Sodium-Glucose Transporter 2 (SGLT2) Inhibitors

Introduction

In healthy individuals, glucose is filtered at the glomerulus and virtually 100% is reabsorbed in the proximal tubule of the nephron. Two sodium glucose co-transporters (SGLTs), SGLT1 and SGLT2, play an important role in renal glucose reabsorption as part of the normal glucose regulation (Figure 11-1). SGLT1 and SGLT2 are expressed in the S2/S3 and S1 segments of the proximal tubule, respectively. Inhibition of the SGLTs interferes with glucose reabsorption and leads to increased glucose excretion. Maximum inhibition of SGLT2 decreases glucose reabsorption by approximately 50%, which suggests that both SGLTs have significant roles in glucose kinetics. SGLT1 also plays an important role in intestinal glucose and galactose absorption.

In addition to increasing glucose excretion, SGLT2 inhibition leads to caloric loss, modest weight reduction and small decreases in systolic blood pressure. Importantly, the increased urinary glucose excretion rate in SGLT2-treated patients with T2D diminishes as plasma glucose decreases, resulting in a very low incidence of hypoglycemia. These agents do not increase insulin secretion like the sulfonylureas and hypoglycemia primarily occurs if used with SFUs and or insulin. Given the beneficial effects, agents that inhibit SGLT2 are increasingly being used in combination with metformin and other agents, including dipeptidyl peptidase-4 inhibitors (DPP-4), glucogonlike peptide 1 (GLP-1) receptor agonists and insulin.

Unlike most other approved non-insulin antidiabetic drugs currently indicated for the treatment of type 2 diabetes (T2D), the direct glucose-lowering effect of SGLT2 inhibitors does not depend on augmentation of endogenous insulin secretion or improvement of insulin sensitivity. It does, however, depend on the ability of the kidney to filter glucose, which in turn is correlated to both the prevailing plasma glucose level and the glomerular filtration rate. Therefore, the glucose-lowering effect of SGLT2 inhibition may be expected to wane with diminished renal function and the prescribing guidelines reflect this issue. The American Diabetes Association (ADA) guidelines state that, in patients with T2D and atherosclerotic cardiovascular disease (ASCVD), heart failure (HF) and/or chronic kidney disease (CKD), SGLT2 inhibitors with proven benefit in these conditions should be used to reduce the risk of ASCVD events, hospitalization for HF and progression of CKD. This use of SGLT2 inhibitors is recommended regardless of baseline glycosylated hemoglobin (A1C), individualized A1C target and metformin use.

Canagliflozin (Invokana)

Canagliflozin is an SGLT2 inhibitor indicated:

• As an adjunct to diet and exercise to improve glycemic control in adults with T2D.
• To reduce the risk of major adverse CV events in adults with T2D and established cardiovascular disease (CVD).
• To reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, CV death and hospitalization for heart failure (HF) in adults with T2D and diabetic nephropathy with albuminuria.

Canagliflozin is not for treatment of type 1 diabetes (T1D) or diabetic ketoacidosis.

Canagliflozin exhibits dose-proportional pharmacokinetics. Following once-daily administration of 100 mg and 300 mg doses, steady-state plasma concentrations of canagliflozin are attained in 4 to 5 days. Following oral administration, C_max of canagliflozin is reached within 1 to 2 hours and the absolute oral bioavailability of canagliflozin is ~65%. Canagliflozin is extensively (99%) bound to plasma proteins (mainly albumin) and is metabolized to inactive glucuronide metabolites. In healthy adults, approximately 33% of an orally-administered dose is excreted in urine, most as metabolites, while 60% is excreted in feces. The elimination half-life canagliflozin is ~12 hours.

Efficacy

The efficacy and safety of canagliflozin were assessed in numerous phase 3 studies in which canagliflozin was used as monotherapy, and as add-on to metformin (MET), sulfonylurea (SFU), MET/pioglitazone, MET/SFU, or insulin (with or without other antihyperglycemic agents). Some trials were performed in special populations: older adults (55 to 80 years of age), patients with moderate renal dysfunctions and those with or at high risk of CV disease. The efficacy of canagliflozin was compared with a DPP-4 inhibitor (sitagliptin) and an SFU (glimepiride). Table 11-1 provides an overview of the designs of these studies.

The primary efficacy end point for these phase 3 studies was the percent change in A1C from baseline to the end of the study. Treatment with canagliflozin produced clinically and statistically significant improvements in A1C compared with placebo. Reductions in A1C were observed across subgroups including age, gender, race and baseline BMI. As shown in Table 11-2, canagliflozin was effective in reducing A1C in a broad range of subjects, both as monotherapy and in dual or triple combinations. In each of the placebo-controlled studies/substudies, both dosages of canagliflozin were significantly superior to placebo in lowering A1C. In the active-comparator trials, canagliflozin was shown to be noninferior to glimepiride and resulted in significant reduction in A1C compared with sitagliptin.

Secondary end points included changes from baseline to the end of the study in fasting plasma glucose (FPG) and 2-hour postprandial glucose (PPG), proportion of patients achieving an A1C target (eg, <7.0%) at the end of the study, and percent change from baseline to the end of the study in body weight, systolic blood pressure (SBP) and fasting plasma lipids. In the placebo-controlled studies, the proportion of patients reaching the A1C target of <7.0% was significantly greater in the canagliflozin groups compared with the placebo group and the difference relative to placebo was statistically significant for the canagliflozin 100 mg and 300 mg groups across studies (Figure 11-2). The treatment effect with canagliflozin was larger with the 300-mg dose than with the 100-mg dose.

Across the placebo-controlled studies, both dosages of canagliflozin produced significant reductions in FPG (Figure 11-3) and noticeable changes from baseline in body weight, regardless of monotherapy or combination therapy (Figure 11-4). FPG and body weight reduction with canagliflozin 300 mg was greater than with the 100-mg dosage. Both doses of canagliflozin also consistently lowered SBP across the placebo-controlled phase 3 studies. Reductions in Diastolic blood pressure (DBP) were also observed with both canagliflozin dosages in each of the phase 3 studies.

