The German CaRe high registry for familial hypercholesterolemia - Sex differences, treatment strategies, and target value attainment.

Background and aims: Familial hypercholesterolemia (FH) is among the most common genetic disorders in primary care. However, only 15% or less of patients are diagnosed, and few achieve the goals for low-density lipoprotein cholesterol (LDL-C). In this analysis of the German Cascade Screening and Registry for High Cholesterol (CaRe High), we examined the status of lipid management, treatment strategies, and LDL-C goal attainment according to the ESC/EAS dyslipidemia guidelines. Methods: We evaluated consolidated datasets from 1501 FH patients diagnosed clinically and seen either by lipid specialists or general practitioners and internists. We conducted a questionnaire survey of both the recruiting physicians and patients. Results: Among the 1501 patients, 86% regularly received lipid-lowering drugs. LDL-C goals were achieved by 26% and 10% of patients with atherosclerotic cardiovascular disease (ASCVD) according to the 2016 and 2019 ESC/EAS dyslipidemia guidelines, respectively. High intensity lipid-lowering was administered more often in men than in women, in patients with ASCVD, at higher LDL-C and in patients with a genetic diagnosis of FH. Conclusions: FH is under-treated in Germany compared to guideline recommendations. Male gender, genetic proof of FH, treatment by a specialist, and presence of ASCVD appear to be associated with increased treatment intensity. Achieving the LDL-C goals of the 2019 ESC/EAS dyslipidemia guidelines remains challenging if pre-treatment LDL-C is very high.

[State of the art: lipoprotein apheresis]. / State of the Art: Lipoproteinapherese.

Lipoprotein apheresis (LA) is usually a last resort in cardiovascular high-risk patients in the context of secondary prevention after lifestyle measures and maximal pharmacotherapy have failed to prevent the occurrence of new atherosclerotic cardiovascular events (ASCVDE) or to achieve the internationally accepted target values for LDL cholesterol (LDL-C). Patients with homozygous familial hypercholesterolemia (hoFH), in whom myocardial infarctions can occur even in children < 10 years of age without adequate therapy, often owe their survival to LA (used here in primary prevention). Severe hypercholesterolemia (HCH) can often be well controlled with modern potent lipid-lowering agents, including PCSK9 approaches, so that the need for LA has decreased here over the years. In contrast, the number of patients in whom elevation of lipoprotein(a) (Lp(a)) is relevant to atherogenesis is increasing in applications to the apheresis committees of the associations of panel physicians (KV). For this indication, LA is currently the only therapeutic procedure approved by the Federal Joint Committee (G-BA). LA significantly reduces the new occurrence of ASCVDE (comparison with the situation before the start of LA), especially in Lp(a) patients. There are convincing observational studies and a German LA Registry with now 10-year data, but there is no randomized controlled trial. This had been requested by the G-BA in 2008, and a corresponding concept was designed but not accepted by the ethics committee. In addition to the highly effective reduction of atherogenic lipoproteins, many discussed pleiotropic effects of LA itself, the medical rounds and motivating discussions also with the nursing staff, which take place within the weekly LA, certainly contribute to the success of the therapy (steady adjustment of all cardiovascular risk factors, lifestyle measures including smoking cessation, adherence of medication intake). This review article summarizes and discusses the study situation, clinical practical experience as well as the future of LA against the background of the currently rapid development of new pharmacotherapies.

The development of lipoprotein apheresis in Saxony in the last years.

METHODS: Three hundred thirty-nine patients (230 men, 109 women) treated with lipoprotein apheresis in Saxony, Germany, in 2018 are described in terms of age, lipid pattern, risk factors, cardiovascular events, medication, and number of new admissions since 2014, and the data are compared with figures from 2010 to 2013. RESULTS: Patients were treated by 45.5 physicians in 16 lipoprotein apheresis centers. With about 10 patients per 100 000 inhabitants, the number of patients treated with lipoprotein apheresis in Saxony is twice as high as in Germany as a whole. The median treatment time was 3 years. Almost all patients had hypertension; type 2 diabetes mellitus was seen significantly more often in patients with low Lipoprotein(a). Cardiovascular events occurred in almost all patients before initiation of lipoprotein apheresis, under apheresis therapy the cardiovascular events rate was very low in this high-risk group. For some cardiovascular regions even no events could be observed. CONCLUSIONS: The importance of lipoprotein apheresis in Saxony had been increasing from 2010 to 2018.

