Introduction
Heart failure (HF), according to the American College of Cardiology (ACC), is a clinical syndrome characterized by symptoms and/or signs resulting from a structural or functional abnormality in the heart. This is confirmed through elevated natriuretic peptide levels and/or clear indications of congestion in the pulmonary or systemic systems. Heart failure can reduce the heart’s ability to pump blood, resulting in reduced cardiac output. This means that vital organs, such as the kidneys, brain, and liver, receive less blood flow and oxygen, ultimately leading to organ failure. Some medical conditions, including diabetes, obesity, hypertension, coronary artery disease, and chronic kidney disease (CKD), can increase the risk of HF. Signs and symptoms of HF include dyspnea, lower extremity edema, and orthopnea. The ACC has defined multiple types of HF, each characterized by left ventricular ejection fraction (LVEF) and symptoms. These classifications provide strategies for patient treatment. Heart failure with reduced ejection fraction (HFrEF) refers to symptomatic HF cases where the LVEF is 40% or lower. Patients with HF with mid-range ejection fraction (HFmrEF) have an LVEF ranging from 41% to 49% and symptoms of HF. Patients with HF with preserved ejection fraction (HFpEF) have symptoms but an LVEF of 50% or higher. In addition, HF with improved ejection fraction (HFimpEF) indicates that a patient initially had symptomatic HF with a baseline LVEF of 40% or lower, but the LVEF has increased by 10% or more and is above 40%.1 In the United States, 6.2 million adults live with HF, and the CDC reported that 379,800 people died of HF in 2018.2 The 2022 AHA/ACC/HFSA joint guidelines recommend sodium-glucose cotransporter 2 (SGLT2) inhibitors as first-line goal-directed medical therapy for HFrEF.3 The FDA approved sotagliflozin (Inpefa), which inhibits both SGLT2 and SGLT1, in May 2023 to reduce the risk of cardiovascular (CV) death, hospitalization for HF, and urgent HF visits in patients with HF or those with type 2 diabetes, CKD, and risk factors for CV disease.3
Mechanism of Action
Sotagliflozin inhibits both SGLT2 and SGLT1 but is a more potent inhibitor of SGLT2. Sodium-glucose cotransporter 2 is a protein located in the proximal convoluted tubules of the kidney and is responsible for the reabsorption of glucose.4 Sotagliflozin inhibits SGLT2, preventing glucose and sodium from being reabsorbed in the kidneys and leading to glucose excretion in the urine. The SGLT2 inhibitors have a diuretic effect that decreases blood volume and reduces preload for the heart. Sodium-glucose cotransporter 1 is located in the brush border of the small intestine and the kidney and is responsible for absorbing dietary glucose and, to a smaller degree, reabsorbing glucose in the kidney.5 As a result, inhibiting SGLT1 results in decreased glucose and sodium absorption and can cause diarrhea. Elevated blood glucose concentrations can lead to the formation of advanced glycation end products, which contribute to inflammation and oxidative stress, both of which are involved in CV disease.6 By lowering postprandial glucose spikes, SGLT1 inhibitors help reduce the production of advanced glycation end products, improving CV health.6
Clinical Trial Overview: SOLOIST‑WHF7
The SOLOIST-WHF was a phase 3, randomized, double-blind, placebo-controlled trial. The trial took place in North America, Latin America, and Europe. The trial included participants 18 to 85 years of age who had previously been hospitalized because of signs and symptoms of HF requiring diuresis and had type 2 diabetes. Participants who had a percutaneous coronary intervention, end-stage HF, stroke, history of solid organ transplantation, obstructive hypertrophic cardiomyopathy, and a glomerular filtration rate (GFR) less than 30 mL/min/1.73 m2 of body surface area were excluded from the study. Participants were assigned to receive sotagliflozin 200 mg orally once a day or placebo. Participants started treatment before or within 3 days of being discharged from the hospital and had follow-up visits at 1 week, 2 weeks, 4 weeks, 4 months, and every 4 months afterward. The study’s enrollment closed because of lack of funding, and to achieve their power, the study investigators changed the primary end point from a composite of the first occurrence of death from CV causes or hospitalization from HF to the total number of deaths from CV causes or hospitalizations or urgent care visits because of HF.
Results7
There were 1222 participants in the study, with 608 in the sotagliflozin group and 614 in the placebo group. Most participants (79.1%) had an LVEF less than 50%. The median age of the participants was 69 years for the sotagliflozin group and 70 years for the placebo group. Around 32.6% of participants in the sotagliflozin group were female, compared with 34.9% in the placebo group. Participants were allowed to continue angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, angiotensin receptor-neprilysin inhibitors, mineralocorticoid receptor antagonists, β-blockers, loop diuretics, and other diuretics. Among the 1222 patients enrolled, a total of 600 primary composite end point events occurred—245 in the sotagliflozin group compared with 355 in the placebo group (R, 0.67; P < .001). Subgroup analyses were done to assess the impact of sotagliflozin across various factors, including age, sex, treatment timing, LVEF, and renal function. These analyses showed that sotagliflozin use led to a significant reduction in CV deaths, hospitalizations, and urgent HF visits in all examined subgroups, including variations in age, sex, treatment timing, LVEF, and renal function.
