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Sodium-glucose co-transporter 2 (SGLT2) inhibitors

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Apr.09.2024

Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors

Summary

Sodium-glucose co-transporter 2 (SGLT2) inhibitors bind and inhibit SGLT2 which is responsible for reabsorbing glucose and sodium in the kidneys.
SGLT2 inhibitors, with or without metformin based on glycemic needs, are appropriate initial therapy for patients with type 2 diabetes mellitus (T2DM) with or at high risk for atherosclerotic cardiovascular disease (ASCVD)/indicators of high-risk, heart failure (HF), or chronic kidney disease (CKD).
In adults with T2DM and HF and/or CKD (with confirmed eGFR of 20 to 60 mL/minute per 1.73 m² and/or albuminuria), an SGLT2 inhibitor should be initiated as first-line therapy in order to minimize the progression of CKD, reduce cardiovascular (CV) events, and reduce hospitalizations for HF; however, the glycemic benefits of SGLT2 inhibitors are reduced at eGFR less than 45 mL/minute per 1.73 m².
SGLT2 inhibitors are generally recommended as a second or third-line option as add-on to metformin therapy in patients with T2DM who do not have ASCVD/indicators of high-risk, HF, or CKD and who need to minimize hypoglycemia and/or promote weight loss.
SGLT2 inhibitors have a minimal risk of hypoglycemia and promote weight loss.
Canagliflozin is indicated for CV risk reduction for reducing major adverse cardiovascular events (MACE; e.g., CV death, non-fatal myocardial infarction, and non-fatal stroke) in adults with T2DM and established CV disease. Canagliflozin is also indicated to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, CV death, and hospitalization for HF in adults with T2DM and diabetic nephropathy with albuminuria.
Dapagliflozin is indicated to reduce the risk of hospitalization for HF in adults with T2DM and established CV disease or multiple CV risk factors. Dapagliflozin is also indicated to reduce the risk of CV death, hospitalization for HF, and urgent heart failure visits in adults with HF. In addition, dapagliflozin is indicated to reduce the risk of sustained eGFR decline, ESKD, CV death, and hospitalization for HF in adults with chronic kidney disease who are at risk of disease progression.
Empagliflozin is indicated to reduce the risk of CV death in adults with T2DM and established CV disease. Empagliflozin is also indicated to reduce the risk of CV death and hospitalization for HF in patients with HF. In addition, empagliflozin is indicated to reduce the risk of sustained eGFR decline, ESKD, CV death, and hospitalization in adults with chronic kidney disease who are at risk of disease progression.
An increased incidence of lower limb amputation has been observed in some clinical trials with SGLT2 inhibitors; however, controversy exists regarding whether there are class or drug-specific amputation risks based on varying study results.
Genitourinary infections are the most common adverse reactions associated with SGLT2 inhibitors.

Pharmacology/Mechanism of Action

Sodium-glucose co-transporter 2 (SGLT2) inhibitors bind and inhibit SGLT2, the transporter responsible for reabsorbing the majority of glucose filtered by the tubular lumen in the kidney. SGLT2 is expressed in the proximal renal tubules. Inhibiting SGLT2 causes a decrease in filtered glucose reabsorption and lowers the renal threshold for glucose (RTG), thereby increasing urinary glucose excretion and improving blood glucose control. These glucose-lowering effects are insulin-independent. SGLT2 inhibitor-induced glycosuria results in a daily caloric deficit of approximately 250 to 450 kcal resulting in a reported 2 to 3 kg weight loss over 12 weeks of therapy. This weight loss has been shown to plateau around 6 months; however, a loss of approximately 3 kg was maintained during long-term therapy. Through inhibition of glucose and sodium reabsorption, SGLT2 inhibitors exert osmotic diuretic and natriuretic effects reducing both systolic and diastolic blood pressure. Though the exact mechanism for the beneficial cardiorenal effects seen in clinical studies of SGLT2 inhibitor therapy is not fully known, it is believed to be related to glycosuria and natriuresis; these effects lead to uricosuria and reduction in plasma uric acid, and a reduction in plasma volume, lowering of cardiac preload, and reduced arterial pressure and stiffness possibly resulting in afterload reduction.[63835] [63838] [63849] [63850]

