Synjardy

Risk Summary

Based on animal data showing adverse renal effects from empagliflozin, SYNJARDY and SYNJARDY XR are not recommended during the second and third trimesters of pregnancy.

The limited available data with SYNJARDY, SYNJARDY XR, or empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. Published studies with metformin HCl use during pregnancy have not reported a clear association with metformin HCl and major birth defect or miscarriage risk (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).

In animal studies, empagliflozin, a component of SYNJARDY and SYNJARDY XR, resulted in adverse renal changes in rats when administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible. No adverse developmental effects were observed when metformin HCl was administered to pregnant rats or rabbits (see Data).

The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20% to 25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Data

Risk Summary

There is limited information regarding the presence of SYNJARDY, SYNJARDY XR, or its components (empagliflozin or metformin HCl) in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk (see Data). Empagliflozin is present in the milk of lactating rats (see Data). Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.

Because of the potential for serious adverse reactions in a breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that use of SYNJARDY or SYNJARDY XR is not recommended while breastfeeding.

Data

Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin HCl during lactation because of small sample size and limited adverse event data collected in infants.

Empagliflozin was present at a low level in rat fetal tissues after a single oral dose to the dams at gestation day 18. In rat milk, the mean milk to plasma ratio ranged from 0.634 to 5, and was greater than one from 2 to 24 hours post-dose. The mean maximal milk to plasma ratio of 5 occurred at 8 hours post-dose, suggesting accumulation of empagliflozin in the milk. Juvenile rats directly exposed to empagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.

SYNJARDY

The safety and effectiveness of SYNJARDY as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older. Use of SYNJARDY for this indication is supported by evidence from a 26-week double-blind, placebo-controlled clinical trial of empagliflozin, with a double-blind active treatment safety extension period of up to 52 weeks in 157 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus and a pediatric pharmacokinetic study [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)].

The safety profile of pediatric patients treated with empagliflozin was similar to that observed in adults with type 2 diabetes mellitus, with the exception of hypoglycemia risk which was higher in pediatric patients treated with empagliflozin regardless of concomitant insulin use [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

Use of SYNJARDY for this indication is also supported by evidence from adequate and well-controlled studies of metformin HCl immediate-release tablets in adults with additional data from a controlled clinical study using metformin HCl immediate-release tablets in pediatric patients 10 to 16 years old with type 2 diabetes mellitus [see Clinical Studies (14)]. In this study, adverse reactions were similar to those described in adults.

The safety and effectiveness of SYNJARDY have not been established in pediatric patients less than 10 years of age.

SYNJARDY XR

Safety and effectiveness of SYNJARDY XR have not been established in pediatric patients.

Empagliflozin

In empagliflozin type 2 diabetes mellitus trials, 2,721 empagliflozin-treated patients were 65 years of age and older and 491 patients were 75 years of age and older. In these trials, volume depletion-related adverse reactions occurred in 2.1%, 2.3%, and 4.4% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively; and urinary tract infections occurred in 10.5%, 15.7%, and 15.1% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively.

In the EMPEROR-Reduced, EMPEROR-Preserved, and EMPA-KIDNEY trials, no overall differences in safety and effectiveness have been observed between patients 65 years of age and older and younger adult patients. EMPEROR-Reduced included 1,188 (64%) patients treated with empagliflozin 65 years of age and older, and 503 (27%) patients 75 years of age and older. EMPEROR-Preserved included 2,403 (80%) patients treated with empagliflozin 65 years of age and older, and 1,281 (43%) patients 75 years of age and older. EMPA-KIDNEY included 1,803 (55%) patients treated with empagliflozin 65 years of age and older, and 758 (23%) patients 75 years of age and older.

Metformin HCl

Clinical studies of metformin HCl did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

Empagliflozin

The glucose lowering benefit of empagliflozin 25 mg decreased in adult patients with worsening renal function. The risks of renal impairment, volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function [see Warnings and Precautions (5.2)]. In the trial of pediatric patients aged 10 to 17 years with type 2 diabetes mellitus, patients with an eGFR less than 60 mL/min/1.73 m2 were not enrolled.

Metformin HCl

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment [see Warnings and Precautions (5.1)].

Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]:

• Before initiating SYNJARDY or SYNJARDY XR, obtain an estimated glomerular filtration rate (eGFR).
• SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR below 30 mL/min/1.73 m2 [see Contraindications (4)].
• Obtain an eGFR at least annually in all patients taking SYNJARDY or SYNJARDY XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug Interactions: The concomitant use of SYNJARDY or SYNJARDY XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].

Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop SYNJARDY or SYNJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart SYNJARDY or SYNJARDY XR if renal function is stable.

Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. SYNJARDY or SYNJARDY XR should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue SYNJARDY or SYNJARDY XR.

Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving SYNJARDY or SYNJARDY XR.

Hepatic Impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of SYNJARDY or SYNJARDY XR in patients with clinical or laboratory evidence of hepatic disease.

Adverse Reactions in a Clinical Trial with Empagliflozin (Add-On Combination Therapy with Metformin HCl and Sulfonylurea) for Glycemic Control in Adults with Type 2 Diabetes Mellitus

In a 24-week placebo-controlled trial of empagliflozin 10 mg or 25 mg administered once daily added to metformin HCl and sulfonylurea, adverse reactions reported in ≥5% of empagliflozin-treated patients and more commonly than in placebo-treated patients are presented in Table 1 (see also Table 4).

Empagliflozin

Clinical Trial of Empagliflozin in Pediatric Patients Aged 10 to 17 Years with Type 2 Diabetes Mellitus

Empagliflozin was administered to 52 patients in a trial of 157 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus with a mean exposure to empagliflozin of 23.8 weeks [see Clinical Studies (14.2)]. Background therapies as adjunct to diet and exercise included metformin HCl (51%), a combination of metformin HCl and insulin (40.1%), insulin (3.2%), or none (5.7%). The mean HbA1c at baseline was 8.0% and the mean duration of type 2 diabetes mellitus was 2.1 years. The mean age was 14.5 years (range: 10-17 years) and 51.6% were aged 15 years and older. Approximately, 50% were White, 6% were Asian, 31% were Black or African American, and 38% were of Hispanic or Latino ethnicity. The mean BMI was 36.0 kg/m2 and mean BMI Z-score was 3.0. Approximately 25% of the trial population had microalbuminuria or macroalbuminuria.

The risk of hypoglycemia was higher in pediatric patients treated with empagliflozin regardless of concomitant insulin use. Hypoglycemia, defined as a blood glucose <54 mg/dL, occurred in 10 (19.2%) patients and in 4 (7.5%) patients treated with empagliflozin and placebo, respectively. No severe hypoglycemic events occurred (severe hypoglycemia was defined as an event requiring the assistance of another person to actively administer carbohydrates, glucagon or take other corrective actions).

Adverse Reactions with Clinical Trials of Metformin HCl

The most common (>5%) established adverse reactions due to initiation of metformin HCl therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.

In a 24-week clinical trial in which extended-release metformin HCl or placebo was added to glyburide therapy, the most common (>5% and greater than placebo) adverse reactions in the combined treatment group were hypoglycemia (13.7% vs 4.9%), diarrhea (12.5% vs 5.6%), and nausea (6.7% vs 4.2%).

Laboratory Test Abnormalities in Clinical Trials of Empagliflozin or Metformin HCl

Empagliflozin

Gastrointestinal Disorders: Constipation
Infections: Necrotizing fasciitis of the perineum (Fournier's gangrene), urosepsis and pyelonephritis
Metabolism and Nutrition Disorders: Ketoacidosis
Renal and Urinary Disorders: Acute kidney injury
Skin and Subcutaneous Tissue Disorders: Angioedema, skin reactions (e.g., rash, urticaria)

Metformin HCl

Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury

SYNJARDY or SYNJARDY XR

SYNJARDY and SYNJARDY XR contain: empagliflozin, a SGLT2 inhibitor, and metformin HCl, a biguanide.

Empagliflozin

Empagliflozin is an inhibitor of SGLT2, the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Empagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, increasing tubuloglomerular feedback and reducing intraglomerular pressure, lowering both pre- and afterload of the heart and downregulating sympathetic activity.

Metformin HCl

Metformin HCl is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. It is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin HCl does not produce hypoglycemia in either patients with type 2 diabetes mellitus or normal subjects (except in special circumstances) [see Warnings and Precautions (5.5)] and does not cause hyperinsulinemia. With metformin HCl therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

Empagliflozin

SYNJARDY

Administration of 12.5 mg empagliflozin/1,000 mg metformin HCl under fed conditions resulted in a 9% decrease in AUC and a 28% decrease in Cmax for empagliflozin, when compared to fasted conditions. For metformin, AUC decreased by 12% and Cmax decreased by 26% compared to fasting conditions. The observed effect of food on empagliflozin and metformin is not considered to be clinically relevant.

