Sodium-Glucose Transporter 2 (SGLT2) Inhibitors Topic Review

As a class, sodium–glucose transporter 2 inhibitors are novel drugs initially developed for glycemic control in patients with type 2 diabetes.
[Cowie MR, et al. Nat Rev Cardiol. 2020;1a]

Their primary mechanism of action is inhibition of SGLT2 in the proximal renal tubules, thereby disrupting glucose reabsorption and leading to increased glucose excretion. In contrast to most non-insulin medications used in type 2 diabetes (T2D) treatment, SGLT2 inhibitors achieve glucose reduction without increasing endogenous insulin secretion or enhancing insulin sensitivity. [Edelman SV. Diagnosis and Management of Type II Diabetes.]

Based on postapproval data, the use of SGLT2 inhibitors subsequently expanded beyond glucose modulation, particularly in cardiovascular (CV) medicine both for prevention of adverse CV events and for the management of heart failure (HF) — even in patients without T2D. Additionally, post hoc analyses of CV outcome trials and dedicated renal outcome trials also provided compelling evidence of renal protection in patients with T2D. While the precise mechanisms governing renoprotective effects remain incompletely understood, potential contributors include systemic and glomerular hemodynamic alterations, metabolic advantages and dampening of inflammatory and oxidative stress pathways. [Dharia A, et al. Annu Rev Med. 2023;1a]

Five SGLT2 inhibitors ― canagliflozin (Invokana, Janssen), dapagliflozin (Farxiga, AstraZeneca), empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly), ertugliflozin (Steglatro, Merck) and sotagliflozin (Inpefa, Lexicon) ― currently have FDA approval for at least one of the following: glycemic control, major adverse CV event (MACE) risk reduction and HF management. Unlike other SGLT2 inhibitors, sotagliflozin also inhibits SGLT1, reducing absorption of glucose and sodium in the intestine.

Indications

The FDA initially approved canagliflozin in 2013. It is currently indicated:[Invokana package insert;1a]

• as an adjunct to diet and exercise to improve glycemic control in adults with T2D;
• to reduce the risk of MACE (CV death, nonfatal myocardial infarction [MI] and nonfatal stroke) in adults with T2D and established cardiovascular disease (CVD); and
• to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, CV death and hospitalization for HF in adults with T2D and diabetic nephropathy with albuminuria greater than 300 mg per day.

Dapagliflozin was first approved by the FDA in 2014. It is currently indicated:[Farxiga package insert;1a]

• as an adjunct to diet and exercise to improve glycemic control in adults with T2D;
• to reduce the risk of hospitalization for HF in adults with T2D and either established CVD or multiple CV risk factors;
• to reduce the risk of CV death, hospitalization for HF and urgent HF visits in adults with HF; and
• to reduce the risk of sustained estimated glomerular filtration rate (eGFR) decline, ESKD, CV death and hospitalization for HF in adults with chronic kidney disease (CKD) at risk of progression.

Empagliflozin received initial FDA approval in 2014. It is currently indicated:[Jardiance package insert;1a]

• as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with T2D;
• to reduce the risk of CV death and hospitalization for HF in adults with HF; and
• to reduce the risk of CV death in adults with T2D and established CVD.

Ertugliflozin was initially approved by the FDA in 2017. It is currently indicated:[Steglatro package insert;1a]

• as an adjunct to diet and exercise to improve glycemic control in adults with T2D.

Sotagliflozin was initially approved by the FDA in 2023. It is currently indicated:[Inpefa package insert;1a]
to reduce the risk of CV death, hospitalization for HF, and urgent HF visit in adults with:

• HF or
• T2D, CKD and other CV risk factors.

