Diabetes management in hospital.

Patients with diabetes represent around 25 % of hospitalized persons. Treatment of diabetes patient is more complicated. Modification or initiation of antidiabetic treatment is often a significant problem during hospitalization on standard medical ward. The aim of this article is to present basic recommendations for in-patient diabetes treatment.

A summary of the EAS consensus concerning the causal relationship between low-density lipoproteins and atherosclerotic cardiovascular diseases, prepared by the Board of the Czech Society for Atherosclerosis.

This article summarised opinion of the European Society for Atherosclerosis on the causal relationship between low density lipoprotein (LDL) and the development of atherosclerosis. The fact that there is a clear causal relationship between the LDL concentration and the development of atherosclerotic cardiovascular disease (ASKVO) is evidenced by congenital lipid metabolism disorders and results of prospective epidemiological studies, Mendelian randomized trials, and randomized controlled trials. It is documented that the effect of LDL exposure on ASKVO development is cumulative; the additive effect of other risk factors is also discussed. In conclusion the facts, underlying the rational approach to the therapy of patients with dyslipidemia, are summarized. Key words: atherosclerotic cardiovascular disease - LDL - low density lipoprotein - EAS.

A comprehensive guidelines-based approach reduces cardiovascular risk in everyday practice: the VARO study.

INTRODUCTION: The aim of study was to investigate the possibility of cardiovascular risk improvement through systematic identification of high-risk individuals and treatment in accordance with current guidelines using modern therapy in daily clinical practice. MATERIAL AND METHODS: Two hundred and sixty-three physicians participated in the study. The physicians were asked to screen for cardiovascular risk factors in patients presenting with unrelated problems and to re-evaluate the attainment of treatment goals in those with already known risk factors. Each physician enrolled up to 20 consecutive patients with hypertension and/or hyperlipidemia. A total of 3015 patients were included. Cardiovascular risk was assessed using the SCORE system. Risk factors were treated in accordance with current national guidelines. The therapy of hyperlipidemia and hypertension was preferentially based on rosuvastatin, amlodipine and valsartan. Further medication was at the discretion of the attending physician. Patients were examined at baseline and after 3 and 6 months. RESULTS: The principal result is that global cardiovascular risk decreased by 35% (from 8.9 ±6.4 to 5.9 ±4.4, p < 0.001). Systolic and diastolic blood pressure decreased by 12.5% (from 152 ±18 to 133 ±11, p < 0.001) and 11.4% (from 88 ±11 to 78 ±7, p < 0.001). The level of total cholesterol decreased 21% (from 6.3 ±1.2 to 5.0 ±0.9, p < 0.001) and the concentration of LDL-C decreased 28% (from 3.9 ±1.1 to 2.8 ±0.8, p < 0.001). HDL-C increased by 7% (from 1.43 ±0.58 to 1.53 ±0.56, p < 0.001) and triglycerides decreased by 25% (from 2.4 ±1.3 to 1.8 ±0.9, p < 0.001). Blood pressure and LDL-C target values were reached in 68% and 34%of patients, respectively. CONCLUSIONS: The VARO study demonstrates that in daily practice settings, both individual risk factors and global cardiovascular risk are significantly improved through the systematic identification of high-risk individuals and their treatment in accordance with current guidelines using modern pharmacotherapy.

Statin non-adherence and residual cardiovascular risk: There is need for substantial improvement.

Although statin therapy has proven to be the cornerstone for prevention and treatment of cardiovascular disease (CVD), there are many patients for whom long-term therapy remains suboptimal. The aims of this article are to review the current complex issues associated with statin use and to explore when novel treatment approaches should be considered. Statin discontinuation as well as adherence to statin therapy remain two of the greatest challenges for lipidologists. Evidence suggests that between 40 and 75% of patients discontinue their statin therapy within one year after initiation. Furthermore, whilst the reasons for persistence with statin therapy are complex, evidence shows that low-adherence to statins negatively impacts clinical outcomes and residual CV risk remains a major concern. Non-adherence or lack of persistence with long-term statin therapy in real-life may be the main cause of inadequate low density lipoprotein cholesterol lowering with statins. There is a large need for the improvement of the use of statins, which have good safety profiles and are inexpensive. On the other hand, in a non-cost-constrained environment, proprotein convertase subtilisin/kexin type 9 inhibitors should arguably be used more often in those patients in whom treatment with statins remains unsatisfactory.

