A view on the quality of diabetes care in Italy and the role of Diabetes Clinics from the 2018 ARNO Diabetes Observatory

A view on the quality of diabetes care in Italy and the role of

Diabetes Clinics from the 2018 ARNO Diabetes Observatory

Enzo Bonora

_*

_{, Salvatore Cataudella}

_{, Giulio Marchesini}

_{, Roberto Miccoli}

_,

Olga Vaccaro

, Gian Paolo Fadini

, Nello Martini

, Elisa Rossi

a

Italian Diabetes Society, Rome, Italy

b

CINECAe Interuniversity Consortium, Bologna, Italy

c

Research & Health Foundation, Bologna, Italy

Received 23 June 2020; received in revised form 3 August 2020; accepted 11 August 2020 Handling Editor: A. Siani

Available online 22 August 2020

KEYWORDS Diabetes mellitus; Quality of care; Adherence; Monitoring; Anti-hyperglycemic agents

Abstract Backgrounds and aims: To investigate relevant indicators of quality of care in a large population-based sample of people with diabetes representative of clinical practice in Italy in 2018.

Methods and results: We analyzed data from 11,300,750 subjects. All administrative healthcare claims collected in 2018 were scrutinized to identify subjects with diabetes and investigate several indicators of quality of care. Subjects with diabetes were identified by anti-hyperglycemic drug prescriptions, disease-specific co-payment exemption and hospital discharge codes. Indicators of quality of care pertained to monitoring (HbA1c, creatinine, lipid profile, microalbuminuria, eye examination, ECG, ultrasonography of carotid and lower limb ar-teries) and diabetes treatment (anti-hyperglycemic agents in subjects with cardiovascular dis-ease, CVD). Subjects attending and nonattending Diabetes Clinics were compared.

We identified 697,208 individuals with diabetes. HbA1c was assessed at least once in the year in 62.7%, creatinine in 62.3%, total cholesterol in 59.6%, microalbuminuria in 34.3%. Frequency of eye examination was 8.2%, ECG 23.5%, carotid ultrasonography 14.3%, lower limb ultrasonogra-phy 7.6%. Among anti-hyperglycemic drugs, SGLT-2 inhibitors were prescribed to ~5% and GLP-1 receptor agonists to ~5% although the proportion of subjects with CVD was ~45%. Subjects attending Diabetes Clinics had higherfigures for all these monitoring and treatment indicators. Conclusions: The implementation of national and international guidelines regarding disease monitoring and treatment is far from being satisfactory, especially among subjects nonattending Diabetes Clinics. Further efforts and investments are needed for better disseminating guidelines, more efficaciously engaging healthcare professionals and more strongly empowering the health-care system to improve diabetes health-care.

ª 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Ital-ian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Introduction

The number of cases of diabetes is increasing worldwide [1]. Incidence and prevalence of the disease are sky-rocking,

especially in less affluent Countries. Several explanations could be mentioned: increased awareness of the disease with systematic search for undiagnosed cases, longer survival of diabetic patients due to improved care, ageing of the

* Corresponding author. Endocrinology, Diabetes and Metabolism University and Hospital Trust of Verona Ospedale Maggiore, Piazzale Stefani, 1, I-37126 Verona, Italy. Fax:þ39 045 802 7314.

E-mail address:enzo.bonora@univr.it(E. Bonora).

https://doi.org/10.1016/j.numecd.2020.08.018

0939-4753/ª 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Available online atwww.sciencedirect.com

Nutrition, Metabolism & Cardiovascular Diseases

population with prolonged time spent in years or decades featured by a deranged glucose homeostasis, worldwide diffusion of an unhealthier lifestyle with positive energy balance leading to overweight and obesity [2].

Diabetes care is among priorities for all Public Health Systems. National and international institutions periodi-cally issue guidelines focusing on diagnosis, monitoring and treatment of diabetes and related disorders (e.g., hy-pertension, dyslipidemia, obesity) [3e6]. The same holds true for Italy [7], a Country which was leader in the world in promulgating a specific law for people with diabetes, back in 1987 [8], which recommended the establishment of a capillary network of Diabetic Clinics. This network of ~500 Diabetes Clinics spread across the Country provided unquestioned benefits such as decreasing rates of hospital admissions for acute complications [9] and reduced rates of mortality [10].

Among many others, guidelines recommend the timing for HbA1c assessment, the intervals between kidney function testing or eye examinations, the use of specific anti-hyperglycemic medications in presence of athero-sclerotic cardiovascular disease (ASCVD) or chronic heart failure (CHF) [3e7].

Quality of care provided by a Public Health System might be described according to adherence to guideline recommendations. In other words, the prescriptions of certain drugs or diagnostic procedures might be used as indicators of quality of care warranted to patients.

Aim of this study was to assess quality of care in a very large sample of people with diabetes living in Italy in year 2018. We focused on diagnostic procedures and drug prescriptions and on possible differences among subjects attending or nonattending Diabetes Clinics.

