From T2DM to heart failure and CKD: New era of care with SGLT2 inhibitors

Prof. Melanie Davies
University of Leicester
04 Jan 2022
From T2DM to heart failure and CKD: New era of care with SGLT2 inhibitors

The cardiorenal benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM), heart failure (HF) and chronic kidney disease (CKD) have led international guidelines to recommend their earlier use to reduce the risk of cardiovascular (CV) events, HF hospitalizations, and CKD progression. At the Endocrinology, Diabetes and Metabolism Hong Kong (EDM HK) 4th Annual Meeting, Professor Melanie Davies of the University of Leicester, Leicester, UK, discussed evidence from T2DM CV outcome trials (CVOTs) and dedicated HF trials of SGLT2 inhibitors that led to these practice-changing recommendations.

Cardiorenal protection in T2DM
SGLT2 inhibitors have been shown to reduce the risk of major adverse CV events (MACE), hospitalization for HF (HHF), and renal outcomes in CVOTs in patients with T2DM. [N Engl J Med 2015;373:2117-2128; N Engl J Med 2017;377:644-657; N Engl J Med 2019;380:347-357]

In the EMPA-REG OUTCOME tri­al, the SGLT2 inhibitor empagliflozin demonstrated a 14 percent relative risk reduction (RRR) in three-point MACE (a composite of CV death, nonfatal myocardial infarction [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 in patients with T2DM and established CV disease (n=7,020). In addition, CV death was reduced by 38 percent (HR, 0.62; 95 percent CI, 0.49 to 0.77; p<0.001), HHF was reduced by 35 percent (HR, 0.65; 95 percent CI, 0.50 to 0.85; p=0.002), while inci­dent or worsening nephropathy was reduced by 39 percent (HR, 0.61; 95 percent CI, 0.53 to 0.70; p<0.001). [N Engl J Med 2015;373:2117-2128]

A recent meta-analysis of CVOTs of SGLT2 inhibitors in T2DM patients showed generally consistent effects on risks of first MACE (in patients with atherosclerotic CV disease [ASCVD]), first HHF, and kidney outcomes across the trials, but significant heterogeneity was found in the effect on CV death. [JAMA Cardiol 2021;6:148-158]

“Empagliflozin is still the only SGLT2 inhibitor that demonstrated a significant reduction in risk of CV death in these CVOTs in people with T2DM,” said Davies. (Figure) [JAMA Cardiol 2021;6:148-158]


“Importantly, empagliflozin’s bene­fits on CV death, HHF and kidney end­points were consistent between sub­groups of patients with overt diabetic kidney disease [DKD], nonovert DKD, and other categories of DKD at base­line,” noted Davies. [Diabetes Obes Metab 2020;22:2335-2347]

Renewed focus on HF
Diabetes is one of the predomi­nant risk factors for HF with preserved ejection fraction (HFpEF), for which evidence-based therapies had been lacking until very recently. [Exp Mol Med 2019;51:1-9]

“In patients with T2DM, the risk of HF remains elevated even if other risk factors are controlled,” pointed out Davies. “In the absence of other risk factors, the risk of HF is the highest in younger T2DM patients aged <55 years [HR vs same-age controls, 2.40; 95 percent CI, 1.63 to 3.54], followed by those ≥55–65 years of age [HR vs same-age controls, 1.61; 95 per­cent CI, 1.31 to 1.97].” [N Engl J Med 2018;379:633-644]

With the high 5-year mortality rates associated with all phenotypes of HF, interventions that reduce the risks of HF and its associated adverse out­comes are needed. [J Am Coll Cardiol 2017;70:2476-2486]

“SGLT2 inhibitors are the only class of glucose-lowering drugs that have demonstrated beneficial effects in HF, including HFpEF,” said Davies.

Empagliflozin beneficial in HF regardless of LVEF
HF trials of empagliflozin in patients with or without T2DM at baseline have demonstrated reductions in CV death or HHF across the spectrum of left ventricular ejection fraction (LVEF). (Table) [N Engl J Med 2021;385:1451- 1461; N Engl J Med 2020;383:1413- 1424; Circulation 2021;143:326-336]


Benefits in HFrEF
In the EMPEROR-Reduced trial in patients with HF with reduced ejection fraction (HFrEF; ie, LVEF ≤40 percent) with or without diabetes (n=3,730; mean age, 66.5–67.2 years; female, 23.5–24.4 percent), empagliflozin demonstrated a 25 percent RRR in the primary composite outcome of first adjudicated CV death or HHF and a 30 percent RRR in adjudicated total (first and recurrent) HHF vs placebo. (Table) [N Engl J Med 2020;383:1413-1424]

A renoprotective effect was also observed, with a slower annual rate of decline in estimated glomerular filtration rate (eGFR) in the empagli­flozin vs placebo arm (eGFR slope difference, +1.73 mL/min/1.73 m2/ year; p<0.001). Patients treated with empagliflozin also had a 50 percent RRR in the composite renal endpoint of end-stage kidney disease (ESKD) or sustained profound decrease in eGFR (HR, 0.50; 95 percent CI, 0.32 to 0.77) vs placebo recipients.