Therapeutic Use

Type 2 Diabetes Mellitus

SGLT2 inhibitors that have proven cardiovascular (CV) benefit are recommended for initial therapy (with or without metformin based on glycemic needs), in patients with type 2 diabetes mellitus (T2DM) and indicators of high-risk or established CV disease.
SGLT2 inhibitors with evidence of reducing heart failure (HF) and/or chronic kidney disease (CKD) progression are recommended for initial therapy (with or without metformin based on glycemic needs), in patients with T2DM and indicators of high-risk or established CKD or HF.
In adults with T2DM and HF and/or chronic kidney disease (CKD) (with confirmed eGFR of 20 to 60 mL/minute per 1.73 m² and/or albuminuria), an SGLT2 inhibitor should be initiated as first-line therapy in order to minimize the progression of CKD, reduce CV events, and reduce hospitalizations for HF; however, the glycemic benefits of SGLT2 inhibitors are reduced at eGFR less than 45 mL/minute per 1.73 m².[50321][64926][60608]
SGLT2 inhibitors are generally recommended as a second or third-line option as add-on to metformin therapy in patients with T2DM who do not have atherosclerotic cardiovascular disease (ASCVD)/indicators of ASCVD high-risk, HF, or CKD and who need to minimize hypoglycemia and/or promote weight loss.[50321][64926][60608]
These drugs are effective in lowering fasting plasma glucose and A1C.
SGLT2 inhibitors have been found to reduce systolic and diastolic blood pressure by 4 to 6 mmHg and 1 to 2 mmHg, respectively.[63835][63850]
SGLT2 inhibitor-induced glycosuria results in a daily caloric deficit of approximately 250 to 450 kcal resulting in a reported 2 to 3 kg weight loss over 12 weeks of therapy. This weight loss has been shown to plateau around 6 months; however, a loss of approximately 3 kg was maintained during long-term therapy.[63835][63838]
SGLT2 inhibitor therapy has been found to have cardiorenal protective effects, such as reductions in CV death, nonfatal myocardial infarction, nonfatal stroke, CV mortality, overall mortality, hospitalizations for HF, need for renal-replacement therapy, renal disease-related death, and albuminuria, as well as, stabilization of or delayed reductions in eGFR.[63835][63849][63850][64322][64324]
Canagliflozin is indicated to reduce the risk of major adverse cardiovascular events (MACE; e.g., CV death, non-fatal myocardial infarction, and non-fatal stroke) and to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, CV death, and hospitalization for HF in adults with T2DM and diabetic nephropathy with albuminuria. Empagliflozin is indicated to reduce the risk of CV death in patients with T2DM and established CV disease.[53972][57718][63835][63850][64322]
SGLT2 inhibitor therapy has been shown to reduce the incidence of heart failure (HF) in selected patients with T2DM. Dapagliflozin is indicated to reduce the risk of hospitalization for HF in adults with T2DM and established CV disease or multiple CV risk factors.[64926][61538][64322][64324]
Dose adjustment should be considered when canagliflozin is coadministered with an UDP-glucuronosyl transferase (UGT) inducer (e.g., rifampin, phenytoin, phenobarbital, ritonavir).[53972]
Specific recommendations for renal impairment and hepatic impairment are presented in the Dosage Comparisons Table. Per guidelines, SGLT2 inhibitors with proven kidney or cardiovascular benefit are recommended for patients with T2D, CKD, and an eGFR of 20 mL/minute/1.73 m² or greater. Once initiated, generally the SGLT2 inhibitor can be continued at lower levels of eGFR, unless not tolerated or kidney replacement therapy is needed. Glucose-lowering efficacy is reduced with SGLT2 inhibitors as eGFR declines, but kidney and cardiovascular benefits are preserved.[66645][68091]

Heart Failure with Reduced Ejection Fraction

SGLT2 inhibitors have been shown to significantly reduce the risk of hospitalization for HF or CV death in persons with T2D with or without ASCVD and to improve HF-related symptoms in persons with established HF regardless of LV ejection fraction, background glucose-lowering therapies, or HF therapies.[50321][64926][60608]
Empagliflozin is indicated to reduce the risk of cardiovascular death plus hospitalization for HF in adults with HF, while dapagliflozin is indicated to reduce the risk of CV death, hospitalization for HF, and urgent HF visits in adults with HF.[57718][56603]
Dapagliflozin and empagliflozin are recommended for patients with HF with reduced ejection fraction of 40% or less (NYHA class II to IV), with and without diabetes mellitus, along with guideline-directed medical therapy (GDMT) to reduce CV death and hospitalization with HF. Before therapy initiation, ensure that the eGFR is 30 mL/minute/1.73 m² or greater for dapagliflozin and eGFR is 20 mL/minute/1.73 m² or greater for empagliflozin.[67375]

Chronic Kidney Disease

Dapagliflozin is indicated to reduce the risk of sustained eGFR decline, end-stage kidney disease (ESKD), cardiovascular (CV) death, and hospitalization for HF in adults with chronic kidney disease at risk of disease progression.[66643]
Empagliflozin is indicated to reduce the risk of sustained eGFR decline, ESKD, CV death, and hospitalization in adults with chronic kidney disease who are at risk of disease progression.[57718]

