Structural repurposing of SGLT2 inhibitor empagliflozin for strengthening anti-heart failure activity with lower glycosuria

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reapproved for heart failure (HF) therapy in patients with and without diabetes. However, the initial glucose-lowering indication of SGLT2i has impeded their uses in cardiovascular clinical practice. A challenge of SGLT2i then becomes how to separate their anti-HF activity from glucose-lowering side-effect. To address this issue, we conducted structural repurposing of EMPA, a representative SGLT2 inhibitor, to strengthen anti-HF activity and reduce the SGLT2-inhibitory activity according to structural basis of inhibition of SGLT2. Compared to EMPA, the optimal derivative JX01, which was produced by methylation of C2-OH of the glucose ring, exhibited weaker SGLT2-inhibitory activity (IC50 > 100 nmol/L), and lower glycosuria and glucose-lowering side-effect, better NHE1-inhibitory activity and cardioprotective effect in HF mice. Furthermore, JX01 showed good safety profiles in respect of single-dose/repeat-dose toxicity and hERG activity, and good pharmacokinetic properties in both mouse and rat species. Collectively, the present study provided a paradigm of drug repurposing to discover novel anti-HF drugs, and indirectly demonstrated that SGLT2-independent molecular mechanisms play an important role in cardioprotective effects of SGLT2 inhibitors.

Real World Study to Evaluate Effect of SGLT2 Inhibitor Dapagliflozin on Markers of Macro and Micro Vascular Complications as add on Treatment in Type 2 Diabetes Patients

Introduction: In patients with type 2 diabetes mellitus,dapagliflozin, the sodium–glucose cotransporter 2 inhibitorhas been shown to improve diabetic control and reduceblood pressure. The main objective of the study is to evaluateefficacy of SGLT2 inhibitor dapagliflozin on markers of macroand micro vascular complications as add on treatment in type2 diabetes patients in real world set up.Material and methods: This was an observational studydone in real world set up. 87 patients were initially selectedamong whom 5 patients were lost in follow up and 2 patientswere excluded as they discontinued the study medicine. 80patients who received dapagliflozin 10 mg once daily for 24weeks in addition to metformin 1000 mg and glimepiride2 mg combination. Changes in both systolic and diastolicblood pressure, HbA1c (Glycated haemoglobin), fasting andpostprandial plasma glucose, lipid profile (including Totalcholesterol, Triglycerides, LDL and HDL cholesterol), serumcreatinine, serum microalbuminuria, eGFR and HOMA IRwere noted. All pathological test was executed at NABLaccredited lab.Results: After 24 weeks from baseline there was almost1.4% reduction in HbA1c. Fasting and post prandial bloodglucose was significantly reduced within 24 weeks. HOMAIR was significantly changed. No marked changes were seenin serum creatinine, microalbuminuria and eGFR. There wasa favorable reduction in lipid profile.Conclusion: Dapagliflozin has a very potent glycemic effectand has a significant impact on markers of macro and microvascular complications as add on treatment in type 2 diabetespatients. In conclusion it can be stated that early addition ofdapagliflozin therapy not only helps T2DM patients to achievetheir glycemic control but also prevents further macro andmicro vascular complications by reducing markers and riskfactors.

Euglycemic diabetic ketoacidosis: another masquerader!

Euglycemic ketoacidosis is defined by the triad of euglycemia, metabolic acidosis and ketonemia or ketonuria. In the current era of diabetic management, it is a serious concern with the usage of sodium glucose co-transporter 2 (SGLT2) inhibitors potentiated by a number of precipitating agents. Empagliflozin though a novel oral hypoglycemic agent in this category may also lead to this potential complication. Here we report a 59 year old male, type 2 diabetic who was on empagliflozin and presented with euglycemic ketoacidosis after a binge of alcohol.

Ertugliflozin: a novel anti-diabetic drug

Diabetes Mellitus is a disorder of global proportion. Despite various treatment modalities presently being available, yet the desired glycaemic control and patient outcomes have not been achieved completely. Sodium glucose co-transporter type 2 inhibitors (SGLT2 inhibitors) are one such promising group of emerging drugs in diabetes treatment. Ertugliflozin prevents the reabsorption of glucose by inhibiting sodium-glucose cotransporter-2 (SGLT2) at proximal convoluted tubules. Ertugliflozin is available as 5mg and 15mg tablets. Ertugliflozin has been related to genital mycotic infections and urinary tract infections. Benefits of Ertugliflozin include better control on blood glucose, body weight and blood pressure.

