Expanding role of SGLT2 inhibitors in T2DM and HF management
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated benefits in cardiovascular (CV) outcome trials in patients with type 2 diabetes mellitus (T2DM). A post hoc analysis of the EMPA-REG OUTCOME trial showed early reductions in CV mortality and hospitalization for heart failure (HHF) with empagliflozin, while new data from the real-world EMPRISE study continue to support empagliflozin’s cardioprotective effect in patients with a broader CV risk profile. In the EMPEROR-Reduced trial, empagliflozin treatment yielded cardiorenal benefits in patients with heart failure with reduced ejection fraction (HFrEF), regardless of T2DM status. The clinical impact of these recent findings was discussed by Professor Guntram Schernthaner of the Rudolfstiftung Hospital and Medical University of Vienna, Vienna, Austria, at the Endocrinology, Diabetes & Metabolism Hong Kong 3rd Annual Meeting (EDMHK 2020).
Empagliflozin reduces MACE, CV death & HHF in T2DM
CV outcome trials in high-risk patients with T2DM have shown significant relative risk reductions (RRRs) in major adverse cardiac events (MACE) with SGLT2 inhibitors. In the EMPA-REG OUTCOME trial, the MACE hazard ratio (HR) for empagliflozin vs placebo was 0.86 (95 percent confidence interval [CI], 0.74 to 0.99; p=0.04), while in the CANVAS clinical trial programme, this HR was 0.86 (95 percent CI, 0.75 to 0.97; p=0.02) for canagliflozin vs placebo. Significant RRRs in HHF were also seen with empagliflozin (HR, 0.65; 95 percent CI, 0.50 to 0.85; p=0.002) and canagliflozin (HR, 0.67; 95 percent CI, 0.52 to 0.87), as well as with dapagliflozin (HR, 0.73; 95 percent CI, 0.61 to 0.88) in the DECLARE-TIMI 58 trial. [N Engl J Med 2015;373:2117-2128; N Engl J Med 2017;377:644-657; N Engl J Med 2019;380:347-357]
Of note, more than 99 percent of patients in the EMPA-REG OUTCOME trial had established CV disease (CVD) at baseline. In comparison, a history of CVD was present at baseline in 65.6 percent of CANVAS participants and 40.6 percent of DECLARE-TIMI 58 participants, respectively. [N Engl J Med 2015;373:2117-2128; N Engl J Med 2017;377:644-657; N Engl J Med 2019;380:347-357]
Empagliflozin is the only SGLT2 inhibitor that has demonstrated a significant RRR in CV death (HR, 0.62; 95 percent CI, 0.49 to 0.77; p<0.001) in a CV outcome trial in high-risk T2DM patients. [N Engl J Med 2015;373:2117-2128]
EMPA-REG OUTCOME: Early reductions in CV death & HHF
A post hoc analysis of the EMPA-REG OUTCOME trial, presented at the American Diabetes Association 80th Scientific Sessions (ADA 2020), demonstrated early benefits with empagliflozin that reached statistical significance within weeks after treatment initiation. [Verma S, et al, ADA 2020, abstract 28-OR]
Investigators evaluated time trajectories of the effect of pooled empagliflozin doses vs placebo on time to CV death, first HHF, and the composite of first HHF or CV death (excluding fatal stroke) in EMPA-REG OUTCOME. HRs for these outcomes were calculated daily from randomization until the last day of observation.
Results showed that the RRR in CV death with empagliflozin vs placebo reached statistical significance by day 59 (HR, 0.28; 95 percent CI, 0.08 to 0.96). (Figure 1)
Notably, the RRR in HHF became statistically significant as early as day 17 after empagliflozin treatment initiation (HR, 0.10; 95 percent CI, 0.01 to 0.87; p=0.0372), while the RRR in the composite of HHF and CV death reached statistical significance by day 27 (HR, 0.28; 95 percent CI, 0.08 to 0.97; p=0.045). These effects remained significant throughout trial follow-up.
“Treatments that reduce the risk of CV and heart failure [HF] outcomes expeditiously are important in management of patients with T2DM and atherosclerotic CVD [ASCVD]. Findings of this post hoc analysis demonstrate the rapidity of benefit onset with empagliflozin in reducing the risk of CV and HF outcomes,” the investigators concluded.
EMPRISE: Consistent real-world benefits in reducing HHF
The RRR in HHF with empagliflozin was corroborated in the real-world EMPRISE study involving 16,443 propensity score (PS)–matched pairs of patients who initiated empagliflozin or sitagliptin between August 2014 and September 2016, identified from three large US healthcare databases. [Circulation 2019;139:2822-2830]
The first interim analysis of EMPRISE demonstrated a 50 percent RRR in the HHF-specific outcome (HR, 0.50; 95 percent CI, 0.28 to 0.91), defined as HF discharge diagnosis in the primary position, and a 49 percent RRR in the HHF-broad outcome (HR, 0.51; 95 percent CI, 0.39 to 0.68), defined as HF discharge diagnosis in any position, with empagliflozin vs sitagliptin after a mean follow-up of 5.3 months.
