Daily Endocrinology Research Analysis

BACKGROUND: Cardiovascular and kidney protective mechanisms with 12 weeks of sodium-glucose cotransporter-2 (SGLT2) inhibitor (dapagliflozin 10 mg daily) were assessed in kidney transplant recipients (KTR) with and without type 2 diabetes (T2D). METHODS: This randomized double-blind, parallel-group, placebo-controlled study enrolled 52 KTR and comprised three sequential physiologic assessments under clamped euglycemia (4-6 mmol/L): baseline, at one week and 12 weeks of treatment. The primary objective was to evaluate blood pressure lowering with dapagliflozin. Secondary outcomes were: iohexol-measured glomerular filtration rate (GFR), natriuresis, body composition, non-invasive cardiac output monitoring, arterial stiffness, heart rate variability, neurohormones, and safety. RESULTS: Fifty-one KTR completed the study - mean age 53±13 years, 62% with hypertension, 57% with T2D, 50% on renin-angiotensin-aldosterone system (RAAS) inhibitors and mean estimated GFR 68.2±24.4 mL/min/1.73m2. Compared to placebo, dapagliflozin did not lower systolic blood pressure at one or 12 weeks, though it did reduce mean arterial pressure after one week (3.9 mmHg 95% CI -7.5, -0.2). Dapagliflozin led to significant, placebo-adjusted reductions in iohexol-measured GFR from baseline to one week (4.2 ml/min/1.73m2; 95% CI -7.14, -1.24 ml/min/1.73m2) and 12 weeks (-3.49 ml/min/1.73m2; 95% CI -6.33, -0.64). Dapagliflozin significantly increased glucosuria without altering proximal sodium handling or evidence of sympathetic activation. Acute decreases in arterial stiffness (carotid augmentation index -3.5%; 95% CI -6.0, -1.1) were observed in the dapagliflozin group after 12 weeks, though this was not significant compared to placebo. Dapagliflozin was generally safe and well tolerated. No episodes of urinary tract or genitourinary infections were observed in either treatment group throughout the trial. CONCLUSION: Dapagliflozin activated expected physiological pathways, though key differences observed in KTR might suggest mechanistic heterogeneity compared to non-transplant populations. Clinical trials evaluating SGLT2 inhibitors in KTR are important to determine whether these mechanistic effects translate to improvements in kidney and cardiovascular outcomes.

BACKGROUND AND HYPOTHESIS: Urinary concentrating capacity largely depends on structural and functional integrity of distal tubule and peritubular compartment whilst fasting urine osmolality represents the closest estimation of the maximal urinary concentrating ability. We hypothesize that a low fasting urine osmolality is associated with high risk for kidney disease progression beyond eGFR reduction and albuminuria in patients with type 2 diabetes. METHODS: In this prospective study, fasting urine osmolality was measured in 1711 participants from SMART2D cohort in Singapore and 1097 participants from SURDIAGENE cohort in France. The primary outcome was a composite of end stage kidney disease or doubling of serum creatinine concentration. The secondary outcome was rapid kidney function decline (RKFD) defined as eGFR decline 5 ml/min/1.73m2 per year or greater. RESULTS: 239 and 82 kidney events were identified during a mean (SD) of 6.6 (1.6) and 7.4 (3.7) years of follow-up in SMART2D and SURDIAGENE cohorts, respectively. Compared to the upper tertile, participants with fasting urine osmolality in the lowest tertile had an increased risk of the composite kidney events after adjustment for known clinical risk factors (adjusted HR 2.94 [1.12-7.69] and 1.74 [0.85-3.58]). They also had higher odds of experiencing RKFD (adjusted OR 1.47 [0.95-2.28] and 1.84 [1.06-3.19], respectively). Exploratory analysis revealed that low fasting urine osmolality was associated with high risk of the primary kidney outcome independent of plasma copeptin concentration or urinary kidney injury molecule-1, an established biomarker of proximal tubule injury. CONCLUSIONS: Low level of fasting urine osmolality is associated with increased risk of kidney disease progression independent of conventional risk factors. This readily accessible biomarker may potentially improve risk-stratification for patients with type 2 diabetes.

PURPOSE: We examined the effect of selenium vs placebo, on remission rate and quality of life (QoL) in the Graves' Selenium Supplementation (GRASS) trial (ID:NCT01611896). METHODS: Double-blinded, placebo-controlled, multi-centre trial, in individuals with newly diagnosed Graves' hyperthyroidism randomised to daily supplementation with 200 µg selenium or placebo tablets during 24 to 30 months depending on timing of antithyroid drug (ATD) withdrawal. Primary outcome was proportion of participants with non-remission, defined as receiving ATD or remaining hyperthyroid (thyroid stimulating hormone<0.1 mIU/L) during the last 12 months of the intervention period or referral to ablative therapy (radioactive iodine or surgery). QoL was serially assessed by the thyroid-related patient-reported outcome ThyPRO and compared to previously collected norm data. RESULTS: Between Dec 7th 2012 and Dec 3rd 2018, 430 participants with Graves' hyperthyroidism were recruited. Non-remission was observed in 114 (53.3%) participants in the placebo group and 118 (54.6%) in the selenium group (OR 1.0 [95% CI 0.7 to 1.5]; p=0.98). There was no beneficial effect of selenium, as compared to placebo, on any ThyPRO scale. The participants' QoL at the end of the study was comparable to that of the general population sample. Thyrotropin receptor antibody levels were similar in the groups at the 18-months and end-of-study follow-up visits. CONCLUSION: In individuals with newly diagnosed Graves' hyperthyroidism, daily supplementation with selenium did not have any effects compared to placebo as add-on to standard antithyroid drugs. The GRASS trial findings do not support the use of selenium supplementation in Graves' hyperthyroidism.