Milan Kvapil

Fluvastatin in the therapy of acute coronary syndrome: Rationale and design of a multicenter, randomized, double-blind, placebo-controlled trial (The FACS Trial)[ISRCTN81331696].

BackgroundActivation of inflammatory pathways plays an important contributory role in coronary plaque instability and subsequent rupture, which can lead to the development of acute coronary syndrome (ACS). Elevated levels of serum inflammatory markers such as C-reactive protein (CRP) represent independent risk factors for further cardiovascular events. Recent evidence indicates that in addition to lowering cholesterol levels, statins also decrease levels of inflammatory markers. Previous controlled clinical trials reporting the positive effects of statins in participants with ACS were designed for very early secondary prevention. To our knowledge, no controlled trials have evaluated the potential benefits of statin therapy, beginning immediately at the time of hospital admission. A previous pilot study performed by our group focused on early initiation of cerivastatin therapy. We demonstrated a highly significant reduction in levels of inflammatory markers (CRP and interleukin-6). Based on these preliminary findings, we are conducting a clinical trial to evaluate the efficacy of another statin, fluvastatin, as an early intervention in patients with ACS.MethodsThe FACS-trial (Fluvastatin in the therapy of Acute Coronary Syndrome) is a multicenter, randomized, double-blind, placebo-controlled study evaluating the effects of fluvastatin therapy initiated at the time of hospital admission. The study will enroll 1,000 participants admitted to hospital for ACS (both with and without ST elevation). The primary endpoint for the study is the influence of fluvastatin therapy on levels of inflammatory markers (CRP and interleukin-6) and on pregnancy associated plasma protein A (PAPP-A). A combined secondary endpoint is 30-day and one-year occurrence of death, nonfatal myocardial infarction, recurrent symptomatic ischemia, urgent revascularization, and cardiac arrest.ConclusionThe primary objective of the FACS trial is to demonstrate that statin therapy, when started immediately after hospital admission for ACS, results in reduction of inflammation and improvement of prognosis. This study may contribute to new knowledge regarding therapeutic strategies for patients suffering from ACS and may offer additional clinical indications for the use of statins.

Comparison of Soybean Oil- and Olive Oil-based Lipid Emulsions on Hepatobiliary Function and Serum Triacylglycerols Level during Realimentation

This study compared the effects of soybean oil- versus olive oil-based lipid emulsions on hepatobiliary function and serum triacylglycerols in patients who required transient parenteral nutrition support for significant weight loss. Patients who received a parenteral ready-to-use industry admixture including either soybean oil- (n = 10) or olive oil-based lipid emulsion (n = 11) for 2 weeks were retrospectively analysed. Cholestatic and cytolytic enzymes, conjugated bilirubin and serum triacylglycerols were sampled before and 1 day after completing parenteral nutrition support. Significant deterioration of cholestatic enzymes occurred in five patients in the soybean oil group and in one in the olive oil group. Serum triacylglycerols significantly deteriorated in seven patients in the soybean oil group and in one patient in the olive oil group. No differences were recorded for cytolytic enzyme abnormalities. In conclusion, the olive oil-based emulsion induced abnormalities of cholestatic enzymes and serum triacylglycerols significantly less frequently than the soybean oil-based emulsion.

Fluvastatin in the first-line therapy of acute coronary syndrome: results of the multicenter, randomized, double-blind, placebo-controlled trial (the FACS-trial)

