CVOT Summit Report 2023: new cardiovascular, kidney, and metabolic outcomes.

The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5-6, 2024 ( http://www.cvot.org ).

CVOT Summit 2022 Report: new cardiovascular, kidney, and glycemic outcomes.

The 8th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Kidney, and Glycemic Outcomes was held virtually on November 10-12, 2022. Following the tradition of previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed outcomes trials as well as key trials important to the cardiovascular (CV) field. This year's focus was on the results of the DELIVER, EMPA-KIDNEY and SURMOUNT-1 trials and their implications for the treatment of heart failure (HF) and chronic kidney disease (CKD) with sodium-glucose cotransporter-2 (SGLT2) inhibitors and obesity with glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists. A broad audience of primary care physicians, diabetologists, endocrinologists, cardiologists, and nephrologists participated online in discussions on new consensus recommendations and guideline updates on type 2 diabetes (T2D) and CKD management, overcoming clinical inertia, glycemic markers, continuous glucose monitoring (CGM), novel insulin preparations, combination therapy, and reclassification of T2D. The impact of cardiovascular outcomes on the design of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) trials, as well as the impact of real-world evidence (RWE) studies on the confirmation of CVOT outcomes and clinical trial design, were also intensively discussed. The 9th Cardiovascular Outcome Trial Summit will be held virtually on November 23-24, 2023 ( http://www.cvot.org ).

Report from the CVOT Summit 2021: new cardiovascular, renal, and glycemic outcomes.

The 7th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Renal, and Glycemic Outcomes, was held virtually on November 18-19, 2021. Pursuing the tradition of the previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed CVOTs. This year's focus was placed on the outcomes of EMPEROR-Preserved, FIGARO-DKD, AMPLITUDE-O, SURPASS 1-5, and STEP 1-5. Trial implications for diabetes and obesity management and the impact on new treatment algorithms were highlighted for endocrinologists, diabetologists, cardiologists, nephrologists, and general practitioners. Discussions evolved from outcome trials using SGLT2 inhibitors as therapy for heart failure, to CVOTs with nonsteroidal mineralocorticoid receptor antagonists and GLP-1 receptor agonists. Furthermore, trials for glycemic and overweight/obesity management, challenges in diabetes management in COVID-19, and novel guidelines and treatment strategies were discussed.Trial registration The 8th Cardiovascular Outcome Trial Summit will be held virtually on November 10-11, 2022 ( http://www.cvot.org ).

Effects of analogue insulin in multiple daily injection therapy of type 2 diabetes on postprandial glucose control and cardiac function compared to human insulin: a randomized controlled long-term study.

BACKGROUND: The prevention of cardiovascular disease, including diastolic cardiac dysfunction with its high prevalence and ominous prognosis, is a therapeutic challenge for patients with type 2 diabetes. Both short and long-acting insulin analogues (AI) have been shown to reduce glucose variability and provide potential benefit for cardiovascular disease although the effects on cardiac function have not yet been evaluated. This long-term, prospective, randomized controlled trial in patients with type 2 diabetes (T2D) tested the hypothesis that a multiple daily injection regimen (MDI) with AI improves postmeal glucose excursions in comparison to human insulin (HI) and that the effects of AI improve diastolic cardiac function. METHODS: For 36 months, MDI treatment in 109 T2D patients was adapted every 3 months (targets: fasting glucose ≤ 110 mg/dl, postmeal glucose ≤ 150 mg/dl) in both groups: AI (insulin detemir and insulin aspart, n = 61) and HI (NPH-insulin and regular HI, n = 48). Diastolic cardiac function (myocardial velocity E' using tissue Doppler imaging and the mitral inflow ratio E/A) and vascular function were assessed before and 2 h after a standardized breakfast (48 g carbohydrates). At baseline, both groups were comparable with regards to demographic, cardiac and metabolic data. Analysis of data included traditional statistics as well as the use of a multiple imputation technique shown in brackets [ ]. RESULTS: At 36 months, the primary endpoint, postmeal glucose, decreased by 20 ± 62 mg/dl, p = 0.038 [p = 0.021] with AI and increased insignificantly with HI (inter-group p = 0.032 [p = 0.047]) to postmeal glucose levels of 161 ± 39 with AI vs. 195 ± 54 mg/dl with HI (inter-group p = 0.002 [p = 0.010]) whereas the levels of fasting glucose and HbA1c were comparable. With AI, postmeal E' improved by 0.6 ± 1.4 cm/s, p = 0.009 [p = 0.002] and fasting E' by 0.4 ± 1.4 cm/s, p = 0.069 [p = 0.013], however, E' remained unchanged with HI. These changes were consistent with those of the traditional parameter E/A. CONCLUSIONS: MDI with AI results in better postmeal glucose control compared to HI. The treatment with AI is associated with improved diastolic cardiac function. ClinicalTrials.gov (NTC00747409).

