Sex- and Gender-Based Pharmacological Response to Drugs.

In humans, the combination of all sex-specific genetic, epigenetic, and hormonal influences of biologic sex produces different in vivo environments for male and female cells. We dissect how these influences of sex modify the pharmacokinetics and pharmacodynamics of multiple drugs and provide examples for common drugs acting on specific organ systems. We also discuss how gender of physicians and patients may influence the therapeutic response to drugs. We aim to highlight sex as a genetic modifier of the pharmacological response to drugs, which should be considered as a necessary step toward precision medicine that will benefit men and women. SIGNIFICANCE STATEMENT: This study discusses the influences of biologic sex on the pharmacokinetics and pharmacodynamics of drugs and provides examples for common drugs acting on specific organ systems. This study also discusses how gender of physicians and patients influence the therapeutic response to drugs.

Updates in Drug Treatment of Severe Hypertriglyceridemia.

PURPOSE OF REVIEW: To provide an insight into the new pharmacological options for the treatment of severe hypertriglyceridemia (sHTG). RECENT FINDINGS: sHTG is difficult to treat. The majority of the traditional pharmacological agents available have limited success in both robustly decreasing triglyceride levels and/or in reducing the incidence of acute pancreatitis (AP), the most severe complication of sHTG. Therapeutic options with novel mechanisms of action have been developed, such as antisense oligonucleotides (ASO) and small interfering RNA (siRNA) targeting APOC3 and ANGPTL3. The review discusses also 2 abandoned drugs for sHTG treatment, evinacumab and vupanorsen. The ASO targeting APOC3, volanesorsen, is approved for use in patients with familial chylomicronemia syndrome (FCS) in Europe. Olezarsen, an N-acetylgalactosamine (GalNAc)-conjugated ASO with the same target, seems to have a better safety and efficacy profile. siRNA targeting APOC3 and ANGPTL3, namely ARO-APOC3 and ARO-ANG3, are also promising for the treatment of sHTG. However, the ultimate clinical goal of any sHTG treatment, the decrease in the risk of AP, has not been definitively achieved till now by any pharmacotherapy, either approved or in development.

PCSK9 Monoclonal Antibodies: New Developments and Their Relevance in a Nucleic Acid-Based Therapy Era.

PURPOSE OF REVIEW: To report on recent data about PCSK9 monoclonal antibodies and to evaluate their relevance in a nucleic acid-based therapy era for lipid lowering and prevention of cardiovascular disease. RECENT FINDINGS: New methods of PCSK9 inhibition based on nucleic acid therapeutics such as antisense oligonucleotides, small interfering RNAs, and CRISPR tools for therapeutic gene editing are reported, and interesting new data regarding the clinical relevance of PCSK9 antibodies are discussed. Promising methods of PCSK9 inhibition are in development, and one of them, the siRNA inclisiran targeting PCSK9, has already been approved for clinical use. However, PCSK9-mAb remains the PCSK9-inhibiting tool with the longest safety data and the only one having positive cardiovascular outcome trials. An ongoing cardiovascular outcome trial with inclisiran is planned to be completed in 2026. Other forms of PCSK9 inhibition, such as antisense oligonucleotides targeting PCSK9 and CRISPR base editing of PCSK9, are still in early phases of development, and their potential clinical relevance remains to be established.

Serum 25-hydroxyvitamin D response to vitamin D supplementation in infants: a systematic review and meta-analysis of clinical intervention trials.