Methods

Identification of cases

Administrative claims concerning prescriptions of drugs, outpatient diagnostic and therapeutic procedures and outpatient specialist consultations are collected andfiled in by all Local Health Districts (LHDs) composing the Ital-ian National Health System (NHS). Many of these LHDs contribute their data to a national consortium named CINECA, established by the Italian Ministry of University and Research to allow statistical analysis and reporting. Other LHDs contribute their data to the Research & Health Foundation for the same purposes. In calendar year 2018, these two institutions received individual data from a total of 11,300,750 Italian residents of any age living in different areas of the Country (37.5% in Northern Italy, 8.5% in Central Italy and 54% in Southern Italy). All data referring to a given subject were linked by a unique anonymous identification code. Both institutions had also available a list of subjects who were exempted from co-payment for some medical services (e.g., drugs or outpatient care) due to the presence of diabetes. In this regard, it is important to emphasize that in Italy not all individuals with diabetes

apply for this exemption for personal reasons and there-fore the list of exempted people does not necessarily include all subjects with diabetes.

Three sources were used to identify subjects with dia-betes from the general population: 1) at least one pre-scription of an anti-hyperglycemic drug (oral or injectable); 2) co-payment exemption due to diabetes; 3) discharge from hospital with a diagnosis of diabetes as primary or secondary cause. The three sources were merged in order to set up a single list of subjects with ascertained diabetes. This approach has been previously used by others and ourselves [11e24]. Noteworthy, no clinical data (e.g. BMI, blood pressure HbA1c, lipids, renal function tests) were available for these subjects. No distinction was possible among varieties of diabetes (type 1, type 2, secondary or type 3, etc.). Only sex, age, resi-dency and administrative claims related to access to medical services were available.

Subjects attending Diabetes Clinics

In Italy the prescription of several anti-hyperglycemic drugs such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RA), so-dium glucose cotransporter-2 (SGLT-2) inhibitors, insulin degludec, is restricted to diabetologists working in Dia-betes Clinics. Moreover, a prescription of a diabetologic visit is a requisite for such an attendance. The combined used of these 2 sources (claims of prescription of restricted drugs and diabetologic visits) was therefore used to identify subjects attending Diabetes Clinics.

Monitoring and treatment

After establishing the list of subjects with diabetes, we scrutinized the claims related to prescriptions of outpa-tient diagnostic exams, specialist consultations and drugs and pertaining to the period from January 1 to December 31, 2018. The prescriptions of all diagnostic exams, pro-cedures and consultations were extracted from files in order to calculate their occurrence and frequency in the index year.

Each Italian resident is registered with a single general practitioner (GP). No claim is produced for visits delivered by these physicians working in primary care. Only outpa-tient consultations delivered by specialist physicians working within the frame of the NHS (secondary and ter-tiary care) yield claims. The same holds true for laboratory tests, imaging and other diagnostic or therapeutic pro-cedures: only those prescribed by physicians working for the NHS in primary, secondary or tertiary care yield administrative claims recorded by LHDs. Medical services delivered outside the frame of the NHS are not scrutinized in this study but they are a small fraction of total (about 10%) [25]. Nonetheless, we are aware that eye examina-tions often occur in private practice.

Presence of CVD or high CVD risk

Subjects with clinical or preclinical ASCVD or at high risk for it were identified with 3 sources: 1) exemption from co-payment of medications or diagnostic procedures due to atherosclerosis (e.g., coronary heart disease or cere-brovascular disease); 2) hospitalizations with a discharge diagnosis (primary or secondary) related to atherosclerosis-specific ICD-9 codes (e.g., myocardial infarction or stroke) [26]; 3) use of anti-platelet agents. Thefirst two sources were used to identify subjects with clinical ASCVD (i.e., prior atherothrombotic event). Sub-jects with CHF were identified with 2 sources: 1) exemp-tion from co-payment of medicaexemp-tions or diagnostic procedures due to heart failure; 2) hospitalizations with a discharge diagnosis of heart failure (primary or second-ary). Diagnoses were retrieved from ICD-9 codes [26]. Recommendations by guidelines

According to recommendations available in guidelines, including the Italian ones, HbA1c should be assessed in diabetic subjects at least twice a year, and serum/plasma lipid profile and creatinine and microalbuminuria at least once a year. Eye examination and ECG should be scheduled every year or every 2 years, and ultrasonography of carotid arteries or lower limb arteries at 2e3 year intervals, unless moderate or severe abnormalities are observed, prompting to more frequent assessments [3e7].

Consistent with a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) [27], guidelines issued by many national scientific societies, including the Italian Diabetes Society [7], and coherently with several state-ments published in the last years, heart protecting drugs such as SGLT-2 inhibitors or GLP-1 RA should be prescribed in patients with clinical or preclinical ASCVD or at high risk for it or with CHF.

Statistics

Continuous variables are reported as mean and standard deviation (SD) or median and interquartile range (IQR) as indicated, whereas categorical variables were reported as percentage and 95% confidence intervals (95% CIs). The latter were computed using formula for a binomial con fi-dence interval approximating with a normal distribution appropriated for large sample size. Continuous variables were compared using unpaired Student’s t test. Categorical variables were compared using chi square test. When appropriate, data were adjusted for age and gender. The statistical significance level was conventionally set at 0.05.

