Trichloroethylene is an organic chemical that has been used in dry cleaning, for metal degreasing, and as a solvent for oils and resins. It has been shown to cause liver and kidney cancer in experimental animals. This article reviews over 80 published papers and letters on the cancer epidemiology of people exposed to trichloroethylene. Evidence of excess cancer incidence among occupational cohorts with the most rigorous exposure assessment is found for kidney cancer (relative risk lRR] = 1.7, 95% confidence interval [Cl] 1.1-2.7), liver cancer (RR = 1.9, 95% Cl 1.0-3.4), and non-Hodgkin's lymphoma (RR = 1.5, 95% Cl 0.9-2.3) as well as for cervical cancer, Hodgkin's disease, and multiple myeloma. However, since few studies isolate trichloroethylene exposure, results are likely confounded by exposure to other solvents and other risk factors. Although we believe that solvent exposure causes cancer in humans and that trichloroethylene likely is one of the active agents, we recommend further study to better specify the specific agents that confer this risk and to estimate the magnitude of that risk.

Aims Dapagliflozin is a selective inhibitor of sodium glucose co-transporter 2 (SGLT2). This study assessed the efficacy and safety of dapagliflozin 10 mg versus placebo in patients with type 2 diabetes (T2D) and moderate renal impairment (estimated glomerular filtration rate [eGFR] 45–59 mL/min/1.73m2; chronic kidney disease [CKD] stage 3A). Materials and methods In this double-blind, parallel group, Phase 3 study (NCT02413398, clinicaltrials.gov) patients with inadequately controlled T2D (HbA1c 7.0–11.0%) were randomized (1:1) to dapagliflozin 10 mg once daily (N=160) or matching placebo (N=161) for 24 weeks. Randomization was stratified by pre-enrolment glucose-lowering therapy. The primary endpoint was change from baseline in HbA1c at Week 24. Results At Week 24, compared with placebo, dapagliflozin significantly decreased HbA1c (difference [95% CI]: −0.34% [−0.53, −0.15], p<0.001), body weight (−1.25 kg [−1.90, −0.59]; p<0.001), fasting plasma glucose (−0.9 mmol/L [−1.5, −0.4]; p=0.001) and systolic blood pressure (−3.1 mmHg [−6.3, 0.0]; p<0.05). Decreases from baseline in eGFR were greater with dapagliflozin than placebo at Week 24 (−2.49 mL/min/1.73m2 [−4.96, −0.02]), however, eGFR returned to baseline levels at Week 27 (3-weeks post-treatment) (0.61 mL/min/1.73m2 [−1.59, 2.81]). No increase in adverse events (AEs; 41.9 vs 47.8%) or serious AEs (5.6 vs 8.7%) were reported with dapagliflozin versus placebo. No AEs of bone fractures, amputations or DKA were reported. Conclusions The findings of this study support the positive benefit/risk profile of dapagliflozin for the treatment of patients with T2D and CKD 3A.

