Expanding role of SGLT2 inhibitors: From cardioprotection in T2DM to HF management and renoprotection
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are playing an increasing role beyond glucose lowering and cardioprotection in patients with type 2 diabetes mellitus (T2DM). They are now recognized by international guidelines as one of the first-line treatments for patients with heart failure with reduced ejection fraction (HFrEF) based on significant benefits demonstrated in HFrEF trials. Their renoprotective effect in patients with T2DM and chronic kidne y disease (CKD) has led to guideline recommendations for their use in these populations, while emerging data from CKD trials may further expand their role in CKD management. At a recent webinar, experts discussed these important developments with a focus on the benefits of empagliflozin in these patient populations.
CV benefits in T2DM
SGLT2 inhibitors are recommended by international guidelines as first-line or early therapies in patients with T2DM and established atherosclerotic cardiovascular (CV) disease or high CV risk, based on significant improvements in CV outcomes shown in large CV outcome trials (CVOTs) in high-risk T2DM patients. [Eur Heart J 2020;41:255-323; Diabetes Care 2019;doi:10.2337/dci19-0066]
Empagliflozin: Early reduction in CV death
“Empagliflozin is the first SGLT2 inhibitor to demonstrate significant CV benefits in high-risk T2DM patients in a large CVOT,” said Professor Silvio Inzucchi of the Section of Endocrinology & Metabolism, Yale School of Medicine in New Haven, Connecticut, US.
In the EMPA-REG OUTCOME trial (n=7,020), empagliflozin on top of standard of care (SoC) was associated with a 14 percent relative risk reduction (RRR) in the primary outcome of 3-point major adverse CV events (MACE; a composite of death from CV causes, nonfatal MI, or nonfatal stroke) (hazard ratio [HR], 0.86; 95.02 percent confidence interval [CI], 0.74 to 0.99; psuperiority=0.04) vs placebo plus SoC. [N Engl J Med 2015;373:2117-2128]
“What is more impressive in EMPA-REG OUTCOME is the 38 percent RRR in CV death with empagliflozin vs placebo [HR, 0.62; 95 percent CI, 0.49 to 0.77; p<0.001],” said Inzucchi. “This benefit was observed early, with divergence of event curves occurring much earlier than typically seen in atherosclerosis trials.”
In addition, a 35 percent RRR in hospitalization for heart failure (HHF) (HR, 0.65; 95 percent CI, 0.50 to 0.85; p=0.002), a 39 percent RRR in incident or worsening nephropathy (HR, 0.61; 95 percent CI, 0.53 to 0.70; p<0.001), and a 32 percent RRR in all-cause mortality (HR, 0.68; 95 percent CI, 0.57 to 0.82; p<0.001) were reported with empagliflozin vs placebo.
A recent meta-analysis of CVOTs of SGLT2 inhibitors in T2DM patients showed generally consistent RRRs in first MACE and first HHF across the trials, but significant heterogeneity was found in associations with CV death. [JAMA Cardiol 2021;6:148-158]
A new pillar of care in HFrEF
“SGLT2 inhibitors have become a new pillar in HFrEF treatment. They are now recognized by the 2021 American College of Cardiology Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment as one of the first-line medications for all patients with HFrEF, along with angiotensin receptor-neprilysin inhibitors, evidence-based beta-blockers, and aldosterone antagonists,” said Professor Nikolaus Marx of the Department of Cardiology, Pneumology, Angiology and Intensive Care, University Hospital Aachen, Germany. [J Am Coll Cardiol 2021;77:772-810]
Empagliflozin’s benefits consistent in HFrEF with or without diabetes
This latest update to the HFrEF treatment pathway is based on significant benefits seen with SGLT2 inhibitors added to SoC in clinical trials in patients with HFrEF with or without diabetes. In the EMPEROR-Reduced trial, for example, empagliflozin demonstrated a 25 percent RRR in the primary composite endpoint of CV death or HHF vs placebo (HR, 0.75; 95 percent CI, 0.65 to 0.86; p<0.001) in patients with New York Heart Association class II–IV HFrEF (n=3,730) with or without diabetes. (Figure 1) The number needed to treat to prevent one primary endpoint event was 19. [N Engl J Med 2020;383:1413-1424]
The trial also showed a 30 percent RRR in total (ie, first and recurrent) HHF with empagliflozin vs placebo (HR, 0.70; 95 percent CI, 0.58 to 0.85; p<0.001). [N Engl J Med 2020;383:1413-1424]
“Half of the patients in the EMPEROR- Reduced trial had no diabetes. Empagliflozin’s beneficial effect on the primary endpoint was consistent in patients with [HR, 0.72; 95 percent CI, 0.60 to 0.87; p=0.0006] or without [HR, 0.78; 95 percent CI, 0.64 to 0.97; p=0.0225] diabetes [pinteraction=0.57],” pointed out Marx. [Circulation 2021;143:337-349]
“Likewise, empagliflozin’s safety profile was comparable to that of placebo in patients with or without diabetes,” said Marx. “In patients with diabetes, rates of severe hypoglycaemic events were similar between the empagliflozin and placebo groups [0.6 percent vs 0.8 percent]. No severe hypoglycaemic events were reported in patients without diabetes in either treatment group.” [Circulation 2021;143:337-349]
“Importantly, no cases of diabetic ketoacidosis were reported in empagliflozin-treated patients with or without diabetes,” he added. [N Engl J Med 2020;383:1413-1424; Circulation 2021;143:337-349]
Renoprotection in T2DM, HFrEF and CKD populations
“SGLT2 inhibitors provide an effective tool for improving the prognosis of patients with T2DM and diabetic kidney disease [DKD] because of their renoprotective and cardioprotective effects,” said Professor Per-Henrik Groop of the Department of Nephrology, University of Helsinki and Helsinki University Hospital, Finland, and the Department of Diabetes, Monash University, Melbourne, Australia.