Dosage Comparison of SGLT2 Inhibitors (Adults) in Type 2 Diabetes Mellitus

Drug	Dosing^a	Renal Impairment^b	Hepatic Impairment	Dose Adjustment for Drug Interactions
Bexagliflozin	20 mg once daily	eGFR 30 mL/minute/1.73 m² or greater: No dosage adjustment needed. eGFR less than 30 mL/minute/1.73 m²: Use is not recommended.	Mild or Moderate impairment: No dosage adjustment needed. Severe impairment: Use has not been studied; not recommended.	No dose adjustment needed.
Canagliflozin	100 to 300 mg once daily	eGFR 60 mL/minute/1.73 m² or greater: No dose adjustment needed. eGFR 30 to 59 mL/minute/1.73 m²: 100 mg once daily eGFR 20 to 29 mL/minute/1.73 m²: 100 mg once daily^h eGFR less than 20 mL/minute/1.73 m²: Do not initiate therapy.ⁱ	Mild or Moderate impairment: No dosage adjustment needed. Severe impairment: Use has not been studied; not recommended.	UGT Enzyme Inducers^c eGFR 60 mL/minute/1.73 m² or greater: Increase dose to 200 mg (taken as two 100 mg tablets) once daily ^{d, e, f} eGFR 45 to 59 mL/minute/1.73 m²: Increase dose to 200 mg (taken as two 100 mg tablets) once daily ^{d, e, g}
Dapagliflozin	5 to 10 mg once daily^j	eGFR 45 mL/minute/1.73 m² or more: No dosage adjustment needed. eGFR 25 to 44 mL/minute/1.73 m²: 10 mg once daily^h eGFR less than 25 mL/minute/1.73 m²: Do not initiate therapy.ⁱ	Mild or Moderate Impairment: No dosage adjustment needed. Severe impairment: Not studied; risk/benefit of use should be individually assessed.	No dosage adjustment needed.
Empagliflozin	10 to 25 mg once daily^k	eGFR 30 mL/minute/1.73 m² or greater: No dosage adjustment needed. eGFR 20 to 29 mL/minute/1.73 m²: 10 mg once daily^h eGFR less than 20 mL/minute/1.73 m²: Do not initiate therapy.ⁱ	No dosage adjustment needed.	No dosage adjustment needed.
Ertugliflozin	5 to 15 mg once daily	eGFR 45 mL/minute/1.73 m² or greater: No dose adjustment needed. eGFR less than 45 mL/minute/1.73 m²: Use is not recommended.	Mild or Moderate impairment: No dosage adjustment needed. Severe impairment: Use has not been studied; not recommended.	No dosage adjustment needed.

^aCanagliflozin is to be taken in the morning before the first meal. Bexagliflozin, dapagliflozin, empagliflozin, and ertugliflozin are to be taken in the morning with or without food.

^bAn SGLT2 inhibitor with proven renal or CV benefit is recommended for patients with T2DM, CKD, and an eGFR of 20 mL/minute/1.73 m² or greater; once initiated the SGLT2 inhibitor can be continued at lower levels of eGFR unless not tolerated or kidney replacement therapy is initiated.

^cUDP-Glucuronosyl transferase (UGT) enzyme inducers.

^dExamples of medications that are potent UGT enzyme inducers are rifampin, phenytoin, phenobarbital, and ritonavir.

^ePatients currently tolerating canagliflozin 100 mg once daily and with an eGFR of 60 mL/minute/1.73 m² or greater.

^fIn patients tolerating canagliflozin 200 mg/day, who require additional glycemic control, the dose may be increased to 300 mg once daily.

^gIn patients taking canagliflozin 200 mg/day who require additional glycemic control, consider another antihyperglycemic agent.

^hNot recommended for glycemic control; however, guidelines recommend use in all patients with T2DM and CKD for CV and renal protection regardless of glycemia or presence of albuminuria.

ⁱMay continue if eGFR declines after initiation unless not tolerated or kidney replacement therapy is initiated. Glucose-lowering efficacy is reduced, but kidney and cardiovascular benefits are preserved.

^jThe dapagliflozin dose for reduction of the risk of hospitalization for HF in adults with T2DM and established CV disease, multiple CV risk factors, or HF with reduced ejection fraction is 10 mg once daily.

^kThe empagliflozin dose for reduction of the risk of cardiovascular death plus hospitalization for HF in adults with HF with reduced ejection fraction is 10 mg once daily. There are insufficient data to support dosing recommendations for initiation of therapy in patients with eGFR less than 20 mL/minute/1.73 m² and HF with reduced ejection fraction.

