EMPA-REG - Empagliflozin for CV risk reduction in T2DM with hx of CVD

Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.

Bottom line: In patients with T2DM and CVD, empagliflozin (at either dose of 10 mg or 25 mg daily) reduced the risk of death (NNT 39) & CV events (NNT 63) over 3 years.

 

    Patients

    • Inclusion
      • Adults with T2DM
        • No glucose-lowering agents in previous 12 weeks: 7-9%
        • Receiving glucose-lowering agents, stable x12 weeks: 7-10%
      • Established CVD, defined as any of the following:
        • MI >2 months ago
        • CAD (confirmed with angiography)
        • Stroke >2 months ago
        • PAD documented by
          • Limb revascularization or amputation
          • Peripheral artery stenosis >50% on angiography or non-invasive evaluation
          • ABI <0.9 on at least 1 side
    • Key exclusion criteria
      • Cancer within last 5 y
      • Stroke/TIA within 2 months
      • Planned cardiac surgery or PCI in next 3 months
      • BMI >45
      • Blood dyscrasias or any disorder causing hemolysis or unstable RBCs
      • eGFR <30 mL/min/1.73 m^2
      • ALT, AST or ALP >3x ULN
    • 11,531 individuals screened across 590 sites in 42 countries -> 7028 randomized -> 7020 analyzed
    • "Average" patient
      • Age 63 y
      • Male 72%
      • White 72%, Asian 22%, Black 5%, other 1%
      • Geography: Europe 41%, North America 20%, Asian 19%, Latin America 15%, Africa 4%
      • CV risk factors
        • CAD 76% (multivessel 47%)
        • MI 46%
        • CABG 24%
        • Stroke 24%
        • PAD 20%
      • Time since T2DM dx: >10 y (57%), 5-10 y (25%), 1-5 y (16%)
      • Wt 87 kg, BMI 31
      • BP 136/77
      • Lipids: total 4.2, LDL 2.2, HDL 1.1 mmol/L
      • A1c 8%
      • Meds
        • Metformin 74%
        • Insulin 49%
        • Sulfonylurea 43%
        • DPP-4 inhibitor 11%
        • Antihypertensives 95%
          • ACEI 80%
          • Beta-blocker 64%
        • ASA 83%
        • Statin 76%

    Interventions & co-interventions (median 2.6 y)

    • I: Empagliflozin 10 mg or 25 mg
      • A1c lowered by 0.5-0.6% at 12 weeks vs placebo
    • C: Matching placebo
    • Co-interventions:
      • 1st 12 weeks after randomization: No change to glycemic management unles fasting glucose >13.3 mmol/L
      • After 12 weeks: Adjustment to glucose-lowering therapy according to local guidelines

    Results @ median 3.1 y

    • Results for both doses of empaglifozin were similar, and therefore pooled
    • Statistically significant reduction in:
      • The primary outcome (CV death, MI, stroke): Hazard ratio (HR) 0.86, 95% confidence interval 0.74-0.99 (p=0.04)
        • 10.5% vs 12.1% (NNT 63)
      • Death: HR 0.68 (0.57-0.82)
        • 5.7% vs 8.3% (NNT 39)
      • HF hospitalization: HR 0.65 (0.50-0.85)
        • 2.7% vs 4.1% (NNT 72)
    • No statistically significant difference:
      • MI: HR 0.87 (0.70-1.09) - 4.8% vs 5.4%
      • Stroke: HR 1.18 (0.89-1.56) - 3.5% vs 3.0%
      • Coronary revascularization: HR 0.86 (0.72-1.04) - 7.0% vs 8.0%
    • Safety
      • Serious adverse events: 38.2% vs 42.3% (NNT 25, p<0.001)
      • Premature discontinuation: 23.4% vs 29.3%
      • Hypovolemia: 5.1% vs 4.9%
      • Acute kidney injury: 1.0% vs 1.6%
      • UTI: 18.0% vs 18.1% (complicated 1.7% vs 1.8%)
      • Genital infection: 6.4% vs 1.8% (NNH 22)
      • DKA: 0.1% vs <0.1%
      • Hypoglycemia (glucose <3.9 mmol/L or requiring assistance): 27.8% vs 27.9%
    • Numerous subgroup analyses were performed, which demonstrated inconsistent subgroup interactions with the primary outcome and CV death

    Issues with internal validity?

    • No: Randomized, allocation-concealed, blinded trial with low loss-to-follow-up (<0.1%) analyzed using intention-to-treat principles 
    • Run-in: 2-week open-label placebo run-in

    Additional considerations

    • The reduction of CV events became apparent after only 3 months. Previous trials of diabetes drugs or glycemic control goals have never demonstrated a benefit this early, suggesting that the apparent benefit of empagliflozin may have resulted from another mechanism. 
    • The reduction int the primary CV event resulted mainly from a reduction in CV death, but not MI or stroke. This further argues against glycemic control as the beneficial mechanism of empagliflozin.