Correlations among different platelet aggregation pathways in a group of healthy volunteers.

Platelet aggregation is a complicated process mediated by different signaling pathways. As the process is highly complex and apparently redundant, the relationships between these pathways are not yet fully known. The aim of this project was to study the interconnections among seven different aggregation pathways in a group of 53 generally healthy volunteers aged 20 to 66 years. Platelet aggregation was induced with thrombin receptor activating peptide 6 (TRAP), arachidonic acid (AA), platelet activating factor 16 (PAF), ADP, collagen, thromboxane A2 analogue U46619 or ristocetin (platelet agglutination) ex vivo in fasting blood samples according to standardized timetable protocol. Additionally, some samples were pre-treated with known clinically used antiplatelet drugs (vorapaxar, ticagrelor or acetylsalicylic acid (ASA)). Significant correlations among all used inducers were detected (Pearson correlation coefficients (rP): 0.3 to 0.85). Of all the triggers, AA showed to be the best predictor of the response to other inducers with rP ranging from 0.66 to 0.85. Interestingly, the antiplatelet response to ticagrelor strongly predicted the response to unrelated drug vorapaxar (rP = 0.71). Our results indicate that a response to one inducer can predict the response for other triggers or even to an antiplatelet drug. These data are useful for future testing but should be also confirmed in patients.

What is the context?• Platelet activation is a complicated process with multiple signaling cascades involved.• A total of seven common platelet triggers (ADP, collagen, TRAP-6, PAF, arachidonic acid/AA/, ristocetin and U46619) were tested.• The process is dependent on many factors including sex, age, concomitant disease(s), pharmacotherapy.What is new?• There were significant correlations between all tested aggregatory cascades.• AA has the highest rate of response predictability in our heterogeneous generally healthy volunteer group.• There was no correlation between impedance aggregometry in whole blood and turbidimetric measurement with platelet-rich plasma.What is the impact?• The effect of antiplatelet drugs can be assessed from the reaction to different trigger(s) at least in this group of healthy patients.• Future studies must test these relationships in patients with different diseases.

The Effect of 4-Methylcatechol on Platelets in Familial Hypercholesterolemic Patients Treated with Lipid Apheresis and/or Proprotein Convertase Subtilisin Kexin 9 Monoclonal Antibodies.

Elevated low-density lipoprotein (LDL) cholesterol levels lead to atherosclerosis and platelet hyperaggregability, both of which are known culprits of arterial thrombosis. Normalization of LDL cholesterol in familial hypercholesterolemia (FH) is not an easy task and frequently requires specific treatment, such as regularly performed lipid apheresis and/or novel drugs such as proprotein convertase subtilisin kexin 9 monoclonal antibodies (PCSK9Ab). Moreover, a high resistance rate to the first-line antiplatelet drug acetylsalicylic acid (ASA) stimulated research of novel antiplatelet drugs. 4-methylcatechol (4-MC), a known metabolite of several dietary flavonoids, may be a suitable candidate. The aim of this study was to analyse the antiplatelet effect of 4-MC in FH patients and to compare its impact on two FH treatment modalities via whole-blood impedance aggregometry. When compared to age-matched, generally healthy controls, the antiplatelet effect of 4-MC against collagen-induced aggregation was higher in FH patients. Apheresis itself improved the effect of 4-MC on platelet aggregation and blood from patients treated with this procedure and pretreated with 4-MC had lower platelet aggregability when compared to those solely treated with PCKS9Ab. Although this study had some inherent limitations, e.g., a low number of patients and possible impact of administered drugs, it confirmed the suitability of 4-MC as a promising antiplatelet agent and also demonstrated the effect of 4-MC in patients with a genetic metabolic disease for the first time.

Sex-Related Differences in Platelet Aggregation: A Literature Review Supplemented with Local Data from a Group of Generally Healthy Individuals.