PURPOSE: For the prevention of nutritional rickets, 400 IU vitamin D daily and circulating 25-hydroxyvitamin D (25OHD) concentrations > 50 nmol/L are recommended, whereas the toxicity threshold is set at 250 nmol/L. We synthesized the evidence for the effect of vitamin D supplementation on incremental 25OHD in infants up to 1 year of age. METHODS: We performed a systematic review and meta-analysis of intervention trials in several databases. A total of 87 records were identified for full-text review and 27 articles with 61 studies were included in the final analysis. RESULTS: The selected 61 studies included 1828 participants. Nineteen cohorts had already mean baseline 25OHD levels ≥ 50 nmol/L. The weighted mean difference in 25OHD following vitamin D supplementation was + 49.4 nmol/L (95% CI 43.6-55.3 nmol/L; P < 0.001). The increment was dose-dependent (P = 0.002), was higher in full-term than in pre-term infants (P < 0.001), was higher in infants with baseline 25OHD < 50 nmol/L as compared to ≥ 50 nmol/L (P = 0.001), and was marginally influenced by the 25OHD test procedure (P = 0.080). Vitamin D3 doses of 400 IU/day were sufficient to achieve 25OHD concentrations ≥ 50 nmol/L in most full-term infants. A 25OHD level of 250 nmol/L was not exceeded in ≥ 97.5% of infants at doses between 200 and 1200 IU/day, but potentially in ≥ 2.5% of infants at a dose of 1600 IU/day. CONCLUSIONS: Vitamin D supplementation of 400 IU/day is sufficient for achieving 25OHD concentrations able to prevent nutritional rickets. A more personalized vitamin D dosing strategy would require 25OHD testing, but also assay standardization.

The IL-6-neutralizing sIL-6R-sgp130 buffer system is disturbed in patients with type 2 diabetes.

Serum levels of interleukin-6 (IL-6) are increased in patients with type 2 diabetes (T2D). IL-6 exerts its pleiotropic effects via the IL-6 α-receptor (IL-6R), which exists in membrane-bound and soluble (sIL-6R) forms and activates cells via the ß-receptor glycoprotein 130 (gp130). The nonsynonymous single-nucleotide polymorphism (SNP) rs2228145 (Asp358Ala) within the IL6R locus is associated with T2D. The aim of this study was to determine whether sIL-6R in combination with soluble gp130 (sgp130) is able to form an IL-6-neutralizing buffer in healthy subjects and whether this is disturbed in T2D. We found that sIL-6R-sgp130 indeed forms an IL-6-neutralizing buffer in the serum of healthy humans, whose capacity is controlled by the SNP of the IL-6R. Circulating sIL-6R-sgp130 levels were lower in T2D subjects (P < 0.001), whereas IL-6 was high and inversely correlated with sIL-6R (r = -0.57, P < 0.001), indicating a severe disturbance of the buffer. This phenomenon is also observed in sex- and age-matched patients with both T2D and atherosclerosis but not in patients with atherosclerosis alone. In conclusion, sIL-6R and sgp130 serum levels were significantly lower in T2D patients compared with healthy subjects or atherosclerosis patients, although IL-6 levels were high. These data suggest that disturbance of the protective buffer may be closely associated with T2D pathophysiology.

Vitamin D supplementation does not prevent the testosterone decline in males with advanced heart failure: the EVITA trial.

PURPOSE: Observational studies indicate a positive association between circulating 25-hydroxyvitamin D (25OHD) and testosterone (T) concentrations. Because low 25OHD concentrations and T deficiency are considered to be a generalized phenomenon in patients with advanced heart failure (HF), we aimed to investigate whether vitamin D supplementation has beneficial effects on T indices in these patients. METHODS: In a pre-specified secondary analysis of the EVITA (effect of vitamin D on mortality in heart failure) randomized controlled trial, we analyzed in male subjects with 25OHD concentrations < 75 nmol/L the effect of a daily vitamin D3 supplement of 4000 IU for 3 years (n = 71) vs. placebo (n = 62) on total T (TT), sex hormone-binding globulin (SHBG), free T (fT), and bioactive T (BAT). We assessed changes from baseline until study termination and between-group differences at study termination. RESULTS: 25OHD increased in the placebo group from 36.6 nmol/L by 9.2 nmol/L (95% CI 3.2-15.1 nmol/L; P = 0.003) and in the vitamin D group from 36.5 nmol/L by 63.9 nmol/L (95% CI 52.6-75.3 nmol/L; P < 0.001), with a significant between-group difference at study termination (P < 0.001). TT and SHBG concentrations did not change significantly, neither in the placebo group nor in the vitamin D group (P = 0.845-0.082), but concentrations of fT and BAT declined significantly in both groups (P = 0.025-0.008). At study termination, there were no between-group differences in TT (P = 0.612), SHBG (P = 0.393), fT (P = 0.861), or BAT (P = 0.960). CONCLUSIONS: In male patients with advanced HF and low 25OHD concentrations, a daily vitamin D3 supplement of 4000 IU for 3 years did not prevent the decline in testosterone indices.

