Subnational estimates of vitamin A supplementation coverage in children: a geospatial analysis of 45 low- and middle-income countries.

OBJECTIVES: Vitamin A supplementation (VAS) can protect children from the adverse health consequences of vitamin A deficiency. Granular data on VAS coverage can guide global and national efforts to achieve universal VAS coverage. To provide geographically precise targeting of VAS programs and to monitor progress in reducing geographic disparities, we aimed to create high-resolution (5 × 5 km2) maps of VAS coverage in children under 5 years across VAS priority countries. STUDY DESIGN: We used cross-sectional data from the Demographic and Health Surveys (DHS) program. METHODS: We used data from the DHS program for United Nations Children's Fund -designated VAS priority countries between 2000 and 2017 with data available from 2005 or later. The outcome variable was the proportion of children under 5 years who received a vitamin A dose in each sampled cluster. We applied a Bayesian geostatistical approach incorporating geographic, climatic, and nutritional covariates to estimate VAS coverage for each cell. We estimated and mapped absolute VAS coverage, Bayesian uncertainty intervals, and exceedance probabilities. RESULTS: Our sample included countries from Latin America and the Caribbean, Asia, and Africa. Most countries had estimated VAS coverage levels <70%, and our exceedance probabilities indicated high certainty that our estimates fell below this threshold in most grid cells. International variations were most notable in the Latin America and the Caribbean region and Africa. Intranational variations were greatest in some South Asian and West and Central African countries. CONCLUSIONS: These prevalence and exceedance maps, especially used with data on indicators of VAS need, could help to improve equity.

[Outcome studies on SGLT-2 inhibitors]. / Outcome-Studien zu SGLT-2-Inhibitoren.

BACKGROUND: Inhibitors of sodium-glucose cotransporters type 2 (SGLT-2) are a class of oral antidiabetic drugs with a novel specific mode of action in the kidneys. OBJECTIVE: The effects of SGLT-2 inhibitors on cardiovascular (CV) and renal endpoints in outcome trials with type 2 diabetes patients. MATERIAL AND METHODS: Differential analysis and interpretation of the results of outcome trials with the SGLT-2 inhibitors empagliflozin, canagliflozin and dapagliflozin in type 2 diabetes mellitus. RESULTS: In the EMPA-REG OUTCOME trial, empagliflozin demonstrated a significant reduction in major cardiac adverse events (MACE), hospitalization for heart failure (HHI), renal endpoints, CV and total mortality vs. placebo in >7000 patients with type 2 diabetes and established CV disease over 3.1 years. In the CANVAS program, canagliflozin demonstrated a significant reduction of MACE, HHI and renal endpoints vs. placebo in >10,000 patients with type 2 diabetes and high CV risk over 2.4 years. In the CREDENCE trial, canagliflozin demonstrated a significant reduction of a combined renal endpoint and CV endpoints vs. placebo in >4000 patients with type 2 diabetes and established kidney disease with albuminuria over 2.6 years. In the DECLARE-TIMI 58 trial, dapagliflozin demonstrated a significant reduction in a combined endpoint of CV death and HHI vs. placebo in >17,000 patients with type 2 diabetes and established CV disease or with multiple CV risk factors over 3.1 years. CONCLUSION: Outcome trials with SGLT-2 inhibitors have collectively demonstrated cardioprotective and nephroprotective effects in patients with type 2 diabetes and high CV risk. The use of SGLT-2 inhibitors is recommended in current guidelines and consensus statements as primary combination partners for metformin in patients with type 2 diabetes and established CV disease, high CV risk, heart failure or kidney disease.

HbA1c target achievement in the elderly: results of the Titration and Optimization trial for initiation of insulin glargine 100 U/mL in patients with type 2 diabetes poorly controlled on oral antidiabetic drugs.

