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Vol. 221. Issue 9.
Pages 517-528 (November 2021)
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Vol. 221. Issue 9.
Pages 517-528 (November 2021)
Original article
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Use of antihyperglycaemic therapy with cardiovascular benefit in patients with type 2 diabetes who require hospitalisation: A cross-sectional study
Uso de terapia antihiperglucemiante con beneficio cardiovascular en pacientes con diabetes tipo 2 que requieren hospitalización: un estudio transversal
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J. Enaa,
Corresponding author
ena_jav@gva.es

Corresponding author.
, J. Carretero-Gómezb, A. Zapatero-Gaviriac, F.J. Carrasco-Sánchezd, M. del Romero-Sánchezc, C. González-Becerrae, J.C. Blazquez-Encinarf, M.J. Iguzquiza-Pellejerog, B. de Escalante Yangüelah, R. Gómez-Huelgasi, on behalf of the Spanish Society for Internal Medicine Diabetes, Obesity, and Nutrition Workgroup 1
a Servicio de Medicina Interna, Hospital Marina Baixa, Villajoyosa, Alicante, Spain
b Servicio de Medicina Interna, Hospital de Zafra, Zafra, Badajoz, Spain
c Servicio de Medicina Interna, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain
d Servicio de Medicina Interna, Hospital Universitario Juan Ramón Jiménez, Huelva, Spain
e Servicio de Medicina Interna, Hospital San Juan de Dios, Tenerife, Spain
f Servicio de Medicina Interna, Hospital Universitario de Torrevieja, Torrevieja, Alicante, Spain
g Servicio de Medicina Interna, Hospital Reina Sofia, Tudela, Navarra, Spain
h Servicio de Medicina Interna, Hospital Clinico Lozano Blesa, Zaragoza, Spain
i Servicio de Medicina Interna, Hospital Regional Universitario de Málaga, Málaga, Spain
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Figures (2)
Tables (4)
Table 1. Characteristics of the 928 patients included in the study.
Table 2. Association between prescribing SGLT2i treatment and various categories for patients with eGFR > 45 mL/min/1.73 m2.
Table 3. Association between prescribing GLP1-RA treatment and various categories.
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Abstract
Objective

To evaluate the use of therapy with cardiovascular benefit in patients with type 2 diabetes mellitus admitted to internal medicine departments.

Methods

One day, cross-sectional study of patients with type 2 diabetes mellitus hospitalised in internal medicine departments. We recorded demographic and anthropometric variables, laboratory data and use of antihyperglycaemic drugs. The endpoint was the proportion and determinants of the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA).

Results

We included 928 patients belonging to 74 hospitals, with a mean age of 78.9 years (SD, 10.86 years), 50% of whom were men. A total of 557 (60%) patients had ischaemic heart disease, 189 (20.4%) had cerebrovascular disease, 293 (31.6%) had heart failure, 274 (29.5%) had chronic kidney disease, and 129 (13.9%) had peripheral arterial disease. Prior to their hospital admission, the patients were taking sulfonylureas (5.7%), biguanides (49.1%), alpha-glucosidase inhibitors (0.2%), pioglitazone (0%), dipeptidyl peptidase 4 inhibitors (39%), SGLT2i (5.8%), GLP1-RA (2.6%) and basal insulin analogues (24%). An age over 75 years was the main determinant for not taking SGLT2i (adjusted OR, 0.28; 95% CI 0.10–0.74; p = .039) or GLP1-RA (adjusted OR, 0.09; 95% CI 0.02–0.46; p = .006).

Discussion

A large proportion of elderly patients with type 2 diabetes mellitus at very high cardiovascular risk are not treated with antihyperglycemic drugs with proven cardiovascular benefit. The most commonly used drugs were metformin and DPP4i. There is room for improvement in the treatment of this very high-risk population.

Keywords:
Type 2 diabetes
Hospitalisation
Cardiovascular risk
Sodium-glucose cotransporter-2 inhibitors
Glucagon-like peptide-1 receptor agonists
Resumen
Objetivo

Evaluar el uso de la terapia con beneficio cardiovascular en pacientes con DM tipo 2 previo al ingreso en servicios de medicina interna.

Métodos

Estudio transversal en un día de los pacientes con DM tipo 2 hospitalizados en servicios de medicina interna. Se recogieron variables demográficas y antropométricas, datos de laboratorio y utilización de fármacos antihiperglucemiantes. La variable desenlace fue la proporción y los determinantes de uso de inhibidores del cotransportador sodio-glucosa 2 (iSGLT2) y de agonistas del receptor del péptido similar al glucagón tipo 1 (AR-GLP1).

Resultados

Se incluyeron 928 pacientes pertenecientes a 74 hospitales. La edad media fue 78,9 años (DE: 10,86), un 50% varones. Un total de 557 (60%) presentaba cardiopatía isquémica, 189 (20,4%) enfermedad cerebrovascular, 293 (31,6%) insuficiencia cardiaca, 274 (29,5%) enfermedad renal crónica y 129 (13,9%) enfermedad arterial periférica. Los antihiperglucemiantes utilizados previo al ingreso fueron: sulfonilureas (5.7%), biguanidas (49.1%), inhibidores de la alfa-glucosidasa (0,2%), pioglitazona (0%), iDPP4 (39%), iSGLT2 (5,8%), AR-GLP1 (2,6%) y análogos de insulina basal (24%). La edad mayor de 75 años fue el factor determinante principal para no utilizar iSGLT2 (OR ajustada 0,28; intervalo de confianza al 95%: 0,10–0,74; p = 0,039) o AR-GLP1 (OR ajustada 0,09; intervalo de confianza al 95%: 0,02–0,46; p = 0,006).