Daily Supplementation with 4000 IU Vitamin D3 for Three Years Does Not Modify Cardiovascular Risk Markers in Patients with Advanced Heart Failure: The Effect of Vitamin D on Mortality in Heart Failure Trial.

BACKGROUND/AIMS: We aimed to investigate the effect of a moderately high vitamin D dose on lipid parameters and biochemical markers of vascular calcification (VC) in patients with established cardiovascular disease. METHODS: We included in this pre-specified secondary analysis of a randomized controlled trial 161 patients with advanced heart failure and 25-hydroxyvitamin D (25OHD) concentrations < 75 nmol/L (vitamin D group: n = 80; placebo group: n = 81), who received a daily vitamin D3 supplement of 4,000 IU for 3 years. We assessed between-group differences of the lipid parameters total-cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and triglycerides, and the VC markers fetuin-A and non-phosphorylated undercarboxylated matrix gla protein (MGP) at study termination, with adjustment for baseline values. RESULTS: Lipid parameters, the percentage of patients with dyslipoproteinemia, and VC markers did not differ significantly between groups at study termination (p values: 0.395-0.939). Likewise, vitamin D achieved no significant treatment effect on these markers in subgroup analyses in patients with 25OHD concentrations < 30 nmol/L, nonusers of lipid-lowering drugs, or diabetic patients (p values: 0.245-0.998). CONCLUSION: Our data indicate that vitamin D does not improve the lipid profile and does not influence the calcification inhibitors fetuin-A and non-phosphorylated undercarboxylated MGP in patients with advanced heart failure.

Effect of vitamin D on all-cause mortality in heart failure (EVITA): a 3-year randomized clinical trial with 4000 IU vitamin D daily.

AIMS: Circulating 25-hydroxyvitamin D (25OHD) levels <75 nmol/L are associated with a nonlinear increase in mortality risk. Such 25OHD levels are common in heart failure (HF). We therefore examined whether oral vitamin D supplementation reduces mortality in patients with advanced HF. METHODS AND RESULTS: Four hundred HF patients with 25OHD levels <75 nmol/L were randomized to receive 4000 IU vitamin D daily or matching placebo for 3 years. Primary endpoint was all-cause mortality. Key secondary outcome measures included hospitalization, resuscitation, mechanical circulatory support (MCS) implant, high urgent listing for heart transplantation, heart transplantation, and hypercalcaemia. Initial 25OHD levels were on average <40 nmol/L, remained around 40 nmol/L in patients assigned to placebo and plateaued around 100 nmol/L in patients assigned to vitamin D. Mortality was not different in patients receiving vitamin D (19.6%; n = 39) or placebo (17.9%; n = 36) with a hazard ratio (HR) of 1.09 [95% confidence interval (CI): 0.69-1.71; P = 0.726]. The need for MCS implant was however greater in patients assigned to vitamin D (15.4%, n = 28) vs. placebo [9.0%, n = 15; HR: 1.96 (95% CI: 1.04-3.66); P = 0.031]. Other secondary clinical endpoints were similar between groups. The incidence of hypercalcaemia was 6.2% (n = 10) and 3.1% (n = 5) in patients receiving vitamin D or placebo (P = 0.192). CONCLUSION: A daily vitamin D dose of 4000 IU did not reduce mortality in patients with advanced HF but was associated with a greater need for MCS implants. Data indicate caution regarding long-term supplementation with moderately high vitamin D doses. TRIAL REGISTRATION INFORMATION: clinicaltrials.gov Idenitfier: NCT01326650.

