Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Current and emerging treatment options for Graves&amp;rsquo; hyperthyroidism

Prakash Abraham1, Shamasunder Acharya21Department of Endocrinology, Aberdeen Royal Infirmary, Aberdeen, UK; 2Department of Endocrinology, John Hunter Hospital, New Lambton NSW, AustraliaAbstract: Radioiodine, antithyroid drugs and surgery have been well established therapies for Graves&amp;rsquo; hyperthyroidism for several decades. However there remain large variations in practice among physicians in the preferred modality and the method of administration. Patient choice and perceptions also play a big role in the choice of treatment. Radioiodine may be given using fixed high doses or by calculated doses following uptake studies. The risks of radioiodine including eye disease and the role of prophylactic steroid therapy are discussed. The commonly used antithyroid drugs include carbimazole, methimazole and propylthiouracil; however a number of other agents have been tried in special situations or in combination with these drugs. The antithyroid drugs may be given in high (using additional levothyroxine in a block&amp;ndash;replace regimen) or low doses (in a titration regimen). This review examines the current evidence and relative benefits for these options as well as looking at emerging therapies including immunomodulatory treatments such as rituximab which have come into early clinical trials. The use of antithyroid therapies in special situations is also discussed as well as clinical practice issues which may influence the choices.Keywords: Graves&amp;rsquo; hyperthyroidism, radioiodine, antithyroid drugs, methimazole, propylthiouraci

Curcumin and/or omega-3 polyunsaturated fatty acids supplementation reduces insulin resistance and blood lipids in individuals with high risk of type 2 diabetes: a randomised controlled trial

Abstract Background Lowering insulin resistance and dyslipidaemia may not only enhance glycaemic control but also preserve the β-cell function, reducing the overall risk of developing type 2 diabetes (T2D). The current study was aimed to evaluate the effects of curcumin and/or long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) supplementation on glycaemic control and blood lipid levels in individuals at high risk of developing T2D. Methods This was a 2 × 2 factorial, randomised, double-blinded, placebo-controlled study. Participants were allocated to either double placebo (PL) or curcumin plus placebo matching for LCn-3PUFA (CC), or LCn-3PUFA plus placebo matching for curcumin (FO), or curcumin plus LCn-3PUFA (CC-FO) for twelve weeks. Primary outcome of the trial was glycaemic indices (HbA1C, fasting glucose and insulin). Insulin resistance and sensitivity is measured using homeostatic model assessment model. Results A total of sixty-four participants (PL, n = 16; CC, n = 15; FO, n = 17, CC-FO, n = 16) were included in the final analysis. Post-intervention, HbA1c and fasting glucose remained unchanged across all the groups. Insulin sensitivity was significantly improved in the CC supplemented group (32.7 ± 10.3%) compared to PL (P = 0.009). FO and CC-FO tended to improve insulin sensitivity by 14.6 ± 8.5% and 8.8 ± 7.7% respectively, but the difference did not reach significance. Triglyceride levels were further increased in the PL (26.9 ± 7.4%), however, CC and CC-FO supplementation reduced the triglycerides, FO resulted in the greatest reduction in triglycerides (− 16.4 ± 4.5%, P < 0.001). Conclusion Reduction in insulin resistance and triglycerides by curcumin and LCn-3PUFA appears to be attractive strategies for lowering the risk of developing T2D. However, this study failed to demonstrate complimentary benefits of curcumin and LCn-3PUFA on glycaemic control. Trail registration ACTRN12615000559516

Exploring the Effectiveness of Smart Technologies in the Management of Type 2 Diabetes Mellitus

