Practice Update: Endocrinology | Volume 1. Number 2. 2016

CHRONIC KIDNEY DISEASE

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EXPERT COMMENTARY Exercise caution in certain patients By Dr Chirag Parikh I n this trial, in patients with type 2 diabetes and estab- lished cardiovascular disease

Empagliflozin slows progression of kidney disease in diabetes The New England Journal of Medicine Take-home message • In this randomised controlled trial, the au- thors evaluated the long-term effects of empagliflozin 10 mg or 25 mg, compared with placebo, on renal function in patients with type 2 diabetes and eGFR ≥30 mL/ min/1.73 m 2 . Compared with the placebo group, the empagliflozin group had lower risk of worsening nephropathy (HR, 0.61; P < 0.001), reduced risk of creatinine level doubling (relative risk reduction, 44%), and reduced risk of renal replacement therapy (relative risk reduction, 55%). • Empagliflozin appears to slow the pro- gression of renal dysfunction in patients with type 2 diabetes and eGFR ≥30 mL/ min 1.73 m 2 . Abstract BACKGROUND Diabetes confers an increased risk of adverse cardiovascular and renal events. In the EMPA-REG OUTCOME trial, empagliflozin, a so- dium-glucose cotransporter 2 inhibitor, reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes at high risk for cardiovascular events. We wanted to determine the long-term renal effects of empagliflozin, an analysis that was a prespecified component of the secondarymicrovascular outcome of that trial. METHODS We randomly assigned patients with type 2 diabetes and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m 2 of body-surface area to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily. Prespecified renal outcomes included incident or worsening ne- phropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) and incident albuminuria. RESULTS Incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 (18.8%) in the placebo group (hazard ratio in the empagliflozin group, 0.61; 95% confidence interval, 0.53 to 0.70; P < 0.001). Doubling of the serum creatinine level occurred in 70 of 4645 patients (1.5%) in the empagliflozin group and in 60 of 2323 (2.6%) in the placebo group, a significant relative risk reduction of 44%. Renal- replacement therapy was initiated in 13 of 4687 patients (0.3%) in the empagliflozin group and in 14 of 2333 patients (0.6%) in the placebo group, representing a 55% lower relative risk in the empagliflozin group. There was no sig- nificant between-group difference in the rate of incident albuminuria. The adverse-event pro- file of empagliflozin in patients with impaired kidney function at baseline was similar to that reported in the overall trial population. CONCLUSIONS In patients with type 2 diabetes at high cardiovascular risk, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016 Jun 14;[Epub ahead of print], Wanner C, Inzucchi SE, Lachin JM, et al.

care, which included RAAS in- hibitors and statins. The relative risk reduction was substantial and in the range of 40% to 50% for the majority of renal endpoints. The renal protection was in addition to the cardiovascular protec- tion seen with empagliflozin. These findings are clinically important as more than one- third of people with type 2 diabetes will develop chronic kidney disease, which leads to progressive GFR decline and eventually requires dialysis. Empagliflozin, like RAAS inhibitors, also produced a short-term decrease in eGFR for several weeks af- ter drug initiation, but then GFR stabilised over time. This haemodynamic effect

was associated with slower pro- gression of kidney disease and lower rates of clinically relevant renal events (doubling of serum creatinine and dialysis) than placebo when added to standard

of empagliflozin is thought to lower intra-glomerular hyperten- sion and is linked with the overall renal benefit seen with this agent. Although no increase in risk of acute kidney injury was seen in patients who were on empaglifloz- in, caution should be exercised in patients who are taking NSAIDs or who will be exposed to other renal insults such as contrast agents or volume depletion.

who had a GFR of at least 30 mL/ min, empagliflozin, a sodium- glucose cotransporter 2 inhibitor,

Dr Chirag Parikh is Professor of Medicine, Yale University School of Medicine and

Director of Program of

Applied Translational Research at the Yale School of Medicine.