SYNJARDY XR

Administration of SYNJARDY XR with food resulted in no change in overall exposure of empagliflozin. For metformin HCl extended-release high-fat meals increased systemic exposure to metformin (as measured by area-under-the-curve [AUC]) by approximately 70% relative to fasting, while Cmax is not affected. Meals prolonged Tmax by approximately 3 hours.

Empagliflozin

The pharmacokinetics of empagliflozin has been characterized in healthy volunteers and patients with type 2 diabetes mellitus and no clinically relevant differences were noted between the two populations. The steady-state mean plasma AUC and Cmax were 1,870 nmol∙h/L and 259 nmol/L, respectively, with 10 mg empagliflozin once daily treatment, and 4,740 nmol∙h/L and 687 nmol/L, respectively, with 25 mg empagliflozin once daily treatment. Systemic exposure of empagliflozin increased in a dose-proportional manner in the therapeutic dose range. Empagliflozin does not appear to have time-dependent pharmacokinetic characteristics. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state.

Metformin HCl

Metformin HCl extended-release

Following a single oral dose of 1,000 mg (2 × 500 mg tablets) metformin HCl extended-release after a meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7 to 8 hours. In both single- and multiple-dose studies in healthy subjects, once daily 1,000 mg (2 × 500 mg tablets) dosing provides equivalent systemic exposure, as measured by AUC, and up to 35% higher Cmax of metformin relative to the immediate-release given as 500 mg twice daily.

Single oral doses of metformin HCl extended-release from 500 mg to 2,500 mg resulted in less than proportional increase in both AUC and Cmax. Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from metformin extended-release tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin Tmax by approximately 3 hours but Cmax was not affected.

SYNJARDY or SYNJARDY XR

No carcinogenicity, mutagenicity, or impairment of fertility studies have been conducted with the combination of empagliflozin and metformin HCl. General toxicity studies in rats up to 13 weeks were performed with the combined components. These studies indicated that no additive toxicity is caused by the combination of empagliflozin and metformin HCl.

Empagliflozin

Carcinogenesis was evaluated in 2-year studies conducted in CD-1 mice and Wistar rats. Empagliflozin did not increase the incidence of tumors in female rats dosed at 100, 300, or 700 mg/kg/day (up to 72 times the exposure from the maximum clinical dose of 25 mg). In male rats, hemangiomas of the mesenteric lymph node were increased significantly at 700 mg/kg/day or approximately 42 times the exposure from a 25 mg clinical dose. Empagliflozin did not increase the incidence of tumors in female mice dosed at 100, 300, or 1,000 mg/kg/day (up to 62 times the exposure from a 25 mg clinical dose). Renal tubule adenomas and carcinomas were observed in male mice at 1,000 mg/kg/day, which is approximately 45 times the exposure of the maximum clinical dose of 25 mg. These tumors may be associated with a metabolic pathway predominantly present in the male mouse kidney.

Empagliflozin was not mutagenic or clastogenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay, the in vitro L5178Y tk+/- mouse lymphoma cell assay, and an in vivo micronucleus assay in rats.

Empagliflozin had no effects on mating, fertility or early embryonic development in treated male or female rats up to the high dose of 700 mg/kg/day (approximately 155 times the 25 mg clinical dose in males and females, respectively).

Metformin HCl

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily dose of 2,000 mg/kg/day based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (Salmonella typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 2 times the MRHD based on body surface area comparisons.

Empagliflozin Add-On Combination Therapy with Metformin HCl in Adult Patients with Type 2 Diabetes Mellitus

A total of 637 patients with type 2 diabetes mellitus participated in a double-blind, placebo-controlled trial to evaluate the efficacy of empagliflozin in combination with metformin HCl.

Patients with type 2 diabetes mellitus inadequately controlled on at least 1,500 mg of metformin HCl per day entered an open-label 2-week placebo run-in. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7% and 10% were randomized to placebo, empagliflozin 10 mg, or empagliflozin 25 mg.

At Week 24, treatment with empagliflozin 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value <0.0001), FPG, and body weight compared with placebo (see Table 7).

At Week 24, the systolic blood pressure was statistically significantly reduced compared to placebo by -4.1 mmHg (placebo-corrected, p-value <0.0001) for empagliflozin 10 mg and -4.8 mmHg (placebo-corrected, p-value <0.0001) for empagliflozin 25 mg.