Comparative Efficacy

Sodium-glucose co-transport 2 (SGLT2) inhibitors are reported to provide a mean A1C reduction of 0.7% (range: 0.4% to 1.16%) from baseline over study durations ranging from 12 to 78 weeks.[63835][63838][63853]
Monotherapy with canagliflozin 300 mg was associated with greater reductions in A1C compared to dapagliflozin and empagliflozin; however, differences between SGLT2 inhibitors were smaller with metformin combination therapy.[63851][63852]
In clinical studies involving adult patients with type 2 diabetes mellitus (T2DM) and history or high risk of cardiovascular events, canagliflozin and empagliflozin have been reported to significantly reduce the risk of the composite outcome of cardiovascular (CV) death, nonfatal myocardial infarction (MI), or nonfatal stroke. Empagliflozin was also found to reduce the risk of death from any cause and hospitalization for heart failure. Canagliflozin reduced the progression to albuminuria and composite outcome of sustained 40% reduction in eGFR, need for renal-replacement therapy or death from renal causes. Dapagliflozin has been shown to reduce the incidence of hospitalization for heart failure.[51525][61538][64324]
Canagliflozin 100 mg significantly reduced the risk of the primary composite endpoint of time to first occurrence of end stage kidney disease (ESKD) (defined as an eGFR less than 15 mL/minute/1.73 m², initiation of chronic dialysis or renal transplant), doubling of serum creatinine, and renal or CV death.[53972][64322]

