Background and Overview

T2DM, is a chronic disease that affects millions of people worldwide. It is characterized by high blood glucose levels due to insulin resistance or insufficient insulin production. T2DM can lead to CVD, and in severe cases, it can result in death. There are two primary treatment options for T2DM: pharmacological and non-pharmacological interventions. Pharmacological treatments involve the use of medications such as metformin, other oral medications, and insulin. Non-pharmacological interventions, on the other hand, entail lifestyle modifications such as weight management, exercise, and diet. Despite the availability of these treatments, managing T2DM can be challenging, and I can attest to this fact.

One promising approach that has emerged in recent years is the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors. These inhibitors prevent glucose reabsorption in the kidneys, leading to glucose excretion in the urine and reduced blood glucose levels. The SGLT2 inhibitors have shown significant promise in managing T2DM, and they should be considered a viable treatment option for our patients.

Researchers designed the EMPA-REG OUTCOME trial to examine the effects of empagliflozin on CV morbidity and mortality in patients with type 2 diabetes at high CV risk. The clinical question being asked by the study in PICO is:

• In patients with T2DM at high CV risk (population), does the addition of empagliflozin (intervention) to standard care (comparison) reduce CV morbidity and mortality (outcome)?
• Journal: N Engl J Med
• DOI: 10.1056/NEJMoa1504720
• Impact factor: The NEJM is a highly reputable journal with a significant impact factor.

Methods

Study Design

• Type of study: Randomized control trial
• Prospective vs. retrospective: Prospective
• Location, duration: 590 sites in 42 countries, median observation time of 3.1 years
• Blinding: Double-blind
• Control: Placebo-controlled
• Main analysis type: Intention-to-treat

Outcomes

• Primary endpoint: Composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke
• Secondary endpoint: Primary outcome plus hospitalization for unstable angina
• Efficacy, safety, adverse events: Genital infection increased in the empagliflozin group, no increase in other adverse events

Interventions

• Study medications: Empagliflozin (10 mg or 25 mg) or placebo once daily
• Ancillary treatments: Standard care for type 2 diabetes and cardiovascular risk factors

Oversight

• Study Population: N = 7020 patients treated
• Experimental arm: n = 4687 patients
• Placebo: n = 2333 patients

Study Population

• Recruitment: Adults with type 2 diabetes at high cardiovascular risk
• Randomization method: Computer-generated random-sequence
• Inclusion criteria: Type 2 diabetes, eGFR of at least 30 ml per minute per 1.73 m^2, established cardiovascular disease
• Exclusion criteria: Specific glucose-lowering drugs, BMI of 45 or less

Statistical Analysis

• Power: At least 90%
• Statistical tests used: Cox proportional-hazards model

Results

The author’s concluded that in patients with type 2 diabetes at high risk for cardiovascular events had a lower rate of primary composite cardiovascular outcome and death from any cause when empagliflozin was added to standard care.

• Baseline characteristics: Similar across treatment and placebo groups
• Comparison of treatment and control groups: Lower rates of the primary outcome in the empagliflozin group (10.5% vs. 12.1%, P = 0.04 for superiority)
• Adverse events: Increased rate of genital infection but no increase in other adverse events

Discussion and Conclusion

Strengths/Limitations

• Strengths: Well-designed RCT, large sample size, clear outcomes
• Limitations: Limited to patients at high cardiovascular risk, short median observation time

Conclusion

• Interpretation of results: Empagliflozin shows promise in reducing cardiovascular morbidity and mortality in type 2 diabetes patients at high cardiovascular risk.
• Bottom line: Empagliflozin may be a valuable addition to standard care for patients with type 2 diabetes at high cardiovascular risk.

Citation

Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720

Glossary

• T2DM: Type 2 diabetes mellitus
• Empagliflozin (Jardiance): Selective inhibitor of sodium glucose cotransporter 2
• eGFR: Estimated glomerular filtration rate or a measure of renal function
• Cox proportional-hazards model: A statistical method for survival analysis