IL-6 blockade by monoclonal antibodies inhibits apolipoprotein (a) expression and lipoprotein (a) synthesis in humans.

Lipoprotein (a) [Lp(a)] is a highly atherogenic lipid particle. Although earlier reports suggested that Lp(a) levels are mostly determined by genetic factors, several recent studies have revealed that Lp(a) induction is also caused by chronic inflammation. Therefore, we aimed to examine whether cytokine blockade by monoclonal antibodies may inhibit Lp(a) metabolism. We found that interleukin 6 (IL-6) blockade by tocilizumab (TCZ) reduced Lp(a) while TNF-α-inhibition by adalimumab in humans had no effect. The specificity of IL-6 in regulating Lp(a) was further demonstrated by serological measurements of human subjects (n = 1,153) revealing that Lp(a) levels are increased in individuals with elevated serum IL-6. Transcriptomic analysis of human liver biopsies (n = 57) revealed typical IL-6 response genes being correlated with the LPA gene expression in vivo. On a molecular level, we found that TCZ inhibited IL-6-induced LPA mRNA and protein expression in human hepatocytes. Furthermore, examination of IL-6-responsive signal transducer and activator of transcription 3 binding sites within the LPA promoter by reporter gene assays, promoter deletion experiments, and electrophoretic mobility shift assay analysis showed that the Lp(a)-lowering effect of TCZ is specifically mediated via a responsive element at -46 to -40. Therefore, IL-6 blockade might be a potential therapeutic option to treat elevated Lp(a) serum concentrations in humans and might be a noninvasive alternative to lipid apheresis in the future.

Lipoprotein Metabolism, Dyslipidemia, and Lipid-Lowering Therapy in Women: A Comprehensive Review.

Lipid-lowering therapy (LLT) is a cornerstone of atherosclerotic cardiovascular disease prevention. Although LLT might lead to different reductions in low-density lipoprotein cholesterol (LDL-C) levels in women and men, LLT diminishes cardiovascular risk equally effectively in both sexes. Despite similar LLT efficacy, the use of high-intensity statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors is lower in women compared to men. Women achieve the guideline-recommended LDL-C levels less often than men. Greater cholesterol burden is particularly prominent in women with familial hypercholesterolemia. In clinical practice, women and men with dyslipidemia present with different cardiovascular risk profiles and disease manifestations. The concentrations of LDL-C, lipoprotein(a), and other blood lipids differ between women and men over a lifetime. Dissimilar levels of LLT target molecules partially result from sex-specific hormonal and genetic determinants of lipoprotein metabolism. Hence, to evaluate a potential need for sex-specific LLT, this comprehensive review (i) describes the impact of sex on lipoprotein metabolism and lipid profile, (ii) highlights sex differences in cardiovascular risk among patients with dyslipidemia, (iii) presents recent, up-to-date clinical trial and real-world data on LLT efficacy and safety in women, and (iv) discusses the diverse medical needs of women and men with dyslipidemia and increased cardiovascular risk.

Phytosterols and Cardiovascular Risk Evaluated against the Background of Phytosterolemia Cases-A German Expert Panel Statement.

Phytosterols (PSs) have been proposed as dietary means to lower plasma LDL-C. However, concerns are raised that PSs may exert atherogenic effects, which would offset this benefit. Phytosterolemia was thought to mimic increased plasma PSs observed after the consumption of PS-enriched foods. This expert statement examines the possibility of specific atherogenicity of PSs based on sterol metabolism, experimental, animal, and human data. Observational studies show no evidence that plasma PS concentrations would be associated with an increased risk of atherosclerosis or cardiovascular (CV) events. Since variants of the ABCG5/8 transporter affect the absorption of cholesterol and non-cholesterol sterols, Mendelian randomization studies examining the effects of ABCG5/8 polymorphisms cannot support or refute the potential atherogenic effects of PSs due to pleiotropy. In homozygous patients with phytosterolemia, total PS concentrations are ~4000% higher than under physiological conditions. The prevalence of atherosclerosis in these individuals is variable and may mainly relate to concomitant elevated LDL-C. Consuming PS-enriched foods increases PS concentrations by ~35%. Hence, PSs, on a molar basis, would need to have 20-40 times higher atherogenicity than cholesterol to offset their cholesterol reduction benefit. Based on their LDL-C lowering and absence of adverse safety signals, PSs offer a dietary approach to cholesterol management. However, their clinical benefits have not been established in long-term CV endpoint studies.