SGLT2 Inhibitor Comparative Efficacy Trials

Citation	Design/Regimen	Results	Conclusion
Comparative Efficacy
Zaccardi F. Diabetes Obes Metab. 2016;18:783-94.[63851]	Systematic review and network meta-analysis of 38 trials to compare the efficacy and safety of SGLT2 inhibitors in the treatment of adults patients with T2DM.	Compared to other SGLT2 inhibitors at any dose, canagliflozin 300 mg had greater mean Reduction in A1C Reduction in FPG Decrease in SBP Increase in LDL cholesterol Canagliflozin 300 mg greater reduction in A1C and FPG compared to highest doses of dapagliflozin and empagliflozin; 10 mg and 25 mg, respectively. No difference in A1C reduction between dapagliflozin 10 mg and empagliflozin 25 mg. No difference in body weight reductions among canagliflozin 300 mg, dapagliflozin 10 mg and empagliflozin 25 mg. Similar incidence of genital infections for all SGLT2 inhibitors. Canagliflozin 100 mg and 300 mg were associated with a significantly increased risk of hypoglycemia compared to placebo, dapagliflozin 10 mg and empagliflozin 10 mg. Dapagliflozin 10 mg had an increased risk of urinary tract infections compared to placebo and empagliflozin 10 mg.	Canagliflozin 300 mg was found to offer greater reductions in A1C, FPG, and SBP compared to other SGLT2 inhibitors. Canagliflozin was found to increase levels of LDL cholesterol. All SGLT2 inhibitors had similar rates of genital infections.
Shyangdan DS, et al. BMJ Open. 2016;6:009417. [63852]	Systematic review and network meta-analysis of 13 trials (minimum study duration of 24 weeks) to compare the efficacy and safety of monotherapy and combination therapy with sodium-glucose cotransporter-2 (SGLT2) inhibitors in the treatment of adults patients with T2DM.	Monotherapy A1C less than 7% Compared to canagliflozin 300 mg, canagliflozin 100 mg (RR 0.72, 95% CI 0.59 to 0.87) and dapagliflozin 10 mg (RR 0.63, 95% CI 0.48 to 0.85) were 28% and 37%, respectively, less likely to achieve an A1C less than 7%. No significant difference between canagliflozin 300 mg and empagliflozin 10 mg or 25 mg. Reduction in A1C Greatest reduction in A1C occurred with canagliflozin 300 mg. Compared to Canagliflozin 300 mg Canagliflozin 100 mg MD 0.2 (95% CI, 0.05 to 0.36) Dapagliflozin 10 mg MD 0.64 (95%CI, 0.45 to 0.83) Empagliflozin 10 mg MD 0.49 (95% CI, 0.29 to 0.69) Empagliflozin 25 mg MD 0.37 (95% CI, 0.16 to 0.58) Weight Reduction Canagliflozin had greater reductions in weight compared to other SGLT2 inhibitors; reached significance compared to empagliflozin 10 mg, empagliflozin 25 mg, and dapagliflozin 10 mg. SBP Reductions All SGLT2 inhibitors decreased SBP. Empagliflozin had significantly greater SBP reductions compared to canagliflozin 300 mg. Combination Therapy with Metformin Greater proportions of patients on empagliflozin 10 mg, empagliflozin 25 mg, and canagliflozin 300 mg achieved A1C less than 7% compared to dapagliflozin 10 mg. Reductions in A1C were greatest with canagliflozin 300 mg but only reached significance when compared to canagliflozin 100 mg.	SGLT2 inhibitors were found to be more effective than placebo in achieving A1C less than 7% and reducing A1C, weight and SBP when used alone or in combination with metformin. Canagliflozin 300 mg monotherapy was associated with greater reductions in A1C compared to other SGLT2 inhibitors. Differences among SGLT2 inhibitors were less in combination therapy.
Zinman B, et al. N Engl J Med. 2015;373:2117-28. [61538]	Randomized, double-blind, placebo-controlled trial (EMPA-REG OUTCOME trial, n = 7,020) to assess the effect of empagliflozin (n = 4,687) on cardiovascular morbidity and mortality versus placebo (n = 2,333), along with standard care, in adult patients with T2DM at high cardiovascular risk.	Composite of death from CV causes, nonfatal MI, or nonfatal stroke Empagliflozin vs. placebo: HR 0.86 (95% CI 0.74 to 0.99, p = 0.04) Death from any cause Empagliflozin vs. placebo: HR 0.68 (95% CI 0.57 to 0.82, p less than 0.001) Death from CV causes Empagliflozin vs. placebo: HR 0.62 (95% CI 0.49 to 0.77, p less than 0.001) Hospitalization for heart failure Empagliflozin vs. placebo: HR 0.65 (95% CI 0.5 to 0.85, p = 0.002) Adverse Reactions Incidence of genital infections was higher with ertagliflozin compared to placebo.	Empagliflozin significantly reduced risk of the composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke compared to placebo when added to standard care in adult patients with type 2 diabetes at high cardiovascular risk. Empagliflozin also significantly reduced death from any cause and hospitalization for heart failure. Genital infections occurred at a higher rate with empagliflozin compared to placebo.
Neal B, et al. N Engl J Med. 2017:377;644-57.[51525]	Integrated analysis of two randomized, double-blind, placebo-controlled trials (CANVAS and CANVAS-R trials, n = 10,142) to compare the effect of canagliflozin (n = 5,795) on cardiovascular, renal, safety outcomes outcomes versus placebo (n = 4,347) in adult patients with T2DM with a history or high risk of CV events.	Death from CV causes, nonfatal MI, or nonfatal stroke Canagliflozin vs. placebo: HR 0.86 (95% CI 0.75 to 0.97, p less than 0.001 for noninferiority and p = 0.02 for superiority) Death from any cause Canagliflozin vs. placebo: HR 0.68 (95% CI 0.74 to 1.01, NS) Death from CV causes Canagliflozin vs. placebo: HR 0.87 (95% CI 0.72 to 1.06, NS) Progression of albuminuria Canagliflozin vs. placebo: HR 0.73 (95% CI 0.67 to 0.79) Regression of albuminuria Canagliflozin vs. placebo: HR 1.7 (95% CI 1.51 to 1.91, NS) Sustained 40% reduction in eGFR, need for renal-replacement therapy or death from renal causes Canagliflozin vs. placebo: HR 0.6 (95% CI 0.47 to 0.77) Adverse Reactions Higher rate of amputation of toes, feet, or legs with canagliflozin vs. placebo; 6.3 vs. 3.4 per 1,000 patient years, p less than 0.001. [HR 1.97 (95% CI 1.41 to 2.75)] Higher rate of fractures with canagliflozin vs. placebo; 15.4 vs. 11.9 per 1,000 patient years, p = 0.02. [HR 1.26, (95% CI 0.99 to 1.52)] Photosensitivity, male genitalia infection, and mycotic genital infection in women (CANVAS only) were significantly higher with canagliflozin.	Patients in the canagliflozin group had a significantly lower risk of the primary composite outcome of death from CV causes, nonfatal MI, or nonfatal stroke. This study shows a potential benefit of canagliflozin slowing the progression to albuminuria and composite outcome of sustained 40% reduction in eGFR, need for renal-replacement therapy or death from renal causes. Canagliflozin was associated with significantly more cases of amputations (toe, foot, or leg) and fractures.
Perkovic V, et al. N Engl J Med. 2019:380:2295-2306.[64322]	Randomized, double-blind, placebo-controlled trial (CREDENCE trial, n = 4,401) to compare canagliflozin 100 mg/day (n = 2,202) with placebo (n = 2,199), in adults with T2DM, an eGFR 30 to less than 90 mL/minute/1.73 m² and albuminuria (urine albumin (mg) to creatinine (g) ratio more than 300 to 5,000) who were receiving standard of care including a maximum-tolerated, labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).	Primary Composite Endpoint (ESKD, doubling of serum creatinine, renal death, or CV death) Canagliflozin vs. placebo: HR 0.70 (95% CI 0.59 to 0.82, p less than 0.0001) ESKD Canagliflozin vs. placebo: HR 0.68 (95% CI 0.54 to 0.86) Doubling of serum creatinine Canagliflozin vs. placebo: HR 0.60 (95% CI 0.48 to 0.76) CV death Canagliflozin vs. placebo: HR 0.78 (95% CI 0.61 to 1) CV deathor hospitalization for HF Canagliflozin vs. placebo: HR 0.69 (95% CI 0.57 to 0.83, p less than 0.001) CV death, non-fatal MI or non-fatal stroke Canagliflozin vs. placebo: HR 0.80 (95% CI 0.67 to 0.95, p less than 0.02) Non-fatal MI Canagliflozin vs. placebo: HR 0.81 (95% CI 0.59 to 1.10) Non-fatal stroke Canagliflozin vs. placebo: HR 0.80 (95% CI 0.56 to 1.15) Hospitalization for HF Canagliflozin vs. placebo: HR 0.61 (95% CI 0.47 to 0.80, p less than 0.001) ESKD, doubling of serum creatinine or renal death Canagliflozin vs. placebo: HR 0.66 (95% CI 0.53 to 0.81), p less than 0.0001) Adverse Reactions Rates of adverse events and serious adverse events were similar overall in the canagliflozin group and the placebo group. There were no significant differences in rates of amputation or fracture.	This trial was stopped early because there was clear evidence of the benefit observed for the primary outcome and composite of ESKD or death from renal and CV causes. In patients with T2DM and kidney disease, the risk of the primary composite outcome of ESKD, doubling of the serum creatinine level, or death from renal or CV causes was lower in the canagliflozin group than in the placebo group. Patients in the canagliflozin group also had lower risks of ESKD, hospitalization for HF, and the composite of CV death, MI, or stroke.
Wiviott SD, et al. N Engl J Med. 2019:380:347-357.[64324]	Randomized, double-blind, placebo-controlled phase 3 trial (DECLARE-TIMI 58, n = 17,160) to compare the effect of dapagliflozin (n = 8,582) on MACE and a composite of CV death or hospitalization for HF versus placebo (n = 8,578) in adult patients with T2DM with a history or high risk of CV events.	Primary Composite Endpoint of Hospitalization for HF, CV death Dapagliflozin vs. placebo: HR 0.83 (95% CI 0.73 to 0.95, p less than 0.005) Primary Composite Endpoint of CV death, MI, Ischemic stroke Dapagliflozin vs. placebo: HR 0.93 (95% CI 0.84 to 1.03) Hospitalization for HF Dapagliflozin vs. placebo: HR 0.73 (95% CI 0.61 to 0.88) CV death Dapagliflozin vs. placebo: HR 0.98 (95% CI 0.82 to 1.17) MI Dapagliflozin vs. placebo: HR 0.89 (95% CI 0.77 to 1.01) Ischemic stroke Dapagliflozin vs. placebo: HR 1.01 (95% CI 0.84 to 1.21)	Treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of CV death or hospitalization for HF, a finding that reflects a lower rate of hospitalization for HF.

