Glycaemic Control in Diabetes.

Reduction of glucose is the hallmark of diabetes therapy proven to reduce micro- and macro-vascular risk in patients with type 1 diabetes. However glucose-lowering efficacy trials in type 2 diabetes didn't show major cardiovascular benefit. Then, a paradigm change in the treatment of patients with type 2 diabetes has emerged due to the introduction of new blood glucose-lowering agents. Cardiovascular endpoint studies have proven HbA1c-independent cardioprotective effects for GLP-1 receptor agonists and SGLT-2 inhibitors. Furthermore, SGLT-2 inhibitors reduce the risk for heart failure and chronic kidney disease. Mechanisms for these blood glucose independent drug target-related effects are still an enigma. Recent research has shown that GLP-1 receptor agonists might have anti-inflammatory and plaque stabilising effects whereas SGLT-2 inhibitors primarily reduce pre- and after-load of the heart and increase work load efficiency of the heart. In addition, reduction of intraglomerular pressure, improved energy supply chains and water regulation appear to be major mechanisms for renoprotection by SGLT-2 inhibitors. These studies and observations have led to recent changes in clinical recommendations and treatment guidelines for type 2 diabetes. In patients with high or very high cardio-renal risk, SGLT-2 inhibitors or GLP-1 receptor agonists have a preferred recommendation independent of baseline HbA1c levels due to cardioprotection. In patients with chronic heart failure, chronic kidney disease or at respective risks SGLT-2 inhibitors are the preferred choice. Therefore, the treatment paradigm of glucose control in diabetes has changed towards using diabetes drugs with evidence-based organ protection improving clinical prognosis.

Digital intervention increases influenza vaccination rates for people with diabetes in a decentralized randomized trial.

People with diabetes (PWD) have an increased risk of developing influenza-related complications, including pneumonia, abnormal glycemic events, and hospitalization. Annual influenza vaccination is recommended for PWD, but vaccination rates are suboptimal. The study aimed to increase influenza vaccination rate in people with self-reported diabetes. This study was a prospective, 1:1 randomized controlled trial of a 6-month Digital Diabetes Intervention in U.S. adults with diabetes. The intervention group received monthly messages through an online health platform. The control group received no intervention. Difference in self-reported vaccination rates was tested using multivariable logistic regression controlling for demographics and comorbidities. The study was registered at clinicaltrials.gov: NCT03870997. A total of 10,429 participants reported influenza vaccination status (5158 intervention, mean age (±SD) = 46.8 (11.1), 78.5% female; 5271 control, Mean age (±SD) = 46.7 (11.2), 79.4% female). After a 6-month intervention, 64.2% of the intervention arm reported influenza vaccination, vers us 61.1% in the control arm (diff = 3.1, RR = 1.05, 95% CI [1.02, 1.08], p = 0.0013, number needed to treat = 33 to obtain 1 additional vaccination). Completion of one or more intervention messages was associated with up to an 8% increase in vaccination rate (OR 1.27, 95% CI [1.17, 1.38], p < 0.0001). The intervention improved influenza vaccination rates in PWD, suggesting that leveraging new technology to deliver knowledge and information can improve influenza vaccination rates in high-risk populations to reduce public health burden of influenza. Rapid cycle innovation could maximize the effects of these digital interventions in the future with other populations and vaccines.

The natural history of classic galactosemia: lessons from the GalNet registry.

BACKGROUND: Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients. METHODS: Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018. RESULTS: Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome. CONCLUSION: This study describes the natural history of classic galactosemia based on the hitherto largest data set.

Efficacy and safety of alirocumab in people with prediabetes vs those with normoglycaemia at baseline: a pooled analysis of 10 phase III ODYSSEY clinical trials.