Objectives: To identify real-world, age-related trends in the use of insulin glargine 100 U/mL (Gla-100) as part of basal-supported oral therapy (BOT). Research design and methods: The prospective, observational Titration and Optimization registry enrolled patients with poorly controlled type 2 diabetes mellitus initiated on Gla-100 BOT. The primary outcome was the proportion of patients with capillary fasting blood glucose (FBG) ≤110 mg/dL on ≥2 occasions and/or who met their individual HbA1c target within 12 months. Results: 2462 patients were analyzed (<65 years: n=1122; 65-74 years: n=771; ≥75 years: n=569). Diabetes duration (6.8, 8.9, and 11.2 years, p<0.0001) and proportion of women (40.7%, 47.9%, and 55.7%, p<0.0001) increased with age. Baseline HbA1c was highest in <65-year-olds (8.6% vs 8.4% and 8.5%, p<0.0001). Gla-100 up-titration until 12 months was highest in <65-year-olds (+11.6 U/day), compared with 65-74 (+10.2 U/day) and ≥75 years (+8.8; p<0.0001) but similar by units per kilogram, as was the decrease in FBG (<65: -64.1 mg/dL; 65-74: -56.1 mg/dL; ≥75: -53.4 mg/dL) and HbA1c (<65: -1.47%; 65-74: -1.31%; ≥75: -1.22%, p<0.0001). At 12 months, 65.9% of participants met the primary endpoint, with no significant difference between age groups. The proportion achieving their individual HbA1c target was lower for <65-year-olds (46.0% vs 54.3% and 54.7%; p<0.02). Symptomatic hypoglycemia incidence was more common in the ≥75-year-old group (3.4% vs 1.4% and 1.4%; p=0.0126). Conclusions: BOT with Gla-100 results in similar improvements of glycemic values with low risk of hypoglycemia across age groups. Given the link between HbA1c and long-term cardiovascular risk, ensuring appropriately stringent target-setting, intensification of basal insulin and making sure hypoglycemia is avoided is of paramount importance. Trial registration number: Database: https://awbdb.bfarm.de; Identifier: 1641; Date of registration: September 23, 2013.

Efficacy and safety of titrated canagliflozin in patients with type 2 diabetes mellitus inadequately controlled on metformin and sitagliptin.

AIMS: To evaluate the efficacy and safety of titrated canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin and sitagliptin. METHODS: In this randomized, double-blind study, patients with T2DM (N = 218) on metformin ≥1500 mg/day and sitagliptin 100 mg received canagliflozin 100 mg or placebo. After 6 weeks, the canagliflozin dose was increased from 100 to 300 mg (or from placebo to matching placebo) if all of the following criteria were met: baseline estimated glomerular filtration rate ≥70 ml/min/1.73 m(2) ; fasting self-monitored blood glucose ≥5.6 mmol/l (≥100 mg/dl); and no volume depletion-related adverse events (AEs) within 2 weeks before dose increase. Endpoints included change in glycated haemoglobin (HbA1c) at week 26 (primary); proportion of patients achieving HbA1c <7.0%; and changes in fasting plasma glucose (FPG), body weight and systolic blood pressure (SBP). Safety was assessed using AE reports. RESULTS: Overall, 85.4% of patients were titrated to canagliflozin 300 mg or matching placebo (mean ± standard deviation time to titration 6.2 ± 0.8 weeks). At week 26, canagliflozin (pooled 100 and 300 mg) demonstrated superiority in HbA1c reduction versus placebo (-0.91% vs. -0.01%; p < 0.001). Canagliflozin provided significant reductions in FPG, body weight and SBP compared with placebo (p < 0.001). The overall AE incidence was 39.8 and 44.4% for canagliflozin and placebo, respectively. Canagliflozin was associated with an increased incidence of genital mycotic infections. CONCLUSIONS: Titrated canagliflozin significantly improved HbA1c, FPG, body weight and SBP, and was generally well tolerated over 26 weeks in patients with T2DM as add-on to metformin and sitagliptin.

Insulin degludec does not increase antibody formation versus insulin glargine: an evaluation of phase IIIa trials.

We examined insulin antibody formation in patients with type 1 (T1D) or type 2 diabetes (T2D) treated with once-daily insulin degludec (IDeg) or insulin glargine (IGlar) to evaluate the impact of antibody formation on efficacy and safety. Insulin antibodies were measured using subtraction radioimmunoassays in six phase IIIa clinical trials using IDeg (n = 2250) and IGlar (n = 1184). Spearman's correlation coefficient was used to evaluate associations between cross-reacting antibodies and change from baseline glycated haemoglobin (HbA1c) and insulin dose. IDeg- and IGlar-specific antibodies remained low [<1% bound/total radioactivity (B/T)] and with low levels of antibodies cross-reacting with human insulin in patients with T1D (<20% B/T) and T2D (<6% B/T). Spearman's correlation coefficients between insulin antibody levels and change in HbA1c or insulin dose were low in both treatment groups. No clinically meaningful differences in adverse event (AE) rates were observed in patients with >10% B/T or without an absolute increase in antibodies cross-reacting with human insulin. IDeg treatment resulted in few immunogenic responses in patients with T1D and T2D; antibody formation was not associated with change in HbA1c, insulin dose or rates of AEs.

Impact of diabetes duration on achieved reductions in glycated haemoglobin, fasting plasma glucose and body weight with liraglutide treatment for up to 28 weeks: a meta-analysis of seven phase III trials.

This meta-analysis of seven randomized, placebo-controlled studies (total 3222 patients) evaluated whether type 2 diabetes (T2D) duration affects the changes in blood glucose control and body weight that can be achieved with liraglutide and placebo. With liraglutide 1.2 mg, shorter diabetes duration was associated with a significantly greater, but clinically non-relevant, difference in glycated haemoglobin (HbA1c) reduction (p < 0.05), i.e. a 0.18% (1.96 mmol/mol) reduction in HbA1c per 10 years shorter diabetes duration. With liraglutide 1.8 mg, shorter diabetes duration was associated with a small but statistically significant trend for greater fasting plasma glucose (FPG) reduction (p < 0.05), i.e. a 0.38 mmol/l reduction in FPG per 10 years shorter diabetes duration. Neither the liraglutide 1.8 mg nor placebo results showed a significant association between HbA1c and diabetes duration and neither the liraglutide 1.2 mg nor placebo results showed a significant association between FPG and diabetes duration. Likewise, neither liraglutide nor placebo showed a significant association between change in weight and diabetes duration. These results suggest diabetes duration has a clinically negligible effect on achievable blood glucose control and weight outcomes with liraglutide and placebo in patients with T2D.

Gender-specific Effects of Treatment with Lifestyle, Metformin or Sulfonylurea on Glycemic Control and Body Weight: A German Multicenter Analysis on 9 108 Patients.

Effects of diabetes treatment are strongly connected to individual factors, but the relevant role of gender has not been addressed so far. This observational study evaluates whether monotherapy with lifestyle, metformin or sulfonylurea has gender-specific effects on glycemic control and/or body weight. Data of 9 108 patients with type 2 diabetes from 129 German diabetes centers were assessed by a standardized, prospective, computer-based diabetes care and outcome documentation system (DPV-Wiss-database; age 63.1±12.8 years, diabetes duration 5.7±7.4 years, HbA1c 55±17.7 mmol/mol [7.2±1.6%], BMI 30.6±6.1 kg/m(2), 49.3% female patients). Antidiabetic concepts included lifestyle intervention (n=5,787), metformin (n=2,180), sulfonylurea (n=943) or other antidiabetic drugs (n=198), respectively. HbA1c and body weight were compared before and after a stable monotherapeutical period of 0.8±0.4 years. Women had a significantly higher reduction of body weight after treatment with lifestyle (women-0.8±0.1 vs. men-0.2±0.1 kg; p<0.05), metformin (women-1.8±0.2 vs. men-1.2±0.2 kg; p<0.05) or sulfonylurea drugs (women-0.9±0.2 vs. men - 0.1±0.2 kg; p<0.05), whereas men displayed significantly higher HbA1c-reductions after treatment with lifestyle (women-6.9±0.2 mmol/mol [- 0.6±0.02%] vs. men-7.5±0.2 mmol/mol [0.7±0.02%]; p<0.05) and metformin only (women-6.3±0.3 mmol/mol [- 0.6±0.03%] vs. men - 7.4±0.3 mmol/mol [- 0.7±0.03%]; p<0.05). No differences were seen for sulfonylurea monotherapy concerning the HbA1c-reduction (women - 5.6±0.5 mmol/mol [- 0.5±0.05%] vs. men-6.4±0.4 mmol/mol [- 0.6±0.04%]; p=0.196). In summary, antidiabetic treatment concepts might result in gender-specific effects on body weight and HbA1c. Gender might therefore represent another important factor in the context of an individualized treatment management of type 2 diabetes.