Repeated lipoprotein apheresis and immune response: Effects on different immune cell populations.

BACKGROUND: Atherosclerosis is considered a chronic inflammation of arterial vessels with the involvement of several immune cells causing severe cardiovascular diseases. Lipoprotein apheresis (LA) improves cardiovascular conditions of patients with severely disturbed lipid metabolism. In this context, little is known about the impact of LA on various immune cell populations, especially over time. METHODS: Immune cells of 18 LA-naïve patients starting weekly LA treatment were analyzed before and after four apheresis cycles over the course of 24 weeks by flow cytometry. RESULTS AND CONCLUSIONS: An acute lowering effect of LA on T cell and natural killer (NK) cell subpopulations expressing CD69 was observed. The non-classical and intermediate monocyte subsets as well as HLA-DR+ 6-sulfo LacNAc+ monocytes were significantly reduced during the apheresis procedure. We conclude that LA has the capacity to alter various immune cell subsets. However, LA has mainly short-term effects than long-term consequences on proportions of immune cells.

COVID-19 and Lipid Disorders.

An elevated cholesterol concentration has been suspected to increase the susceptibility for SARS-COV-2 infection. Cholesterol plays a central role in the mechanisms of the SARS-COV-2 infection. In contrast, higher HDL-cholesterol levels seem to be protective. During COVID-19 disease, LDL-cholesterol and HDL-cholesterol appear to be decreased. On the other hand, triglycerides (also in different lipoprotein fractions) were elevated. Lipoprotein(a) may increase during this disease and is most probably responsible for thromboembolic events. This lipoprotein can induce a progression of atherosclerotic lesion formation. The same is suspected for the SARS-COV-2 infection itself. COVID-19 patients are at increased risk of incident cardiovascular diseases, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure, and thromboembolic disorders. An ongoing lipid-lowering therapy, including lipoprotein apheresis, is recommended to be continued during the COVID-19 disease, though the impact of lipid-lowering drugs or the extracorporeal therapy on prognosis should be studied in further investigations.

[State of the Art: Statin Therapy]. / State of the Art: Therapie mit Statinen.

This review summarizes the pharmacology and clinical use of HMG-CoA reductase inhibitors, statins. LDL-Cholesterol lowering with statins reduces atherosclerotic cardiovascular risk by approx. one quater per year of treatment. The efficacy and safety of statins are demonstrated by randomized trials irrespective of the patient's age. The synthetic statins, rosuvastatin and atorvastatin, are superior with regard to LDL-C lowering, half-life and drug-interactions compared to the older statins such as simvastatin. Modern lipid lowering therapy uses individualized statin-based combination therapies.

Low-density lipoprotein cholesterol goal attainment in Germany: Results from the DA VINCI study.

Background and aims: Cardiovascular mortality is high in Germany. For patients with high or very high cardiovascular risk, the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines recommend intensive lipid lowering therapy (LLT). This study aimed to assess dyslipidaemia management and achievement of the ESC/EAS guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals. Methods: This European 18-country, cross-sectional, observational DA VINCI study (EUPAS22075) collected data during a single visit between June 2017 and November 2018 and included LLT in the preceding 12 months and the patients' most recent LDL-C measurement. Achievement of the risk-based 2016 and 2019 ESC/EAS LDL-C goals while receiving stabilized LLT was assessed. Data from the German cohort are presented here. Results: Seven German sites enrolled a total of 421 primary and secondary prevention patients, 327 were receiving stabilized LLT at the time of LDL-C measurement, i.e. statin monotherapy of high (16%; n = 53), moderate (49%; n = 160) or low (7%; n = 24) intensity, ezetimibe combination (18%; n = 58), proprotein convertase subtilisin/kexin type 9 antibody combination (3%; n = 9), and other LLT (7%; n = 23). The 2016 and 2019 risk-based LDL-C goals were attained by 46% (n = 149) and 28% (n = 92) of patients, respectively. Conclusions: There is a large gap between ESC/EAS recommendations and LDL-C goal achievement in routine clinical practice in high and very high-risk patients in Germany. Low-to-moderate-intensity statin monotherapy was the most frequently used LLT; use of high-intensity statins and combination therapy was limited. In addition to optimizing statin intensity, combination with non-statin LLT may be needed in most of these patients.

Hypertriglyceridaemia: contemporary management of a neglected cardiovascular risk factor.