AIM: To assess the lipid-lowering efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in people with hypercholesterolaemia and prediabetes at baseline vs people with normoglycaemia at baseline in a pooled analysis of 10 ODYSSEY phase III trials. METHODS: People classified as having prediabetes had baseline HbA1c ≥39 mmol/mol (5.7%) and <48 mmol/mol (6.5%), or two baseline fasting plasma glucose values ≥5.6 mmol/l (100 mg/dl) but no more than one fasting plasma glucose value ≥7.0 mmol/l (126 mg/dl), or had specific terms reported in their medical history; people diagnosed with diabetes at baseline were excluded, and the remainder were classified as having normoglycaemia. Participants received alirocumab or control (placebo/ezetimibe) for 24-104 weeks, with maximally tolerated statin in most cases. The primary efficacy endpoint was LDL cholesterol reductions from baseline to week 24 in the intention-to-treat population using the mixed-effect model with a repeated measures approach. RESULTS: Reductions in LDL cholesterol from baseline to week 24 with alirocumab were 44.0-61.8% (prediabetes group) and 45.8-59.5% (normoglycaemia group). In both subgroups, LDL cholesterol reductions were generally similar in those with and without baseline triglycerides ≥1.7 mmol/l (150 mg/dl). Alirocumab was not associated with changes in HbA1c or fasting plasma glucose over time in either subgroup (up to 24 months' follow-up). Adverse event rates were generally similar in those with and without prediabetes. CONCLUSIONS: Over a mean follow-up of 24-104 weeks, alirocumab treatment resulted in significant LDL cholesterol reductions from baseline that were similar in participants with prediabetes and those with normoglycaemia at baseline, with no effect on glycaemia and a safety profile similar to that of the control.

Can LDL cholesterol be too low? Possible risks of extremely low levels.

Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important.

Efficacy and safety of alirocumab in insulin-treated patients with type 1 or type 2 diabetes and high cardiovascular risk: Rationale and design of the ODYSSEY DM-INSULIN trial.

AIMS: The coadministration of alirocumab, a PCSK9 inhibitor for treatment of hypercholesterolaemia, and insulin in diabetes mellitus (DM) requires further study. Described here is the rationale behind a phase-IIIb study designed to characterize the efficacy and safety of alirocumab in insulin-treated patients with type 1 (T1) or type 2 (T2) DM with hypercholesterolaemia and high cardiovascular (CV) risk. METHODS: ODYSSEY DM-INSULIN (NCT02585778) is a randomized, double-blind, placebo-controlled, multicentre study that planned to enrol around 400 T2 and up to 100 T1 insulin-treated DM patients. Participants had low-density lipoprotein cholesterol (LDL-C) levels at screening≥70mg/dL (1.81mmol/L) with stable maximum tolerated statin therapy or were statin-intolerant, and taking (or not) other lipid-lowering therapy; they also had established CV disease or at least one additional CV risk factor. Eligible patients were randomized 2:1 to 24weeks of alirocumab 75mg every 2weeks (Q2W) or a placebo. Alirocumab-treated patients with LDL-C≥70mg/dL at week 8 underwent a blinded dose increase to 150mg Q2W at week 12. Primary endpoints were the difference between treatment arms in percentage change of calculated LDL-C from baseline to week 24, and alirocumab safety. RESULTS: This is an ongoing clinical trial, with 76 T1 and 441 T2 DM patients enrolled; results are expected in mid-2017. CONCLUSION: The ODYSSEY DM-INSULIN study will provide information on the efficacy and safety of alirocumab in insulin-treated individuals with T1 or T2 DM who are at high CV risk and have hypercholesterolaemia not adequately controlled by the maximum tolerated statin therapy.

[Diabetology as an interdisciplinary challenge]. / Diabetologie als fächerübergreifende interdisziplinäre Herausforderung.

Type 2 diabetes mellitus is a growing chronic disease with a complex pathophysiology and multiple therapeutic options. Clinical prognosis is determined by multimorbidity and cardiovascular complications. For example, the prognosis of patients with diabetes hospitalized for heart failure is very poor with up to 50% mortality rate over the 3 years thereafter. Therefore, three levels have to be addressed in our approach to interdisciplinary diabetes care: screening and prevention, efficient patient-centered drug therapy, and a strategy for care including social environment of the patient suffering from complex diseases. Thus, we need diabetes specialists in out- and in-patient settings. Transsectoral interdisciplinary approaches to clinical care, as exemplary shown for the treatment of the diabetes foot syndrome, should be developed for other comorbidities, like renal and heart failure, respectively. The basis in the therapy of the cardiometabolic high-risk patient is prevention and multimodal treatment of cardiovascular risk factors. In this context, it is interesting to note that new cardiovascular outcome trials with a so-called safety design have shown that the GLP-1 receptor agonist liraglutide and the SGLT-2 inhibitor empagliflozin can reduce cardiovascular event rates. In addition, empagliflozin has significantly reduced the rate of hospitalization for heart failure. The latter has been included in the recent guidelines on heart failure by the European Society of Cardiology.

