SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat diet-induced obese rats

Yokono, Masanori; Takasu, Toshiyuki; Hayashizaki, Yuka; Mitsuoka, Keisuke; Kihara, Rumi; Muramatsu, Yuko; Miyoshi, Sosuke; Tahara, Atsuo; Kurosaki, Eiji; Li, Qun; Tomiyama, Hiroshi; Sasamata, Masao; Shibasaki, Masayuki; Uchiyama, Yasuo

doi:10.1016/j.ejphar.2014.01.040

Cited by 168 publications

(149 citation statements)

References 37 publications

Supporting

Mentioning

139

Contrasting

Unclassified

Order By: Relevance

“…In diet-induced obese rats treated with dapagliflozin (21), ipragliflozin (22), or tofogliflozin (23), lipolysis is accelerated and circulating ketone body levels are increased, especially in the fasting state or when animals are fed in pairs. In patients with T2D, empagliflozin-induced glycosuria lowers plasma glucose and insulin levels and raises fasting and postmeal glucagon concentrations.…”

Section: Rationalementioning

confidence: 99%

CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

2016

View full text Add to dashboard Cite

The striking and unexpected relative risk reductions in cardiovascular (CV) mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) observed in the EMPA-REG OUTCOME trial using an inhibitor of sodium-glucose cotransporter 2 (SGLT2) in patients with type 2 diabetes and high CV risk have raised the possibility that mechanisms other than those observed in the trialdmodest improvement in glycemic control, small decrease in body weight, and persistent reductions in blood pressure and uric acid leveldmay be at play. We hypothesize that under conditions of mild, persistent hyperketonemia, such as those that prevail during treatment with SGLT2 inhibitors, b-hydroxybutyrate is freely taken up by the heart (among other organs) and oxidized in preference to fatty acids. This fuel selection improves the transduction of oxygen consumption into work efficiency at the mitochondrial level. In addition, the hemoconcentration that typically follows SGLT2 inhibition enhances oxygen release to the tissues, thereby establishing a powerful synergy with the metabolic substrate shift. These mechanisms would cooperate with other SGLT2 inhibition-induced changes (chiefly, enhanced diuresis and reduced blood pressure) to achieve the degree of cardioprotection revealed in the EMPA-REG OUTCOME trial. This hypothesis opens up new lines of investigation into the pathogenesis and treatment of diabetic and nondiabetic heart disease.First among cardiovascular (CV) end point trials of glucose-lowering agents (1), the EMPA-REG OUTCOME trialdusing 10 or 25 mg/day sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin against placebo in 7,020 patients with type 2 diabetes (T2D) who were at increased CV riskdreported a 14% reduction in major CV events and marked relative risk reductions in CV mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) over a median time period of 2.6 years (2). Of note, all the pathologic categories of CV death (ischemic, pump failure, arrhythmic, embolic) contributed to the overall reduction in CV death in a patient cohort well treated with the use of renin-angiotensin-aldosterone inhibitors, statins, and acetylsalicylic acid. Furthermore, separation of the cumulative incidence functions between pooled-dose groups and placebo was already evident months after randomization. This unusual time course and the discrepancy between the relative risk reduction of the primary end point (nonfatal myocardial infarction, stroke, and CV mortality) and CV mortality itself suggests that active treatment affected case fatality rates more than event rates. In other words, empagliflozin treatment appeared mostly to rescue patients from impending cardiac decompensation. This interpretation is supported by the recent post hoc analyses of heart failure, documenting a large benefit in first and recurrent heart failure hospitalization across virtually every patient subgroup (3). Despite the fact that the diagnosis of heart failure was based on investigator reporting, th...

show abstract

Section: Rationalementioning

confidence: 99%

CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

2016

View full text Add to dashboard Cite

show abstract

“…4 Animal data show that the use of these agents can stimulate ketogenesis and, at the same time, reduce their renal excretion. 12 In humans there are data to show that fatty acid oxidation and ketone body production increases on initiation of these drugs. 13,14 Furthermore, on starting an SGLT-2 inhibitor, the resultant decreased circulating glucose, in association with the patient's insulinopenia or insulin resistance, results in decreased glycogen synthesis.…”

Section: Discussionmentioning

confidence: 99%

Possible risk factors for the development of sodium-glucose co-transporter 2 inhibitor- associated diabetic ketoacidosis in type 2 diabetes

et al. 2016

View full text Add to dashboard Cite

“…[26][27][28] By their effect on renal tubules SGLT-2 inhibitors may mimic starvation status and cause an increase in ketone production and renal re-absorption as has been documented with phlorizin. 26,[29][30][31][32][33] Lower than expected hyperglycaemia in SGLT-2 inhibition associated with DKA may be a result of a combination of factors including partial treatment of DKA, fasting or carbohydrate avoidance, dehydration, alcohol consumption and glycosuria. 34,35 Presentation Presentation of DKA in these patients is usually typical with classical symptoms and high glucose levels.…”

Section: Pathophysiologymentioning

confidence: 99%