Glycemic control and use of glucose-lowering medications in hospital-admitted type 2 diabetes patients over 80 years

Treatment guidelines for type 2 diabetes (T2D) recommend avoidance of hypoglycemia and less stringent glycemic control in older patients. We examined the relation of glycemic control to glucose-lowering medications use in a cohort of patients aged>80 years with a diagnosis of T2D and a hospital admission in the Capital Region of Denmark in 2012–2016. We extracted data on medication use, diagnoses, and biochemistry from the hospitals’ records. We identified 5,172 T2D patients with high degree of co-morbidity and where 17% had an HbA1c in the range recommended for frail, comorbid, older patients with type 2 diabetes (58–75 mmol/mol (7.5–9%)). Half of the patients (n = 2,575) had an HbA1c <48 mmol/mol (<6.5%), and a majority of these (36% of all patients) did not meet the diagnostic criteria for T2D. Of patients treated with one or more glucose-lowering medications (n = 1,758), 20% had HbA1c-values <42 mmol/mol (<6%), and 1% had critically low Hba1c values <30 mmol/mol (<4.9%), In conclusion, among these hospitalized T2D patients, few had an HbA1c within the generally recommended glycemic targets. One third of patients did not meet the diagnostic criteria for T2D, and of the patients who were treated with glucose-lowering medications, one-fifth had HbA1c-values suggesting overtreatment.


Discussion
Based on hospital electronic health records covering the entire population of the Capital Region of Denmark (1.8 million inhabitants) from 2012 to 2016, we investigated the demographics and the degree of glycemic control in relation to glucose-lowering medications in patients with type 2 diabetes aged 80 years or more. Our main findings were (1) almost half of the patients had an HbA 1c <48 mmol/mol (<6,5%), and of these 72% (n = 1865, 36% of all patients) were not treated with a glucose-lowering medication and thus did not fulfil the diagnostic criteria of type 2 diabetes; (2) of the patients treated with one or more glucose-lowering medications (often including insulin and/or sulphonylureas), 20% had HbA 1c -values below 42 mmol/mol (6%) and 1% had critically low HbA 1c values <30 mmol/mol (<4.9%), indicating overtreatment. Conversely, 8% of all patients had Hba1c values >75 mmol/mol (>9%), indicating possible undertreatment.
A surprising finding was that based on HbA 1c -value, 36% (n = 1,865) of all the admitted patients did meet the criteria for their diagnosis of type 2 diabetes. The diagnoses were all registered by a physician authorized in Denmark and could have been registered many years prior to the index admission. Thus, one potential explanation for our finding could be that type 2 diabetes is not a chronic disease but rather a condition that may in some cases remit with old age -a notion that has been proposed before 32,33 . Hence, Abdelhafiz et al. proposed that frailty among older people with type 2 diabetes might lead to the remission of type 2 diabetes with the suggested mechanisms being weight loss accompanied by reduced amounts of visceral fat and thereby improved insulin sensitivity 32 . Such a mechanism bears resemblance to that described for patients having bariatric surgery and/or substantial weight loss and afterwards experience remission of their type 2 diabetes 34   www.nature.com/scientificreports www.nature.com/scientificreports/ We report that only 17% of included patients had an HbA 1c between 58-75 mmol/mol (7.5-9%), the interval generally recommended for elderly with significant comorbidities and limited life expectancy. That our patients were indeed highly comorbid is evidenced by the Charlson comorbidity score, where 94% scored 2 or more 36 . Of those with an HbA 1c <42 mmol/mol (<6.0%), 25% were treated with one or more glucose-lowering medications. These findings are in line with findings from other studies that have raised concerns about the potential overtreatment of older people with type 2 diabetes 12,23,24,37-39 . Among these is a large register-based study by Tseng et al. including 652,738 patients from the Veteran Health Administration. They reported that approximately 50% of patients aged 75 years or older, who were treated with insulin and/or sulphonylureas, had an HbA 1c <53 mmol/mol (<7%) 12 . Similarly, results from The Fremantle Diabetes Cohort Study, which included 367 patients over the age of 75 with type 2 diabetes showed that approximately three of five (61%) of the patients had an HbA 1c <53 mmol/mol (<7%) 37 . As treatment needs to be individualized according to a patient's preferences and resources as well as life expectancy it is of interest that in our cohort dementia was registered as a diagnosis for 16% and non-skin malignancy for 19% of the included patients. Studies of frail patients with type 2 diabetes and limited life expectancy, such as nursing home residents, have suggested that particularly elderly with dementia are overtreated with glucose-lowering medications. Thus, in a nursing home population, 46-74% of the patients had an HbA 1c <53 mmol/mol (<7%) 24,39,40 . Although the distributions of Hba 1c -values in the mentioned nursing home studies were similar to ours, cognitive and functional impairment may be more frequent in the nursing home setting. One percent (n = 70) of our population had hypoglycemia as the primary cause of admission. However, this is likely an underestimate of the number of patients at high risk of hypoglycemia. In older people, hypoglycemia can go undiscovered and be difficult to recognize due to unspecific symptoms 11 . Thus, the substantial proportion of patients, who in the context of near-normal Hba1c (i.e. below 42 mmol/mol (6%)) continued treatment with a sulphonylurea (n = 70) or insulin (n = 82) could be considered at high risk of hypoglycemic events 11,16 . Thus, our study adds to the evidence suggesting that the recommendations favoring looser glycemic control in elderly, comorbid people similar to our population has not been fully adopted into clinical practice.
Our study has important strengths such as the large sample size, the high data quality from rather accurate national registers with the possibility of linking biochemical data with health record data and drug use. Nonetheless, this register-based study also has some limitations. In our study, only 34% of elderly patients with a diagnosis of type 2 diabetes were treated with glucose-lowering medications. Other studies on glycemic control in older people, including the mentioned studies of nursing home residents and larger cohort studies report a much higher proportion of patients treated with glucose-lowering medication. Thus, between 85-100% of the patients received glucose-lowering medication in other cohort studies of a general population with type 2 diabetes 12,23,37 , and up to 86% were pharmacologically treated in studies investigating glycemic control in nursing home residents 24,39,40 . Our lower treatment prevalence is most likely due to the fact that many patients in our cohort did not meet the criteria for type 2 diabetes at the time of study. Since our study was based on a cohort identified by a hospital admission, and data analyses were limited to the time around hospital admission, we did not have information on the duration of diabetes or the glycemic control and use of antidiabetic medication over time. Access to this information could have strengthened our interpretation particularly the reason for the high proportion of patients not fulfilling the diagnostic criteria for type 2 diabetes. There is some indication that our cohort does not fully reflect the population in the capital region of Denmark. Thus, in our cohort, 54% were female, while the concurrent female proportion in the general population was 65%. The reason for such relative underrepresentation of females in our cohort is unclear. Another issue is that 56% had a hemoglobin below reference level, which theoretically could lead to an underestimation of the HbA 1c -values. However, as proposed by samples from another Danish population, mild to moderate anemia does not seem have significant impact on the interpretation of HbA 1c -values 41 .  www.nature.com/scientificreports www.nature.com/scientificreports/ In this hospital-based cohort consisting of more than 5000 patients, few patients ≥80 years with type 2 diabetes had an HbA 1c within the limits generally recommended for this population. Many patients were not treated with glucose-lowering medications and had HbA 1c -values that could not justify a diagnosis of type 2 diabetes. Of   www.nature.com/scientificreports www.nature.com/scientificreports/ those treated with one or more glucose-lowering medications, quite many had either high or low HbA 1c -values, suggesting under-and overtreatment, respectively. Our study supports the assumption that a diagnosis of type 2 diabetes may remit with age. Moreover, it suggests that recommendations for glycemic control in elderly patients with type 2 diabetes are not fully implemented in clinical practice.