Hypertriglyceridaemia represents one of the most prevalent lipid abnormalities, however it is often eclipsed by focus on LDL cholesterol and is frequently overlooked by clinicians, despite it being an important cardiovascular risk factor. For most patients, hypertriglyceridaemia arises from a combination of environmental factors and multiple genetic variations with small effects. Even in cases with apparent familial clustering of hypertriglyceridaemia, a monogenetic cause is rarely identified. Common secondary causes include obesity, uncontrolled diabetes, alcohol, and various commonly used drugs. Correction of these factors, along with lifestyle optimisation, should be prioritised prior to commencing medication. The goal of drug treatment is to reduce the risk of cardiovascular disease in those with moderate hypertriglyceridaemia and the risk of pancreatitis in those with severe hypertriglyceridaemia. Recent and ongoing trials demonstrate the important role of triglycerides (TG) in determining residual risk in patients with cardiovascular disease (CVD) already established on statin therapy. Novel and emerging data on omega-3 fatty acids (high-dose icosapent ethyl) and the selective PPAR modulator pemafibrate are eagerly awaited and may provide further clarity for clinicians in determining which patients will benefit from TG lowering and help inform clinical guidelines. There are numerous novel therapies on the horizon that reduce TG by decreasing the activity of proteins that inhibit lipoprotein lipase such as apolipoprotein C-III (including Volanesorsen which was recently approved in Germany) and ANGPTL 3/4 which may offer promise for the future.

Why Some Patients Undergoing Lipoprotein Apheresis Therapy Develop New Cardiovascular Events?

Lipoprotein apheresis (LA) is an effective tool to reduce cardiovascular events (CVEs) in high-risk patients with elevations of low density lipoprotein-cholesterol (LDL-C) and/or Lipoprotein(a) (Lp(a)). All patients included into this retrospective analysis had experienced CVEs before the start of the LA therapy. We compared personal and lab data in two groups: CVEx/0 (n 60) with no new events during LA therapy, CVEx/1+ (n 48) with at least one new event. Patients of Group CVEx/1+ were about 5 years older when they had started the extracorporeal therapy, and they experienced more CVEs prior to that timepoint. There was a positive correlation between the number of CVEs before and during LA therapy. No differences were seen with respect to lipid concentrations, even after a correction of LDL-C concentrations for the LDL-C transported with Lp(a) particles. LA sessions effectively reduced both LDL-C and Lp(a). Lp(a) levels measured before LA sessions were lower than those measured initially. It appeared difficult to reach the target values for LDL-C published in the ESC/EAS Guideline in 2019, although all patients were maximally treated including drugs when tolerated. In conclusion, it will be important to initiate an LA therapy earlier, at least after a second CVE and at a younger age.

Extracorporeal apheresis therapy for Alzheimer disease-targeting lipids, stress, and inflammation.

Current therapeutic approaches to Alzheimer disease (AD) remain disappointing and, hence, there is an urgent need for effective treatments. Here, we provide a perspective review on the emerging role of "metabolic inflammation" and stress as a key factor in the pathogenesis of AD and propose a novel rationale for correction of metabolic inflammation, increase resilience and potentially slow-down or halt the progression of the neurodegenerative process. Based on recent evidence and observations of an early pilot trial, we posit a potential use of extracorporeal apheresis in the prevention and treatment of AD. Apolipoprotein E, lipoprotein(a), oxidized LDL (low density lipoprotein)'s and large LDL particles, as well as other proinflammatory lipids and stress hormones such as cortisol, have been recognized as key factors in amyloid plaque formation and aggravation of AD. Extracorporeal lipoprotein apheresis systems employ well-established, powerful methods to provide an acute, reliable 60-80% reduction in the circulating concentration of these lipid classes and reduce acute cortisol levels. Following a double-membrane extracorporeal apheresis in patients with AD, there was a significant reduction of proinflammatory lipids, circulating cytokines, immune complexes, proinflammatory metals and toxic chaperones in patients with AD. On the basis of the above, we suggest designing clinical trials to assess the promising potential of such "cerebropheresis" treatment in patients with AD and, possibly, other neurodegenerative diseases.

Actual situation of lipoprotein apheresis in patients with elevated lipoprotein(a) levels.

