Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta‐analysis

Aims To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of rongliflozin in a cohort of healthy Chinese people and people with type 2 diabetes mellitus (T2DM). Materials and methods We examined the effects of a single ascending dose (SAD) of rongliflozin (10‐200 mg) in combination with food (20 mg) in 50 healthy people, and a multiple ascending dose (MAD) of rongliflozin (10‐50 mg once daily for 12 days) in 36 people with T2DM. Results No serious adverse events (AEs) or discontinuations as a result of AEs (related to rongliflozin) occurred in either study. In healthy participants and those with T2DM, rongliflozin was rapidly absorbed, with a time to maximum plasma concentration of 0.63 to 1.75 hours. Systemic exposure (maximum observed serum concentration and area under the curve) to rongliflozin and its inactive major metabolites (T1444, T1454 and T1830) increased in proportion to dose. In the SAD and MAD studies, there was a dose‐related increase in urinary glucose excretion (UGE) ranging from 10 to 50 mg rongliflozin. This increase in UGE was associated with dose‐related decreases in serum glucose values in people with T2DM in the MAD group. In the SAD group, UGE plateaued at 50 to 200 mg. Conclusions Rongliflozin was well tolerated in all participants. The PK and PD measurements obtained for rongliflozin demonstrate a dose‐response relationship when the drug is administered at doses ranging from 10 to 50 mg in healthy people and in people with T2DM.

Section: Discussionmentioning

confidence: 60%

Pharmacokinetics and pharmacodynamics of rongliflozin, a novel selective inhibitor of sodium‐glucose co‐transporter‐2, in people with type 2 diabetes mellitus

Zhang

Zhu

et al. 2019

“…Although the ADVANCE study clearly demonstrated renoprotection with intensified glycaemic control using a sulphonylurea‐based regimen, this trial was completed before the widespread use and clinical investigation of newer glucose‐lowering agents, which may improve the outlook of diabetic kidney disease . These include sodium‐glucose co‐transporter‐2 inhibitors and glucagon‐like peptide‐1 receptor agonists which have been shown to confer end‐organ protection, at least in part via glucose‐independent mechanisms . Dipeptidyl peptidase‐4 (DPP‐4) inhibitors appear to be neutral in terms of cardiovascular protection .…”

Section: Perspectivesmentioning

confidence: 99%

Renal protection: What have we learnt from ADVANCE about kidney disease in type 2 diabetes?

Knudsen

Cooper

2020

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial was a landmark randomized controlled clinical trial in 11 140 type 2 diabetic patients from 215 centers in 20 countries with a two‐by‐two factorial design. In the blood pressure‐lowering arm, patients were treated using a fixed combination of the ACE‐inhibitor, perindopril, and the thiazide‐like diuretic, indapamide, or placebo, whereas in the glucose‐lowering arm, the intervention compared the sulphonylurea gliclazide plus other glucose‐lowering drugs, targeting a glycated hemoglobin value of 6.5% or less, with standard glucose control. Primary end‐points were major macro‐ and microvascular events in both arms. This review gives an overview of the results of the primary randomized trial, results from observational follow‐up studies, and results of several biomarker studies and discusses the perspectives of these data in the context of recent major outcome trials for current medical treatment.

“…Trial‐level analyses support a role for early change in albuminuria as a surrogate endpoint for progression of CKD in clinical trials; in patients with high baseline albuminuria the decrease of albuminuria of 30% might be considered as a surrogate endpoint for progression of CKD . In a meta‐analysis of RCTs to assess the efficacy and safety of SGLT‐2is in patients with T2D and DKD (eGFR <60 mL/min/1.73 m 2 ), SGLT‐2is can reduce albuminuria by 23%.…”

Section: Sglt‐2 Inhibitorsmentioning

confidence: 99%

Type 2 diabetes and the kidney: Insights from cardiovascular outcome trials

Giugliano

Nicola

Maiorino

et al. 2019

Diabetic kidney disease (DKD) still remains a progressive condition that is associated with higher risk of end-stage kidney disease and significant cardiovascular morbidity and mortality. Twelve cardiovascular outcome trials in type 2 diabetes (T2D) have been published to date. Most trials with dipeptidyl-peptidase inhibitors (SAVOR-TIMI 53 with saxagliptin, EXAMINE with alogliptin, TECOS with sitagliptin, and CAR-MELINA with linagliptin) and with glucagon-like peptide-1 receptor agonists (GLP-1RAs) (ELIXA with lixisenatide, LEADER with liraglutide, SUSTAIN-6 with semaglutide, EXCSEL with exenatide once-weekly, and HARMONY with albiglutide) pointed towards reduced albuminuria, which is a surrogate endpoint possibly heralding renal function preservation. The three trials with sodium-glucose co-transporter-2 inhibitors (SGLT-2is) (empagliflozin, canagliflozin and dapagliflozin) also showed a salutary effect on long-term estimated glomerular filtration rate, suggesting that SGLT-2is are more effective at mitigating loss of kidney function than incretinbased therapies; moreover, SGLT-2is also have the advantage of plausible haemodynamic mechanisms for improved renal outcomes. Despite some residual limitations linked to differences in study populations and patient characteristics, the cardiorenal protective actions of SGLT-2is, and to a lesser extent some GLP-1RAs, make them favourable medications for patients with T2D at increased cardiorenal risk.There is room for optimism that their use may change the paradigm of the ineluctable progression of DKD.