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SotagliflozinEdit

Sotagliflozin is a pharmaceutical agent that functions as a dual inhibitor of the glucose transporters SGLT1 and SGLT2. It was developed by Lexicon Pharmaceuticals in collaboration with Sanofi and has been studied for improving glycemic control in people with diabetes. By targeting both intestinal glucose absorption and renal glucose reabsorption, sotagliflozin aims to reduce circulating glucose levels through a distinct mechanism compared with agents that act solely on the kidneys or the pancreas. In clinical research, sotagliflozin has been evaluated as an add-on therapy to insulin in type 1 diabetes and as an adjunct to standard therapies in type 2 diabetes, with mixed outcomes and ongoing evaluation of safety and efficacy. Lexicon Pharmaceuticals Sanofi Zynquista LX4211

Mechanism of action

  • SGLT2 inhibition in the kidney proximal tubule reduces glucose reabsorption, increasing urinary glucose excretion and thereby lowering blood glucose levels. This action is shared with other drugs in the same class, often referred to as SGLT2 inhibitors.
  • SGLT1 inhibition in the small intestine decreases the absorption of dietary glucose, contributing to additional reductions in postprandial blood glucose.
  • The combination of SGLT1 and SGLT2 blockade aims to provide a broader degree of glucose lowering and potential secondary effects such as modest weight loss and blood pressure changes, relative to targeting a single transporter. SGLT1 SGLT2

Medical uses and clinical development

  • Type 1 diabetes: Sotagliflozin has been investigated as an add-on to insulin therapy to improve glycemic control and reduce insulin dose requirements in people with type 1 diabetes. Trials evaluated effects on HbA1c, fasting glucose, and body weight, as well as the risk of adverse events associated with combination therapy. Type 1 diabetes Diabetic ketoacidosis
  • Type 2 diabetes: Studies examined sotagliflozin as an add-on to standard therapy for type 2 diabetes, aiming to improve HbA1c and provide additional metabolic benefits alongside established treatments. Type 2 diabetes
  • Other indications: Given the broader effects on glucose handling, researchers have explored potential utility in related metabolic conditions; however, the primary focus in most late-stage programs has been on type 1 and type 2 diabetes. Diabetes mellitus

Safety, risks, and controversies

  • Diabetic ketoacidosis (DKA): A central safety concern in trials of sotagliflozin, particularly when used in type 1 diabetes or in patients with insulin deficiency. Cases of ketoacidosis have prompted careful risk assessment and monitoring guidelines for patients on sotagliflozin. Diabetic ketoacidosis
  • Genital and urinary infections: As with other SGLT inhibitors, there is an elevated risk of genital infections and urinary tract infections in some patients, reflecting the mechanism of increased urinary glucose excretion. Genital infection Urinary tract infection
  • Volume depletion and hypotension: The diuretic effect associated with glucose excretion can contribute to dehydration and low blood pressure in susceptible individuals, necessitating monitoring of hydration status and renal function. Hypotension
  • Safety signaling and regulatory review: The safety profile of sotagliflozin has led to cautious regulatory consideration in several jurisdictions. Decisions have emphasized risk–benefit balance, particularly in populations at higher baseline risk for DKA or dehydration. Regulatory affairs FDA EMA

Pharmacokinetics and administration

  • Oral administration: Sotagliflozin is designed for oral use, with systemic exposure supporting its dual mechanism of action. Pharmacokinetic properties influence dosing strategies and potential interactions with food or concomitant medications. Pharmacokinetics Oral administration
  • Metabolism and excretion: Understanding of metabolic pathways and routes of elimination informs safety monitoring, especially in patients with renal or hepatic impairment. Metabolism Renal function Hepatic impairment

Regulatory status and current use

  • Regulatory status has been variable across jurisdictions, reflecting ongoing evaluation of efficacy signals and safety risks. In some regions, broad approval has not been granted, and the role of sotagliflozin in standard diabetes management remains limited. Clinicians consider patient-specific factors, comorbidities, and risk of adverse events when contemplating this therapy. FDA EMA Regulatory affairs
  • The broader class of SGLT inhibitors has gained prominence in diabetes care for cardiovascular and renal benefits in several populations, which shapes ongoing discussions about where dual SGLT1/SGLT2 inhibitors fit within treatment algorithms. Cardiovascular Renal SGLT inhibitors

Chemistry and development history

  • Chemical class and development: Sotagliflozin represents a dual inhibitor strategy targeting both SGLT1 and SGLT2 transporters, a design intended to broaden glucose-lowering effects beyond what single-target agents offer. The date and sequence of development reflect early 21st-century pharmaceutical research in metabolic disease. LX4211 SGLT1 SGLT2
  • Company involvement: The collaboration between Lexicon Pharmaceuticals and Sanofi facilitated the research program and subsequent regulatory discussions surrounding sotagliflozin. Sanofi Lexicon Pharmaceuticals

See also