The process of platelet aggregation is often influenced by several factors including sex and age. A literature review confirmed the existence of sex-related differences in platelet aggregation. Although 68 out of 78 papers found such differences, there are still some controversies regarding these differences, which can be due to multiple factors (age, trigger, concomitant disease, sample handling, etc.). These outcomes are discussed in line with novel results obtained from a local study, in which blood samples from a total of 53 overall healthy women and men with ages ranging from 20 to 66 years were collected. Aggregation was induced with seven different triggers (ristocetin, thrombin receptor activating peptide 6 [TRAP-6], arachidonic acid [AA], platelet-activating factor 16 [PAF-16], ADP, collagen, or thromboxane A2 analog U-46619) ex vivo. In addition, three FDA-approved antiplatelet drugs (vorapaxar, ticagrelor, or acetylsalicylic acid [ASA]) were also tested. In general, women had higher aggregation responses to some agonists (ADP, TRAP), as well as lower benefit from inhibitors (ASA, vorapaxar). The aggregatory responses to AA and TRAP decreased with age in both sexes, while responses to ADP, U-46619, and PAF were affected by age only in women. In conclusion, more studies are needed to decipher the biological importance of sex-related differences in platelet aggregation in part to enable personalized antiplatelet treatment.

The Antiplatelet Effect of 4-Methylcatechol in a Real Population Sample and Determination of the Mechanism of Action.

A polyphenol-rich diet has beneficial effects on cardiovascular health. However, dietary polyphenols generally have low bioavailability and reach low plasma concentrations. Small phenolic metabolites of these compounds formed by human microbiota are much more easily absorbable and could be responsible for this effect. One of these metabolites, 4-methylcatechol (4-MC), was suggested to be a potent anti-platelet compound. The effect of 4-MC was tested ex vivo in a group of 53 generally healthy donors using impedance blood aggregometry. The mechanism of action of this compound was also investigated by employing various aggregation inducers/inhibitors and a combination of aggregometry and enzyme linked immunosorbent assay (ELISA) methods. 4-MC was confirmed to be more potent than acetylsalicylic acid on both arachidonic acid and collagen-triggered platelet aggregation. Its clinically relevant effect was found even at a concentration of 10 µM. Mechanistic studies showed that 4-MC is able to block platelet aggregation caused by the stimulation of different pathways (receptors for the von Willebrand factor and platelet-activating factor, glycoprotein IIb/IIIa, protein kinase C, intracellular calcium elevation). The major mechanism was defined as interference with cyclooxygenase-thromboxane synthase coupling. This study confirmed the strong antiplatelet potential of 4-MC in a group of healthy donors and defined its mechanism of action.

The efficacy and safety of dapagliflozin in women and men with type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Women remain underrepresented in clinical trials and those with type 2 diabetes mellitus are at high risk for cardiovascular (CV) events. The sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin reduces the risk of CV death or heart failure hospitalisations in individuals with type 2 diabetes. Here, we performed a pre-specified analysis to examine whether sex modifies these effects. METHODS: The DECLARE-TIMI 58 trial randomised 17,160 patients with type 2 diabetes with or at risk for atherosclerotic disease to dapagliflozin or placebo (median follow-up 4.2 years). The dual efficacy outcomes were CV death or heart failure hospitalisations, and major adverse cardiovascular events (MACE; CV death, myocardial infarction or ischaemic stroke). The renal-specific composite outcome was a sustained ≥40% drop in eGFR to <60 ml min-1 [1.73 m]-2, new end-stage renal disease or renal death. Cox models were run separately by sex with treatment-by-sex interaction testing for each outcome. RESULTS: At baseline, women (n = 6422, 37.4%) had higher HbA1c, longer type 2 diabetes duration, and were on fewer glucose-lowering medications. There was no evidence of modification of the effect of dapagliflozin by sex for (1) CV death or heart failure hospitalisations: women (3.8% vs 4.5%; HR 0.84, 95% CI 0.66, 1.07) and men (5.3% vs 6.4%; HR 0.83, 95% CI 0.71, 0.96; pinteraction = 0.90); (2) MACE: women (6.3% vs 6.8%; HR 0.93, 95% CI 0.77, 1.12) and men (10.0% vs 10.7%; HR 0.93, 95% CI 0.83, 1.05; pinteraction = 0.99); or (3) renal-specific composite: women (1.4% vs 2.8%; HR 0.50, 95% CI 0.35, 0.70) and men (1.5% vs 2.5%; HR 0.55, 95% CI 0.42, 0.73; pinteraction = 0.64). The overall safety profile of dapagliflozin was similar for women and men. CONCLUSIONS/INTERPRETATION: Dapagliflozin offers comparable CV and renal benefits and a comparable safety profile in women and men. FUNDING: AstraZeneca. TRIAL REGISTRATION: clinicaltrials.gov NCT01730534.

