.5) n (%) (0.6) (0.7) (0.5) (0.6) (0.8) (0.8) (0.7) (0.5) (0.6) (0.6) (0.5) (0.6) (0.7) (0.8) Glinides, 139 82 27 41 19 14 42 37 15 12 44 66 20 57 (1.4) 63 (2.0) n (%) (1.5) (1.6) (0.9) (1.6) (1.1) (1.3) (1.6) (2.3) (1.8) (0.9) (1.3) (1.6) (2.2) Insulin, 1168 720 448 312 414 132 110 350 289 178 109 481 515 350 (3.1) 106 (4.2) n (%) (3.7) (3.9) (3.4) (3.6) (4.4) (3.7) (3.9) (3.8) (4.1) (3.9) (2.5) (3.5) (3.9) Any high-risk 1343 820 523 360 478 192 140 397 310 182 569 581 AD, 405 (1.9) 122 (1.5) 120 (3.4) (2.2) (2.4) (2.0) (2.2) (2.7) (1.9) (1.9) (2.2) (3.0) (3.1) (1.9) (2.7) n (%) Only low risk 253 138 115 61 64 111 109 38 49 11 4 42 113 104 14 AD, (0.3) (0.3) (0.3) (0.2) (0.3) (0.5) (0.3) (0.3) (0.4) (0.5) (0.4) (0.4) (0.2) (0.5) (0.8) n (%) Lifestyle 80 51 11 25 40 42 10 6 4 0 18 26 33 9 modification, 29 (0.3) (0.3) (0.3) (0.1) 0.4) (0.4) (0.3) (0.2) (0.3) (1.5) (0.0) (0.4) (0.2) (0.4) (0.8) n (%) NIAD 198 105 53 46 88 93 33 36 8 2 26 92 77 16 monotherapy, 93 (0.4) (0.4) (0.4) (0.3) (0.3) (0.6) (0.4) (0.3) (0.3) (0.5) (0.3) (0.4) (0.3) (0.5) (1.3) n (%) NIAD 150 82 52 41 47 34 25 54 20 6 11 83 60 3 combination, 68 (0.5) (0.6) (0.6) (0.5) (0.6) (0.7) (0.7) (0.6) (0.6) (0.6) (0.4) (0.3) (0.5) (0.8) (1.1) J.n Clin. (%) Med. 2022, 11, x FOR PEER REVIEW 10 of 15 Insulin 548 332 216 137 231 75 52 161 127 77 56 155 281 80 monotherapy, 141 (4.4) (4.6) (4.7) (4.5) (4.2) (5.0) (4.2) (4.4) (5.0) (5.7) (5.3) (2.9) (4.3) (5.6) (4.3) n (%) Insulin + 620 388 232 175 183 57 58 189 162 101 53 326 234 26 NIAD, 209 (2.6) (3.1) (3.4) (2.7) (3.2) (3.8) (3.2) (3.5) (3.1) (3.3) (3.2) (2.2) (3.2) (3.2) (3.1) n (%) AD: antidiabetic drug; eGFR: estimated Glomerular Filtration Rate; NIAD: non-insulin antidiabetic AD: antidiabetic drugs. drug; High-risk eGFR: ADs: estimated Glomerular sulfonylureas, Filtrationlow-risk glinides, insulin; Rate; NIAD: ADs:non-insulin metformin,antidiabetic drugs. High- SGLT-2 inhibitors, risk ADs: sulfonylureas, glinides, insulin; low-risk ADs: metformin, SGLT-2 inhibitors, GLP-1 receptor agonists, GLP-1 receptor agonists, DPP4 inhibitors, alfa-glucosidase inhibitors, pioglitazone. DPP4 inhibitors, alfa-glucosidase inhibitors, pioglitazone. Insulin monotherapy Insulin + NIAD Sulfonylureas Glinides Any High-risk AD Global 6 5.7 5.3 5.0 5 4.4 4.6 4.2 4 3.5 3.2 3.1 3.3 3.0 3.3 3.1 3.1 3 2.7 2.9 2.2 2.3 2.5 2.2 2.2 1.9 1.9 1.8 2 1.6 1.4 1.5 1.5 1.1 1.3 1.2 0.7 0.8 0.6 0.6 0.9 0.9 0.6 1 0.6 0.5 0.5 0.0 0 HbA1c < 6.5 HbA1c 6.5- HbA1c 7-7.9%HbA1c 8-8.9% HbA1c ≥9% Missing All 6.9% HbA1c n = 138,374 T2DM patients older than 75. AD: Antidiabetic Drug Figure 4. Registered hypoglycemia according to the use of high-risked antidiabetic drugs and Figure 4. Registered hypoglycemia according to the use of high-risked antidiabetic drugs and HbA1c HbA1c categories. n = 138,374, T2DM patients older than 75. AD: antidiabetic drug. categories. n = 138,374, T2DM patients older than 75. AD: antidiabetic drug. 4.4.Discussion Discussion InInthis thisreal-world real-world population population of of patients patientswith withT2DM T2DMolderolderthan 7575 than years, 26.6% years, 26.6%of of those treated with antidiabetic drugs associated with a high risk of hypoglycemia those treated with antidiabetic drugs associated with a high risk of hypoglycemia had an had an HbA1c<<7% HbA1c 7%and, and, thus, thus, they they might might be be at at potential potentialrisk riskofofovertreatment. overtreatment.This proportion This proportion was higher in patients treated with sulfonylureas (47.8%) and glinides was higher in patients treated with sulfonylureas (47.8%) and glinides (43.5%) (43.5%) than those than those on insulin (28.1%). These results were lower using the threshold of an HbAc1 < 6.5%. on insulin (28.1%). These results were lower using the threshold of an HbAc1 < 6.5%. Nowadays, there is a consensus that there is a risk of overtreatment in patients older Nowadays, there is a consensus that there is a risk of overtreatment in patients older than 75 years or who are frail and for whom intensive treatment offers few clinical benefits than 75 years or who are frail