These findings confirm the robustness of empagliflozin’s HHF benefit in routine clinical practice involving patients with a broader CV risk profile, against a dipeptidyl peptidase 4 (DPP-4) inhibitor as the active comparator. [Cardiovasc Diabetol 2019;18:115]
Benefits in older patients
A 3-year interim analysis of EMPRISE, presented at ADA 2020, demonstrated empagliflozin’s benefits vs DDP-4 inhibitors in the subgroup of older T2DM patients aged ≥66 years. Among 11,579 pairs of PS-matched patients (mean age, 72 years) who initiated empagliflozin or a DPP-4 inhibitor between August 2014 and September 2017, HRs for the HHF-specific and HHF-broad outcomes with empagliflozin vs DPP-4 inhibitors were 0.43 (95 percent CI, 0.30 to 0.63) and 0.57 (95 percent CI, 0.47 to 0.69), respectively, after a mean follow-up of 5.8 months. The HR for the modified MACE endpoint of MI, stroke or all-cause mortality was 0.63 (95 percent CI, 0.50 to 0.79), favouring empagliflozin. [Patorno E, et al, ADA 2020, abstract 133-LB]
EMPEROR-Reduced: Empagliflozin cuts CV death or HHF in HFrEF
In patients with HFrEF with or without T2DM, empagliflozin demonstrated a 25 percent RRR in CV death or HHF (HR, 0.75; 95 percent CI, 0.65 to 0.86; p<0.001) in the EMPEROR-Reduced trial. (Figure 2) This primary endpoint was achieved after 3,370 patients with class II–IV HFrEF (left ventricular ejection fraction [LVEF] ≤40 percent), with or without T2DM, were randomized to receive empagliflozin 10 mg QD (n=1,863; mean age, 67.2 years; female, 23.5 percent; Asian, 18.1 percent) or placebo (n=1,867; mean age, 66.5 years; female, 24.4 percent; Asian, 17.9 percent) in addition to recommended therapy for HF and followed up for a median of 16 months. [N Engl J Med 2020, doi: 10.1056/NEJMoa2022190]
Total (first and recurrent) HHF, a key secondary endpoint, saw a 30 percent RRR with empagliflozin vs placebo (HR, 0.70; 95 percent CI, 0.58 to 0.85; p<0.001).
Renal protection with empagliflozin in HFrEF
The rate of on-treatment decline in estimated glomerular filtration rate (eGFR), another key secondary endpoint of EMPEROR-Reduced, was significantly slower in the empagliflozin vs placebo group (-0.55 mL/min/1.73 m2/year vs -2.28 mL/min/1.73 m2/year; difference in eGFR slope, +1.73 mL/min/1.73 m2/year; p<0.001). (Figure 3) [N Engl J Med 2020, doi: 10.1056/NEJMoa2022190]
The trial recruited patients with eGFR ≥20 mL/min/1.73 m2. [Eur J Heart Fail 2019;21:1270-1278] Mean eGFR at baseline was 61.8 mL/min/1.73 m2 in the empagliflozin group vs 62.2 mL/min/1.73 m2 in the placebo group. [N Engl J Med 2020, doi: 10.1056/NEJMoa2022190]
With eGFR slope being a measure of long-term kidney function, these results suggest that empagliflozin can delay kidney disease progression in HFrEF patients.
Impact on clinical practice
Cardiorenal-protective glucose-lowering therapies, including SGLT2 inhibitors, are now recommended by international guidelines as the first add-on to metformin in T2DM patients with cardiorenal risk, including those with ASCVD, HF or chronic kidney disease, based on evidence from CV outcome trials. [Diabetologia 2018;61:2461-2498; Diabetes Care 2019;42:S90-S102; Eur Heart J 2016;37:315-381; J Am Coll Cardiol 2019, doi: 10.1016/j.jacc.2019.03.010; Cardiovasc Diabetol 2019;18:115]
However, these therapies remain underused in T2DM patients with established CVD. [PLoS ONE 2020, doi: 10.1371/journal.pone.0229621; Ganz M, et al, ADA 2020, poster 1426-P] Of note, DPP-4 inhibitors remain more widely used than SGLT2 inhibitors despite a large body of evidence showing no clear benefit with DPP-4 inhibitors on cardiorenal outcomes and a cost similar to SGLT2 inhibitors. [Cardiovasc Diabetol 2020;19:185]
The inertia in using cardiorenal-protective glucose-lowering therapies in high-risk T2DM patients has led experts to call for a shift from an HbA1c target–driven treatment approach to one with parallel and independent consideration of ASCVD, HF and renal risks, in accordance with current guidelines. [Cardiovasc Diabetol 2020;19:185]