Safety

The incidence of patients who experienced any adverse events (AE) during the phase 3 trials was generally similar across treatment groups (Table 11-2). The incidence of AEs considered related to study drug was higher in the canagliflozin 100 mg and 300 mg groups compared with the non-canagliflozin group. These differences largely reflected a higher incidence of AEs related to osmotic diuresis and a higher incidence of AEs related to female or male genital mycotic infections in the canagliflozin groups. The incidence of discontinuations due to AEs was higher in the canagliflozin groups relative to the non-canagliflozin group, with no notable difference in the incidence of serious AEs, serious AEs leading to discontinuation, or deaths. The incidence of subjects with serious AEs that were considered related to study drug was also low, with similar incidences in the combined canagliflozin and non-canagliflozin groups.

The incidence of specific AEs reported by ≥2% of patients in the four 26-week phase 3 placebo-controlled trials are shown in Table 11-3.

In pooled data from all phase 3 clinical trials, the incidence of hypoglycemia was low in both canagliflozin treatment arms and all non-canagliflozin treatments. However, in several trials, canagliflozin was administered as an add-on to other agents associated with hypoglycemia. A separate analysis was conducted based on patients in placebo-controlled trials that did not include such agents. In this pooled population, the incidence of hypoglycemic episodes was overall low, slightly higher in the canagliflozin 100-mg (3.8%) and 300-mg groups (4.3%) relative to the placebo group (2.2%). The event rates per subject-year exposure for the canagliflozin 100-mg and 300-mg groups were greater (0.22 and 0.18, respectively) relative to placebo group (0.10), and with no apparent dose-relationship. The incidence of severe hypoglycemia was low, with one subject in each canagliflozin group reported to have had a severe hypoglycemic episode.

Because canagliflozin increases urinary glucose excretion, it acts as an osmotic diuretic with an increase in urine output. In pooled safety results from placebo- and active-controlled trials, a dose-dependent increase in the incidence of volume depletion-related adverse events was observed in patients receiving canagliflozin (2.3% and 3.4% with 100 mg and 300 mg, respectively) compared with placebo (1.5%). Factors that increased the incidence of volume depletion-related adverse reactions were age greater than 75 years, use of loop diuretics, and moderate renal impairment (eGFR 30 to <60 mL/min/1.73 m²). None of the events were serious or led to discontinuation.

Cardiovascular Outcome Trial of Canagliflozin (CANVAS)

T2D is associated with an elevated risk for cardiovascular (CV) and renal disease; however, treatment with SGLT2 inhibitors, including canagliflozin, may reduce these risks. Two clinical trials, CANVAS and CANVAS-R, investigated the impact of canagliflozin on CV, kidney and safety outcomes in an integrated analysis.

Enrolled patients had T2D and were either ≥30 years of age with a history of symptomatic atherosclerotic CVD or ≥50 years of age with ≥2 risk factors for CVD. In CANVAS, enrolled patients were randomized 1:1:1 to receive 300 mg canagliflozin daily, 100 mg canagliflozin daily, or matching placebo. Patients in CANVAS-R were randomized 1:1 to 100 mg canagliflozin daily, with an optional increase to 300 mg at week 13, or placebo. In total, 10,142 patients were enrolled, with 9,734 completing the trial.

The primary endpoint of the trials was a composite of death from CV causes, nonfatal MI, or nonfatal stroke. Integrated analysis found that significantly fewer canagliflozin-treated patients had a primary outcome event compared to placebo (26.9 vs 31.5 patients per 1000 patient-years; HR = 0.86; P <0.001 for noninferiority; P = 0.02 for superiority; Figure 11-5-A). Statistical significance was not reached for the three individual components of the primary outcome—death from CV causes (Figure 11-5-B), nonfatal MI, or nonfatal stroke.

In terms of renal outcomes, progression of albuminuria occurred less frequently in canagliflozin-treated patients (89.4 vs 128.7 patients per 1000 patient-years; HR=0.73), as did the composite outcome of sustained 40% reduction in eGFR, the need for renal replacement therapy, or death from renal causes (5.5 vs 9.0 patients per 1,000 patient-years, HR=0.60), whereas regression of albuminuria occurred more frequently (293.4 vs 187.5 patients per 1,000 patient-years; HR=1.70) in the canagliflozin group. The CREDENCE trial (see the SGLT2 Inhibitors and Chronic Kidney Disease section below) specifically assessed the renal outcomes of canagliflozin.

Although serious adverse events were less common among canagliflozin-treated patients (104.3 vs 120.0 patients per 1,000 patient-years; HR=0.93), there was a higher risk for amputation of toes, feet, or legs with canagliflozin than with placebo (6.3 vs 3.4 patients per 1000 patient-years, HR=1.97). The rate of all fractures was also higher in the canagliflozin group compared to placebo (15.4 vs 11.9 patients per 1,000 patient-years; HR=1.26). Additionally, a trend towards greater risk for low-trauma fracture events was observed for canagliflozin-treated patients (11.6 vs 9.2 patients per 1,000 patient-years; HR=1.23). Previously reported adverse events of interest were observed with canagliflozin, including infections of male or female genitalia, volume depletion and diuresis.

Overall, the CANVAS trial program demonstrated that treatment with canagliflozin significantly lowered the risk of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke in patients with T2D and an increased risk of CVD, but also increased the risk for amputation and fracture. Subsequent analyses, including a large cohort study of more than 300,000 adults, have largely exonerated canagliflozin (see Selected Warning and Precautions with SGLT2 Inhibitors below). The substantial CVD benefits of canagliflozin justify its use in routine care.

Prescribing Canagliflozin

Canagliflozin is supplied as 100-mg or 300-mg tablets. The recommended dosing and administration of canagliflozin is as follows:

• For patients with an eGFR of 60 mL/min/1.73 m² or greater, the recommended starting dose is 100 mg once daily, taken before the first meal of the day.
• Dose can be increased to 300 mg once daily in patients tolerating canagliflozin 100 mg once daily who have an eGFR ≥60 mL/min/1.73 m² and require additional glycemic control.
• Canagliflozin is limited to 100 mg once daily in patients who have an eGFR of 30 to <60 mL/min/1.73 m².
• Canagliflozin should not be initiated in patients with an eGFR below 30 mL/min/1.73 m²; if eGFR falls below 30 mL/min/1.73 m² in patients with albuminuria greater than 300 mg/g who are already taking canagliflozin, a 100 mg once daily dose may be continued to reduce the risk of ESKD, serum creatinine doubling, CV death and hospitalization for HF.
• Canagliflozin is contraindicated in patients with a history of a serious hypersensitivity reaction to canagliflozin-containing products, or in patients on dialysis.