and for whom intensive treatment offers few clinical benefits but may cause important adverse effects, such as hypoglycemia. Therefore, these subjects are candidates for deprescribing [2–6,20–22,31]. In our database, glycemic goals were fre- quently achieved by older adults: nearly 60% had an HbA1c < 7%, 38% had an HbA1c < 6.5%, and the use of high-risk antidiabetic drugs such as insulin (23%), glinides (6.7%), and sulfonylureas (17.8%) was frequent. This unexpectedly high use of sulfonylureas is probably due to their initiation well before the introduction of other NIADs with a lower J. Clin. Med. 2022, 11, 5134 9 of 13 but may cause important adverse effects, such as hypoglycemia. Therefore, these subjects are candidates for deprescribing [2–6,20–22,31]. In our database, glycemic goals were frequently achieved by older adults: nearly 60% had an HbA1c < 7%, 38% had an HbA1c < 6.5%, and the use of high-risk antidiabetic drugs such as insulin (23%), glinides (6.7%), and sulfonylureas (17.8%) was frequent. This unexpectedly high use of sulfonylureas is probably due to their initiation well before the introduction of other NIADs with a lower risk of hypoglycemia, but also because of the lower cost compared to other newer alternatives [32]. In recent years, there has been a progressive replacement of sulfonylureas with dipeptidyl peptidase 4 inhibitors (DPP4i) [26,33–38], especially, in older adults. As has been published previously, in our database, 17.8% of T2DM patients older than 75 were still treated with sulfonylureas, while 16.1% received a DPP4i in the same study period [30]. However, in several studies around the world, the prescription of DPP4i progressively outperformed sulfonylureas in older adults [26,33,37,38]. This could explain the progressive decrease in sulfonylureas use observed in our database from 2007 to 2018 [28]. In the last decade, different studies have shown that overtreatment, defined as having an HbA1c < 7% in patients treated with insulin, sulfonylureas, or glinides, is a frequent issue in older adults, ranging from 26% to 62% [12–18,24–26]. These wide differences could be related to the different types of populations or prescribing habits, but also to the age threshold used in each study. Most of them included patients older than 65 [12–16], but others were older than 70 [16,17,25], or even over 75 [18,26]. In our study, we used the threshold of 75, following the recommendations of European and national primary care guidelines [3,4]. In one study from the US including 42,669 T2DM patients older than 75, potential overtreatment was 26% [18], while in a small study in Italy with 387 patients, it was 62% [24]. Results in people over 70 were 38.8% in Holland [16] and 29.9% in the UK [17]. In our study, in people over 75, slight differences in sex or age groups were found, but they were greater in the presence of the studied comorbidities, from 30.6% with CKD to 34.8% in patients with HF. The higher risk of overtreatment in patients treated with sulfonylureas and glinides in comparison to insulin is related to the fact that the mean HbA1c is higher in patients treated with insulin. Primary care professionals must consider discussing deintensification as part of routine care to determine the goals of care and make shared decisions according to patient health status, glycemic control, and patient preferences and values [19–22]. Deintensification may include deprescribing antidiabetics and other medications or reducing home blood glucose monitoring and diabetes-specific assessments that no longer improve quality of life and life expectancy in older adults. When deprescribing, professionals may not only consider the reduction of insulin doses and the simplification of complex insulin regimes but also stopping sulfonylurea treatment and starting an antidiabetic that does not induce hypoglycemia [3–6,20–22]. In addition to advising against intensive glycemic control in these patients, it would be necessary to introduce the practice of deprescribing if a person’s level of HbA1c is below 7.0%, either lowering doses, switching to