The role of co-morbidity in the selection of antidiabetic pharmacotherapy in type-2 diabetes.

Metformin is, if not contraindicated and if tolerated, usually preferred over other antidiabetic drugs for the first line treatment of type-2 diabetes. The particular decision on which antidiabetic agent to use is based on variables such as efficacy, cost, potential side effects, effects on weight, comorbidities, hypoglycemia, risk, and patient preferences. However, there is no guidance how to consider these in the selection of antidiabetic drug treatment. In this work, we aimed to summarize available evidence and tried to give pragmatic treatment recommendations from a clinical practice perspective.There are clear contraindications for some drugs in those with impaired renal and liver function and precautions in those with heart failure for the use of metformin (NYHA III-IV) and glitazones. On the other hand, GLP-1 analogs, DPP-4 inhibitors and acarbose are generally less critical and can be used in the majority of patients. We identified the following gaps with respect to the selection of antidiabetic drug treatment in patients with co-morbid disease conditions: 1) Guidelines fail to give advice on the use of specific antidiabetic drugs in patients with co-morbidity. 2) The literature is deficient in studies documenting antidiabetic drug use in patients with severely impaired renal function, diabetic retinopathy, cerebrovascular disease and systolic heart failure. 3) Further there are no specific data on patients with multiple of these co-morbid disease conditions. We postulate that differential use of antidiabetic drugs in patients with co-morbid disease constellations will help to reduce treatment related complications and might improve prognosis.

Rosiglitazone, but not glimepiride, improves myocardial diastolic function in association with reduction in oxidative stress in type 2 diabetic patients without overt heart disease.

The effects of thiazolidinediones on cardiac function are controversial in humans with type 2 diabetes (T2DM) and in animals. Given the high prevalence and prognostic relevance of diastolic myocardial dysfunction in T2DM, we tested the hypothesis that by reducing oxidative stress rosiglitazone, but not glimepiride, may improve diastolic function. This randomised cross-over study investigated 12 metformin-treated T2DM patients without cardiovascular disease before and after 16 weeks of additional therapy with rosiglitazone (8 mg daily) or glimepiride (3 mg daily). Systolic and diastolic myocardial velocity (E') were assessed with tissue Doppler. In spite of similar non-significant lowering of glycosylated haemoglobin (HbA1C), rosiglitazone, but not glimepiride, significantly improved E' (p=0.04), reduced malondialdehyde (p=0.028), lowered high-sensitivity C-reactive protein (hsCRP) (p=0.019), and increased adiponectin (p=0.002). For rosiglitazone, multivariate regression analysis revealed malondialdehyde reduction as an independent determinant of treatment-induced improvement in E'. The rosiglitazone-induced improvements of diastolic function and oxidative stress may be of prognostic relevance in choosing therapy for T2DM patients without overt heart disease.

Rhythmic gene expression in pituitary depends on heterologous sensitization by the neurohormone melatonin.

In mammals, many daily cycles are driven by a central circadian clock, which is based on the cell-autonomous rhythmic expression of clock genes. It is not clear, however, how peripheral cells are able to interpret the rhythmic signals disseminated from this central oscillator. Here we show that cycling expression of the clock gene Period1 in rodent pituitary cells depends on the heterologous sensitization of the adenosine A2b receptor, which occurs through the nocturnal activation of melatonin mt1 receptors. Eliminating the impact of the neurohormone melatonin simultaneously suppresses the expression of Period1 and evokes an increase in the release of pituitary prolactin. Our findings expose a mechanism by which two convergent signals interact within a temporal dimension to establish high-amplitude, precise and robust cycles of gene expression.

Beneficial effects of ramipril on myocardial diastolic function in patients with type 2 diabetes mellitus, normal LV systolic function and without coronary artery disease: a prospective study using tissue Doppler.

Angiotensin-converting enzyme (ACE) inhibitors can improve cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM). Myocardial diastolic function (Ve) is a known marker of cardiovascular prognosis. It could potentially indicate the effects of preventive therapy if evaluated by tissue Doppler. We tested the hypothesis that treatment with the ACE inhibitor ramipril has beneficial effects on Ve. In this study, 16 subjects on insulin therapy (eight receiving 10 mg ramipril/day compared to eight matched controls who were not treated with an ACE inhibitor) were followed up for a period of nine months. Myocardial and vascular function were assessed by tissue Doppler and ultrasound. In the ramipril group, Ve improved significantly after nine months of treatment (7.8+/-0.9 cm/s to 8.6+/-0.9 cm/s, p<0.04). Systolic blood pressure and intima media thickness (IMT) demonstrated a trend towards improvement. In controls, Ve remained unchanged and there was a trend towards deterioration in stiffness index beta (p<0.07). In conclusion, the observed improvement of myocardial diastolic function with ramipril in patients with T2DM is an encouraging result. It might contribute to the overall improvement that has been observed with hard cardiovascular end points.