Dapagliflozin (Farxiga)

Dapagliflozin is an SGLT2 inhibitor indicated:

• 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 and hospitalization for HF in adults with HF with reduced ejection fraction (New York Heart Association [NYHA] class II-IV).
• To reduce the risk of sustained eGFR decline, ESKD, CV death and hospitalization for HF in adults with chronic kidney disease (CKD) at risk of progression.

Dapagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Increases in the amount of glucose excreted in the urine have been observed in healthy subjects and in patients with T2D following the administration of dapagliflozin. Dapagliflozin dose of 10 mg per day in patients with T2D for 12 weeks resulted in excretion of approximately 70 g of glucose (approximately 30 to 40 standard sugar cubes) in the urine per day at week 12. A near maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume. The mean plasma terminal half-life for dapagliflozin is approximately 12.9 hours following a single 10-mg oral dose.

Efficacy

Dapagliflozin has been studied as monotherapy and in combination with metformin, pioglitazone, glimepiride, sitagliptin (with or without metformin), or insulin (with or without other oral antidiabetic therapy). The efficacy of dapagliflozin was compared with an SFU (glipizide) added on to metformin. Dapagliflozin has also been studied in patients with T2D and moderate renal impairment.

Treatment with dapagliflozin as monotherapy and in combination with metformin, glimepiride, pioglitazone, sitagliptin, or insulin produced statistically significant improvements in mean change from baseline at week 24 in A1C compared with control (Table 11-4). Reductions in A1C were seen across subgroups including gender, age, race, duration of disease, and baseline BMI. In addition, the proportion of patients reaching the A1C target of <7.0% was significantly greater in the dapagliflozin groups compared with the placebo group (Figure 11-6). Both doses of dapagliflozin produced significant reductions in FPG (Figure 11-7) and noticeable changes from baseline in body weight (Figure 11-8).

A systematic literature review and network meta-analysis (NMA) of RCTs involving anti-diabetes treatments added to metformin were conducted, enrolling subjects with T2D inadequately controlled on metformin monotherapy. Comparators included dapagliflozin, DPP-4 inhibitors, TZDs, SFUs and GLP-1 analogues. Outcomes of interest were mean change from baseline A1C, weight, SBP and incidence of hypoglycemia. Compared with DPP-4 inhibitors, TZDs and SFUs, dapagliflozin offers similar A1C control after 1 year when added to metformin, with similar or reduced risk of hypoglycemia. The mean change in A1C from baseline was similar across comparators. Non-SFUs showed significantly lower risk of hypoglycemia relative to SFUs. Dapagliflozin had a significant effect on weight change: the relative difference was -2.74 kg (-5.35, -0.10) compared with DPP-4 inhibitors and -4.67 kg (-7.03, -2.35) compared with SFUs.

The mechanism of dapagliflozin depends on filtration of glucose at the glomerulus. With reduced renal function, dapagliflozin is expected to be less efficacious. Urinary glucose excretion is about 50% lower in patients with T2D treated with dapagliflozin having CKD stage 3 compared with patients with normal or mildly impaired renal function. In a study examining the efficacy and safety of dapagliflozin in patients with T2D and moderate renal impairment, it was found that dapagliflozin did not improve glycemic control in these patients, but did reduce weight and blood pressure.

Cardiovascular Outcome Trial of Dapagliflozin (DECLARE-TIMI 58)

The DECLARE–TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) trial evaluated the effects of dapagliflozin on CV and renal outcomes in patients with T2D and either established ASCVD or multiple risk factors for ASCVD. Key enrollment criteria included age ≥40 years, glycated hemoglobin ≥6.5% to <12.0% and creatinine clearance ≥60 ml/min/1.73 m². Eligible patients were included in a 4-to-8-week run-in period, where placebo was administered and blood and urine testing were performed. A total of 17,160 patients completed the run-in period and were then randomized 1:1 to receive dapagliflozin 10 mg daily or matching placebo. Of the randomized patients, 40.6% had established ASCVD and 59.4% had multiple risk factors for ASCVD. Use of other select glucose-lowering agents were permitted at the discretion of the treating physician.

The two primary efficacy endpoints of the trial were a composite of major adverse cardiovascular events (MACE) and a composite of CV death or hospitalization for heart failure (HHF). The first secondary endpoint was a renal composite outcome, defined as a sustained decrease of ≥40% in eGFR to <60 ml/min/1.73 m², new ESRD, or death from renal or CV causes. The other secondary endpoint was death from any cause. In-person follow-up was performed every 6 months for laboratory testing and assessment of clinical and safety events, with contact by telephone every 3 months between in-person visits. Patients were followed for a median of 4.2 years.

During the trial, dapagliflozin had favorable effects of several CV risk factors, including glycated hemoglobin, weight and systolic and diastolic blood pressure. In terms of the primary endpoint of MACE, dapagliflozin met the criterion for noninferiority (Figure 11-9-A; P <0.001) but was not superior to placebo (P = 0.17). As for the composite of CV death or HHF, dapagliflozin was superior to placebo (Figure 11-9-B; P = 0.005). Improvement in the composite of CV death or HHF with dapagliflozin was due to a lower rate of HHF (HR=0.73), since there was no difference between treatments in terms of CV death (HR=0.98). The benefit of dapagliflozin on the composite of CV death or HHF was similar between patients with established ASCVD (HR=0.83) and those with multiple risk factors for ASCVD (HR=0.84). The incidence of the renal composite outcome was lower in the dapagliflozin group compared to the placebo group (Figure 11-10-A; 4.3% vs 5.6%; HR=0.76), and there was no difference in the rate of death from any cause between treatment groups (Figure 11-10-B; 6.2% vs 6.6%; HR=0.93).

