LX4211, a Dual SGLT1/SGLT2 Inhibitor, Improved Glycemic Control in Patients With Type 2 Diabetes in a Randomized, Placebo-Controlled Trial

Zambrowicz, Brian; Freiman, Joel; Brown, Phil; Frazier, Kenneth; Turnage, Anne; Bronner, Johanna; Ruff, Dennis; Shadoan, Melanie K.; Banks, Phillip; Mseeh, Faika; Rawlins, David B.; Goodwin, Nicole C.; Mabon, Ross; Harrison, Bryce A.; Wilson, Alan G. E.; Sands, Arthur; Powell, David R.

doi:10.1038/clpt.2012.58

Cited by 212 publications

(263 citation statements)

References 57 publications

Supporting

Mentioning

244

Contrasting

Unclassified

Order By: Relevance

“…As monotherapy in T2D, sotagliflozin 150/300 mg once daily for 28 days lowered placebo-subtracted FPG by 39 and 55 mg/dL and HbA 1c by 0.66 and 0.76%, respectively, in patients with baseline HbA 1c 8.1% (31). Of note, in another study, sotagliflozin 400 mg QD in combination with metformin resulted in greater reductions in FPG and HbA 1c compared with sotagliflozin 200 mg QD despite similar amounts of UGE (32).…”

Section: Effects Of Dual Sglt1/2 Inhibitors On Glycemiamentioning

confidence: 97%

Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport

et al. 2015

View full text Add to dashboard Cite

Type 2 diabetes is a chronic disease with disabling micro-and macrovascular complications that lead to excessive morbidity and premature mortality. It affects hundreds of millions of people and imposes an undue economic burden on populations across the world. Although insulin resistance and insulin secretory defects play a major role in the pathogenesis of hyperglycemia, several other metabolic defects contribute to the initiation/worsening of the diabetic state. Prominent among these is increased renal glucose reabsorption, which is maladaptive in patients with diabetes. Instead of an increase in renal glucose excretion, which could ameliorate hyperglycemia, there is an increase in renal glucose reabsorption, which helps sustain hyperglycemia in patients with diabetes. The sodium-glucose cotransporter (SGLT) 2 inhibitors are novel antidiabetes agents that inhibit renal glucose reabsorption and promote glucosuria, thereby leading to reductions in plasma glucose concentrations. In this article, we review the long journey from the discovery of the glucosuric agent phlorizin in the bark of the apple tree through the animal and human studies that led to the development of the current generation of SGLT2 inhibitors.It took nearly 200 years from the isolation of phlorizin, a chemical found in apple tree bark that inhibits sodium-glucose cotransporters (SGLTs) (1), to the approval of the first medications inhibiting SGLTs for treatment of type 2 diabetes (T2D). During this time, several SGLTs were discovered and the roles of SGLT1 and SGLT2 in intestinal and renal glucose reabsorption have been elucidated in studies in genetically manipulated rodents, humans with SGLT gene mutations, healthy humans, and humans with diabetes (Fig. 1). This review provides an overview of the basic and clinical research that led to the translation of the initial findings of increased glucosuria with phlorizin to the development and approval of SGLT inhibitors and a summary of the clinical trial results obtained to date. Identification, Distribution, and In Vitro Characterization of the SGLT InhibitorsIn the 1980s and 1990s, Wright and colleagues cloned SGLT1 (2) and SGLT2 (2,3) and did much of the in vitro characterization, demonstrating that SGLT1 has a higher affinity for glucose than SGLT2 (K m for glucose ;0.4 mmol/L and 2 mmol/L, respectively), whereas SGLT2 has a higher capacity (4). SGLT1 is expressed at high levels in the intestine and is also expressed in the kidney, heart, and skeletal muscle, whereas SGLT2 is expressed almost exclusively in the kidney (4). Renal SGLT2 expression is increased in hyperglycemic rodents (5,6) and in humans with T2D (7). Intestinal SGLT1 expression is regulated by diet and other factors (8) and is

show abstract

Section: Effects Of Dual Sglt1/2 Inhibitors On Glycemiamentioning

confidence: 97%

Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Sotagliflozin was selected as the optimal drug candidate from this programme ( Figure 1). 11 The ability of sotagliflozin in vitro to inhibit SGLT1 and SGLT2 was established. Sotagliflozin inhibited SGLT2 with an IC 50 (concentration causing half of maximal inhibition) of 0.0018 µΜ, and it inhibited SGLT1 with an IC 50 of 0.036 µM.…”