[Diabetes mellitus and frequently associated endocrine diseases]. / Häufig miteinander assoziiert. Diabetes und endokrinologische Erkrankungen.

The simultaneous occurrence of type 1 or type 2 diabetes with various hormonal diseases (e.g. thyroid, adrenal, pituitary disease) is a frequent observation. A chronically poorly controlled metabolism can alter the hormone parameters of the diabetic. In contrast, an acute loss of metabolic control may be a sign of a newly manifesting hormonal disease, and needs always prompt an appropriate diagnostic work-up and treatment. In view of the frequency both of diabetes mellitus and thyroid disease, a regular check--at least yearly and always in case of unclear worsening of diabetic control--of thyroid gland function is mandatory. The aim is to provide appropriate treatment, and thus to stabilize the patient's metabolic status, as early as possible.

[Current treatment with oral antidiabetic agents]. / So liegen Sie mit der Stoffwechseleinstellung im Plan.

In the large majority of type 2 diabetics, the initial phase of the disease is characterized by insulin resistance. A primary insulin secretion disorder is seen only in normal-weight patients, and requires a differentiated therapeutic approach. Glinides make possible flexible meal-oriented stimulation of insulin secretion. Insulin resistance can be influenced by insulin sensitizers. In the overweight patient, biguanides (metformin) effectively lower blood sugar, either alone or in combination with other oral antidiabetic agents. Acarbose, and glitazone can delay progression to diabetes. Furthermore, acarbose, biguanides, and in particular glitazone, reduce cardiovascular events. For normal-weight patients, sulfonylureas are considered the first-line drug for monotherapy. Progressive insulin secretion deficiency and usually persistent insulin resistance requires insulin substitution in combination with oral antidiabetic agents or as conventional/intensified insulin therapy.

What is the role of general internists in the tertiary or academic setting?

The changing demography of European populations mandates a vital role for internists in caring for patients in each level of healthcare. Internists in the tertiary or academic setting are highly ranked in terms of their responsibilities: they are clinicians, educators, researchers, role models, mentors and administrators. Contrary to the highly focused approach of sub-specialties, general internists working in academic settings can ensure that coordinated care is delivered in the most cost-conscious and efficient way. Moreover, internal medicine is one of the most appropriate specialties in which to teach clinical reasoning skills, decision-making and analytical thinking, as well as evidence based, patient oriented medicine. Internists deal with challenging patients of the new millennium with a high burden of chronic diseases and polypharmacy; practice personalised medicine with a wide scientific background and so they are the perfect fit to establish and implement new tools for scientific research. In conclusion, internal medicine is developing a new identity as a specialty in its own right. The European Federation of Internal Medicine supports the concept of academic internists and calls upon the member countries to construct academic (general) internal medicine departments in their respective countries. As 'internal medicine is the cornerstone of every national healthcare system', academic (general) internal medicine should strive to be the cornerstone of every integrated, patient-centred, modern medical care and training system.

Antitumor effect of MAb EMD 55900 depends on EGF-R expression and histopathology.

The proliferative stimulus of the epidermal growth factor (EGF) in human epithelial cells is mediated by its binding to the external domain of the EGF receptor (EGF-R). The purpose of this study was to investigate whether growth arrest of tumors treated with anti-EGF-R MAb (EMD 55900) was dependent on EGF-R expression and distinct histopathologic criteria of those neoplasms. Nine different adenocarcinomas, squamous cell carcinomas and two neoplastic epithelial cell lines (A431 and Detroit 562), which were characterized by high EGF-R expression, were xenotransplanted onto NMRI-nu/nu mice and treated with an anti-EGF-R antibody (EMD 55900). Results revealed that EGF-R expression and distinct histopathologic growth patterns play an important role for the therapeutic effect of the EGF-R antibody treatment. Tumors with high epithelial cellularity and little connective tissue responded to EMD 55900 treatment to a greater degree of growth reduction than tumors with lower cellularity. These results will be helpful for evaluation of patients who would benefit from tumor therapy with anti-EGF-R antibody.

Polymerase chain reaction in the detection of tumor cells: new approaches in diagnosis and follow-up of patients with thyroid cancer.