In terms of safety, fewer patients in the dapagliflozin group discontinued treatment during the trial, reported a serious adverse event, or had major hypoglycemia, acute kidney injury, or bladder cancer. Diabetic ketoacidosis was more common in the dapagliflozin group (0.3% vs 0.1%; HR=2.18; P = 0.02), as were genital infections that were serious or led to treatment discontinuation (0.9% vs 0.1%; HR=8.36; P <0.001). Of the patients who experienced diabetic ketoacidosis, more than 80% were using insulin at baseline.

In summary, DECLARE–TIMI 58 demonstrated that dapagliflozin was noninferior to placebo with respect to MACE; although dapagliflozin did not significantly lower the rate of MACE, it did result in a significantly lower rate of CV death or HHF compared to placebo.

In a separate publication, the relationship between baseline left ventricular ejection fraction (EF) and the benefit of dapagliflozin on reducing CV death and HHF was evaluated. Of the 17,160 patients randomized in DECLARE–TIMI 58, 3.9% had heart failure with reduced EF (HFrEF), 7.7% had HF without known reduced EF, and 88.4% had no history of HF at baseline. Dapagliflozin was found to reduce HHF in patients with and without HFrEF and reduced CV death and all-cause mortality in patients with HFrEF.

In a separate sub-analysis of the DECLARE–TIMI 58 trial, the two primary endpoints were assessed in a subgroup of 3,584 patients with prior MI. In this population of patients, 5.2% of dapagliflozin-treated patients and 17.8% of placebo-treated patients experienced MACE (HR=0.84; P = 0.039). This benefit was not observed in patients without prior MI (HR 1.00; P = 0.97), including in patients with established ASCVD but no history of MI. For the endpoint of CV death or HHF, treatment benefits with dapagliflozin were also observed in patients with prior MI: 8.6% for dapagliflozin and 10.5% for placebo (HR 0.81; P = 0.046). In patients without prior MI, corresponding rates for this endpoint were 3.9% vs 4.5% (HR 0.85; P = 0.055). Overall, this sub-analysis demonstrated the benefit of dapagliflozin in reducing CV risk in patients with T2D and prior MI.

Safety

Common adverse reactions associated with the use of dapagliflozin include female genital mycotic infections, nasopharyngitis, urinary tract infections, back pain, increased urinations, male genital mycotic infections (almost exclusively in uncircumcised males), nausea, influenza, dyslipidemia and constipation (Table 11-5). Patients with a history of genital mycotic infections were more likely to develop the condition when taking dapagliflozin. Elderly patients and patients with impaired renal function may be more susceptible to increases in serum creatinine and decreases eGFR after taking dapagliflozin.

Dapagliflozin causes an osmotic diuresis, which may lead to reductions in intravascular volume. As a result, symptomatic hypotension can occur after initiating dapagliflozin in patients with impaired renal function (eGFR <60 mL/min/1.73 m²), elderly patients, or patients on loop diuretics. Volume status should be assessed and corrected before initiating dapagliflozin in patients at risk, and monitored after starting therapy. Dapagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when these agents are used in combination with dapagliflozin. Adverse reactions related to volume depletion, including dehydration, hypovolemia, orthostatic hypotension, or hypotension, have been reported.

Prescribing Dapagliflozin

Dapagliflozin is available in 5 mg and 10 mg tablets, which are yellow, biconvex, round and film-coated:

• To improve glycemic control, the recommended starting dose is 5 mg once daily, taken in the morning, with or without food.
• Dose can be increased to 10 mg once daily in patients tolerating dapagliflozin 5 mg once daily who require additional glycemic control.
• Dapagliflozin is not recommended for glycemic control in patients with an eGFR <45 mL/min/1.73 m²; for the other indications, it may be initiated unless eGFR is below 25 mL/min/1.73 m².
• For indications other than improved glycemic control, the recommended starting dose is 10 mg once daily.
• If eGFR is <25 mL/min/1.73 m², initiation of dapagliflozin is not recommended; however, patients whose eGFR decreases below 25 mL/min/1.73 m² while on dapagliflozin may continue taking 10 mg daily to reduce the risk of further decline in kidney function and CV events.
• Dapagliflozin is contraindicated in patients with a history of a serious hypersensitivity reaction to dapagliflozin-containing products, or patients on dialysis.

Empagliflozin (Jardiance)

Empagliflozin is an SGLT2 inhibitor indicated:

• To reduce the risk of CV death and hospitalization for HF in adults with HF.
• To reduce the risk of CV death in adult patients with T2D and established CVD.
• As an adjunct to diet and exercise to improve glycemic control in adults with T2D.

Empagliflozin is the only SGLT2 inhibitor approved for use in patients with both types of HF: HF with reduced EF and HF with preserved EF. Empagliflozin blocks the reabsorption of glucose (blood sugar) by the kidney via inhibition of SGLT2, increases glucose excretion and lowers blood glucose levels in patients with diabetes who have elevated blood glucose levels.

Systemic exposure of empagliflozin increases in a dose-proportional manner in the therapeutic dose range. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state, which was consistent with empagliflozin half-life. Approximately 95.6% of the drug-related radioactivity is eliminated in feces (41.2%) or urine (54.4%) after administration of empagliflozin. Peak plasma concentrations of empagliflozin are reached at 1.5 hours postdose. The apparent terminal elimination half-life is estimated to be 12.4 hours.

Efficacy

In terms of glycemic control, empagliflozin has been studied as monotherapy and in combination with metformin, SFU, pioglitazone, linagliptin and insulin. It has also been studied in patients with T2D with mild or moderate renal impairment.

In patients with T2D, treatment with empagliflozin reduced A1C compared with placebo. The reduction in A1C for empagliflozin compared with placebo was observed across subgroups including gender, race, geographic region, baseline BMI and duration of disease (Table 11-6). The proportion of patients reaching the A1C target of <7.0% was significantly greater in the empagliflozin groups compared with the placebo group (Figure 11-11). Reductions in FPG and body weight were also observed with empagliflozin-treated patients compared with placebo (Figure 11-12 and Figure 11-13).