Impact of an acceptance facilitating intervention on diabetes patients' acceptance of Internet-based interventions for depression: a randomized controlled trial.

AIMS: To (1) determine diabetes patients' acceptance of Internet-based interventions (IBIs) for depression, to (2) examine the effectiveness of an acceptance facilitating intervention (AFI) and to (3) explore subgroup specific effects. METHODS: 141 diabetes patients from two inpatient rehabilitation units and one outpatient clinic in Germany were randomly allocated to an intervention (IG) and a no-intervention control group (CG). The IG received an AFI consisting of a personal information session before filling-out a questionnaire on patients' acceptance of IBIs, predictors of acceptance (performance expectancy, effort expectancy, social influence, facilitating conditions, and Internet anxiety) as well as sociodemographic, depression-related and diabetes-related variables. The CG filled out the questionnaire immediately. Patients' acceptance of IBIs was measured with a four-item scale (sum-score ranging from 4 to 20). RESULTS: The CG showed a low (50.7%) to medium (40.8%) acceptance with only 8.5% of all diabetes patients reporting a high acceptance of IBIs for depression. The AFI had no significant effect on acceptance (IG: M=10.55, SD=4.69, n=70; KG: M=9.65, SD=4.27, n=71; d=0.20 [95%-CI: -0.13;0.53]) and the predictors of acceptance. Yet, subgroup analyses yielded a trend for depressed, diabetes-related distressed, female and younger (<59) participants and for those who do not frequently use the Internet to profit from the AFI. CONCLUSION: Diabetes patients show a rather low acceptance toward IBIs for depression. Findings indicate that the AFI is likely to be effective in the subgroup of depressed, diabetes-related distressed, female or younger diabetes patients, but not in the whole target population. Hence, AFIs might need to be tailored to the specific needs of subpopulations.

Daily insulin doses and injection frequencies of neutral protamine hagedorn (NPH) insulin, insulin detemir and insulin glargine in type 1 and type 2 diabetes: a multicenter analysis of 51 964 patients from the German/Austrian DPV-wiss database.

BACKGROUND: We performed a comparative analysis of the use of long-acting insulin (analogues) neutral protamine hagedorn (NPH), detemir (Det) and glargine (Gla), and quantified injection frequencies and daily insulin doses in patients with type 1 and 2 diabetes in daily practice. METHODS: A total number of 51 964 patients from 336 centres in Germany and Austria with type 1 and 2 diabetes with exclusive insulin therapy were retrospectively analysed. RESULTS: A total number of 42.1%/75.9% (type 1/type 2) of patients used NPH, 19.9%/6.7% Det and 38.0%/17.4% Gla, with similar glycaemic control and proportion of severe hypoglycaemia for NPH/Det/Gla in type 1 (Mean HbA(1c) 7.98%/7.98%/8.07%; mean proportion of severe hypoglycaemia 11.06%/11.93%/10.86%) and type 2 diabetes (Mean HbA(1c) 7.61%/7.78%/7.61%; mean proportion of severe hypoglycaemia 5.66%/4.48%/5.03%). In type 1 diabetes, the mean daily injection frequencies of NPH versus Det versus Gla were 1.9 vs 1.8 vs 1.1, and total daily insulin injections were 5.3 vs 5.6 vs 5.0. The adjusted mean daily basal insulin doses were 0.36, 0.39 and 0.31 IU/kg, mean daily total insulin dose was lowest for Gla (0.74 IU/kg), followed by NPH (0.76 IU/kg) and Det (0.81 IU/kg). In type 2 diabetes patients, mean daily injection frequencies were 1.6 for NPH, 1.4 for Det and 1.1 for Gla, total daily insulin injections were 4.0 vs 4.1 vs 3.6. The mean daily basal insulin dosages were 0.30 IU/kg (NPH), 0.33 IU/kg (Det) and 0.29 IU/kg (Gla), mean total insulin doses per day were 0.63 IU/kg (NPH), 0.77 IU/kg (Det) and 0.67 IU/kg (Gla). CONCLUSIONS: In a 'real-world' setting, the injection frequencies and doses of basal and total insulin per day are lowest with the use of insulin glargine compared with NPH-insulin or insulin detemir at similar glycaemic control and rates of severe hypoglycaemia.

