Albuminuria-lowering effect of dapagliflozin alone and in combination with saxagliptin and effect of dapagliflozin and saxagliptin on glycaemic control in patients with type 2 diabetes and chronic kidney disease (DELIGHT): a randomised, double-blind, placebo-controlled trial

Abstract

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.

Effects of sodium‐glucose cotransporter‐2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

“…The renoprotective benefits of dapagliflozin were observed among patients with a relatively high level of renal function at baseline (mean eGFR, 85 mL/min/1.73 m), indicating a potential role for dapagliflozin in the early prevention of CKD in patients with T2D . The DELIGHT study reported the renoprotective effects of dapagliflozin in patients with T2D and moderate‐to‐severe CKD who were undergoing antihypertensive treatments . Treatment with dapagliflozin for 24 weeks resulted in significant reductions in albuminuria, with a mean change from baseline in urine albumin‐to‐creatinine ratio of −21.0% (95% confidence interval [CI], −34.1 to −5.2; P = .011) and in eGFR, with a mean change from baseline of –2.4 mL/min per 1.73 m (95% CI, −4.2 to −0.5; P = .011) as compared to placebo .…”

“…Dapagliflozin was associated with a significant reduction in the risk of the composite end point of CV death or hospitalization for heart failure (HF) in patients with T2D and established CVD or CV risk, while significant reductions in the risk of the composite end point of CV death, nonfatal myocardial infarction (MI) or nonfatal stroke were observed with empagliflozin in patients with T2D and established CVD, and with canagliflozin in patients with T2D and established CVD or multiple CV risk factors . Empagliflozin, canagliflozin and dapagliflozin were also associated with a reduction in the risk of hospitalization for HF, as well as a reduction in the risk of kidney disease progression . The American Diabetes Association (ADA) 2019 Standards of Medical Care in Diabetes, the ADA and European Association for the Study of Diabetes 2018 consensus report and the American Association of Clinical Endocrinologists/American College of Endocrinology 2019 consensus report have taken into consideration the CV and renal complications of T2D when providing a revised treatment strategy for T2D, recommending SGLT‐2i therapy with proven CV or renal benefit in patients with established CVD or chronic kidney disease (CKD) with or without CVD .…”

“…3,4 Empagliflozin, canagliflozin and dapagliflozin were also associated with a reduction in the risk of hospitalization for HF, [3][4][5] as well as a reduction in the risk of kidney disease progression. [5][6][7][8][9][10] The American Diabetes Association (ADA) 2019 Standards of Medical Care in Diabetes, the ADA and European Association for the Study of Diabetes 2018 consensus report and the American Association of Clinical Endocrinologists/American College of Endocrinology 2019 consensus report have taken into consideration the CV and renal complications of T2D when providing a revised treatment strategy for T2D, recommending SGLT-2i therapy with proven CV or renal benefit in patients with established CVD or chronic kidney disease (CKD) with or without CVD. [11][12][13] This review considers the increased risk of CVD and renal complications in patients with T2D, and discusses the potential mechanisms for the cardioprotective and renoprotective effects of SGLT-2i therapy in patients with T2D.…”

Use of sodium–glucose co‐transporter‐2 inhibitors in patients with and without type 2 diabetes: implications for incident and prevalent heart failure

“…The DELIGHT study investigated the effect of dapagliflozin (with or without the DPP‐4i saxagliptin) on lowering albuminuria in patients with T2D and moderate‐to‐severe CKD (UACR 30–3500 mg/g and eGFR 25–75 mL/min/1.73 m 2 ) being treated with ACEIs or angiotensin II receptor blockers . Following 24 weeks of treatment, significant mean changes from baseline in UACR were observed with dapagliflozin (−21.0%, 95% CI −34.1 to −5.2) or with dapagliflozin plus saxagliptin (−38.0%, 95% CI −48.2 to −25.8) compared with placebo …”

Renal effects of sodium–glucose cotransporter-2 inhibitors in patients with type 2 diabetes and renal impairment

“…The DELIGHT study (N = 448) assessed the albuminurialowering effects of dapagliflozin (with or without the DPP-4i saxagliptin) in patients with T2D and moderate-to-severe chronic kidney disease (CKD) (UACR of 30-3500 mg/g and eGFR of 25-75 mL/min/1.73 m 2 ) who were receiving RAASis [64]. Patients treated with dapagliflozin or with dapagliflozin plus saxagliptin had significant reductions in the UACR over the course of the study, while the UACR remained relatively stable in the placebo group.…”