Discusión

Una gran proporción de pacientes ancianos con DM tipo 2 de muy alto riesgo cardiovascular no recibe terapia antihiperglucemiante con fármacos de probado beneficio cardiovascular. El tratamiento más frecuentemente utilizado fue metformina e iDPP4. Existe un margen de mejora en el tratamiento en esta población de muy alto riesgo.

Palabras clave:
Diabetes tipo 2
Hospitalización
Riesgo cardiovascular
Inhibidores del cotransportador sodio-glucosa 2
Agonistas del péptido similar al glucagón tipo 1
Full Text
Introduction

The clinical practice recommendations for the treatment of patients with type 2 diabetes has recently undergone significant changes.1 These changes are the result of cardiovascular safety studies performed with sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA).2–6 Empagliflozin, canagliflozin, and dapagliflozin are SGLT2 inhibitors that have been shown to reduce the composite outcome of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (endpoint called MACE) compared to other diabetes treatments. Similarly, they have also been shown to reduce kidney damage and the risk of decompensation due to heart failure.2–4 In the case of GLP1-RA drugs, both liraglutide and semaglutide have shown cardiovascular benefits by reducing the MACE composite endpoint.5,6

For patients with clinical cardiovascular disease, it is recommended that treatment include an SGLT2i or a GLP1. For patients with chronic kidney disease or clinical heart failure and atherosclerotic cardiovascular disease, it is recommended that treatment include an SGLT2 inhibitor. Within the treatment algorithm, GLP1-RAs are now recommended as the first injectable medication to be used if a patient does not reach the glycaemic control target, always provided there is no symptomatic hyperglycaemia, in which case the use of insulin is advisable.

However, the cardiovascular safety clinical trials with antihyperglycemic drugs include a population in which older patients (such as those over the age of 75), as well as fragile patients or those with severe comorbidities, are typically under-represented. In Spain, one of the counties with the longest life expectancy, the prevalence of type 2 diabetes in patients over the age of 75 approaches 23%.7 Real life studies show that only 15.7% of patients with diabetes have a cardiovascular risk similar to that of patients included in some of the cardiovascular safety studies.8 Regarding patients with type 2 diabetes who are admitted to hospital, their mean age is 73, with 40% presenting established cardiovascular disease (%).9 Chronic kidney disease is another highly prevalent risk factor in patients with diabetes and which determines cardiovascular prognosis. Studies carried out in ambulatory patients with diabetes in Spain show a reduced glomerular filtration prevalence below 60 mL/min/1.73 m2 of 28%;10 however, this proportion can reach 55% for those patients with diabetes admitted to hospital.11

Given that patients with diabetes who are admitted to internal medicine wards comprise a population with high cardiovascular risk, our aim in this study is to understand the use of antihyperglycemic drugs with cardiovascular benefits. Likewise, we study the possible determinants in selecting therapies with cardiovascular benefit.

Methods

Observational, cross-sectional study based on a review of electronic medical records. The study was approved by the Hospital Marina Baixa Research Committee (Villajoyosa, Alicante). We followed the STROBE recommendations in the creation and reporting of this cross-sectional study.12

Study design

A questionnaire was created to collect the prescribing habits for antihyperglycemic drugs in hospitalised patients in internal medicine wards. Data collection was carried out on a specific day between 20 May and 07 June 2019.

Study population

Patients with type 2 diabetes admitted during the study period to the internal medicine wards of Spanish hospitals were included. This anonymous questionnaire collected information related to the following variables: demographic data, anthropometric data, laboratory data, frailty and cognitive impairment assessment, prescription of antihyperglycemic drugs and dosage.

Primary endpoint

The primary endpoint was defined as the use of SGLT2i and GLP1-RA drugs in patients with high cardiovascular risk, or with heart failure as per the indications according to the summary of product characteristics and the funding conditions of the National Healthcare System. In Spain, the funding for SGLT2i drugs is reserved for patients with type 2 diabetes with a glomerular filtration rate higher than 45 mL/min/1.73 m2; on the other hand, the funding for GLP1-RA drugs is reserved for patients with type 2 diabetes with a body mass index greater than 30 kg/m2 and whose glomerular filtration rate is higher than 15 mL/min/1.73 m2.

Definitions

Frailty: frail patients were defined as those included in groups 5 to 9 on the Rockwood frailty scale.13

Kidney failure: the presence of kidney failure was defined according to the KDIGO 2012 guidelines and was classified depending on the estimated glomerular filtration rate and the degree of proteinuria measured in a urine sample collected in the morning.14 Creatinine values, estimated glomerular filtration rates, and albuminuria/creatinine ratios were retrieved from the medical records with the patient in stable condition prior to hospital admission.