An elevation of lipoprotein(a) (Lp(a)) is an internationally recognized atherogenic risk factor, documented in epidemiological studies, in studies with Mendelian randomization and in genome-wide association studies (GWAS). At present, no drug is available to effectively reduce its concentration. In Germany, an elevation of Lp(a) associated with progressive cardiovascular diseases is officially recognized as an indication for a lipoprotein apheresis (LA). The number of patients who were treated with LA with this abnormality was steadily increasing in the years 2013-2016 - the official data are reported. In all new patients, who started to be treated at our LA center in 2017 (n = 20) the increased Lp(a) was a main indication for extracorporeal therapy, though some of them also showed clearly elevated LDL cholesterol (LDL-C) concentrations despite being treated with a maximal tolerated lipid-lowering drug therapy. A diabetes mellitus was seen in 5 patients. The higher was the Lp(a) level before the first LA session, the higher was the cardiovascular risk. Lp(a) concentrations measured before LA sessions were usually about 20% lower than those before the start of the LA therapy. Acutely, Lp(a) levels were reduced by about 70%. Following LA sessions the Lp(a) levels increased and in the majority reach pre-session concentrations after one week. Thus a weekly interval is best for the patients, but a few may need two sessions per week to stop the progress of atherosclerosis. The interval mean values were about 39% lower than previous levels. Several papers had been published showing a higher efficiency of LA therapy on the incidence of cardiovascular events in patients with high Lp(a) values when comparing with hypercholesterolemic patients with normal Lp(a) concentrations. Russian specific anti-Lp(a) columns positively affected coronary atherosclerosis. PCSK9 inhibitors reduce Lp(a) concentrations in many patients and in this way have a positive impact on cardiovascular outcomes. In the future, an antisense oligonucleotide against apolipoprotein(a) may be an alternative therapeutic option, provided a clear-cut reduction of cardiovascular events will be demonstrated.

Short- and long-term effects of lipoprotein apheresis on plasma hormones in patients with therapy-resistant dyslipidemia.

BACKGROUND AND AIMS: Lipoprotein apheresis (LA) is a highly effective method to improve the clinical and metabolic situation in patients with therapy-resistant disorders of lipid metabolism. Cholesterol is the substrate for the synthesis of all steroid hormones. If repeated massive reduction of LDL-cholesterol may interfere with human adrenal steroidogenesis, and could become clinically relevant is unknown, so far. Thus, the aim of this study was to determine possible short- and long-term effects of LA on blood plasma levels of ACTH, cortisol, aldosterone, DHEAS, renin and testosterone. METHODS: In total, 39 patients, treated with one of four LA techniques were studied: 1. Lipid Filtration (LF; n = 7), 2. Dextran Sulfate Adsorption (DSA; n = 7), 3. Membrane Filtration Optimised Novel Extracorporeal Treatment (MONET; n = 8), and 4. Direct Absorption of Lipoproteins (DALI; n = 15). Hormone levels were analyzed before and after five LA sessions with an interval of 20 weeks covering a total observation time of two years. In addition patients were comprehensively characterized by clinical and laboratory data. RESULTS: Patients treated with LA revealed an acute reduction of steroid hormones and ACTH, independent of apheresis technology but no long-term insufficiency in steroidogenesis was observed. Plasma renin levels were stable in LF patients and were highly elevated in patients under DSA, MONET and DALI apheresis throughout the observation period. CONCLUSIONS: In summary, these data suggest that although different LA techniques considerably differ in their acute effects on hormone levels during LA, they did not alter long-term hormone levels sustainably.

Experience with proprotein convertase subtilisin/kexine type 9 inhibitors (PCSK9i) in patients undergoing lipoprotein apheresis.

PURPOSE: We analyzed efficacy and safety of PCSK9i in patients undergoing lipoprotein apheresis (LA) and in patients treated at our outpatient department for metabolic disorders. METHODS: The medical records of 40 LA patients, taking PCSK9i were reviewed with respect to LDL-cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) lowering as well as occurrence of adverse events. Furthermore, we analyzed the data of 152 patients of our outpatient department, undergoing PCSK9i therapy. RESULTS: Mean pre-apheresis LDL-C value was reduced by PCSK9i from 3.71 ±â€¯1.19 to 1.78 ±â€¯0.84 mmol/l (53 ±â€¯12%). The relative lowering of the pre-apheresis Lp(a) was 20 ±â€¯12% (from 191 ±â€¯63.5 to 152 ±â€¯51.9 nmol/l). 25% of LA patients could stop LA after reaching LDL-C target after initiation of PCSK9i. 75% of the patients are continuing the regular LA therapy, showing an insufficient LDL-C lowering following PCSK9i injections or/and additionally elevated Lp(a) or/and adverse effects of PCSK9i, leading to the discontinuation of injections. The number of LA patients has grown from 112 in 2016 to 128 nowadays due to an increasing percentage of patients with elevated Lp(a) (79% and 89% respectively). The mean reduction rate of LDL-C under PCSK9i therapy in outpatients was 53.03%. In 34% of patients the target value could not be reached. 43% of persons suffered from adverse effects. CONCLUSIONS: 3/4 of LA patients could not stop extracorporeal treatment after PCSK9i administration. In hypercholesterolemic patients with coexisting elevated Lp(a) and progressive cardiovascular disease the combination of LA and PCSK9i could be beneficial. The total patients' number in LA units increases due to persons with Lp(a)-hyperlipoproteinemia.