Empagliflozin was compared to glimepiride as add-on to metformin in patients with T2D in a large phase 3 trial. As add-on therapy to metformin, empagliflozin was shown to be noninferior to glimepiride at 52 and 104 weeks and superior to glimepiride at 104 weeks, in terms of reductions in A1C level. At week 104, adjusted mean difference in change from baseline in A1C with empagliflozin vs glimepiride was -0.11% (95% CI -0.19 to -0.02; P = 0.0153 for superiority).

The efficacy and safety of empagliflozin added to multiple daily injections of insulin in obese patients with T2D was examined in a 52-week trial. Patients inadequately controlled on insulin with or without metformin (mean A1C 8.3% [67 mmol/mol]; insulin dose 92 international units/day) were randomized and treated with once-daily empagliflozin 10 mg, empagliflozin 25 mg, or placebo. Adjusted mean ± SE changes from baseline in A1C at week 18 (primary endpoint) were greater for empagliflozin 10 mg and empagliflozin 25 mg vs placebo, respectively (both P <0.001). More patients attained A1C <7% (<53 mmol/mol) with empagliflozin (31% to 42%) vs placebo (21%; both P <0.01). At week 52, further reductions with insulin titration resulted in greater changes from baseline in A1C in the empagliflozin groups. Empagliflozin 10 mg and empagliflozin 25 mg significantly reduced insulin doses (-9 to -11 international units/day) and weight (-2.4 to -2.5 kg) vs placebo (all P <0.01) at week 52.

Safety

Common adverse events seen in clinical trials include urinary tract infection, genital mycotic infection, upper respiratory tract infection, increased urination, dyslipidemia, arthralgia and nausea (Table 11-7). Like dapagliflozin and canagliflozin, empagliflozin increases the risk for genital mycotic infections. Patients with a history of chronic or recurrent genital mycotic infections were more likely to develop the condition.

Empagliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. Empagliflozin may increase the risk of hypotension in patients at risk for volume contraction, particularly in patients with renal impairment, the elderly, in patients with low systolic blood pressure and in patients on diuretics. Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased when empagliflozin is used in combination with insulin secretagogues or insulin, a lower dose of which may be required to reduce the risk of hypoglycemia in these patients. Before initiating empagliflozin, volume contraction should be assessed and corrected if indicated; signs and symptoms of hypotension should be monitored.

Empagliflozin increases serum creatinine and decreases eGFR. The risk of impaired renal function with empagliflozin is increased in elderly patients and patients with moderate renal impairment. Renal function should be evaluated prior to initiating empagliflozin and periodically thereafter.

In clinical trials, adverse reactions related to volume depletion (e.g., BP ambulatory decreased, SBP decreased, dehydration, hypotension, hypovolemia, orthostatic hypotension and syncope) were reported by 0.3%, 0.5% and 0.3% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.

Cardiovascular Outcome Trial of Empagliflozin (EMPA-REG OUTCOME)

Type 2 diabetes is a major risk factor for CVD. Although antidiabetic drugs have the potential to reduce rates of CV events, this relationship has not yet been convincingly shown. The EMPA-REG-OUTCOME trial was a randomized, double-blind, placebo-controlled trial that examined the effect of once-daily empagliflozin, at either 10 mg or 25 mg, vs placebo on CV morbidity and mortality in adult patients with T2D and established CVD. Eligible patients entered a 2-week placebo run-in period in which background glucose-lowering therapy was unchanged, followed by randomization in a 1:1:1 ratio to receive either 10 mg or 25 mg of empagliflozin or placebo once daily. For the first 12 weeks after randomization, background glucose-lowering therapy remained unchanged unless intensification was required. After 12 weeks, investigators were encouraged to adjust glucose-lowering therapy to achieve glycemic control and to treat other CV risk factors to achieve the best standard of care, according to local guidelines.

The primary outcome was a composite of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke. The secondary outcome was a composite of the primary outcome plus hospitalization for unstable angina. In total, 7,020 patients from 42 countries were treated and included in the primary analysis.

Overall, the primary outcome occurred in a significantly lower percentage of patients in the empagliflozin group compared to the placebo group (Figure 11-14-A; hazard ratio [HR] 0.86; 95% CI, 0.74 to 0.99; P = 0.04 for superiority). Empagliflozin also resulted in a significantly lower risk of death from CV causes (Figure 11-14-B; HR, 0.62; 95% CI, 0.49 to 0.77; P <0.001), death from any cause (HR 0.68; 95% CI, 0.57 to 0.82, P <0.001), and hospitalization for HF (HR 0.65; 95% CI, 0.50 to 0.85; P = 0.002). For the secondary outcome, empagliflozin was noninferior to placebo (HR 0.89; 95% CI, 0.78 to 1.01; P <0.001 for noninferiority).

Safety was assessed based on adverse events that occurred during or within 7 days following the last dose of a study drug. The proportion of patients who had adverse events was similar between treatments and included the proportion of patients experiencing confirmed hypoglycemia, acute renal failure, diabetic ketoacidosis, thromboembolic events, bone fracture and events consistent with volume depletion. Genital mycotic infection was found to occur in a higher percentage of patients in the pooled empagliflozin group compared with placebo.

Overall, compared with placebo, the EMPA-REG-OUTCOME trial demonstrated that when added to standard of care, empagliflozin significantly lowered rates of the primary composite CV outcome and of death from any cause in patients with T2D at high risk for CV events. The results from this trial support the long-term use of empagliflozin and provide evidence for a reduction in CV risk.

Prescribing Empagliflozin

Empagliflozin is available in 10 mg and 25 mg tablets, which are yellow, biconvex, round and film-coated:

• The recommended starting dose is 10 mg once daily, taken in the morning, with or without food.
• Dose can be increased to 25 mg once daily in patients tolerating empagliflozin 10 mg once daily who require additional glycemic control.
• Insufficient data exist to provide dosing recommendations in patients with T2D and established CVD with an eGFR below 30 mL/min/1.73 m² and patients with HF and an eGFR <20 mL/min/1.73 m².
• Empagliflozin is contraindicated in patients with a history of a serious hypersensitivity reaction to empagliflozin-containing products, or in patients on dialysis.