Very high cardiovascular risk: patients with very high cardiovascular risk were defined as those with prior medical history of acute myocardial infarction, acute coronary syndrome, stroke or transitory ischaemic attack, coronary revascularization procedures, aortic aneurysm, and peripheral artery disease. Patients with type 2 diabetes and proteinuria were also included in this group, as well patients with a sustained glomerular filtration rate below 30 mL/min/1.73 m2, or, in other words, those with chronic kidney disease.15

Bias risk

The questionnaire was sent to members of the Spanish Society for Internal Medicine Diabetes, Obesity, and Nutrition Workgroup for volunteer participation in data collection. The final sample included participation from 73 researchers (10.6%) out of a total of 684 members of the workgroup. The bias risk was estimated to be small as the study gathered data on antihyperglycemic drug prescription in patients prior to their hospital admission.

Sample size

According to the literature data, the population of patients with type 2 diabetes with very high cardiovascular risk aged over 70 years that would be eligible for SGLT2i or GLP1-RA therapy is around 25–40%.9 A 95% confidence interval with a precision of  ± 5% provides an effective sample size of n ≥ 369. The prevalence of diminished glomerular filtration or the presence of proteinuria in patients with type 2 diabetes in Spain is about 35%:10 in patients with type 2 diabetes with glomerular filtration below 60 mL/min/1.73 m2, this value reached 55% in a large cross-sectional study carried out in Spain.11 A 95% confidence interval with a precision of  ± 5% provides an effective sample size of n ≥ 381.

Statistical analysis

The categorical data is presented as numbers and percentages; the continuous data with normal distribution as mean± standard deviation (SD) and the non-normally distributed continuous variables as average and interquartile range (IQR). The one-way analysis of variance (ANOVA) and the Kruskal-Wallis tests were used to compare the continuous variables between the groups according to the normality of the distribution, and the Chi-squared test was used for the categorical variables.

A logistic regression analysis was performed to identify the determinants associated with the use of SGLT2i and GLP1-RA drugs according to the funding conditions of our National Healthcare System. Two statistical models were created, one whose response variable was the presence of SGLT2i in diabetes treatment prior to admission, and another in which the response variable was the use of GLP1-RA in diabetes treatment prior to admission. Variables presenting an association with a p value of <0.10 in the univariate analysis were considered independent variables. All analyses were performed using the SPSS software (v.22). A p value of  < 0.05 was considered statistically significant.

Ethical and legal requirements

All data were made anonymous when taken. Clinically unidentifiable information was made available to the researchers. The study was approved by the Hospital Marina Baixa Research Committee and was classified as an audit of current practices in comparison with the best available evidence, meaning it was not necessary to obtained informed patient consent.

ResultsParticipants

Seventy-four hospitals out of a total of 224 belonging to the National Healthcare System participated in collecting the data, representing some 34% (95% confidence interval [95% CI]: 28.0–40.3%). During the study period, a total of 3,290 patients were admitted to the internal medicine wards, of which 908 (27.6%) had a primary or secondary diagnosis of diabetes mellitus. The main reasons for patient admission to the internal medicine ward were infectious disease (46%) or cardiovascular disease (34.5%). Only 6.4% of admissions were related to primary diagnoses of glycaemic decompensation.

Descriptive data

The mean age of the patients included in the study was 78.9 years, and mean duration of diabetes since diagnosis was 11 years (Table 1). Mean body mass index was 29. Some 60% had established cardiovascular disease, defined by a history of coronary artery disease (27%), cerebrovascular disease (20.4%), or peripheral artery disease (13.9%); approximately one third of the patients had experienced a prior episode of heart failure. The mean estimated glomerular filtration rate was 56.4 mL/min/1.73 m2. The degree of glycaemic control measured by HbA1c value (HbA1c ≤ 8%) was acceptable in 62.7% of the patients.

Table 1.

Characteristics of the 928 patients included in the study.

Characteristic  No. of observations   
Age, years  919  78.9 ± 10.9 
Female sex (%)  919  455 (49.7) 
Race (%)  918   
Caucasian    890 (97.2) 
Latino    19 (2.0) 
Black    3 (0.3) 
Body mass index, kg/m2  915  29.0 ± 6.4 
>30 (%)    304 (33.2) 
≤30 (%)    611 (67.8) 
Smoker (%)  916   
Active    97 (10.5) 
Ex-smoker    309 (33.3) 
Non-smoker    510 (55.7) 
Hypertension (%)  917  775 (83.5) 
Dyslipidaemia (%)  915  602 (64.9) 
Duration of diabetes, years, average (IQR)  865  11 (6–17) 
Microvascular disease (%)  916   
Retinopathy    114 (12.3) 
Polyneuropathy    81 (8.7) 
Kidney disease    274 (29.5) 
Glycated haemoglobin (%)  764  7.2 ± 2.5 
<7%    381 (41.1) 
7–8%    200 (21.6) 
8.1–10%    73 (7.9) 
>10%    110 (11.9) 
Barthel Index (%)  891  60.1 ± 35.6 
Independent    215 (23.2) 
Slight dependency    249 (26.8) 
Moderate dependency    129 (13.9) 
Severe dependency    94 (10.1) 
Total dependency    204 (22.0) 
Cognitive impairment (%)  898  250 (27.3) 
Frailty score, average (IQR)  857  5 (3–7) 
Estimated glomerular filtration rate, mL/min/1.73 m2  889  56.4 ± 27.1 
>90    126 (13.6) 
60–89    263 (28.4) 
45–59    142 (15.3) 
30–45    182 (19.6) 
15–29    138 (14.9) 
<15 or dialysis    38 (4.1) 
Albuminuria/creatinine ratio, mg/g  456   
<30 mg/g    274 (29.5) 
30–300 mg/g    132 (14.2) 
>300 mg/g    50 (5.4) 
Established cardiovascular disease (%)  917  557 (60.8) 
Coronary artery disease  549  251 (27.4) 
Cerebrovascular disease  548  189 (20.6) 
Peripheral artery disease  548  129 (14.1) 
Previous episode of heart failure (%)  556  293 (32.0) 
Antihyperglycemic drugs (%)
Metformin  909  456 (49.8) 
Sulfonylurea  907  53 (5.8) 
Meglitinides  904  61 (6.7) 
Thiazolidinediones  900 
iDPP4  911  362 (39.6) 
iSGLT2  910  54 (5.9) 
AR-GLP1  909  24 (2.6) 
Insulin  818  223 (24) 
Cardiovascular treatment (%)
Antiplatelet drugs  928  372 (40.6) 
ACEI  928  256 (27.9) 
ARB-II  928  257 (28.0) 
Beta blockers  928  336 (36.7) 
Statins or ezetimibe  928  500 (54.6) 
Loop diuretics  928  427 (46.7) 
Calcium channel blockers  928  199 (21.7) 
ARNI  928  13 (1.4) 