Results

The combined use of the three sources allowed the iden-tification of 697,208 subjects with ascertained diabetes out of 11,300,750 residents, with a prevalence of the disease of 6.2%. Age of subjects with diabetes was 69  15 years (mean SD), with a median of 71 [IQR 18]. Men were 51% of the sample. As many as 66.9% of diabetic subjects aged 65 years, 0.7% were children or adolescents (age 0e19 years) and the remaining 32.3% were young adults or subjects of mature age (20e64 years).

As shown inTable 1, the proportion of diabetic subjects having at least two prescriptions of HbA1c was ~35% and those having at least one prescription were ~63%. A similar proportion of subjects had a prescription of creatinine and less than 60% received a prescription of total and/or HDL cholesterol and/or triglycerides. Microalbuminuria was prescribed to about one third of subjects. An eye exami-nation was prescribed to ~8% of them. An electrocardio-gram was prescribed to ~23% of subjects, ultrasonography scanning of carotid arteries to ~14% and of lower limbs to ~8%.

Subjects attending Diabetes Clinics were slightly less than 30%. The comparison of these subjects with

non-Table 1 Percentage [95% CIs] of subjects with laboratory testing or instrumental assessment or outpatient consultations by attendance at Diabetes Clinics. All NZ 697,208 Attending NZ 201,439 (28.9%) Nonattending NZ 495,769 (71.1%) p-value Gender (% male) 51.1 55.5 48.6 <0.001

Age (years; mean SD) 68.6 14.6 67.2 14.2 69.5 17.0 <0.001 HbA1c (at least 2/yr) 34.7 [34.6e34.8] 63.2 [63.0e63.4] 23.1 [23.0e23.2] <0.001a HbA1c (at least 1/yr) 62.7 [62.6e62.8] 91.1 [91.0e91.2] 51.3 [51.2e51.4] <0.001a Creatinine (at least 1/yr) 62.3 [62.2e62.4] 79.3 [79.1e79.5] 55.4 [55.3e55.5] <0.001a Total cholesterol (at least 1/yr) 59.6 [59.5e59.7] 85.1 [84.9e85.3] 49.2 [49.1e49.3] <0.001a Triglycerides (at least 1/yr) 58.6 [58.5e58.7] 84.5 [84.3e84.7] 48.1 [48.0e48.2] <0.001a HDL cholesterol (at least 1/yr) 56.0 [55.9e56.1] 82.6 [82.4e82.8] 45.2 [45.1e45.3] <0.001a Microalbuminuria (at least 1/yr) 34.3 [34.2e34.4] 62.6 [62.4e62.8] 22.8 [22.7e22.9] <0.001a Eye examination (at least 1/yr) 8.2 [8.1e8.3] 9.7 [9.6e9.8] 7.6 [7.5e7.7] <0.001a ECG (at least 1/yr) 23.5 [23.4e23.6] 36.5 [36.3e36.7] 18.3 [18.2e18.4] <0.001a Carotid ultrasonography (at least 1/yr) 14.3 [14.2e14.4] 26.6 [26.4e26.8] 9.3 [9.2e9.4] <0.001a Lower limb ultrasonography (at least 1/yr) 7.6 [7.5e7.7] 11.5 [11.4e11.6] 6.1 [6.0e6.2] <0.001a

attending patients revealed that allfigures of monitoring indicators were significantly higher in attending vs. non-attending subjects, with proportions sometimes being 2 to 3-fold higher (Table 1).

Table 2reports prescriptions of exams in attending vs.

nonattending subjects after stratification for age (the me-dian was the cutpoint). The lower prescriptions in non-attending vs. attending subjects were observed irrespective of being younger or older and differences were consistent in the two age categories.

About 10% of subjects did not receive any prescription of anti-hyperglycemic drug (overall 11.1%, attending 12.0%, nonattending 10.7%). As many as ~90% of subjects received at least one prescription of an anti-hyperglycemic drug (oral or injectable). Among drug-treated individuals ~88% had a prescription of a noninsulin drug and ~26% of insulin (~98% insulin analogs).Table 3 summarizes prescriptions of anti-hyperglycemic medications. Metformin (alone or in combination with other agents) was the most prescribed noninsulin drug, followed by sulphonylurea (alone or in fixed combination with metformin or more rarely with pioglitazone) and repaglinide. Overall, sulphonylurea re-ceptor (SUR) agonists (gliclazide, glimepiride, glibencla-mide, glipizide, repaglinide) were prescribed to ~30% of drug-treated subjects. Acarbose was prescribed to ~3% and pioglitazone to ~4% of drug-treated subjects. Among newer anti-hyperglycemic agents, DPP-4 inhibitors (alone or in fixed combination with metformin or pioglitazone) were prescribed to ~14% of drug-treated patients, SGLT-2 inhibitors (alone or in fixed combination with metfor-min) to ~5% and GLP-1 RA to ~5% (including the fixed combinations with basal insulin). Consistent with current regulatory restrictions in Italy, only subjects attending Diabetes Clinics received prescriptions of the newer anti-hyperglycemic agents. For such reason we did not perform any formal statistical assessment of differences observed between attending and nonattending subjects.