The whey fermentation product malleable protein matrix decreases TAG concentrations in patients with the metabolic syndrome: a randomised placebo-controlled trial.

Animal and human studies suggest that a malleable protein matrix (MPM) from whey decreases plasma lipid concentrations and may positively influence other components of the metabolic syndrome such as glucose metabolism and blood pressure (BP). The primary objective of this double-blind, multi-centre trial was to investigate the effects of a low-fat yoghurt supplemented with whey MPM on fasting TAG concentrations in patients with the metabolic syndrome. A total of 197 patients were randomised to receive MPM or a matching placebo yoghurt identical in protein content (15 g/d). Patients were treated during 3 months with two daily servings of 150 g yoghurt each to compare changes from baseline in efficacy variables. MPM treatment resulted in a significantly larger reduction of TAG concentrations in comparison to placebo (relative change -16%, P=0·004). The difference was even more pronounced in subjects with elevated fasting TAG (≥200 mg/dl) at baseline (-18%, P=0·005). The relative treatment difference in fasting plasma glucose was -7·1 mg/dl (P=0·089). This effect was also more pronounced in subjects with impaired fasting glucose at baseline (-11 mg/dl, P=0·03). In patients with hypertension, the relative treatment difference in systolic BP reached -5·9 mmHg (P=0·054). The relative treatment difference in body weight was -1·7 kg (P=0·015). The most common adverse events were gastrointestinal in nature. Conclusions from the present study are that consumption of a low-fat yoghurt supplemented with whey MPM twice a day over 3 months significantly reduces fasting TAG concentrations in patients with the metabolic syndrome and improves multiple other cardiovascular risk factors.

Lipid lowering in patients with chronic kidney disease: a SHARP turn in the wrong direction?

The question whether lipid-lowering treatment is associated with a decrease in cardiovascular morbidity and mortality in patients with chronic kidney disease has been disputed for a while, with recent trials in patients on haemodialysis failing to show benefit. Recently, the long-awaited results of the SHARP (Study of Heart And Renal Protection) trial were published. This randomized trial compared the effects of either simvastatin 20 mg plus ezetimibe 10 mg daily or placebo on the occurrence of a first major vascular event in 9720 patients with chronic kidney disease. There was a 17% relative risk reduction but no benefit on survival. We address our concerns regarding the conclusions drawn from this trial. The trial has a major design flaw by comparing the effects of two different lipid-lowering drugs with placebo. Although the SHARP trial showed that lipid lowering may be beneficial for patients with chronic kidney disease, the clinically as well as economically important question remains unanswered as to whether it was statin therapy and/or ezetimibe that mediated this effect. A great opportunity to investigate superiority, equipoise, or potential inferiority of ezetimibe compared to statins was missed.

Ezetimibe alone or in combination with simvastatin increases small dense low-density lipoproteins in healthy men: a randomized trial.