ACEI: angiotensin-converting enzyme inhibitor; ARB-II: angiotensin II receptor blocker; ARNI: angiotensin receptor-neprilysin inhibitor; GLP1-RA: glucagon-like peptide-1 receptor agonist; iDPP4: dipeptidyl peptidase-4 inhibitor; SGLT2i: sodium-glucose cotransporter-2 inhibitor.

Regarding the use of antihyperglycemic therapy, the most used drugs were metformin (49.1%), DPP-4 inhibitors (39%), and insulin (35.2%). The use of SGLT2i and GLP1-RA was 5.8% and 2.6%, respectively.

The use of primary treatments for cardiovascular disease was antiplatelet drugs (40.1%), ACEIs (27.6%), ARB-II (27.7%), beta blockers (36.2%), diuretics (46%) and statins or ezetimibe (53.9%).

Measured endpoints

A total of 547 (60.4%) patients showed estimated glomerular filtration rate values per the CKD-EPI formula greater than 45 mL/min/1.73 m2, the limit established in our country for funding the prescription of SGLT2i therapy. Among these patients, 65 (12.2%) had peripheral artery disease as a potential contraindication for SGLT2i use. The distribution of SGLT2i use in patients with high risk of cerebrovascular disease, defined as coronary disease, cerebrovascular disease, chronic kidney disease, and congestive heart failure, was less than 10% in all cases (Fig. 1).

Figure 1.

Flowchart of patients who received treatment with iSGLT2.

(0.13MB).

A total of 286 patients had obesity, defined as a body mass index greater than 30 kg/m2, the estimated limit for funding GLP1-RA therapy in our country. Due to the small number of observations, the GLP1-RA drugs with demonstrated cardiovascular benefit (liraglutide and semaglutide) have been grouped with those with demonstrated cardiovascular safety (long-acting exenatide, lixisenatide, and albiglutide). The distribution of GLP1-RA use in patients with very high cardiovascular risk amounts to a maximum value of 6.4% (Fig. 2).

Figure 2.

Flowchart of patients who received treatment with AR-GLP1.

(0.11MB).
Determinants for the use of sodium-glucose cotransporter-2 inhibitors

Table 2 shows the association between use of SGLT2i treatment and various demographic and epidemiological variables in individuals with an estimated glomerular filtration rate higher than 45 mL/min/1.73 m2 (n = 548). In the univariate analysis, we found a statistically significant association between SGLT2i prescription and age, body mass index, and dependency level. Presence of cardiovascular disease and chronic kidney disease, history of heart failure, male sex, the presence of dementia, or glycated haemoglobin values were not associated with SGLT2i use prior to hospital admission. In the multivariate analysis, patients older than 75 years of age showed lower use of SGLT2i drugs compared to patients under the age of 65 (adjusted odds ratio: 0.28; 95% CI: 0.10–0.74; p = 0.039).

Table 2.

Association between prescribing SGLT2i treatment and various categories for patients with eGFR > 45 mL/min/1.73 m2.

