pf-04971729 and Glycosuria

The sodium glucose cotransporter 2 (SGLT2) inhibitors canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin represent a novel class of medications to manage type 2 diabetes through urinary excretion of glucose. These drugs block glucose reabsorption by the kidneys to increase glucosuria. These drugs provide hemoglobin A1C reduction, promote weight loss, and remain hypoglycemic-neutral when not used in combination with insulin or secretagogues. Canagliflozin and empagliflozin have shown cardiovascular benefit. The potential to reduce the risk of cardiovascular death in patients with type 2 diabetes, along with the benefit of weight reduction, makes these new agents useful tools for the primary care provider.

Topics: Benzhydryl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Canagliflozin; Diabetes Mellitus, Type 2; Glucose; Glucosides; Glycated Hemoglobin; Glycosuria; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Weight Loss

This study compared the blood pressure-lowering effect of ertugliflozin (1, 5, 25 mg), hydrochlorothiazide (HCTZ; 12.5 mg) and placebo in 194 patients with type 2 diabetes mellitus and hypertension for 4 weeks using ambulatory blood pressure monitoring. Endpoints (change from baseline to week 4) were: 24-h mean systolic blood pressure (SBP; primary); daytime, night-time, seated predose SBP, 24-h, daytime, night-time, seated predose diastolic blood pressure, 24-h urinary glucose excretion and fasting plasma glucose (FPG; secondary). Safety and tolerability were monitored. Significant decreases in placebo-corrected 24-h mean SBP (-3.0 to -4.0 mmHg) were recorded for all doses of ertugliflozin (for HCTZ, this was -3.2 mmHg). Daytime, but not night-time SBP was consistently reduced. Ertugliflozin produced dose-dependent significant decreases in FPG and increases in urinary glucose excretion. No notable changes in plasma renin activity or urinary aldosterone were seen. The most common adverse events were urinary tract infection, genital fungal infection, upper respiratory tract infection and musculoskeletal pain.

Topics: Aldosterone; Antihypertensive Agents; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Fasting; Female; Glycosuria; Heart Rate; Humans; Hydrochlorothiazide; Hypertension; Hypoglycemic Agents; Male; Renin

A new class of potent and highly selective SGLT2 inhibitors is disclosed. Compound 31 (HSK0935) demonstrated excellent hSGLT2 inhibition of 1.3 nM and a high hSGLT1/hSGLT2 selectivity of 843-fold. It showed robust urinary glucose excretion in Sprague-Dawley (SD) rats and affected more urinary glucose excretion in Rhesus monkeys. Finally, an efficient synthetic route has been developed featuring a ring-closing cascade reaction to incorporate a double ketal 1-methoxy-6,8-dioxabicyclo[3.2.1]octane ring system.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; CHO Cells; Cricetulus; Diabetes Mellitus, Type 2; Glucose; Glycosuria; Humans; Hypoglycemic Agents; Kidney; Macaca mulatta; Male; Mice, Inbred ICR; Rats, Sprague-Dawley; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors