Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Christian Deaton, Mercer University College of Pharmacy

Kidney disease develops in approximately 35% of patients with type 2 diabetes mellitus (T2DM) and is associated with increased mortality.  It is suggested that intensive glucose-lowering strategies have the possibility to reduce surrogate markers of renal complications in patients with type 2 diabetes; however, evidence for improvement in advanced renal complications is limited. [1]

Empagliflozin (Jardiance®) belongs to the drug class of sodium-glucose cotransporter 2 (SGLT2) inhibitors and is approved by the Food and Drug Administration (FDA) for management of T2DM.  By inhibiting SGLT2 in the proximal tubules, empagliflozin reduces reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose. [2]

Since SGLT2 inhibitors act on the kidney and the amount of glucose excreted is dependent on the glomerular filtration rate (GFR), it is suggested that SGLT2 inhibitors could also have a positive influence on the long-term cardiovascular (CV) safety of patients with T2DM, as well as possess cardio-protective effects. [3]

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes [4]
Design Multi-center, randomized, double-blind, placebo-controlled; N= 7,034
Objective To determine the long-term CV safety of empagliflozin, as well as investigate potential benefits on macro/micro-vascular outcomes
Study Groups Empagliflozin 10 mg (n= 2,361); empagliflozin 5 mg (n= 2,340) placebo (n= 2,333)
Methods Patients who were drug-naïve or on background glucose-lowering therapy, and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo superimposed upon the standard of care.
Duration September 2010 through April 2013
Primary Outcome Measure A composite of three major adverse cardiovascular events: the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.
Baseline Characteristics
Age, avg 63.1
75 years old and older, n 652
Male, n 5,026
Race, n
White 5,089
Asian 1,518
Black 357
Smoking History, n 930
History of MI, n 3,275
Single vessel CAD, n 743
Multi-vessel CAD, n 3,285
Glucose-lowering therapy, n
Metformin 745
Insulin 954
Metformin + sulfonylurea 1,383
Metformin + insulin 1,420
Antihypertensive therapy, n 6,641
Results
Empagliflozin Placebo p-value
Death from cardiovascular causes 10.5% 12.1% p<0.001
Death from any cause 5.7% 8.3% p<0.001
Hospitalization for heart failure 2.7% 4.1% p<0.002
Adverse Events Common Adverse Events: hypoglycemia (29%)
Serious Adverse Events: death (4%), genital infection (6%)
Percentage that Discontinued due to Adverse Events: 17%
Study Author 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.

 

Sodium-glucose cotransporter 2 inhibitors are a fairly new class of medications with markedly less, published data compared to the other cornerstone medications used for T2DM.  The study revealed that patients with T2DM at high risk for cardiovascular events receiving empagliflozin in addition to standard care had a significantly lower risk of microvascular outcome events versus those patients in the placebo group.  Patients in the empagliflozin group also had a significantly lower risk of progression to macroalbuminuria or clinically relevant renal outcomes, such as a doubling of the serum creatinine level or initiation of renal-replacement therapy.  Generalization of the findings to African American patients also has limitations because of the small sample size that was studied.

 

References

  1. De Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss NS, Himmelfarb J. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA 2011;305:2532-9
  2. Zanoli L, Granata A, Lentini P, et al. Sodium-glucose linked transporter-2 inhibitors in chronic kidney disease. ScientificWorldJournal. 2015;2015:317507.
  3. Zinman B, Inzucchi SE, Lachin JM, et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™). Cardiovasc Diabetol. 2014;13:102.
  4. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016.
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