AIMS: The predominance of small dense low-density lipoproteins (sdLDLs) has been associated with increased cardiovascular risk. The effect of ezetimibe on LDL subfraction distribution has not been fully elucidated. This study assessed by gradient gel electrophoresis the effects of ezetimibe alone, simvastatin alone, and their combination on sdLDL subfraction distribution. METHODS AND RESULTS: A single-centre, randomized, parallel three-group open-label study was performed in 72 healthy men with a baseline LDL-cholesterol (LDL-C) concentration of 111 +/- 30 mg/dL (2.9 +/- 0.8 mmol/L). They were treated with ezetimibe (10 mg/day, n = 24), simvastatin (40 mg/day, n = 24), or their combination (n = 24) for 14 days. Blood was drawn before and after the treatment period. Generalized estimating equations were used to assess the influence of drug therapy on LDL subfraction distribution, controlling for within-subject patterns (clustering). We adjusted for age, body mass index, and baseline concentrations of LDL-C and triglycerides. Ezetimibe alone changed LDL subfraction distribution towards a more atherogenic profile by significantly increasing sdLDL subfractions (LDL-IVA +14.2%, P = 0.0216 and LDL-IVB +16.7%, P = 0.039; fully adjusted Wald chi(2) test). In contrast, simvastatin alone significantly decreased the LDL-IVB subfraction (-16.7%, P = 0.002). This effect was offset when simvastatin was combined with ezetimibe (LDL-IVB +14.3%, P = 0.44). All three treatments decreased the large, more buoyant LDL-I subfraction, the effects of ezetimibe being the most pronounced (ezetimibe -13.9%, P < 0.0001; combination therapy -7.3%, P = 0.0743; simvastatin -4.6%, P < 0.0001). CONCLUSION: In healthy men, treatment with ezetimibe alone is associated with the development of a pro-atherogenic LDL subfraction profile. Potentially atheroprotective effects of simvastatin are offset by ezetimibe. This study is registered with ClinicalTrials.gov, identifier no. NCT00317993.

The effect of vitamin D on fibroblast growth factor 23: a systematic review and meta-analysis of randomized controlled trials.

The phosphaturic hormone fibroblast growth factor 23 (FGF23) is a risk marker of cardiovascular and all-cause mortality. We therefore aimed to synthesize the evidence for the effect of vitamin D administration on circulating FGF23 concentrations. We performed a systematic review and meta-analysis of randomized, placebo-controlled trials (RCTs) in several databases from inception to January 2020. A total of 73 records were identified for full-text review, and 21 articles with 23 studies were included in the final analysis. The selected studies included 1925 participants with 8-156 weeks of follow-up. The weighted mean difference in FGF23 in the vitamin D versus placebo group was +21 pg/ml (95% CI: 13-28 pg/ml; P < 0.001) with considerable heterogeneity among studies (I2 = 99%). The FGF23 increment was higher in patients with end-stage kidney/heart failure than in other individuals (+300 pg/ml [95% CI: 41-558 pg/ml] vs. +20 pg/ml [95% CI: 12-28 pg/ml], Pinteraction = 0.03), and if baseline 25-hydroxyvitamin D concentrations were <50 nmol/l instead of ≥50 nmol/l (+34 pg/ml [95% CI: 18-51 pg/ml] vs. +9 pg/ml [95% CI: 3-14 pg/ml]; Pinteraction = 0.002). Moreover, the FGF23 increment was influenced by vitamin D dose/type (vitamin D dose equivalent ≤ 2000 IU/day: +2 pg/ml [95% CI: 0-3 pg/ml]; vitamin D dose equivalent > 2000 IU/day: +18 pg/ml [95% CI: 6-30 pg/ml]; administration of activated vitamin D: +67 pg/ml [95% CI: 16-117 pg/ml]; Pinteraction = 0.001). Results were not significantly influenced by study duration (Pinteraction = 0.14), age class (Pinteraction = 0.09), or assay provider (Pinteraction = 0.11). In conclusion, this meta-analysis of RCTs demonstrates that vitamin D administration of >2000 IU/d vitamin D or activated vitamin D significantly increased concentrations of the cardiovascular risk marker FGF23, especially in patients with end-stage kidney/heart failure.