Dapagliflozin versus saxagliptin as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin

ABSTRACT Objective: This analysis compared the efficacy and safety of the sodium-glucose cotransporter-2 (SGLT2) inhibitor, dapagliflozin, and the dipeptidyl peptidase-4 (DPP4) inhibitor, saxagliptin, both added on to metformin. Materials and methods: This was a post-hoc analysis from a double-blind, randomized, 24-week clinical trial (NCT01606007) of patients with type 2 diabetes (T2D) inadequately controlled with metformin. We compared the dapagliflozin 10 mg (n = 179) and saxagliptin 5 mg (n = 176) treatment arms. Results: Dapagliflozin showed significantly greater mean reductions versus saxagliptin in HbA1c (difference versus saxagliptin [95% CI]: −0.32% [-0.54, −0.10]; p < 0.005), fasting plasma glucose (-0.98 [-1.42, −0.54] mmol/L; p < 0.0001), body weight (-2.39 [-3.08, −1.71] kg; p < 0.0001) and systolic blood pressure (SBP) (-3.89 [-6.15, −1.63] mmHg; p < 0.001). More dapagliflozintreated than saxagliptin-treated patients achieved the composite endpoint of HbA1c reduction ≥ 0.5%, weight loss ≥ 2 kg, SBP reduction ≥ 2 mmHg and no major/minor hypoglycemia (24% versus 7%). No major events of hypoglycemia were reported. More patients on dapagliflozin (6%) versus saxagliptin (0.6%) experienced genital infections. Conclusion: Dapagliflozin demonstrated greater glycemic efficacy than saxagliptin with additional benefits on weight and SBP, and the safety profile was consistent with previous studies.

Efectos cardiovasculares de los nuevos fármacos no insulínicos en diabetes / Cardiovascular effects of new non-insulinic anti-diabetes drugs]

La diabetes mellitus constituye actualmente un grave problema de salud pública a nivel mundial, que incrementa el riesgo de presentar complicaciones tanto microvasculares como macrovasculares. Aunque lograr los objetivos de glucemia recomendados reduce el riesgo de complicaciones microvasculares, el efecto de los fármacos para tratar la hiperglucemia sobre las complicaciones macrovasculares y la muerte cardiovascular es motivo de preocupación. En este contexto, las agencias regulatorias han modificado la normativa para la aprobación de nuevos fármacos en diabetes, de forma que establecen la necesidad de demostrar que son capaces de disminuir la glucemia junto con una evaluación sólida de la seguridad cardiovascular. El objetivo de este trabajo es revisar los efectos cardiovasculares de las nuevas familias de fármacos no insulínicos, en especial en su efecto sobre el riesgo de eventos cardiovasculares mayores. En los últimos años, finalmente, se ha confirmado que algunos fármacos para tratar la diabetes no solo son seguros desde el punto de vista cardiovascular, sino que incluso han mostrado capacidad para reducir el riesgo de enfermedad cardiovascular en la diabetes mellitus tipo 2. La evidencia obtenida ha determinado la actualización de algunas guías terapéuticas vigentes cuando el riesgo cardiovascular debería considerarse una variable fundamental al momento de la elección terapéutica en pacientes con diabetes.

Diabetes mellitus is currently a serious public health problem worldwide, that increases the risk of presenting microvascular and macrovascular complications. Although achieving the recommended blood glucose goals reduces the risk of microvascular complications, the effect of the drugs used to treat hyperglycemia on macrovascular complications and cardiovascular death is a cause for concern. In this context, the regulatory agencies have modified the regulations for the approval of new drugs in diabetes, by adding the need to demonstrate that they are capable of lowering blood glucose levels together with a solid assessment of cardiovascular safety. The objective of this study is to review the cardiovascular effects of the new families of non-insulin drugs, with special emphasis on their effect on the risk of major cardiovascular events. In recent years, it has finally been confirmed that some of the drugs used to treat diabetes are not only safe from a cardiovascular point of view, but have even shown capacity to reduce the risk of cardiovascular disease in type 2 diabetes mellitus. The evidence obtained determined the updating of some current therapeutic guidelines when cardiovascular risk should be considered a fundamental variable at the time of therapeutic choice in patients with diabetes.

Cetosis normoglicémica en adolescente con diabetes tipo 1 recibiendo insulina y dapaglifozina: Reporte de un caso / Euglycemic ketosis in an adolescent with type 1 diabetes on insulin and dapaglifozin: Case report

Dapaglifozina, un inhibidor del cotransportador de sodio-glucosa 2 (I-SGLT2) induce glucosuria y reduce la glicemia en adultos con diabetes tipo 2. Objetivo: Presentar una cetosis diabética “normoglicémica” en una adolescente con diabetes tipo 1 (DM1) que recibía dapaglifozina y alertar sobre el riesgo del uso I-SGLT2 que parece promisorio, pero no está aprobado en niños ni en DM1. Caso clínico: Paciente de 17 años sin cetosis durante 9 años con DM1, inició dapaglifozina 10 mg/día para reducir la insulina y el peso. Durante 11 meses de tratamiento tuvo cetonas capilares indetectables, redujo el índice de masa corporal 23,9 a 21,1 kg/m², la insulina basal 40 a 17 U, la hemoglobina glicosilada 8,3 a 7,5%, la glicemia capilar 175 a 161 mg/dl y la variabilidad de la glucosa (desvío estándar 85 a 77). Inesperadamente aparecieron náuseas y vómitos. La paciente portaba bomba de insulina con monitorización continua de glucosa, bien calibrada (glucosas intersticiales concordantes con glicemias), que mostraba glucosa estable bajo 200 mg/dl. Recibió insulina pero los vómitos persistieron; en tres horas, aparecieron deshidratación y desmayos, con cetonas 4,6 nmol/l y glicemia 224 mg/dl. Recibió suero fisiológico, ondansetrón, carbohidratos y varias dosis de insulina con pronta recuperación del estado general e hidratación, sin embargo, la cetosis continuó durante 24 horas. Cabe destacar que la bomba estaba funcionando bien y no se cambió la cánula. Al superar la cetosis, continuó con la misma cánula con buen control metabólico. Conclusión: Es importante sospechar la cetosis diabética normoglicémica por ser de riesgo vital.

