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Association of estimated plasma volume and weight loss after long-term administration and subsequent discontinuation of the sodium-glucose cotransporter-2 inhibitor tofogliflozin.

ABSTRACT: Sodium-glucose cotransporter-2 inhibitors (SGLT2) are drugs that have been reported to have several effects through the regulation of plasma volume, for example, antihypertensive effects. This study aimed to clarify the impact of long-term administration and subsequent discontinuation of the SGLT2 inhibitor tofogliflozin on estimated plasma volume (ePV), brain natriuretic peptide (BNP) and the relationship between changes in ePV, BNP and body weight (BW). Data from 157 participants with type 2 diabetes receiving tofogliflozin monotherapy in a phase 3 study were analysed. Changes in variables or correlations among them during a 52-week administration and a 2-week post-treatment period were investigated. Percent change in ePV was calculated using the Strauss formula. Significant decreases in BW, ePV and ln-transformed BNP (ln-BNP) were noted by week 52. %ΔBW was not significantly correlated with %ΔePV and Δln-BNP, while %ΔePV was significantly correlated with Δln-BNP. Two weeks after discontinuation of tofogliflozin, BW, ePV and ln-BNP were significantly increased. %ΔBW was significantly correlated with %ΔePV and Δln-BNP. Furthermore, ePV and BNP were significantly higher than baseline levels.

SUBMITTER: Matsubayashi Y

PROVIDER: S-EPMC8252731 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Association of estimated plasma volume and weight loss after long-term administration and subsequent discontinuation of the sodium-glucose cotransporter-2 inhibitor tofogliflozin.

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