Cost-Effectiveness of Empagliflozin in Patients With Diabetic Kidney Disease in the United States: Findings Based on the EMPA-REG OUTCOME Trial.

RATIONALE & OBJECTIVE: Benefits of sodium-glucose cotransporter 2 inhibitors on kidney outcomes have been demonstrated in clinical trials. Among patients with type 2 diabetes and established cardiovascular (CV) disease enrolled in the EMPA-REG OUTCOME study (ClinicalTrials.gov identifier NCT01131676), empagliflozin added to standard of care (SOC) reduced the risk of incident or worsening nephropathy compared with SOC alone. This analysis evaluated the cost-effectiveness of empagliflozin versus SOC alone in the subpopulation with diabetic kidney disease (DKD) from the perspective of US commercial insurers and Medicare. STUDY DESIGN: Discrete event simulation model. SETTING & POPULATION: Patients with DKD in a US health care system. INTERVENTIONS: Empagliflozin 10 or 25mg with SOC versus SOC alone. SOC included glucose-lowering therapies and medications to treat CV risk factors. OUTCOMES: Incremental cost-effectiveness ratios (2020 US dollars per quality-adjusted life-year [QALY] gained). Costs and QALYs were discounted 3.0% per year. MODEL, PERSPECTIVE, & TIME FRAME: Cost-effectiveness analysis, commercial insurers and Medicare perspective, lifetime horizon. RESULTS: The incremental cost-effectiveness ratio of empagliflozin with SOC versus SOC alone was $25,974 per QALY. Empagliflozin added 0.67 QALYs and $17,322 per patient over a lifetime horizon. Results were driven by fewer clinical events (including CV death, heart failure hospitalization, albuminuria progression, and a composite kidney outcome) experienced by patients receiving empagliflozin with SOC versus SOC alone. Results were sensitive to rates of CV death, nonfatal myocardial infarction, and heart failure hospitalization, as well as to drug costs and time horizon. Probabilistic sensitivity analyses indicated 91% of simulations at <$50,000 per QALY. LIMITATIONS: The EMPA-REG OUTCOME study was not powered to assess treatment benefits in a subgroup and excluded patients with estimated glomerular filtration rate<30mL/min/1.73m2. CONCLUSIONS: Based on the EMPA-REG OUTCOME study, this cost-effectiveness analysis suggests that, for commercial insurers and Medicare, adding empagliflozin to SOC may be a cost-effective treatment option for patients with DKD.

Empagliflozin for the Treatment of Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes Mellitus.

BACKGROUND AND AIMS: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of drugs that lower glucose by inducing renal glycosuria. We aimed to explore whether SGLT2 inhibitor added to the usual care for patients with type 2 diabetes mellitus (T2DM) and biopsy-proven nonalcoholic steatohepatitis (NASH) will benefit NASH histology. METHODS: In this investigator-initiated, single-arm, open-label, pilot study, nine biopsy-proven NASH patients with T2DM were given empagliflozin 25 mg daily for 24 weeks. Liver biopsy was repeated at the end of treatment. The histological outcomes were compared with the placebo group of a previous 48-week clinical trial. RESULTS: There was a significant reduction in body mass index (median change, Δ = -0.7 kg per m2, p = 0.011), waist circumference (Δ = -3 cm, p = 0.033), systolic blood pressure (Δ = -9 mmHg, p = 0.024), diastolic blood pressure (Δ = -6 mmHg, p = 0.033), fasting blood glucose (Δ = -1.7 mmol/L, p = 0.008), total cholesterol (Δ = -0.5 mmol/L, p = 0.011), gamma glutamyl transpeptidase (Δ = -19 U/L, p = 0.013), volumetric liver fat fraction (Δ = -7.8%, p = 0.017), steatosis (Δ = -1, p = 0.014), ballooning (Δ = -1, p = 0.034), and fibrosis (Δ = 0, p = 0.046). All histological components either remained unchanged or improved, except in one patient who had worsening ballooning. Empagliflozin resulted in significantly greater improvements in steatosis (67% vs. 26%, p = 0.025), ballooning (78% vs. 34%, p = 0.024), and fibrosis (44% vs. 6%, p = 0.008) compared with historical placebo. CONCLUSION: This pilot study provides primary histological evidence that empagliflozin may be useful for the treatment of NASH. This preliminary finding should prompt larger clinical trials to assess the effectiveness of empagliflozin and other SGLT2 inhibitors for the treatment of NASH in T2DM patients. Trial registry number ClincialTrials.gov number, NCT02964715.