Abbreviations: CI, confidence interval; CV, cardiovascular; DM, diabetes mellitus; ESKD, end-stage kidney disease; FPG, fasting plasma glucose; HF, heart failure; HR, hazard ratio; MACE, major adverse cardiovascular events; MD, mean difference; MI, myocardial infarction; NS, not significant; RR, relative risk; SBP, systolic blood pressure;

Adverse Reactions/Toxicities

Genitourinary Infections

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are associated with an increased risk of serious urinary tract infection (UTI), including urosepsis and pyelonephritis. Cases of urosepsis reported to the FDA required hospitalization. In a couple of cases, patients required hemodialysis to treat renal failure. The median time to onset was 45 days (range 2 to 270 days). Genital mycotic infections and UTIs are the most common adverse reactions experienced in both male and female patients prescribed SGLT2 inhibitors. Patients with a history of genital mycotic infection, including vaginitis or balanitis, may be more likely to develop a genital mycotic infection on SGLT2 inhibitor therapy. Patients should be told to report any signs of urinary tract infection and seek medical attention if they experience symptoms such as a feeling of burning when urinating or the need to urinate often or right away, pain in the lower part of the stomach area or pelvis, fever, or blood in the urine. If urinary tract infection is suspected, treat promptly if indicated.[60400][53972][56603][57718][62718][68485]

Volume Depletion

SGLT2 inhibitors result in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment was associated with an increase in the incidence of volume depletion related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). Those at risk include those with dehydration or hypovolemia, particularly in patients with impaired renal function (i.e., eGFR less than 60 mL/minute/1.73 m²), older adults 75 years of age or greater, those receiving diuretics, or individuals with low systolic blood pressure. Volume status should be assessed and corrected before initiating SGLT2 inhibitors in individuals with one or more of these characteristics. Monitor for signs and symptoms after initiating therapy.[53972] [56603][57718][62718][63835][68485]

