Effects of diuretics on sodium-dependent glucose cotransporter 2 inhibitor-induced changes in blood pressure in obese rats suffering from the metabolic syndrome

Rahman, Asadur; Kittikulsuth, Wararat; Fujisawa, Yoshihide; Sufiun, Abu; Rafiq, Kazi; Hitomi, Hirofumi; Nakano, Daisuke; Sohara, Eisei; Uchida, Shinichi; Nishiyama, Akira

doi:10.1097/hjh.0000000000000871

Cited by 47 publications

(39 citation statements)

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“…In addition, SGLT2 inhibitors can potentially reduce SNS activity that is augmented in part due to hyperglycemia [41, 48], although empagliflozin did not affect SNS activity in younger patients with type 1 diabetes [46]. More recently, some experimental studies showed that SGLT2 treatment could improve circadian rhythm and lability of BP, indicating a possible major cardioprotective role for this class of drugs [49–51]. In the EMPA-REG OUTCOME trial, empagliflozin treatment has elicited marked risk reduction for CV mortality and hospitalization as a result of worsening heart failure in patients with T2DM and established CVD [10].…”

Section: Discussionmentioning

confidence: 99%

Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial

Tanaka

Shimabukuro

Okada

et al. 2017

Cardiovasc Diabetol

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BackgroundType 2 diabetes mellitus (T2DM) is characterized by systemic metabolic abnormalities and the development of micro- and macrovascular complications, resulting in a shortened life expectancy. A recent cardiovascular (CV) safety trial, the EMPA-REG OUTCOME trial, showed that empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, markedly reduced CV death and all-cause mortality and hospitalization for heart failure in patients with T2DM and established CV disease (CVD). SGLT2 inhibitors are known to not only decrease plasma glucose levels, but also favorably modulate a wide range of metabolic and hemodynamic disorders related to CV pathways. Although some experimental studies revealed a beneficial effect of SGLT2 inhibitors on atherosclerosis, there is a paucity of clinical data showing that they can slow the progression of atherosclerosis in patients with T2DM. Therefore, the EMBLEM trial was designed to investigate whether empagliflozin treatment can improve endothelial function, which plays a pivotal role in the pathogenesis of atherosclerosis, in patients with T2DM and established CVD.MethodsThe EMBLEM trial is an ongoing, prospective, multicenter, placebo-controlled double-blind randomized, investigator-initiated clinical trial in Japan. A total of 110 participants with T2DM (HbA1c range 6.0–10.0%) and with established CVD will be randomized (1:1) to receive either empagliflozin 10 mg once daily or a placebo. The primary endpoint of the trial is change in the reactive hyperemia (RH)-peripheral arterial tonometry-derived RH index at 24 weeks from baseline. For comparison of treatment effects between the treatment groups, the baseline-adjusted means and their 95% confidence intervals will be estimated by analysis of covariance adjusted for the following allocation factors: HbA1c (<7.0 or ≥7.0%), age (<65 or ≥65 years), systolic blood pressure (<140 or ≥140 mmHg), and current smoking status (nonsmoker or smoker). Key secondary endpoints include the change from baseline for other vascular-related markers such as arterial stiffness, sympathetic nervous activity, and parameters of cardiac and renal function. Importantly, serious adverse effects independently on the causal relationship to the trial drugs and protocol will be also evaluated throughout the trial period.DiscussionEMBLEM is the first trial to assess the effect of empagliflozin on endothelial function in patients with T2DM and established CVD. Additionally, mechanisms associating empagliflozin-mediated actions with endothelial function and other CV markers will be evaluated. Thus, the trial is designed to elucidate potential mechanisms by which empagliflozin protects CV systems and improves CV outcomes. Trial registration Unique Trial Number, UMIN000024502 (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000028197)Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-017-0532-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial

Tanaka

Shimabukuro

Okada

et al. 2017

Cardiovasc Diabetol

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“…A recent phase III study and a meta‐analysis have shown that SGLT2i significantly reduce 24‐hour ambulatory BP, with significant reductions in both daytime and nighttime BP . Other recent studies have demonstrated that administration of the SGLT2i empagliflozin can change the circadian rhythm of BP from a nondipper to a dipper profile in salt‐treated, obese Otsuka Long Evans Tokushima Fatty (OLETF) rats and likewise with luseogliflozin administered to SHR/NDmcr‐cp (+/+) rats, a model of metabolic syndrome . Similarly, in human studies BP reduction by an SGLT2 inhibitor has been shown to be associated with the restoration of a disrupted circadian rhythm of BP from a nondipper to a dipper pattern in hypertensive subjects with impaired glucose metabolism and insulin resistance …”

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confidence: 99%

Nocturnal hypertension in diabetes: Potential target of sodium/glucose cotransporter 2 (SGLT2) inhibition