Ertugliflozin (Steglatro)

Ertugliflozin is an SGLT2 inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D. By inhibiting SGLT2, ertugliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Ertugliflozin is also available in combination with sitagliptin as a once-daily fixed-dose combination tablet, Steglujan.

Efficacy

The safety and efficacy of ertugliflozin were assessed in seven randomized, double-blind, placebo- or active comparator-controlled clinical studies: VERTIS MONO, VERTIS MET, VERTIS SITA, VERTIS SITA2, VERTIS SU, VERTIS FACTORIAL and VERTIS RENAL. These trials enrolled a total of 4863 patients with T2D and studied ertugliflozin as monotherapy and in combination with antidiabetic medications, including MET, DPP-4 inhibitors and SFUs. A summary of changes from baseline in A1C from these studies is shown in Table 11-8.

VERTIS MONO enrolled patents with T2D inadequately controlled (A1C 7% to 10.5%) on diet and exercise to receive placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg, administered once daily. At week 26, compared with placebo, ertugliflozin significantly reduced A1C (Table 11-8), increased the proportion of patients achieving A1C <7% (Figure 11-15), reduced FPG (Figure 11-16) and improved weight loss (Figure 11-17).

VERTIS MET evaluated the efficacy and safety of ertugliflozin in combination with MET. Patients with T2D inadequately controlled (A1C 7% to 10.5%) on MET monotherapy (≥1,500 mg/day for ≥8 weeks) were randomized to placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg administered once daily in addition to continuation of background MET therapy. At week 26, treatment with ertugliflozin significantly reduced A1C compared to placebo. Treatment with ertugliflozin also resulted in a greater proportion of patients achieving A1C <7%, reduced FPG, and improved weight loss compared to placebo.

The safety and efficacy of add-on combination therapy with MET and sitagliptin were assessed in VERTIS SITA2. A total of 463 patients with T2D inadequately controlled (A1C 7% to 10.5%) on MET (≥1,500 mg/day for ≥8 weeks) and sitagliptin 100 mg once daily were randomized to placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg. At week 26, compared with placebo, treatment with ertugliflozin significantly reduced A1C , resulted in a higher proportion of patients achieving A1C <7%, reduced FPG, and improved weight loss.

The efficacy and safety of ertugliflozin plus MET was compared to glimepiride plus MET in VERTIS SU. A total of 1326 patients with inadequately controlled T2D (A1C 7% to 9%) on MET monotherapy (≥1,500 mg/day for ≥8 weeks) were randomized to glimepiride, ertugliflozin 5 mg, or ertugliflozin 15 mg in addition to continuation of background MET therapy. The mean daily dose of glimepiride was 3.0 mg. After 52 weeks of treatment, ertugliflozin 15 mg was noninferior to glimepiride. Ertugliflozin 5 mg did not satisfy the criterion for noninferiority. Mean changes in body weight from baseline to week 52 were 0.6 kg, -2.6 kg, and -3.0 kg in the glimepiride, ertugliflozin 5 mg and ertugliflozin 15 mg groups, respectively.

VERTIS FACTORIAL evaluated the efficacy and safety of ertugliflozin 5 mg or 15 mg in combination with sitagliptin 100 mg compared to the individual components in patients with inadequately controlled T2D (A1C 7.5% to 11%) on MET monotherapy (≥1,500 mg/day for ≥8 weeks). Patients were randomized of one of five treatment groups: ertugliflozin 5 mg, ertugliflozin 15 mg, sitagliptin 100 mg, ertugliflozin 5 mg plus sitagliptin 100 mg, or ertugliflozin 15 mg plus sitagliptin 100 mg. At week 26, ertugliflozin 5 mg or 15 mg plus sitagliptin 100 mg significantly reduced A1C compared to ertugliflozin or sitagliptin alone. More patients in the ertugliflozin plus sitagliptin groups also achieved A1C <7% compared to the individual component groups.

The VERTIS SITA trial evaluated the efficacy and safety of initial combination therapy with ertugliflozin and sitagliptin. A total of 291 patients with T2D inadequately controlled (A1C 8% to 10.5%) on diet and exercise were randomized to placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg in combination with 100 mg sitagliptin once daily. At week 26, treatment with ertugliflozin in combination with sitagliptin significantly reduced A1C compared with sitagliptin and placebo. Ertugliflozin in combination with sitagliptin also resulted in a higher proportion of patients achieving A1C of <7%, reduced FPG, and improved weight loss compared with placebo.

Efficacy in Patients with Moderate Renal Impairment

The efficacy of ertugliflozin was assessed in VERTIS RENAL, which enrolled patients with T2D and moderate renal impairment (eGFR ≥30 to <60 mL/min/1.73 m²). Most patients were receiving background insulin (55.9%) and/or sulfonylurea (40.3%) therapy and approximately 50% had a history of heart disease or HF. Compared to placebo, ertugliflozin did not significantly reduce A1C from baseline to week 26 in this study.

Safety

The safety of ertugliflozin was evaluated in a pool of three 26-week, placebo-controlled trials (VERTIS MONO, VERTIS MET and VERTIS SITA2) in which ertugliflozin was used as monotherapy in one trial and as add-on therapy (with MET or with MET and sitagliptin) in the other two trials. Adverse reactions occurring more commonly with ertugliflozin than placebo and occurring in ≥2% of patients treated with either ertugliflozin 5 mg or 15 mg are shown in Table 11-9.

As with other SGLT2 inhibitors, ertugliflozin causes osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion, particularly in patients with impaired renal function (eGFR ≤60 mL/min/1.73 m²). In patients with moderate renal impairment, adverse reactions related to volume depletion were reported in 0%, 4.4%, and 1.9% of patients treated with placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively. SGLT2 inhibitors also increase serum creatinine and decrease eGFR. Patients with moderate renal impairment (eGFR 30 to <60 mL/min/1.73 m²) may be more susceptible to these changes. The incidence of renal-related adverse reactions was 0.6%, 2.5%, and 1.3% in patients treated with placebo, ertugliflozin 5 mg and ertugliflozin 15 mg, respectively. Renal function should be evaluated prior to initiating ertugliflozin and periodically thereafter.