Dapagliflozin, an insulin-independent sodium-glucose cotransporter 2 inhibitor (SGLT2-I) induces glycosuria and reduces hyperglycemia in adults with type 2 diabetes. Objective: To present an “euglycemic” diabetic ketosis in an adolescent with type 1 diabetes (T1D) receiving dapagliflozin, to alert about the risk of a drug not approved in children nor in T1D. Case report: A 17 years old adolescent with T1D during 9 years, was started on dapagliflozin 10 mg / day to reduce insulin dose and weight. During 11 months on treatment, capillaries ketones were undetectable and she exhibited a reduction in body mass index 23.9 to 21.1 kg/m2, basal insulin 40 to 17 U, glycated hemoglobin 8.3 to 7.5%, capillary glucose 175 to 161 mg/dl and glucose variability (standard deviation) 85 to 77. Suddenly nausea and vomits appeared. The patient was on an insulin pump and well calibrated continuous glucose monitoring, showing stable glucose levels under 200 mg/dl, and an insulin bolus was delivered. Vomiting without hyperglycemia persisted; three hours later, she was severely dehydrated and fainting, with ketones 4.6 nmol/l and glucose 224 mg/dl. She received IV saline fluids, ondansetron, carbohydrates and several insulin boluses. Hydration and general condition improved soon, however despite several insulin doses, ketosis continued for 24 hours. It is remarkable that the pump was working well and the cannula was not changed. After the ketosis was resolved, she continued using the same cannula with good metabolic control. Conclusion: Euglycemic ketosis is a life-threatening condition that must be suspected.

Generality of structure-activity relationship of deoxylations of the sugar moiety in SGLT2 inhibitors / 中国药学杂志

OBJECTIVE: To study the generality of the structure-activity relationships (SARs) of 3-deoxylation and 6-deoxylation of the sugar moiety in SGLT2 inhibitors. METHODS: Based on the earlier study, 3-deoxycanagliflozin (compound 5), 6-deoxyipra-gliflozin (compound 6), 6-deoxyempagliflozin (compound 7) and 3-deoxyempagliflozin(compound 8) were synthesized and evaluated by in vitro hSGLT2 and hSGLT1 inhibitory assay. RESULTS: The deoxylated SGLT2 inhibitors were synthesized from their corresponding aryl halides 9a-9c and 3-/6-deoxylated perbenzylated gluconolactones 11a-11b. In vitro hSGLT2 and hSGLT1 inhibitory assay showed that compounds 5 and 8 almost lost SGLT2 inhibitory activity, while compounds 6 and 7 exhibited similar activities to their corresponding parent compounds. CONCLUSION: It seems a general rule that 6-deoxylation of the sugar moiety in SGLT2 inhibitors has no effect on the SGLT2 inhibitory activity, whereas the effect of 3-deoxylation on SGLT2 inhibitory activity depends on the structures of the specific SGLT2 inhibitors, which does not show a universal rule.

A facile synthetic route and study of crystalline form of novel SGLT2 inhibitor 6-deoxycanagliflozin / 中国药学杂志

OBJECTIVE: To develop a facile synthetic route of novel SGLT2 inhibitor 6-deoxycanagliflozin and find its pharmaceu-tically acceptable crystalline forms.

Design, synthesis and hypoglycemic activity of 3, 6-anhydrodapagliflozin / 中国药学杂志

OBJECTIVE: To determine the effect of replacement of the glucose moiety by 3, 6-anhydroglucose moiety in SGLT2 inhibitors on the hypoglycemic activity by studying the hypoglycemic activity of 3, 6-anhydrodapagliflozin.

A Novel Therapeutic Agent for Type 2 Diabetes Mellitus: SGLT2 Inhibitor

Type 2 diabetes mellitus (T2DM) is a complex endocrine and metabolic disorder, and a major public health problem that is rapidly increasing in prevalence. Although a wide range of pharmacotherapies for glycemic control is now available, management of T2DM remains complex and challenging. The kidneys contribute immensely to glucose homeostasis by reabsorbing glucose from the glomerular filtrate. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new class of antidiabetic agents that inhibit glucose absorption from the kidney independent of insulin, offer a unique opportunity to improve the outcomes of patients with T2DM. In this review, we provide an overview of two globally-approved SGLT2 inhibitors, dapagliflozin and canagliflozin, and discuss their effects and safety. This information will help clinicians to decide whether these drugs will benefit their patients.