Dosage and administration

Prior to initiating SGLT2 inhibitors, prescribing physicians should assess renal function and volume status. In patients with volume depletion, this should be corrected before initiating treatment.[Invokana package insert, Farxiga package insert, Jardiance package insert, Steglatro package insert, Inpefa package insert]

Canagliflozin

The recommended dosage of canagliflozin is 100 mg orally once daily, taken before the first meal of the day. For additional glycemic control, the dosage of canagliflozin may be increased to the maximum recommended dosage of 300 mg once daily. With renal impairment (an eGFR of 30 to < 60 mL/min/1.73 m²), the recommended dosage is 100 mg once daily. Canagliflozin is not recommended for patients with eGFR < 30 mL/min/1.73m². Patients with albuminuria greater than 300 mg per day taking canagliflozin may continue canagliflozin 100 mg once daily to reduce the risk of ESKD, doubling of serum creatinine, CV death and hospitalization for HF.[Invokana package insert;1a]

Canagliflozin is contraindicated in patients with a serious hypersensitivity reaction to the drug.[Invokana package insert;1a]

Dapagliflozin

To improve glycemic control, the recommended starting dose of dapagliflozin is 5 mg orally once daily, taken in the morning, with or without food. In patients tolerating dapagliflozin 5 mg once daily who require additional glycemic control, the dose can be increased to 10 mg once daily. To reduce the risk of hospitalization for HF in patients with T2D and established CVD or multiple CV risk factors, the recommended dose of dapagliflozin is 10 mg orally once daily. In patients with T2D and eGFR of < 45 mL/min/1.73 m², dapagliflozin is not recommended for glycemic control.[Farxiga package insert;1a]

Dapagliflozin is contraindicated in patients with a serious hypersensitivity reaction to the drug.[Farxiga package insert;1b]

Empagliflozin

The recommended dosage of empagliflozin for all indications in adult patients, and for glycemic control in pediatric patients (≥ 10 years old) is 10 mg orally once daily in the morning, taken with or without food. For additional glycemic control, the dosage of empagliflozin may be increased to 25 mg once daily in patients who are tolerating 10 mg once daily. Use for glycemic control is not recommended in patients with an eGFR of < 30 mL/min/1.73 m².[Jardiance package insert;1a]

Empagliflozin is contraindicated in patients with a hypersensitivity to empagliflozin or any of the components of the drug, and patients on dialysis.[Jardiance package insert;1a]

Ertugliflozin

The recommended starting dose of ertugliflozin is 5 mg once daily, taken in the morning, with or without food. For additional glycemic control, the dose may be increased to 15 mg once daily in patients tolerating ertugliflozin 5 mg. Use of ertugliflozin is not recommended in patients with an eGFR of < 45 mL/min/1.73 m².[Steglatro package insert;1a]

Ertugliflozin is contraindicated in patients with a hypersensitivity to ertugliflozin or any of the components of the drug, and patients on dialysis.[Steglatro package insert;1a]

Sotagliflozin

The recommended starting dose of sotagliflozin is 200 mg orally once daily not more than 1 hour before the first meal of the day. After at least 2 weeks, the dose should be uptitrated to 400 mg orally once daily as tolerated. If necessary, the dose should be downtitrated to 200 mg.[Inpefa package insert;2a]

Sotagliflozin is contraindicated in patients with a history of serious hypersensitivity reaction to the drug.[Inpefa package insert;1a]

Guideline recommendations

The 2023 American Diabetes Association (ADA) Standards of Care in Diabetes practice guidelines contain the following recommendations on the use of SGLT2 inhibitors for cardiorenal risk reduction:[ElSayed NH, et al. Diabetes Care. 2023;S149b]

• In patients with T2D, and atherosclerotic CVD (ASCVD) or indicators of high ASCVD risk (≥ 55 years of age with 2 or more additional risk factors including obesity, hypertension, smoking, dyslipidemia or albuminuria), glucagon-like peptide-1 receptor agonists (GLP-1 RA) with proven CVD benefit or SGLT2 inhibitors with proven CVD benefit should be added to comprehensive CV risk management; if the glycated hemoglobin (A1C) is above target after the initiation of GLP-1 RA, the addition of SGLT2 inhibitors with proven CVD benefit should be considered.
• In patients with T2D, and current or prior symptoms of HF with documented HF with reduced ejection fraction or HF with preserved ejection fraction, SGLT2 inhibitors with proven HF benefit should be added to comprehensive CV risk management.
• In patients with T2D, and CKD with eGFR ≥ 20 mL/min/1.73 m², SGLT2 inhibitors with primary evidence of reducing CKD progression should be added to maximally tolerated dose of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers; once initiated, the treatment with SGLT2 inhibitors should be continued until the initiation of dialysis or transplantation.

