Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Caitlin Higgins, Mercer University College of Pharmacy

Jardiance® (empagliflozin) is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM).  According to the package insert, empagliflozin should not be initiated if glomerular filtration rate (GFR) is below 45 mL/min/1.73 meters squared (m2).  Empagliflozin is contraindicated in patients with severe renal impairment, end-stage renal disease, or those receiving dialysis. [1]

A review article discusses the role of SGLT2 inhibitors, in which the drug class mechanism of action was stated to improve glucose control by increasing urinary glucose excretion.  The SGLT2 inhibitors were suggested to be most effective under normal circumstances, in which the adult kidney filters about 180 grams of glucose per day; it is noted that effectiveness is decreased in the presence of renal dysfunction. [2]

According to Diabetes Care, it was suggested that if an A1C target is not achieved after approximately three months, a combination of metformin and one of the following six treatment options should be initiated: sulfonylurea, thiazolidinedione, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, or basal insulin. Patient preferences, as well as various patient, disease, and drug characteristics were suggested to guide drug choice. [3]

A review of the management of hyperglycemia in T2DM states that metformin is placed as a first line therapy and it can lower glycated hemoglobin (A1C) values by 1% to 1.5% and was suggested to cause weight loss. [4]

Currently, the SGLT2 inhibitors lower A1C by 0.5% to 1%, depending on the agent and the dosage used.  The drug class is associated with modest reductions in weight (-1.5 to -3.5 kg) and systolic blood pressure (-3 to -5 mmHg).  The SGLT2 inhibitors were suggested to be best suited for obese or hypertensive patients. [2]

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Title: Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes [5]
Design Multicenter (590 sites in 42 countries), randomized, double-blind, placebo-controlled trial; N= 7,020
Objective To determine the long-term renal effects of empagliflozin
Study Groups Empagliflozin (n= 4,685) versus placebo (n= 2,333)
Methods Patients with T2DM and an estimated GFR of at least 30 ml/min/1.73 m2 were randomly assigned to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily.  Prespecified renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) and incident albuminuria (urinary albumin-to-creatinine ratio, ≥30 in patients with a normal albumin level).
Duration Median duration: treatment of 2.6 years; median observation time: 3.1 years
Primary Outcome Measure Composite of three major adverse cardiovascular events (3-point MACE): the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke
Secondary Outcome Measure Composite microvascular outcome that included the first occurrence of any of the following: the initiation of retinal photocoagulation, vitreous hemorrhage, diabetes-related blindness, or incident or worsening nephropathy
Baseline Characteristics Patients with baseline GFR of <59 ml/min/1.73 m2 Patients with baseline GFR of >60 ml/min/1.73 m2
Baseline Characteristic Placebo

(n= 607)

Empagliflozin

(n= 1,212)

Placebo

(n= 1,726)

Empagliflozin

(n= 3,473)

Age, year 67.1 +/- 8.2 67.1 +/- 7.6 61.9 +/- 8.6 61.7 +/- 8.5
Male sex, n (%) 418 (68.9) 816 (67.3) 1262 (73.1) 2518 (72.5)
Interval of >10 years since diagnosis of T2DM, n (%) 422 (69.5) 794 (65.5) 917 (53.1) 1876 (54.0)
Estimated GFR, mL/min/1.73 m2 48.7 +/- 7.8 48.4 +/- 8.2 82.7 +/- 16.6 83.1 +/- 17.1
Urinary albumin-to-creatinine ratio <30, n (%) 283 (46.6) 566 (46.7) 1099 (63.7) 2223 (64.0)
Urinary albumin-to-creatinine ratio of 30 to 300, n (%) 205 (33.8) 411 (33.9) 145 (8.4) 286 (8.2)
Urinary albumin-to-creatinine ratio of >300, n (%) 115 (18.9) 223 (18.4) 145 (8.4) 286 (8.2)
Results Renal Outcome Measure Empagliflozin,

n (%)

 

Placebo,

n (%)

 

P-value
Nephropathy or cardiovascular death 675/4170 (16.2) 497/2102 (23.6) <0.001
Nephropathy 525/4124 (12.7) 388/2061 (18.8) <0.001
Macroalbuminuria 459/4091 (11.2) 330/2033 (16.2) <0.001
Doubling of serum creatinine level with GFR <45 ml/min/1.732 70/4645 (1.5) 60/2323 (2.6) <0.001
Initiation of renal-replacement therapy 13/4687 (0.3) 14/2333 (0.6) 0.04
Albuminuria in patients with normal albumin level at baseline 1430/2779 (51.5) 704/1374 (51.2) 0.25
Doubling of serum creatinine level with GFR <45 ml/min/1.73m2, initiation of renal-replacement therapy, or death from renal disease 81/4645 (1.7) 71/2323 (3.1) <0.001
Adverse Events Common Adverse Events
Patients with baseline GFR of <59 ml/min/1.73m2 Patients with baseline GFR of >60 ml/min/1.73m2
Event Placebo

(n= 607)

Empagliflozin

(n= 1,212)

Placebo

(n= 1,726)

Empagliflozin

(n= 3,473)

Confirmed hypoglycemia, n (%) 233 (38.4) 391 (32.3) 417 (24.2) 912 (26.3)
Urinary tract infection, n (%) 132 (21.7) 278 (22.9) 291 (16.9) 564 (16.2)
Acute renal failure, n (%) 87 (14.3) 136 (11.2) 68 (3.9) 110 (3.2)
Serious Adverse Events
Serious adverse event***, n (%) 321 (52.9) 552 (45.5) 667 (38.6) 1237 (35.6)
Death, n (%) 40 (6.6) 68 (5.6) 79 (4.6) 108 (3.1)
Discontinuation due to Adverse Events
Discontinuation due to adverse event, n (%) 167 (27.5) 278 (22.9) 286 (16.6) 535 (15.4)
*** A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability, requires or prolongs hospitalization, is associated with a congenital anomaly or birth defect, or is deemed to be serious for any other reason.
Study Author Conclusions In patients with T2DM 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.

This study was based on an analysis that was a component of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients.  A significantly lower rate of major CV events, death from CV causes, death from any cause, and hospitalization for heart failure was reported in the empagliflozin versus placebo group. [6]

The A1C lowering potential is much less with SGLT2 inhibitors when compared to metformin, the mainstay of therapy.  At this time, the SGLT2 drug class (including empagliflozin) should be considered as a preferred add-on therapy, to be used in combination with other agents in obese T2DM patients who are at a high risk for CV disease.

References

  1. Jardiance® [package insert]. Indianapolis, IN: Boehringer Ingelheim Pharmaceuticals, Inc.; 2016.
  2. Whalen K, Miller S, Onge ES. The Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Treatment of Type 2 Diabetes. Clin Ther. 2015;37(6):1150-66.
  3. Approaches to Glycemic Treatment. Diabetes Care. 2016;39 Suppl 1:S52-9.
  4. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered appro Diabetes Care 2012;35:1364-79.
  5. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016;375(4):323-34.
  6. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-28.
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