Safety of SGLT2 inhibitors in very elderly diabetic type 2 patients in real life

Introduction: Sodium glucose cotransporter 2 inhibitors (SGLT2i) are the latest antidiabetic treatments that reduces mortality and cardiovascular outcomes. Its use in real life in very elderly patients is limited by its possible side effects. Material and methods: We conducted a retrospective study of patients treated with SGLT2i in our community (La Rioja) since 2014. The safety (adverse effects) and prognosis (mortality, cardiac decompensation, and cardiovascular events) during the first 24 months of treatment were evaluated. Results: We included 235 patients treated with SGLT2i, 114 of them were men (48.5%), and the mean age was 79.6 ± 3.9 years. The most used SGLT2i was empagliflozin (55.7%). The mean Hb1Ac at the time of inclusion was 7.9 ± 1.4, showing a decrease in 47.7% of the included patients during the follow up. The initial values of creatinine and glomerular filtration rate at the time of inclusion (0.94 ± 0.3 and 68.3 ± 16.4) presented an improvement at 24 months of treatment (


INTRODUCTION
In the United States, 21.8% of 75 years or older patients have diabetes [1].Sodium glucose cotransporter 2 inhibitors (SGLT2i) are the latest antidiabetic treatments that reduce renal glucose reabsorption in the proximal convoluted tubule, leading to increased urinary glucose excretion [2,3].EMPA-REG outcome (2015), CANVAS (2017) and DECLARE-TIMI (2019) trials demonstrates the efficacy of SGLT2i in mortality and cardiovascular outcomes and determinate the safety of this pharmacological group, but include patients with a mean age less than 70 years [4][5][6].
We conducted this study to analyze tolerability and safety related to SGLT2i in very elderly (> 75 years) T2DM patients.

MATERIAL AND METHODS
We conducted a retrospective study of patients treated with SGLT2i in our community (La Rioja) since 2014.All patients older than 75 years (very elderly) were included, excluding those whose follow-up was not performed.Data was collected by the Department of Pharmacy Inspection of the community of La Rioja.Demographic information (age and sex), comorbidities (obesity, diabetes mellitus up to 10 years, target organ damage, hypertension, atrial fibrillation, heart failure, chronic kidney disease, history of cerebrovascular disease and cardiovascular disease) antidiabetic treatment [metformin, repaglinide, sulfonylurea, thiazolinediones, Dipeptidyl peptidase 4 inhibitors (DPP4i), Glucagon-like peptide-1 receptor agonists (GLP1a) and insulin] at the time of inclusion and at 24 months, the type of SGLT2i and the maximum dose were registered.To assess the tolerability of SGLT2i treatment adverse reactions (hypoglycemia, acute kidney injury, ketoacidosis, weight loss, hypotension, urinary and genital infection) and interruption cause were recorded.Values of Hb1Ac, creatinine and glomerular filtrate performed at inclusion, 12 and 24 months were registered.To assess prognosis, mortality during follow-up, HF decompensation (hospital admission and emergency assistance) and cardiovascular diseases during 24 months before SGLT2i treatment were recorded.
Normally distributed continuous variables were expressed as mean ± standard deviation (SD).If the variables were not normally distributed, median values with an interquartile range were used.Categorical variables were expressed as numbers and percentages.We analyzed normally distributed continuous variables by Student's t-test, proportions by χ2 test, and continuous variables with skewed distribution by Mann-Whitney test.The strength of the association between the outcome variable (mortality) and each variable considered was assessed by means of odds ratios (ORs) and their 95% confidence intervals (95% CIs).The P-values for all tests were two-sided, and statistical significance was set at P < 0.05.Statistical analysis was performed with SPSS version 22 (SPSS, Chicago, IL, USA).

DISCUSSION
Aging may influence the efficacy of SGLT2i due to the decrease in glomerular filtration rate and age-dependent reduction of SGLT2 expression [8].In the main trials that study the cardiovascular benefits of SGLT2i, less than 10% of the participants were older than 75 years, even knowing that T2DM is a very frequent entity in patients of this age [9][10][11].The efficacy profile and adverse reactions due to SGLT2i do not change with age, not even in elderly (> 65 years old) or very elderly patients [12].Adverse events were lower in our study compared to those described in the literature, reaching more than 50% with canagliflozin and empagliflozin trials [10,11].Several factors influence the increase in genitourinary infections in very elderly patients, such as menopause, urinary retention, prostatic hypertrophy, increased postvoid residual urine, urinary incontinence and increased comorbidities [13].The most described adverse event was genitourinary infections, with a much higher frequency in our real life study compared to previous trials, but without requiring SGLT2i treatment suspension [9][10][11].
On the other hand, the frequency of acute kidney injury and hypoglycemia was lower, not reaching 1% in our study in contrast to previously published, probably due to the low rate of treatment with sulfonylureas and insulin in our patients [9][10][11].Most of the patients showed a glomerular filtration rate greater than 60 ml/min/1.73m2,with a slight worsening of renal function during the first year, improved after two years of treatment, similar to younger patients.The mean age of our patients and the low proportion of adverse effects and treatment suspension of SGLT2i, demonstrate the safety of this pharmacological group in very elderly patients.On the other hand, the Hb1Ac values of our patients were similar to previous trials, with a greater decrease throughout the follow-up, which demonstrates the efficacy of SGLT2i in patients older than 75 years [9][10][11].
In conclusion, SGLT2i treatment is effective, safe, and well tolerated in very elderly patients in real life.Despite the fact that genitourinary infections are the most frequent adverse events, they do not imply treatment interruptions.