The 2022 American College of Cardiology (ACC) and American Heart Association (AHA) Guideline for the Management of Heart Failure contains the following recommendations on the use of SGLT2 inhibitors:[Heidenreich PA, et al. J Am Coll Cardiol. 2022;e307-e308]

• In patients with symptomatic chronic HF with reduced ejection fraction (HFrEF), SGLT2 inhibitors are recommended to reduce hospitalization for HF and CV mortality, irrespective of the presence of type 2 diabetes (Class 1 Recommendation).
• In patients with HF with mildly reduced ejection fraction (HFmrEF), SGLT2 inhibitors can be beneficial in decreasing HF hospitalizations and CV mortality (Class 2a Recommendation).
• In patients with HF with preserved ejection fraction (HFpEF), SGLT2 inhibitors can be beneficial in decreasing HF hospitalizations and CV mortality (Class 2a Recommendation).

Efficacy

The efficacy and safety of SGLT2 inhibitors have been assessed in numerous large randomized controlled trials (RCTs). Broadly, these trials can be categorized into three groups based on the types of primary efficacy endpoint(s) assessed: glycemic outcomes trials, cardiovascular (CV) outcomes trials (including HF management trials) and renal outcomes trials. In the following sections, we provide a brief overview of these trials and their results for each of the five approved SGLT2 inhibitors, starting with the glycemic control trials and discussing cardiorenal outcome trials after.

Canagliflozin – Glycemic Control Trials

Twelve double-blind RCTs evaluated the efficacy of canagliflozin for glycemic control.[Invokana package insert;26a] Nine of these trials were placebo-controlled, with one assessing the efficacy of canagliflozin as monotherapy and six as an add-on to metformin; sulfonylurea; metformin and sulfonylurea; metformin and sitagliptin; metformin and pioglitazone; and insulin. The two remaining placebo-controlled trials tested the efficacy of canagliflozin monotherapy in special patient populations: older adults (55 to 80 years old) and patients with moderate renal impairment. Three trials of canagliflozin were active comparator-controlled, including a comparison to glimepiride (a sulfonylurea) as an add-on to metformin therapy, a comparison to sitagliptin as an add-on to metformin and sulfonylurea, and a comparison of canagliflozin in combination with extended-release metformin (metformin XR) vs. either agent alone as initial therapy. In all of these trials, canagliflozin demonstrated superiority to the placebo and noninferiority to glimepiride and sitagliptin with respect to glycemic control outcomes (see Table 1).

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Dapagliflozin – Glycemic Control Trials

Thirteen double-blind RCTs, including both placebo- and comparator-controlled studies assessed the efficacy of dapagliflozin for glycemic control.[Farxiga package insert;8a] Dapagliflozin was compared to placebo in nine trials, including three trials as monotherapy (one in patients with moderate renal impairment) and in six trials as an add-on to metformin, a sulfonylurea, metformin and a sulfonylurea, pioglitazone, sitagliptin, and insulin. Four trials compared dapagliflozin vs. an active comparator: two trials of initial combination therapy with metformin XR (vs. dapagliflozin and metformin XR alone), one trial in combination with exenatide XR as an add-on to metformin (vs. dapagliflozin and exenatide XR only as an add-on to metformin), and one trial against glipizide as an add-on to metformin. Dapagliflozin was superior to the placebo, superior in combination with metformin XR to either agent alone and in combination with exenatide XR to either drug separately, and noninferior to glipizide (Table 2).

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Empagliflozin – Glycemic Control Trials

Eleven double-blind RCTs assessed the glycemic control efficacy of empagliflozin.[Jardiance package insert;20a] Of the nine placebo-controlled trials, three tested its efficacy as monotherapy: one in the general adult population of patients with T2D and two in special populations — one in patients with renal impairment and one in pediatric patients 12 to 17 years of age. The remaining six placebo-controlled trials evaluated empagliflozin as an add-on to existing agents (metformin, metformin and sulfonylurea), or in combination with other agents (linagliptin, pioglitazone, insulin) with or without other antihyperglycemic medications. Empagliflozin was also tested in two active-controlled trials: one in which a combination of empagliflozin with metformin was compared to either agent alone as initial therapy, and one in which empagliflozin was tested against glimepiride (both in combination with metformin). Empagliflozin demonstrated superiority to the placebo in all trials, as well as noninferiority to glimepiride and superiority, in combination with metformin, to either agent alone (Table 3).