Hypoglycemia

SGLT2 inhibitors have a low risk of hypoglycemia as monotherapy; however, the risk may increase with concomitant administration with sulfonylureas and/or insulin.[63258][63858] Consider reducing the dosage of concomitantly administered insulin secretagogues or insulin.[53972][56603][57718][62718][68485]

Lower Limb Amputation and Bone Fractures

An increased incidence of lower limb amputation has been observed in some clinical trials with Sodium-glucose co-transporter 2 (SGLT2) inhibitors; however, controversy exists regarding whether there are class or drug-specific amputation risks based on varying study results. Canagliflozin was associated with a 2-fold increase in lower limb (toe, foot, and leg) amputations in the CANVAS and CANVAS-R studies involving patients with established or at high risk for cardiovascular disease. Safety information from large, more recent clinical trials suggests that the risk of amputation, while still increased with canagliflozin, is lower than previously described by these studies, particularly when appropriately monitored.[51525][60785][61951] A meta-analysis of 5 randomized controlled trials (n =36,067) looking at the association between amputation risk and SGLT2 inhibitors concluded that SGLT2 inhibitors (canagliflozin, empagliflozin, or dapagliflozin) are not associated with an increased risk of amputation.[69627] In a study evaluating the association of amputations and peripheral artery disease (PAD, also known as peripheral vascular disease) in patients with type 2 diabetes mellitus (T2DM), the risk of amputation in patients treated with SGLT2 inhibitors and incretin mimetics was not higher compared with other antidiabetic medications. Pre-existing PAD was the greatest driver of amputation risk.[69629] In studies with SGLT2 inhibitors, lower limb infections, gangrene, ischemia, and diabetic foot infection (including osteomyelitis) were the most common risk factors leading to the need for amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, PAD, and neuropathy. Monitor persons for diabetic foot infection (including osteomyelitis) of the legs and feet and instruct persons to notify their health care professional immediately if they notice any new pain or tenderness, unusual sensations, skin color changes, or sores or ulcers involving the lower limbs, and initiate appropriate treatment.[53972][57718][62718][68485] The association between SGLT2 inhibitors and risk of fractures is also debatable. Canagliflozin, empagliflozin, and dapagliflozin have been associated with an increased risk of fractures; however, in a cohort study of older adults with chronic kidney disease (CKD), starting a SGLT2 inhibitor versus a dipeptidyl peptidase-4 (DPP-4) inhibitor was not associated with a higher risk of skeletal fracture, regardless of eGFR.[69631] In another study of older adults with T2DM, initiation of a SGLT2 inhibitor was not associated with an increased risk of fracture compared with initiating a DPP-4 Inhibitor or glucagon-like peptide-1 agonist (GLP-1 RA).[69632] Despite these findings, consider factors that contribute to fracture risk before initiating therapy.[53974][56603][57718]

Necrotizing Fasciitis

SGLT2 inhibitor therapy has been associated with a serious, rare, life-threatening infection called necrotizing fasciitis (tissue necrosis) of the perineum, also referred to as Fournier's gangrene, in both male and female patients (38 to 78 years of age). Among the identified and reported cases, all patients required both hospitalization and surgical debridement and some experienced diabetic ketoacidosis, acute kidney injury and septic shock; there was one death. The average time to onset was 9.2 months (range 5 days to 25 months). Signs and symptoms of Fournier's gangrene include tenderness, erythema, swelling in the genital or perineal area, fever, and malaise. If Fournier's gangrene is suspected, discontinue SGLT2 inhibitor therapy, immediately initiate antibiotic treatment and, if necessary, perform surgical debridement.[63482]

Drug Interactions

In general, the propensity of the SGLT2 inhibitors to exhibit drug-drug interactions is low, as the SGLT2 inhibitors do not induce or inhibit the hepatic CYP450 isoenzyme system.[53972][56603][57718][62718][68485]

