SGLT2 Inhibition for the Prevention and Treatment of Diabetic Kidney Disease: A Review

Alicic, Radica Z.; Johnson, Eric J.; Tuttle, Katherine R.

doi:10.1053/j.ajkd.2018.03.022

Cited by 113 publications

(97 citation statements)

References 80 publications

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“…Although the exact mechanisms underlying the renoprotective effects of SGLT‐2is are not fully elucidated, direct haemodynamic and renovascular effects probably play important roles . The natriuretic effects of SGLT‐2is lead to increased delivery of sodium chloride at the macula densa, which reactivates tubuloglomerular feedback and reduces glomerular hyperfiltration and renal blood flow (Figure ) . SGLT‐2i–associated natriuresis may also modulate cellular energy use in the proximal tubule .…”

Section: Mechanisms Of CV and Renal Protection With Sglt‐2 Inhibitorsmentioning

confidence: 99%

“…6 The natriuretic effects of SGLT-2is lead to increased delivery of sodium chloride at the macula densa, which reactivates tubuloglomerular feedback and reduces glomerular hyperfiltration and renal blood flow (Figure 4). 44,94,96 SGLT-2i-associated natriuresis may also modulate cellular energy use in the proximal tubule. 97 Further, decreased atrial natriuretic peptide levels F I G U R E 4 Proposed mechanism for the renoprotective effects of SGLT-2is.…”

Section: Microvascular Effectsmentioning

confidence: 99%

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

Chilton

2019

Diabetes Obesity Metabolism

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Sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2is) have been shown to mitigate the risks of cardiovascular (CV) and renal complications in patients with type 2 diabetes (T2D) and CV risk factors or CV disease (CVD). In CV outcomes trials (CVOTs) of patients with T2D and established CVD or multiple CV risk factors, empagliflozin and canagliflozin were associated with significant reductions in the risks of major adverse CV events (MACE), hospitalization for heart failure (HF) and kidney disease progression. In the DECLARE–TIMI 58 study, in which the majority of patients did not have established CVD, dapagliflozin was associated with significant reductions in the composite end point of CV death or hospitalization for HF and was noninferior to placebo with regard to MACE; although patients had relatively good renal function, dapagliflozin also showed renal benefits similar to those seen with empagliflozin and canagliflozin. This article reviews the increased risk of CVD and renal disease in patients with T2D and discusses the potential mechanisms of the cardioprotective and renoprotective effects of SGLT‐2i therapy. The observed improvements in CV and renal outcomes with SGLT‐2is in CVOTs suggest a class effect in this patient population and have influenced treatment guidelines for the way add‐on therapy to metformin is initiated in patients with T2D and high CV risk. The overall cardioprotective and renoprotective effects of SGLT‐2is in patients with T2D and high CV risk are most likely attributable to multiple mechanisms, including cardiac, haemodynamic, metabolic, anti‐inflammatory and renal effects.

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Section: Mechanisms Of CV and Renal Protection With Sglt‐2 Inhibitorsmentioning

confidence: 99%

Section: Microvascular Effectsmentioning

confidence: 99%

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

Chilton

2019

Diabetes Obesity Metabolism

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“…In loss‐of‐function allele combinations, SLC5A2 mutations can produce a mild hyperaldosteronism attributable to natriuresis, but cause neither hypoglycaemia nor hypotension . Recent outcomes studies have shown that SGLT2 inhibitors can reduce the risk of major cardiovascular adverse events (AEs), including death, as well as attenuate the progression of renal disease …”

Section: Introductionmentioning

confidence: 99%

“…13,14 Recent outcomes studies have shown that SGLT2 inhibitors can reduce the risk of major cardiovascular adverse events (AEs), including death, 15,16 as well as attenuate the progression of renal disease. [17][18][19] For many individuals, type 2 diabetes is a chronic progressive condition requiring increasingly potent interventions as the disease evolves. Estimates of the percentage of the population requiring therapeutic intensification per year range from the low teens 20 to nearly 50%, 21 depending on the cohort chosen.…”

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confidence: 99%

A 96‐week, multinational, randomized, double‐blind, parallel‐group, clinical trial evaluating the safety and effectiveness of bexagliflozin as a monotherapy for adults with type 2 diabetes