  SGLT2i useOR (95% CI)  p  Adjusted OR (95% CI)  p 
Age  Yes (%)  No (%)    0.010    0.103 
<65 years  11 (14.5)  65 (85.5)     
65–75 years  14 (10.1)  124 (89.9)  0.67 (0.29–1.55)    0.56 (0.21–1.48)   
>75 years  16 (4.9)  313 (95.1)  0.30 (0.13–0.68)    0.33 (0.12–0.92)   
Body mass index        0.028    0.031 
<18  6 (100)  Not calculable       
18–24.9  3 (2.7)  109 (97.3)     
25–30  12 (6.6)  169 (93.4)  2.58 (0.71–9.35)    3.18 (0.84–12.06)   
>30  20 (11.5)  153 (88.5)  4.75 (1.34–16.38)    5.21 (1.46–18.64)   
Dependency level        0.013    0.034 
Independent  16 (10.6)  135 (89.4)     
Slight  12 (8.3)  133 (91.7)  0.76 (0.35–1.67)    0.86 (0.33–2.21)   
Moderate  2 (3.2)  60 (96.8)  0.28 (0.06–1.26)    0.48 (0.09–2.37)   
Severe  8 (17.7)  37 (82.3)  1.82 (0.72–4.59)    3.32 (1.00–11.02)   
Total  3 (2.4)  124 (97.6)  0.20 (0.06–0.72)    0.38 (0.09–1.47)   
Sex
Male  24 (8.3)  266 (91.7)  0.519     
Female  17 (6.7)  236 (93.3)  0.79 (0.42–1.52)       
Dementia diagnosis        0.210     
No  33 (8.7)  346 (91.3)       
Yes  8 (5.1)  148 (94.9)  0.56 (0.25–1.25)       
Heart disease        0.516     
No  16 (5.9)  255 (94.1)       
Yes  25 (8.3)  277 (91.7)  1.43 (0.75–2.75)       
Heart failure        0.398     
No  12 (6.9)  162 (93.1)       
Yes  13 (10.1)  115 (89.9)  1.43 (0.75–2.75)       
HbA1c, %        0.108     
<7.0  11 (4.8)  220 (95.2)       
7.0–8.0  14 (11.5)  107 (88.5)  2.61 (1.15–5.96)       
8.1–8.5  4 (11.1)  32 (88.9)  2.50 (0.75–8.32)       
>8.5  5 (7.6)  61 (92.4)  1.64 (0.55–4.90)       
eGFR, mL/min/1.73 m2        0.598     
>90  10 (8.8)  103 (91.2)       
60–90  22 (8)  253 (92)  0.89 (0.41–1.96)       
45–60  9 (5.8)  146 (94.2)  0.63 (0.25–1.62)       
Albuminuria/creatinine ratio        0.444     
<30 mg/g  16 (8.3)  176 (91.7)       
30–300  6 (10.5)  51 (89.5)  1.29 (0.48–3.48)       
>300  14 (100)  Not calculable       

eGFR: estimated glomerular filtration rate; HbA1c: glycated haemoglobin; SGLT2i: sodium-glucose cotransporter-2 inhibitor.

Determinants for the use of glucagon-like peptide-1 receptor agonists

Table 3 shows the association between use of GLP1-RA treatment and various demographic and epidemiological variables in individuals with a body mass index greater than 30 kg/m2 (n = 302). In the univariate analysis, we found a statistically significant association between GLP1-RA prescription, age, and estimated glomerular filtration. Dependency level, presence of cardiovascular disease, history of heart failure, male sex, the presence of dementia, or glycated haemoglobin values were not associated with GLP1-RA use prior to hospital admission. Only age maintained statistical significance in the multivariate analysis. Patients older than 75 years of age showed lower use of GLP1-RA drugs compared to patients under the age of 65 (adjusted odds ratio: 0.09; 95% CI: 0,02–0,46; p = 0,006).

Table 3.

Association between prescribing GLP1-RA treatment and various categories.

  GLP1-RA useOR (95% CI)  p  Adjusted OR (95% CI)  p 
  Yes (%)  No (%)    0.000    0.011 
Age             
<65 years  5 (13.5)  32 (86.5)     
65–75 years  9 (12.2)  65 (87.8)  0.89 (0.27–2.86)    1.22 (0.36–4.10)   
>75 years  3 (1.6)  188 (98.4)  0.10 (0.02–0.45)    0.16 (0.03–0.73)   
Dependency level
Independent  6 (8)  69 (92)  0.268     
Slight  8 (9.4)  77 (90.6)  1.19 (0.39–3.61)       
Moderate  1 (2.2)  45 (97.7)  0.26 (0.03–2.19)       
Severe  1 (3.4)  28 (96.6)  0.41 (0.05–3.57)       
Total  1 (1.6)  62 (98.4)  0.19 (0.02–1.58)       
Sex
Male  7 (5.5)  119 (94.5)  0.963     
Female  10 (6)  166 (94)  1.02 (0.38–2.77)       
Dementia diagnosis        0.158     
No  15 (6.8)  204 (93.2)       
Yes  2 (2.4)  80 (97.6)  0.34 (0.76–1.52)       
Heart disease        0.566     
No  8 (6.5)  114 (94.5)       
Yes  9 (5)  171 (95)  1.33 (0.5–3.56)       
Heart failure        0.843     
No  4 (5.1)  73 (94.9)       
Yes  5 (4.8)  98 (95.2)  0.07 (0.28–4.14)       
HbA1c, %        0.324     
<7.0  6 (4.8)  120 (95.2)       
7.0–8.0  3 (5.2)  56 (94.8)  1.07 (0.26–4.44)       
8.1–8.5  4 (13.8)  25 (86.2)  3.20 (0.84–12.18)       
>8.5  3 (6.6)  42 (93.4)  1.43 (0.34–5.97)       
Estimated FG, mL/min/1.73 m2        0.011     
>90  12 (10.7)  100 (89.3)      0.110 
60–90  4 (2.3)  169 (97.7)  0.27 (0.08–0.92)    0.27 (0.08–0.92)   
45–60  1 (6.6)  14 (93.4)  0.82 (0.09–7.31)    0.82 (0.09–7.31)   
Albuminuria/creatinine ratio        0.841     
<30 mg/g  3 (2.9)  99 (97.1)       
30–300  2 (3.9)  49 (96.1)  1.35 (0.22–8.33)       
>300  1 (5)  19 (95)  1.94 (80.19–19.77)       

eGFR: estimated glomerular filtration; GLP1-RA: glucagon-like peptide-1 receptor agonist; HbA1c: glycated haemoglobin.