Cardiovascular Outcomes with Ertugliflozin

The CV outcomes for ertugliflozin were investigated in VERTIS CV, a randomized, multicenter, double-blind trial that enrolled 8246 patients with T2D and established atherosclerotic CVD (coronary, cerebrovascular and peripheral). Eligible patients were randomized (1:1:1) to once daily ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo, along their background medication. The primary outcome was the time to first major adverse CV event (MACE; a composite of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke). Ertugliflozin demonstrated non-inferiority to placebo with respect to the primary outcome, with 11.9% of patients in the pooled ertugliflozin groups and 11.9% in the placebo group experiencing a MACE (HR 0.97; P <0.001 for non-inferiority). Ertugliflozin was also non-inferior for death from CV causes or hospitalization for HF (HR 0.88), death from CV causes (HR 0.92) and death from renal causes, renal replacement therapy, or doubling of the serum creatinine level (HR 0.81).

In an 18-week sub-study of VERTIS CV which assessed the safety and efficacy of ertugliflozin in 330 patients with T2D inadequately controlled by metformin and sulfonylurea, ertugliflozin was associated with greater decreases in A1C compared to placebo (differences in least squares [LS] mean: ertugliflozin 5 mg vs. placebo -0.66%; ertugliflozin 15 mg vs. placebo -0.75%; P <0.001 for all). Ertugliflozin was associated with greater improvements in body weight reduction and fasting plasma glucose, but did not significantly improve blood pressure. Another 18-week VERTIS CV sub-study assessed the safety and efficacy of ertugliflozin in 1065 patients with T2D managed by insulin, with or without metformin. Both ertugliflozin doses resulted reduced A1C more efficiently than placebo (including patients with or without metformin therapy). The difference in LS mean for ertugliflozin 5 mg vs. placebo was -0.58%, and that for ertugliflozin 15 mg vs. placebo -0.65% (P <0.001 for both). Ertugliflozin also provided greater reductions in body weight (placebo-adjusted LS mean change -1.6 kg and -1.9 kg for 5 mg and 15 mg; P <0.001 for both), systolic blood pressure and FPG. In the two VERTIS CV sub-studies, the safety profile was consistent with prior studies of ertugliflozin and other SGLT2 inhibitors.

Prescribing Ertugliflozin

• Ertugliflozin is supplied as film-coated tablets containing either 5 mg or 15 mg of ertugliflozin.
• The recommended starting dose is ertugliflozin 5 mg once daily, taken in the morning, with or without food. In patients tolerating ertugliflozin 5 mg once daily, the dose may be increased to a maximum recommended dose of 15 mg once daily if additional glycemic control is needed.
• Assess renal function prior to initiation of treatment and as clinically indicated thereafter.
• Initiation of therapy is not recommended in patients with an eGFR of <45 mL/minute/1.73 m².
• Ertugliflozin is contraindicated in patients with a history of serious hypersensitivity reaction to ertugliflozin-containing products, or in patients on dialysis.

SGLT2 Inhibitors and Heart Failure

Heart failure and T2D are commonly comorbid and pathophysiologically related; for example, increased aldosterone signaling may play a role in both diabetic cardiomyopathy and insulin resistance. In patients with T2D, the risk of developing HF (including both HF with reduced EF and HF with preserved EF) is doubled compared to the general population. The diabetic cardiomyopathy that is one of the causes of HF often occurs subclinically before T2D is even diagnosed. In addition to diabetic cardiomyopathy, the hyperglycemia, insulin resistance and insulinemia that characterize T2D also contribute to ischemic cardiomyopathy by promoting inflammation, dyslipidemia and endothelial dysfunction, which lead to coronary artery disease. Furthermore, patients with T2D have worse hospitalization rates, prognosis, and quality of life, along with an increased costs of care. There is a large unmet need for more treatment options for patients with T2D and HF and HF in general.

In addition to their benefits in glycemic control, multiple CV outcome trials have demonstrated that SGLT2 inhibitors also have marked cardioprotective effects, particularly in the reduction of hospitalization for HF (HHF). The first trial to investigate the CV outcomes of an SGLT2 inhibitor (empagliflozin) in patients with T2D was EMPA-REG OUTCOME. Reduction in HHF was one of the exploratory endpoints in this trial, and empagliflozin demonstrated superiority over placebo (HR = 0.65; P = 0.002). In the EMPEROR trial, empagliflozin also showed superiority over placebo with respect to CV death or HHF among patients with HF with preserved EF (13.8% with empagliflozin vs 17.1% with placebo; HR = 0.79; P <0.001). In the CANVAS trial, which investigated the CV outcomes of canagliflozin in patients with established atherosclerotic CVD or at high risk for CV events, canagliflozin was also shown to be superior to the placebo in preventing hospitalization for HF (HR = 0.67). In DECLARE-TIMI58, dapagliflozin demonstrated superiority to the placebo (HR = 0.83; P = 0.005) with respect to a composite of HHF and CV death, which marked the first inclusion of this outcome as a primary endpoint in a CV outcome trial of an SGLT inhibitor. Finally, in a prespecified analysis in the VERTIS CV trial, ertugliflozin also demonstrated a significantly lower risk of first HHF compared to the placebo. Based on the results from these trials, dapagliflozin, canagliflozin, and empagliflozin received FDA approval to reduce the risk of CV death and HHF.

SGLT2 inhibitors are the first class of glucose-lowering drugs that have been demonstrated to reduce the risk of HF in patients with T2D. While the mechanism by which this effect is mediated is not understood, proposed explanations include increased natriuresis, reduced blood pressure, renal protection and improved myocardial energetics, among others.

