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Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are antihyperglycemic agents acting on the SGLT-2 proteins expressed in the proximal convoluted tubules. These drugs exert their effect by preventing the reabsorption of filtered glucose from the tubular lumen. To date, there are four SGLT-2 inhibitors: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin that are approved by Food Drug Administration (FDA) for their use in adults. The indications for use vary per agent, but all four agents are approved for use in adults with type 2 diabetes mellitus (DM) to improve blood sugar control adjunct to diet and exercise.[1]

FDA-approved indications for SGLT-2 Inhibitors

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Off-label use of SGLT2 Inhibitors

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Canagliflozin was the first SGLT-2 inhibitor approved on March 29, 2013; it is indicated in adult patients with type 2 DM to improve blood glucose control in addition to diet and exercise. It is also shown to decrease the risk of cardiovascular (CV) adverse events in type 2 DM subjects with underlying CV illness and minimize the risk of end-stage renal disease (ESRD), CV mortality, hospitalization for heart failure, and albuminuria in patients with diabetic nephropathy.[1]

Dapagliflozin received FDA approval in January 2014. The drug is indicated in adult patients with type 2 DM to improve blood glucose control in addition to diet and exercise. Other indications include minimizing the hospitalization attributed to heart failure in type 2 DM patients with underlying CV illness or several CV risk factors, decreasing the risk of CV mortality and hospitalization in adult subjects with underlying heart failure, and decreasing ejection fraction (EF) with New York Heart Association (NYHA) classification II-IV.[10] Dapagliflozin is also indicated to minimize the risk of the continued decline of estimated glomerular filtration rate (eGFR), ESRD, CV mortality, and hospitalization for heart failure in chronic kidney disease (CKD) patients at risk of progressive disease.[1]

In May of 2023, the FDA expanded the indication of dapagliflozin to include heart failure across the entire spectrum of left-ventricular ejection fraction (LVEF). This includes HF with mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF).[11] The FDA has previously approved dapagliflozin for HFrEF. The expanded indication of dapagliflozin is based on clinical data from the DELIVER trial, which demonstrated the clinical benefits of dapagliflozin for patients with HF regardless of left-ventricular function. In the DELIVER trial involving more than 6200 patients, dapagliflozin demonstrated a clinically significant reduction in the primary composite endpoint of worsening heart failure or cardiovascular death in patients with HFmrEF and HFpEF.[7] In addition, dapagliflozin demonstrated the benefit across the range of ejection fractions in subsequent studies. The pooled meta-analysis of 11,007 participants in DAPA-HF and DELIVER indicated that dapagliflozin 10 mg once daily decreased the risk of death from cardiovascular causes and all-cause mortality. It also reduced recurrent hospitalization for HF, the composite of death from CV causes, MI, or stroke.[12]

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Soon after the approval of dapagliflozin, empagliflozin was the third SGLT inhibitor to receive approval from the FDA in August 2014.[13] Empagliflozin is indicated in adult patients with type 2 DM to improve the control of blood glucose in addition to diet and exercise, decrease the risk of CV adverse events in type 2 DM subjects with underlying ASCVD, and minimize the risk of CV mortality and heart failure hospitalization in adult subjects with underlying heart failure and decreased EF. In patients with atherosclerotic cardiovascular disease and type 2 diabetes, empagliflozin is preferred as it improves CV outcomes and reduces all-cause mortality.[14] Empagliflozin is also FDA-approved for HFpEF. The EMPEROR-Preserved trial indicated that empagliflozin significantly decreased hospitalization risk, regardless of patients’ diabetes status.[15][16]

The latest SGLT inhibitor to receive approval from the FDA was ertugliflozin in 2017 and is indicated for adult subjects with type 2 DM to improve the control of blood glucose in addition to diet and exercise.[17]

According to the AHA/ACC/HFSA Guidelines, in patients with HFrEF (ejection fraction ≤ 40%), SGLT2 inhibitors decrease hospitalization related to heart failure and cardiovascular mortality, irrespective of type 2 diabetes. In patients with type 2 DM and established CVD or at high cardiovascular risk, SGLT2 inhibitors are suggested to reduce HF hospitalizations. Consequently, guideline-directed medical therapy (GDMT) for (HFrEF) now includes SGLT-2 inhibitors. Dapagliflozin and empagliflozin are included in GDMT for stage C HFrEF(Structural heart disease with symptoms of heart failure).[18] In addition, SGLT2 inhibitors may be the first drug class to improve cardiovascular outcomes in patients with HFpEF.[19]

According to KDIGO guidelines, SGLT2 inhibitors are recommended for patients to prevent CKD progression. Clinicians must recognize that the recommendation does not apply to immunocompromised patients with a kidney transplant. SGLT2 inhibitors are also beneficial for patients with CKD who do not have diabetes; however, the evidence is strong for patients with type 2 diabetes. SGLT2 inhibitors with established clinical benefits in diabetic kidney disease include canagliflozin, dapagliflozin, and empagliflozin.[5]

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