Empagliflozin and Kidney Function Decline in Patients with Type 2 Diabetes: A Slope Analysis from the EMPA-REG OUTCOME Trial

Aims To investigate the effects of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors vs. dipeptidyl peptidase‐4 (DPP‐4) inhibitors on renal function preservation (RFP) using real‐world data of patients with type 2 diabetes in Japan, and to identify which subgroups of patients obtained greater RFP benefits with SGLT2 inhibitors vs. DPP‐4 inhibitors. Methods We retrospectively analysed claims data recorded in the Medical Data Vision database in Japan of patients with type 2 diabetes (aged ≥18 years) prescribed any SGLT2 inhibitor or any DPP‐4 inhibitor between May 2014 and September 2016 (identification period), in whom estimated glomerular filtration rate (eGFR) was measured at least twice (baseline, up to 6 months before the index date; follow‐up, 9 to 15 months after the index date) with continuous treatment until the follow‐up eGFR. The endpoint was the percentage of patients with RFP, defined as no change or an increase in eGFR from baseline to follow‐up. A proprietary supervised learning algorithm (Q‐Finder; Quinten, Paris, France) was used to identify the profiles of patients with an additional RFP benefit of SGLT2 inhibitors vs. DPP‐4 inhibitors. Results Data were available for 990 patients prescribed SGLT2 inhibitors and 4257 prescribed DPP‐4 inhibitors. The proportion of patients with RFP was significantly greater in the SGLT2 inhibitor group (odds ratio 1.27; P = 0.01). The Q‐Finder algorithm identified four clinically relevant subgroups showing superior RFP with SGLT2 inhibitors (P < 0.1): no hyperlipidaemia and eGFR ≥79 mL/min/1.73 m2; eGFR ≥79 mL/min/1.73 m2 and diabetes duration ≤1.2 years; eGFR ≥75 mL/min/1.73 m2 and use of antithrombotic agents; and haemoglobin ≤13.4 g/dL and LDL cholesterol ≥95.1 mg/dL. In each profile, glycaemic control was similar in the two groups. Conclusion SGLT2 inhibitors were associated with more favourable RFP vs. DPP‐4 inhibitors in patients with certain profiles in real‐world settings in Japan.

Section: Introductionmentioning

confidence: 77%

Identification of subgroups of patients with type 2 diabetes with differences in renal function preservation, comparing patients receiving sodium‐glucose co‐transporter‐2 inhibitors with those receiving dipeptidyl peptidase‐4 inhibitors, using a supervised machine‐learning algorithm (PROFILE study): A retrospective analysis of a Japanese commercial medical database

Zhou

Watada

Tajima

et al. 2019

“…The initial short‐term decline in eGFR observed with SGLT‐2is that heralds better eGFR preservation over the long term is believed to be a result of osmotic diuresis, lower blood pressure and preglomerular vasoconstriction. The latter is secondary to restoration of a normal tubuloglomerular feedback activity (driven by the increased Na+ delivery to the macula densa) that counteracts attenuation of glomerular hyperfiltration at the single nephron level. Moreover, recent results have suggested that the albuminuria‐lowering effect of SGLT‐2is may also be the result of decreased tubular cell injury possibly related to decreased inflammation, antioxidative stress effects and also lower serum uric acid levels .…”

Section: Discussionmentioning

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.

“…Previous research, including observational studies and a randomized controlled trial, has shown that eGFR tends to decline over time among patients with T2DM; some studies have found that groups of patients may experience varying rates of renal function decline, with some exhibiting rapid decline and others slower decline . The observational studies, in particular, have also reported differences in the rate of eGFR change based on certain patient characteristics including age, ethnicity, positive or negative proteinuria at baseline and hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…Previous research has showed that renal function, as measured by estimated glomerular filtration rate (eGFR), can vary considerably, especially among people with diabetes . These studies have also suggested that eGFR improvement among people with T2DM is possible, leading to increased complexity when considering optimal treatment.…”

Section: Introductionmentioning

confidence: 99%

Temporal variation of renal function in people with type 2 diabetes mellitus: A retrospective UK clinical practice research datalink cohort study

Spanopoulos

Zaccardi

Tebboth

et al. 2019

Aim To characterize the longitudinal variability of estimated glomerular filtration rate (eGFR) in people with type 2 diabetes mellitus (T2DM), including variation between categories and individuals. Methods People with T2DM and sufficient recorded serum creatinine measurements were identified from the Clinical Practice Research Datalink (T2DM diagnosis from 1 January 2009 to 1 January 2011 with 5 years follow‐up); eGFR was calculated using the CKD‐EPI equation. Results In total, 7766 individuals were included; 32.8%, 50.2%, 12.4%, 4.0% and 0.6% were in glomerular filtration rate (GFR) categories G1, G2, G3a, G3b and G4, respectively. Overall, eGFR decreased by 0.44 mL/min/1.73 m2 per year; eGFR increased by 0.80 mL/min/1.73 m2 between index and year 1, then decreased by 0.75 mL/min/1.73 m2 annually up to year 5. Category G1 showed a steady decline in eGFR over time; G2, G3a and G3b showed an increase between index and year 1, followed by a decline. Category G4 showed a mean eGFR increase of 1.85 mL/min/1.73 m2 annually. People in categories G3‐G4 moved across a greater number of GFR categories than those in G1 and G2. Individual patients' eGFR showed a wide range of values (change from baseline at year 5 varied from −80 to +59 mL/min/1.73 m2). Conclusion Overall, eGFR declined over time, although there was considerable variation between GFR categories and individuals. This highlights the difficulty in prescribing many glucose‐lowering therapies, which require dose adjustment for renal function. The study also emphasizes the importance of regular monitoring of renal impairment in people with T2DM.