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Sodium-glucose cotransporter 2 inhibitor, tofogliflozin, shows better improvements of blood glucose and insulin secretion in patients with high insulin levels at baseline.

ABSTRACT: AIMS/INTRODUCTION:Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of drugs for the treatment of type 2 diabetes mellitus that improve control of plasma glucose and bodyweight, giving great hope for the clinical utility of these agents. However, it is unclear for which patients SGLT2 inhibitors will be useful. MATERIALS AND METHODS:We analyzed data from long-term tofogliflozin monotherapy in an open-label, randomized controlled trial in Japanese patients with type 2 diabetes mellitus. Patients were divided into tertiles by baseline insulin level: group low (L): insulin ?5.6 ?U/mL, group medium (M): 5.6< insulin ?10 ?U/mL and group high (H): insulin >10 ?U/mL. RESULTS:Glycated hemoglobin and fasting plasma glucose levels, along with bodyweight, were significantly reduced from the baseline in all groups. The changes in levels of plasma glucose area under the curve for 2 h, C-peptide index area under the curve for 2 h during the meal tolerance tests and the insulin secretion index were the largest in the H group. The incidence of drug-related adverse events was not different among the three groups. DISCUSSION:Although tofogliflozin was effective regardless of baseline insulin level, it showed the highest efficacy in the H group.

SUBMITTER: Tobe K

PROVIDER: S-EPMC6031493 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Sodium-glucose cotransporter 2 inhibitor, tofogliflozin, shows better improvements of blood glucose and insulin secretion in patients with high insulin levels at baseline.

Tobe Kazuyuki K Suganami Hideki H Kaku Kohei K

Journal of diabetes investigation 20171113 4

<h4>Aims/introduction</h4>Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of drugs for the treatment of type 2 diabetes mellitus that improve control of plasma glucose and bodyweight, giving great hope for the clinical utility of these agents. However, it is unclear for which patients SGLT2 inhibitors will be useful.<h4>Materials and methods</h4>We analyzed data from long-term tofogliflozin monotherapy in an open-label, randomized controlled trial in Japanese patients with type ...[more]

PMID: 29032638

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Project description:Sodium-glucose co-transporter 2 inhibitors (SGLT2is) reduce albuminuria and hard renal outcomes (decline of renal function, renal replacement therapy and renal death) in patients with/without type 2 diabetes at high cardiovascular or renal risk. The question arises whether baseline albuminuria also influences renal outcomes with SGLT2is as reported with renin-angiotensin-aldosterone system inhibitors. Post hoc analyses focusing on albuminuria and renal outcomes of four cardiovascular outcome trials [EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), CANVAS (Canagliflozin Cardiovascular Assessment Study), DECLARE-TIMI 58 (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) and VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial)] and some renal data from two heart failure trials [Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) and EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction)] showed renal protection with SGLT2is without significant interaction (P > 0.10) when comparing renal outcomes according to baseline levels (A1, A2 and A3) of urinary albumin:creatinine ratio (UACR), a finding confirmed in a dedicated meta-analysis. Two trials [CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) and DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease)] specifically recruited patients with CKD and UACRs of 200-5000 mg/g. A post hoc analysis of CREDENCE that distinguished three subgroups according to UACR (300-1000, 1000-3000 and >3000 mg/g) showed a greater relative reduction in UACR in patients with lower baseline albuminuria levels (P for interaction = 0.03). Patients with a UACR >1000 mg/g showed a significantly greater reduction in absolute (P for interaction < 0.001) and a trend in relative (P for interaction = 0.25) risk of renal events versus those with lower UACR levels. In conclusion, baseline UACR levels do not significantly influence the nephroprotection by SGLT2is, yet the greater protection in patients with very high UACRs in CREDENCE deserves confirmation. The underlying mechanisms of renal protection with SGLT2is might be different in patients with or without (high) UACR.

Project description:ObjectiveTofogliflozin, a highly selective inhibitor of sodium/glucose cotransporter 2 (SGLT2), induces urinary glucose excretion (UGE), improves hyperglycemia and reduces body weight in patients with Type 2 diabetes (T2D). The mechanisms of tofogliflozin on body weight reduction were investigated in detail with obese and diabetic animal models.MethodsDiet-induced obese (DIO) rats and KKAy mice (a mouse model of diabetes with obesity) were fed diets containing tofogliflozin. Body weight, body composition, biochemical parameters and metabolic parameters were evaluated.ResultsIn DIO rats tofogliflozin was administered for 9 weeks, UGE was induced and body weight gain was attenuated. Body fat mass decreased without significant change in bone mass or lean body mass. Food consumption (FC) increased without change in energy expenditure, and deduced total calorie balance (deduced total calorie balance=FC-UGE-energy expenditure) decreased. Respiratory quotient (RQ) and plasma triglyceride (TG) level decreased, and plasma total ketone body (TKB) level increased. Moreover, plasma leptin level, adipocyte cell size and proportion of CD68-positive cells in mesenteric adipose tissue decreased. In KKAy mice, tofogliflozin was administered for 3 or 5 weeks, plasma glucose level and body weight gain decreased together with a reduction in liver weight and TG content without a reduction in body water content. Combination therapy with tofogliflozin and pioglitazone suppressed pioglitazone-induced body weight gain and reduced glycated hemoglobin level more effectively than monotherapy with either pioglitazone or tofogliflozin alone.ConclusionBody weight reduction with tofogliflozin is mainly due to calorie loss with increased UGE. In addition, tofogliflozin also induces a metabolic shift from carbohydrate oxidation to fatty acid oxidation, which may lead to prevention of fat accumulation and inflammation in adipose tissue and liver. Tofogliflozin may have the potential to prevent obesity, hepatic steatosis and improve insulin resistance as well as hyperglycemia.

Dataset Information

Sodium-glucose cotransporter 2 inhibitor, tofogliflozin, shows better improvements of blood glucose and insulin secretion in patients with high insulin levels at baseline.

Publications

Sodium-glucose cotransporter 2 inhibitor, tofogliflozin, shows better improvements of blood glucose and insulin secretion in patients with high insulin levels at baseline.

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