New England Journal of Medicine Bernard Zinman, M.D., Christoph Wanner, M.D et al September 17, 2015

EMPA-REG Outcome trial

Empagliflozin, Cardiovascular Outcomes, and Mortality

in Type 2 Diabetes

-Anirudhya J

SGLT2 Inhibitors

• New class of oral anti-diabetic drugs which act by inhibiting Sodium-glucose transporter 2 in the proximal tubule, thereby decreasing renal glucose re-absorption and increasing urinary glucose excretion.

• Includes Canagliflozin, Dapagliflozin and Empagliflozin.

• Empagliflozin was approved by FDA in Aug, 2014.

Empagliflozin

Advantages:• Lower rate of the primary composite cardiovascular

outcome and of death from any cause• Weight loss and reduction in BP without increase in heart

rate

• Disadvantages : • Genital infection and UTI• Not to be used in CKD > Stage 3

Aim

To study the effects of empagliflozin in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk.

Why this trial ?

• Several health authorities have stressed on the need to demonstrate cardiovascular safety of new antidiabetes drugs.

• In Sep 2010, US FDA and EMA implemented an immediate suspension of Rosiglitazone as it was found to have increased risk of cardiovascular events including acute MI and CVA.

• Study population :7020

• Study period : September 2010 - April 2013

• Study place : Multi-centric study conducted in various hospitals in USA and Europe

• Type of study : Randomized, double-blind, placebo-controlled trial

Inclusion criteria

Eligible patients with type 2 diabetes were :• Adults (≥18 years of age) • With a BMI of 45 or less • Estimated GFR of at least 30 ml per minute per

1.73 m2 of body-surface area.

Method

Patients meeting the inclusion criteria were randomly assigned in a 1:1:1 ratio to receive1.10 mg Empagliflozin

2.25 mg Empagliflozin

3.Placebo

Methodology contd…

• Background glucose-lowering therapy was to remain unchanged for the first 12 weeks after randomization.

• Other cardiovascular risk factors including dyslipidemia and hypertension were treated throughout the trial.

• Patients were instructed to attend the clinic at prespecified times, which included a follow-up visit 30 days after the end of treatment.

Study outcomes

The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

The key secondary outcome was a composite of the primary outcome plus hospitalization for unstable angina.

Hence we infer • that the mechanisms behind the cardiovascular

benefits of empagliflozin are multidimensional and possibly involve changes in arterial stiffness, cardiac function, and cardiac oxygen demand as well as cardiorenal effects- reduction in albuminuria, reduction in uric acid, and established effects on hyperglycemia, weight, visceral adiposity, and blood pressure.

• It was observed that genital infection and UTI was more common in patients treated with empagliflozin.

• The proportions of patients with confirmed hypoglycemic adverse events, acute renal failure, diabetic ketoacidosis, thromboembolic events, bone fracture, and events consistent with volume depletion were similar in the two study groups.

Conclusion

Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care.

Thank you