The Reasons for the Low Uptake of New Antidiabetic Drugs with Cardiovascular Effects-A Family Doctor Perspective.

Chronic diseases, such as type 2 diabetes (T2D), are difficult to manage because they demand continuous therapeutic review and monitoring. Beyond achieving the target HbA1c, new guidelines for the therapy of T2D have been introduced with the new groups of antidiabetics, glucagon-like peptide-1 receptor agonists (GLP-1ra) and sodium-glucose cotransporter-2 inhibitors (SGLT2-in). Despite new guidelines, clinical inertia, which can be caused by physicians, patients or the healthcare system, results in T2D not being effectively managed. This opinion paper explores the shift in T2D treatment, challenging assumptions and evidence-based recommendations, particularly for family physicians, considering the patient's overall situation in decision-making. We looked for the possible reasons for clinical inertia and the poor application of guidelines in the management of T2D. Guidelines for antidiabetic drugs should be more precise, providing case studies and clinical examples to define clinical contexts and contraindications. Knowledge communication can improve confidence and should include clear statements on areas of decision-making not supported by evidence. Precision medicine initiatives in diabetes aim to identify subcategories of T2D patients (including frail patients) using clustering techniques from data science applications, focusing on CV and poor treatment outcomes. Clear, unconditional recommendations for personalized T2D management may encourage drug prescription, especially for family physicians dealing with diverse patient contexts and clinical settings.

Influence of Age, Gender, Frailty, and Body Mass Index on Serum IL-17A Levels in Mature Type 2 Diabetic Patients.

BACKGROUND The cytokine IL-17A is emerging as a marker of chronic inflammation in cardio-metabolic conditions. This study aimed to identify relevant factors that in older primary care patients with type 2 diabetes (T2D) could influence serum IL-17A concentrations. The results have a potential to improve risk stratification and therapy options for these patients. MATERIAL AND METHODS The study was conducted during a period of 4 months, in 2020, in the south-eastern region of Croatia. Patients from primary health care, diagnosed with T2D (N=170, M: F 75: 95, ≥50 years old), were recruited at their visits. Those with malignant diseases, on chemotherapy or biological therapy, with amputated legs, or at hemodialysis, were excluded. The multinomial regression models were used to determine independent associations of the groups of variables, indicating sociodemographic and clinical characteristics of these patients, with increasing values (quartiles) of serum IL-17A. RESULTS The regression models indicated the frailty index and sex bias are the key modifying factors in associations of other variables with IL-17A serum values. CONCLUSIONS Sex bias and the existence of different frailty phenotypes could be the essential determining factors of the serum IL-17A levels in community-dwelling patients with T2D age 50 years and older. The results support the concept of T2D as a complex disorder.

A Critical Appraisal of the Diagnostic and Prognostic Utility of the Anti-Inflammatory Marker IL-37 in a Clinical Setting: A Case Study of Patients with Diabetes Type 2.

BACKGROUND: The role of the cytokine interleukin-37 (IL-37) has been recognized in reversing inflammation-mediated metabolic costs. The aim was to evaluate the clinical utility of this cytokine as a diagnostic and prognostic marker in patients with type 2 diabetes (T2D). METHODS: We included 170 older (median: 66 years) individuals with T2D (females: 95) and classified as primary care attenders to assess the association of factors that describe patients with plasma IL-37 levels (expressed as quartiles) using multinomial regression models. We determined the diagnostic ability of IL-37 cut-offs to identify diabetes-related complications or patient subgroups by using Receiver Operating Characteristic analysis (c-statistics). RESULTS: Frailty status was shown to have a suppressive effect on IL-37 circulating levels and a major modifying effect on associations of metabolic and inflammatory factors with IL-37, including the effects of treatments. Situations in which IL-37 reached a clinically significant discriminating ability included the model of IL-37 and C-Reactive Protein in differentiating among diabetic patients with low-normal/high BMI ((<25/≥25 kg/m2), and the model of IL-37 and Thyroid Stimulating Hormone in discriminating between women with/without metabolic syndrome. CONCLUSIONS: The study has revealed limitations in using classical approaches in determining the diagnostic and prognostic utility of the cytokine IL-37 in patients with T2D and lain a foundation for new methodology approaches.