Thyroid cancers are the most common endocrine malignancies and are being diagnosed with increasing frequency. In addition to other measures, diagnosis is based on fine-needle aspiration cytology examination. Recently, new assays using reverse transcription-polymerase chain reaction (PCR) are being tested to improve sensitivity and specificity of primary diagnosis and detection of recurrent thyroid cancer. In the preoperative diagnosis of thyroid cancer, several tissue- and/or tumor-specific mRNA have been described and in several cases, a higher sensitivity and specificity could be achieved using molecular techniques compared to conventional methods. In the postoperative follow-up of patients with thyroid cancer, conflicting data have been published and the use of PCR techniques revealed several problems of the molecular approach, which are based on some technical as well as biologic limitations. Despite these problems, which are discussed in detail in this review, molecular techniques may nevertheless improve the sensitivity and accuracy of fine-needle aspiration of thyroid nodules, fine-needle aspiration of metastases, and detection of recurrent disease in peripheral blood samples.

Prevalence of thyroid disorders in the working population of Germany: ultrasonography screening in 96,278 unselected employees.

Germany continues to be iodine deficient despite considerable improvement in the past years. To assess the current prevalence of diffuse and/or nodular thyroid disorders, a cross-sectional observational study in a nonrandom sample of the working population was carried out throughout Germany in 2001 and 2002. A total of 96,278 employees 18-65 years of age from 214 companies or other private or public institutions voluntarily underwent ultrasonographic examinations by 230 experienced investigators. To compare the prevalence of different abnormal findings in relation to age and gender, descriptive statistics and the Kruskal-Wallis test were used. Data from volunteers with previous thyroid treatment (13.0% of total sample) were not included in the analysis. Abnormal findings (goiter and/or nodules > 0.5 cm) were observed in 33.1% (men, 32.0%; women, 34.2%) of the examined patient population, an enlarged thyroid without nodules in 9.7% (men, 11.9%; women, 7.6%), nodules only without enlargement of the thyroid in 14.3% (men, 11.5%; women, 17.0%), and nodular goiter in 9.1% (men, 8.6%; women, 9.6%). Nodules (with or without goiter) between 0.5 and up to 1.0 cm were found in 10.0%, and nodules above 1.0 cm in 11.9% of the population. Rates of abnormal findings increased with age in both genders. Goiter was more common in men, nodules in women. In light of these findings, the prevalence of thyroid disorders in Germany continues to be high. Although the study may slightly overestimate the prevalence, about one third of the working population is affected and remains unaware of this condition. These results emphasize the importance of effective sonographic screening to detect early thyroid abnomalities in order to initiate preventive and therapeutic measures to prevent the onset or progression of disease and its sequels.

Validation of a new automated immunoassay for measurement of intact osteocalcin.

Bone turnover is assessed indirectly by measurement of biochemical markers of bone turnover. Osteocalcin, a 49-amino-acid protein is a major noncollagenous protein of bone matrix, synthesized by osteoblasts and odontoblasts. Various assays exist for assessment of osteocalcin and concentrations in the same serum or plasma sample may vary enormously. The used antibodies may recognize intact osteocalcin and/or circulating fragments of osteocalcin. We here describe and validate a new automated immunoassay system for measurement of intact osteocalcin (DPC IMMULITE assay) using monoclonal antibodies (mouse) against the C-terminus of osteocalcin (AA 44-49). For detection polyclonal antibodies (goat) directed against the N-terminus (AA 1-17) conjugated with alkaline phosphatase are used. While different laboratory assays show marked clinical discordance, we evaluated our results comparatively to an established IRMA method (Nichols). We observed a highly significant correlation between both assays (r = 0.9352, p < 0.0001, n = 286) for healthy persons and also for patient samples (osteoporosis, diabetes type 1, rheumatoid arthritis). Very low inter- and intraassay covariance as well as highly significant linearity (analytical recovery near 100%) tested by serial dilutions were demonstrated for the DPC IMMULITE intact osteocalcin assay. We conclude that the IMMULITE assay is a useful method for assessment of intact osteocalcin giving valuable results in comparison to an established non-automated assay.

[Iodine and thyroid autoimmunity]. / Jod und thyreoidale Autoimmunität.

The pathogenetic mechanisms leading to the development of autoimmune disease of the thyroid are based on several different factors. The resultant immune response is related to both the genetic predisposition and other influencing factors such as iodine intake, a very important modulator of thyroid autoimmunity. To a large extent, the details of the mechanisms that induce the immune response and lead to chronic autoimmune thyroid reactions are still poorly understood. In genetically predisposed individuals the iodine intake modulates autoimmune thyroid reactions. Especially with acute or chronic increase of iodine intake it leads to a significant increase in the incidence and intensity of autoimmune thyroid disease. There is a need to further investigate whether the results of experimental animal studies can be generalised to humans. Epidemiological data from countries with sufficient or high nutritional iodine intake clearly show that in comparison to countries with iodine deficiency there is an increase in the incidence of autoimmune thyroid disease and a change in the pattern of manifestation, e.g. in the proportion of autoimmune thyroiditis and hyperthyroidism due to Graves' disease. At the same time, thyroid diseases related to iodine deficiency significantly decrease, which is to be expected with a continuously higher iodine intake.