Validation of a Novel Method for Determining the Renal Threshold for Glucose Excretion in Untreated and Canagliflozin-treated Subjects With Type 2 Diabetes Mellitus

Polidori, David; Sha, Sue; Ghosh, A.K.; Plum‐Mörschel, Leona; Heise, Tim; Rothenberg, Paul

doi:10.1210/jc.2012-4205

Cited by 81 publications

(91 citation statements)

References 15 publications

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“…The effects of SGLT2 inhibitors on renal glucose kinetics were assessed using controlled glucose infusion experiments in rats (13) and humans (14,15). These experiments showed that SGLT2 inhibition leads to a reduction in T M G and RT G while maintaining a threshold-like relationship between PG and the UGE rate (Fig.…”

Section: Role Of Sglt2 and Sglt1 In Renal Glucose Reabsorptionmentioning

confidence: 99%

“…In such patients, SGLT2 inhibitors can be used as monotherapy, and in clinical trials, compared with placebo/active comparator, they lowered fasting PG (FPG) by 20- Results (mean 6 SE) from a graded glucose infusion study in Zucker diabetic fatty (ZDF) rats (13). Right panel: Results (mean 6 SD) from a stepwise hyperglycemic clamp study in human subjects with T2D (15). In both studies, canagliflozin treatment produces a left shift in the relationship between blood glucose and UGE with no apparent change in the slope, leading to a reduction in RT G .…”

Section: Monotherapymentioning

confidence: 99%

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Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport

et al. 2015

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Type 2 diabetes is a chronic disease with disabling micro-and macrovascular complications that lead to excessive morbidity and premature mortality. It affects hundreds of millions of people and imposes an undue economic burden on populations across the world. Although insulin resistance and insulin secretory defects play a major role in the pathogenesis of hyperglycemia, several other metabolic defects contribute to the initiation/worsening of the diabetic state. Prominent among these is increased renal glucose reabsorption, which is maladaptive in patients with diabetes. Instead of an increase in renal glucose excretion, which could ameliorate hyperglycemia, there is an increase in renal glucose reabsorption, which helps sustain hyperglycemia in patients with diabetes. The sodium-glucose cotransporter (SGLT) 2 inhibitors are novel antidiabetes agents that inhibit renal glucose reabsorption and promote glucosuria, thereby leading to reductions in plasma glucose concentrations. In this article, we review the long journey from the discovery of the glucosuric agent phlorizin in the bark of the apple tree through the animal and human studies that led to the development of the current generation of SGLT2 inhibitors.It took nearly 200 years from the isolation of phlorizin, a chemical found in apple tree bark that inhibits sodium-glucose cotransporters (SGLTs) (1), to the approval of the first medications inhibiting SGLTs for treatment of type 2 diabetes (T2D). During this time, several SGLTs were discovered and the roles of SGLT1 and SGLT2 in intestinal and renal glucose reabsorption have been elucidated in studies in genetically manipulated rodents, humans with SGLT gene mutations, healthy humans, and humans with diabetes (Fig. 1). This review provides an overview of the basic and clinical research that led to the translation of the initial findings of increased glucosuria with phlorizin to the development and approval of SGLT inhibitors and a summary of the clinical trial results obtained to date. Identification, Distribution, and In Vitro Characterization of the SGLT InhibitorsIn the 1980s and 1990s, Wright and colleagues cloned SGLT1 (2) and SGLT2 (2,3) and did much of the in vitro characterization, demonstrating that SGLT1 has a higher affinity for glucose than SGLT2 (K m for glucose ;0.4 mmol/L and 2 mmol/L, respectively), whereas SGLT2 has a higher capacity (4). SGLT1 is expressed at high levels in the intestine and is also expressed in the kidney, heart, and skeletal muscle, whereas SGLT2 is expressed almost exclusively in the kidney (4). Renal SGLT2 expression is increased in hyperglycemic rodents (5,6) and in humans with T2D (7). Intestinal SGLT1 expression is regulated by diet and other factors (8) and is

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Section: Role Of Sglt2 and Sglt1 In Renal Glucose Reabsorptionmentioning

confidence: 99%

Section: Monotherapymentioning

confidence: 99%

Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport

et al. 2015

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“…Canagliflozin reduces blood glucose levels through an insulin-independent mechanism by lowering the renal threshold for glucose and increasing urinary glucose excretion, which results in a mild osmotic diuresis and net caloric loss (11)(12)(13). In phase 3 studies, canagliflozin improved glycemic control, reduced body weight and blood pressure, and was generally well tolerated across a broad range of patients with type 2 diabetes (10,14).…”