[PCSK9 inhibitors : New treatment option in clinical practice]. / PCSK9-Inhibitoren : Neue Therapieoption im klinischen Alltag.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors leading to their degradation in the liver. Inhibition of PCSK9 leads to an increase in LDL receptors and as a result to a reduction of LDL cholesterol in blood. Currently, two antibodies against PCSK9 are available for clinical treatment in Germany, evolocumab (Repatha®) and alirocumab (Praluent®). Clinical studies have shown that treatment with these antibodies, which must be subcutaneously injected by patients every 2 or 4 weeks, in addition to an already existing lipid therapy can lower the LDL cholesterol level in blood by an average of 50-60 %. Data from previous study programs show that this treatment is safe although long-term data are still lacking. The results of currently running cardiovascular endpoint studies are not yet available, whereby a beneficial effect is to be expected after the preliminary analyses. These novel effective therapy approaches open up new perspectives for the treatment of patients whose LDL cholesterol values are still in excess of the corresponding target values despite previous maximum lipid-reducing therapy and suffer from a preexisting cardiovascular disease, statin intolerance, genetic forms of familiar hypercholesterolemia and patients on LDL apheresis.

[New AHA and ACC guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk : Statement of the D•A•CH Society for Prevention of Cardiovascular Diseases, the Austrian Atherosclerosis Society and the Working Group on Lipids and Atherosclerosis (AGLA) of the Swiss Society for Cardiology]. / Neue AHA- und ACC-Leitlinie zur Risikoreduktion von Herz-Kreislauf-Erkrankungen durch Cholesterinsenkung : Stellungnahme der D•A•CH-Gesellschaft Prävention von Herz-Kreislauf-Erkrankungen e. V., der Österreichischen Atherosklerose Gesellschaft und der Arbeitsgruppe Lipide und Atherosklerose (AGLA) der Schweizer Gesellschaft für Kardiologie.

Guidelines for the reduction of cholesterol to prevent atherosclerotic vascular events were recently released by the American Heart Association and the American College of Cardiology. The authors claim to refer entirely to evidence from randomized controlled trials, thereby confining their guidelines to statins as the primary therapeutic option. The guidelines derived from these trials do not specify treatment goals, but refer to the percentage of cholesterol reduction by statin medication with low, moderate, and high intensity. However, these targets are just as little tested in randomized trials as are the cholesterol goals derived from clinical experience. The same applies to the guidelines of the four patient groups which are defined by vascular risk. No major statin trial has included patients on the basis of their global risk; thus the allocation criteria are also arbitrarily chosen. These would actually lead to a significant increase in the number of patients to be treated with high or maximum dosages of statins. Also, adhering to dosage regulations instead of cholesterol goals contradicts the principles of individualized patient care. The option of the new risk score to calculate lifetime risk up to the age of 80 years in addition to the 10-year risk can be appreciated. Unfortunately it is not considered in the therapeutic recommendations provided, despite evidence from population and genetic studies showing that even a moderate lifetime reduction of low-density lipoprotein (LDL) cholesterol or non-HDL cholesterol has a much stronger effect than an aggressive treatment at an advanced age. In respect to secondary prevention, the new American guidelines broadly match the European guidelines. Thus, the involved societies from Germany, Austria and Switzerland recommend continuing according to established standards, such as the EAS/ESC guidelines.

[Lipid therapy for patients with coronary heart disease and diabetes. Current state and perspectives]. / Lipidtherapie bei koronarer Herzkrankheit und Diabetes. Gegenwärtiger Stand und Perspektiven.

For patients with diabetes mellitus and coronary heart disease high-dose statin therapy is recommended independent of basal low density lipoprotein (LDL) cholesterol levels and with a target value <70 mg/dl (1.8 mmol/l). Drug combinations which lower LDL, e.g. cholesterol absorption inhibitors, are an option. Fibrates have not been proven to have a cardiovascular advantage but these drugs could be of value in diabetic microangiopathy. A low level of high density lipoprotein (HDL) cholesterol is the most common phenomenon in diabetes. Clinical endpoint studies for the combination with nicotinic acid were negative but therapeutic alternatives are lacking. Therefore, statin therapy is the primary lipid lowering therapy also for diabetic dyslipidemia.

[SREBP-1 and fatty liver. Clinical relevance for diabetes, obesity, dyslipidemia and atherosclerosis]. / SREBP-1 und Fettleber. Klinische Bedeutung für Diabetes, Adipositas, Dyslipidämie und Atherosklerose.

