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SGLT2 inhibition has been shown to preserve renal function and decrease albuminuria in animal models, but do these results apply to humans?
Empagliflozin may produce a clinically meaningful drop in the urine albumen-to-creatinine ratio (UACR) in patients with T2DM and micro- or macroalbuminuria, according to a pooled analysis of industry-sponsored trials published online in Diabetologia.
The results may support a renoprotective effect of SGLT2 inhibition.
“The quantity of the observed albuminuria-lowering effect was clinically meaningful and was only partially explained by expected empagliflozin-related improvements in variables otherwise associated with albuminuria reduction, namely HbA1c, weight and BP,” wrote first author David Cherney, MD, PhD of Toronto General Hospital (Toronto, Canada), and colleagues.
In animal models, SGLT2 inhibition has been shown to preserve renal function, and decrease glomerulosclerosis, renal fibrosis, and albuminuria. Whether or not these results apply to humans has been an open question.
In the study, researchers pooled data from five industry-sponsored phase III randomized clinical trials. One of the studies was the EMPA-REG RENAL trial, which included patients with chronic kidney disease. The analysis included 636 patients with T2DM and microalbuminuria (UACR 30-300 mg/g) and 215 with macroalbuminuria (UACR >300 mg/g). The main outcome was percent change from baseline to week 24 in the geometric mean for UACR. Results were controlled for clinical confounders including baseline log-transformed UACR, HbA1c, systolic blood pressure (SBP), and estimated glomerular filtration rate (GFR).
• Microalbuminuria gGroup: 32% drop in UACR for empagliflozin vs placebo UACR (P<0.001)
♦ Similar results for empagliflozin 10 mg and 25 mg (P=0.431)
• Macroalbuminuria group: 41% drop in UACR compared to placebo (P<0.001)
♦ Similar results for empagliflozin 10 mg and 25 mg (P=0.084)
• These effects occurred within the first 12 weeks, and were maintained through 24 weeks
• Only about half of the decrease in UACR in patients with micro- or macroalbuminuria was related to improvements in HbA1c, SBP, or weight
The authors pointed out that these results should be hypothesis-generating only, because the trials from which the data was drawn were designed to assess the glucose-lowering effects of SGTL2 inhibition, not its renal effects.
Nevertheless, they proposed several mechanisms that could explain these findings. First, SGLT2 inhibition may have direct renal effects. In T1DM, SGLT2 inhibition has been found to decrease renal hyperfiltration, which may improve glomerular hypertension. Second, SGLT2 inhibition decreases blood pressure and arterial stiffness, which has been linked to renal protection. Third, SGLT2 inhibition may decrease inflammation related to renal disease, as suggested by in vitro and in vivo studies showing a decrease in inflammatory markers with SGLT2 inhibition. Also, SGLT2 inhibition decreases uric acid by about 15%, which may have beneficial effects on UACR. Finally, changes in circulating fluid volume may affect urinary albumen excretion.
However, the authors concluded “Our results further support a direct renal effect of SGLT2 inhibitors. Prospective studies are needed to explore the potential of this intervention to alter the course of kidney disease in high-risk patients with diabetes.”
• A pooled analysis of five phase III clinical trials found a clinically meaningful drop in the urine albumen-to-creatinine ratio (UACR) in patients with T2DM and micro- or macroalbuminuria.
• Only about half of the decrease in UACR in patients with micro- or macroalbuminuria was related to improvements in factors usually related to reduction in albuminuria (HbA1c, SBP, and weight).
• The results suggest a direct renoprotective role for SGLT2 inhibition.
One or more authors reports speaker honorary, consulting, research grants, advisory board membership, board membership, and/or share ownership for one or more of the following: Boehringer Ingelheim, Astrazeneca, Eli Lilly, Genzyme, Merck Sharp and Dohme, Novartis, Novo Nordisk, Roche, Abbott, Abb Vie, Cebix, Janssen, Medscape, and/or Medix Laboratories.
Drs. von Eynatten, Kaspers, Lund, and Woerle are employees of Boehringer Engelheim.
Reference: Cherney D, et al. The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes. Diabetologia. 2016 Jun 17.