Metformin -associated lactic acidosis.

Lactic acidosis is a feared complication of metformin therapy. In our article we describe 2 case reports of patients treated with metformin, who developed this complication. In the first case, which was fatal, cummulation of lactate was a result of acute kidney failure caused by diarrhea. In the second patient, lactic acidosis developed in the terrain of preexisting chronic kidney disease, when dyspepsia and decreased fluid intake caused progression into acute kidney failure. In this case, treatment of lactic acidosis was successful. Death of the first patient was probably caused by the presence of serious comorbidities and other complications which developed early after her addmission to intensive care unit. Lactic acidosis can be prevented by strict avoidance of metformin use in case of contraindications and interruption of its use during intercurrent disease.

Diabetes mellitus in complex older patients.

Care of the elderly diabetic patients requires a special approach. What must be considered is not only individualiza-tion, and in more fragile elderly patients easing the targets for long-term compensation of diabetes, but also appropriate antidiabetic therapy needs to be chosen. Most patients suffer from polymorbidity and are at a greater risk for occurrence and consequences of hypoglycemia and cognitive impairment. The treatment procedure for sturdy elderly patients with diabetes is not any different from younger patients, while appropriate drugs for fragile patients are gliptins, possibly in combination with a long-term insulin analogue. Key words: antidiabetic therapy - complications - diabetes mellitus - level of robustness - old age.

[Diabetes mellitus and cognitive disorders from the diabetologists perspective]. / Diabetes mellitus a poruchy kognice z pohledu diabetologa.

Diabetes mellitus is associated with cognitive impairment which may convert to vascular or neurodegenerative dementia. Impairment of cognitive functions affects patients with type 1 and especially type 2 diabetes, with a number of vascular, metabolic and psychosocial factors involved in its development. As hyperglycemia and hypoglycemia also play an important role, important is the correct strategy of diabetes therapy which utilizes a combination of metformin with modern safe antidiabetics (incretin drugs, gliflozins, insulin analogues). It seems that some antidiabetic drugs (metformin, incretin drugs) and nasal form of application of insulin could improve cognition in diabetics.Key words: antidiabetic drugs - diabetes mellitus - hyperglycemia - hypoglycemia - cognition.

[Diabetes mellitus in older adults from the point of view of the clinical diabetologist]. / Diabetes mellitus ve starsím veku z pohledu klinického diabetologa.

Disorders of glucose homeostasis affect quite a large part of the older population and their incidence including manifest diabetes is growing. Diabetes in older adults is associated with an increased risk of geriatric syndrome expressed in various ways (decrease in muscle size, functional disability, frailty) and early mortality. Diabetes care for the elderly requires, also in view of heterogeneity of diabetes itself, an individual specific approach. This involves not only diagnostics and a clinical picture, but also the treatment goals and the therapy of diabetes and complications in itself. Diabetes treatment includes both regimen adjustments and use of antidiabetic drugs in different combinations and regimens in accordance with up-to-date specialist recommendations.Key words: treatment goals - diabetes mellitus - pharmacological therapy - age.

[Victoza changes diabetes and lives of patients 5 years already]. / Victoza mení diabetes a zivoty pacientu jiz 5 let.

Victoza (liraglutide) is a modern antidiabetic drug of GLP1 (glucagone like peptide) analogue group; since 2009 registered in Czech republic. VICTOZA is used in therapy of type 2 diabetic patients with preserved endougenous insulin secretion, usually in combination with other peroral antidiabetic drugs or with basal insulin. VICTOZA is applied once a day subcutaneously. The characteristical antidiabetic effect with ß cell protection is enhanced with supportive weigth reduction effect. Positive cardiovascular influence is expected, however data from recent studies are not available at this time. In clinical practice, the mild upper dyspepsia after initiation of therapy is the most common side effect, usually subsiding in several days. Alltogether, VICTOZA is a well tolerated antidiabetic medication decreasing glycated hemoglobin up to 15 mmol/l with minimal risk of hypoglycaemia.