UGT Inducers

Canagliflozin interacts with potent UGT inducers. Concomitant administration of canagliflozin and rifampin resulted in a 51% decrease in canagliflozin area under the curve (AUC). Rifampin is a nonselective UGT enzyme inducer, including UGT1A9 and UGT2B4. Canagliflozin dose adjustment should be considered when coadministered with potent UGT enzyme inducers, such as rifampin, phenytoin, phenobarbital, and ritonavir. In patients taking a UGT enzyme inducer who have an eGFR greater than 60 mL/minute/1.73 m², and are currently tolerating a canagliflozin dose of 100 mg once daily, increase the dose of canagliflozin to 200 mg (taken as two 100 mg tablets) once daily. In patients who require additional glycemic control after this increase, the dose may be increased to 300 mg once daily if tolerating canagliflozin 200 mg/day and the eGFR is more than 60 mL/minute/1.73 m². In patients taking a UGT enzyme inducer who have an eGFR less than 60 mL/minute/1.73 m², and are currently tolerating a canagliflozin dose of 100 mg once daily, increase the dose of canagliflozin to 200 mg (taken as two 100 mg tablets) once daily. Consider other antihyperglycemic therapy in patients who require additional glycemic control despite the 200 mg/day dose.[53972]
Bexagliflozin interacts with UGT inducers. Concomitant administration of bexagliflozin with UGT inducers may significantly reduce exposure to bexagliflozin and lead to decreased efficacy. Consider adding another antihyperglycemic agent in patients who require additional glycemic control.[68485]
Other SGLT-2 inhibitors are not known to interact. Decreases in the AUCs of dapagliflozin and ertugliflozin with coadministration of rifampin were not deemed clinically relevant; however, it may be prudent to monitor for changes in blood glucose during concomitant administration. The effect of UGT induction has not been studied with empagliflozin.[56603][57718] [62718]

Safety Issues

Renal Impairment

Postmarketing cases of acute kidney injury, some requiring hospitalization and dialysis, have been reported with SGLT2 inhibitor therapy. According to ADA guidelines, randomized clinical outcome trials of advanced kidney disease or high cardiovascular disease risk with normal kidney function have not shown that SGLT2 inhibitors promote acute kidney injury.[64926] Despite these findings, the manufacturers of the various SGLT2 inhibitors recommend that before initiating SGLT2 inhibitors, practitioners should consider predisposing factors for acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, concomitant medications, such as diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and nonsteroidal antiinflammatory drugs (NSAIDs). Temporary discontinuation of SGLT2 inhibitor therapy may be considered in patients with fluid losses (e.g., gastrointestinal illness or excessive heat exposure) or reduced fluid intake (e.g., acute illness or fasting). If acute kidney injury occurs, promptly discontinue SGLT2 inhibitors and treat the renal impairment.[60874][53972][56603][57718][62718][68485]

Diabetic Ketoacidosis

Postmarketing cases of diabetic ketoacidosis (DKA) have been reported in patients with type 1 and type 2 diabetes mellitus receiving SGLT2 inhibitors; some cases have been fatal. The risk of ketoacidosis may be greater with higher doses. In some but not all cases, factors predisposing to ketoacidosis such as acute febrile illness, infection, reduced caloric intake, ketogenic diet, surgery, reduction in dose of exogenous insulin or discontinuation of exogenous insulin or insulin secretagogue, pancreatic insulin insufficiency from any cause, volume depletion, or alcohol abuse were identified. If ketoacidosis is suspected, discontinue therapy and institute treatment, which may include insulin, fluids, and carbohydrate replacement.[59629][53972][56603][57718][62718][68485]

Lower Limb Amputations

An increased incidence of lower limb amputation has been observed in some clinical trials with sodium-glucose co-transporter 2 (SGLT2) inhibitors.[57718] Canagliflozin was associated with a 2-fold increased risk of lower limb amputations in patients with established or at risk of cardiovascular disease in the CANVAS and CANVAS-R studies. Safety information from large, more recent clinical trials suggests that the risk of amputation, while still increased with canagliflozin, is lower than previously described, particularly when appropriately monitored. Thus, canagliflozin product labels no longer carry a boxed warning regarding this concern. A majority of amputations involved the toe and midfoot, but amputations of the leg both above and below the knee were also reported. Results from four empagliflozin outcome trials demonstrated lower limb amputation event rates of 4.3 and 5 events per 1,000 patient-years in the placebo group and the empagliflozin 10 mg or 25 mg dose group, respectively. The occurrence of lower limb amputation event rates in a long-term cardio-renal outcomes trial in persons with chronic kidney disease was 2.9 and 4.3 events per 1,000 patient years in the placebo group and empagliflozin treatment groups, respectively.[57718] Data indicate there is an increased risk for amputations in those with a diabetic foot infection who have a prior history of amputations, peripheral vascular disease, and neuropathy.[57718][51525][53972] Health care professionals and patients should continue to recognize the importance of preventative foot care and monitor for new pain, tenderness, sores or ulcers involving the lower limbs, and infections in the legs and feet.[57718][51525][53972] Consider pre-existing risk factors that may predispose patients to the need for amputation when choosing a medication regimen to manage diabetes mellitus.[51525][53972]

Monitoring Glycemic Control

Utilizing a urine glucose test or 1,5-anhydroglucitol (1,5-AG) assay to assess glycemic control is not recommended in patients taking SGLT2 inhibitors. It is recommended that patients taking any SGLT2 inhibitor use an alternative method for monitoring glycemic control.[53972][56603][57718][62718][68485]

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