a safer medication, or stopping medications [19–22]. A metanalysis of randomized clinical trials confirmed that deprescribing is safe in these patients [23]. Despite that, deprescribing is uncommon in clinical practice [24–26], even in individuals with limited life expectancy [17,25]. Surprisingly, hypoglycemia was registered in only 1596 patients (1.2%), out of which 73.2% were on insulin, 9% on sulfonylureas, and 8.7% on glinides. Its frequency was slightly higher in women and increased with age, as well as with decreased kidney function and greater levels of HbA1c. This low registration has been previously reported by other authors [39,40] and probably reflects the limitations of the EHR in primary care: only severe or very frequent events are probably recorded. In any case, in our EHR, they remain active as a reminder/alert for health care professionals. Moreover, the higher frequency observed in patients treated with glinides and sulfonylureas probably represents the switch from sulfonylureas to glinides due to previous episodes of hypoglycemia that remain recorded as a health problem. It might be surprising that poorer glycemic control was associated with an increased risk of hypoglycemia. However, this is probably attributable J. Clin. Med. 2022, 11, 5134 10 of 13 to the greater use of high-risk antidiabetic drugs, especially insulin, in these patients. In fact, observational studies have yielded conflicting results; some of them have found an increased risk of hypoglycemia at lower HbA1c levels [10], whereas others have shown an increased risk of hypoglycemia at both lower and higher HbA1c levels [8,11]. For instance, Lipska et al. found that severe hypoglycemia was common among patients with type 2 diabetes across all levels of glycemic control, and the risk tended to be higher in patients with either near-normal or very poor glycemic control [8]. Additionally, Ling et al. found that sulfonylurea and insulin use were more relevant predictors of severe hypoglycemia and death than glucose levels [11]. Mild-to-moderate events are usually underestimated in database studies since they can only be detected if they are recognized and reported by patients to their providers and are subsequently recorded within the clinical notes and coded as a health problem. For instance, in a US study, ascertainment of events using natural language processing (NLP) that identifies whether hypoglycemia is mentioned in clinical notes increased the capture of non-serious events more than 20-fold in comparison to the structured data recorded [39]. This study also showed that hypoglycemia was highly prevalent, with over 10% of patients per year experiencing at least one event that was documented [39]. Likewise, in another US study using the same methodology, in 317,399 T2DM patients, the prevalence of recorded hypoglycemia was 4%, while, according to the NLP, it was 8% [40]. These figures, even higher than ours, seem to be also lower than expected, as 55% of T2DM patients in that study were using insulin [40]. Our study has several limitations. Since most of the selected clinical conditions were based on those diagnoses recorded in the database, under-registration and misclassification cannot be ruled out. Moreover, we were not able to identify frailty in our database and had to assume that an age older than 75 years is a high-risk category in all cases. Furthermore, HbA1c is not always contemporary with the active medication at the study cutoff point. We assume that the risk probably persisted until the end of the study period. Finally, the main limitation is related to the low registration of hypoglycemia as a health problem in our EHR, suggesting that only the most severe or repeated cases were recorded. In addition, other acute or chronic complications were not considered in our analysis as they have been published previously [29]. The strengths of our study include a population-based design; the use of a primary care database with a large number of subjects; and, unlike other population-based studies, the fact that HbA1c and eGFR values were available in almost 90% of cases. 