[History of insulin production in Czechoslovakia]. / Historie výroby inzulinu v Ceskoslovensku.

The aim of the article is an effort to capture the history of insulin production in Czechoslovakia. Information has been obtained mainly from two Czech journals: "Casopis lékaru ceských" (published since 1862) and "Praktický lékar" (published since 1921). At first, imported insulin in the form of insulin injections or substances from which insulin was prepared appeared at the market in Czechoslovakia. During years 1923-1945, insulin was produced by five companies, since 1945 only by one company "Léciva".

[Perioperative care and diabetes]. / Perioperacní péce a diabetes.

The perioperative care of diabetic patients is specific due to the necessity of adequate glycaemic correction, as well as owing to the occurrence of complications not taking place in nondiabetic patients. The present antidiabetic treatment therefore mostly needs to be adjusted to the perioperative period, but this is largely not necessary in the case of small and short surgeries. The perioperative care of diabetic patients must be carefully organized and scheduled. The main rules include adequate monitoring of blood glucose and insulin therapy, provision of nutrition and surgery performance in the morning.Key words: antidiabetic treatment - perioperative care of the diabetic patient.

Fat- and fiber-related diet behavior among type 2 diabetes patients from distinct regions.

PURPOSE: Diet and eating habits are of key importance in patients with type 2 diabetes mellitus (T2DM). The purpose of this comparative study was to analyze fat- and fiber-related behavior (FFB) in patients with T2DM from distinct cultural areas. PATIENTS AND METHODS: Observational study was carried out in the Czech Republic (CR) (n=200), the US (n=207), and Yemen (n=200). Patients completed the Fat- and Fiber-related Diet Behavior Questionnaire (FFBQ). RESULTS: Differences in all aspects of FFB among countries were found (P<0.05). The best fat-related behavior reported was from patients from the CR. Patients from the US showed the worst fat-related behavior in total. On the other hand, patients from the US reported the best fiber-related behavior. Patients from Yemen reached the worst scores in all fat-related domains. Patients from all studied countries reported the best results in the "modify meat" and "avoid fat as flavoring" and the worst in the "substitute high fiber" subscales. CONCLUSION: Professionals involved in the diet education of T2DM patients should be aware of the specificity of diet in their country when advising patients keeping general recommendations. We suggest them to be as specific as possible and concentrate on fiber-related behavior.

Efficacy and safety of saxagliptin in older participants in the SAVOR-TIMI 53 trial.

OBJECTIVE: To examine the safety and cardiovascular (CV) effects of saxagliptin in the predefined elderly (≥65 years) and very elderly (≥75 years) subpopulations of the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial. RESEARCH DESIGN AND METHODS: Individuals ≥40 years (n = 16,492; elderly, n = 8,561; very elderly, n = 2,330) with HbA1c ≥6.5% (47.5 mmol/mol) and ≤12.0% (107.7 mmol/mol) were randomized (1:1) to saxagliptin (5 or 2.5 mg daily) or placebo in a double-blind trial for a median follow-up of 2.1 years. RESULTS: The hazard ratio (HR) for the comparison of saxagliptin versus placebo for the primary end point (composite of CV mortality, myocardial infarction, or ischemic stroke) was 0.92 for elderly patients vs. 1.15 for patients <65 years (P = 0.06) and 0.95 for very elderly patients. The HRs for the secondary composite end points in the entire cohort, elderly cohort, and very elderly cohort were similar. Although saxagliptin increased the risk of hospitalization for heart failure in the overall saxagliptin population, there was no age-based treatment interaction (P = 0.76 for elderly patients vs. those <65 years; P = 0.34 for very elderly patients vs. those <75 years). Among saxagliptin-treated individuals with baseline HbA1c ≥7.6% (59.6 mmol/mol), the mean change from baseline HbA1c at 2 years was -0.69%, -0.64%, -0.66%, and -0.66% for those ≥65, <65, ≥75, and <75 years old, respectively. The incidence of overall adverse events (AEs) and serious AEs was similar between saxagliptin and placebo in all cohorts; however, hypoglycemic events were higher for saxagliptin versus placebo regardless of age. CONCLUSIONS: The SAVOR-TIMI 53 trial supports the overall CV safety of saxagliptin in a robust number of elderly and very elderly participants, although the risk of heart failure hospitalization was increased irrespective of age category. AEs and serious AEs as well as glycemic efficacy of saxagliptin in elderly patients are similar to those found in younger patients.