Empagliflozin Initial Combination Therapy with Metformin HCl

A total of 1,364 patients with type 2 diabetes mellitus participated in a double-blind, randomized, active-controlled trial to evaluate the efficacy of empagliflozin in combination with metformin HCl as initial therapy compared to the corresponding individual components.

Treatment-naïve patients with inadequately controlled type 2 diabetes mellitus entered an open-label placebo run-in for 2 weeks. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7% and 10.5% were randomized to one of 8 active-treatment arms: empagliflozin 10 mg or 25 mg; metformin HCl 1,000 mg, or 2,000 mg; empagliflozin 10 mg in combination with 1,000 mg or 2,000 mg metformin HCl; or empagliflozin 25 mg in combination with 1,000 mg or 2,000 mg metformin HCl.

At Week 24, initial therapy of empagliflozin in combination with metformin HCl provided statistically significant reductions in HbA1c (p-value <0.01) compared to the individual components (see Table 8).

Empagliflozin Add-On Combination Therapy with Metformin HCl and Sulfonylurea

A total of 666 patients with type 2 diabetes mellitus participated in a double-blind, placebo-controlled trial to evaluate the efficacy of empagliflozin in combination with metformin HCl plus a sulfonylurea.

Patients with inadequately controlled type 2 diabetes mellitus on at least 1,500 mg per day of metformin HCl and on a sulfonylurea, entered a 2-week open-label placebo run-in. At the end of the run-in, patients who remained inadequately controlled and had an HbA1c between 7% and 10% were randomized to placebo, empagliflozin 10 mg, or empagliflozin 25 mg.

Treatment with empagliflozin 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value <0.0001), FPG, and body weight compared with placebo (see Table 9).

Glycemic Control Trial of Empagliflozin in Pediatric Patients Aged 10 to 17 Years with Type 2 Diabetes Mellitus

DINAMO (NCT03429543) was a 26-week, double-blind, randomized, placebo-controlled, parallel group trial, with a double-blind active treatment safety extension period up to 52 weeks to assess the efficacy of empagliflozin. The trial enrolled pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus (HbA1c 6.5 to 10.5%). Patients treated with metformin HCl (at least 1,000 mg daily or maximally tolerated dose), with or without insulin therapy, and those with a history of intolerance to metformin HCl therapy were enrolled. Patients were randomized to 3 treatment arms (empagliflozin 10 mg, a dipeptidyl peptidase-4 (DPP-4) inhibitor, or placebo) over 26 weeks. Patients in the empagliflozin 10 mg group who failed to achieve HbA1c <7.0% at Week 12 underwent a second randomization at Week 14 to remain on the 10 mg dose or increase to 25 mg. Patients on placebo were re-randomized at Week 26 to one of the empagliflozin doses (10 mg or 25 mg) or a DPP-4 inhibitor.

A total of 157 patients were treated with either empagliflozin (10 mg or 25 mg; N=52), a DPP-4 inhibitor (N=52), or placebo (N=53). Background therapies as adjunct to diet and exercise included metformin HCl (51%), a combination of metformin HCl and insulin (40.1%), insulin (3.2%), or none (5.7%). The mean HbA1c at baseline was 8.0% and the mean duration of type 2 diabetes mellitus was 2.1 years. The mean age was 14.5 years (range: 10-17 years) and 51.6% were aged 15 years and older. Approximately, 50% were White, 6% were Asian, 31% were Black or African American, and 38% were of Hispanic or Latino ethnicity. The mean BMI was 36.0 kg/m2 and mean BMI Z-score was 3.0. Patients with an eGFR less than 60 mL/min/1.73 m2 were not enrolled in the trial. Approximately 25% of the trial population had microalbuminuria or macroalbuminuria.

At Week 26, treatment with empagliflozin was superior in reducing HbA1c from baseline versus placebo (see Table 11).

Glycemic Control Trial of Metformin HCl Immediate-Release in Pediatric Patients Aged 10 to 16 Years with Type 2 Diabetes Mellitus:

A double-blind, placebo-controlled trial was conducted in pediatric patients aged 10 to 16 years with type 2 diabetes mellitus (mean FPG 182.2 mg/dL), where patients were treated with metformin HCl immediate-release tablets (up to 2,000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks). The results are displayed in Table 12.

Mean baseline body weight was 205 lbs and 189 lbs in the metformin HCl immediate-release and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -3.3 lbs and -2.0 lbs in the metformin HCl and placebo arms, respectively.