Table 4 reports drug prescriptions in attending vs.

nonattending subjects after stratification for median age. Elderly subjects were treated more frequently with DPP-4 inhibitors and older anti-hyperglycemic agents, such as sulphonylureas, repaglinide and acarbose, whereas they received less prescriptions of metformin, SGLT-2 inhibitors and GLP-1 RA. Once more, no statistics was performed between attending and nonattending patients because many drugs could not be prescribed by GPs.

Lipid lowering drugs were prescribed to 53.0% of sub-jects, hypertensive medications to 74.5% and anti-platelets agents to 42.8%. Thisfinding suggests that many patients had a high or very high CVD risk.

Subjects with clinical or preclinical or high risk of ASCVD were 310,925 (44.6%) of whom those receiving anti-hyperglycemic drugs were 295,451. Subjects with clinical ASCVD (prior atherothrombotic events) were 48,402 (7%). Subjects with CHF were 13,202 (1.9%) of whom those treated with anti-hyperglycemic drugs were 11,678. The two conditions were not mutually exclusive.

Table 5 reports the prescriptions of anti-hyperglycemic

drugs in these subjects, including stratifications accord-ing to attendance at the Diabetes Clinics. In the whole sample (attending and nonattending subjects), the pro-portions of patients receiving prescriptions of GLP-1 RA or SGLT-2 inhibitors were low: ~5% GLP-1 RA, ~6% SGLT-2 inhibitors in those with ASCVD; ~2.5% GLP-1 RA, ~4% SGLT-2 inhibitors in those with CHF. In subjects attending Diabetes Clinics, the only setting currently allowed to provide prescriptions of these agents in Italy, the pro-portions were definitely higher: ~15% GLP-1 RA, ~19% SGLT-2 inhibitors among those with ASCVD; ~8.5% GLP-1 RA, ~14% SGLT-2 inhibitors among those with CHF. When these analyses were restricted to subjects with clinical ASCVD, excluding those identified only by use of anti-platelet agents, prescriptions of anti-hyperglycemic agents of these two classes by specialists of Diabetes

Table 2 Percentage [95% CIs] of subjects with laboratory testing or instrumental assessment or outpatient consultations stratified according to median age (71 years) and attendance at Diabetes Clinics.

Age<71 years p-value Age71 years p-value Attending (NZ 110,786) Notattending (NZ 228,021) Attending (NZ 90,653) Notattending (NZ 267,748) Gender (% male) 58.9 52.0 <0.001 51.4 45.7 <0.001 HbA1c (at least 2/yr) 61.1 [60.8e61.4] 21.2 [20.0e21.4] <0.001 65.7 [65.4e66.0] 25.1 [24.9e25.3] <0.001 HbA1c (at least 1/yr) 89.2 [89.1e89.4] 47.9 [47.7e48.1] <0.001 93.4 [93.2e93.6] 54.1 [53.9e54.3] <0.001 Creatinine (at least 1/yr) 74.1 [73.8e74.3] 50.0 [49.8e50.2] <0.001 85.6 [85.4e85.8] 60.1 [59.9e60.3] <0.001 Total cholesterol (at least 1/yr) 82.4 [82.2e82.6] 47.4 [47.2e47.6] <0.001 88.4 [88.2e88.6] 50.8 [50.6e51.0] <0.001 Triglycerides (at least 1/yr) 81.9 [81.7e82.1] 46.6 [46.4e46.8] <0.001 87.7 [87.5e87.9] 49.4 [49.2e49.6] <0.001 HDL cholesterol (at least 1/yr) 80.1 [79.9e80.4] 44.1 [43.9e44.3] <0.001 85.7 [85.5e85.9] 46.2 [46.0e46.4] <0.001 Microalbuminuria (at least 1/yr) 61.1 [60.8e61.4] 22.3 [22.1e22.5] <0.001 64.4 [64.1e64.7] 23.3 [23.1e23.5] <0.001 Eye examination (at least 1/yr) 8.2 [8.0e8.4] 6.7 [6.6e6.8] <0.001 11.4 [11.2e11.6] 8.4 [8.3e8.5] <0.001 ECG (at least 1/yr) 34.2 [33.9e34.5] 17.1 [16.9e17.3] <0.001 39.3 [39.0e39.6] 19.2 [19.1e19.3] <0.001 Carotid ultrasonography (at least 1/yr) 23.3 [23.1e23.6] 8.4 [8.3e8.5] <0.001 30.5 [30.2e30.8] 10.0 [9.9e10.1] <0.001 Lower limb ultrasonography (at least 1/yr) 10.4 [10.2e10.5] 5.9 [5.8e6.0] <0.001 12.9 [12.7e13.1] 6.2 [6.1e6.3] <0.001 Attending vs. nonattending, p-values are gender adjusted.

Clinics were superimposable (~10% GLP-1 RA, ~15% SGLT-2 inhibitors).