BackgroundStatins have been proved to be effective in reduction of mortality and morbidity when started in the early secondary prevention in stabilized patients after acute coronary syndrome (ACS). The safety and efficacy of statin administration directly in the first-line therapy in unstable ACS patients is not clear. The aim of our study was, therefore, to assess the effect of statin treatment initiated immediately at hospital admission of patients with ACS.MethodsThe trial was stopped prematurely after enrollment of one hundred and fifty-six patients with ACS that were randomized at admission to fluvastatin 80 mg (N = 78) or placebo (N = 78). Study medication was administered immediately after randomization and then once daily for 30 days; all patients were then encouraged to continue in open-label statin therapy and at the end of one-year follow-up 75% in the fluvastatin group and 78% in the placebo group were on statin therapy.ResultsWe did not demonstrate any difference between groups in the level of C-reactive protein, interleukin 6, and pregnancy-associated plasma protein A on Day 2 and Day 30 (primary endpoint). Fluvastatin-therapy, however, significantly reduced one-year occurrence of major adverse cardiovascular events (11.5% vs. 24.4%, odds ratio (OR) 0.40, 95% CI 0.17-0.95, P = 0.038). This difference was caused mainly by reduction of recurrent symptomatic ischemia (7.7% vs. 20.5%, OR 0.32, 95% CI 0.12-0.88, P = 0.037).ConclusionsThis study failed to prove the effect of fluvastatin given as first-line therapy of ACS on serum markers of inflammation and plaque instability. Fluvastatin therapy was, however, safe and it may reduce cardiovascular event rate that supports immediate use of a statin in patients admitted for ACS.Trial registrationNCT00171275

Common carotid artery intima-media thickness is not increased but distensibility is reduced in normotensive patients with type 2 diabetes compared with control subjects.

This study evaluated carotid artery parameters in normotensive patients with type 2 diabetes compared with non-diabetic control subjects. Using a high-resolution B-mode ultrasound scanner, common carotid artery intima-media thickness (IMT) and carotid tree atheroma thickness were measured in 82 patients with type 2 diabetes and 41 controls. The distensibility of the common carotid artery was calculated using the Reneman equation. Distensibility was significantly decreased and atheroma thickness was significantly increased in the diabetes group. There was no significant difference in IMT between the two groups. Stepwise linear regression analysis revealed an association between common carotid artery distensibility and post-ischaemic dilatation of the brachial artery (a measure of endothelial function), body mass index and diabetes duration in patients with type 2 diabetes. In conclusion, common carotid artery IMT in normotensive patients with type 2 diabetes is comparable to that of control subjects, whereas atheroma thickness is higher and arterial stiffness more pronounced in those with type 2 diabetes, indicating the existence of atherosclerotic changes in normotensive type 2 diabetes patients.

A missense variant in GLP1R gene is associated with the glycaemic response to treatment with gliptins.

Gliptins act by increasing endogenous incretin levels. Glucagon‐like peptide‐1 receptor (GLP1R) and glucose‐dependent insulinotropic peptide receptor (GIPR) are their indirect drug targets. Variants of GLP1R and GIPR have previously been associated with the incretin effect. The aim of the present pilot study was to examine associations of the GLP1R and GIPR gene variants with the glycaemic response to gliptins. A total of 140 consecutive patients with type 2 diabetes were followed‐up 6 months after initiation of gliptin treatment. GLP1R rs6923761 (Gly168Ser) and GIPR rs10423928 genotyping was performed using real‐time PCR, with subsequent high‐resolution melting analysis. The main study outcome was reduction in glycated haemoglobin (HbA1c) after treatment. GLP1R Gly168Ser variant was significantly associated with reduction in HbA1c in an additive model (β = −0.33, p = 0.011). The mean reduction in HbA1c in Ser/Ser homozygotes was significantly lower compared with Gly‐allele carriers [0.12 ± 0.23% vs. 0.80 ± 0.09% (1.3 ± 2.5 mmol/mol vs. 8.7 ± 1.0 mmol/mol); p = 0.008]. In conclusion, GLP1R missense variant was associated with a reduced response to gliptin treatment. The genotype‐related effect size of ∼0.7% (8 mmol/mol) is equal to an average effect of gliptin treatment and makes this variant a candidate for use in precision medicine.

Fear of driving license withdrawal in patients with insulin-treated diabetes mellitus negatively influences their decision to report severe hypoglycemic events to physicians

Background Under current European Union legislation, two severe hypoglycemic events within 12 months is grounds for driving license withdrawal. The aim of the study reported here was to determine whether fear of such a withdrawal could lead to patients concealing severe hypoglycemia from physicians, which could negatively impact further treatment decisions. Methods A total of 663 patients with insulin-treated diabetes were anonymously surveyed about whether they would conceal severe hypoglycemic events from their physicians, if revealing them could result in driving license withdrawal. This investigation utilized an adapted and expanded questionnaire by Graveling et al. Results Of all diabetic patients surveyed, 26.17% would most likely not report hypoglycemia, and 25.86% were undecided. In a group of patients with type 1 diabetes, 31.83% would likely not report hypoglycemic events, and 25.06% were undecided. The patients least likely to report severe hypoglycemic events were those who indicated that vehicles were partly essential for work, and who also had more than two hypoglycemic events monthly. Conclusion A considerable percentage of diabetic patients would likely conceal severe hypoglycemic events from their physicians due to fear of driving license withdrawal. Patient failure to report severe hypoglycemic events can potentially lead to physicians being misinformed regarding the patient’s condition, which could lead to inadequate monitoring and treatment.