SGLT2 Inhibitors and Chronic Kidney Disease (CKD)

Chronic kidney disease is a condition characterized by a progressive loss of kidney function. It is defined as the long-term (3 months or more) presence of estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m² or of at least one marker of kidney damage. CKD is common condition, affecting ~15% of the general US population, 25-40% of patients with T2D and 20-67% of patients with HF. Patients with CKD are at increased risk of CVD, end-stage kidney disease (ESKD) and early death. Hyperglycemia-induced glomerular hyperfiltration is a key mechanism of the development of CKD in patients with T2D. Dysregulation of a number of metabolic, inflammatory and hemodynamic pathways further contributes to CKD progression. Until recently, few effective treatments to prevent CKD progression in patients with T2D existed. This changed when results from three large trials which demonstrated that, in addition to their cardioprotective effects, the SGLT2 inhibitors canagliflozin, dapagliflozin and empagliflozin also reduce the risk of CKD progression.

CREDENCE was a large, double-blind trial of canagliflozin in patients with T2D and nephropathy. Inclusion criteria included CKD (defined in the study as an eGFR of 30-<90 mL/min/1.73 m²) and albuminuria (defined as an urinary albumin-to-creatinine ratio of >300 to 5000). The median urinary albumin-to-creatinine ratio was 927. Canagliflozin was shown to be superior to the placebo in reducing the composite of ESKD, a doubling of serum creatinine level, or death from renal or CV causes (the primary outcome; HR = 0.70; P = 0.00001; see Figure 11-18-A), the renal-specific composite of ESKD, a doubling of serum creatinine level, or death from renal causes (a prespecified secondary outcome; HR = 0.66; P <0.001; see Figure 11-18-B), and the relative risk of ESKD (a prespecified secondary outcome; HR = 0.68; P = 0.002).

DAPA-CKD was another large, double-blind trial that tested the efficacy of a SGLT2 inhibitor (dapagliflozin) in patients with CKD; however, the patient population was broader than in CREDENCE and included both patients with and without T2D. Dapagliflozin demonstrated superiority to the placebo in the primary outcome (composite of a sustained decline in the eGFR of at least 50%, ESKD, or death from renal or CV causes; HR = 0.61; P<0.001; see Figure 11-19-A) and in the prespecified renal composite outcome (eGFR of at least 50%, ESKD, or death from renal causes; HR = 0.56; P<0.001; see Figure 11-19-B). The beneficial effects of dapagliflozin were similar in patients with and without T2D.

Based on the results from CREDENCE and DAPA-CKD, the FDA approved canagliflozin for the treatment of patients with T2D and diabetic nephropathy with albuminuria, and dapagliflozin in patients with CKD, regardless of T2D. Empagliflozin demonstrated positive results in CKD in the EMPA-KIDNEY trial, which was stopped early following an interim assessment. However, the detailed results of EMPA-KIDNEY have not yet been published. SGLT2 inhibitors are believed to exert their renoprotective effects by counteracting SGLT2-mediated kidney hypertrophy and the downstream inflammation, fibrosis and tubulointerstitial damage in the kidneys.

Selected Warnings and Precautions With SGLT2 Inhibitors

The four FDA-approved SGLT2 inhibitors have the same basic mechanism of action: they inhibit SGLT2. As such, there are several safety concerns shared by this group of drugs, including hypotension, ketoacidosis, acute kidney injury and impairment in renal function, hypoglycemia with concomitant use of insulin and insulin secretagogues, genital mycotic infections, lower limb amputations and others. However, each SGLT2 inhibitor may have its own unique safety and risk profile. For example, canagliflozin is the only SGLT2 inhibitor with a boxed warning for lower limb amputation, due to it doubling the risk of amputation in patients with T2D.

Hypotension

The SGLT2 inhibitors cause intravascular volume contraction. Therefore, symptomatic hypotension may occur after initiating treatment with these agents, especially in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²), elderly patients (≥65 years), in patients with low systolic blood pressure and in patients on diuretics. Therefore, before initiating any SGLT2 inhibitor, volume status should be assessed and corrected if indicated. After initiating therapy, patients should be monitored for signs and symptoms of hypotension.

Ketoacidosis

Reports of ketoacidosis (including euglycemic ketoacidosis), a serious life-threatening condition requiring urgent hospitalization, have been identified in postmarketing surveillance in patients with T1D and T2D receiving SGLT2 inhibitors, including fatal cases. SGLT2 inhibitors are not indicated for the treatment of patients with T1D.

Patients treated with SGLT2 inhibitors who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, since ketoacidosis associated with SGLT2 inhibitors may be present even if blood glucose levels are <250 mg/dL. If ketoacidosis is suspected, treatment with SGLT2 inhibitors should be discontinued, the patient should be evaluated and prompt treatment for ketoacidosis should be initiated.

Acute Kidney Injury and Impairment in Renal Function

SGLT2 inhibitors causes intravascular volume contraction and can cause renal impairment. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving SGLT2 inhibitors; some reports involved patients younger than 65 years of age. SGLT2 inhibitors also increases serum creatinine and decreases eGFR. Patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m²) may be more susceptible to these changes. Renal function should be evaluated prior to initiating SGLT2 inhibitors and periodically thereafter. All SGLT2 inhibitors are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m².

Hypoglycemia with Concomitant Use of Insulin and Insulin Secretagogues

Insulin and insulin secretagogues are known to cause hypoglycemia. SGLT2 inhibitors may increase the risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with SGLT2 inhibitors.

Genital Mycotic Infections

SGLT2 inhibitors increases the risk for genital mycotic infections. Patients who have a history of genital mycotic infections or who are uncircumcised are more likely to develop genital mycotic infections.

Lower Limb Amputations

An approximately 2-fold increased risk for lower limb amputation has been observed in clinical studies with canagliflozin. However, subsequent data, including from a large cohort study which included more than 300,000 patients, has shown that the absolute risk is very low (equivalent to 1 additional amputation per 556 patients) and negligible compared to the benefit of canagliflozin use. A causal association between other SGLT2 inhibitors and lower limb amputation has not been definitively established.

Before initiating any SGLT2 inhibitor, factors that predispose patients to the need for amputation should be considered, including a history of prior amputation, peripheral vascular disease, neuropathy and diabetic foot ulcers. Patients receiving SGLT2 inhibitors should be monitored for signs and symptoms of infection, new pain or tenderness, or sores or ulcers involving the lower limbs. Treatment with SGLT2 inhibitors should be discontinued if these complications occur.