Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin

Abstract

Sodium glucose cotransporter 2 (SGLT2) inhibitors reduce HbA1c, blood pressure, and weight in patients with type 2 diabetes. To investigate the effect of renal function on reductions in these parameters with the SGLT2 inhibitor empagliflozin, we assessed subgroups by baseline estimated glomerular filtration rate (eGFR; Modification of Diet in Renal Disease) in pooled data from five 24-week trials of 2286 patients with type 2 diabetes randomized to empagliflozin or placebo. Reductions in HbA1c with empagliflozin versus placebo significantly diminished with decreasing baseline eGFR. Reductions in systolic blood pressure (SBP) with empagliflozin were maintained in patients with lower eGFR. The mean placebo-corrected changes from baseline in systolic blood pressure at week 24 with empagliflozin were -3.2 (95% confidence interval -4.9,-1.5) mmHg, -4.0 (-5.4, -2.6) mmHg, -5.5 (-7.6, -3.4) mmHg, and -6.6 (-11.4, -1.8) mmHg in patients with an eGFR of 90 or more, 60 to 89, 30 to 59, and under 30 ml/min/1.73m, respectively. Similar trends were observed for diastolic blood pressure. Weight loss with empagliflozin versus placebo tended to be attenuated in patients with a lower eGFR. Results were consistent in a 12-week ambulatory blood pressure monitoring trial in 823 patients with type 2 diabetes and hypertension. Thus, unlike HbA1c reductions, systolic blood pressure and weight reductions with empagliflozin are generally preserved in patients with chronic kidney disease.

Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta‐analysis

“…In total, 27 studies yeilded data on biomarkers or on cardiovascular, renal or safety outcomes, with substantial contributions from three large cardiovascular outcome trials of empagliflozin, canagliflozin and dapagliflozin . Of the 27 studies, 18 were individual trials, eight were pooled analyses and one was a regulatory report for ertugliflozin (Figure and Supporting Information Table S2). The eight pooled analyses and one regulatory report combined data from 41 individual trials from which results were not individually available for the CKD population.…”

“…Because of their renal‐based mechanism of action, and the potential that the balance of benefits and risks may differ among individuals with chronic kidney disease (CKD), SGLT2 inhibitors are currently not approved for use in individuals with an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m 2 for empagliflozin and canagliflozin, and <60 mL/min/1.73 m 2 for dapagliflozin and ertugliflozin . The glucose‐lowering effect of SGLT2 inhibitors depends on glomerular filtration and is progressively attenuated as kidney function declines . In contrast, other non‐glycaemic effects, such as reductions in blood pressure and albuminuria, appear similar across different levels of kidney function, raising questions about the effects on cardiovascular, renal and safety outcomes in indviduals with reduced eGFR.…”

“…11,12 The glucose-lowering effect of SGLT2 inhibitors depends on glomerular filtration and is progressively attenuated as kidney function declines. 13,14 In contrast, other non-glycaemic effects, such as reductions in blood pressure and albuminuria, appear similar across different levels of kidney function, [13][14][15] raising questions about the effects on cardiovascular, renal and safety outcomes in indviduals with reduced eGFR.…”

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

“…In parallel, attenuation of weight loss would be expected with declining renal function. However, surprisingly, the reduction in body weight is found to be independent of eGFR and the underlying mechanism is still not understood. Given the post hoc nature of the analysis, any proffered mechanism for this weight loss pattern would probably be speculative.…”

SGLT2 inhibition to address the unmet needs in diabetic nephropathy

“…Enhanced natriuresis and osmotic diuresis, leading to sustained reduction in plasma volume, as well as reduced sympathetic tone and arterial stiffness have been proposed as underlying mechanisms . At variance with the anti‐hyperglycemic effect, the BP lowering activity of SGLT2i is preserved and even enhanced in advancing CKD . The underlying mechanism is unclear; however, patients with CKD are more salt sensitive and the natriuretic effect of SGLT2i may thus result in more pronounced BP diminution in these subjects .…”