Euglycemic diabetic ketoacidosis caused by empagliflozin complicated by failure to thrive in a geriatric patient.

Euglycemic diabetic ketoacidosis (euDKA) is a rare but deadly complication of sodium-glucose cotransport-2 (SGLT-2) inhibitors. Primarily indicated for the treatment of Type 2 Diabetes Mellitus, the incidence of euDKA is expected to rise as SGLT-2 inhibitors become a mainstay therapy for diabetics with heart failure. Diagnosis of euDKA can be difficult given the presence of normoglycemia and is especially challenging among geriatric patients that are complicated by additional comorbidities. We present a case of an elderly male with multiple comorbidities who presented for dehydration and altered mentation from a nursing home facility. Laboratory investigations showed signs of acute renal failure, uremia, electrolyte abnormalities, and severe metabolic acidosis due to high levels of plasma beta-hydroxybutyrate. He was admitted to the medical intensive care unit (ICU) for further management. A presumptive diagnosis of euDKA was strongly suspected due to his laboratory data and medication reconciliation which revealed the recent initiation of empagliflozin. The patient was promptly started on a standardized treatment protocol for DKA with continuous infusion of regular insulin with strict glucose monitoring, along with intravenous fluids, and a small dose of sodium bicarbonate infusion as per current standard guidelines. With the rapid improvement in symptoms and metabolic derangements, the diagnosis was confirmed. Geriatric patients from nursing home facilities are a high-risk cohort who if not properly cared for by nursing staff can develop dehydration, malnutrition and worsening frailty including sarcopenia that exposes them to increased risk of medication side effects, such as euDKA. Clinicians should consider euDKA in their differential diagnosis in elderly patients with overt or relative insulinopenia who are receiving SGLT-2 inhibitors when presenting with acute changes in health and mentation.

Fournier's Gangrene in an HIV-Positive Patient on Empagliflozin for the Treatment of Diabetes Mellitus.

Fournier's gangrene is a severe polymicrobial infection that results in necrosis of the perineal and genital fasciae with rapid progression. This case report describes a 55-year-old male with a past medical history of HIV, type 2 diabetes, and hypertension who was diagnosed with Fournier's gangrene after the administration of empagliflozin (Jardiance). The patient presented with a worsening ulcer of the right groin and was diagnosed with Fournier's gangrene based on clinical and radiographic findings. He underwent surgical debridement of the wound. The patient was treated with empiric vancomycin, piperacillin-tazobactam, and clindamycin. Wound cultures grew Streptococcus anginosus and Staphylococcus epidermidis. His antibiotic regimen was simplified to ampicillin-sulbactam. The patient required reconstructive surgery for wound closure after debridement. He received an additional 18 days of augmentin therapy with the resolution of the infectious process. At the time of Fournier's gangrene onset, the patient's last HbA1C level was 8.2%, despite treatment with glipizide and empagliflozin. This case suggests an association between empagliflozin and Fournier's gangrene in the setting of active HIV infection.

A Case of Severe Metabolic Acidosis due to Jardiance-Induced Euglycemic Diabetic Ketoacidosis.

