Retrospective study finds they offer a class effect for cardiovascular benefit

It is difficult to overstate the impact that findings from studies of SGLT2 inhibitors have had on the treatmeant of type 2 diabetes, and more recently, heart failure. First published Sept. 28, this report on a retrospective study of empagliflozin drives home those points, which is why it was selected as part of the BreakingMED year-end clinical review.

The short-term use of sodium glucose cotransporter 2 (SGLT2) inhibitors among people with type 2 diabetes was associated with a lower risk of serious cardiovascular events compared to the use of dipeptidyl peptidase-4 (DPP-4) inhibitors, according to the authors of a retrospective cohort study.

This result was consistent across a variety of SGLT2 inhibitors, suggesting “a class effect for the cardiovascular benefits of SGLT2 inhibitors,” Kristian B. Filion, PhD, McGill University, Montreal, Quebec, Canada, and colleagues reported in the BMJ.

Filion and colleagues pointed out that randomized control trials have shown that SGLT2 inhibitors reduce the incidence of major adverse cardiovascular disease among patients with type 2 diabetes who have had previous cardiovascular disease. For example, in the EMPAgliflozin Removal of Excess of Glucose OUTCOME trial, participants randomized to empagliflozin had decreased rates of major adverse cardiovascular events (hazard ratio 0.86, 95% confidence interval 0.74 to 0.99) and of hospital admission for heart failure (hazard ratio, 0.65; 95% CI, 0.50 to 0.85; P=0.002) compared with those randomized to placebo. Similar results were shown in this trial assessing canagliflozin.

However, in these trials, the SGLT2 inhibitors were compared with placebo, so their efficacy compared with second- and third-line antidiabetic treatments is unknown. And, while several observational studies have demonstrated that SGLT2 inhibitors show a reduced risk of adverse cardiovascular outcomes compared with other antidiabetic drugs, Filion and colleagues pointed out that some of those studies had “important limitations that make it difficult to interpret the results.”

In this study, Filion and colleagues compared the risks of major adverse cardiovascular events (MACE), MACE components—including death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke— all-cause mortality, and heart failure associated with SGLT2 inhibitors in treating patients with type 2 diabetes, compared with DPP-4 inhibitors (which are usually prescribed as a second line or third line treatment of type 2 diabetes).

This was a retrospective multi-database cohort study in which Filion and colleagues used administrative healthcare databases from the Canadian provinces of Alberta, British Columbia, Manitoba, Nova Scotia, Ontario, Quebec, and Saskatchewan, as well as the United Kingdom Clinical Practice Research Datalink, to match 209,867 new users of an SGLT2 inhibitor with the same number of new users of a DPP-4 inhibitor.

SGLT2 inhibitor patients were classified as current users of the SGLT2 inhibitors canagliflozin, dapagliflozin, or empagliflozin alone, or in combination with other antidiabetic drugs, while DPP-4 inhibitor patients were classified as current users of DPP4 inhibitors alogliptin, linagliptin, saxagliptin, sitagliptin, or vildagliptin alone, or in combination with other non-SGLT2 inhibitor antidiabetic drugs.

Compared with DPP-4 inhibitors, SGLT2 inhibitors were associated with a decreased risk of major adverse cardiovascular events (MACE), with an incidence rate per 1000 person years of 11.4 versus 16.5 (hazard ratio 0.76).

The beneficial effects of SGLT2 inhibitors were also shown with these individual MACE Endpoints:

  • Myocardial infarction (incidence rate of 5.1 for SGLT2 inhibitors versus 6.4 for DPP-4 inhibitors; HR 0.82).
  • Cardiovascular death (3.9 versus 7.7; HR 0.60).
  • Heart failure (3.1 versus 7.7; HR 0.43).
  • All-cause mortality (8.7 versus 17.3; HR 0.60).
  • Ischemic stroke (2.6 versus 3.5; HR 0.85).

Filion and colleagues pointed out that the strong association with MACE was mostly driven by the incidence of cardiovascular death.

The benefits of each of the three SGLT2 inhibitors for MACE were similar, with hazard ratios ranging from 0.73 for dapagliflozin to 0.79 for canagliflozin. The benefits of SGLT2 inhibitors were also demonstrated across patient subgroups (age, sex, past insulin use, and history of cardiovascular disease or history of heart failure).

“These findings suggest that SGLT2 inhibitors offer cardioprotective benefits among people with type 2 diabetes in a real-world setting, although additional studies are needed to determine if these benefits persist long term,” concluded Filion and colleagues.

The authors noted some potential limitations to their study: the study’s observational nature opens it to possible residual or unmeasured confounding bias; misclassification of exposure is possible since data for prescriptions represent dispensed drugs, not consumption of drugs; the mean duration of follow-up was under a year, which means it is possible that the observed findings are related to short term hemodynamic effects of SGLT2 inhibitors rather than disease modifying benefits in the long term,” the study authors wrote.

Michael Bassett, Contributing Writer, BreakingMED™

Filion has no disclosures.

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Topic ID: 76,12,730,446,914,12,192,669,925