EMPEROR-Reduced Trial (Chronic Heart Failure with Left Ventricular Ejection Fraction ≤ 40%)

EMPEROR-Reduced (NCT03057977) was a double-blind trial conducted in adults with chronic heart failure [New York Heart Association (NYHA) functional class II-IV] with left ventricular ejection fraction (LVEF) ≤40% to evaluate the efficacy of empagliflozin as adjunct to standard of care heart failure therapy. Of 3,730 patients, 1,863 were randomized to empagliflozin 10 mg once daily and 1,867 to placebo once daily and were followed for a median of 16 months.

EMPEROR-Preserved Trial (Chronic Heart Failure with Left Ventricular Ejection Fraction > 40%)

EMPEROR-Preserved (NCT03057951) was a double-blind trial conducted in patients with chronic heart failure NYHA Class II-IV with LVEF >40% to evaluate the efficacy of empagliflozin as adjunct to standard of care therapy. Of 5,988 patients, 2,997 patients were randomized to empagliflozin 10 mg once daily and 2,991 patients to placebo once daily and were followed for a median of 26 months.

Baseline Disease Characteristics and Demographics

EMPA-KIDNEY included patients with type 2 diabetes mellitus (n=2,936) and patients without type 2 diabetes mellitus (n=3,673). The mean age of the study population was 63 years (range: 18 to 94 years) and 67% were male. Approximately 58% of the study population were White, 36% Asian, and 4% Black or African American. At baseline, the mean eGFR was 37 mL/min/1.73 m2, 21% of patients had an eGFR equal to or above 45 mL/min/1.73 m2, and 44% had an eGFR 30 to less than 45 mL/min/1.73 m2. The median UACR was 329 mg/g, 20% of patients had a UACR <30 mg/g, 28% had a UACR 30 to ≤300 mg/g, and 52% had a UACR >300 mg/g. The most common etiologies of CKD were diabetic nephropathy/diabetic kidney disease (31%), glomerular disease (25%), hypertensive/renovascular disease (22%) and other/unknown (22%). At baseline, 85% of patients were treated with angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), 64% with statins, and 34% with antiplatelet agents.

In EMPA-KIDNEY, history of type 2 diabetes mellitus was present in 44% of the patients, and 23% of these patients were treated with metformin HCl (329 patients in the empagliflozin group and 334 in the placebo group). In the type 2 diabetes mellitus subpopulation, the mean age was 68 years, 67% were males, 59% White, 33% Asian and 6% Black or African American. In the type 2 diabetes mellitus subpopulation, at baseline, the mean eGFR was 36 mL/min/1.73 m2, 17% of patients had an eGFR equal to or above 45 mL/min/1.73 m2, and 45% had an eGFR 30 to less than 45 mL/min/1.73 m2; the median UACR was 256 mg/g, 22% of patients had a UACR <30 mg/g, 31% had a UACR 30 to ≤300 mg/g, and 47% had a UACR >300 mg/g. The most common etiologies of CKD at baseline in this subpopulation were diabetic nephropathy/diabetic kidney disease (67%), glomerular disease (6%), hypertensive/renovascular disease (14%) and other/unknown (13%). In this subpopulation, at baseline, 85% of patients were treated with ACE inhibitor or ARB, 79% with statins, and 48% with antiplatelet agents.

Results

In EMPA-KIDNEY, empagliflozin 10 mg, compared with placebo, reduced the risk of the primary composite endpoint of sustained ≥40% eGFR decline, sustained eGFR <10 mL/min/1.73 m2, progression to end-stage kidney disease, or CV or renal death. The treatment effect reflected a reduction in a sustained ≥40% eGFR decline, sustained eGFR <10 mL/min/1.73 m2, progression to end-stage kidney disease, and CV death. There were few renal deaths during the trial. Empagliflozin also reduced the risk of first and recurrent hospitalization; information collected on the reason for hospitalization was insufficient to further characterize the benefit. Because of the metformin HCl component, SYNJARDY and SYNJARDY XR are not indicated for use in patients with CKD without type 2 diabetes mellitus [see Indications and Usage (1)].

The effect of empagliflozin in reducing the risk of the primary composite endpoint was consistent in patients with type 2 diabetes mellitus [HR 0.65 (95% CI 0.54, 0.78)], and in patients with type 2 diabetes mellitus and metformin HCl as background therapy [HR 0.72 (95% CI 0.48, 1.09)].