EMPA-REG renal outcomes – do SGLT2 inhibitors help the kidneys? By Dr Peter Lin P atients with diabetes unfortunately have both macrovascular and microvascular complications. Our goal is to protect Incident or worsening nephropathy 12.7% 18.8% HR: 0.61 (0.53–0.70) Progression to macroalbuminuria 11.2% 16.2% HR: 0.62 (0.54–0.72) Doubling the serum creatinine level 1.5% 2.6% HR: 0.56 (0.39–0.79)

P < 0.001

P < 0.001

P < 0.001

them from both. The EMPA-REG study, which used empagli- flozin, showed a CV death benefit in patients who had established CV disease and also showed reductions in hospitalisation for heart failure. This is the first agent for diabetes to show positive CV outcomes since metformin. The bottom line is that the EMPA-REG study has now shown both macrovascular and microvascular benefits. This current paper looks at the microvascu- lar complications of diabetes in the EMPA- REG study with a particular focus on the renal microvasculature. There was about a 40% re- duction in the renal endpoints as listed below. This was on top of good ACE inhibitor or ARB usage. The only thing that was not reduced

Renal replacement therapy

0.3%

0.6% HR: 0.45 (0.21–0.97)

P < 0.04

Normal albumin level to albuminuria

51.5% 51.2% HR: 0.95 (0.87–1.04)

P = 0.25

was the patient developing albuminuria, but all the other endpoints were positive. Many mechanisms have been proposed to help explain these findings. The most obvious one is better glucose control. Despite all the investigators’ efforts, the HbA 1c was lower on the empagliflozin side. This could mean less glucose to stick to the glomerulus and hence less damage. Also, SGLT2 inhibitors reduce the pressure inside the glomerulus, which can help reduce protein excretion. This reduced glomerular pressure also explains the initial drop in eGFR which then stabilises over time. With less pres- sure there is less injury to the glomerular cells, which could help maintain renal function. In

the past, ACE inhibitors and ARBs showed a similar pressure reduction. The authors also mentioned several other mechanisms, such as improvement in arterial stiffness. The bottom line is that the EMPA-REG study has now shown both macrovascular and microvascular benefits. This is the first time that an antidiabetic agent has shown both benefits in the same study and in a relatively short period of 3 years. Hopefully, this will usher in a new era where we can help reduce the multiple complications of diabetes.

Dr Peter Lin is Director of Primary Care Initiatives at the Canadian Heart Research Centre, Canada.

JOURNAL SCAN Effects of single-dose liraglutide on renal function and vasoactive hormones Diabetes, Obesity & Metabolism Take-home message • The authors of this double-blind, controlled, crossover trial evaluated the effects of a single dose of liraglutide compared with placebo on renal function and vasoactive hormones in 11 men with type 2 diabetes. They found no difference between liraglutide and placebo in terms of GFR, renal blood flow, renal perfusion, or oxygenation. During the liraglutide phase, there was a significant decrease in angiotensin II concentration (P = 0.02), a nonsignificant increase in sodium clearance (P = 0.06), and increased blood pressure and heart rate. They found no effects on other renin–angiotensin system constituents, atrial natriuretic peptides, or catecholamines. • The authors suggest that the decrease in angiotensin II found with a single dose of liraglutide may be a factor in renal protection with GLP-1 receptor agonists. Abstract

-6.8 to 3.6 mL/min/1.73 m 2 ] or on RBF (95% CI -39 to 30 mL/min) and did not change local renal blood perfusion or oxygenation. The fractional excretion of lithium increased by 14% (P = 0.01) and sodium clearance tended to increase (P = 0.06). Liraglutide increased diastolic and sys- tolic blood pressure (3 and 6 mmHg) and heart rate (2 beats per min; all P < 0.05). Angiotensin II (ANG II) concentration decreased by 21% (P = 0.02), but there were no effects on other renin-angiotensin system components, atrial natriuretic peptides (ANPs), methanephrines or excretion of catecholamines. CONCLUSIONS Short-term liraglutide treatment did not affect renal haemodynamics but decreased the proximal tubular sodium reab- sorption. Blood pressure increased with short-term as opposed to long-term treatment. Catecholamine levels were unchanged and the results did not support a GLP-1-ANP axis. ANG II levels decreased, which may contribute to renal protection by GLP-1 receptor agonists. Short-term effects of liraglutide on kidney function and vasoac- tive hormones in type 2 diabetes: A randomized clinical trial. Diabetes Obes Metab 2016;18:581-589, Skov J, Pedersen M, Holst JJ, et al.

trial in 11 male patients with type 2 diabetes. Measurements included (51) Cr-EDTA plasma clearance estimated glomerular filtration rate (GFR) and MRI-based renal blood flow (RBF), tissue perfusion and oxygenation. RESULTS Liraglutide had no effect on GFR [95% confidence interval (CI)

AIMS To investigate the effects of a single dose of 1.2 mg liraglutide, a once-daily glucagon-like peptide-1 (GLP-1) receptor agonist, on key renal variables in patients with type 2 diabetes. METHODS The study was a placebo-controlled, double-blind, crossover

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