Discussion

Our results show that the quality of care in Italy in 2018 is far from being satisfactory from many standpoints, espe-cially in subjects nonattending Diabetes Clinics who were ~70%. Subjects with diabetes received an insufficient pre-scription of laboratory exams necessary to adequately monitor the disease: HbA1c, serum lipids, serum creati-nine and microalbuminuria prescriptions were impres-sively lower than the recommended and wished 100%. Subjects attending Diabetes Clinics received definitely higher, although still suboptimal, prescriptions of these essential exams.

Prescriptions of anti-hyperglycemic medications in many subjects were not aligned to current guidelines [3e7] and positions of experts committed by ADA and EASD [27]. Upon considering these guidelines, too many subjects were treated with SUR agonists, which have no cardioprotective and renoprotective effects and are asso-ciated with an increase in body weight and risk of hypo-glycemia. Too many subjects were treated with insulin, which has today many safer and/or more convenient al-ternatives, such as GLP-1 RA. The high percentage of pa-tients treated with metformin is consistent with the concept that this drug should be used in most type 2 diabetic patients, unless contraindicated or not tolerated [27], but the high proportion of subjects treated with SUR agonists, even in patients attending Diabetes Clinics, is in strong disagreement with the current recommendations to use these drugs only when cost is an issue or in 3rde5th

line of treatment [27], and not to use them in elderly and fragile subjects [28]. The finding that the prescription of SUR agonists was common in elderly subjects (~36% among elderly patients nonattending Diabetes Clinics and ~47% among those attending Diabetes Clinics) is quite alarming because it is in striking contrast with guidelines. The latter suggest to avoid the risk of hypoglycemia and drug-to-drug interactions due to polypharmacy in elderly subjects with diabetes [28]. Among these elderly subjects many were also treated with insulin. On the contrary, the proportion of subjects treated with SGLT-2 inhibitors or GLP-1 RA was definitely lower than recommended [27]. In particular, these two classes should be in the first/second-line of treatment in subjects with ASCVD or CHF or kidney disease, conditions very frequently found in patients with diabetes also in Italy [29,30]. In our population the pro-portion of subjects with clinical or preclinical ASCVD or at high risk for ASCVD and/or with CHF (~45%) was definitely higher than the proportion of subjects who received a prescription of SGLT-2 inhibitors or GLP-1 RA (~10%). In subjects attending Diabetes Clinics, however,figures were higher, although probably suboptimal: subjects with ASCVD who received a prescription of SGLT-2 inhibitors or GLP-1 RA were ~34%, and subjects with CHF who received a prescription of these drugs were ~22%, Yet, the propor-tion of subjects treated with DPP-4 inhibitors, the most manageable and free of side effects among anti-hyperglycemic agents, seems to be very low when considering that 2/3 of the population aged65 years.

A partial justification for these lower than recom-mended prescriptions of newer anti-hyperglycemic agents is that in Italy only specialist physicians (i.e., diabetologists and endocrinologists) whereas GPs cannot prescribe DPP-4 inhibitors, GLP-RA and SGLT-2 inhibitors. Therefore,

Table 3 Percentage [95% CIs] of subjects receiving a prescription of a given anti-hyperglycemic medications among drug-treated diabetic subjects by attendance at Diabetes Clinics.

All NZ 619,849 Attending NZ 177,241 Nonattending NZ 442,608 Metformin 66.1 [66.0e66.2] 63.2 [63.1e63.3] 67.6 [67.5e67.7] Sulphonylureas 17.2 [17.1e17.3] 24.3 [24.2e24.4] 14.5 [14.4e14.6] Repaglinide 8.9 [8.8e9.0] 12.2 [12.1e12.3] 10.1 [10.0e10.2] DPP-4 inhibitor/metformin (fixed) 8.0 [7.9e8.1] 32.1 [32.0e32.2] 0.0

DPP-4 inhibitors 6.0 [5.9e6.1] 22.1 [22.0e22.2] 0.0

Sulphonylurea/metformin (fixed) 4.4 [4.3e4.5] 2.2 [2.1e2.3] 4.3 [4.2e4.4] GLP-1 receptor agonists 3.9 [3.85e3.95] 14.7 [14.5e14.9] 0.0

Acarbose 2.8 [2.76e2.84] 4.2 [4.1e4.3] 2.9 [2.8e3.0] SGLT-2 inhibitor/metformin (fixed) 2.7 [2.66e2.74] 11.2 [11.1e11.3] 0.0

Pioglitazone/metformin (fixed) 2.4 [2.36e2.44] 2.4 [2.3e2.5] 2.5 [2.4e2.6] SGLT-2 inhibitors 2.4 [2.36e2.44] 9.5 [9.4e9.6] 0.0

Pioglitazone 1.6 [1.57e1.63] 2.5 [2.4e2.6] 1.0 [0.97e1.03] Pioglitazone/alogliptin (fixed) 0.3 [0.29e0.31] 0.9 [0.86e0.94] 0.0