Insulin resistance and visceral fat distribution usually play a major role in the development of clinical aspects of the metabolic syndrome, such as dyslipidemia, diabetes and atherosclerosis. In this review, the focus will be on some novel relationships with a fatty liver, for which susceptibility appears to be mediated by the activity of transcription factors, such as sterol regulatory element-binding protein 1 (SREBP-1). In addition to this molecular aspect therapeutic life-style modifications, such as weight reduction which are associated with increased insulin sensitivity and a decrease of fat in the liver will be discussed.

[Combined analyses of paraoxonase-1 and IGF-2 polymorphism in polycystic ovary syndrome]. / Kombinierte Analyse von Paraoxonase-1- und IGF-2-Polymorphismen bei polyzystischem Ovarsyndrom.

BACKGROUND: Apart from impaired reproductive function patients with polycystic ovary syndrome (PCOS) also have signs and symptoms belonging to the metabolic syndrome. A genetic basis for PCOS is likely as the syndrome clusters in families. Putative candidate genes are paraoxonase (PON)-1 gene and the IGF-2 INS1/VTR IGF cluster, which have been shown to be genetically linked to lipid metabolism o insulin sensitivity, two major aspects of the PCOS phenotype. PATIENTS AND METHODS: The ApaI polymorphism (rs:680) in the IGF-2 cluster and the -108 polymorphism (rs:705 379) in PON-1 were evaluated in a collective of 153 PCOS patients and 178 age and BMI matched controls for an association to PCOS. RESULTS: The polymorphism in the IGF-2 cluster was identified in both groups in comparable frequencies (PCOS/control: A: 0.351/0.325; G: 0.648/0.674; OR: 0.8886, 95 %CI 0,648-1.2236) and equal genotype distribution (PCOS/control: GG: 0.399/0.461; AG: 0.4962/0.4277; AA: 0.1042/0.111). Frequencies of the PON-1 polymorphism were also comparable (PCOS/control: T: 0.493/0.483; C: 0.5633/0.5168; OR: 0.9569 95 % CI: 0.707-1.43024), but the distribution (PCOS/control: CC: 0.2679/0.2032; CT: 0.4768/0.628; TT: 0.258/0.169) was significantly different. The combined analyses of both polymorphism revealed that the genotypes IGF-2 (GG)/ PON-1 (TT) with OR 1.64741 (95 % CI 0.7388 - 3.6735) and IGF-2 (AA)/ PON-1 (TT) with OR 2.6733 (95 % CI 0.7579 - 9.4291) were more frequent in the PCOS group, whereas the genotype IGF-2 (AA)/ PON-1 (CC) did not occur in the PCOS group at all. According to the molecular analyses significant differences in serum parameters were identified. CONCLUSION: This investigation indicates, that only the combined analyses of putative candidate genes allowed a genotype-phenotype correlation in PCOS.

Increased low grade inflammatory serum markers in patients with Polycystic ovary syndrome (PCOS) and their relationship to PPARgamma gene variants.

The Polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder in premenopausal women and is associated with features of the insulin resistance syndrome, altered glucose homeostasis, and central obesity. Inflammation appears to be a link between obesity and insulin resistance, because adipose tissue is one major source of proinflammatory cytokines. Since peroxisome proliferator-activated receptor (PPAR)gamma affects adipocyte differentiation as well as insulin sensitivity, we investigated whether the levels of proinflammatory factors in PCOS patients are related to sequence variations of the PPAR gamma gene. Proinflammatory cytokine levels, i.e. IL-1 beta, IL-6, IL-7, IL-8, IL-17 and TNFalpha, were evaluated in PCOS patients (n=21) in comparison to obese controls (n=120). Next to this the complete coding sequence of the PPAR gamma gene was investigated by resequencing all probands. We show that the levels of IL-8 and IL-17 were unchanged, IL-1 beta, IL-6 and TNFalpha were elevated and the level of IL-7 was decreased in PCOS patients compared to obese controls. Sequence analyses of the PPAR gamma gene indicated that neither the common polymorphisms P12A or H478 H, nor novel polymorphisms (E79Q, V32G, -39 T>C, c.480 +33 t > g,) or unique sequence variations (S22S, A23A, T41A, S226C, K272 T, I484I, c.819 +24 a>c) detected in this investigation revealed evidence for a direct association of PPAR gamma with altered IL-7, IL-1beta, IL-6 and TNFalpha levels in PCOS patients. So, alterations in inflammatory serum markers appear to be a feature of PCOS per se, and are independent of PPAR gamma variants.