The extra-pancreatic effects of GLP-1 receptor agonists: a focus on the cardiovascular, gastrointestinal and central nervous systems.

The glucagon-like peptide-1 receptor agonists (GLP-1RAs) exenatide, liraglutide and lixisenatide have been shown to improve glycaemic control and beta-cell function with a low risk of hypoglycaemia in people with type 2 diabetes. GLP-1 receptors are also expressed in extra-pancreatic tissues and trial data suggest that GLP-1RAs also have effects beyond their glycaemic actions. Preclinical studies using native GLP-1 or GLP-1RAs provide substantial evidence for cardioprotective effects, while clinical trial data have shown beneficial actions on hypertension and dyslipidaemia in people with type 2 diabetes. Significant weight loss has been reported with GLP-1RAs in both people with type 2 diabetes and obese people without diabetes. GLP-1RAs also slow down gastric emptying, but preclinical data suggest that the main mechanism behind GLP-1RA-induced weight loss is more likely to involve their effects on appetite signalling in the brain. GLP-1RAs have also been shown to exert a neuroprotective role in rodent models of stroke, Alzheimer's disease and Parkinson's disease. These extra-pancreatic effects of GLP-1RAs could provide multi-factorial benefits to people with type 2 diabetes. Potential adverse effects of GLP-1RA treatment are usually manageable but may include gastrointestinal effects, increased heart rate and renal injury. While extensive further research is still required, early data suggest that GLP-1RAs may also have the potential to favourably impact cardiovascular disease, obesity or neurological disorders in people without diabetes in the future.

Composite efficacy parameters and predictors of hypoglycaemia in basal-plus insulin therapy--a combined analysis of 713 type 2 diabetic patients.

AIMS: We aimed to identify predictors of hypoglycaemia in patients with poorly controlled type 2 diabetes treated with a single daily bolus of insulin glulisine on top of insulin glargine and oral antidiabetic drugs (basal-plus regimen). METHODS: We retrospectively analysed four large basal-plus trials including 713 patients (47% female) with type 2 diabetes, mean age of 59.9 ± 9.5 years and diabetes duration of 11 ± 7.0 years. Predictors for symptomatic, severe and nocturnal hypoglycaemia were identified by multivariate logistic regression analyses, calculation of odds ratios (ORs) and Wald 95% confidence intervals (CIs). RESULTS: Mean numbers of hypoglycaemic events per year were 4.64 ± 11.4 (symptomatic < 60 mg/dl), 0.59 ± 2.28 (nocturnal) and 0.03 ± 0.22 (severe). A total of 44.5% of patients reached the composite endpoint of glycated haemoglobin (HbA1c) <7.0% plus no severe hypoglycaemia, and 26.7% reached the composite of HbA1c <7.0% plus no symptomatic hypoglycaemia. Predictors of nocturnal and symptomatic hypoglycaemia were female gender (OR 1.82; 95% CI 1.07-3.11 and OR 1.89; 95% CI 1.31-2.78), diabetes duration >10 versus <5 years (OR 2.61; 95% CI 1.03-6.59 and OR 2.01; 95% CI 1.15-3.51) and higher basal insulin dose (per unit of increase) (OR 1.01; 95% CI 1.00-1.03 and OR 1.01; 95% CI 1.00-1.02). Conversely, a higher body mass index (BMI) (27-30 vs. <27 kg/m(2) and >30 vs. <27 kg/m(2) ) conferred a reduced risk of symptomatic hypoglycaemia with an OR of 0.53 (95% CI 0.31-0.90) and an OR of 0.61 (95% CI 0.39-0.97). CONCLUSIONS: Female gender, a long diabetes duration and higher basal insulin dose were predictors of hypoglycaemia, while protection was provided by BMI > 30. These results may help to successfully establish basal-plus insulin regimen in individual patients on their transition from basal-only to basal-bolus treatment.

