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%
- 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)
- Death: HR 0.68 (0.57-0.82)
- HF hospitalization: HR 0.65 (0.50-0.85)
- 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.