Discussion

This study shows that a high percentage of patients with type 2 diabetes mellitus admitted to internal medicine wards in Spanish hospitals are at very high cardiovascular risk. Specifically, 35% of patients were admitted with cardiovascular disease as a primary diagnosis. Moreover, 60% of patients had established cardiovascular disease, and 54% had chronic kidney disease. Some 32% of patients had previously experienced at least one episode of congestive heart failure. Despite the patients’ high cardiovascular risk, use of antihyperglycemic drugs with cardiovascular benefit prior to admission has been scarce. Specifically, SGLT2i use was less than 6% for the population and GLP1-RA use did not reach even 3% of patients. The analysis of the determinants for use showed that SGLT2i prescription was associated with the presence of a higher body mass index or a lower dependency level for activities of daily living. For GLP1-RA drug prescription, we observed an association with a lower age range and a lower estimated glomerular filtration rate.

Only 60% of patients with glomerular filtration over 30 mL/min/1.73 m2 received treatment with metformin while the cardiovascular safety studies with empagliflozin, canagliflozin, and dapagliflozin placed this percentage at around 73–80%.2–4 A hypothesis that could explain this data point is that the metformin sold in English-speaking countries and the USA is an extended-release formulation with better tolerability and a higher cost. The scarce use of antihyperglycemic drugs with cardiovascular benefit has also been confirmed in other studies. In the study performed by Fadini et al.16, SGLT2i use was 1.8% and GLP1-RA use was 3.9% in a total of 563 patients with a mean age of 69 years and recent cardiovascular disease who had an initial follow-up in out-patient services. After experiencing the cardiovascular event, prescriptions increased for statins, ACEIs, ARB-II, diuretics, and antiplatelet drugs, but no noticeable changes occurred in the prescription of SGLT2i and GLP1-RA. The use of other drugs, such as antiplatelet drugs, statins, ACEIs, ARB-II, and ARNIs showed a wide margin of improvement even in patients with established cardiovascular disease.

In contrast to the referenced study, our patients had a mean age of 79 years and higher dependency levels for activities of daily living; these factors could justify the use of drugs with a better tolerability profile, such as DPP-4 inhibitors and metformin. Some studies show the efficacy and safety of SGLT2i and GLP1-RA used in combination in older patients with significant comorbidities,17 but as of yet there is very little clinical experience.

Among the limitations, as with all retrospective studies, we must highlight the flaws in collecting some of the data due to a lack of availability. Nor do we have information on the prescribing physicians, meaning we do not know the level of adherence to the clinical practice guidelines according to specialties, which represents a limitation for incorporating educational measures. On the other hand, it must be taken into account that the therapeutic positioning statement report recommends caution when treating people over the age of 75 with SGLT2i or GLP1-RA due to the little information available in the literature. Low use of hypoglycaemic agents with proven cardiovascular benefit can also be explained by the typical lag seen between the inclusion of recommendations in the clinical practice guidelines up until their implementation in real life.18 Despite the widespread dissemination of clinical practice guidelines on type 2 diabetes treatment via scientific societies such as the American Diabetes Association, the European Association for the Study of Diabetes, or the Spanish Diabetes Society guidelines,1,19,20 their implementation in real life practice may be hindered by lack of knowledge, resistance to change, or organisational or financial obstacles.21–23 For example, in Europe the use of drugs with recognised benefit on diabetic nephropathy showed wide variation for the use of renin-angiotensin system blockers, with values between 74–84%, or the use of statins in patients aged over 40, with values between 40% and 83%.24 However, in our study, the very low percentage of SGLT2i use in patients with a history of diabetic nephropathy is worthy of note.

We believe the results of our study are generalizable and that the use of antihyperglycemic drugs with cardiovascular benefit in the older population continues to remain scarce. Our data come from a total of 74 (34%) hospitals that belong to the National Healthcare System, representing a total of 3,290 patients admitted to internal medicine wards at the time of the study. The data was collected by members of the Internal Medicine Society Diabetes, Obesity, and Nutrition Workgroup. Special attention was paid to the study and control of diabetes in patients in the internal medicine wards, so it is possible that the inclusion of other hospitals could have indicated an even lower proportion of use of antihyperglycemic drugs with cardiovascular benefit.

The implications of our study are clear: it is necessary to implement the use of antihyperglycemic drugs with proven cardiovascular benefits in high-risk patients. To do this, we would need studies in populations that are not typically represented in clinical trials, such as the elderly population.

Funding

This study has been completed with research funding aid from the Spanish Society for Internal Medicine Diabetes, Obesity, and Nutrition Workgroup.

Conflicts of interest

The authors declare that they do not have any conflicts of interest.

Acknowledgments

To Dr José Manuel Casas for creating the electronic information data collection sheet and his help with the statistical analysis.