[Diabetes mellitus and malignancies]. / Diabetes mellitus a zhoubné nádory.

The epidemiological studies have proven an increased incidence of cancer in patients with diabetes and the ne-gative effect of diabetes on their prognosis. The relation to type 2 diabetes was found in hepatic, pancreatic and endometrial malignancies, in colorectal, breast and bladder cancers. Diabetes as well as malignancies are multifactorial diseases with a number of common risk factors: age, gender, race, overweight and obesity, diet, physical activity. A higher incidence of malignancies in diabetic patients is not only a result of sharing these risk factors, as diabetes itself predisposes to carcinoma development. Possible mechanisms producing this effect include hyperinsulinemia, hyperglycemia, oxidative stress, chronic inflammation, obesity related factors and effect of diabetic complications. The development of malignancies in diabetics is also affected by the diabetes treatment. Exogenous insulin and its analogues and stimulators of insulin secretion are linked to an increased risk of cancer while insulin sensitizers to its decrease. Special attention is given to metformin which, apart from the indirect effect by influencing the levels of insulin and glycemia, has a direct anticancerogenic effect. In the clinical practice, it is ne-cessary to give attention to the screening of diabetes related tumours, consistent glycemic control and choice of appropriate diabetes treatment in patients with a high cancer risk.Key words: clinical practice - diabetes mellitus - effects of diabetes treatment - malignancies.

[History of diabetes treatment in Czechoslovakia prior to 1989]. / Historie lécby diabetu v Ceskoslovensku do roku 1989.

The article aims to outline the historical development of treatment of diabetes in Czechoslovakia. Information has been obtained mainly from two Czech journals, Casopis lékaru ceských (The Journal of Czech Physicians, published since 1862) and Praktický lékar (The General Practitioner, published since 1921). Until the discovery of insulin, the treatment of diabetes was based on the use of different diets and a great benefit was obtained by spa treatment. In 1923, imported insulin appeared on the market in Czechoslovakia; insulin injections or substances from which insulin was prepared. In the years 1923-1945, insulin was produced by five companies, then insulin and oral antidiabetics were manufactured just by one firm Léciva (Pharmaceuticals).

[Diabetes mellitus and pancreatic cancer - cause or result?]. / Inkretinová mimetika v lécbe diabetu 2. typu.

Incretin glucagon like peptid-1 receptor agonists are also known as incretin mimetics. These are the new drugs for the treatment of type 2 diabetes, which have a significant antihyperglycemic effect. For the individual treatment can be used short- acting and long-acting drugs. In addition to glucose effect there are influenced another factors, especially weight and hypertension. The patophysiological mechanism of their action, pharmacological and clinical differences and their use in clinical practice are described.Key words: glucagon-like peptid 1 - glucagon-like peptid 1 agonists short-acting/long-acting - clinical effects.

An analysis of fat-related and fiber-related behavior in men and women with type 2 diabetes mellitus: key findings for clinical practice.

BACKGROUND: Despite the efforts of health care providers, adherence of patients with type 2 diabetes to the recommended diet is poor. The aim of this study was to describe the eating habits with emphasis on fat and fiber-related behavior (FFB) as well as the relationship between FFB behavior and parameters of diabetes control in men and women with type 2 diabetes mellitus. METHODS: The subjects in this observational cross-sectional study were 200 patients (54.5% male, mean age 66.2 ± 10.1 years, mean Diabetes Control and Complications Trial [DDCT] glycosylated hemoglobin [HbA1c] 7.6% ± 1.7%) recruited from diabetes outpatient clinics in the Czech Republic. The subjects filled out the Fat- and Fiber-related Diet Behavior Questionnaire. The most recent patient data on diabetes control and drug therapy were derived from patient medical records. RESULTS: Patients tend to modify the dishes they are used to, rather than remove them completely from their diet and replace them by other types of foods. It is easier to perform healthier fat-related behaviors than fiber-related ones. Women scored significantly better than men on the fat-related diet habits summary scale (P = 0.002), as well as on "modify meat" (P = 0.001) and "substitute specially manufactured low-fat foods" (P = 0.045) subscales. A better score on the fat-related diet habits summary scale was significantly associated with higher HbA1c (ρ = -0.248; P = 0.027) and higher waist circumference (ρ = -0.254; P = 0.024) in women. CONCLUSION: Type 2 diabetes patients are likely to vary in their FFB behavior, and their dietary habits depend on gender. Health care professionals should pay attention to these facts when providing specific education. Emphasis should be placed on how to increase the fiber intake in diabetic patients.

