The effects of dapagliflozin on cardio‐renal risk factors in patients with type 2 diabetes with or without renin‐angiotensin system inhibitor treatment: a post hoc analysis

Abstract

Aims Renin‐angiotensin system inhibitors (RASi) are the most effective treatments for diabetic kidney disease but significant residual renal risk remains, possibly because of other mechanisms of kidney disease progression unrelated to RAS that may be present. Sodium‐glucose co‐transporter‐2 inhibitors reduce albuminuria and may complement RASi by offering additional renal protection. This post hoc analysis investigated the effects of dapagliflozin on cardio‐renal risk factors in patients with type 2 diabetes (T2D) with increased albuminuria treated with or without RASi at baseline. Materials and methods We evaluated the effects of dapagliflozin 10 mg/day over 12–24 weeks across 13 placebo‐controlled studies in patients with T2D with a urinary albumin‐to‐creatinine ratio (UACR) ≥30 mg/g at baseline. Patients were divided into two subgroups based on treatment with or without RASi at baseline. Results Compared with patients with RASi at baseline (n = 957), patients without RASi (n = 302) were younger, had a shorter duration of diabetes (7 vs. 12 years), higher estimated glomerular filtration rate (eGFR) and lower UACR, serum uric acid (sUA), body weight and systolic blood pressure. Placebo‐adjusted treatment effects of dapagliflozin on UACR, eGFR, glycated haemoglobin and haematocrit over 24 weeks were similar across groups. Mean reductions in body weight and sUA were more distinct in patients without RASi treatment at baseline. Conclusions Treatment with dapagliflozin over 24 weeks provides similar clinically relevant improvements in metabolic and haemodynamic parameters, and similar reductions in UACR, in patients with T2D with elevated albuminuria treated with or without RASi at baseline.

Renal haemodynamic and protective effects of renoactive drugs in type 2 diabetes: Interaction with SGLT2 inhibitors

“…On the other hand, one could hypothesize that due to overlapping pathways the effects of SGLT2 inhibitors on a RAS inhibitor background are reduced, which would be called sub‐additive. However, in both a mechanistic clinical trial and in a post‐hoc analysis investigating the effect of SGLT2 inhibitors on cardiorenal risk factors in people with T2D with and without RAS inhibitors, the results were not modulated by the use of RAS inhibitors, suggesting the pre‐SGLT2 inhibitor effect of RAS inhibitors to be much less 33,83 . Similar observations were performed in the large outcome trials and outcomes were not affected by concomitant RAS treatment.…”

Benefits and harms of sodium‐glucose co‐transporter‐2 inhibitors (SGLT2‐I) and renin–angiotensin–aldosterone system inhibitors (RAAS‐I) versus SGLT2‐Is alone in patients with type 2 diabetes: A systematic review and meta‐analysis of randomized controlled trials

“…The remaining nine articles met the inclusion criteria and were included in the review. 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 …”

“…Two studies reported the effect of SGLT2 inhibition vs placebo on estimated GFR changes across the subgroup of RAAS‐I users. 29 , 35 In the EMPA‐REG OUTCOME trial, the initial change in estimated GFR in patients taking the combination of empagliflozin and RAAS‐Is was higher than for those taking empagliflozin alone (Table 2 ). The long‐ and post‐treatment changes were also similar for both groups.…”

“…The long‐ and post‐treatment changes were also similar for both groups. In the study that pooled data across 13 trials, the effect of dapagliflozin on estimated GFR was similar in patients with or without RAAS inhibition 35 (Table 2 ).…”

SGLT2 Inhibitors: Slowing of Chronic Kidney Disease Progression in Type 2 Diabetes

“…It is possible that SGLT2i drugs have a protective effect on the glomerulus in the longer term due to the constriction of the afferent arteriole, which in turn lowers the intraglomerular pressure and reduces the amount of protein filtered through the glomerulus (albuminuria). It has also been suggested that RAASi therapies might have a complementary and renoprotective effect on intraglomerular pressure through dilation of the efferent arteriole, although subgroup analysis of CVOT data does not appear to support this hypothesis [ 40 , 42 ].…”