Section: Preclinical Studies Of Sotagliflozinmentioning

confidence: 99%

Development of sotagliflozin, a dual sodium-dependent glucose transporter 1/2 inhibitor

Lapuerta

Zambrowicz

Strumph

et al. 2015

Diabetes and Vascular Disease Research

103

View full text Add to dashboard Cite

The sodium-dependent glucose transporter 2 (SGLT2) inhibitors are an important emerging class for the treatment of diabetes. Development of SGLT2 inhibitors has been oriented around a desire for high selectivity for the SGLT2 protein relative to the SGLT1 protein. More recently, genetic and pharmacology research in mice has indicated that gastrointestinal SGLT1 inhibition may also be an appropriate therapeutic target to treat diabetes. Combining SGLT1 and SGLT2 inhibition in a single molecule would provide complementary insulin-independent mechanisms to treat diabetes. Therefore, sotagliflozin (LX4211) has been developed as a dual inhibitor of SGLT1 and SGLT2. The differentiating clinical features of dual inhibitor of SGLT1 and SGLT2 include a large postprandial glucose reduction, elevation of glucagon-like peptide 1 and modest urinary glucose excretion. These features may have clinical implications for the use of sotagliflozin in the treatment of both type 1 and type 2 diabetes.

show abstract

“…85,86 In a 28-day study in subjects with type 2 diabetes, LX 4211 produced modest glucosuria (less than typically seen with selective SGLT-2 inhibitors), yet decreased the FPG concentration by 52-68 mg/dl, suggesting a significant inhibitory effect on gut glucose absorption. 87 In a phase 2, 12-week study involving 299 patients with type 2 diabetes on metformin monotherapy, LX 4211 (400 mg) reduced A1C by 0.92% from a baseline of 8.1%. 88 These results, although preliminary, suggest that combined SGLT-1/SGLT-2 inhibitors may have advantages over selective SGLT-2 inhibitors.…”

Section: Sglt-2 and Sglt-1 Inhibitorsmentioning

confidence: 99%

Novel Agents for the Treatment of Type 2 Diabetes

DeFronzo¹,

Triplitt²,

Abdul‐Ghani³

et al. 2014

Diabetes Spectrum

View full text Add to dashboard Cite

In Brief Impaired insulin secretion, increased hepatic glucose production, and decreased peripheral glucose utilization are the core defects responsible for the development and progression of type 2 diabetes. However, the pathophysiology of this disease also includes adipocyte insulin resistance (increased lipolysis), reduced incretin secretion/sensitivity, increased glucagon secretion, enhanced renal glucose reabsorption, and brain insulin resistance/neurotransmitter dysfunction. Although current diabetes management focuses on lowering blood glucose, the goal of therapy should be to delay disease progression and eventual treatment failure. Recent innovative treatment approaches target the multiple pathophysiological defects present in type 2 diabetes. Optimal management should include early initiation of combination therapy using multiple drugs with different mechanisms of action. This review examines novel therapeutic options that hold particular promise.

show abstract

LX4211, a Dual SGLT1/SGLT2 Inhibitor, Improved Glycemic Control in Patients With Type 2 Diabetes in a Randomized, Placebo-Controlled Trial

Cited by 212 publications

References 57 publications

Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport

Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport

Development of sotagliflozin, a dual sodium-dependent glucose transporter 1/2 inhibitor

Novel Agents for the Treatment of Type 2 Diabetes

Contact Info

Product

Resources

About