Cardiovascular risk factors in patients with premature cardiovascular events attending the University of Dresden Lipid Clinic.

OBJECTIVES: Despite improved treatment, premature cardiovascular (CV) events remain a major health problem. Aim of this study was to evaluate the patterns of risk factors in patients with premature CV events. METHODS: CV risk factors (CVRF) were evaluated in 130 patients with a history of CV events (myocardial infarction, stroke, limb ischemia, stent and bypass intervention in any vessel bed) under 50 years of age attending our lipid clinic. Patients were also stratified according to their Lp(a) concentrations: group 1: 0-45 nmol/l (<18 mg/dl); group 2: >45-120 nmol/l (>18-50 mg/dl); group 3: >120 nmol/l (>50 mg/dl). RESULTS: The most common risk factors in our patients were male sex (75%), current (61%) and previous smoking (9%), arterial hypertension (70%), and a positive family history of early CV events (54%) and hyperlipidemia (69%). Only 27% had a BMI >30 kg/m2 and 14% had diabetes mellitus. 69% of patients with premature CV disease (CVD) showed Lp(a) levels > 120 nmol/l (>50 mg/dl). Patients with the highest Lp(a) showed a tendency of more frequent positive family histories of hyperlipidemia. They had experienced their first CV event on average 3 years earlier than those with low Lp(a). CV events predominantly involved coronary arteries. 85% of patients experienced at least one coronary event. CONCLUSION: In patients with premature CV disease male sex, smoking, hypertension, a positive family history and elevated Lp(a) are the most important CV risk factors. Lp(a) should be considered in the management of young patients with CV disease.

Metabolic and Non-Metabolic Peripheral Neuropathy: Is there a Place for Therapeutic Apheresis?

As the rate of obesity and the incidence of diabetes mellitus have been increasing, diabetic neuropathy has become the most common cause of peripheral neuropathy in developed countries. In addition, a variety of pathogenetically heterogeneous disorders can lead to impairment of the peripheral nervous system including amyloidosis, vitamin deficiencies, uremia and lipid disorders, alcohol abuse, autoimmune and infectious diseases as well as exposure to environmental toxins. We have noted that a combination of these disorders may aggravate the manifestations of peripheral diabetic neuropathy, an effect, which is most pronounced when metabolic and non-metabolic pathologies lead to cumulative damage. Current treatment options are limited and generally have unsatisfactory results in most patients. Therapeutic apheresis (INUSpherese®) allows the removal of metabolic, inflammatory, immunologic and environmental contributors to the disease process and may be an effective treatment option. We reviewed the developments in therapeutic apheresis for metabolic and non-metabolic peripheral neuropathy, including the current literature as well as data from our university diabetes center.

Correction to: Intravenous Ferric Carboxymaltose in Patients with Type 2 Diabetes Mellitus and Iron Deficiency: CLEVER Trial Study Design and Protocol.

In the original publication, the text in Table 2 stated 'Hypersensitivity to the active substance, to Ferinject, or to any of its excipients'.