Vitamin D and Vascular Disease.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Vitamin D deficiency has been identified as a potential risk factor for a number of diseases unrelated to the classical skeletal pathophysiology, such as cancer and CVD, but the effects of vitamin D supplementation are less clear. Purpose of this narrative review is to discuss the evidence suggesting an association between vitamin D status and CVD as well as the results of supplementation studies. Vitamin D deficiency has been associated with CVD risk factors such as hypertension, dyslipidemia and diabetes mellitus as well as with cardiovascular events such as myocardial infarction, stroke and heart failure. While vitamin D deficiency might contribute to the development of CVD through its association with risk factors, direct effects of vitamin D on the cardiovascular system may also be involved. Vitamin D receptors are expressed in a variety of tissues, including cardiomyocytes, vascular smooth muscle cells and endothelial cells. Moreover, vitamin D has been shown to affect inflammation, cell proliferation and differentiation. While observational studies support an association between low plasma vitamin D levels and increased risk of CVD, Mendelian randomization studies do not support a causal association between the two. At present, high quality randomized trials do not find evidence of significant effects on CVD endpoints and do not support supplementation of vitamin D to decrease CVD events.

A 3 year post-intervention follow-up on mortality in advanced heart failure (EVITA vitamin D supplementation trial).

AIMS: Vitamin D supplementation is widely used in the clinical setting, but its effects on mortality and cardiovascular outcomes in patients with heart failure are unclear. This paper reports outcome data that were collected during follow-up of 3 years after closure of the EVITA trial (a 3 year randomized, placebo-controlled, intervention study with 4000 IU vitamin D daily in patients with advanced heart failure), to capture potential latency effects of vitamin D supplementation on clinical outcomes. METHODS AND RESULTS: The prespecified primary endpoint was overall mortality. Secondary endpoints included hospitalization, mechanical circulatory support implantation, high urgent listing for heart transplantation, and heart transplantation. For group comparisons, we used Cox regression models with a time-dependent categorical covariate. The calculated net difference in circulating 25-hydroxyvitamin D between the vitamin D and placebo groups dropped from 60.9 nmol/L at the end of the active study period to 3.2 nmol/L at the end of the post-intervention period. During the entire 6 year period, 73 patients (36.5%) died in the placebo group and 76 (38.8%) in the vitamin D group. Out of these 149 patients, 36 and 39 died during the first 3 years, and 37 and 37 during the second 3 years, respectively. The hazard ratio (HR) for mortality in the vitamin D versus the placebo group was 1.06 [95% confidence interval (CI): 0.68-1.66] for the first 3 years and 1.07 (95% CI: 0.68-1.70) for the 3 year post-intervention follow-up. Compared with the placebo group, the HRs for hospitalization and for mechanical circulatory support implant were significantly higher in the vitamin D group during vitamin D supplementation (HR = 1.31, 95% CI: 1.01-1.68 and HR = 2.01, 95% CI: 1.08-3.76, respectively) but not after vitamin D discontinuation (HR = 1.10, 95% CI: 0.62-1.94 and HR = 0.99, 95% CI: 0.38-2.56, respectively). There was no significant time-dependent effect on the risk of high urgent listing for heart transplantation and heart transplantation. CONCLUSIONS: No beneficial latency effects of vitamin D supplementation on overall mortality could be demonstrated. Instead, the disappearance of unfavourable findings in the vitamin D group (higher HRs for hospitalization and for mechanical circulatory support implant) after vitamin D discontinuation supports the assumption of adverse vitamin D effects on the cardiovascular system at doses of 4000 IU daily.

Patterns and predictors of statin prescription in patients with type 2 diabetes.