Methods
Study cohort and data sources. The study was a retrospective cohort study using data from the Capital Region of Denmark from January 1, 2012 to May 15, 2016. We analyzed the first hospital admission for each patient, where an HbA 1c measurement in proximity to the hospital admission (±90 days) was available. On admission, patients were required to be at least 80 years of age and have a prior diagnosis of type 2 diabetes (ICD-10 code DE11). Diagnoses were obtained from the regional system feeding data to The Danish National Patient Register 42 . Drug utilization was obtained from The Electronic Patient Medication module, which is a database for in-hospital drug-use in the Capital Region of Denmark 43 . HbA 1c -values, as well as biochemical status (blood lipids (cholesterol, LDL and HDL), kidney function (creatinine, eGFR), hemoglobin levels and TSH), were gathered from The Clinical Laboratory Information System 44 . Body Mass Index (BMI) was obtained from the medical health records. Data sources were linked using the unique and permanent Danish identification number 45 . Exposure and comorbidity. Exposure to a glucose-lowering medication was defined as an active prescription of a glucose-lowering medication (Anatomical Therapeutic Chemical classification (ATC)-code A10) at the time of discharge from the hospital and with at least one administration during the hospital admission. To evaluate patient comorbidity, we used diagnoses to calculate The Charlson Comorbidity Index, which is a measure of comorbidity burden and has been shown to be correlated with life expectancy 36 .
Statistical methods. Data are presented using standard descriptive statistics including median and interquartile ranges. Data management was conducted using R 46 . ethics. According

Data availability
The dataset used in this study is not available due to local law.  Table 4. Antidiabetic medication at the time of hospital discharge in relation to HbA 1c -values (obtained ±90 days before hospital admission) for very old patients with type 2 diabetes. Values are displayed in absolute numbers. HbA 1c -values are divided into categories and displayed in mmol/mol. Patients count more than once if administered more than one kind of antidiabetic. DPP-4i: dipeptidylpeptidase-4 inhibitor, SGLT-2i: sodiumglucose cotransporter-2 inhibitor, SU: sulfonylurea, GLP-1RA: Glucagon-like peptide-1 receptor agonist.