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Efficacy and Safety of Canagliflozin, a Sodium–Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes

et al. 2015

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OBJECTIVEThis study assessed the efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in adults with type 1 diabetes. RESEARCH DESIGN AND METHODSThis 18-week, double-blind, phase 2 study randomized 351 patients (HbA 1c 7.0-9.0% [53-75 mmol/mol]) on multiple daily insulin injections or continuous subcutaneous insulin infusion to canagliflozin 100 or 300 mg or placebo. The primary end point was the proportion of patients achieving at week 18 both HbA 1c reduction from baseline of ‡0.4% ( ‡4.4 mmol/mol) and no increase in body weight. Other end points included changes in HbA 1c , body weight, and insulin dose, as well as hypoglycemia incidence. Safety was assessed by adverse event (AE) reports. RESULTSMore patients had both HbA 1c reduction ‡0.4% and no increase in body weight with canagliflozin 100 and 300 mg versus placebo at week 18 (36.9%, 41.4%, 14.5%, respectively; P < 0.001). Both canagliflozin doses provided reductions in HbA 1c , body weight, and insulin dose versus placebo over 18 weeks. The incidence of hypoglycemia was similar across groups; severe hypoglycemia rates were low (1.7-6.8%). Overall incidence of AEs was 55.6%, 67.5%, and 54.7% with canagliflozin 100 and 300 mg and placebo; discontinuation rates were low (0.9-1.3%). Increased incidence of ketone-related AEs (5.1%, 9.4%, 0%), including the specific AE of diabetic ketoacidosis (DKA) (4.3%, 6.0%, 0%), was seen with canagliflozin 100 and 300 mg versus placebo. CONCLUSIONSCanagliflozin provided reductions in HbA 1c , body weight, and insulin dose with no increase in hypoglycemia, but increased rates of ketone-related AEs, including DKA, in adults with type 1 diabetes inadequately controlled with insulin.Type 1 diabetes is an autoimmune disease characterized by progressive destruction of pancreatic b-cells, resulting in loss of endogenous insulin production and hyperglycemia (1). Consequently, treatment of type 1 diabetes requires lifelong insulin therapy to maintain normal blood glucose levels. Type 1 diabetes is associated with increased morbidity and mortality related to microvascular and macrovascular

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“…An inherited deficiency of SGLT2 can produce renal glucosuria, with some affected individuals excreting as much as 100 g of urinary glucose per day (5). Canagliflozin is an orally active inhibitor of SGLT2 that reduces proximal tubular glucose reabsorption and increases urinary glucose excretion (10)(11)(12)(13). Treatment produces a significant loss of glucose, with beneficial effects on glycemic control, body weight, and blood pressure (12,(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

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Efficacy and Safety of Canagliflozin, an Inhibitor of Sodium–Glucose Cotransporter 2, When Used in Conjunction With Insulin Therapy in Patients With Type 2 Diabetes

et al. 2014

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OBJECTIVEThere are limited data about the effects of sodium-glucose cotransporter 2 inhibitors when used with insulin. We report the efficacy and safety of canagliflozin in patients with type 2 diabetes using insulin. RESEARCH DESIGN AND METHODSThe CANagliflozin CardioVascular Assessment Study is a double-blind, placebocontrolled study that randomized participants to placebo, canagliflozin 100 mg, or canagliflozin 300 mg once daily, added to a range of therapies. The primary end point of this substudy was the change in HbA 1c from baseline at 18 weeks among patients using insulin; 52-week effects were also examined. RESULTSIndividuals receiving insulin at baseline were randomized to receive placebo (n 5 690), canagliflozin 100 mg (n 5 692), or canagliflozin 300 mg (n 5 690). These individuals were 66% male and had a median age of 63 years, mean HbA 1c of 8.3% (67 mmol/mol), BMI of 33.1 kg/m 2 , estimated glomerular filtration rate of 75 mL/min/1.73 m 2 , fasting plasma glucose of 9.2 mmol/L, and a median daily insulin dose of 60 IU. Most individuals were using basal/bolus insulin. Reductions in HbA 1c with canagliflozin 100 and 300 mg versus placebo were 20. 62% (95% CI 20.69, 20.54; 26.8 mmol/mol [95% CI 27.5,25.9]; P < 0.001) and 20. 73% (95% CI 20.81, 20.65; 28.0 mmol/mol [95% CI 28.9,27.1]; P < 0.001) at 18 weeks and 20. 58% (95% CI 20.68, 20.48; 26.3 mmol/mol [95% CI 27.4, 25.2]) and 20.73% (95% CI 20. 83, 20.63; 28.0 mmol/mol [95% CI 29.1,26.9]) at 52 weeks. There were significant falls in fasting plasma glucose, body weight, and blood pressure at both time points and there was a greater incidence of hypoglycemia, genital mycotic infections, and hypovolemia with both canagliflozin doses. CONCLUSIONSCanagliflozin added to insulin therapy improved glycemic control and decreased body weight. There was a greater frequency of several anticipated side effects, although few led to discontinuation of treatment.

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Validation of a Novel Method for Determining the Renal Threshold for Glucose Excretion in Untreated and Canagliflozin-treated Subjects With Type 2 Diabetes Mellitus

Cited by 81 publications

References 15 publications

Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport

Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport

Efficacy and Safety of Canagliflozin, a Sodium–Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes

Efficacy and Safety of Canagliflozin, an Inhibitor of Sodium–Glucose Cotransporter 2, When Used in Conjunction With Insulin Therapy in Patients With Type 2 Diabetes

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