Cross-Talk between the Cytokine IL-37 and Thyroid Hormones in Modulating Chronic Inflammation Associated with Target Organ Damage in Age-Related Metabolic and Vascular Conditions.

Chronic inflammation is considered to be the main mechanism contributing to the development of age-related metabolic and vascular conditions. The phases of chronic inflammation that mediate the progression of target organ damage in these conditions are poorly known, however. In particular, there is a paucity of data on the link between chronic inflammation and metabolic disorders. Based on some of our own results and recent developments in our understanding of age-related inflammation as a whole-body response, we discuss the hypothesis that cross-talk between the cytokine IL-37 and thyroid hormones could be the key regulatory mechanism that justifies the metabolic effects of chronic tissue-related inflammation. The cytokine IL-37 is emerging as a strong natural suppressor of the chronic innate immune response. The effect of this cytokine has been identified in reversing metabolic costs of chronic inflammation. Thyroid hormones are known to regulate energy metabolism. There is a close link between thyroid function and inflammation in elderly individuals. Nonlinear associations between IL-37 and thyroid hormones, considered within the wider clinical context, can improve our understanding of the phases of chronic inflammation that are associated with target organ damage in age-related metabolic and vascular conditions.

Clustering Inflammatory Markers with Sociodemographic and Clinical Characteristics of Patients with Diabetes Type 2 Can Support Family Physicians' Clinical Reasoning by Reducing Patients' Complexity.

Diabetes mellitus type 2 (DM2) is a complex disease associated with chronic inflammation, end-organ damage, and multiple comorbidities. Initiatives are emerging for a more personalized approach in managing DM2 patients. We hypothesized that by clustering inflammatory markers with variables indicating the sociodemographic and clinical contexts of patients with DM2, we could gain insights into the hidden phenotypes and the underlying pathophysiological backgrounds thereof. We applied the k-means algorithm and a total of 30 variables in a group of 174 primary care (PC) patients with DM2 aged 50 years and above and of both genders. We included some emerging markers of inflammation, specifically, neutrophil-to-lymphocyte ratio (NLR) and the cytokines IL-17A and IL-37. Multiple regression models were used to assess associations of inflammatory markers with other variables. Overall, we observed that the cytokines were more variable than the marker NLR. The set of inflammatory markers was needed to indicate the capacity of patients in the clusters for inflammatory cell recruitment from the circulation to the tissues, and subsequently for the progression of end-organ damage and vascular complications. The hypothalamus-pituitary-thyroid hormonal axis, in addition to the cytokine IL-37, may have a suppressive, inflammation-regulatory role. These results can help PC physicians with their clinical reasoning by reducing the complexity of diabetic patients.

Low Psychological Resilience in Older Individuals: An Association with Increased Inflammation, Oxidative Stress and the Presence of Chronic Medical Conditions.

The term resilience, which has been present in science for almost half a century, stands for the capacity of some system needed to overcome an amount of disturbance from the environment in order to avoid a change to another stable state. In medicine, the concept of resilience means the ability to deal with daily stress and disturbance to our homeostasis with the intention of protecting it from disturbance. With aging, the organism becomes more sensitive to environmental impacts and more susceptible to changes. Mental disturbances and a decline in psychological resilience in older people are potentiated with many social and environmental factors along with a subjective perception of decreasing health. Distinct from findings in younger age groups, mental and physical medical conditions in older people are closely associated with each other, sharing common mechanisms and potentiating each other's development. Increased inflammation and oxidative stress have been recognized as the main driving mechanisms in the development of aging diseases. This paper aims to reveal, through a translational approach, physiological and molecular mechanisms of emotional distress and low psychological resilience in older individuals as driving mechanisms for the accelerated development of chronic aging diseases, and to systematize the available information sources on strategies for mitigation of low resilience in order to prevent chronic diseases.