BACKGROUND: The benefit of statins for prevention of cardiovascular events in type 2 diabetes is established, but a gap exists between guideline recommendations and clinical practice. The aim of the study was to identify patient-related factors predicting statin prescription. METHODS: We assessed the quality of care in 51,640 patients with type 2 diabetes in a German diabetes registry. Patients were stratified according to primary and secondary prevention. Five-year risk for cardiovascular events was calculated in primary prevention patients. A multivariate adjusted logistic regression model was constructed to determine which parameters influenced statin prescription. RESULTS: 34% had established atherosclerotic disease and 25.5% received a statin. Prescription was significantly higher in the secondary compared to the primary prevention group (38.1% [95% CI 37.4-38.9%] vs. 18.5% [95% CI 18.0-19.0%], respectively). In primary prevention the odds for statin prescription increased with estimated cardiovascular risk (OR 1.17 per 5% increase in 5-year risk, 95% CI 1.11-1.22). Positive predictors for statin prescription were secondary prevention, hypertension, former smoking, baseline LDL-cholesterol, and microalbuminuria. The odds of receiving a statin had an inverted U-shaped relation with age (nadir, 66 years), age at first diagnosis of diabetes (nadir, 56 years), and body mass index (nadir, 32 kg/m2). The model predicted prescription in 70% of the patients correctly. CONCLUSION: The majority of patients with type 2 diabetes are not receiving statins. The predominant factors determining statin prescription are the patient's prevention status and, in primary prevention, estimated cardiovascular risk. The results suggest that although physicians are aware of the general concept of cardiovascular risk, they fail to consistently implement guidelines.

A randomized controlled trial on the efficacy of carbohydrate-reduced or fat-reduced diets in patients attending a telemedically guided weight loss program.

BACKGROUND: We investigated whether macronutrient composition of energy-restricted diets influences the efficacy of a telemedically guided weight loss program. METHODS: Two hundred overweight subjects were randomly assigned to a conventional low-fat diet and a low-carbohydrate diet group (target carbohydrate content: >55% energy and <40% energy, respectively). Both groups attended a weekly nutrition education program and dietary counselling by telephone, and had to transfer actual body weight data to our clinic weekly with added Bluetooth technology by mobile phone. Various fatness and fat distribution parameters, energy and macronutrient intake, and various biochemical risk markers were measured at baseline and after 6, and 12 months. RESULTS: In both groups, energy intake decreased by 400 kcal/d compared to baseline values within the first 6 months and slightly increased again within the second 6 months. Macronutrient composition differed significantly between the groups from the beginning to month 12. At study termination, weight loss was 5.8 kg (SD: 6.1 kg) in the low-carbohydrate group and 4.3 kg (SD: 5.1 kg) in the low-fat group (p = 0.065). In the low-carbohydrate group, triglyceride and HDL-cholesterol levels were lower at month 6 and waist circumference and systolic blood pressure were lower at month 12 compared with the low-fat group (P = 0.005-0.037). Other risk markers improved to a similar extent in both groups. CONCLUSION: Despite favourable effects of both diets on weight loss, the carbohydrate-reduced diet was more beneficial with respect to cardiovascular risk factors compared to the fat-reduced diet. Nevertheless, compliance with a weight loss program appears to be even a more important factor for success in prevention and treatment of obesity than the composition of the diet. TRIAL REGISTRATION: Clinicaltrials.gov as NCT00868387.

Vitamin D and cardiovascular disease.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Recently vitamin D deficiency has been identified as a potential risk factor for many diseases not traditionally associated with vitamin D, such as cancer and CVD. This review discusses the evidence suggesting an association between low 25-hydroxyvitamin D levels and CVD and the possible mechanisms mediating it. Vitamin D deficiency has been associated with CVD risk factors such as hypertension and diabetes mellitus, with markers of subclinical atherosclerosis such as intima-media thickness and coronary calcification as well as with cardiovascular events such as myocardial infarction and stroke as well as congestive heart failure. It could be suggested that vitamin D deficiency contributes to the development of CVD through its association with risk factors, such as diabetes and hypertension. However, direct effects of vitamin D on the cardiovascular system may also be involved. Vitamin D receptors are expressed in a variety of tissues, including cardiomyocytes, vascular smooth muscle cells and endothelial cells and vitamin D has been shown to affect inflammation and cell proliferation and differentiation. While much evidence supports a potential antiatherosclerotic effect of vitamin D, prospective, placebo-controlled randomized as well as mechanistic studies are needed to confirm this association. Since vitamin D deficiency is easy to screen for and treat, the confirmation of such an association could have important implications for both, patient care and health policy.