[PCSK9 inhibitors - new possibilities in the treatment of hypercholesterolemia: For which patients will be indicated?Czech atherosclerosis society statement]. / PCSK9 inhibitory - nové moznosti v lécbe hypercholesterolemie: U koho budou indikovány?Stanovisko Ceské spolecnosti pro aterosklerózu.

First line drug for the treatment of hypercholesterolemia are statins, which reduce LDL-cholesterol up to 50 %; such reduction is sufficient for most patients to achieve the target values. The exceptions are patients with familial hypercholesterolemia and patients with statin intolerance. To achieve target LDL-cholesterol in these two groups of patients will be possible with new drugs - PCSK9 inhibitors, which decrease LDL-cholesterol by an additional 50-60 %. The first two PCSK9 inhibitors (alirocumab and evolocumab) already had been approved for clinical use by European regulatory authorities. The primary indication for combination statin with PCSK9 inhibitor should be undoubtedly patients with a confirmed diagnosis of familial hypercholesterolemia, who are treated in the Czech Republic primarily in specialized centers of MedPed project. Furthermore, this treatment should be available for other patients at very high risk of cardiovascular diseases, who cannot achieve target LDL-cholesterol (eg. for statins intolerance).

[Hyperlipoproteinemia and dyslipidemia as rare diseases. Diagnostics and treatment]. / Hyperlipoproteinemie a dyslipidemie jako vzácná onemocnení: diagnostika a lécba.

Hyperlipoproteinemia (HLP) and dyslipidemia (DLP) are of course mainly perceived as diseases of common incidence and are typically seen as the greatest risk factors (RF) in the context of the pandemic of cardiovascular diseases. This is certainly true and HLP or DLP overall affect tens of percents of adults. However we cannot overlook the fact that disorders (mostly congenital) of lipid metabolism exist which, though not formally defined as such, amply satisfy the conditions for classification as rare diseases. Our account only includes a brief overview of the rare HLPs based on the dominant disorder of lipid metabolism, i.e. we shall mention the rare primary forms of hypercholesterolemia, primary forms of hypertriglyceridemia and the rare primary combined forms of HLP. In recent years an amazing progress has been reached relating to these diseases, in particular in the area of exact identification of the genetic defect and the mechanism of defect formation, however each of these diseases would require a separate article, though outside the field of clinical internal medicine. Therefore we shall discuss homozygous familial hypercholesterolemia (FH) in greater depth, partially also the "severe" form of heterozygous FH and in the following part the lipoprotein lipase deficiency; that means, diseases which present an extreme and even fatal risk for their carriers at a young age, but on the other hand, new therapeutic possibilities are offered within their treatment. An internist then should be alert to the suspicion that the described diseases may be involved, know about their main symptoms, where to refer the patient and how to treat them. Also dysbetalipoproteinemia (or type III HLP) will be briefly mentioned. Homozygous FH occurs with the frequency of 1 : 1 000 000 (maybe even more frequently, 1 : 160 000), it is characterized by severe isolated hypercholesterolemia (overall cholesterol typically equal to 15 mmol/l or more), xanthomatosis and first of all by a very early manifestation of a cardiovascular disease. Myocardial infarction is not an exception even in childhood. The therapy is based on high-dose statins, statins in combination with ezetimib and now also newly on PCSK9 inhibitors. Lomitapid and partly also mipomersen hold great promise for patients. LDL apheresis then represents an aggressive form of treatment. Lipoprotein lipase deficiency (type I HLP) is mainly characterized by severe hypertriglyceridemia, serum milky in colour, and xanthomatosis. A fatal complication is acute recurrent pancreatitis. A critical part of the treatment is diet, however it alone is not enough to control a genetic disorder. The only approved treatment is gene therapy. Experimentally, as an "off label" therapy, it is used in case studies with a lomitapid effect. We have our own experience with this experimental therapy. Dysbetalipoproteinemia is a congenital disorder of lipoprotein metabolism, characterized by high cholesterol (CH) and triglyceride (TG) levels. The underlying cause of this disease is the defect of the gene providing for apolipoprotein E. It is clinically manifested by xanthomatosis, however primarily by an early manifestation of atherosclerosis (rather peripheral than coronary).Key words: Lipoprotein lipase deficiency - dysbetalipoproteinemia - familial hypercholesterolemia - gene therapy - homozygous FH - LDL apheresis - lomitapid - mipomersen - PCSK9 inhibitors - rare diseases.

[Practical approach to statin intolerance]. / Praktický prístup ke statinové intoleranci.

