PHARMANEWS PARO PRESENTS
The study of heart and kidney protection with empagliflozin in non-diabetic patients (EMPA-KIDNEY Trial)
#13
Introduction There are many anti-hyperglycemic
A new study on the horizon...
options for the treatment of Type 2 Diabetes Mellitus (T2DM). When a patient
is
initially
diagnosed
with
T2DM, they will typically be started on oral agents before initiating insulin. Of the oral agents, sodium-glucose cotransporter 2 (SGLT2) inhibitors have, evidence for cardiovascular benefit in diabetic patients. Currently, there are 4
SGLT2
inhibitors
approved
in
Canada – empagliflozin, canagliflozin, zapagliflozin,
and
ertugliflozin
(1);
both empagliflozin and canagliflozin have evidence for cardiovascular and mortality
benefit
(2,3),
but
only
empagliflozin will be discussed for the remainder of this article because it is the focus of a new international study.
Recently, a new ongoing clinical trial has started to look into the effects of empagliflozin in patients with chronic kidney disease (CKD) while excluding diabetes (4). While nephropathy and cardiovascular
disease
are
common
complications of long-term diabetes, the purpose of this study is to look into further applications of empagliflozin since it has been well-tolerated and has shown
to
reduce
kidney
and
cardiovascular complications either as monotherapy or add-on therapy in diabetes management. It is believed that the
mechanism
inhibitors
work
by
which
to
improve
SGLTs renal
function may not require a concurrent diagnosis
of
diabetes
to
provide
a
benefit.
Chronic Kidney Disease (CKD) CKD is defined as kidney damage that progresses for 3 or more months. Renal dysfunction and renal disease are very commonly associated with diabetes, especially if blood glucose is uncontrolled, unmanaged, or comorbidities are present (hypertension, cardiovascular disease, smoking). Diabetic nephropathy is commonly identified by a slow but progressive increase in albuminuria (identified with albumincreatinine ratio, ACR filtration rate (eGFR)
≥
2.0mg/mmol) and a decrease in estimated glomerular
≤ 60 mL/min (approx. decreasing by 1-2 mL/min/year in early
stages) (5). Patients with CKD can experience a reduced quality of life and may eventually require dialysis if CKD goes unmanaged.
Mechanism of action SGLT2 inhibitors are proteins that inhibit SGLT-2, a transporter in the proximal tubule of the nephron responsible for 90% of glucose reabsorption back into circulation (6,7). SGLT2 inhibitors have been shown to successfully block the reabsorption of glucose into the body, thus causing glucosuria. Due to the nature of the sodium-glucose transporter, a sodium molecule is excreted with glucose when the transporter is blocked, which is believed to reduce plasma sodium levels that could, in turn, contribute to improving cardiovascular conditions (reduced plasma volume and blood pressure, reduced fluid overload due to heart failure) (7). It is due to this mechanism that it is believed chronic strain on the kidneys through intraglomerular hypertension can be improved regardless of whether a patient has diabetes or not. Along with its ability to improve glycemic control, empagliflozin has been shown to significantly reduce the mortality rates of major adverse cardiovascular events ( 38% RRR), hospitalizations for heart failure (35% RRR), and deaths for any cause (32% RRR) in diabetic patients (2). Further research is required to investigate its impact on renal function, particularly in CKD, as inthe EMPA-KIDNEY Trial.
Figure 1. Mechanistic concept of the effects of RAS and SGLT-2 inhibition on intraglomerular pressure. Image from Reference 7.
Relevance & Conclusion The EMPA-KIDNEY Trial is still ongoing and is in the early stages of research. Their study rationale
Be sure to look out for this
was recently published on 25 October 2018 and can
important publication in the
be
accessed
here
(7).
Randomization
of
6000
participants was completed on 9 February 2021. If
near future! More information
the study is successful in showing that empagliflozin
can be found at the
is effective in non-diabetic CKD patients, it will have very beneficial clinical applications in reducing renal disease progression and mortality while improving the quality of life in CKD patients, irrespective of a diabetes diagnosis.
EMPA-KIDNEY website: https://www.empakidney.org
References 1. RxTx [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2016 [updated 2019 Feb 01; cited 2021 Feb 20]. Gleevec [Diabetes mellitus]. Available from: http://www.e-therapeutics.ca. Also available in paper copy from the publisher. 2. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, and Inzucchi SE. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 September 17;373(22):2117-2128. 3. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law Gordon, Desai M, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 201;377:644-657. 4. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29 - . Identifier NCT00287391, EMPA-KIDNEY (the study of heart and kidney protection with empagliflozin); 2019 July 20 [cited 2021 Feb 20];[about 10 pages]. Available from: https://www.clinicaltrials.gov/ct2/show/study/NCT03594110. 5. McFarlane, Cherney D, Gilber RE, Senior P. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada: Chronic Kidney Disease in Diabetes. Can J Diabetes 2018;42(Suppl 1):S201S2019. 6. Neumiller JJ, Jr White JR, Campbell RK. Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus. Drugs. 2010 Mar 5;70(4):377-85. 7. Herrington WG, Preiss D, Hayne R, von Eynatten M, Staplin N, Hauske SJ, George JT, Green JB, Landray MJ, Baigent C, Wanner C. The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study. Clin Kidney J. 2018 Oct 28;11(6):749-761.
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