Cardiorenal benefits of empagliflozin in elderly patients with T2DM, HF or CKD

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated cardiorenal benefits in patients with type 2 diabetes mellitus (T2DM) and those with heart failure (HF) or chronic kidney disease (CKD) with or without diabetes. However, misconceptions may lead to inertia in treatment initiation in elderly patients. At a Boehringer Ingelheim–sponsored symposium organized by the Hong Kong Geriatrics Society, Professor Silvio Inzucchi of Yale School of Medicine, New Haven, Connecticut, US, and Professor Michael Böhm of Saarland University, Saarbrücken, Saarland, Germany, presented pivotal trial and real-world data demonstrating empagliflozin’s cardiorenal benefits and safety in elderly patients with these closely interrelated cardio-renalmetabolic (CRM) conditions.

Profile of CRM conditions in the elderly
“T2DM, cardiovascular disease [CVD] and CKD are closely interrelated and often coexist,” said Inzucchi. “T2DM has become an increasingly frequent cause of CKD, especially among older individuals.” [Lancet 2010;375:2215-2222; Lancet 2020;395:709-733]

“In elderly patients, HF with preserved ejection fraction [HFpEF] is more common than HF with reduced ejection fraction [HFrEF],” said Bohm. [Eur J Heart Fail 2002;4:779-786] “Among patients with HFpEF, 60–70 percent are >65 years of age, and 20–40 percent have comorbid T2DM and/or CKD.” [Eur J Heart Fail 2023;25:936-955]

Empagliflozin’s cardiorenal benefits in elderly patients
T2DM patients with high CV risk
Cardiorenal benefits of empagliflozin vs placebo in patients with T2DM and established CVD are consistent across age groups, including the elderly, according to subgroup analyses of the EMPA-REG OUTCOME trial. [Ridderstrale M, et al, ESC 2016, abstract 5803; Monteiro P, et al, ESC 2016, abstract 5801; Bergenstal RM, et al, ADS-ADEA 2016]

“No heterogeneity was seen across age groups in empagliflozin’s effects on reducing CV death [all patients: hazard ratio (HR), 0.62; age <65 years: HR, 0.72; age 65–<75 years: HR, 0.54; age ≥75 years, 0.55; p_interaction=0.484], hospitalization for HF [HHF] or CV death [all patients: HR, 0.66; age <65 years: HR, 0.78; age 65–<75 years: HR, 0.59; age ≥75 years: HR, 0.52; p_interaction=0.240], and incident or worsening nephropathy [all patients: HR, 0.61; age <65 years: HR, 0.61; age 65–<75 years: HR, 0.65; age ≥75 years: HR, 0.54; p_interaction=0.733],” said Inzucchi.

Across age groups, reported adverse events (AEs) were consistent with empagliflozin’s known safety profile.

HFpEF, HFmrEF and HFrEF patients
“Elderly patients with HF are undertreated with evidence-based therapies,” said Bohm. [Am Heart J 2000;139:85-93; Am Heart J 2004;148:951-957; Eur J Heart Fail 2022;24:1047-1062] “Low blood pressure [BP] and impaired kidney function are misperceived contraindications leading to inertia in HF treatment initiation in elderly patients. Studies showed that these misperceived barriers are not justified.” [J Am Geriat Soc 2002;50:1659-1666; J Card Fail 2023;29:434-444; Eur J Heart Fail 2022;24:1063-1065]

“In the EMPEROR-Preserved trial in patients with HFpEF or HF with mildly reduced ejection fraction [HFmrEF] with or without diabetes, empagliflozin showed consistent effects across age groups in reducing CV death or first HHF [primary outcome] and first HHF vs placebo,” said Bohm. “The effects appeared to be even more pronounced in elderly patients.” (Table) [J Am Coll Cardiol 2022;80:1-18; N Engl J Med 2021;385;1451-1461]