FDA-approved dosing: Sotagliflozin 200 mg by mouth once a day for 2 weeks, then titrate to 400 mg by mouth once a day, as tolerated. Because food increases the absorption of sotagliflozin, the package labeling recommends that it not be taken more than 1 hour before the first meal of the day.
Adverse Effects
According to the FDA-approved label, reported side effects are hypotension, UTIs, diarrhea, diabetic ketoacidosis, and genital mycotic infections.8 Serious adverse events led 3% of the participants in the sotagliflozin group to withdraw from the trial.7 In the sotagliflozin group of the SOLOIST-WHF trial, the incidence of severe hypotension, UTIs, diarrhea, and severe hypoglycemia was 6.0%, 4.8%, 6.1%, and 1.5%, respectively.7 Rates of acute kidney injury in the sotagliflozin and placebo groups were similar, around 4%.
Drug Interactions
Only a few reported drug-drug interactions are reported in the package labeling for sotagliflozin, including increased digoxin concentration when combined with sotagliflozin 400 mg requiring therapeutic drug monitoring. Sotagliflozin undergoes glucuronidation by uridine 5ʹ diphospho-glucuronosyltransferase (UGT1A9), and administration of inducers, such as rifampin, will decrease sotagliflozin concentrations. Combined use of SGLT2 inhibitors and lithium decreases the serum concentrations of lithium and requires adjustment to therapeutic drug monitoring.8 Sotagliflozin taken concurrently with insulin or sulfonylureas may increase the risk of hypoglycemia.
Special Populations
Pregnancy—Sotagliflozin is not recommended during the second or third trimester of pregnancy or while breastfeeding.3
Geriatric—The effectiveness of sotagliflozin is similar in older and younger adult patients. Adult patients 65 years and older may experience more volume depletion and hypotension.
Renal Impairment—Sotagliflozin was evaluated in patients with CKD and HF.3 Patients with an estimated GFR (eGFR) less than 30 mL/min/1.73 m2 experienced more volume-related adverse events. Patients with an eGFR of 25 mL/min/1.73 m2 or receiving dialysis were not included in the studies.3 Treatment was discontinued if the patient’s eGFR decreased below 15 mL/min/1.73 m or if the patient was initiated on chronic dialysis.
Hepatic Impairment—Sotagliflozin is not recommended in patients with moderate or severe hepatic impairment.3
Patient Education
Sotagliflozin should not be taken more than 1 hour before eating.8 Tablets should not be cut, crushed, or chewed. Swallow whole. If a dose is missed by more than 6 hours, take the dose at the next scheduled time. Sotagliflozin may cause dizziness, dehydration, and weakness. Seek medical attention if swelling of the face, throat, or hives occur. If painful urination starts to occur, contact your physician immediately because this may be a sign of UTI. Watch for signs of ketoacidosis like nausea, vomiting, abdominal pain, rapid breathing, confusion, or fatigue.9 If you observe these symptoms, conduct a home urine test for ketones. If positive for ketones, stop taking sotagliflozin, drink plenty of fluids, and seek medical attention.9
References
1. Gibson G, Blumer V, Mentz RJ, Lala A. Universal definition and classification of heart failure. American College of Cardiology. July 12, 2021. Accessed August 18, 2023. https://www.acc.org/Latest-in-Cardiology/Articles/2021/07/12/12/31/Universal-Definition-and-Classification-of-Heart-Failure
2. Centers for Disease Control and Prevention. Heart failure. Updated January 5, 2023. Accessed August 18, 2023. https://www.cdc.gov/heartdisease/heart_failure.htm
3. Lexicon Pharmaceuticals, Inc. Heart failure treatment | INPEFA® (sotagliflozin). INPEFA HCP. Accessed August 18, 2023. https://www.inpefahcp.com/
4. Wilcox CS. Antihypertensive and renal mechanisms of SGLT2 (sodium-glucose linked transporter 2) inhibitors. Hypertension. 2020;75(4):894-901. https://doi.org/10.1161/HYPERTENSIONAHA.119.11684
5. Dominguez Rieg JA, Rieg T. What does sodium-glucose co-transporter 1 inhibition add: prospects for dual inhibition. Diabetes Obes Metab. 2019;21 suppl 2(suppl 2):43-52. https://doi.org/10.1111/dom.13630
6. Hanssen NMJ, Kraakman MJ, Flynn MC, Nagareddy PR, Schalkwijk CG, Murphy AJ. Postprandial glucose spikes, an important contributor to cardiovascular disease in diabetes? Front Cardiovasc Med. 2020;7:570553. https://doi.org/10.3389/fcvm.2020.570553
7. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384(2):117-128. https://doi.org/10.1056/NEJMoa2030183
8. Lexicon Pharmaceuticals. Inpefa (sotagliflozin) [internet]. 2023. Accessed August 18, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216203s000lbl.pdf
9. Zhang L, Tamilia M. Euglycemic diabetic ketoacidosis associated with the use of a sodium-glucose cotransporter-2 inhibitor. CMAJ. 2018;190(25):E766-E768. https://doi.org/10.1503/cmaj.17131