Pioglitazone/glimepiride (fixed) 0.2 [0.19e0.21] 0.3 [0.27e0.33] 0.1 [0.09e0.11] Basal analogs 21.9 [21.8e22.0] 38.2 [38.0e38.4] 16.1 [16.0e16.2] Prandial analogs 17.8 [17.7e17.9] 23.2 [23.0e23.4] 15.4 [15.3e15.5] Premixed analogs 1.2 [1.17e1.23] 1.2 [1.1e1.3] 1.1 [1.07e1.13] Basal analog/GLP-1 receptor agonist (fixed) 0.8 [0.78e0.83] 2.8 [2.7e2.9] 0.0

Human rapid acting 0.5 [0.48e0.52] 0.7 [0.66e0.74] 0.5 [0.48e0.52] Human premixed 0.1 [0.09e0.11] 0.1 [0.09e0.11] 0.1 [0.09e0.11] Human intermediate acting 0.1 [0.09e0.11] 0.0 0.1 [0.09e0.11]

subjects nonattending Diabetes Clinics were deprived from the opportunity to receive these medications. However, these subjects should be ideally referred to Diabetes Clinics to have access to recommended medications. In this regard, it is worth mentioning that the fraction of patients attending Diabetes Clinics in Italy declined pro-gressively in the last three decades, from almost 90% in the late eighties to about 30% nowadays. A phenomenon partially due to an increased commitment of diabetes specialists in caring foot lesions, assisting pregnant dia-betic women, managing modern technology in type 1 diabetes care, screening and staging chronic complications without a concomitant increased recruitment of human resources (e.g., specialist physicians).

Overall, all indicators of quality of care were more coherent with recommendations of guidelines in patients attending Diabetes Clinics as compared to nonattending ones. This could explain thefinding that patients attending Italian Diabetes Clinics have a lower mortality rate [10].

As compared to a previous study based upon data collected by our same Observatory in 2010 [16], the quality of care was only moderately improved. Subjects receiving at least one HbA1c prescription were 58% in 2010 vs. 63% in 2018 and those who were prescribed microalbuminuria were 27% in 2010 vs. 34% in 2018. Focusing on patients attending the Italian Diabetes Clinics, the quality of care greatly improved in the last 15 years mainly in terms of serum lipids and microalbuminuria monitoring. These parameters were prescribed in 63% and 34% of subjects in 2004 [31] and were prescribed in 85% and 63% in our observation of 2018. As to other Western countries, our present data show a better performance in prescribing when compared to data from USA [32,33], a worse per-formance when compared to data from Norway [34], and a

similar performance when compared to data from Switzerland [35].

As to the proportion of subjects treated with newer anti-hyperglycemic agents, our data are substantially similar to those registered in USA [36] but quite different from those observed in other Countries where pre-scriptions of these medications are higher because they are not limited by regulatory constraints as currently in Italy [37,38]. Unfortunately, we cannot make a comparison of prescriptions of these drugs by specialists because data from other Countries do not distinguish prescriptions made in primary and in secondary care settings.

Strengths of this study are: the very large sample, the nationwide coverage of the study-population, the comprehensive assessment of many process indicators (diagnostic exams and drugs prescriptions). A limit of the study is the lack of clinical information (e.g., HbA1c, BMI, type of diabetes, duration of the disease, details on ASCVD, etc.) which might be instrumental to a better description of the clinical context in which prescriptions were made. Another limit is the lack of information on exams pre-scribed outside the framework of the Italian Public Health System which were, however, a small fraction of total [25]. A further limit could be an unbalanced proportion of subjects from the three main areas of the Country (North, Center, South). However, when we compared our sample with the entire Country data collected by the Italian Na-tional Institute of Statistics (ISTAT) [39], we found consis-tent results: median age was 46 year in our sample and 46 year in the entire Country and females were 51% in our sample and 51% in the entire Country.

In conclusion, despite the fact that Italy has a more than 30-year-old law recommending a particular attention to subjects with diabetes and a capillary network of Diabetes

Table 4 Percentage [95% CIs] of subjects receiving a prescription of a given anti-hyperglycemic medications among drug-treated diabetic subjects stratified according to attendance at Diabetes Clinics and median age.

Attending p-value Nonattending p-value <71 years

(NZ 97,736) 71 years(NZ 79,505) <71 years(NZ 206,760) 71 years(NZ 235,848)

