Meta-Analysis Details Benefits of Various SGLT2 Inhibitors in Diabetics

Clare Arnott, MBBS

A recent meta-analysis of 4 major clinical trials is providing clinicians with data more related to the potential cardiovascular benefits of the SGLT2 inhibitor class in type 2 diabetics.

Published in the Journal of the American Heart Association, the analysis highlights the ability of the class by highlighting benefits related to SGLT2 inhibitor use including a 12% reduction in major adverse cardiovascular events, a 17% reduction in cardiovascular death, and a 32% reduction in hospitalizations for heart failure—with benefits of use seen regardless of history of cardiovascular disease (CVD).

"In this meta-analysis of large event-driven SGLT2 inhibitor outcome trials we found SGLT2 inhibitors protected against cardiovascular disease and death in diverse subsets of patients with type 2 diabetes regardless of their cardiovascular disease history," said Clare Arnott, MD of the George Institute for Global Health, in a press release. "While the extent of this protective effect may vary across patient types, the consistency of the findings suggests significant and broad cardiovascular protection can be achieved from use of this drug class."

Using data from the EMPA-REG OUTCOME, DECLARE, CANVAS, AND CREDENCE trials, investigators sought to evaluate the cardiovascular benefits and effect on safety outcomes of SGLT2 inhibition on a population and individual basis in patients without and with established CVD, impaired renal function, or heart failure. Briefly, the trials included in the analysis examined 3 SGLT2 inhibitors—canagliflozin, empagliflozin, and dapagliflozin—and their impact on a multitude of efficacy and safety outcomes in patients with type 2 diabetes mellitus.

Efficacy outcomes of interest included in the analysis were cardiovascular death, fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, hospitalization for heart failure, the composite of cardiovascular death or hospitalization for heart failure, all-cause mortality, and MACE, which investigators defined as a composite of cardiovascular death, nonfatal MI, or nonfatal stroke. Safety outcomes included total serious adverse events, severe hypoglycemia, metabolic acidosis, amputation, and bone fracture.

Data on a total of 38,723 patients were included—7020 from EMPA-REG OUTCOME, 10,142 from the CANVAS program, 17,160 from DECLARE-TIMI 58, and 4401 from CREDENCE. Among participants from the 4 studies, the mean age of study participants ranged from 63.1 and 63.9 years, the proportion of women ranged between 28.5% and 37.4%, and the mean glycosylated hemoglobin ranged between 8.1% and 8.3%.

At baseline, the history of CVD in each study ranged from 40.6% to 100%, proportions with a baseline history of reduced renal function ranged from 7.4% to 59.8%, proportions with baseline macroalbuminuria ranged from 7.5% to 88.0%, and the proportion with a baseline history of heart failure ranged from 10.1% to 14.8%. When examining adverse events, 3828 MACE outcomes, 1192 hospitalizations for HF, 1506 cardiovascular deaths, and 2612 deaths from any cause were reported by investigators.

Upon analysis, SGLT2 inhibition was found to be associated with a 12% relative reduction in MACE (HR 0.88; 95% CI, 0.82—0.94)—investigators noted this effect was consistent across all 4 studies included (I2=0%; P for interaction=.477). In regard to cardiovascular death, SGLT2 inhibition was linked to a 17% relative risk reduction. Additionally, SGLT2 inhibition was associated with a reduced risk of MI (HR 0.88; 95% CI, 0.80—0.97; I2 =0%; P=.996) but had no impact on stroke risk (HR 0.96; 95% CI, 0.86—1.09; I2 =0%; P for interaction=0.785).

In regard to the subgroup of 22,870 patients with CVD at baseline, SGLT2 inhibition was associated with a beneficial impact on secondary prevention (HR 0.86; 95% CI, 0.80—0.93), which was greater than that seen when examining SGLT2 inhibition on primary prevention (HR 0.94; 95% CI, 0.82–1.07). The risk for MI in the secondary prevention cohort (HR 0.86; 95% CI, 0.78–0.96) was also lower than the risk for MI in the primary prevention cohort (HR 0.97; 95% CI, 0.78–1.19) when examining the impact of SGLT2 inhibition.

When examining the impact of SGLT2 inhibitor use among patients with impaired renal function, investigators observed separately significant evidence of protection compared with placebo among patients with reduced kidney function for every efficacy outcome. Results indicated SGLT2 inhibition helped patients achieve greater proportional risk reductions for MACE (HR 0.80; 95% CI, 0.70—0.90) than their counterparts with preserved renal function (HR 0.92; 95% CI, 0.85–0.99). Furthermore, a similar effect was apparent when observing stroke risk among those with reduced renal function (HR 0.75; 95% CI, 0.59–0.96) compared to those with preserved function (HR 1.05; 95% CI, 0.91– 1.20; I2=81.4%).

When examining safety outcomes, analyses revealed SGLT2 inhibition was associated with a lower relative risk of serious adverse events (HR 0.91; 95% CI, 0.88—0.94). No differences were observed in regard to rates of severe hypoglycemia or feature, but risk increases were observed for diabetic ketoacidosis (HR 2.46; 95% CI, 1.43–4.24) and amputation (HR 1.23; 95% CI, 1.05–1.44).

Based on the results of the study, investigators suggest SGLT2 inhibition protects against cardiovascular disease and death in multiple subgroups of patients with type 2 diabetes mellitus and this effect is not mitigated based on history of CVD.

"Our study has shown that we have a class of drug in our treatment arsenal that could potentially have a significant impact on the cardiovascular complications of type 2 diabetes," said Arnott, in the aforementioned release.

This study, “Sodium-Glucose Cotransporter 2 Inhibition for the Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis,” was published online in the Journal of The American Heart Association.