Characterization of Renal Glucose Reabsorption in Response to Dapagliflozin in Healthy Subjects and Subjects With Type 2 Diabetes

DeFronzo, Ralph A.; Hompesch, Marcus; Kasichayanula, Sreeneeranj; Liu, Xiaoni; Hong, Ying; Pfister, Marc; Morrow, Linda; Leslie, Bruce R.; Boulton, David W.; Ching, Agatha; LaCreta, Frank; Griffen, Steven C.

doi:10.2337/dc13-0387

Cited by 248 publications

(288 citation statements)

References 25 publications

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“…A study in rodents with sergliflozin demonstrated that SGLT2 inhibition markedly reduced the Tm without significant change in the glucose threshold or splay (43). In contrast, in humans dapagliflozin produced a decrease in the Tm as well as a marked reduction in both the threshold and splay in diabetic and nondiabetic individuals (20) (Fig. 4).…”

Section: Mechanism Of Glucosuriamentioning

confidence: 99%

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

Abdul‐Ghani

Norton

2015

American Journal of Physiology-Renal Physiology

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125

103

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Abdul-Ghani MA, Norton L, DeFronzo RA. Renal sodium-glucose cotransporter inhibition in the management of type 2 diabetes mellitus. Am J Physiol Renal Physiol 309: F889 -F900, 2015. First published September 9, 2015; doi:10.1152/ajprenal.00267.2015.-Hyperglycemia is the primary factor responsible for the microvascular, and to a lesser extent macrovascular, complications of diabetes. Despite this well-established relationship, approximately half of all type 2 diabetic patients in the US have a hemoglobin A 1c (HbA1c) Ն7.0%. This is associated in part with the side effects, i.e., weight gain and hypoglycemia, of currently available antidiabetic agents and in part with the failure to utilize medications that reverse the basic pathophysiological defects present in patients with type 2 diabetes. The kidney has been shown to play a central role in the development of hyperglycemia by excessive production of glucose throughout the sleeping hours and enhanced reabsorption of filtered glucose by the renal tubules secondary to an increase in the threshold at which glucose spills into the urine. Recently, a new class of antidiabetic agents, the sodium-glucose cotransporter 2 (SGLT2) inhibitors, has been developed and approved for the treatment of patients with type 2 diabetes. In this review, we examine their mechanism of action, efficacy, safety, and place in the therapeutic armamentarium. Since the SGLT2 inhibitors have a unique mode of action that differs from all other oral and injectable antidiabetic agents, they can be used at all stages of the disease and in combination with all other antidiabetic medications. type 2 diabetes; kidney; sodium-glucose cotransport; SGLT2 inhibition HYPERGLYCEMIA is the sine qua non of type 2 diabetes mellitus (T2DM) and is the principal risk factor for the development of diabetic microvascular complications, i.e., retinopathy, nephropathy, and neuropathy. T2DM patients also manifest multiple other metabolic abnormalities including obesity, hypertension, and dyslipidemia, which complicate management of the diabetic patient and predispose to the development of atherosclerotic cardiovascular complications. The United Kingdom Prospective Diabetes Study (UKPDS) (95) and the Diabetes Control and Complications Trial (DCCT) (24) have demonstrated that for every 1% decrease in hemoglobin A 1c (HbA 1c ) there is a 37% reduction in the risk of microvascular complications. However, despite the irrefutable evidence for the importance of maintaining optimal glycemic control (HbA 1c Ͻ6.5-7%), approximately half of the people with diabetes in the United States and worldwide fail to achieve this target of glycemic control and manifest a HbA 1c Ͼ7% (5a, 37). Weight gain and hypoglycemia, which are encountered with many current antihyperglycemic therapies, are major obstacles that preclude the achievement of the treatment goal in many T2DM patients.Although lowering the HbA 1c decreases the risk of microvascular complications, many clinical trials have demonstrated that tight glycemic control fails to pro...