Metformin 67.5 [67.3e67.8] 57.8 [57.5e58.2] <0.001 73.5 [73.3e73.7] 62.1 [61.9e62.3] <0.001 Sulphonylureas 22.2 [22.0e22.5] 26.8 [26.6e27.1] <0.001 11.6 [11.4e11.7] 17.2 [17.0e17.3] <0.001 Repaglinide 8.5 [8.3e8.7] 16.9 [16.6e17.1] <0.001 6.1 [5.9e6.1] 13.7 [13.6e13.8] <0.001 DPP-4 inhibitors/metformin (fixed) 29.6 [29.3e29.9] 35.2 [34.9e35.5] <0.001 0.0 0.0 e DPP-4 inhibitors 13.0 [12.7e13.1] 33.4 [33.1e33.7] <0.001 0.0 0.0 e Sulphonylureas/metformin (fixed) 1.7 [1.59e1.74] 2.8 [2.7e2.9] <0.001 2.4 [2.38e2.51] 5.9 [5.8e6.0] <0.001 GLP-1 receptor agonists 20.3 [20.1e20.5] 7.8 [7.6e8.0] <0.001 0.0 0.0 e Acarbose 3.2 [3.1e3.3] 5.5 [5.4e5.7] <0.001 2.3 [2.27e2.4] 3.4 [3.36e3.50] <0.001 SGLT-2 inhibitors/metformin (fixed) 15.6 [15.4e15.8] 5.6 [5.5e5.8] <0.001 0.0 0.0 e Pioglitazone/metformin (fixed) 2.8 [2.7e2.9] 2.0 [1.9e2.1] <0.001 2.4 [2.33e2.45] 1.9 [1.88e1.98] <0.001 SGLT-2 inhibitors 12.8 [12.7e13.0] 5.3 [5.1e5.4] <0.001 0.0 0.0 e Pioglitazone 2.7 [2.6e8] 2.4 [2.3e2.5] <0.001 1.0 [0.92e1.00] 1.0 [0.94e1.01] NS Pioglitazone/alogliptin (fixed) 1.0 [0.9e1.1] 0.9 [0.80e0.92] <0.005 0.0 0.0 e Pioglitazone/glimepiride (fixed) 0.3 [0.26e0.32] 0.3 [0.23e0.30] NS 0.1 [0.11e0.13] 0.1 [0.09e0.11] <0.05 Basal analogs 38.6 [38.3e38.9] 37.7 [37.3e38.0] <0.001 14.6 [14.4e14.7] 17.5 [17.4e17.6] <0.001 Prandial analogs 24.5 [24.2e24.7] 21.7 [21.4e21.9] <0.001 14.1 [13.9e14.2] 16.6 [16.4e16.7] <0.001 Premixed analogs 1.1 [1.0e1.2] 1.2 [1.09e1.23] <0.001 1.0 [0.96e1.04] 1.1 [1.07e1.14] <0.001 Basal/GLP-1 receptor agonists (fixed) 3.2 [3.1e3.3] 2.3 [2.16e2.35] <0.001 0 0 e Human rapid acting 0.9 [0.89e1.01] 0.4 [0.37e0.45] <0.001 0.4 [0.41e0.46] 0.5 [0.48e0.53] <0.001 Human premixed 0.0 [0.02e0.03] 0.1 [0.05e0.08] <0.001 0.1 [0.07e0.09] 0.1 [0.07e0.10] NS Human intermediate acting 0.0 [0.01e0.03] 0.0 [0.01e0.03] NS 0.1 [0.05e0.07] 0.1 [0.10e0.13] <0.001

Table 5 Percentage [95% CIs] of subjects receiving a prescription a given anti-hyperglycemic drugs to diabetic subjects (%) with atherosclerotic cardiovascular disease (ASCVD) or chronic heart failure (CHF) by attendance at Diabetes Clinics (DC).

ASCVD All NZ 295,451 ASCVD No DC NZ 203,843 ASCVD DC NZ 91,608 CHF All NZ 11,678 CHF No DC NZ 8,499 CHF DC NZ 3,179

Metformin 64.7 [64.5e64.9] 68.5 [68.3e68.7] 58.2 [57.9e58.6] 46.7 [45.8e47.7] 47.3 [46.2e48.3] 46.5 [45.5e47.4]

Sulphonylureas 18.4 [18.2e18.5] 15.7 [15.5e15.8] 22.8 [22.5e23.1] 15.0 [14.3e15.6] 12.6 [11.9e13.3] 18.5 [17.7e19.4]

Repaglinide 12.4 [12.3e12.5] 12.9 [12.7e13.0] 13.2 [13.0e13.5] 18.8 [18.1e19.6] 20.4 [19.5e21.2] 17.6 [16.8e18.4]

DPP-4 inhibitors and metformin (fixed) 9.6 [9.5e9.7] 0.0 30.8 [30.5e31.1] 5.4 [5.0e5.8] 0.0 19.6 [18.8e20.5]

DPP-4 inhibitors 7.0 [6.9e7.1] 0.0 22.5 [22.3e22.8] 10.0 [9.4e10.5] 0.0 35.2 [34.2e36.2]

Sulphonylureas and metformin (fixed) 3.8 [3.8e3.9] 4.6 [4.5e4.7] 2.1 [2.0e2.2] 3.8 [3.4e4.1] 4.3 [3.9e4.7] 2.8 [2.5e3.2]

GLP-1 receptor agonists 3.8 [3.7e3.9] 0.0 12.4 [12.2e12.7] 1.8 [1.5e2.0] 0.0 6.4 [5.9e6.9]

Acarbose 3.5 [3.46e3.6] 3.4 [3.3e3.5] 4.5 [4.4e4.6] 3.8 [3.4e4.1] 3.4 [3.0e3.8] 5.6 [5.1e6.1]

SGLT-2 inhibitors and metformin (fixed) 3.2 [3.09e3.22] 0.0 10.1 [9.9e10.3] 1.6 [1.4e1.8] 0.0 5.7 [5.2e6.2]