Appendix A
Researchers in the Spanish Society for Internal Medicine Diabetes, Obesity, and Nutrition Workgroup

Olga  Gavin Blanco  Hospital de Alcañiz (Teruel) 
Pilar  Álvarez Padin  Hospital Santos Reyes. Aranda de Duero (Burgos) 
Mar  Segarra Soria  Hospital General Universitario de Elda (Valencia) 
Javier  Ena Muñoz  Hospital Marina Baixa. Villajoyosa (Alicante) 
Luis Ángel  Sánchez Muñoz  Hospital Clínico Universitario de Valladolid 
Antonio  Zapatero Gaviria  Hospital Universitario de Fuenlabrada (Madrid) 
Anna  Pardo  Hospital HM Delfos. Barcelona 
Víctor  Arenas García  Hospital Universitario San Agustín. Avilés (Asturias) 
Manuel Lorenzo  López Reboiro  Hospital Comarcal de Monforte de Lemos (Lugo) 
María Paz  Vaquero Herrero  Hospital Comarcal de Benavente (Zamora) 
Juana  Carretero Gómez  Hospital de Zafra (Badajoz) 
Araceli  Menéndez Saldaña  Hospital de Cantoblanco (Madrid) 
Marta Nataya  Solís Marquínez  Hospital Álvarez Buylla. Mieres (Asturias) 
Amelia  García Olid  EPHAG. Andújar (Jaén) 
Lourdes  Mateos Polo  Centro Asistencial de Salamanca 
Philip  Wikman  Hospital Universitario San Juan de Alicante 
Agustín Diego  Chacón Moreno  Hospital Universitario Gregorio Marañón. Madrid 
Julio César  Blázquez Encinar  Hospital Universitario de Torrevieja (Alicante) 
Sara  Fuente Cosío  Hospital Comarcal de Jarrio. Coaña (Asturias) 
Francisco Javier  Carrasco Sánchez  Hospital Universitario Juan Ramón Jiménez. Huelva 
Silvia  Loscos Aranda  Hospital Miguel Servet. Zaragoza 
Angel  Jiménez Rodríguez  Hospital Infanta Elena. Valdemoro (Madrid) 
Daniel  Toresano López  Hospital Universitario Marqués de Valdecilla. Santander (Cantabria) 
Concepción  González Becerra  HSJD Tenerife 
Beatriz  Valero Novella  Hospital General Universitario de Alicante 
Antón  Otero Moreiras  Complejo Hospitalario de Vigo (Pontevedra) (H. Meixoeiro) 
Fernando Javier  Sánchez Lora  Hospital Universitario Virgen de la Victoria. Málaga 
María de los Ángeles  Tejero Delgado  Hospital Universitario Central de Asturias 
Ismael  Said Criado  Hospital Vithas Fátima. Vigo 
Elisa  Ruiz Arabí  Fundación Jiménez Díaz. Madrid 
Judit  Aranda Lobo  Hospital Moisès Broggi Sant Joan Despí. Barcelona 
Joaquín  Llorente García  Hospital Universitario San Agustín. Avilés (Asturias) 
María Elena  Aguirre Alastuey  Hospital Universitario San Agustín. Avilés (Asturias) 
Joaquín  Castro Jiménez  Hospital Santa Bárbara. Puerto Llano (Ciudad Real) 
María Luisa  Taboada Martínez  Hospital Universitario Cabueñes (Asturias) 
Amara  González Noya  Complejo Hospitalario de Ourense 
Paula  Dios Díez  Complejo Asistencial Universitario de León 
Pedro  Abad Requejo  Hospital del Oriente de Asturias 
Antonio  Rabassa  Hospital Universitario Sant Joan. Reus (Tarragona) 
Aychel Elena  Roura  Hospital Clínico Universitario Virgen de la Arrixaca. Murcia 
José Ignacio  Ferullo  Fundació Hospital de l'Espirit Sant. Barcelona 
José María  Calvo Romero  Hospital Ciudad de Coria (Cáceres) 
Esther  Usandizaga de Antonio  Hospital Moisès Broggi Sant Joan Despí. Barcelona 
Cristina  Martín Domínguez  Fundación Hospital de Jove. Gijón (Asturias) 
María del Mar  García Andreu  Hospital Royo Villanova. Zaragoza 
María Victoria  Villalba García  Hospital Universitario Gregorio Marañón. Madrid 
Cristina  Soler i Ferrer  Hospital de Sta. Caterina de Salt. Girona 
María José  Luque Calderón  Hospital Perpetuo Socorro. Badajoz 
Mónica  Ríos Prego  Complejo Hospitalario Universitario de Pontevedra 
Olga  Madridano Cobo  Hospital Infanta Sofía. Madrid 
Paula M.  Pesqueira Fontán  Complejo Hospitalario de Vigo (Pontevedra) (H. Meixoeiro) 
Montserrat  García Cors  Hospital General de Catalunya. Sant Cugat del Valles (Barcelona) 
Vanesa  Díaz  Hospital Universitario San Agustín. Avilés (Asturias) 
Rosa María  Gámez Mancera  Hospital Universitario Virgen del Rocío. Seville 
Alejandro  Parra Virto  Hospital Universitario Gregorio Marañón. Madrid 
Begoña  Cortés Rodríguez  EPHAG. Andújar (Jaén) 
María del Carmen  López Ríos  Hospital Universitario Virgen del Rocío. Seville 
Víctor Miguel  Cánovas García  Hospital Vinalopó. Elche (Alicante) 
Ana Isabel  Pujades Tárraga  Hospital Lluís Alcanyís. Xativa (Valencia) 
María  Gómez Antúnez  Hospital Universitario Gregorio Marañón. Madrid 
