Renal sodium-glucose cotransporter inhibition in the management of type 2 diabetes mellitus

Abdul‐Ghani, Muhammad; Norton, Luke

doi:10.1152/ajprenal.00267.2015

Cited by 128 publications

(116 citation statements)

References 108 publications

(146 reference statements)

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“…The driving force for this state of affairs was most probably the ever-increasing glucosuria, which reached 4 g per day by week 5. In contrast to what is proposed in humans [3], probably SGTL1 activity did not kick-in in the L and L þ D groups because SGLT1 gene expression was not increased. Hence, when the L and L þ D rats were not eating they must have been drinking: water intake that was at normal SHR levels in obese V rats (about 20 ml/day) increased to a maximum of 30 ml in obese D rats, but progressively increased in L and L þ D rats reaching 50-60 ml/day by week 5 (approximately 10% of body weight).…”

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confidence: 98%

“…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].…”

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confidence: 99%

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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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confidence: 99%

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

Joles

Palm²

2016

Journal of Hypertension

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“…The result is a modest decrease in extracellular volume of ∼5–10% (21). This natriuretic effect, combined with the more long-term reduction in body weight, contributes, in part, to decreases in systolic/diastolic blood pressure (4–5/1–2 mmHg), which is observed with all SGLT2 inhibitors (22). Blood pressure reduction is not accompanied by an increase in heart rate and is independent of background antihypertensive therapy (22), suggesting that SGLT2 inhibition might reduce sympathetic tone or influence other hormonal factors that contribute to decreased blood pressure without increasing heart rate.…”

Section: Metabolic Effects Of Sodium–glucose Cotransporter 2 Inhibitorsmentioning

confidence: 99%

SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study

2016

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Although cardiovascular (CV) mortality is the principal cause of death in individuals with type 2 diabetes (T2DM), reduction of plasma glucose concentration has little effect on CV disease (CVD) risk. Thus, novel strategies to reduce CVD risk in T2DM patients are needed. The recently published BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) study demonstrated that in T2DM patients with high CVD risk empagliflozin reduced the primary major adverse cardiac event end point (CV death, nonfatal myocardial infarction, nonfatal stroke) by 14%. This beneficial effect was driven by a 38% reduction in CV mortality with no significant decrease in nonfatal myocardial infarction or stroke. Empagliflozin also caused a 35% reduction in hospitalization for heart failure without affecting hospitalization for unstable angina. Although sodium–glucose cotransporter 2 inhibitors exert multiple metabolic benefits (decreases in HbA1c, body weight, and blood pressure and an increase in HDL cholesterol), all of which could reduce CVD risk, it is unlikely that the reduction in CV mortality can be explained by empagliflozin’s metabolic effects. More likely, hemodynamic effects, specifically reduced blood pressure and decreased extracellular volume, are responsible for the reduction in CV mortality and heart failure hospitalization. In this Perspective, we will discuss possible mechanisms for these beneficial effects of empagliflozin and their implications for the care of T2DM patients.

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“…Unlike conventional diuretics, SGLT2-Is reduce serum uric acid. 20 In addition, SGLT2-Is reduce, but do not increase, the heart rate. 7, 21 The precise mechanisms of these unique features as diuretics must be further clarified; however, unlike conventional diuretics, SGLT2-Is are expected to be almost perfect and ideal diuretics.…”

Section: Prognostic Improvements By Sglt2 Inhibitors In Hfmentioning

confidence: 99%

Diuretic Action of Sodium-Glucose Cotransporter 2 Inhibitors and Its Importance in the Management of Heart Failure

Kimura

2016

Circ J

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Primarily, the sodium-glucose cotransporter 2 (SGLT2) inhibitors suppress the cotransport of glucose and sodium from the tubular lumen of the proximal tubules to the blood, and excrete glucose into the urine. Therefore, glucose and caloric balances become negative, reducing both the blood glucose level and insulin secretion. On the other hand, the proximal tubular fluid, constituted with low chloride concentration because of SGLT2 inhibition, is transferred to the loop of Henle. Under low chloride conditions, the reabsorption mechanisms in the loop of Henle do not work, similar to when loop diuretics are given. Subanalysis data on heart failure (HF) from the EMPA-REG OUTCOME trials are discussed, assuming that SGLT2 inhibitors are loop diuretics. Renin-angiotensin system inhibitors and β-blockers contribute to prognostic improvements of HF, independent of SGLT2 inhibitors, and therefore, both regimens are essential for the treatment of HF. On the other hand, the prognostic improvements by SGLT2 inhibitors are not significant under treatment including conventional diuretics such as loop diuretics and aldosterone antagonists, suggesting that the prognostic improvement in HF by SGLT2 inhibitors is mostly through their diuretic action. (Circ J 2016; 80: 2277 -2281

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Renal sodium-glucose cotransporter inhibition in the management of type 2 diabetes mellitus

Cited by 128 publications

References 108 publications

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

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

SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study

Diuretic Action of Sodium-Glucose Cotransporter 2 Inhibitors and Its Importance in the Management of Heart Failure

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