Multiple complications and frequent severe hypoglycaemia in 'elderly' and 'old' patients with Type 1 diabetes.

AIM: Elderly and old patients with Type 1 diabetes represent a growing population that requires thorough diabetes care. The increasing relevance of this subgroup, however, plays only a minor role in the literature. Here, we describe elderly patients with Type 1 diabetes on the basis of a large multi-centre database in order to point out special features of this population. METHOD: Data of 64609 patients with Type 1 diabetes treated by 350 qualified diabetes treatment centres were assessed and analysed by age group. RESULTS: Compared with the age group ≤ 60 years, patients aged >60 years (n=3610 61-80 years and n=377 >80 years old) were characterized by a longer diabetes duration (27.7 vs. 7.7 years), an almost double risk for severe hypoglycaemia (40.1 vs. 24.3/100 patient-years), a lower level of HbA(1c) [60 vs. 67 mmol/mol (7.6 vs. 8.3%)] and higher percentages of microalbuminuria (34.5 vs. 15.6%), diabetic retinopathy (45.2 vs. 8.3%), myocardial infarction (9.0 vs. 0.4%) or stroke (6.8 vs. 0.3%). Elderly patients used insulin pumps less frequently (12.2 vs. 23.8%), but more often used conventional premixed insulin treatment (10.8 vs. 3.8%). Differences between elderly and younger patient groups were significant, respectively. CONCLUSION: Diabetes care of elderly patients with Type 1 diabetes involves individualized treatment concepts. Increased hypoglycaemia risk and functional impairment attributable to diabetes-associated and/or age-related disorders must be taken into account.

Hypogonadism and anemia in an athlete.

We report the case of a highly trained endurance athlete (22-year-old) who developed anemia (Hb 9.5 mg/dl) over a period of 6 months. Iron deficient or haemolytic anemia, as well as chronic loss of blood, were excluded. Further, laboratory analyses revealed that this athlete exhibited very low levels of testosterone due to a partial hypogonadotropic hypogonadism. Following testosterone supplementation, red blood cell indices improved. Although hypogonadotropic hypogonadism is well known to be associated with reduced hematopoesis, it rarely causes anemia in athletes. This should be considered as a possible cause for anemia. Extreme training, unbalanced nutrition or the combination of both, have been shown to be causally involved in the development of secondary hypogonadotropic hypogonadism.

Ectopic ACTH-syndrome due to a neuroendocrine tumour of the appendix.

Ectopic ACTH production causes 10% of Cushing's syndromes. The diagnostic workup is difficult, can last more than 6 months (> 50% of cases), and the underlying tumour is still frequently not located (12%). Carcinoid tumours of the appendix are frequent and are revealed in 0.3% of patients undergoing routine appendectomy. However, neuroendocrine tumours of the appendix with ACTH production are an extremely rare entity. Here we report the case of a female patient with clinically overt Cushing's syndrome due to ectopic ACTH-production from a carcinoid tumour of the appendix. During the diagnostic workup, repeated endocrine tests, multiple different imaging modalities and frequent and lengthy hospitalisations were necessary. Wrongly, even a neurosurgical pituitary exploration was performed. After 12 months from the initial admission, the tumour was finally detected by an ¹8F-fluoro-L-dihydroxyphenylalanine (¹8FDOPA PET) and an appendectomy followed by right hemicolectomy were performed. The patient recovered rapidly and the symptoms from the hypercortisolism were no more present.In this case, we discuss the multitude of problems, which may delay the diagnosis and the pitfalls, that should be avoided in order to locate the tumour and to initiate adequate therapy as early as possible. Furthermore, our case demonstrates the complexity of diagnostic procedures, which demand most of the times a multidisciplinary approach. In this setting, regular follow-ups in short time intervals and the use of novel imaging techniques can finally cut the diagnostic "Gordian knot".