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Ertugliflozin – Glycemic Control Trials

The glycemic control efficacy of ertugliflozin was evaluated in nine double-blind RCTs: seven placebo-controlled and two active-comparator-controlled trials.[Steglatro package insert;15a] Two placebo-controlled trials assessed the efficacy of ertugliflozin monotherapy: one in the general population of adult patients with T2D and one in patients with moderate renal impairment. The remaining five placebo-controlled trials assessed ertugliflozin as an add-on combination therapy with metformin, metformin and sitagliptin, insulin (with or without metformin), and metformin and sulfonylurea, and as initial combination therapy with sitagliptin. The two active-controlled trials included a comparison with glimepiride as an add-on to metformin and a comparison of ertugliflozin in combination with sitagliptin versus either agent alone. Ertugliflozin was superior to the placebo in all placebo-controlled trials, except in the trial in patients with moderate renal impairment. It was noninferior to glimepiride at the 15 mg dose, but not the 5 mg dose. Finally, the combination of ertugliflozin and sitagliptin was superior to either agent alone (Table 4).

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Canagliflozin – CV and Renal Outcome Trials

Two large double-blind, placebo-controlled RCTs, CANVAS and CANVAS-R, assessed the efficacy of canagliflozin in preventing major adverse cardiovascular events (MACE) in patients with T2D.[Invokana package insert;10a] Both trials included patients age ≥ 30 years with established coronary artery disease, cerebrovascular disease or peripheral artery disease or age ≥ 50 years with at least two  risk factors for CVD. The primary outcome — a composite of CV death, nonfatal MI and nonfatal stroke — occurred significantly less often in patients who received canagliflozin compared with  those who received placebo (Table 5).

CREDENCE, also a double-blind, placebo-controlled RCT, tested the efficacy of canagliflozin for cardiorenal protection in patients with T2D, an eGFR of ≥ 30 to < 90 mL/min/1.73 m², and albuminuria (urine albumin/creatinine ratio of ˃ 300 to ≤ 5,000 mg/g). All patients were receiving maximally tolerated daily doses of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). Significantly fewer patients in the canagliflozin group experienced the primary endpoint (a composite of endpoint of ESKD, doubling of serum creatinine, and renal or CV death) compared to those in the placebo group (Table 5).

Dapagliflozin – CV, HF, and Renal Outcome Trials

The CV risk reduction efficacy of dapagliflozin was evaluated in DECLARE, a double-blind, placebo-controlled RCT that enrolled patients with T2D and either established CVD or age ≥ 55/60 years (men/women) with at least one additional CV risk factor (dyslipidemia, hypertension or current tobacco use).[Farxiga package insert;35a] The primary endpoints were a composite of hospitalization for HF or CV death and a composite of CV death, MI or ischemic stroke. While dapagliflozin did not significantly reduce the risk for MACE, it did significantly lower the risk for hospitalization for HF or CV death (Table 5).

The efficacy of dapagliflozin for the management of HF was assessed in two double-blind, placebo-controlled RCTs, DAPA-HF and DELIVER.[Farxiga package insert;41a] The DAPA-HF trial enrolled patients with HFrEF, ie, a left ventricular ejection fraction (LVEF) of ≤ 40%, while the DELIVER trial enrolled patients with HFmrEF or HFpEF, ie, a LVEF of > 40%. Notably, neither trial required T2D as an inclusion criterion. The shared primary endpoint was a composite of hospitalization for HF, CV death (including and excluding death of undetermined cause in DAPA-HF and DELIVER, respectively) or urgent HF visit. Dapagliflozin significantly reduced the primary endpoint event rate in both DAPA-HF and DELIVER (Table 5).

DAPA-CKD, a double-blind, placebo-controlled RCT in patients with CKD (defined as an eGFR of 25 to 75 mL/min/1.73 m²) and albuminuria (albumin/creatinine ratio of 200 to 5,000 mg/g) who were on a maximallytolerated ACEi or ARB tested the renoprotective efficacy of dapagliflozin.[Farxiga package insert;38a] The event rate for the primary efficacy endpoint — a composite of ≥ 50% sustained eGFR decline, ESKD, CV death or renal death — was significantly reduced in the dapagliflozin group compared with the placebo group (Table 5).

