The Effect of Sodium–Glucose Cotransporter Inhibitors on Renal Function as Adjunctive to Insulin in Adults with Type 1 Diabetes: An Updated Multilevel Meta-analysis of Randomized Controlled Trials

Abstract

Introduction This systematic review aimed to summarize the existing evidence from published randomized controlled trials (RCTs) on the impact of sodium–glucose cotransporter (SGLT) inhibitors on albuminuria levels and renal function in patients with type 1 diabetes mellitus (T1D). Methods The literature search was performed through Medline (via PubMed), Cochrane Library, and Scopus until November 11, 2023. Double-independent study selection, data extraction, and quality assessment were performed. Evidence was pooled with three-level mixed-effects meta-analysis. Results In total, 5221 participants with T1D among 11 RCTs were analyzed. All RCTs had low risk of bias according to the Cochrane Collaboration tool (RoB 2). SGLT inhibitors were associated with a significantly greater reduction in urine albumin-to-creatinine ratio (UACR) compared to controls (MD = − 23.13%; 95% CI = [− 33.69, − 12.57]; P < 0.001; level of evidence high). On the basis of subgroup analysis, this effect was consistent across all available SGLT inhibitors, irrespective of the dosage. Finally, a neutral class effect was observed on the estimated glomerular filtration rate (eGFR, MD = − 1.03 mL/min/1.73 m 2 ; 95% CI = [− 2.26, 0.19]; P = 0.1; level of evidence moderate). Only empagliflozin was associated with a significant reduction in eGFR compared to placebo (MD = − 2.23 mL/min/1.73 m 2 ; 95% CI = [− 3.62, − 0.84]; P = 0.002). Conclusion Our findings suggest that adjunctive therapy with SGLT inhibitors results in a significant reduction in albuminuria, while their use is associated with a neutral effect on creatinine clearance, as a measure of renal function. Future renal outcome trials are needed to assess SGLT inhibitors’ role in the pharmacological armamentarium against diabetic nephropathy in T1D. Supplementary Information The online version contains supplementary material available at 10.1007/s13300-023-01523-0.

The Role of Sodium-Glucose Co-Transporter-2 Inhibitors on Diuretic Resistance in Heart Failure

“…Similar findings have been previously attributed to SGLT-2 inhibitors due to glycosuria [ 60 ]. Mild volume depletion (presented with symptomatic hypotension or orthostatic hypotension, polyuria, dehydration, dizziness, vertigo, presyncope, thirst, and rarely orthostatic hypotension), weight loss, a reduction in SBP, the potential deterioration of renal function (increases in serum creatinine levels, decreases in the eGFR), acute kidney injury or failure, potential changes in hematocrit and hemoglobulin, liver function deterioration, diabetic ketoacidosis, and hypoglycemia can also be attributed to the pharmacology of the SGLT-2 inhibitor class [ 37 , 50 , 57 , 61 ], which causes osmotic diuresis, natriuresis, glucosuria, and caloric wasting [ 60 ]. For instance, in their study, Wilcox et al reported two cases, one with syncope attributed possibly to orthostatic hypotension and another presented with hypokalemia that required oral potassium chloride to be administered [ 39 ].…”

“…SGLT-2 inhibitors are considered relatively safe drugs that could actually provide a reno-protective effect rather than harming the kidneys [ 37 , 43 , 49 , 53 , 54 , 57 , 59 , 61 ]. Indeed, although there are a handful of studies that refer to small decreases in the eGFR, which have been observed shortly after the addition of an SGLT-2 inhibitor in the medication of patients hospitalized for ADHF [ 45 , 49 ], the deterioration of renal function was mostly not persistent after hospital discharge [ 45 , 49 , 62 ].…”