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Empagliflotsiini, kardiovaskulaaritapahtumat ja kuolleisuus korkean kardiovaskulaaririskin omaavilla tyypin 2 diabetesta sairastavilla potilailla

Näytönastekatsaukset
Jorma Komulainen ja Leo Niskanen
7.2.2018

Näytön aste: B

Tyypin 2 diabetesta sairastavilla potilailla, joilla on korkea kardiovaskulaaririski, empagliflotsiinin lisääminen muuhun glykemialääkitykseen näyttää vähentävän vaikeiden kardiovaskulaaritapahtumien riskiä, mukaan lukien kardiovaskulaarikuolema.

Among patients with Type 2 Diabetes and high cardiovascular risk, adding empagliflozin to other glycemia treatment decreased the risk of serious cardiovascular outcomes, including death from cardiovascular disease.

In a multicentre RCT study «Zinman B, Wanner C, Lachin JM ym. Empagliflozin, C...»1, 7 020 patients with type 2 diabetes and on a standard care regimen, were randomized to receive 10 mg or 25 mg empagliflozin or placebo once daily. The median follow-up was 3.1 years. Patients had HbA1c level of 7.0% or more. They were at least 18 years of age, with body mass index of 45 or less, and with an established cardiovascular disease. Their HbA1c level needed to be between 7.0–9.0% (no glucose-lowering agent for at least 12 weeks before randomization) or between 7.0–10.0% (stable glucose-lowering agent for at least 12 weeks before randomization). The primary composite outcome in the time-to-event analysis was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The study was designed as a noninferiority study.

The mean age of patients was 63 years. Their mean body mass index was 30.6 and mean HbA1c 8.1%. More than half of the patients had over 10 years duration of the disease.

The primary outcome occurred less often in the pooled empagliflozin group than in the placebo group (10.5% vs. 12.1%; hazard ratio in the empagliflozin group, 0.86; 95.02% CI, 0.74 to 0.99; P<0.001 for non-inferiority; P = 0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9%; hazard ratio, 0.65; 95% CI, 0.50 to 0.85; P = 0.002) and in any causes (5.7% vs. 8.3%; hazard ratio, 0.68; 95% CI, 0.57 to 0.82; P<0.001).

The mean glycated hemoglobin level at the randomization was 8.1%. After 12 weeks, during which glucose-lowering therapy was to remain unchanged, the adjusted mean differences in the glycated hemoglobin level between patients receiving empagliflozin and those receiving placebo were −0.54 percentage points (95% CI, −0.58 to −0.49) in the 10-mg group and −0.60 percentage points (95% CI, −0.64 to −0.55) in the 25-mg group. At week 94, the adjusted mean differences in the glycated hemoglobin level between patients receiving empagliflozin and those receiving placebo were −0.42 percentage points (95% CI, −0.48 to −0.36) and −0.47 percentage points (95% CI, −0.54 to −0.41), respectively; at week 206, the differences were −0.24 percentage points (95% CI, −0.40 to −0.08) and −0.36 percentage points (95% CI, −0.51 to −0.20).

The proportions of patients who had adverse events, serious adverse events, and adverse events leading to the discontinuation of a study drug were similar in the empagliflozin group and the placebo group.

  • Study quality: High
  • Applicability: Efficacy results may not be generalized to T2D patients with lower cardiovascular risk. The safety results on the other hand may be generalized to those T2D with lower risk.
  • Comment:
    • The markedly decreased risk for major adverse cardiovascular events, heart failure and death are mechanistically difficult to explain. However, studies exploring this issue are ongoing. Especially intriguing are studies planned on patients with heart failure (with or without diabetes). The results are in line with another SGLT2-inhibitor-study (CANVAS) made on canagliflozin (not marketed in Finland at the moment). Both studies showed also significant reduction in renal outcomes with SGLT2-inhibitor as compared to placebo.
    • The level of evidence is downgraded to B because of inaccuracy of the primary outcome measure.

Kirjallisuutta

  1. Zinman B, Wanner C, Lachin JM ym. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015;373:2117-28 «PMID: 26378978»PubMed