International guidelines therefore recommend the use of SGLT2 inhibitors in patients with T2DM and CKD/DKD, to reduce the risk of CKD progression. [Diabetes Care 2020;43:S1; Diabetologia 2020;63:221; Nephrol Dial Transplant 2019;34:208; Eur Heart J 2020;41:255; Kidney Int 2020;98:S1]
“DKD is present in at least half of T2DM patients worldwide, and is associated with increased risks of adverse outcomes,” said Groop. [Nat Rev Dis Primers 2015;1:15018; J Am Soc Nephrol 2009;20:1813-1821; Diabetologia 2018;61:2300-2309; J Am Soc Nephrol 2013;24:302-308; Kidney Int 2017;92:388] “Multifactorial SoC including renin-angiotensin-aldosterone system inhibitors does not adequately reduce the risk of end-stage renal disease [ESRD] in T2DM patients with DKD.” [N Engl J Med 2001;345:861-869; N Engl J Med 2001;345:851-860]
“In the EMPA-REG OUTCOME trial, empagliflozin demonstrated a remarkable 39 percent RRR in incident or worsening nephropathy vs placebo [HR, 0.61; 95 percent CI, 0.53 to 0.70; p<0.001], with preservation of kidney function seen over time,” he noted. [N Engl J Med 2016;375:323-334; J Am Soc Nephrol 2018;29:2755-2769]
SGLT2 inhibitors have also demonstrated a renoprotective effect in patients with HFrEF with or without diabetes. In the EMPEROR-Reduced trial, which included HFrEF patients with estimated glomerular filtration rate (eGFR) as low as 20 mL/min/1.73 m2, the annual rate of eGFR decline was significantly slower with empagliflozin vs placebo (-0.55 mL/min/1.73 m2/year vs -2.28 mL/min/1.73 m2/year). (Figure 2) Patients treated with empagliflozin also had a 50 percent RRR in the composite renal endpoint of ESRD or sustained profound decrease in eGFR vs placebo recipients (HR, 0.50; 95 percent CI, 0.32 to 0.77). [N Engl J Med 2020;383:1413-1424]
“Notably, the extent of empagliflozin’s positive impact on the composite renal endpoint was similar between HFrEF patients with CKD [HR, 0.53; 95 percent CI, 0.31 to 0.91] and those without [HR, 0.46; 95 percent CI, 0.22 to 0.99],” pointed out Groop. [Circulation 2021;143:310-321]
With some SGLT2 inhibitors demonstrating renal and CV benefits in DKD and CKD trials, the phase III EMPA-KIDNEY trial is designed to evaluate empagliflozin’s effect in patients with CKD across a broad range of GFR categories, with or without albuminuria or diabetes. (Figure 3) Patients in the event-driven trial are randomized to receive empagliflozin or placebo, on top of SoC, and followed up for 30–48 months for the primary composite endpoint of time to first occurrence of CKD progression (defined as ESRD, a sustained decline in eGFR to <10 mL/min/1.73 m², renal death, or a sustained decline of ≥40 percent in eGFR from randomization) or CV death. [N Engl J Med 2019;380:2295-2306;
N Engl J Med 2020;383:1436-1446; NCT03594110]
“Albuminuria and GFR predict CKD prognosis. In the clinic, we do encounter DKD patients without albuminuria, and approximately 20 percent of patients with DKD will never develop albuminuria. However, patients without albuminuria were excluded from previous DKD and CKD trials of two other SGLT2 inhibitors. That is why the EMPA-KIDNEY trial is so important,” commented Groop. (Figure 3)
SGLT2 inhibitors such as empagliflozin have become the SoC for cardioprotection in patients with T2DM and for first-line treatment of HFrEF in patients with or without diabetes. Emerging data from CKD trials may uncover their potential in CKD treatment following evidence of their renoprotective effect seen in T2DM and HFrEF populations.