Current word count-250 words Background: We assessed the effects of the SGLT2 inhibitor dapagliflozin alone and in combination with the DPP4 inhibitor saxagliptin on albuminuria and HbA1c in patients with type 2 diabetes and chronic kidney disease in a double-blind placebo-controlled multicentre multinational study (DELIGHT study; clinicaltrials.gov, NCT02547935). Methods: After a 4-week single-blind placebo lead-in period, 448 participants were randomised (1:1:1; using computer-generated codes) to dapagliflozin 10 mg (n=145), dapagliflozin 10 mg and saxagliptin 2.5 mg (n=155) or placebo (n=148) once daily for 24 weeks. Inclusion criteria included urinary albumin-to-creatinine ratio (UACR) 30-3500 mg/g, eGFR 25-75 mL/min/1•73 m 2 , HbA1c 7-11% (53-97 mmol/mol) and stable doses of ACEi/ARB and glucose lowering treatment for ≥12 weeks. Primary endpoints were change from baseline in UACR (dapagliflozin and dapagliflozin/saxagliptin) and HbA1C (dapagliflozin/saxagliptin) at Week 24. Findings: Dapagliflozin and dapagliflozin/saxagliptin significantly reduced UACR versus placebo. This effect was sustained over the study period; at Week 24, change in UACR was −21•0% (95% CI, −34•1, −5•2; p=0•011) for dapagliflozin (n=132) and −38•0% (−48•2, −25•8; p<0•001) for dapagliflozin/saxagliptin (n=139) compared with placebo (n=134). HbA1c was reduced with dapagliflozin/saxagliptin (n=137) compared with placebo (n=118) (Week 24; −0•58% [−0•80 to −0•37; p<0•001]). The proportion of patients with adverse events (79/145 [54•5%], 104/152 [68•4%] and 81/148 [54•7%]) or serious adverse events (12/145 [8•3%], 12/152 [7•9%] and 16/148 [10•8%]) was similar across groups. There were no new drug-related safety signals. Interpretation: Dapagliflozin alone and dapagliflozin/saxagliptin conferred significant improvements in albuminuria in these patients; dapagliflozin/saxagliptin conferred a clinically significant reduction in both albuminuria and HbA1c at Week 24.

Dapagliflozin is associated with greater reductions in HbA1c and weight than saxagliptin in management of type 2 diabetes mellitus (T2DM). The present post hoc analyses compared the durability of these effects over short‐ and long‐term follow‐up in patients with T2DM who were inadequately controlled with metformin (≥1500 mg/day) and who were receiving either dapagliflozin (10 mg/day) or saxagliptin (5 mg/day). Failure of glycaemiccontrol was assessed using the slope of the change in HbA1c from baseline‐over‐time regression line (coefficient of failure [CoF]). CoF was compared directly (dapagliflozin vs saxagliptin) over the short term (NCT01606007, 24 weeks) and indirectly (placebo‐adjusted) over the long term (NCT00528879 and NCT00121667, 102 weeks). A low CoF value indicated greater durability. CoF was lower for dapagliflozin versus saxagliptin over 18–24 weeks (−1.38%/year; 95% CI, −2.41 to −0.35; P = .009) and 20–102 weeks (−0.37%/year; 95% CI, −0.73 to −0.02; P = .04). Fewer dapagliflozin‐treated patients versus saxagliptin‐treated patients required rescue medication or discontinued the study because of failure to achieve glycaemic control at 24 weeks (3.4% vs 9.4%; P = .0191). In patients with T2DM who were inadequately controlled with metformin, dapagliflozin was associated with greater durability of glycaemic control than saxagliptin over 18–24 and 20–102 weeks.

High protein intake may increase intraglomerular pressure through dilation of the afferent arteriole. Sodium-glucose cotransporter-2 (SGLT2) inhibitors may reduce intraglomerular pressure through activation of tubuloglomerular feedback. Given these opposing effects, we assessed whether the effect of dapagliflozin on glomerular filtration rate (GFR) and urinary albumin-to-creatinine ratio (UACR) was modified by estimated dietary protein intake using data from three separate randomized controlled trials (DELIGHT, IMPROVE and DIAMOND). The median protein intake was 58.4, 63.6 and 90.0 g/d, respectively. In the DELIGHT trial (n = 233), dapagliflozin compared to placebo caused an acute and reversible dip in GFR of 2.1 and 2.2 mL/min/1.73 m 2 , and reduced UACR by 20.5% and 28.4% in participants with high and low protein intake, respectively. Similarly, in IMPROVE (n = 30) and DIAMOND (n = 53), the effect of dapagliflozin on GFR and UACR was comparable in participants with high and low protein intake (all P for interaction > 0.40). This post hoc, exploratory analysis of three clinical trials suggests that dietary protein intake does not modify the individual response of clinical kidney variables to dapagliflozin.