Statins significantly decrease the cardiovascular risk and the reduction of cholesterol by statins has become a milestone in the prevention of cardiovascular diseases for a large group of patients. In spite of that an adequate use of statins in many patients is limited by adverse symptoms which lead to interruption of the therapy in some patients and low adherence to the therapy in others. Therefore the subject of statin intolerance is of great clinical importance. Statin intolerance can be defined as an incidence of myalgia or other adverse symptoms associated with a statin therapy, which lead to its interruption. Nonetheless, even if such symptoms develop during the statin therapy, these adverse effects are frequently not associated with the treatment and most patients with an anamnesis suggesting episodes of such symptoms are able to tolerate an adequate statin therapy. It is therefore of great clinical importance to identify the actual cases of statin intolerance in order to avoid the unnecessary interruption of the statin therapy in the patients who would benefit from it. Regarding patients with a proven statin intolerance, statins should be administered according to an altered scheme and if tolerated, the dose should be gradually increased until the highest tolerated level is reached. When this careful approach is followed, most patients are able to tolerate some level of statin therapy at least. Besides that, there may be also other lipid-reducing drugs needed to reach the required goals. If the achievement of the lipid target values is difficult, a rigorous control of the risk factors may help in reducing the cardiovascular risk.

Statin Intolerance: the Clinician's Perspective.

Muscle problems and other adverse symptoms associated with statin use are frequent reasons for non-adherence and discontinuation of statin therapy, which results in inadequate control of hyperlipidemia and increased cardiovascular risk. However, most patients who experience adverse symptoms during statin use are able to tolerate at least some degree of statin therapy. Given the profound cardiovascular benefits derived from statins, an adequate practical approach to statin intolerance is, therefore, of great clinical importance. Statin intolerance can be defined as the occurrence of myalgia or other adverse symptoms that are attributed to statin therapy and that lead to its discontinuation. In reality, these symptoms are actually unrelated to statin use in many patients, especially in those with atypical presentations following long periods of treatment. Thus, the first step in approaching patients with adverse symptoms during the course of statin therapy is identification of those patients for whom true statin intolerance is unlikely, since most of these patients would probably be capable of tolerating adequate statin therapy. In patients with statin intolerance, an altered dosing regimen of very low doses of statins should be attempted and, if tolerated, should gradually be increased to achieve the highest tolerable doses. In addition, other lipid-lowering drugs may be needed, either in combination with statins, or alone, if statins are not tolerated at all. Stringent control of other risk factors can aid in reducing cardiovascular risk if attaining lipid treatment goals proves difficult.

Implementation of cardiovascular disease prevention guidelines into clinical practice: an unmet challenge?

Prevention through evaluation and treatment of cardiovascular risk factors is an efficient approach to reduce the risk of cardiovascular events, however, the problem remains that the available treatment options are underused. Implementation of cardiovascular disease prevention guidelines into clinical practice is therefore important for decreasing the burden of cardiovascular disease in general population. However, there are many barriers to this process, including questionable relevance of scientific results for clinical practice, personal preferences and expertise of the doctors, patient attitudes, lack of time, and economical factors. All these factors need to be taken into account for any change in the clinical practice to be successful. With respect to cardiovascular disease prevention, insufficient screening for risk factors, inappropriate risk estimation and hesitation to keep to the guidelines-based treatment targets contribute most to inadequate control of risk factors, and this has been repeatedly demonstrated to be difficult to improve. In this context, our studies demonstrate that the emphasis on systematic application of principles of cardiovascular prevention results in improved control of cardiovascular risk factors. Adequate support for transforming guidelines-based knowledge into practicable habit appears therefore important for successful prevention of cardiovascular disease in clinical practice and may translate into substantial reduction of cardiovascular risk in general population.

Ivabradine, coronary heart disease, and heart failure: time for reappraisal.

Ivabradine is generally considered to be a safe drug with well-established and substantial benefits. Nevertheless, recently published results from the SIGNIFY trial suggest that ivabradine has rather inconsistent effects on cardiovascular outcomes. In addition, careful examination of all available data from ivabradine trials reveals signals of harm that have not yet been appropriately addressed, including a markedly increased incidence of atrial fibrillation and increased risk of cardiovascular events in patients with heart rates below 70 bpm. These concerns warrant consideration, since they could have implications for the future use of ivabradine.

Statins, glycemia, and diabetes mellitus: another point of view.