Halvorsen

Walford

Massaro

et al. 2019

Diabetes Obesity Metabolism

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Aim To explore the safety and effectiveness of extended exposure to bexagliflozin as a monotherapy for type 2 diabetes. Methods Adults with diabetes (n = 288) from the USA, Colombia and Mexico were randomized 1:1 to receive bexagliflozin (20 mg) or placebo for 96 weeks. The primary endpoint was the placebo‐adjusted change in HbA1c at 24 weeks. Dosing was continued an additional 72 weeks to assess safety and the durability of the treatment effect. Secondary endpoints measured changes from baseline in body mass and systolic blood pressure (SBP) and diastolic blood pressure (DBP) at week 24, and the change, over study duration, in HbA1c. Results The placebo‐adjusted change in HbA1c from baseline to week 24 was −0.79% (−8.6 mmol/mol) [95%CI −0.53, −1.06 (−5.8, −11.6), P < .0001]. The unadjusted change from baseline through week 96 was −0.55% (−6.0 mmol/mol) ± 1.184% (12.9) (SD) for the bexagliflozin arm compared with 0.53% (5.8 mmol/mol) ± 1.215% (13.3) for the placebo arm (P < .0001). Significant decreases in body mass, SBP and DBP could be attributed to bexagliflozin exposure. The incidence of serious adverse events was lower in the bexagliflozin‐treated group (2.8%) than in the placebo group (8.5%). Urinary tract infections occurred less frequently in the active arm (14.5%) than in the placebo arm (20.6%). Conclusions Bexagliflozin at 20 mg/d was well tolerated and provided a durable, clinically meaningful improvement in glycaemic control over 96 weeks to participants in this phase 2 trial. A substantial reduction in weight and blood pressure was produced by bexagliflozin, with no increase in significant adverse event rates.

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“…Despite optimal diabetes care, including good glycemic control and treatment of hypertension through renin–angiotensin system inhibition, a large residual risk for developing DKD and its progression remains, and there is a great unmet need for treatment. In clinical trials that investigated the cardiovascular safety of SGLT2i, secondary effects of preventing or reducing albuminuria and the decline in eGFR spurred further investigation into their potential application in DKD. The following ongoing clinical trials are currently testing the efficacy and safety of SGLT2i on primary outcomes in CKD patients with a lower eGFR, with and without type 2 diabetes mellitus: Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation, Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (NCT03036150), and Study of Heart and Kidney Protection With Empagliflozin.…”

Section: Discussionmentioning

confidence: 99%

Protective effect of sodium–glucose cotransporter 2 inhibitors in patients with rapid renal function decline, stage G3 or G4 chronic kidney disease and type 2 diabetes

Miyoshi

Kameda

Yamashita³

et al. 2019

J of Diabetes Invest

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Aims/Introduction The risk of end‐stage kidney disease increases in proportion to the decline in the estimated glomerular filtration rate (eGFR). Although protective effects of sodium–glucose cotransporter 2 inhibitors (SGLT2i) on the eGFR decline were shown in several large‐scale clinical trials, there are no studies investigating patients with a high risk of end‐stage kidney disease. We investigated the efficacy and safety of SGLT2i in advanced renal dysfunction patients (stage G3 or G4 of chronic kidney disease) with a rapid decline in eGFR. Materials and Methods This retrospective, longitudinal study enrolled patients with type 2 diabetes who were treated with SGLT2i, and whose eGFR was <60 mL/min/1.73 m2 and had declined >20% over 2 years (%ΔeGFR−2y) before initiating SGLT2i. The primary end‐point was the change in eGFR 2 years after initiation (%ΔeGFR+2y) compared with %ΔeGFR−2y. Results A total of 17 patients among 553 patients treated with SGLT2i for ≥2 years were included in the study. The average age, glycated hemoglobin and eGFR at SGLT2i initiation were 68.5 years, 7.3% and 38.3 mL/min/1.73 m2, respectively. %ΔeGFR+2y in patients who were treated with SGLT2i was significantly increased compared with the patients not treated with SGLT2i (2.3 and −21.7%, respectively; P < 0.0001). A multiple regression analysis showed that only the proportion of the rate of eGFR decline was the independent factor associated with improvement of %ΔeGFR+2y. There was no increase in serious adverse events including acute kidney injury. Conclusions SGLT2i was safe, and prevented further eGFR decline in patients with type 2 diabetes and advanced renal dysfunction.

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SGLT2 Inhibition for the Prevention and Treatment of Diabetic Kidney Disease: A Review

Cited by 113 publications

References 80 publications

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

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

A 96‐week, multinational, randomized, double‐blind, parallel‐group, clinical trial evaluating the safety and effectiveness of bexagliflozin as a monotherapy for adults with type 2 diabetes

Protective effect of sodium–glucose cotransporter 2 inhibitors in patients with rapid renal function decline, stage G3 or G4 chronic kidney disease and type 2 diabetes

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