Effect of sodium‐glucose cotransporter 2 inhibitors on the rate of decline in kidney function: A systematic review and meta‐analysis

Abstract

Aim To investigate the influence of sodium/glucose cotransporter‐2 inhibitors (SGLT‐2i) on renal function during the course of its administration, particularly in the initial weeks. Materials and Methods Randomized controlled trials (RCTs) related to SGLT‐2i were searched in databases (MEDLINE, EMBASE, and Cochrane Central Register) from the database's inception to August 31, 2021. All RCTs reported the kidney outcomes of SGLT2i versus active or placebo control were included, regardless of the presence of diabetes in the patients and the baseline estimated glomerular filtration rate (eGFR). The Cochrane Collaboration risk of bias tool was used to assess the quality of the included studies. All outcome comparisons were performed using the RevMan 5.4 software. Results Eleven RCTs with 58 534 participants reporting prespecified renal outcomes were identified. There was no heterogeneity in the baseline eGFR and urine albumin‐to‐creatinine ratio in the included studies. In the initial 2–4 weeks, there was an acute decline of eGFR in the SGLT‐2i group compared with placebo group (weighted mean difference [WMD] −3.35 ml/min/1.73 m 2 ; 95% CI, −3.81 to −2.90; I 2 = 35%, p = .15); When compared to baseline eGFR in the SGLT‐2i group, the WMD was −4.02 ml/min/1.73 m 2 (95% confidence interval [CI], −3.61 to −4.44; I 2 = 0%, p = .45). The renoprotective effect gradually appeared, and the decline rate of eGFR in the SGLT‐2i group was sustained slower than placebo. However, the statistically significant benefit of SGLT‐2i did not appear until the 104th week (the second year) (WMD 0.35 ml/min/1.73 m 2 , 95% CI, 0.04 to 0.66; I 2 = 45%, p = .08). Subgroup analysis showed SGLT‐2i had a similar benefit on renal function regardless of baseline eGFR values. Conclusion SGLT‐2i consistently slowed the deterioration of eGFR since the early stage of administration, even in patients with chronic kidney disease. However, there was an acute decline in eGFR in the initial 2–4 weeks; afterwards the renoprotective effect of SGLT‐2i gradually appeared and remained stable in the next few years.

Improved Glycaemic Control and Nephroprotective Effects of Empagliflozin and Paricalcitol Co-Therapy in Mice with Type 2 Diabetes Mellitus

“…Renal concentrations of antioxidants, IL-10, and adiponectin increased, whilst the oxidative stress markers, proinflammatory cytokines, leptin, resistin, TGF-β, iNOS, NGAL, and KIM-1 declined with both monotherapies compared to the PC animals. Our findings are aligned with many reports that have underscored the beneficial nephroprotective effects of SGLT2i [15,[20][21][22] and Pcal [24,[27][28][29] that could include glycaemic control with inhibition of renal lipotoxicity, oxidative stress, and inflammation.…”

“…Others have also shown that SGLT2i increased β-cell mass and insulin production by simultaneously inducing proliferation and inhibiting apoptosis in the pancreas of diabetic animals [47,48]. In clinical settings, SGLT2i also reduced albuminuria, modulated the levels of adipokines, and slowed the progression of chronic kidney disease [15,[20][21][22]. On the other hand, the synthetic analogue of active VD 3 , Pcal, also exerted antidiabetic actions by increasing insulin production following impedance of oxidative stress and inflammation of pancreatic β-cells in rats injected with STZ [49].…”

“…Many studies have reported renoprotective effects for the new anti-diabetic drugs, SGLT2i, that counteract hyperglycaemia by simultaneously promoting glucosuria and natriuresis [20][21][22]. In detail, treating diabetic mice with SGLT2i attenuated hyperglycaemia, dyslipidaemia, renal lipotoxicity, glomerular damage, and albuminuria, as well as increased renal PPARα and PPARγ with concurrent decreases in several inflammatory and oxidative stress markers [41][42][43][44].…”

“…The inhibitors of SGLT2 (SGLT2i) are novel antidiabetic agents that reduce blood glucose levels by simultaneously promoting glucosuria and natriuresis [19]. More recently, numerous experimental and clinical studies have reported that different analogues of SGLT2i delayed the onset and progression of DN, mainly by reducing oxidative stress and inflammation, whilst improving glomerular filtration [20][21][22][23]. Similarly, the synthetic analogue of active vitamin D (VD3), paricalcitol (Pcal; 19-nor-1α-25-2(OH) D2), is mainly used to treat hyperparathyroidism associated with chronic kidney disease.…”

Is Environmental Cadmium Exposure Causally Related to Diabetes and Obesity?

“…Loss of tubular gluconeogenesis and a switch to glycolysis are known pathologic features of CKD [ 23 ]. In clinical trials, SGLT2 inhibitors were effective to attenuate the deterioration of kidney function in CKD patients [ 24 ].…”