The Primavera study protocol design: evaluating the effect of continuous erythropoiesis receptor activator (C.E.R.A.) on renal function in non-anemic patients with chronic kidney disease.

Erythropoiesis stimulating agents (ESA) are widely used for hemoglobin correction in patients suffering from renal anemia. However, their beneficial non-hematopoietic effects on renal deterioration have not been adequately assessed. The Primavera study is the first prospective, controlled trial to assess whether ESA treatment could ameliorate progression of chronic kidney disease (CKD) in non-anemic patients. Primavera is a single-blind, 24-month trial in which patients are randomized to placebo or to C.E.R.A., a continuous erythropoietin receptor activator. Patients with type 2 diabetes or who have undergone kidney transplantation are eligible to enter the study if they have CKD stage III (estimated GFR [eGFR] 30-59 mL/min/1.73 m(2)), urinary albumin to creatinine ratio (UACR) ≥ 50 g/g and ≤ 1500 g/g, or total urine protein ≥ 50mg/24h and ≤ 1500mg/24h, and hemoglobin 11-14 g/dL. The primary efficacy endpoint is the change in eGFR from baseline to month 24. Secondary efficacy endpoints are the changes in UACR, serum cystatin C and serum creatinine from baseline. Safety endpoints include adverse events and discontinuation due to pre-specified adverse events. An interim analysis will be performed after all patients have completed the first year. The planned sample size is 400 patients (200 type 2 diabetics, 200 transplant recipients) conferring 90% power to detect a prespecified significant difference of 1.5 mL/min/1.73 m(2) in the annual reduction in eGFR between treatment groups. The results of Primavera are expected in 2013.

[Graves' ophthalmopathy from the internist's perspective]. / Endokrine Orbitopathie aus internistischer Sicht.

Graves' orbitopathy (GO) is the most frequently observed extrathyroidal manifestation of Graves' disease occurring in up to 40% of patients. Most patients with Graves' orbitopathy are tested positive for TSH receptor autoantibodies (TRAb), which are pathognomonic for Graves' disease and also play a central pathogenetic role in the development of GO. For the diagnosis of Graves' disease, symptoms of hyperthyroidism, low TSH and high fT3 and/or fT4 levels and positive TRAbs are typical. All patients with Graves' disease must be regularly examined for extrathyroidal manifestations, especially for Graves' orbitopathy. For hyperthyroidism, treatment with antithyroidal drugs, such as thiamazole or propylthiouracil is initiated to quickly restore euthyroidism, which also frequently leads to improvement of Graves' orbitopathy. Smoking cessation is also heavily mandated. In cases of relapse or ineffective antithyroidal treatment, radioiodine therapy or thyroid surgery is a further definitive therapeutic option to treat hyperthyroidism. The management of Graves' orbitopathy remains clinically challenging and demands involvement of a multidisciplinary team including endocrinologists, ophthalmologists, surgeons, radiotherapists and nuclear medicine specialists.

Is the ADA/EASD algorithm for the management of type 2 diabetes (January 2009) based on evidence or opinion? A critical analysis.

The ADA and the EASD recently published a consensus statement for the medical management of hyperglycaemia in patients with type 2 diabetes. The authors advocate initial treatment with metformin monotherapy and lifestyle modification, followed by addition of basal insulin or a sulfonylurea if glycaemic goals are not met (tier 1 recommendations). All other glucose-lowering therapies are relegated to a secondary (tier 2) status and only recommended for selected clinical settings. In our view, this algorithm does not offer physicians and patients the appropriate selection of options to individualise and optimise care with a view to sustained control of blood glucose and reduction both of diabetes complications and cardiovascular risk. This paper critically assesses the basis of the ADA/EASD algorithm and the resulting tiers of treatment options.