Adherence in adults with type 1 diabetes mellitus correlates with treatment satisfaction but not with adverse events.

PURPOSE: Diabetes self-care and self-monitoring adherence has a positive effect on the metabolic control of the disease. The aim of this study was to analyze the adherence to self-care recommendations and to identify its correlates in adults with type 1 diabetes mellitus. PATIENTS AND METHODS: One hundred and eleven patients with type 1 diabetes were enrolled in an observational cross-sectional study conducted at the Diabetes Center of the University Hospital in Hradec Králové, Czech Republic. Diabetes self-care adherence was measured by the Self Care Inventory-Revised, and treatment satisfaction by the Diabetes Treatment Satisfaction Questionnaire-status version. Additional data were collected from self-administered questionnaires and medical records. The Mann-Whitney test, Spearman correlations, and multiple linear regressions were used in the statistical analysis. RESULTS: The mean age of patients was 42.4 years; 59.5% of them were females and 53.2% of all patients used an insulin pump. The mean glycosylated hemoglobin (HbA1c) was 66.2 ± 15.3 mmol/mol and the mean insulin dosage was 0.6 ± 0.3 IU insulin/kg/day. The number of hypoglycemic episodes (including severe) that patients had in the last month before taking the survey was 3.6 ± 3.2. Self-care adherence was associated with treatment satisfaction (0.495; P = 0.004) along with frequency of self-monitoring of before meal blood glucose (0.267; P = 0.003). It was not associated with the incidence of hypoglycemic events or any other insulin therapy-related problems or with socio-demographic or clinical characteristics. CONCLUSION: Treatment satisfaction is one of the key factors that need to be targeted to maximize benefits to patients. Self-care adherence in adults with type 1 diabetes did not correlate with socio-demographic and clinical characteristics, nor with adverse events.

Effects of body fat reduction on plasma adipocyte fatty acid-binding protein concentration in obese patients with type 1 diabetes mellitus.

OBJECTIVES: The influence of body fat reduction on adipocyte fatty acid-binding protein (A-FABP) in obese patients with type 1 diabetes mellitus (T1DM) was investigated to examine whether it relates to the etiopathogenesis of insulin resistance (IR) and obesity. METHODS: We studied 14 obese patients with T1DM and IR (42.6±9.4 years, BMI 32.4±2.1 kg/m2) and 13 non-obese control patients with T1DM (36.9±13.9 years, BMI 22.6±2.1 kg/m2). Plasma FABP was measured by ELISA and plasma free fatty acids (FFA) were measured spectrophotometrically before weight reduction, immediately after 7 days of fasting and after 21 days on a low-calorie diet. The control group was studied only after overnight fasting. Body composition was examined using bioimpedance spectroscopy. The means ± SD, T-test, one-way ANOVA and Spearman's correlation were used for statistical evaluation. RESULTS: All patients tolerated the period of fasting. Obese T1DM patients lost 6.1±1.1 kg. There was a significant decrease in body mass index and body fat measured 21 days after weight reduction (p<0.05). Plasma FABP and FFA concentrations in obese T1DM patients before weight reduction were significantly higher than in controls, further increased significantly after fasting (p<0.05) and were restored thereafter. Significant positive correlations between FABP and FFA and between FABP and BMI (p<0.05) were found. CONCLUSION: Increased plasma FABP indicates insulin resistance in obese patients with T1DM. Weight reduction in T1DM patients is associated with a desirable decrease of body fat and transiently increased FABP. This increase might be a temporary adaptation of metabolism to non-stress fasting.