Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial

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Abstract

In a pooled analysis of short-term trials, short-term treatment with the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin reduced albuminuria in patients with type 2 diabetes and prevalent albuminuria. In this exploratory analysis of the EMPA-REG OUTCOME trial, we report the short-term and long-term effects of empagliflozin on albuminuria in patients with type 2 diabetes and established cardiovascular disease, according to patients' baseline albuminuria status.

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Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications.

Hiddo J.L. Heerspink, Bruce A. Perkins, David H. Fitchett … (2016)

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by ≈5 mL·min(-1)·1.73 m(-2) and ≈30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate 30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis, such as the impact on blood pressure, heart failure, kidney protection, and mortality, will be a major management focus.

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Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL.

Dick de Zeeuw, Giuseppe Remuzzi, Hans-Henrik Parving … (2004)

Proteinuria or albuminuria is an established risk marker for progressive renal function loss. Albuminuria can be effectively lowered with antihypertensive drugs that interrupt the renin-angiotensin system (RAS). We investigated whether albuminuria could not only serve as a marker of renal disease, but also function as a monitor of the renoprotective efficacy of RAS intervention by the angiotensin II (Ang II) antagonist, losartan, in patients with diabetic nephropathy. The data from the RENAAL (Reduction in End Points in Noninsulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan) study, a double-blind, randomized trial, were used to examine the effects of losartan on the renal outcome [i.e., the primary composite end point of doubling of serum creatinine, end-stage renal disease (ESRD) or death] in 1513 type 2 diabetic patients with nephropathy. We examined the effect of the degree of albuminuria at baseline, initial antiproteinuric response to therapy, and the degree of remaining (residual) albuminuria on renal outcome (either the primary composite end point of RENAAL or ESRD). We also evaluated the contribution to renal protection of the antiproteinuric effect of losartan independently of changes in blood pressure. Baseline albuminuria is almost linearly related to renal outcome, and is the strongest predictor among all measured well-known baseline risk parameters. After adjusting for baseline risk markers of age, gender, race, weight, smoking, sitting diastolic blood pressure, sitting systolic blood pressure, total cholesterol, serum creatinine, albuminuria, hemoglobin, and hemoglobin A(1c) (HbA(1c)) patients with high baseline albuminuria (> or =3.0 g/g creatinine) showed a 5.2-fold (95% CI 4.3-6.3) increased risk for reaching a renal end point, and a 8.1-fold (95% CI 6.1-10.8) increased risk for progressing to ESRD, compared to the low albuminuria group (<1.5 g/g). The changes in albuminuria in the first 6 months of therapy are roughly linearly related to the degree of long-term renal protection: every 50% reduction in albuminuria in the first 6 months was associated with a reduction in risk of 36% for renal end point and 45% for ESRD during later follow-up. Albuminuria at month 6, designated residual albuminuria, showed a linear relationship with renal outcome, almost identical to the relationship between baseline albuminuria and renal risk. Losartan reduced albuminuria by 28% (95% CI -25% to -36%), while placebo increased albuminuria by 4% (95% CI +8% to -1%) in the first 6 months of therapy. The specific (beyond blood pressure lowering) renoprotective effect of the Ang II antagonist, losartan, in this study is for the major part explained by its antialbuminuric effect (approximately 100% for the renal end point, and 50% for ESRD end point). Albuminuria is the predominant renal risk marker in patients with type 2 diabetic nephropathy on conventional treatment; the higher the albuminuria, the greater the renal risk. Reduction in albuminuria is associated with a proportional effect on renal protection, the greater the reduction the greater the renal protection. The residual albuminuria on therapy (month 6) is as strong a marker of renal outcome as is baseline albuminuria. The antiproteinuric effect of losartan explains a major component of its specific renoprotective effect. In conclusion, albuminuria should be considered a risk marker for progressive loss of renal function in type 2 diabetes with nephropathy, as well as a target for therapy. Reduction of residual albuminuria to the lowest achievable level should be viewed as a goal for future renoprotective treatments.

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Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects.

Hiddo J. L. Heerspink, Mehul Desai, Meg Jardine … (2017)

Sodium-glucose cotransporter 2 inhibition with canagliflozin decreases HbA1c, body weight, BP, and albuminuria, implying that canagliflozin confers renoprotection. We determined whether canagliflozin decreases albuminuria and reduces renal function decline independently of its glycemic effects in a secondary analysis of a clinical trial in 1450 patients with type 2 diabetes receiving metformin and randomly assigned to either once-daily canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride uptitrated to 6-8 mg. End points were annual change in eGFR and albuminuria over 2 years of follow-up. Glimepiride, canagliflozin 100 mg, and canagliflozin 300 mg groups had eGFR declines of 3.3 ml/min per 1.73 m(2) per year (95% confidence interval [95% CI], 2.8 to 3.8), 0.5 ml/min per 1.73 m(2) per year (95% CI, 0.0 to 1.0), and 0.9 ml/min per 1.73 m(2) per year (95% CI, 0.4 to 1.4), respectively (P<0.01 for each canagliflozin group versus glimepiride). In the subgroup of patients with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, urinary albumin-to-creatinine ratio decreased more with canagliflozin 100 mg (31.7%; 95% CI, 8.6% to 48.9%; P=0.01) or canagliflozin 300 mg (49.3%; 95% CI, 31.9% to 62.2%; P<0.001) than with glimepiride. Patients receiving glimepiride, canagliflozin 100 mg, or canagliflozin 300 mg had reductions in HbA1c of 0.81%, 0.82%, and 0.93%, respectively, at 1 year and 0.55%, 0.65%, and 0.74%, respectively, at 2 years. In conclusion, canagliflozin 100 or 300 mg/d, compared with glimepiride, slowed the progression of renal disease over 2 years in patients with type 2 diabetes, and canagliflozin may confer renoprotective effects independently of its glycemic effects.

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Author and article information

Journal

Title: The Lancet Diabetes & Endocrinology

Abbreviated Title: The Lancet Diabetes & Endocrinology

Publisher: Elsevier BV

ISSN (Print): 22138587

Publication date Created: August 2017

Publication date (Print): August 2017

Volume: 5

Issue: 8

Pages: 610-621

Article

DOI: 10.1016/S2213-8587(17)30182-1

PubMed ID: 28666775

SO-VID: b2084480-1dd5-4218-8de1-89d7b087c154

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Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial

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Most cited references 22

Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications.

Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL.

Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects.

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