The release of the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial in 2015 showing dramatic benefits of the SLGT-2 inhibitor empagliflozin on the composite cardiovascular endpoint—and in particular heart failure hospitalization, cardiovascular and total mortality—fueled the excitement of this newer class of antidiabetic medications as cardioprotective agents.¹ More recently, the release of the CANVAS (Canagliflozin Cardiovascular Assessment Study) results with the drug canagliflozin confirmed a benefit for the composite cardiovascular endpoint as well as for heart failure hospitalization, despite non-significant results for cardiovascular and total mortality.² While randomized clinical trials such as these provide definitive evidence regarding the efficacy of a given agent against its comparator, the often strict entry criteria of such trials make their applicability to the larger real-world population of patients with diabetes inconclusive.

The recently published CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors) study by Kosoborod et al.³ is an elegantly done real-world comparative effectiveness study involving the evaluation of hospitalization for heart failure and total mortality among new users of SGLT-2 inhibitors compared to other glucose-lowering drugs. The study involved data from 309,056 patients obtained from medical claims, primary care/hospital records and national registries from the US, Norway, Denmark, Sweden, Germany and the UK who were newly initiated on either an SGLT-2 inhibitor or other glucose lowering drug, with propensity score matching to ensure balance in baseline characteristics among the 154,528 patients in each group. The greatest exposure time was observed from canagliflozin (53%) followed by dapagliflozin (42%) and empagliflozin (5%). There was an overall 39% lower risk of heart failure hospitalization (p < 0.001), 51% reduction in total death (p < 0.001), and 46% reduction in the composite of heart failure hospitalization or death (p < 0.001). Similar effects were seen across countries, despite geographic differences in the use of specific SGLT-2 inhibitors (canagliflozin used 76% of the time in the US and dapagliflozin 92% in Europe), suggesting a class effect of these therapies.

The CVD-REAL study is unique in being the largest real-world study examining the effectiveness of SGLT-2 inhibitors on heart failure hospitalizations and death. While the study did not examine other outcomes such as myocardial infarction, stroke or the composite cardiovascular disease outcomes that have been evaluated in recently published clinical trials of SGLT-2 inhibitors,^1,2 the results for the examined outcome are remarkably similar (and perhaps greater for total death) to that reported by the EMPA-REG OUTCOME trial of empagliflozin (which showed a 35% reduction in heart failure hospitalization and a 32% reduction in all-cause death),¹ despite the fact that only 5% of exposure time in the current study was from this agent. When comparing to the CANVAS trial results of canagliflozin,² the reduction in heart failure hospitalization was also similar (33% reduction seen in CANVAS), but CANVAS showed only a 13% non-significant reduction in all-cause death. Notably, the majority of patients (87%) in CVD-REAL did not have prior cardiovascular disease, unlike EMPA-REG OUTCOME in which all patients had prior cardiovascular disease and CANVAS in which the majority (66%) of patients had prior cardiovascular disease. A recent comparison of the primary and secondary prevention cohorts in CANVAS concluded there was no heterogeneity in the effect of canagliflozin in the primary cardiovascular outcome or in heart failure hospitalization,⁴ however, despite the risk reduction for the primary endpoint not being significant for the primary prevention versus secondary prevention cohort.

While the CVD-REAL study was observational in nature, the potential validity of the study is high due to the robust propensity matching and multiple sensitivity analyses done, although the authors acknowledge the possibly of residual, unmeasured confounding cannot be excluded. It would have been desirable (and perhaps in the future can be considered) to examine individual endpoints such as myocardial infarction and stroke (as these did not show a benefit in the individual trials), as well as safety (given issues such as lower limb amputations in CANVAS and genital infections in EMPA-REG OUTCOME, for example). Finally, while the results were stratified by database examined, seeing results stratified by the specific SGLT2 inhibitor would have been desirable.

Overall, the CVD-REAL study is an extremely important contribution in being the first large-scale real-world population examination of the possible benefits (at least in terms of heart failure hospitalization and total mortality) of SGLT2 inhibitors and gives a strong suggestion that at least for these outcomes, the benefits are a class effect. Further validation from other large claims-databases with results on the specific SGLT2-I used in the real-world setting (and especially with greater representation of patients on empagliflozin given this was only 5% of the CVD-REAL sample), as well as on other specific and ideally the composite outcomes used in the published clinical trials will provide further data allowing for more direct comparisons and documenting the benefits of these therapies beyond the clinical trial setting.

References

1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular otucomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57.
3. Kosiborod M, Cavender MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation 2017;136:249-59.
4. Mahaffewy KW, Neal B, Perkovic V, et al. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS program (Canagliflozin Cardiovascular Assessment Study). Circulation 2017. [Epub ahead of print]

Keywords: Diabetes Mellitus, Type 2, Cardiotonic Agents, Secondary Prevention, Propensity Score, Glucose, Hospital Records, Glucosides, Hypoglycemic Agents, Benzhydryl Compounds, Heart Failure, Myocardial Infarction, Stroke, Cardiovascular Diseases, Registries, Primary Prevention, Risk Reduction Behavior, Primary Health Care, Lower Extremity, Cohort Studies, Metabolic Syndrome

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