Glycemic effects of statins have recently become a topic of heated debate. On closer inspection, however, the prevailing opinion regarding this issue may prove to be unsubstantiated. We suggest that the harmful effect of statin-induced diabetes is likely overestimated, and the consequences of the glycemic effects of statins may, theoretically, apply to a greater number of patients beyond just those with statin-induced diabetes. Most notably, though, careful consideration of the issue suggests, albeit surprisingly, that the clinical implications of the glycemic effects of statins may actually be rather limited.

[Prevention of cardiovascular diseases in clinical practice: is it possible to achieve improvement?]. / Prevence kardiovaskulárních onemocnení v bezné klinické praxi: lze dosáhnout zlepsení?

Prevention through evaluation and treatment of cardiovascular risk factors is an efficient approach to reduce the risk of cardiovascular events, however, the problem remains that the available treatment options are underused. Implementation of cardiovascular disease prevention guidelines into clinical practice is therefore important for decreasing the burden of cardiovascular disease in general population. However, there are many barriers to this process, including questionable relevance of scientific results for clinical practice, personal preferences and expertise of the doctors, patient attitudes, lack of time, and economical factors. All these factors need to be taken into account for any change in the clinical practice to be successful. With respect to cardiovascular disease prevention, insufficient screening for risk factors, inappropriate risk estimation and hesitation to keep to the guidelines-based treatment targets contribute most to inadequate control of risk factors, and this has been repeatedly demonstrated to be difficult to improve. In this context, our studies demonstrate that the emphasis on systematic application of the principles of cardiovascular prevention results in improved control of cardiovascular risk factors. Adequate support for transforming the guidelines-based knowledge into practicable habit appears therefore important for successful prevention of cardiovascular disease in clinical practice and may translate into substantial reduction of cardiovascular risk in general population.

The effect of simvastatin and fenofibrate on the expression of leukocyte adhesion molecules and lipopolysaccharide receptor CD14 in type 2 diabetes mellitus.

BACKGROUND: Mixed hyperlipidemia is often associated with type 2 diabetes mellitus and contributes to atherosclerosis progression in diabetes patients. Leukocyte activation plays an important role in atherogenesis. Both statins and fibrates are used in the treatment of mixed dyslipidemia, but their specific effect on leukocyte function remains to be elucidated. We have therefore compared the effect of simvastatin and fenofibrate on several leukocyte activation markers in diabetes patients. METHODS: Twenty patients with type 2 diabetes and mixed hyperlipidemia were sequentially treated with simvastatin (20 mg/day) and fenofibrate (200 mg/day) in a randomized cross-over study (12 weeks each treatment). We measured adhesion molecules LFA-1, VLA-4 and CD18; in addition, lipopolysaccharide receptor CD14 on monocytes was analyzed as a marker of innate immunity. Leukocyte expression of these molecules was quantified using flow cytometry. Laboratory examinations were done at baseline and at the end of each treatment. Baseline values were compared to those of 29 healthy controls. RESULTS: Expression of integrin CD18 (in all leukocyte populations), lipopolysaccharide receptor and VLA-4 (on lymphocytes only) was significantly higher in patients than in controls. Both treatments resulted in significant decrease in CD18 and CD14 expression; LFA-1 and VLA-4 were not influenced. CONCLUSIONS: Both simvastatin and fenofibrate had similar favorable effect on leukocyte activation markers. This result supports the use of both statins and fibrates for the treatment of mixed hyperlipidemia in patients with type 2 diabetes mellitus.

Inhibition of multifunctional dipeptidyl peptidase-IV: is there a risk of oncological and immunological adverse effects?

Inhibitors of dipeptidyl peptidase-IV (DPP-IV) are a novel class of anti-diabetes drugs; inhibiting the breakdown of incretins, they increase their biological availability and decrease thus blood glucose levels. However, in addition to regulating glucose homeostasis, DPP-IV has many diverse functions, such as modulating cell growth, differentiation and transformation and immune function. Within the immune system, DPP-IV exerts mainly stimulating effects, while its relation to malignancies is highly variable. Therefore, long-term inhibition of this enzyme could have serious side effects including immune dysregulation or increased risk of cancer. Although the data on the effects of DPP-IV inhibitors in humans are scarce, the increased risk of infections and the tendency towards a higher incidence of some tumours fall in line with experimental evidence suggesting the possibility of their adverse immunological and oncological effects. Further research is obviously needed to clarify the effector mechanisms of DPP-IV inhibitors on immune function and tumour biology. Most important, however, is obtaining reassuring safety data from adequately powered, long-term trials of DPP-IV inhibitors in humans. In the meantime, all the potential risks of DPP-IV inhibitors should be kept in mind, and this class of drugs needs to be regarded with some degree of caution.