The Effect of Ramipril Therapy on Cytokines and Parameters of Incipient Diabetic Nephropathy in Patients with Type 1 Diabetes Mellitus

We compared the levels of transforming growth factor β1 (TGF-β1), vascular endothelial growth factor (VEGF) and other biochemical parameters in patients with type 1 diabetes mellitus with and without incipient diabetic nephropathy (iDN) and compared them with healthy control subjects. We also measured the effect of 3 and 6 months of ramipril treatment in diabetes patients with iDN. Compared with healthy controls, TGF-β1 levels were increased in both groups of diabetes patients, whereas VEGF was only elevated in patients with iDN. Ramipril did not have a significant effect on TGF-β1 or VEGF levels. We observed a significant decrease in microalbuminuria and cystatin C following ramipril treatment. Increased VEGF levels in patients with iDN suggest a role for this cytokine in the pathogenesis of diabetic nephropathy. Cystatin C would make a suitable marker for the screening and assessment of iDN, and for the evaluation of the therapeutic efficacy of drugs.

KCNQ1 gene polymorphism is associated with glycaemic response to treatment with DPP-4 inhibitors

AIMS Only afew gene variants were associated with the response to dipeptidylpeptidase-4 inhibitors (DPP4I). KCNQ1 gene variants were previously related both to type 2 diabetes (T2D) and incretin effect. We hypothesized that T2D related KCNQ1 variants would be associated with smaller glucose-lowering effect of DDP4I. METHODS We performed a retrospective study in 137 Caucasian subjects with T2D who were followed for 6months after initiation of DPP4I treatment. Genotyping for KCNQ1 rs163184 and rs151290 was performed using PCR-HRMA and PCR-RFLP methods, respectively. The main clinical outcome was reduction in HbA1c (ΔHbA1c) after 6-month DPP4I treatment. RESULTS KCNQ1 rs163184 T>G variant was associated with the response to DPP4I treatment in genetic additive model (β=-0.30, p=0.022). For each G allele in the rs163184 genotype, we observed a 0.3% (3.3mmol/mol) less reduction in HbA1c during treatment with a DPP4I. Both the GG homozygotes and G-allele carriers had significantly smaller HbA1c reduction in comparison with the TT homozygotes. CONCLUSIONS KCNQ1 rs163184 T>G variant was associated with a reduced glycaemic response to DPP4I. The difference of 0.6% (6.5mmol/mol) in HbA1c reduction between the TT and GG homozygotes might be of clinical significance if replicated in further studies.

Insulin Resistance and Compensatory Insulin Secretion in Middle‐Aged Persons with Hypertriglyceridemia

Insulin secretion and insulin sensitivity were measured in hypertriglyceridemic patients using the frequently sampled intravenous glucose tolerance test. Three groups of men who were matched for age and body mass index were studied: eight healthy control subjects (C), seven patients with mild hypertriglyceridemia and normal glucose tolerance (TG), and seven with well-controlled type 2 diabetes with hypertriglyceridemia (TG-DM). The first-phase insulin response was increased by 116% in the TG group and decreased by 59% in the TG-DM group. The second phase of insulin secretion was increased in both TG groups (TG by 310% and TG-DM by 250%). The mean insulin sensitivity index (SI) was reduced by 50% in the TG group and by 60% in the TG-DM group. Glucose effectiveness (SG) was reduced by 30% in the TG-DM group compared with the control subjects.

An international, multicenter, observational survey to evaluate diabetes control in subjects using insulin for the treatment of type 1 and type 2 diabetes mellitus in the Czech Republic and Slovak Republic: study protocol for a cross-sectional survey

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