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Section: Mechanism Of Glucosuriamentioning

confidence: 99%

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

Abdul‐Ghani

Norton

2015

American Journal of Physiology-Renal Physiology

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125

103

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“…72 ,73 Dapagliflozin reduces the TmG in people with type 2 diabetes, but most importantly, it reduces the renal threshold at which glucose spills into the urine to ~ 40 mg/dl. 74 Like canagliflozin, dapagliflozin is effective in lowering both FPG and PPG concentrations, resulting in an A1C reduction of ~ 0.7-0.8% with a starting A1C of ~ 8.0-8.2%. 73,75 Reduction in the mean day-long plasma glucose concentration resulted in improved tissue sensitivity to insulin by 25-30% and enhanced β-cell function by 90-100%, 76 from correction of glucotoxicity.…”

Section: Sglt-2 and Sglt-1 Inhibitorsmentioning

confidence: 99%

Novel Agents for the Treatment of Type 2 Diabetes

DeFronzo¹,

Triplitt²,

Abdul‐Ghani³

et al. 2014

Diabetes Spectrum

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In Brief Impaired insulin secretion, increased hepatic glucose production, and decreased peripheral glucose utilization are the core defects responsible for the development and progression of type 2 diabetes. However, the pathophysiology of this disease also includes adipocyte insulin resistance (increased lipolysis), reduced incretin secretion/sensitivity, increased glucagon secretion, enhanced renal glucose reabsorption, and brain insulin resistance/neurotransmitter dysfunction. Although current diabetes management focuses on lowering blood glucose, the goal of therapy should be to delay disease progression and eventual treatment failure. Recent innovative treatment approaches target the multiple pathophysiological defects present in type 2 diabetes. Optimal management should include early initiation of combination therapy using multiple drugs with different mechanisms of action. This review examines novel therapeutic options that hold particular promise.

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“…Given their mode of action, which is heavily dependent on the glucose filtered load and therefore on glomerular filtration rate (GFR) (15,16), the efficacy of SGLT2 inhibitors in reducing plasma glucose is expected to be decreased with decreasing renal function. Since glucose-lowering agents for patients with CKD stages 3 and 4 are limited and frequently require dose adjustments, the identification of the cutoff of estimated GFR (eGFR) below which clinically significant reductions in plasma glucose cannot be achieved with SGLT2 inhibitors is crucial.…”

Section: Glucose-lowering Efficacy Of Sglt2 Inhibitors In Patients Wimentioning

confidence: 99%

“…The main nonglycemic effects include blood pressure reduction and weight loss. Given the mode of action, the glucose-lowering efficacy of SGLT2 inhibitors depends on renal function and on plasma glucose levels (15,16).…”

mentioning

confidence: 99%

SGLT2 Inhibitors and the Diabetic Kidney

et al. 2016

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Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, especially cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addition to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfiltration. Experimental studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubular cells. SGLT2 inhibitors reduced glomerular hyperfiltration in patients with type 1 diabetes, and in patients with type 2 diabetes, they caused transient acute reductions in glomerular filtration rate, followed by a progressive recovery and stabilization of renal function. Interestingly, recent studies consistently demonstrated a reduction in albuminuria. Although these data are promising, only dedicated renal outcome trials will clarify whether SGLT2 inhibitors, in addition to their glycemic and blood pressure benefits, may provide nephroprotective effects.Diabetes is a worldwide growing public health problem with high risks of severe microvascular and macrovascular complications. Diabetic nephropathy (DN) is a major burden among the chronic complications of diabetes, given that it affects ;30% of patients with diabetes. Indeed, DN is the most common cause of end-stage renal disease in the U.S. (1) and worldwide. Known risk factors for DN include hyperglycemia, hypertension, dyslipidemia, smoking, and obesity as well as ethnic, familial, and genetic predispositions (2). Key clinical trials have demonstrated that early interventions, especially those aimed at primary prevention, are by far more effective and that it is only possible to slow progression once DN is established (2). Thus, large intervention trials on the impact of long-term intensified glucose control on chronic diabetes complications, both in type 1 and type 2 diabetes (2-6), have documented the critical role of glycemic control i...

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Characterization of Renal Glucose Reabsorption in Response to Dapagliflozin in Healthy Subjects and Subjects With Type 2 Diabetes

Cited by 248 publications

References 25 publications

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

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

Novel Agents for the Treatment of Type 2 Diabetes

SGLT2 Inhibitors and the Diabetic Kidney

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