Lack of Informations about COVID-19 Vaccine: From Implications to Intervention for Supporting Public Health Communications in COVID-19 Pandemic.

Lack of knowledge and mistrust towards vaccines represent a challenge in achieving the vaccination coverage required for population immunity. The aim of this study is to examine the opinion that specific demographic groups have about COVID-19 vaccination, in order to detect potential fears and reasons for negative attitudes towards vaccination, and to gain knowledge on how to prepare strategies to eliminate possible misinformation that could affect vaccine hesitancy. The data collection approach was based on online questionnaire surveys, divided into three groups of questions that followed the main postulates of the health belief theory-a theory that helps understanding a behaviour of the public in some concrete surrounding in receiving preventive measures. Ordinary least squares regression analyses were used to examine the influence of individual factors on refusing the vaccine, and to provide information on the perception of participants on the danger of COVID-19 infection, and on potential barriers that could retard the vaccine utility. There was an equal proportion of participants (total number 276) who planned on receiving the COVID-19 vaccine (37%), and of those who did not (36.3%). The rest (26.7%) of participants were still indecisive. Our results indicated that attitudes on whether to receive the vaccine, on how serious consequences might be if getting the infection, as well as a suspicious towards the vaccine efficacy and the fear of the vaccine potential side effects, may depend on participants' age (<40 vs. >40 years) and on whether they are healthcare workers or not. The barriers that make participants' unsure about of receiving the vaccine, such as a distrust in the vaccine efficacy and safety, may vary in different socio-demographic groups and depending on which is the point of time in the course of the pandemic development, as well as on the vaccine availability and experience in using certain vaccine formulas. There is a pressing need for health services to continuously provide information to the general population, and to address the root causes of mistrust through improved communication, using a wide range of policies, interventions and technologies.

Alopecia in preexisting autoimmune thyroid disease in family medicine practice: can hyperprolactinemia induce hair loss? A case report.

Management of hair loss in women presents several challenges for general practitioners, who are the first in identifying its cause and consequences in everyday clinical practice. It is usually associated with multiple secondary factors, including endocrine disorders, drug side effects, and physical or emotional stress. We report a possible pathophysiological link between hyperprolactinemia and alopecia in a patient with preexisting autoimmune thyroid disease, which has not been documented in a significant number in the literature. A 27-year-old female patient with a previous history of an autoimmune thyroid disease on hormone substitution therapy presented to a family doctor with signs of frontal alopecia that had started several months previously. On examination, frontal alopecia was confirmed. Laboratory results and thyroid ultrasound confirmed autoimmune thyroid disease, with reduced parathyroid hormone and elevated prolactin. Her female sex hormones were in the normal range. Due to elevated prolactin levels, computed tomography of the pituitary gland was performed, which excluded any brain pathology. Based on available data, there is no published systematic analysis on hyperprolactinemia-induced alopecia in previous autoimmune diseases (large cohort studies). This report indicates that, due to moderately elevated prolactin values, consideration of alternative causes and further diagnostics are necessary to exclude a prolactin-producing tumor of the pituitary gland.

Neutrophil-to-Lymphocyte Ratio as a Cardiovascular Risk Marker May Be Less Efficient in Women Than in Men.

