Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes

Nicole Venezia, Pharm.D., Mercer University College of Pharmacy

Empagliflozin (Jardiance®) is a sodium-glucose co-transporter 2 (SGLT2) indicated, in addition to diet and exercise, to improve glycemic control in adults with type 2 diabetes.1

A recent, published study in The New England Journal of Medicine assessed the effects of empagliflozin on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk.2

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes2
Design Randomized, double-blind, placebo-controlled trial, at 590 sites located in 42 countries.

(N = 7028)

Objective To assess the effects of empagliflozin on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk
Study Groups 1:1:1 randomizationà 10 mg empagliflozin (n = 2345), 25 mg empagliflozin (n = 2342), placebo (n = 2333)

 

Methods Eligible patients underwent a 2-week, open label, placebo run-in period during which background glucose-lowering therapy was unchanged. Background glucose-lowering therapy remained unchanged for the first 12 weeks after randomization, unless intensification of therapy was required due to blood glucose ≥240 mg/dL. After the 12 weeks, investigators were able to adjust glucose-lowering therapy. Patients were treated with blood pressure-lowering and cholesterol-lowering medications based on local guidelines. Patients were given pre-specified times for follow up visits at clinic, including a visit 30 days after the end of treatment.
Duration September 2010 – April 2013
Primary Outcome Measure The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction (excluding silent myocardial infarction,) or nonfatal stroke. The key secondary outcome was a composite of the primary outcome, in addition to hospitalization from unstable angina.
Baseline Characteristics All eligible patients were adults 18 years or older, BMI ≤45, and GFR ≥30 mL/min. All eligible patients had established cardiovascular disease at baseline.
  Empagliflozin 10 mg Empagliflozin 25 mg Placebo
Average Age 63.0 ± 8.6 63.2 ± 8.6 63.2 ± 8.8
Male 70.5% 71.9% 72.0%
Caucausian 72.8% 72.4% 71.9%
Asian 21.5% 21.4% 21.9%
Black/African American 5.1% 5.0% 5.1%
Weight 85.9 ± 18.8 kg 86.5 ± 19.0 kg 86.6 ± 19.1 kg
BMI 30.6 ± 5.2 30.6 ± 5.3 30.7 ± 5.2
CV risk factor 99.5% 99.2% 98.9%
Coronary Artery Disease 76.0% 75.3% 75.6%
Multi-vessel coronary artery disease 46.0% 47.0% 47.1%
History of myocardial infarction 47.2% 46.2% 46.4%
Coronary artery bypass graft 25.3% 24.8% 24.1%
History of stroke 22.8% 23.4% 23.7%
Peripheral artery disease 19.8% 22.1% 20.5%
Single vessel coronary artery disease 11.00% 10.2% 10.2%
Cardiac failure 10.2% 9.5% 10.5%
Glycated hemoglobin 8.07 ±0.86 8.06 ±0.84 8.08 ±0.84
Results The primary outcome occurred in a significantly lower percentage of patients in the empagliflozin group (490 of 4687 [10.5%]) versus placebo (282 of 2333 [12.1%]; hazards ratio of pooled empagliflozin 0.86; 95.02% CI, 0.57-0.82, p<0.001).

Empligliflozin resulted in significantly lower risk of death from cardiovascular causes (hazard ratio, 0.62; 95% CI, 0.49-0.77, p<0.001), significantly lower risk of death from any cause (hazard ratio, 0.68; 95% CI, 0.57-0.82, p<0.001), and significantly lower risk of hospitalization from heart failure (hazard ratio, 0.65; 95% CI, 0.50-0.85, p=0.0020.

 

There were no significant differences between the empaglifozin group versus placebo for occurrences of myocardial infarction or stroke.

 

The number needed to be treated with empagliflozin to prevent one death is 39 patients.

Adverse Events Common Adverse Events:

Patients reporting adverse events were similar in the empagliflozin group and placebo group. Genital infection was reported in a higher percentage in patients of the pooled empagliflozin group. Urosepsis was more frequently reported in the empagliflozin group; however, urinary tract infections (UTI), complicated UTI, and pyelonephritis were similar.

  Empagliflozin 10 mg (n = 2345) Empagliflozin 25 mg (n = 2342) Placebo

(n = 2333)

Hypoglycemia 656 (27.9%) 647 (27.6%) 650 (27.9)
Event consistent with UTI Male 180 (10.9%)

Female 246 (35.5%)

Male 170 (10.1%)

Female 246 (37.3%)

Male 158 (9.4%)

Female 265 (40.6%)

Complicated UTI 34 (1.4%) 48 (2.0%) 41 (1.8%)
Genital Infection Male 25 (1.5%)

Female 17 (2.6%)

Male 89 (5.4%)

Female 64 (9.2%)

Male 77 (4.6%)

Female 71 (10.8%)

Acute Renal Failure 121 (5.2%) 125 (5.3%) 155 (6.6%)
Serious Adverse Events:
  Empagliflozin 10mg Empagliflozin 25 mg Placebo
Any 876 (37.4%) 647 (27.6%) 988 (42.3%)
Death 97 (4.1%) 30 (1.3%) 119 (5.1%)
Percentage that Discontinued due to Adverse Events:
Empagliflozin 10 mg Empagliflozin 25 mg Placebo
416 (17.7%) 397 (17.0%) 453 (19.4%)
Study Author Conclusions Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin had a significantly lower rate of the primary composite outcome and of death from any cause, when compared to placebo.

 

The study summarized above suggests that utilization of an SLGT2 inhibitor, empagliflozin (Jardiance®) can reduce the risk of cardiovascular-related deaths and death from any cause. 2

According to the Centers for Disease Control and Prevention (CDC), as of 2014, 29.1 million people (9.3%) of the United States population has type 2 diabetes.3 Additionally, in 2011, it was reported that about one-third of people aged 35 years or older with diabetes reported having heart disease or stroke.4

References:

  1. Boehringer Ingelheim. https://www.jardiance.com/. Accessed December 13, 2015.
  2. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. The New England Journal of Medicine. November 26, 2015. 373(22): 2117-2128.
  3. Centers for Disease Control and Prevention (CDC). 2014 National Diabetes Statistics Report. http://www.cdc.gov/diabetes/data/statistics/2014statisticsreport.html. Last reviewed October 24, 2014. Accessed December 13, 2015.
  4. Centers for Disease Control and Prevention (CDC). Crude and Age-Adjusted Percentage of People with Diabetes Aged 35 Years or Older Reporting Any Heart Disease or Stroke, 1997 – 2011. http://www.cdc.gov/diabetes/statistics/cvd/fig3.htm. Last reviewed November 19, 2013. Accessed December 13, 2015.
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