Pedro Pablo  Casado Escribano  Hospital Universitario La Princesa. Madrid 
Ana Isabel  Ostos Ruiz  Hospital San Juan de la Cruz de Úbeda (Jaén) 
Anna  Arjol  Hospital de Mollet del Vallés (Barcelona) 
Francisco  Estrada Álvarez  Hospital Valle del Nalón. Riaño, Langreo (Asturias) 
Paola  Tarabini-Castellani  Hospital Universitario de Álava (Vitoria) 
Rita  Godoy  Hospital Dos de Mayo (Barcelona) 
Covadonga  Rodríguez Mangas  Hospital Doctor José Molina Orosa. Arrecife (Las Palmas) 
Marta  Bacete Cebrián  Hospital Universitario Gregorio Marañón. Madrid 
Marta  Lobo Antuña  Hospital Fundación Jiménez Díaz. Madrid 
José Luis  Beato Pérez  Complejo Hospitalario Universitario Albacete 
Cristina  Macía Rodríguez  Hospital POVISA. Vigo (Pontevedra) 
Paloma  Agudo  Hospital 12 de Octubre. Madrid 
Begoña  de Escalante Yangüela  Hospital Clínico Lozano Blesa. Zaragoza 
José Nicolás  Alcalá Pedrajas  Hospital Comarcal de Pozoblanco (Córdoba) 
Luis  Giménez Miranda  Hospital Universitario Virgen del Rocío. Seville 
Francisco Javier  Polo Romero  Hospital de Hellín (Albacete) 
Marta  Ortega Reina  Hospital Universitario Virgen del Rocío. Seville 
María Jesús  Igúzquiza Pellejero  Hospital Reina Sofía de Tudela (Navarra) 
José Manuel  Varela Aguilar  Hospital Universitario Virgen del Rocío. Seville 
M. Elena  Casuso Sáenz  Hospital de Laredo (Cantabria) 
Carlos  Delgado Verges  Hospital Universitario Cabueñes (Asturias) 
Begoña  Marí Alfonso  Corporació sanitària Parc Tauli. Sabadell (Barcelona) 
José Luis  Cabrerizo García  Hospital Clínico Lozano Blesa. Zaragoza 
Rebeca  Fernández Regueiro  Hospital Universitario Cabueñes (Asturias) 
María Mercedes  Ferreiro-Mazon Jenaro  Hospital Universitario Gregorio Marañón. Madrid 
Rafael  Castillo Rubio  Hospital de Liria (Valencia) 
Cristina  Llamazares Mendo  Hospital Universitario Gregorio Marañón. Madrid 
Inmaculada  Mejías Real  Hospital Infanta Margarita. Cabra (Córdoba) 
Carlos  de Andrés David  Consorcio Hospital General Universitario de Valencia 
Guillermo  Soria Fernández-Llamazares  Hospital Universitario Gregorio Marañón. Madrid 
María Isabel  Pérez Soto  Hospital Vinalopó. Elche (Alicante) 
Cristina  Helguera Amezua  Hospital Universitario Cabueñes (Asturias) 
Virginia  Gracia Lorenzo  Hospital del Tajo. Aranjuez (Madrid) 
Ornella  Flores Lledó  Consorci Sanitari de Terrassa (Barcelona) 
Víctor  Mato Jimeno  Hospital Universitario Gregorio Marañón. Madrid 
Diego José  García González  Complejo Hospitalario Universitario Insular Materno-Infantil. Las Palmas 
Cristina  Ausín García  Hospital Universitario Gregorio Marañón. Madrid 
Sergio  Moragón Ledesma  Hospital Universitario Gregorio Marañón. Madrid 
Alberto  Muela Molinero  Complejo Asistencial Universitario de León 
María Montserrat  Chimeno Viñas  Complejo Asistencial de Zamora 
Borja  García Tello  Hospital Clínico Lozano Blesa. Zaragoza 
Juan Francisco  López Caleya  Hospital Universitario Cabueñes (Asturias) 
Rosa  Fernández-Madera Martínez  Hospital Universitario Cabueñes (Asturias) 
María del Mar  Martínez López  Hospital Universitario Cabueñes (Asturias) 
Sagrario María  Santos Seoane  Hospital Universitario Cabueñes (Asturias) 
Carlota  Argüello  Hospital Universitario Central de Asturias 
Arturo  Muñoz Blanco  Hospital Infanta Sofía. Madrid 
Claudia  Morán Casta  Hospital Universitario Central de Asturias 
Carmen  Yllera  Hospital Universitario Central de Asturias 
Lucía  Mejide Rodríguez  Hospital Universitario Central de Asturias 
María  Folgueras  Hospital Universitario Central de Asturias 
Sara  Rodríguez Suárez  Hospital Universitario Central de Asturias 
María  Guil García  Hospital Regional Universitario de Málaga 

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The names of the components of the Spanish Society for Internal Medicine Diabetes, Obesity, and Nutrition Workgroup are listed in Appendix A.

Please cite this article as: Ena J, Carretero-Gómez J, Zapatero-Gaviria A, Carrasco-Sánchez FJ, del Romero-Sánchez M, González-Becerra C, et al. Uso de terapia antihiperglucemiante con beneficio cardiovascular en pacientes con diabetes tipo 2 que requieren hospitalización: un estudio transversal. Rev Clin Esp. 2021;221:517–527.

Copyright © 2020. Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI)
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