5. Conclusions One in four older adults with T2DM treated with antidiabetic drugs associated with a high risk of hypoglycemia might be at risk of overtreatment. This risk is higher in those treated with sulfonylureas or glinides than with insulin. Chronic kidney disease is a frequent comorbidity among this subpopulation and should be considered in treatment choices. Less stringent glycemic goals, the deintensification of the treatment, and/or changes to the antidiabetic treatment using other drugs with a lower risk of hypoglycemia should be considered in the high-risk population, avoiding drugs that are contraindicated in patients with chronic renal failure. Finally, recording hypoglycemia as a health problem in the EHR was low, although it was more frequent in patients receiving insulin. Author Contributions: Methodology, J.R. and B.V.; Writing—original draft, M.M.-C.; Writing— review & editing, D.M., L.R.-L., N.M.-B., M.C. and J.F.-N. All authors have read and agreed to the published version of the manuscript. Funding: This study was supported by the Institut Universitari d’Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol) and partially funded by Merck Sharp & Dohme de España S.A Spain, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Institutional Review Board Statement: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of the Primary Health Care University J. Clin. Med. 2022, 11, 5134 11 of 13 Research Institute (IDIAP) Jordi Gol (approval number: P17/015). In accordance with the Spanish regulations on observational studies, this retrospective study using pseudo-anonymized data did not require obtaining informed consent from the patient. Informed Consent Statement: Not applicable. Data Availability Statement: The data that support the findings of this study are available in the SIDIAP database (System for the Development of Research in Primary Care). Restrictions apply to the availability of these data, which were used under license for this study. Acknowledgments: This study was possible thanks to the commitment of physicians and nurses working in the Catalan Health Institute to provide optimal care to patients with diabetes. CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM CB15/00071) is an initiative from Instituto de Salud Carlos III, Madrid, Spain. Conflicts of Interest: Manel Mata-Cases has received advisory and/or speaking fees from Astra- Zeneca, Bayer, Boehringer Ingelheim, GSK, Lilly, Menarini, MSD, Novartis, NovoNordisk, and Sanofi. He has received research grants from Institut Universitari d’Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol) (Barcelona, Spain); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III (Madrid, Spain); and The Strategic Plan for Health Research and Innovation, Generalitat de Catalunya (Barcelona, Spain). Dídac Mauricio has received advisory and/or speaking fees from Almirall, Esteve, Ferrer, Janssen, Lilly, MSD, Menarini, NovoNordisk, and Sanofi. Jordi Real has no conflict of interest to declare. Bogdan Vlacho has no conflict of interest to declare. Laura Romera- Liebana has received a speaker honorarium from Boehringer Ingelheim. Nuria Molist-Brunet has no conflict of interest to declare. Marta Cedenilla is a full-time employee of Merck Sharp & Dohme Spain. Josep Franch-Nadal has received advisory and or speaking fees from Astra-Zeneca, Ascensia, Boehringer Ingelheim, GSK, Lilly, MSD, Novartis, NovoNordisk, and Sanofi; he has received research grants for his institution from Astra-Zeneca, GSK, Lilly, MSD, Novartis, NovoNordisk, Sanofi, and Boehringer Ingelheim. References 1. International Diabetes Federation. IDF Diabetes Atlas, 10th ed.; International Diabetes Federation: Brussels, Belgium, 2021; Available online: https://www.diabetesatlas.org (accessed on 9 May 2022). 2. Davies, M.J.; D’Alessio, D.A.; Fradkin, J.; Kernan, W.N.; Mathieu, C.; Mingrone, G.; Rossing, P.; Tsapas, A.; Wexler, D.J.; Buse, J.B. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018, 41, 2669–2701. [CrossRef] [PubMed] 3. 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