The global epidemic of diabetes, with increasing prevalence of type 2 diabetes (T2D), is placing a huge burden on health care management and financial systems. Unless new strategic solutions are developed, the increasing prevalence of T2D will result in a significant rise in morbidity, health care costs, and complications associated with diabetes. The introduction of smart devices in diabetes management may provide meaningful improvements in clinical outcomes, patient engagement, as well as potential cost reductions for the health care system. Future research may be capable of providing new smart and interactive solutions to the growing multidisciplinary diabetes team and, most important, to reduce the morbidity associated with T2D.sch_pod1. Diabetes: the silent pandemic and its impact on Australia has been supported by an unrestricted educational grant from Novo Nordisk. Baulkham Hills, NSW, Australia: Baker IDI Heart & Diabetes Institute. 2012. Available at: https://www.baker.edu.au/-/media/Documents/impact/diabetesthe-silent-pandemic.ashx?la=en 2. Noh RM, Graveling AJ, Frier BM. Medically minimising the impact of hypoglycaemia in type 2 diabetes: a review. Expert Opin Pharmacother. 2011;12(14):2161-2175. 3. Number of smartphone users worldwide 2014-2020. Statista. June 2015. Available at: https://www.statista.com/statistics/330695/number-of-smartphone-users-worldwide/. Accessed February 23, 2017. 4. Berkeley J. Planet of the phones. Economist. February 2015. Available at: http://www.economist.com/news/leaders/21645180-smartphone-ubiquitous-addictive-and-transformative-planet-phones. Accessed February 23, 2017. 5. Australia's mobile digital economy-ACMA confirms usage, choice, mobility and intensity on the rise. ACMA. December 2013. Available at: http://www.acma.gov.au/theACMA/Library/Corporate-library/Corporate-publications/australia-mobile-digital-economy. Accessed November 20, 2016. 6. Google. Google cloud platform security. December 2016. Available at: https://cloud.google.com/security/. Accessed December 1, 2016. 7. Apple. iOS Security, report no.: 9.3 or later. 2016. Available at: https://www.apple.com/business/docs/iOS_Security_Guide.pdf. Accessed November 28, 2016.12pub4739pub

Additional file 2: of Curcumin and long-chain Omega-3 polyunsaturated fatty acids for Prevention of type 2 Diabetes (COP-D): study protocol for a randomised controlled trial

Outcome measures. (PPTX 46 kb

Radioiodine therapy (RAI) for Graves' disease (GD) and the effect on ophthalmopathy: a systematic review

An association between radioiodine therapy (RAI) for Graves' disease (GD) and the development or worsening of Graves' ophthalmopathy (GO) is widely quoted but there has been no systematic review of the evidence.We undertook a systematic review of randomized controlled trials (RCTs) to assess whether RAI for GD is associated with increased risk of ophthalmopathy compared with antithyroid drugs (ATDs) or surgery. We also assessed the efficacy of glucocorticoid prophylaxis in the prevention of occurrence or progression of ophthalmopathy, when used with RAI.We identified RCTs regardless of language or publication status by searching six databases and trial registries. Dual, blinded data abstraction and quality assessment were undertaken. Random effects meta-analyses were used to combine the study data. Ten RCTs involving 1136 patients permitted 13 comparisons. Two RCTs compared RAI with ATD. Two RCTs compared RAI with thyroidectomy. Four RCTs compared the use of adjunctive ATD with RAI vs. RAI. Five RCTs examined the use of glucocorticoid prophylaxis with RAI.RAI was associated with an increased risk of ophthalmopathy compared with ATD [relative risk (RR) 4.23; 95% confidence interval (CI): 2.04-8.77] but compared with thyroidectomy, there was no statistically significant increased risk (RR 1.59, 95% CI 0.89-2.81). The risk of severe GO was also increased with RAI compared with ATD (RR 4.35; 95% CI 1.28-14.73). Prednisolone prophylaxis for RAI was highly effective in preventing the progression of GO in patients with pre-existing GO (RR 0.03; 95% CI 0.00-0.24). The use of adjunctive ATD with RAI was not associated with any significant benefit on the course of GO.RAI for GD is associated with a small but definite increased risk of development or worsening of Graves' ophthalmopathy compared with ATDs. Steroid prophylaxis is beneficial for patients with pre-existing GO.</p