Quality of life (QoL), as measured by Kansas City Cardiomyopathy Ques­tionnaire Clinical Summary Score (KC­CQ-CSS), was improved at 52 weeks with empagliflozin vs placebo (absolute difference, +1.7; 95 percent CI, 0.5 to 3; p=0.0058).

“The data from HFrEF trials of SGLT2 inhibitors provide conclusive evidence of their benefits in this patient population,” noted Davies. [Lancet 2020;396:819-829]

Benefits in HFpEF
“What’s really exciting in HF is the benefit of empagliflozin in HFpEF shown recently in the EMPEROR-Preserved trial, which included HFpEF patients typical of those seen in the clinic,” said Davies.

EMPEROR-Preserved included 5,988 patients with HFpEF (LVEF >40 percent) with or without diabetes at baseline (mean age, 71.8–71.9 years; female, 44.6–44.7 percent; body mass index, 29.77– 29.90 kg/m2; atrial fibrillation, 50.6–51.5 percent; hypertension, 90.4–90.8 per­cent). Results showed a 21 percent RRR in the primary composite outcome of first adjudicated CV death or HHF in patients randomized to receive empagli­flozin vs placebo. (Table) [N Engl J Med 2021;385:1451-1461]

“Empagliflozin’s benefit on the pri­mary endpoint was consistent across subgroups, including in Asian patients. Among 411 Asian patients in the trial, em­pagliflozin demonstrated an impressive 35 percent RRR in the primary endpoint vs placebo,” said Davies.

The benefit of empagliflozin on the pri­mary outcome was driven by a 29 percent RRR in first HHF vs placebo. In addition, a 27 percent RRR in adjudicated total (first and recurrent) HHF was observed. (Table)

Patients in the empagliflozin arm also had a slower rate of eGFR decline vs pla­cebo recipients (eGFR slope difference, +1.36 mL/min/1.73 m2/year; 95 percent CI, 1.06 to 1.66; p<0.001).

Safety and tolerability
In both trials, empagliflozin was well tolerated. Adverse events (AEs) more frequently reported with empagliflozin vs placebo were uncomplicated genital and urinary tract infections (2.2 percent vs 0.7 percent) and hypotension (6.6 percent vs 5.2 percent) in EMPEROR-Preserved, and uncomplicated genital tract infections (1.7 percent vs 0.6 per­cent) in EMPEROR-Reduced. [N Engl J Med 2020;383:1413-1424; N Engl J Med 2021;385:1451-1461]

“The safety profile of empaglifloz­in was reassuring even in the older and more comorbid patient population of EMPEROR-Preserved, with no increase in selected AEs of interest vs placebo,” noted Davies. “In EMPEROR-Preserved, serious AEs were less frequent with em­pagliflozin vs placebo [47.9 percent vs 51.6 percent]. Rates of hypoglycaemic events [2.4 percent vs 2.6 percent] and ketoacidosis [0.1 percent vs 0.2 percent] were low and did not differ significantly between the treatment arms.”

CKD: Accumulating evidence
The cardiorenal benefits of SGLT2 inhibitors shown in T2DM CVOTs have led to dedicated CKD trials to evaluate their effects in patients with CKD with or without T2DM. The DAPA-CKD trial, for example, demonstrated a significant re­duction in CKD progression or death from renal or CV causes with dapagliflozin vs placebo in diabetic and nondiabetic pa­tients with eGFR >25–<75 mL/min/1.73 m2 and urine albumin-to-creatinine ratio (UACR) >200 mg/g. [N Engl J Med 2020; 383:1436-1446]

“The phase III EMPA-KIDNEY trial will provide important evidence on em­pagliflozin’s cardiorenal effect in a broad CKD population. It will enrol patients with eGFR ≥20–<45 mL/min/1.73 m2, and those with eGFR ≥45–<90 mL/min/1.73 m2 and UACR ≥200 mg/g,” said Davies. [N Engl J Med 2019;380:2295-2306; N Engl J Med 2020;383:1436-1446; NCT03594110]

ADA, ESC, KDIGO guidelines: Use SGLT2 inhibitors earlier
The positive results with SGLT2 in­hibitors have led international guidelines to recommend their earlier use in high-risk patient populations.

“The American Diabetes Association [ADA] 2021 diabetes guidelines recom­mend early use of an SGLT2 inhibitor with proven cardiorenal benefits in T2DM patients with indicators of high risk or established ASCKD, HF, or CKD – inde­pendently of baseline HbA1c, individual­ized HbA1c target or first-line metformin use – to reduce the risk of CV events or CKD progression,” highlighted Davies. [Diabetes Care 2021;44:S111-S124]

The European Society of Cardiology (ESC) 2019 guidelines on diabetes, pre­diabetes and CV disease also recom­mended the use of an SGLT2 inhibitor in T2DM patients with high CV risk or ASCVD – regardless of whether they are drug-naïve or already on metformin. [Eur Heart J 2020;41:255]

Similarly, the Kidney Disease: Im­proving Global Outcomes (KDIGO) 2020 guidelines recommended an SGLT2 in­hibitor plus metformin as first-line thera­py in patients with T2DM and CKD with eGFR ≥30 mL/min/1.73 m2. “However, SGLT2 inhibitors should not be initiated in those with eGFR <30 mL/min/1.73 m2 and should be discontinued in those on dialysis,” said Davies. [Kidney Int 2020;98:S1-S115]

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