Pioglitazone and metformin (fixed) 2.3 [2.28e2.39] 2.4 [2.37e2.50] 2.2 [2.1e2.3] 0.8 [0.7e1.1] 0.9 [0.7e1.1] 0.7 [0.5e0.8]

SGLT-2 inhibitors 2.7 [2.65e2.77] 0.0 8.8 [8.6e9.0] 2.2 [1.9e2.4] 0.0 8.0 [7.4e8.6]

Pioglitazone 1.5 [1.48e1.56] 1.1 [1.03e1.12] 2.3 [2.2e2.4] 1.0 [0.8e1.2] 1.0 [0.8e1.2] 0.9 [0.7e1.1]

Pioglitazone and alogliptin (fixed) 0.3 [0.24e0.28] 0.0 0.8 [0.75e0.86] 0.1 [0.03e0.14] 0.0 0.3 [0.2e0.4]

Pioglitazone and glimepiride (fixed) 0.2 [0.14e0.17] 0.1 [0.10e0.13] 0.2 [0.20e0.26] 0.1 [0.04e0.16] 0.0 0.2 [0.1e0.3]

Basal analogs 20.3 [20.2e20.5] 19.5 [19.3e19.7] 21.6 [21.4e21.9] 40.9 [40.0e41.8] 41.6 [40.5e42.6] 39.8 [38.7e40.4]

Prandial analogs 25.7 [25.6e25.9] 20.7 [20.5e20.9] 36.6 [36.3e36.9] 42.6 [41.7e43.5] 38.6 [37.6e39.7] 53.7 [52.6e54.7]

Premixed analogs 1.3 [1.24e1.32] 1.1 [1.06e1.16] 0.8 [0.75e0.86] 1.9 [1.6e2.1] 1.6 [1.4e1.9] 1.1 [0.8e1.3]

Basal analogs and GLP-1 RA (fixed) 0.9 [0.85e0.92] 0.0 2.7 [2.6e2.8] 0.6 [0.5e0.7] 0.1 [0.1e0.3] 2.1 [1.8e2.4]

Human rapid acting 0.4 [0.41e0.46] 0.5 [0.45e0.51] 0.4 [0.31e0.39] 1.2 [1.0e1.4] 1.4 [1.1e1.6] 0.9 [0.7e1.1]

Human premixed 0.1 [0.07e0.09] 0.1 [0.09e0.12] 0.0 [0.01e0.04] 0.2 [0.10e0.24] 0.2 [0.1e0.3] 0.1 [0.01e0.12]

Human intermediate acting 0.1 [0.07e0.09] 0.1 [0.08e0.11] 0.0 [0.03e0.05] 0.2 [0.08e0.24] 0.2 [0.1e0.3] 0.0

ASCVD and CHF were not mutually exclusive conditions. No statistics was performed because of the limitation in the prescriptions of several drugs by GPs. Only drug-treated subjects are presented.

of diabet es care in Italy in 20 18 19 51

Clinics, the implementation of national and international guidelines regarding monitoring and treatment of the disease is far from being satisfactory, especially in patients nonattending Diabetes Clinics. Further efforts and in-vestments are needed for better disseminating guidelines, more efficaciously engaging healthcare professionals and more strongly empowering the healthcare system and the network of Diabetes Clinics in order to improve outcomes in Italian people with diabetes. Yet, current regulatory constraints in the prescription of cardioprotective and renoprotective drugs should be mitigated.

Funding

The Italian Diabetes Association is gratefully acknowl-edged for funding.

Availability of data

All available data were included in this paper.

Author’s contribution

EB, SC and ER researched data and wrote the manuscript; GMR, RM, OV, GPF and NM reviewed and edited the manuscript. EB takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.

Declaration of competing interest

EB received honoraria for participating in advisory boards of Abbott, Astrazeneca, Becton Dickinson, Boehringer Ingelheim, Bristol-Myers Squibb, Bruno Farmaceutici, Janssen, Johnson&Johnson, Lilly, MSD, Mundipharma, Novartis, Novo Nordisk, Roche, Sanofi, Servier, Takeda. GM received honoraria for participating in advisory boards from Pfizer, Gilead, Novartis, Eli Lilly, Mundipharma. GPF received honoraria or lecture fees from Abbott, AstraZe-neca, Boehringer, Lilly, MSC, Mundipharma, Novartis, Novonordisk, Sanofi, Servier.pharma, Novartis, Novo-nordisk, Sanofi, Servier.

Acknowledgments

The authors acknowledge the precious collaboration of the representatives of the LHDs contributing to the ARNO Observatory: R. Roni (Trento), A. De Marco (Dolomiti), S. Zardo (Serenissima), E. Salvatico (Veneto Orientale), A. Ferrarese (Polesana), A.M. Grion (Euganea), M. Giardino (Pedemontana), A. Maroni (Berica), L. Mezzalira (Scali-gera), T. Brocca (Florence), R. Di Turi (Rome 3), I. Senesi (Teramo), G. La Bella (Naples 1), R. Moscogiuri (Taranto).

The authors would like to thank the following members of the Research & Health Foundation: L. Dondi, G. Ronconi, A. Pedrini, C. Piccinni, S. Calabria and A. Maggioni. References

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