Cardiovascular disease (CVD) is the leading cause of death in women, although traditionally, it has been considered as a male dominated disease. Chronic inflammation plays a crucial role in the development of insulin resistance, diabetes type 2 and CVD. Since studies on women were scarce, in order to improve diagnosis and treatment of CVD, there is a need to improve understanding of the role of inflammation in the development of CVD in women. The neutrophil-to-lymphocyte ratio (NLR) is an inexpensive and widely available marker of inflammation, and has been studied in cardio-metabolic disorders. There is a paucity of data on sex specific differences in the lifetime course of NLR. Men and women differ to each other in sex hormones and characteristics of immune reaction and the expression of CVD. These factors can determine NLR values and their variations along the life course. In particular, menopause in women is a period associated with profound physiological and hormonal changes, and is coincidental with aging. An emergence of CV risk factors with aging, and age-related changes in the immune system, are factors that are associated with an increase in prevalence of CVD in both sexes. The aim of this review is to comprehend the available evidence on this issue, and to discuss sex specific differences in the lifetime course of NLR in the light of immune and inflammation mechanisms.

Prescribing Analgesics to Older People: A Challenge for GPs.

BACKGROUND: Due to population aging, there is an increase in the prevalence of chronic diseases, and in particular musculoskeletal diseases. These trends are associated with an increased demand for prescription analgesics and an increased risk of polypharmacy and adverse medication reactions, which constitutes a challenge, especially for general practitioners (GPs), as the providers who are most responsible for the prescription policy. OBJECTIVES: To identify patterns of analgesics prescription for older people in the study area and explore associations between a long-term analgesic prescription and comorbidity patterns, as well as the prescription of psychotropic and other common medications in a continuous use. METHODS: A retrospective study was conducted in 2015 in eastern Croatia. Patients were GP attenders ≥40 years old (N = 675), who were recruited during their appointments (consecutive patients). They were divided into two groups: those who have been continuously prescribed analgesics (N = 432) and those who have not (N = 243). Data from electronic health records were used to provide information about diagnoses of musculoskeletal and other chronic diseases, as well as prescription rates for analgesics and other medications. Exploratory methods and logistic regression models were used to analyse the data. RESULTS: Analgesics have been continuously prescribed to 64% of the patients, mostly to those in the older age groups (50-79 years) and females, and they were indicated mainly for dorsalgia symptoms and arthrosis. Non-opioid analgesics were most common, with an increasing tendency to prescribe opioid analgesics to older patient groups aged 60-79 years. The study results indicate that there is a high rate of simultaneous prescription of analgesics and psychotropic medications, despite the intention of GPs to avoid prescribing psychotropic medications to patients who use any option with opioid analgesics. In general, receiving prescription analgesics does not exceed the prescription for chronic diseases over the rates that can be found in patients who do not receive prescription analgesics. CONCLUSION: Based on the analysis of comorbidities and parallel prescribing, the results of this study can improve GPs' prescription and treatment strategies for musculoskeletal diseases and chronic pain conditions.

Lack of Relationships Between Serum Prolactin Concentrations and Classical Cardiovascular Risk Factors in Eastern Croatian Older Adults.

BACKGROUND Relationships between serum prolactin concentrations and various CV risk factors in older adults have rarely been assessed. The aim of this study was to examine the relationships between serum prolactin concentrations and CV risk factors in older patients with multiple CV risk factors. MATERIAL AND METHODS This case-control study included 92 patients, 50-89 years old (median, 69 years), with multiple CV risk factors. We used data from general practice electronic health records and biochemical laboratory tests. Patients were divided according to categories of CV risk factors. RESULTS Serum prolactin concentrations were significantly higher in elderly people (£65 vs. >65) and in men (70.65±58.02 vs. 150.82±114.05 mIU/L), as well as in patients with lower renal function (156.70±127.23 vs. 72.53±37.25 mIU/L, the bottom vs. top quartile of creatinine clearance), higher serum homocysteine and TSH concentrations, and in those who used NSAID and statins. Parameters indicating chronic inflammation (CRP) and renal function decline (creatinine clearance) were significantly and independently correlated with increased serum prolactin concentrations in multiple regression analysis. CONCLUSIONS When assessing the relationships between prolactin and CV risk factors in older people with multiple CV risk factors, the effect of renal function decline and chronic inflammation should receive attention.