Empagliflozin – CV and HF Outcome Trials

The CV risk reduction efficacy of empagliflozin was evaluated in EMPA-REG OUTCOME, a double-blind, placebo-controlled RCT that enrolled patients with T2D and established CVD.[Jardiance package insert;31a] The primary efficacy outcome was the first occurrence of MACE (defined as CV death, nonfatal MI or nonfatal stroke). Empagliflozin significantly reduced the number of MACE events compared with placebo (Table 5).

Empagliflozin for the management of HF was tested in two double-blind, placebo-controlled RCTs, EMPEROR-Reduced and EMPEROR-Preserved.[Jardiance package insert;34a] As the trial names suggest, EMPEROR-Reduced and EMPEROR-Preserved were conducted in patients with HFrEF (LVEF ≤ 40%) and HFpEF (LVEF > 40%), respectively. Neither trial required T2D for enrollment. The primary endpoint in both trials was a composite of CV death or hospitalization for HF. Compared with placebo, empagliflozin resulted in a significantly lower rate of primary endpoint events (Table 5).

Ertugliflozin – CV Outcome Trial

Ertugliflozin efficacy for the prevention of adverse CV outcomes was tested in VERTIS-CV, a large, double-blind, randomized, placebo-controlled trial.[Steglatro package insert;21a] Ertugliflozin failed to demonstrate superiority to the placebo in this trial, with primary outcome events (first occurrence of CV death, nonfatal MI, or nonfatal stroke) occurring at statistically equivalent rates in the ertugliflozin and placebo groups (Table 5).

Sotagliflozin – HF Outcome Trials

The efficacy of sotagliflozin for the management of HF was tested in SOLOIST and SCORED, two double-blind, placebo-controlled RCTs.[Inpefa package insert;14a] The trial population in SOLOIST consisted of patients with T2D admitted to a hospital, HF unit, infusion center or emergency department for worsening HF. The study population in SCORED consisted of patients with T2D, CKD (defined as an eGFR of 25 to 60 mL/min/1.73 m²) and additional CV risk factors (eg, HF, obesity, dyslipidemia, hypertension, elevated cardiac and inflammatory biomarkers). The primary endpoint in both trials was a composite of CV death, hospitalization for HF and urgent HF visit. In both SOLOIST and SCORED, sotagliflozin significantly reduced the primary endpoint event rate compared with placebo (Table 5).

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Safety

Experience in clinical trials and “real world” clinical practice has confirmed the generally good safety profile of SGLT2 inhibitors.[Nelinson DS, et al. J Osteopath Med. 2021;4b][Mascolo A, et al. Front Cardiovasc Med. 2022;2b] The spectrum of adverse events (AEs) reported for SGLT2 inhibitors includes both those common to all class members (eg, genital infections) and those reported in only some agents (eg, increased frequency of lower limb amputations observed with canagliflozin). AEs of note and the frequency with which they were observed in clinical trials of each SGLT2 inhibitor are shown in Table 6 below.

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During the early clinical trials of SGLT2 inhibitors, safety concerns emerged with regard to several AEs, including urinary tract infections (UTIs), diabetic ketoacidosis (DKA), bone fracture and lower limb amputations; subsequently, most of these concerns either resolved or were proven less worrisome.[Nelinson DS, et al. J Osteopath Med. 2021;4b]A 2019 meta-analysis found no association between UTIs, DKA or bone fracture and SGLT2 inhibitors as a class, with the exception of dapagliflozin, which was associated with increased risk for UTI.[Donnan JR, et al. BMJ Open. 2019;1a] An increased risk for lower limb amputation associated with canagliflozin in the CANVAS clinical trial program led the FDA to require a black box warning in the prescribing information for this agent. However, the subsequent CREDENCE trial showed no increased risk, and the FDA removed the black box warning. In general, with rare exceptions, current evidence does not indicate an increased risk of AEs of concern with SGLT2 inhibitor use as compared to either the placebo or active controls.

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