Kario

Weber

Ferrannini

2018

J of Clinical Hypertension

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“…This is the hypothesis tested by Rahman et al as reported in this issue of the Journal of Hypertension. In a rat model of the metabolic syndrome, the spontaneously hypertensive/ NIH-corpulent rat (SHRcp) rat, they report very promising reductions in both blood glucose and blood pressure by the SGLT2 inhibitor luseogliflozin (L), especially in combination with the diuretics furosemide plus hydrochlorothiazide (D) [7]. Of course, the question is: at what cost are these benefits gained?…”

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“…Rahman et al performed meticulous balance studies for sodium, potassium and chloride over the whole course of their study [7]. Despite the increase in body weight net sodium and potassium balance fell over the entire period reaching levels just above zero for the L þ D by week 5.…”

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confidence: 99%

“…The fall in blood pressure and restoration of a diurnal blood pressure rhythm, by combining an SLGT2 inhibitor with powerful diuretics in this model of type2 diabetes, is heralded as good news [7]. For many patients, this may well be true but it is conceivable that if the volume contraction is too severe the beneficial effects during the day may turn out bad at night.…”

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Combining sodium-dependent glucose co-transporter 2 inhibition with conventional diuretics

Joles

Palm²

2016

Journal of Hypertension

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See original paper on page 893 F amilial renal glucosuria resulting from a defect in the proximal tubular sodium-dependent glucose cotransporter (SGLT)2 is regarded as an innocent condition without associated morbidity [1,2]. To alleviate hyperglycemia in type 2 diabetes, for instance in the setting of obesity and hypertension, the induction of renal glucosuria by SGLT(2) inhibition therefore appears an interesting therapeutic option [3], which, importantly, does not require insulin. SGLT2 mediates the co-transport of glucose and sodium, effectively removing practically all glucose from the primary filtrate [4]. Although quantitatively, the resulting osmotic diuresis should be massive, in humans generally this is limited [5], probably because in humans inhibition of SGLT2 can lead to downstream increases in SGLT1 activity that quantitatively somewhat limits glucosuria [1]. Moreover, mild hypovolemia induced by osmotic diuresis can stimulate sodium reabsorption [6]. Thus, in order to reduce both hyperglycemia and hypertension in the metabolic syndrome a combination of SGLT2 inhibition with combined loop and thiazide diuretics should be very effective. This is the hypothesis tested by Rahman et al. as reported in this issue of the Journal of Hypertension. In a rat model of the metabolic syndrome, the spontaneously hypertensive/ NIH-corpulent rat (SHRcp) rat, they report very promising reductions in both blood glucose and blood pressure by the SGLT2 inhibitor luseogliflozin (L), especially in combination with the diuretics furosemide plus hydrochlorothiazide (D) [7]. Of course, the question is: at what cost are these benefits gained?As compared with vehicle (V), both L and L þ D similarly reduced postprandial blood glucose, HbA1C, as well as blood glucose and plasma insulin during an oral glucose tolerance test. Thus combining an SGLT2 inhibitor with diuretics clearly did not affect its antidiabetic efficacy in this model. However, although both D and L þ D decrease 24-h SBP and mean arterial pressure (MAP) a little more than L alone, the dipper pattern of MAP was restored best by L þ D, reaching pressure differences between active (dark) and nonactive (light) phases of about 7-8 mmHg. These pressure dips are similar to those observed in normotensive Wistar-Kyoto rats or nonobese hypertensive SHR rats. How is this achieved?Weight loss, osmotic diuresis or natriuresis were factors studied by Rahman et al. that could have contributed to the antihypertensive actions of the SGLT2 inhibitors. All three could be involved in the present study. Weight loss was not observed in SHRcp rats but the similar weight increase over the 5-week experimental period in the obese V, D and L rats (about 100 g) was reduced by about 50% in the L þ D rats (Supplemental figures). This is quite astounding because food intake was about 20% higher in the L and L þ D obese rats than in the V and D obese rats. Thus the L and L þ D rats were ingesting considerably more food but failed to put on more weight (L) or even lost weight (L þ D)! This woul...

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Effects of diuretics on sodium-dependent glucose cotransporter 2 inhibitor-induced changes in blood pressure in obese rats suffering from the metabolic syndrome

Abstract: These data suggest that a SGLT2 inhibitor elicits its beneficial effects on glucose metabolism and hypertension in study participants with metabolic syndrome undergoing treatment with diuretics.

Cited by 47 publications

References 43 publications

Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial

Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial

Nocturnal hypertension in diabetes: Potential target of sodium/glucose cotransporter 2 (SGLT2) inhibition

Combining sodium-dependent glucose co-transporter 2 inhibition with conventional diuretics

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