No interaction with age was found for empagliflozin’s effect of attenuating the decline of estimated glomerular filtration rate (eGFR) in EMPEROR-Preserved (p_interaction=0.32). No clinically relevant differences in AEs were observed between empagliflozin and placebo across age groups. [J Am Coll Cardiol 2022;80:1-18]

Similarly, in the EMPEROR-Reduced trial in HFrEF patients with or without diabetes, empagliflozin’s effect of reducing the risk of CV death or first HHF (primary outcome) was consistent across age groups (all patients: HR, 0.75; age <65 years: HR, 0.71; age 65–<75 years: HR, 0.72; age ≥75 years: HR, 0.86; p_trend=0.25). Effects on the renal composite endpoint (p_trend=0.94) and rate of eGFR decline (p_trend=0.78) were also consistent across age groups. “Rates of AEs were similar between empagliflozin and placebo across age groups,” said Bohm. [N Engl J Med 2020;383:1413-1424; Eur J Heart Fail 2022;24:2297-2304]

“These homogeneous results across age groups and HF phenotypes suggest that old age should not be a barrier to using empagliflozin in HF,” Bohm emphasized.

CKD patients
The EMPA-KIDNEY trial demonstrated empagliflozin’s cardiorenal benefits and safety in patients with CKD with or without diabetes, showing a 28 percent relative risk reduction (RRR) in kidney disease progression or CV death (primary endpoint) vs placebo (HR, 0.72; 95 percent confidence interval [CI], 0.64–0.82; p<0.001). “This benefit was similar between older and younger patients [age ≥70 years: HR, 0.65; 95 CI, 0.52–0.81] [age ≥60–<70 years: HR, 0.81; 95 percent CI, 0.64–1.04] [age <60 years: HR, 0.72; 95 percent CI, 0.59–0.88], and between patients with diabetes [HR, 0.64; 95 percent CI, 0.54–0.77] and those without diabetes [HR, 0.82; 95 percent CI, 0.68–0.99] at baseline,” said Inzucchi. “No significant safety signals were observed.” [N Engl J Med 2023;388:117-127]

Real-world data in elderly patients
A real-world study evaluated empagliflozin’s effect on reducing the burden of total CV hospitalizations in older patients with T2DM. “In the cohort of 11,429 propensity score–matched pairs of patients who initiated empagliflozin or sitagliptin [mean age, 71.85 years; CVD, 47.7 percent for empagliflozin vs 48.4 percent for sitagliptin; HF, 11.9 percent vs 11.6 percent], empagliflozin demonstrated a 20 percent RRR in total CV hospitalizations [HR, 0.80; 95 percent CI, 0.69–0.93] and a 30 percent RRR in HHF [HR, 0.70; 95 percent CI, 0.51–0.98] vs sitagliptin after a mean follow-up of 6.3 months,” said Inzucchi. [Am Heart J 2022;254:203-215]

Practical tips on choosing and using SGLT2 inhibitors
SGLT2 inhibitors have modest effects in lowering HbA_1c, BP and body weight, and are not associated with an increased risk of hypoglycaemia. Robust evidence supports empagliflozin’s cardiorenal benefits across a spectrum of CRM conditions. [Diabetes Care 2022;45:S1-S2]

“Cardiorenal benefits of empagliflozin are independent of HbA_1c,” said Inzucchi. “The label-directed eGFR cutoff of 30 mL/min/1.73 m² in patients with T2DM is because empagliflozin’s glycaemic efficacy depends on kidney function. For HF patients with or without T2DM, the eGFR cut-off is 20 mL/min/1.73 m².” [Circulation 2018;138:1904-1907; Am J Kidney Dis 2019;74:713-715; Jardiance Hong Kong Prescribing Information, May 2022]

“Genital infections, a common AE of SGLT2 inhibitors, are typically mild to moderate and usually occur early during treatment exposure. These can be prevented by providing practical hygiene advice to patients and their partners, and managed with topical or appropriate oral treatments, in addition to raising awareness of this AE at the start of SGLT2 inhibitor treatment,” Inzucchi advised. [Diabetes Ther 2018;9:1757-1773]