Metabolic acidosis is frequently encountered in the inpatient setting. It can occur due to either the accumulation of endogenous acids that consumes bicarbonate (high anion gap metabolic acidosis) or loss of bicarbonate from the gastrointestinal tract or the kidney. Jardiance® (empagliflozin) (Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, USA) is a sodium-glucose co-transporter 2 (SGLT2) inhibitor, which reduces renal tubular glucose reabsorption, thereby decreasing blood glucose level without stimulating insulin release. This class of drugs is known for reducing cardiovascular events and delay in the progression of chronic kidney disease in patients with type 2 diabetes mellitus (T2DM). However recent data has shown that SGLT2 inhibitors, particularly empagliflozin, carry the risk of inducing euglycemic diabetic ketoacidosis under certain circumstances such as acute illness, and decreased carbohydrate intake, decrease in dose, or discontinuation of insulin. We herein report a 23-year-old female with poorly controlled diabetes mellitus on empagliflozin, who presented with dyspnea and coronavirus disease SARS-CoV-2 (COVID-19) infection and found to have severe unexplained euglycemic metabolic acidosis, with elevated urine ketones.

Pharmacokinetics, Safety, and Bioequivalence of Two Empagliflozin Formulations after Single Oral Administration under Fasting and Fed Conditions in Healthy Chinese Subjects: An Open-label Randomized Single-dose Two-sequence, Two-treatment, Two-period Crossover Study.

OBJECTIVES: To evaluate the pharmacokinetic properties and safety of empagliflozin, and the bioequivalence of test formulation empagliflozin tablet compared with the brand-name drug Jardiance (reference formulation) after single oral administration under fasting and fed conditions in healthy Chinese subjects. METHODS: An open-label randomized single-dose two-sequence, two-treatment, two-period crossover study was conducted in healthy Chinese subjects, with 30 subjects under fasting condition and another 30 subjects under fed condition. Under each condition, subjects received a single oral administration of either the test or reference empagliflozin formulation, and then they received a single oral dose of the other formulation after a 7-day washout period. RESULTS: A total of 29 subjects under each condition completed the study. The maximum plasma drug concentration, the area under the plasma concentration-time curve (AUC) from 0 to t (AUC0-t ), and the AUC from 0 to infinity (AUC0-∞ ) of test formulation and reference formulation was 186.90 ± 47.21 and 190.60 ± 40.94 ng/ml, 1303.04 ± 234.28 and 1267.78 ± 217.07 ng·hour/ml, and 1328.08 ± 243.84 and 1293.22 ± 224.82 ng·hour/ml under fasting condition, and 151.55 ± 23.86 and 154.08 ± 30.40 ng/ml, 1215.65 ± 197.62 and 1199.26 ± 186.23 ng·hour/ml, and 1241.76 ± 202.47 and 1225.54 ± 192.10 ng·hour/ml under fed condition, respectively. CONCLUSIONS: The two formulations of empagliflozin were bioequivalent, and both were generally well tolerated under fasting and fed conditions.

Bilateral gangrene of fingers in a patient on empagliflozin: First case report.

BACKGROUND: Sodium glucose cotransporter 2 (SGLT2) inhibitors use has been associated with toe amputations and non-healing ulcers and gangrene mostly of lower extremities. There are no case reports about association of Empagliflozin with finger ulcers or gangrene. This is the first case report of Empagliflozin (Jardiance) an SGLT2 inhibitor causing gangrene of fingers and second case in literature about any SGLT2 inhibitor causing gangrene of upper extremity. CASE SUMMARY: A 76-year-old man with type 2 diabetes mellitus sustained minimal trauma to both middle fingers, which started healing. He was started on empagliflozin a week later for management of type 2 diabetes mellitus and started developing gangrene to both middle finger tips along with neuropathic pain which worsened over the course of next four months. Investigations were negative for vascular insufficiency, infection and vasculitis and imaging of hand was normal. Discontinuation of empagliflozin slowed progression of gangrene and caused symptomatic improvement with reduction in neuropathic pain. CONCLUSION: This case report suggests possible association of empagliflozin and finger gangrene and recommends that more research and awareness among clinicians is needed in this area.