APOA5 Ala315>Val, identified in patients with severe hypertriglyceridemia, is a common mutation with no major effects on plasma lipid levels.

BACKGROUND: The importance of the apolipoprotein A5 (APOA5) gene in determining plasma triglyceride (TG) levels has been demonstrated in transgenic and knockout mice and confirmed by human association studies in different ethnic groups. METHODS: We screened for nonsynonymous APOA5 mutations in patients with plasma TG levels >10 mmol/L. The coding sequence and promoter region of the APOA5 gene were sequenced in 95 individuals with severe hypertriglyceridemia (HTG). A large population sample of 3,202 individuals was screened by PCR and restriction analysis for presence of detected mutation. RESULTS: In total, three heterozygous carriers of 944C>T (Ala315>Val) were identified in the severe HTG patients, while 22 carriers were identified in the population sample. The rare allele frequency of the Val315 was significantly higher in the HTG sample than in controls (0.016 vs. 0.003, p<0.01, respectively). Most of the control Ala315Val carriers, however, had plasma lipid levels (TGs, total cholesterol and high-density lipoprotein cholesterol) within the usual range detected in the population. CONCLUSIONS: APOA5 Ala315>Val does not play any dominant/important role in the genetic determination of plasma TG levels, but the increased frequency in HTG patients compared to controls suggests that it might interact with other gene variants to cause HTG.

Rosiglitazone in the prevention of diabetes and cardiovascular disease: dream or reality?

Results of the recently published DREAM trial seemingly demonstrate that the PPAR-gamma agonist rosiglitazone is effective in the prevention of diabetes. However, a more detailed inspection of the trial shows that rosiglitazone is masking rather than preventing the progression to diabetes. This questionable effect was achieved at the price of unnecessarily treating approximately five subjects who would remain nondiabetic anyway for each case of "prevented" diabetes, with all the associated costs and risks. The trial also raises the unexpected possibility that rosiglitazone may substantially increase the risk of cardiovascular events, which would be particularly harmful in the high-risk patients with diabetes. This possibility is further supported by the results of several recent meta-analyses. In addition, these serious safety concerns should be carefully weighed against the weak evidence of benefit which, so far, is limited to laboratory endpoints. Therefore, rather than extending the use of rosiglitazone to the prevention of diabetes, the DREAM trial calls in question the safety of this drug as such in any patient and casts some doubt upon the whole class of PPAR-gamma agonists. With respect to its wide use in clinical practice, the potential risks of rosiglitazone warrant careful investigation and, in the meantime, this drug should be used with caution.

Fenofibrate and rosiglitazone improve quality of lipoproteins in patients with type 2 diabetes mellitus.

BACKGROUND: Particle size distribution in both HDL and LDL is reflected in the fractional esterification rate of cholesterol by lecithin cholesterol acyltransferase (LCAT) in plasma depleted of apoB containing lipoproteins (FER(HDL)). We studied FER(HDL) in a group of patients with type 2 diabetes and determined the impact of two different PPAR agonists (fenofibrate and rosiglitazone) on this marker of lipoprotein particle quality. PATIENTS AND METHODS: 66 patients with type 2 diabetes (26 women) and 32 control subjects (19 women) were included in the study. 33 patients received fenofibrate and 33 rosiglitazone as add on therapy. Average duration of treatment was 4 months. Plasma lipoprotein glucose levels were determined using an automated analyzer (COBAS Mira, Roche). LDL cholesterol concentrations were calculated by Friedewald formula. FER(HDL) was determined by a radioassay after precipitating apo-B containing particles of plasma. The assays were performed at baseline and at the end of each treatment. SPSS base program was used for statistical evaluation. RESULTS: Both fenofibrate and rosiglitazone resulted in a significant decrease of FER(HDL) (24.62 +/- 11.27%/h vs. 19.93 +/- 10.34%/h; 20.0 +/- 6.1%/h vs. 15.8 +/- 5.8%/h, p < 0.001). Rosiglitazone was significantly more effective in FER(HDL) lowering than fenofibrate (p < 0,02) CONCLUSIONS: Both fenofibrate and rosiglitazone improve FER(HDL) in patients with type 2 diabetes. The effect is more pronounced for rosiglitazone. Qualitative change of plasma lipoproteins reflected by FER(HDL) can contribute to antiatherogenic action of PPAR agonists. On contrary, changes of lipoprotein composition induced by PPAR agonists cannot explain adverse cardiovascular effects observed in some large clinical trials with PPAR agonists.