Lipid-modifying therapy and low-density lipoprotein cholesterol goal attainment in patients with familial hypercholesterolemia in Germany: The CaReHigh Registry.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is amongst the most common genetic disorders encountered in primary care. Yet, only a minority of affected patients is diagnosed and treated. This interim analysis of the CaRe High Registry aims at examining the state of treatment and attainment of lipid goals in German FH patients. METHODS: The CaRe High registry includes FH patients from lipid clinics and private practices. Data have been collected using questionnaires filled in by the recruiting physicians and by interviewing the participating patients. RESULTS: We examined 512 F H patients diagnosed according to clinical criteria. Median age at the time of the first FH diagnosis was 39 (25th and 75th percentile: 27-50) years, median treatment naïve LDL cholesterol (LDL-C) was 239.4 mg/dl (6.19 mmol/l), 25th to 75th percentile 191.8-342.5 mg/dl (4.96-8.86 mmol/l). 27% of the participants did not receive lipid-lowering drugs. Among the patients treated with lipid-lowering drugs, 19% received a PCSK9 inhibitor (PCSK9i) in combination with a statin, 9% were treated with a PCSK9i alone and 3% were treated with a combination of PCSK9i and a non-statin drug. Patients with pre-existing CVD were more likely to be treated with lipid-lowering drugs and more likely to receive a PCSK9i, but LDL-C targets were only achieved by a minority of patients (<20%). Gap to target LDL-C was lowest and the median achieved LDL-C reduction was 1.4 times higher with PCSK9i treatment than with (oral) lipid-lowering therapy without PCSK9i. CONCLUSIONS: The Care High registry has included patients with the typical clinical features of familial hypercholesterolemia. PCSK9i treatment in addition to standard therapy allows attainment of target values in many patients with initially very high LDL-C.

The anorexigenic peptide neurotensin relates to insulin sensitivity in obese patients after BPD or RYGB metabolic surgery.

Neurotensin is a peptide with effects on appetite and intestinal lipid absorption. Experimental data suggest a role in glucose homeostasis, while human data is missing. Here, 20 morbidly obese subjects either underwent biliopancreatic diversion with duodenal switch (BPD), or Roux-en-Y gastric bypass (RYGB) in a randomized fashion. Before and 1 year after surgery, anthropometric data, body composition, clinical biochemistry, insulin sensitivity by means of euglycemic hyperinsulinemic clamps (HEC) and fasting plasma proneurotensin 1-117 were analyzed. Plasma proneurotensin increased significantly more 1 year after BDP than RYGB (P = 0.028), while weight loss was comparable. After metabolic surgery, proneurotensin correlated positively with insulin sensitivity (M-value) (r = 0.55, P < 0.001), while an inverse relationship with fasting glucose, HOMA-IR and HbA1c was observed (P < 0.05 for all components). After adjustment for age and gender, proneurotensin and BMI remained independently related with delta of M-value (ß = 0.46 and ß = 0.51, P < 0.05, resp.). From these data we conclude that proneurotensin positively correlates with insulin sensitivity uniquely after weight loss induced by metabolic surgery in humans. BDP leads to a stronger increase in the anorexigenic peptide compared to RYGB.

Intravenous Ferric Carboxymaltose in Patients with Type 2 Diabetes Mellitus and Iron Deficiency: CLEVER Trial Study Design and Protocol.

INTRODUCTION: HbA1c is the gold standard for glycemic control in pre-diabetes and diabetes. However, its validity has been questioned, especially in the presence of imbalanced iron homeostasis. The CLEVER trial aims to evaluate the relationship between iron deficiency and HbA1c (a biomarker for the diagnosis and therapeutic monitoring of type 2 diabetes) in a randomized, placebo-controlled, multicenter clinical trial. METHODS: The CLEVER (intravenous ferric CarboxymaLtosE for improVement of mEtabolic parameters in type 2 diabetes patients with iRon deficiency) trial is a randomized, single-blind, proof-of-concept study with two treatment arms. 140 men and women diagnosed with type 2 diabetes and iron deficiency will receive either placebo or ferric carboxymaltose (500 or 1000 mg) as intravenous infusions. The primary outcome measure is the change in HbA1c level between baseline and after 12 weeks of treatment. Secondary endpoints include change of iron status and metabolic markers as well as treatment safety and tolerability. Furthermore, the potential clinical improvement in quality of life and the reliability of HbA1c measurement in patients with type 2 diabetes and iron deficiency will be investigated. RESULTS: Both excessive iron and iron deficiency are associated with metabolic disorders; excessive iron is a risk factor for the development of diabetes, whereas iron deficiency is associated with obesity and insulin resistance. It has been suggested that iron increases insulin secretion in pancreatic beta-cells. CLEVER is the first study to investigate the hypothesis that intravenous substitution with ferric carboxymaltose reduces HbA1c levels in patients with type 2 diabetes and iron deficiency, thereby improving metabolic status and quality of life. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT01513369). FUNDING: GWT-TUD GmbH acts as sponsor of the clinical trial. Financial support is provided by Vifor Pharma.